logo

Quick View

OR SEARCH CITATIONS

My Activity
Publications
CONTENT TYPES

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Biomater. Sci. Eng. 2017, 3, 9, 2166-2175
RETURN TO ISSUEPREVArticleNEXT

Mimicking the Bioactivity of Fibroblast Growth Factor-2 Using Supramolecular Nanoribbons

View Author Information
† Simpson Querrey Institute for Bionanotechnology, Northwestern University, 303 E. Superior Street, Chicago, Illinois 60611, United States
‡Department of Materials and Science & Engineering, §Department of Chemistry, and ∥Department of Biomedical Engineering, Northwestern University, 2220 Campus Drive, Evanston, Illinois 60208, United States
⊥ Department of Medicine, Northwestern University, 251 E. Huron Street, Chicago, Illinois 60611, United States
Cite this: ACS Biomater. Sci. Eng. 2017, 3, 9, 2166-2175
Publication Date (Web):August 6, 2017
https://doi.org/10.1021/acsbiomaterials.7b00347
Copyright © 2017 American Chemical Society
RIGHTS & PERMISSIONS
Editors ChoiceACS Editors' Choice
Article Views
3101
Altmetric
-
Citations
11
LEARN ABOUT THESE METRICS

Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

PDF (6 MB)
Supporting Info (1)»
SUBJECTS:

Abstract

High Resolution Image
Download MS PowerPoint Slide

Fibroblast growth factor (FGF-2) is a multifunctional growth factor that has pleiotropic effects in different tissues and organs. In particular, FGF-2 has a special role in angiogenesis, an important process in development, wound healing, cell survival, and differentiation. Therefore, incorporating biological agents like FGF-2 within therapeutic biomaterials is a potential strategy to create angiogenic bioactivity for the repair of damaged tissue caused by trauma or complications that arise from age and/or disease. However, the use of growth factors as therapeutic agents can be costly and does not always bring about efficient tissue repair due to rapid clearance from the targeted site. An alternative would be a stable supramolecular nanostructure with the capacity to activate the FGF-2 receptor that can also assemble into a scaffold deliverable to tissue. We report here on peptide amphiphiles that incorporate a peptide known to activate the FGF-2 receptor and peptide domains that drive its self-assembly into supramolecular nanoribbons. These FGF2-PA nanoribbons displayed the ability to increase the proliferation and migration of the human umbilical vein endothelial cells (HUVECs) in vitro to the same extent as the native FGF-2 protein at certain concentrations. We confirmed that this activity was specific to the FGFR1 signaling pathway by tracking the phosphorylation of downstream signaling effectors such ERK1/2 and pH3. These results indicated the specificity of FGF2-PA nanoribbons in activating the FGF-2 signaling pathway and its potential application as a supramolecular scaffold that can be used in vivo as an alternative to the encapsulation and delivery of the native FGF-2 protein.

KEYWORDS:

Introduction

ARTICLE SECTIONS
Jump To
Growth factors (GFs) play a key role in regulating important cellular behaviors such as survival, proliferation, migration, and differentiation.(1, 2) These proteins are secreted to regulate a diverse number of cellular processes, such as tissue development or repair, and are usually bound and tightly regulated by their interactions with extracellular matrix (ECM) components. Multiple strategies to encapsulate and deliver GFs using biomaterials have been developed to replace or repair damaged tissues.(3, 1, 4) GFs can be incorporated into biomaterials using various chemical conjugation and/or physicochemical methods to improve retention and delivery.(5-8) For example, a mutant variant of VEGF (VEGF121-cys) was covalently attached through Michael addition chemistry to a PEG scaffold for the induction of in vivo vascularization.(9) Another alternative is to chemically attach heparin, a glycosaminoglycan capable of binding multiple GFs, into the polymer scaffold, as a way to deliver growth factors without relying on recombinant GF variants.(10, 11) However, both of these methods can be synthetically challenging and require the use of significant amounts of protein. Other major drawbacks of GF delivery in polymeric scaffolds include short half-life and rapid tissue clearance of proteins, which prevents an effective GF signaling response in tissues of interest.(8, 12, 13) In general, the delivery of therapeutic amounts of GFs can be costly and have serious side effects such as the emergence of angiogenic malignancies (tumors) and nonspecific responses in other organs such as the kidney or atheroma.(14, 15)
An alternative would be to utilize short bioactive peptide sequences that signal GF receptors as native GFs do but contained within a stable supramolecular scaffold in order to avoid their rapid degradation by enzymes. In previous work, these protein-mimetic sequences have been identified by analyzing fragments of the native GF protein, using computational studies, or by using phage-display technology.(16-19) The short peptide sequences can be readily incorporated into peptide-based matrices, which have proven to be effective biomaterials for a diverse number of in vitro and in vivo applications by being cost-effective, increasing the regenerative activity on the wounded area, and being nontoxic.(20-24) One of the most important GFs for regenerative biomaterials is basic fibroblast growth factor (bFGF, also known as FGF-2).(25, 26) FGF-2 is a member of the receptor tyrosine kinase (RTK) family, which are GFs that control many essential cell activities important for tissue development, cell survival, cell differentiation, and homeostasis. Other important members of the RTK family include VEGF (vascular endothelial growth factor), EGF (epidermal growth factor), and PDGF (platelet-derived growth factor), which are also commonly encapsulated within biomaterials for in vivo applications.(5, 27) In particular, FGF-2 has been shown have a pleiotropic effect in different tissues and organs, including an important role in angiogenesis and wound healing as well as in embryonic development and neural survival and differentiation.(28-30, 26, 31) Thus, signaling of the FGF-2 receptor (FGFR) by a bioactive biomaterial could have many important applications ranging from therapies for myocardial infarction(32, 29) to muscle regeneration and spinal cord injury,(33) among many others. A short peptide sequence (YRSRKYSSWYVALKR) was identified by Baird et al.(34) which activates the FGFR and thus mimics the bioactivity of FGF-2. The approach utilized to identify the bioactive peptide was to screen various sequences derived from FGF-2. They found that the peptide domain 106–120 in FGF-2 is a partial agonist of FGFR determined in a proliferation assay with 3T3 fibroblast cells.(34) Later, Zamora et al. incorporated the sequence in a branched peptide construct termed F2A4-K-NS, which contains two copies on the FGF-2 mimetic peptide alongside a heparin binding sequence (NH2-YRSRKYSSWYVALKRK(NH2-YRSRKYSSWYVALKR)-(Ahx-Ahx-Ahx)-RKRLDRIAR-CONH2, where Ahx = aminohexanoic acid). This peptide mimetic was able to bind FGFR1 and activate the corresponding proliferation-signaling cascade via the phosphorylation of ERK1/2 and also enhanced angiogenesis in vivo when encapsulated within Matrigel implants.(35)
We report here on the incorporation of the FGF-2 mimetic sequence in a peptide amphiphile (PA) capable of self-assembling in aqueous media into one-dimensional nanostructures. The objective has been to create a bioactive supramolecular scaffold of filamentous structures that could be used to encapsulate cells. PAs that form filamentous networks were developed in the Stupp laboratory,(36-40) and their in vitro and in vivo bioactivity has been demonstrated in several cell cultures and preclinical models for regenerative medicine. Some of these applications include the differentiation of neural progenitor cells into neurons,(41) axon regeneration after spinal cord injury,(42, 43) hard tissue formation such as enamel(44) and bone,(45, 46, 24) vascularization on demand,(47, 48, 21) and cartilage regeneration.(49) PA molecules that form the filamentous nanostructures are composed of three main segments: a single lipid tail for hydrophobic collapse, a β-sheet domain that drives one-dimensional self-assembly, charged residues for solubility, and a bioactive signal at one terminus of the peptide. In this work, we have investigated by physical and biological experiments a filament-forming PA molecule containing the FGF-2 mimetic peptide.

Materials and Methods

ARTICLE SECTIONS
Jump To

Peptide Synthesis

FGF2-PA (C16V3A3K3GYRSRKYSSWYVALKR), mutant FGF2-PA (C16V3A3K3GYARSEKYSSVYVALSR), scrambled FGF2-PA (C16V3A3K3GWRSKKYSLYYVASRR), and the FGF-2 peptide mimetic (Ac-YRSRKYSSWYVALKR) were synthesized using standard 9-fluorenyl methoxycarbonyl (Fmoc) solid-phase peptide synthesis (SPPS) on Rink amide 4-methylbenzhydrylamine resin (Millipore, Billerica, MA) with the Liberty 12-Channel Automated Microwave Peptide Synthesizer (CEM, Matthews, NC). The standard conditions for synthesis involve loading the resin (0.50 mmol) and coupling all the desired Fmoc-amino acids, starting with Fmoc-Arg(Pbf)-OH (1 mmol) using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 0.95 mmol), and N,N-diisopropylethylamine (DIEA, 3 mmol) in N,N-dimethylformamide (DMF). Palmitic acid (4 mmol) using HBTU (0.95 mmol) and DIEA (3 mmol) in DMF was used to cap N-terminus of the PAs. In the case of the FGF-2 mimetic peptide, the N-terminus was capped using a 10:2.5:100 (v/v/v) mixture of acetic anhydride, DIEA, and DMF for 30 min. The PA was subsequently cleaved from the resin using a 95:5 TFA/TIPS (trifluoroacetic acid/triisopropyl silane) cocktail for 4 h. PAs and crude peptide were purified by reverse-phase high-performance liquid chromatography (HPLC) with a 2–95% ACN/H20 (0.1% TFA) gradient for 60 min using a Varian Modular HPLC system (Agilent, Santa Clara, CA). The desired PA fractions were collected, evaporated under vacuum, and lyophilized into a solid powder. Purified PAs were further characterized by analytical LC/MS using a 6520 Quadrupole Time-of-Flight (Q-TOF) LCMS (Agilent, Santa Clara, CA) (see Figure S1).

Peptide Amphiphile Preparation

The desired amount of PA powder was weighed out in an Eppendorf tube in order to make 500 μL of a 1 mM PA stock solution in 25 mM HEPES at pH 7.4 buffer. The PA solution was subsequently annealed in 80 °C water bath for 30 min and slowly cooled down overnight to room temperature as previously described.(38)

Transmission Electron Microscopy

Images for conventional and cryo-TEM were obtained using a Hitachi HT-7700 Biological TEM (Hitachi High Technologies America, Schaumburg, IL) equipped with a LaB6 filament working at an accelerating voltage of 100 kV. For Cryo-TEM, PA samples were plunged frozen using a Vitrobot Mark IV (FEI, Hillsboro, OR) operating at 25 °C with 100% humidity. The PA sample (8 μL) was deposited on 300 square mesh copper grids with a lacey carbon film (Ted Pella, Redding, CA), blotted, and plunged into a liquid ethane reservoir cooled by liquid nitrogen. Following vitrification, the sample was transferred to a Gatan 626 cryo-holder (Gatan, Pleasanton, CA) under liquid nitrogen with the aid of a transfer stage. Images were acquired using an Orius SC 1000A CCD camera. All PA formulations were imaged at concentrations of 500 μM in 25 mM HEPES at pH 7.4 buffer. For conventional TEM, PA samples were dried on carbon film 300 square mesh copper grids (Ted Pella, Redding, CA) and stained with 0.5% uranyl acetate (UA) solution. Banding pattern was analyzed using ImageJ by measuring the pixel value of the gray scaled microscopic images, where a value of 0 represents white, and a value of 200 or above represents black.

Atomic Force Microscopy

PA samples were diluted to 200 μM in DI H2O and spin coated on freshly cleaved mica substrates at a spin rate of 6000 rpm for 1 min. AFM characterization was performed using a Bruker Dimension ICON atomic force microscope (Bruker, Billerica, MA) at ambient conditions. Tapping mode was utilized with single-beam silicon cantilevers with a nominal oscillation frequency of 300 kHz.

Circular Dichroism

CD measurements were performed at a concentration of 1 mM PA after annealing in 25 mM HEPES at pH.74 buffer using a Jasco J-815 CD spectrophotometer (Jasco Analytic Instruments, Easton, MD) at 25 °C using a 0.01 mm path length demountable quartz cuvette over a wavelength range of 190–260 nm with a step size of 1 nm and a data accumulation of n = 3.

Cell Culture

HUVECs (pooled donor, LONZA, Allendale, New Jersey) were grown to 70–80% confluence for each experiment (P2–P4) in a T-75 cell culture flask using complete media (EndoGRO-VEGF Complete Culture Media Kit, Millipore, Billerica, MA) supplemented with 1% penicillin–streptomycin. Media were changed every 3 days.

Proliferation Assay

Confluent cells were washed with PBS and detached with 2 mL of 0.05% Trypsin for 1 min at 37 °C. Cells were then diluted with 8 mL of complete media and counted using a hemocytometer. Cells were pelleted by centrifuge for 5 min at 2,000 rpm and resuspended with 0.5% FBS starvation media (EBM-2 media, LONZA, Allendale, New Jersey) supplemented with 1% penicillin–streptomycin and to make a 1 × 105 cell/mL stock solution. 100 μL of this stock solution was then pipetted into each well of a 96-well plate, and cells were allowed to attach and spread for 6 h on a cell incubator at 37 °C with 5% CO2. Afterward, media were aspirated, and all PA samples diluted in 0.5% FBS starvation media were added to the cells. Cell number was quantified after 16 h of sample incubation using the Quant-iT PicoGreen dsDNA kit proliferation assay (ThermoFisher Scientific, Waltham, MA) following the manufacturer’s protocol. Fluorescence measurements were obtained with the Cytation 3 cell imaging multimode reader (BioTek Instruments, Winooski, VT). Fold increase calculations were made by normalizing the data of each sample to the t = 0 starvation condition. Experiments were performed in 3 sets of quadruplicates.

LIVE/DEAD Assay

After 16 h of PA sample incubation, cells were washed and incubated with the LIVE/DEAD (ThermoFisher Scientific, Waltham, MA) assay dyes following the manufacturer’s protocol (1 μM of calcein AM and ethidium homodimer-1). Cells were then washed and imaged with the Cytation 3 cell imaging multimode reader. Quantification of cell viability was performed as a percent ratio of calcein AM positive cells over total number of cells from the images of two wells per sample.

Metabolic Activity Assay

1 ×105 cells were plated in a 96-well plate and allowed to remain overnight in complete media. Cells were washed with PBS and 0.5% FBS starvation media before PA samples diluted in 0.5% FBS starvation media were incubated for 8 h. A solution of CellTiter MTS solution (Promega, Madison, WI) was added as recommended by the manufacturer’s protocol. After 2 h of incubation with the MTS reagent, absorbance measurements at 490 nm were taken using the Cytation 3 cell imaging multimode reader. Metabolic activity calculations for each sample were normalized to cells grown in starvation conditions. Experiments were performed in 2 sets of quadruplets.

Migration Assay

The 48-well NeuroProbe reusable multiwell chemotaxis chambers (NeuroProbe, Gaithersburg, MD) were used for this experiment following the manufacturer’s protocol. Briefly, HUVECs growing to 70–80% confluence on a T-75 flask were starved overnight, trypsinized, and diluted into 1 × 106 cell stock in 0.1% BSA RPMI media. Lower chambers were filled with 29 μL of the PA sample solution diluted in 0.1% BSA RPMI media, while 50 μL of the cell stock solution was added to the upper chambers. The chamber was incubated overnight at 37 °C with 5% CO2. Later, cells on the nonmigrated side of the membrane were removed with a wiper blade. Cells on the migrated side were stained with DAPI (1:10,000, Molecular Probes Thermo Scientific, Grand Island, NY) for 10 min, and fluorescent images were taken (5 images for each well) at 10× magnification using a Nikon Eclipse TE2000 inverted microscope (Nikon, Melville, NY) and analyzed with ImageJ. Chambers were separated using a polycarbonate membrane with 8 μm pores coated with 0.1 mg/mL collagen IV (Sigma-Aldrich, St. Louis, MO). Experiments were performed in 3 sets of triplicates.

Western Blot

1 ×105 cells were plated on 6-well plates and allowed to grow to 80–90% confluence over 3 days using complete media. Confluent cells were then washed with PBS and starved for 24 h using 0.5% FBS starvation media. Afterward, 1 mL of PA samples diluted in 0.5% FBS starvation media were incubated for 5 min, and cells were subsequently washed and lysed. Protein extracts obtained from cell cultures were separated by a SDS– polyacrylamide gel and electro-transferred to a nitrocellulose membrane (Bio-Rad). Membranes were blocked and incubated first with primary antibodies overnight at 4 °C and then with their corresponding secondary HRP-conjugated antibodies (1:3000; Santa Cruz Biotechnology, Dallas, TX). Protein signal was detected using the ECL chemiluminescent system (Amersham, GE Healthcare, Malborough, MA). Densitometry analysis, standardized to GADPH as a control for protein loading, was performed using ImageJ software. For quantification, two different sets of experiments in duplicate were analyzed. Finally, the preparations were placed in a coverslip with mounting solution for imaging. The following primary antibodies were used: mouse anti-FGFR1 (1:1000, Abcam, Cambridge, MA), mouse anti-phospho-FGFR1 (1:1000, Abcam, Cambridge, MA), mouse anti-GAPDH (1:1000, Sigma-Aldrich, St. Louis, MO), rabbit anti-ERK1/2 (1:2000, Abcam, Cambridge, MA), mouse anti-phospho-ERK1/2 (1:10000, Abcam, Cambridge, MA), and rabbit anti-PH3 (proliferation marker, 1:1000, Cell Signaling, Danvers, MA), 1:1000, Abcam).

Immunocytochemistry

1 ×105 cells were incubated in a 48-well cell culture plate containing 12 mm round coverslips and grown overnight with complete media. On the second day, media were exchanged for 0.5% FBS starvation media and incubated for 24 h. After this period, 200 μL PA samples diluted in 0.5% FBS starvation media were incubated in starvation media for 5 min. Cells were washed and fixed (4% PFA for 15 min at RT) and subsequently incubated with primary antibodies and appropriate Alexa 488 or Alexa 555 secondary antibodies (1:500, Molecular Probes Thermo Scientific, Grand Island, NY). Phospho FGFR1 (1:1000) was used to stain the activated FGF receptor 1, vinculin was used to stain the cytoskeleton (1:2000, Sigma-Aldrich, St. Louis, MO), and DAPI (1:500) was used to stain nuclei.

Fluorescent Imaging Analysis

Fluorescent preparations were viewed, and micrographs were captured with a Nikon A1R confocal laser-scanning microscope with GaAsP detectors. Images were assembled in Adobe Photoshop (v. 7.0), with adjustments for contrast, brightness, and color balance to obtain optimum visual reproduction of data.

Statistical Analysis

Statistical analysis was performed using Graphpad Prism v.6 software. Analysis of variance (ANOVA) with the posthoc test was used for all multiple group experiments. P values <0.05 were deemed significant. Values in graphs are the mean ± SEM.

Results and Discussion

ARTICLE SECTIONS
Jump To

Self-Assembly of FGF2-PA into Nanoribbons

We designed the FGF-2 mimetic PA (FGF2-PA) molecule using C16V3A3K3 as the nonbioactive backbone (K3-PA), known to form nanofibers with bioactive sequences displayed at the C-terminus.(21, 38, 50) The FGF2-PA was synthesized with the sequence C16V3A3K3GYRSRKYSSWYVALKR, containing the FGF-2 peptide sequence separated by a single glycine from the K3-PA backbone. The FGF-2 PA was subsequently purified and characterized with HPLC and MALDI-TOF MS (see Materials and Methods and Figure S1). In order to promote self-assembly, the PA sample was prepared by annealing a 1 mM solution of FGF2-PA in 25 mM HEPES at pH 7.4 buffer in an 80 °C water bath for 30 min and cooled overnight to room temperature. This annealing procedure has proven to produce thermodynamically stable PA nanostructures.(38) We found by TEM and AFM that the FGF2-PA forms after the annealing procedure coiled nanoribbons, micrometers in length with an average width of ∼32 nm (Figures 1A and S2). The extent of coiling varied widely in the nanostructures with a helical pitch that ranged from 30 to 215 nm. Also, the ribbons seemed to be dynamic in nature with no preference for left- or right-handed coiled structures (cryo-TEM on Figure 1A and Figure S2E). This type of coiling has been observed before in PA molecules possessing a high proportion of aromatic residues, and it is believed to arise from π–π interactions.(51, 52) Interestingly, however, the FGF2-PA nanoribbons contained an internal striation or banding pattern parallel to the length of the nanoribbons as revealed when stained with 0.5% uranyl acetate (UA) (conventional TEM on Figure 1A and Figure S2A and B). If the FGF2-PA solution was not annealed, bundles of aggregated ribbons would form otherwise but still maintaining the banding pattern (Figure S2D). Since the K3-PA backbone forms fibers in the absence of a bioactive sequence (Figure S8A), it is evident that intermolecular interactions between the FGF2 mimetic peptides influence the observed nanoribbon morphology.

Figure 1

Figure 1. Nanostructure characterization of the FGF2-PAs. (A) Cryo-TEM (left), conventional TEM (middle), and AFM (right) images of FGF2-PA nanoribbons (in the cryo-TEM images, areas revealing helical turns along the nanoribbon are highlighted by white arrows). (B) Cryo-TEM (left), conventional TEM (middle), and AFM (right) images of mutant FGF2-PA nanoribbons (in the cryo-TEM images, areas where ribbons do not fold into helical structures are highlighted by white arrows).

High Resolution Image
Download MS PowerPoint Slide
To understand the biological specificity of FGF2-PA nanostructures, we also synthesized a PA molecule we refer to as the “mutant FGF2-PA”, containing the sequence C16V3A3K3GYARSEKYSSVYVALSR, where four amino acids from the FGF-2 peptide mimetic sequence were mutated (highlighted in orange on Figure 1B and Figure S3). The first two mutations, Y106A and W114V, replaced the bulky aromatic residues tyrosine and tryptophan by the smaller hydrophobic residues alanine and valine, respectively. The other two mutations, R109E and K119S, switched the positive charged residues, arginine and lysine, for a negatively charged one, glutamate, and a serine residue. The rationale behind these mutations was partly based on a previous study that reported decreased mitogenic activity when positively charged residues were exchanged with negatively charged ones, and bulky aromatic residues were exchanged with small hydrophobic ones in the receptor binding domain of FGF-2.(53) TEM and AFM showed that the mutant FGF2-PA was able to still form micrometer length nanoribbons with widths similar to that of FGF2-PA (Figures 1 and S4). The mutant FGF2-PA also formed coiled nanoribbons but to a lesser extent than FGF-2 PA nanostructures (cryo-TEM in Figure 1 and Figure S4). The changes in coiling are likely due to a decrease of aromatic interactions due to the removal of one tyrosine residue and tryptophan. The banding pattern was also evident in this case when the nanoribbons were stained with 0.5% UA (conventional TEM on Figure 1B and Figure S4A). Overall, the FGF2-PA and mutant FGF2-PA formed very similar nanostructures and can therefore be compared in our biological experiments based on their differences in sequence. A third PA was synthesized to determine the effect of amino acid sequence on the FGF-2 mimetic peptide, and we refer to it here as the scrambled FGF2-PA; its sequence is C16V3A3K3GWRSKKYSLYYVASRR (Figure S10). Instead of replacing amino acid residues, we exchanged the position of six amino acids, Y106 was switched for W114, R109 switched for K119, and S113 switched for L118. We found that the scrambled FGF2-PA was able to form nanoscale ribbons but with a much thinner width of 16 nm on average. The nanostructures formed by this PA molecule did not exhibit a propensity to coil and also did not reveal the banding pattern observed in supramolecular assemblies of the other two molecules (Figure S11A and B). We again see that the supramolecular structure changes when the bioactive sequence is altered, and therefore in subsequent experiments, we focused on FGF2-PA and the mutant FGF2-PA given their similarities in nanoscale morphology.
Circular dichroism (CD) provided a way to investigate the intermolecular interactions within the PA nanostructures. From the CD data, we can determine the presence of a peptide secondary structure forming within the nanoribbons. Both the FGF2-PA and mutant FGF2-PA possessed CD minima around 218 nm, but only the mutant FGF2-PA had a significant CD maximum around 203 nm (Figure 2A). These CD signals typically correspond to β-sheet hydrogen bonding.(54) However, the K3-PA without any bioactive sequence, displayed a stronger β-sheet signal. The FGF-2 mimetic peptide, which does not assemble into a supramolecular structure, has a CD spectrum characteristic of random coil peptides. This is expected since residues 106–120 in the actual native FGF-2 protein do not form any type of secondary structure.(55, 56) The data show how the random coil conformation of the FGF-2 mimetic peptide in FGF-2 PA nanoribbons prevents the formation of extensive H-bonding through its K3-PA backbone. Therefore, we hypothesize that the weak β-sheet signal of the FGF2-PA and the mutant FGF2-PA nanoribbons are mostly associated with the V3A3K3 PA backbone, not the bioactive or mutant peptide sequence. The scrambled FGF2-PA also revealed an even weaker β-sheet signal with a CD compared to that of the other PAs (Figure S12). With this information, we propose that both the bioactive sequence portion of FGF2-PA and mutant FGF2-PA have random coil conformation, as it would be in the native FGF-2 protein (Figure 2B).

Figure 2

Figure 2. CD and TEM analysis of FGF2-PA and mutant FGF2-PA nanostructures. (A) CD spectra of FGF2-PA (blue line), mutant FGF2-PA (orange line), FGF-2 mimetic peptide (green line), and K3-PA backbone at 1 mM in 25 mM HEPES at pH 7.4 buffer after annealing. Inset: close-up of the β-sheet region for FGF2-PA, mutant FGF2-PA, and FGF-2 mimetic peptide, showing the weakness in β-sheet signal compared to that of the K3-PA backbone PA. (B) Proposed conformations of the FGF-2 peptide, FGF2-PA, and mutant FGF2-PA (length scale on the left side). (C and D) Banding pattern analysis of the section of a UA stained FGF2-PA nanoribbon and a mutant FGF2-PA nanoribbon (white double-headed arrows). The graphs on the right show that the low gray values (gray bars) correspond to the darker areas (UA deposition) in the TEM images and that the higher gray values correspond to the lighter areas.

High Resolution Image
Download MS PowerPoint Slide
By understanding the intermolecular interactions found in the PA nanostructures using CD, we envision that once the FGF2-PA molecules are in solution, hydrophobic collapse immediately occurs through the aliphatic carbon tails, causing the molecules to self-assemble into nanofiber-like structures. Then, growth of the supramolecular structure occurs parallel and perpendicular to the long axis of the ribbons via interactions among highly aromatic/hydrophobic residues of the FGF-2 mimetic peptide sequence. This would result in “fused” nanofiber-like structures within the nanoribbons, as indicated by the banding patterns in TEM images of FGF2-PA and mutant FGF2-PA (Figures 1 and 2C and D). This pattern is highly periodic in both nanoribbons, where the dark regions correspond to the UA deposition around the edges of each cylindrical fiber structure (see TEM images on Figure 2C and D). Given that approximately six dark regions are observed across the 32 nm-wide nanoribbons, we hypothesize that there are around five cylindrical fiber-like structures within each nanoribbon. This proposed supramolecular structure is consistent with a length of ∼4 nm of the PA molecules as shown in Figure 2B since the nanofibers within the nanoribbon have a diameter of approximately 8 nm. The graphs on Figure 2C and D quantify the periodicity of the nanoribbons by measuring the distance between the dark and lighter regions as depicted in the UA stained TEM images, where the lighter areas correspond to the cores of fibers, while the dark regions (gray bars) correspond to their edges. Other amphiphilic molecules that self-assemble into lamellar ribbons composed of aligned nanofibers have also shown similar banding patterns by negative staining in TEM.(57) In our case, the hydrophobic and aromatic nature of the FGF-2 mimetic peptide seems to be favorable for intermolecular interactions that promote highly ordered nanoribbon structures, even though these types of residues are not always necessary to form ribbon-like nanostructures.(58) Alternatively, the sequence of the mutant FGF2-PA has fewer aromatic residues but sufficient hydrophobic residues to also form banded nanoribbon structures.

Evaluating the Proliferation and Migration of HUVECs Using FGF2-PA Nanoribbons

One of the basic functions of the native FGF-2 protein is the ability to promote proliferation, survival, and migration of endothelial cells.(26) Therefore, we introduced FGF2-PA nanoribbons in cell culture media of human umbilical vein endothelial cells (HUVECs) to evaluate their bioactivity relative to the native protein. We used these cells given their sensitive response to growth factors, especially those pertaining to the RTK family such as VEGF and PDGF. To assess the ability of FGF2-PA and mutant FGF2-PA nanostructures to promote proliferation of HUVECs, we first plated the cells in starvation media and allowed them to attach for 6 h (t = 0) before incubating the cells with the supramolecular nanostructures at various concentrations ranging from 1 μM to 250 nM for 16 h (proliferation was quantified using the PicoGreen dsDNA assay). The native FGF-2 protein, FGF-2 mimetic peptide, and starvation only conditions were used as controls. After this period, the dsDNA of each cell sample was quantified and normalized to cells grown at t = 0. We found that the FGF2-PA was able to enhance cell proliferation at 750, 500, and 250 nM concentrations (Figures 3A and S5A). Moreover, the proliferative activity of FGF2-PA was comparable to that of 1.50 nM of native FGF-2 protein. Neither the mutant FGF2-PA nor the FGF-2 mimetic peptide revealed any significant effect in proliferation at the concentrations screened (Figure S5B and C). The FGF-2 mimetic peptide was even incubated at higher concentrations (500 μM–0.0700 μM), but no proliferative effect was observed (Figure S9). When analyzing the activity of the scrambled FGF2-PA ribbons, only a modest activity was observed (Figure S11B). Given the observed dissimilarity in supramolecular structure between the scrambled FGF2-PA and the FGF2-PA, all subsequent experiments focus on comparisons between FGF2-PA and the mutant FGF2-PA. We also tested K3-PA nanofibers and did not observe any effect on proliferation (see Figure S8B). This confirmed that the backbone (C16V3A3K3) did not play a significant role in that activity and therefore that the bioactivity observed for FGF2-PA nanostructures has its origin in the presence of the FGF-2 mimetic sequence.

Figure 3

Figure 3. Cell proliferation, migration, and viability assays. (A) HUVEC proliferation after 16 h of incubation with FGF2-PA (blue bars), mutant FGF2-PA (orange bars), and FGF-2 mimetic peptide at 750 and 500 nM with native FGF-2 protein at 1.50 and 0.150 nM as positive controls. (B) Fluorescent images of cells after being incubated with FGF2-PA and mutant FGF2-PA for 16 h stained with calcein AM and ethidium homodimer-1. (C) Graph showing >90% metabolic activity for HUVECS incubated with 750 and 500 nM of FGF2-PA, mutant FGF2-PA, and FGF-2 mimetic peptide. (D) Graph showing significant migration of HUVECs using the chemotaxis chamber setup with starved cells incubated with FGF2-PA, mutant FGF2-PA, and FGF-2 mimetic peptide at 750 and 500 nM and with native FGF-2 protein at 3.00, 1.50, and 0.150 nM (*P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001, with starvation media used as a negative control).

High Resolution Image
Download MS PowerPoint Slide
After the FGF2-PAs were incubated for 16 h, cell survival was monitored using calcein AM and ethidium homodimer-1 dyes. As expected from the proliferation experiment results, an increase in viable cells was observed when cells were incubated with FGF2-PA, as indicated by green fluorescence (Figures 3B and S6A). Conversely, fewer viable cells were observed when cells were incubated with mutant FGF2-PA, FGF-2 mimetic peptide, and starvation media conditions. Overall, quantification of calcein AM positive cells incubated with all the samples confirms that cells were alive but only proliferated in the presence of FGF2-PA nanostructures (Figure S6B). The various PAs were also tested for metabolic activity using the Cell Titer MTS assay (Figures 3C and S7). Cells were shown to be metabolically active when incubated with FGF2-PA, mutant FGF2-PA, and the FGF-2 mimetic peptide at concentrations ranging from 2 μM to 250 nM (Figure S7). This indicates that at the concentrations used in our experiments, the PAs are nontoxic but that only the FGF2-PA seems to have a specific proliferative activity. Lastly, a fluorescent caspase activity assay was performed to confirm cell survival at the bioactive concentrations. In the assay, the FGF2-PAs did not promote the activation of the caspase-3 dependent apoptosis pathway, a key indicator of cell survival (Figure S7D).
The native FGF-2 protein is also an important growth factor in promoting the migration of endothelial cells, a key process in tissue development and repair. Therefore, a migration assay using a chemotaxis chamber setup was used to evaluate the ability of FGF2-PA nanostructures to have this type of bioactivity expected in the protein. FGF2-PAs, FGF-2 mimetic peptide, and native FGF-2 protein were incubated in the lower chambers and starved cells on the top chamber, separated by a collagen-coated porous membrane. After incubation overnight, migration bioactivity similar to that observed with 3.00 nM native FGF-2 protein was found using 750 and 500 nM of the FGF2-PA, mirroring our observations with the proliferation assay. As expected, the mutant FGF2-PA and the FGF-2 mimetic peptide were found to be inactive (Figure 3D). Thus, the FGF2-PA nanoribbons are able to effectively promote HUVEC survival, proliferation, and migration with the same degree as the native FGF-2 protein, while all of these elements of bioactivity are not observed in the mutant FGF2-PA and the FGF-2 mimetic peptide.

FGFR1 Signaling Pathway Activation with FGF2-PA Nanoribbons

In order verify that the observed bioactivity of FGF2-PA nanostructures in vitro is indeed linked to the FGF-2 signaling pathway, we carried out Western blot protein analysis and immunocytochemistry experiments. For these experiments, HUVECs were starved for 24 h and then incubated for 5 min with FGF2-PA, mutant FGF2-PA, FGF-2 mimetic peptide, or native FGF-2 protein. First, we investigated the phosphorylation of FGFR1 (FGF receptor 1), one of the FGF-2 receptors which upon binding ligand activates proliferation and migration signaling pathways in endothelial cells.(59) While the total FGFR1 expression remained constant under all conditions, phosphorylated FGFR1 (pFGFR1), indicating active signaling, was only observed when cells were incubated with 750 and 500 nM of FGF2-PA nanoribbons or at various concentrations of native FGF-2 protein (upper panel, Figure 4A). Expression of pFGFR1 under these conditions was significantly higher compared with starvation conditions, exposure to mutant FGF2-PA nanoribbons, or exposure to FGF-2 mimetic peptide (Figure 4B). Next, we examined the expression of phosphorylated ERK1/2 (pERK1/2), one of the most important downstream effectors of the FGFR1 signaling cascade and a clear indicator of a proliferative response. In similar fashion, pERK1/2 was significantly overexpressed when cells where incubated with FGF2-PA and the native FGF-2 protein (middle panel in Figure 4A and B). The presence of pERK1/2 was of course expected given the observed phosphorylation of the upstream effector FGFR1. The last signaling effector analyzed was the phospho-histone 3 (pH3) mitotic marker, a definite indicator that cells undergo mitosis and proliferate through the FGFR1 pathway.(60) As expected, there was a clear expression of pH3 when the media contained FGF2-PA and native FGF-2 protein, whereas there was none detected when we used the mutant FGF2-PA or the FGF-2 mimetic peptide to modify the media and also in the starvation control (lower panel of Figure 4A and B). We conclude that the Western blot analysis of the FGFR1 signaling pathway confirms that proliferation observed during in vitro experiments induced by the FGF2-PA nanoribbons or the native FGF-2 protein is associated with the FGFR1 signaling pathway.

Figure 4

Figure 4. Effect of FGF2-PA on activation of cell signaling. (A) Western blot analysis shows upregulation of the pFGFR1 receptor, pERK1/2 proliferation signaling pathway, and pH3 proliferation marker promoted by FGF2-PA at 750 and 500 nM, native FGF-2 protein at 3.00, 1.50, and 0.150 nM and starvation conditions. Mutant FGF2-PA and FGF-2 mimetic peptide at 750 and 500 nM failed to induce any significant FGF-2 signaling. (B) Bar graph presenting quantitative analysis of the Western blot data using densitometry (intensity values normalized to GADPH). (*P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001, with starvation media used as a negative control). (C) Confocal images of vinculin staining (red), nuclei (DAPI, blue), and phosphorylated FGFR1 (green).

High Resolution Image
Download MS PowerPoint Slide
Additional immunocytochemistry experiments were performed to corroborate the presence of pFGFR1. FGF2-PA, mutant FGF2-PA, FGF-2 mimetic peptide, and native FGF-2 protein were incubated for 5 min in starvation media before cells were fixed and stained with the corresponding antibody. Vinculin staining revealed that HUVEC cells were attached and spread after the different treatments. Cells incubated with 750 and 500 nM of FGF2-PA and native FGF-2 protein revealed punctuated fluorescence from pFGFR1 (green) around the nucleus, whereas the other conditions did not reveal the expression of the activated receptor (Figure 4C). This type of nuclear localization of p-FGFR1 has been observed before when the receptor is activated.(61) These images further confirm the effective activation of FGFR1 by FGF2-PA nanoribbons with complementary SEM images suggesting interactions between the FGF2-PA nanoribbons and cell surfaces (Figure S13).
Both the in vitro cell experiments and the protein Western blot analysis have confirmed that the bioactivity induced by FGF2-PA nanoribbons is specifically linked to FGFR1 signaling and is as potent as that associated with the native FGF-2 protein. Moreover, mutant FGF2-PA nanoribbons were not specific enough to induce significant bioactivity, ruling out any activity induced by the nanoribbon structure. Zamora et al. previously found that the FGF-2 mimetic peptide in its monomeric state cannot induce bioactivity in endothelial cells. Therefore, they synthesized a new molecule termed F2A4-K-NS, which contains two copies on the FGF-2 mimetic peptide in order to promote receptor binding and bioactivity.(35) Similarly, we found that the FGF-2 mimetic peptide was only bioactive when displayed in a supramolecular nanostructure, most likely due to the multivalency of bioactive signals on the surfaces of the nanoribbons capable of dimerizing and activating the FGFR1 signaling cascade.

Conclusions

ARTICLE SECTIONS
Jump To
We have developed a PA molecule that self-assembles into coiled supramolecular nanoribbons that mimic the bioactivity of one of the most important growth factors in biological development and regeneration, FGF-2. The bioactivity of the coiled supramolecular structures was observed in human umbilical vein endothelial cells, promoting both their proliferation and migration. Moreover, we confirmed that the bioactivity is directly linked to signaling of the FGF receptor by the nanostructures and is comparable in intensity to the native protein. Bioactive supramolecular nanostructures such as the ones reported here offer an alternative to protein therapies which often have unacceptably short half-lives. The nanostructures could also be easily integrated into scaffolds for regenerative medicine therapies.

Supporting Information

ARTICLE SECTIONS
Jump To

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsbiomaterials.7b00347.

  • PA chemical structures and characterization as well as additional TEM and SEM micrographs, CD spectra, proliferation, and cell viability studies (PDF)

The authors declare no competing financial interest.

Terms & Conditions

Electronic Supporting Information files are available without a subscription to ACS Web Editions. The American Chemical Society holds a copyright ownership interest in any copyrightable Supporting Information. Files available from the ACS website may be downloaded for personal use only. Users are not otherwise permitted to reproduce, republish, redistribute, or sell any Supporting Information from the ACS website, either in whole or in part, in either machine-readable form or any other form without permission from the American Chemical Society. For permission to reproduce, republish and redistribute this material, requesters must process their own requests via the RightsLink permission system. Information about how to use the RightsLink permission system can be found at http://pubs.acs.org/page/copyright/permissions.html.

Acknowledgment

ARTICLE SECTIONS
Jump To

The studies reported here were supported by the National Institute of Health PPG (5P01HL108795-05) and by the National Institute of Health Bioengineering Research Partnership (BRP) (5R01EB003806-09) research grants. C.M.R.P. gratefully acknowledges support from the National Institute of Health NIBIB Supplement Award (3R01EB003806-09S1). Additional support for T.A. to perform atomic force microscopy experiments was provided by the U.S. Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences, under award no. DE- FG02-00ER45810. Z.A. received postdoctoral support from the Beatriu de Pinós Fellowship 2014 BP-A 00007 (Agència de Gestió d’Ajust Universitaris i de Recerca, AGAUR). PA synthesis was performed in the Peptide Synthesis Core Facility of the Simpson Querrey Institute at Northwestern University. The U.S. Army Research Office, the U.S. Army Medical Research and Materiel Command, and Northwestern University provided funding to develop this facility, and ongoing support is being received from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF NNCI-1542205). Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. CD experiments were performed using the Keck Biophysics Facility at Northwestern University. TEM and AFM experiments were performed at the EPIC facility of the NUANCE Center at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF NNCI-1542205); the MRSEC program (NSF DMR-1121262) at the Materials Research Center; the International Institute for Nanotechnology (IIN); the Keck Foundation; and the State of Illinois, through the IIN. We thank Mark McClendon for SEM experiments and Mark Seniw for schematic illustrations and helpful discussions.

Abbreviations

GF

growth factor

ECM

extracellular matrix

FGF-2

fibroblast growth factor

RTK

receptor tyrosine kinase

PA

peptide amphiphile

HUVECs

human umbilical vein endothelial cells

cryo-TEM

cryogenic transmission electron microscopy

EBM

endothelial basal media

Cryo-TEM

cryogenic transmission electron microscopy

AFM

atomic force microscopy

CD

circular dichroism

UA

uranyl acetate

pFGFR1

phosphorylated fibroblast growth factor 1

pERK

phosphorylated extracellular-regulated kinase

pH3

phospho-histone H3

DAPI

(4′,6-diamidino-2-phenylindole)

References

ARTICLE SECTIONS
Jump To

This article references 61 other publications.

  1. 1
    Barrientos, S.; Stojadinovic, O.; Golinko, M. S.; Brem, H.; Tomic-Canic, M. Growth factors and cytokines in wound healing Wound Repair Regen 2008, 16 (5) 585– 601 DOI: 10.1111/j.1524-475X.2008.00410.x
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    1
    Growth factors and cytokines in wound healing
    Barrientos Stephan; Stojadinovic Olivera; Golinko Michael S; Brem Harold; Tomic-Canic Marjana
    Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society (2008), 16 (5), 585-601 ISSN:.
    Wound healing is an evolutionarily conserved, complex, multicellular process that, in skin, aims at barrier restoration. This process involves the coordinated efforts of several cell types including keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. The migration, infiltration, proliferation, and differentiation of these cells will culminate in an inflammatory response, the formation of new tissue and ultimately wound closure. This complex process is executed and regulated by an equally complex signaling network involving numerous growth factors, cytokines and chemokines. Of particular importance is the epidermal growth factor (EGF) family, transforming growth factor beta (TGF-beta) family, fibroblast growth factor (FGF) family, vascular endothelial growth factor (VEGF), granulocyte macrophage colony stimulating factor (GM-CSF), platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), interleukin (IL) family, and tumor necrosis factor-alpha family. Currently, patients are treated by three growth factors: PDGF-BB, bFGF, and GM-CSF. Only PDGF-BB has successfully completed randomized clinical trials in the Unites States. With gene therapy now in clinical trial and the discovery of biodegradable polymers, fibrin mesh, and human collagen serving as potential delivery systems other growth factors may soon be available to patients. This review will focus on the specific roles of these growth factors and cytokines during the wound healing process.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1M%252FlslGktQ%253D%253D&md5=7792cfbb76f359dab3ba2a5935a9c567
  2. 2
    Behm, B.; Babilas, P.; Landthaler, M.; Schreml, S. Cytokines, chemokines and growth factors in wound healing J. Eur. Acad. Dermatol Venereol 2012, 26 (7) 812– 20 DOI: 10.1111/j.1468-3083.2011.04415.x
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    2
    Cytokines, chemokines and growth factors in wound healing
    Behm, B.; Babilas, P.; Landthaler, M.; Schreml, S.
    Journal of the European Academy of Dermatology and Venereology (2012), 26 (7), 812-820CODEN: JEAVEQ; ISSN:1468-3083. (Wiley-Blackwell)
    A review. In wound healing, a variety of mediators have been identified throughout the years. The mediators discussed here comprise growth factors, cytokines and chemokines. These mediators act via multiple (specific) receptors to facilitate wound closure. As research in the last years has led to many new findings, there is a need to give an overview on what is known, and on what might possibly play a role as a mol. target for future wound therapy. This review aims to keep the reader up to date with selected important and novel findings regarding growth factors, cytokines and chemokines in wound healing.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVKjtLnF&md5=fb4320634f5e4e6eb80e84967a5f4e59
  3. 3
    Pashuck, E. T.; Stevens, M. M. Designing Regenerative Biomaterial Therapies for the Clinic Sci. Transl. Med. 2012, 4 (160) 160sr4 DOI: 10.1126/scitranslmed.3002717
    [ Crossref], [ PubMed], Google Scholar
    There is no corresponding record for this reference.
  4. 4
    Pashuck, E. T.; Stevens, M. M. Designing regenerative biomaterial therapies for the clinic Sci. Transl. Med. 2012, 4 (160) 160sr4 DOI: 10.1126/scitranslmed.3002717
    [ Crossref], [ PubMed], Google Scholar
    There is no corresponding record for this reference.
  5. 5
    Belair, D. G.; Le, N. N.; Murphy, W. L. Design of growth factor sequestering biomaterials Chem. Commun. 2014, 50 (99) 15651– 15668 DOI: 10.1039/C4CC04317K
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    5
    Design of growth factor sequestering biomaterials
    Belair, David G.; Le, Ngoc Nhi; Murphy, William L.
    Chemical Communications (Cambridge, United Kingdom) (2014), 50 (99), 15651-15668CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    A review. Growth factors (GFs) are major regulatory proteins that can govern cell fate, migration, and organization. Numerous aspects of the cell milieu can modulate cell responses to GFs, and GF regulation is often achieved by the native extracellular matrix (ECM). For example, the ECM can sequester GFs and thereby control GF bioavailability. In addn., GFs can exert distinct effects depending on whether they are sequestered in soln., at two-dimensional interfaces, or within three-dimensional matrixes. Understanding how the context of GF sequestering impacts cell function in the native ECM can instruct the design of sol. or insol. GF sequestering moieties, which can then be used in a variety of bioengineering applications. This Feature Article provides an overview of the natural mechanisms of GF sequestering in the cell milieu, and reviews the recent bioengineering approaches that have sequestered GFs to modulate cell function. Results to date demonstrate that the cell response to GF sequestering depends on the affinity of the sequestering interaction, the spatial proximity of sequestering in relation to cells, the source of the GF (supplemented or endogenous), and the phase of the sequestering moiety (sol. or insol.). We highlight the importance of context for the future design of biomaterials that can leverage endogenous mols. in the cell milieu and mitigate the need for supplemented factors.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlOltr%252FJ&md5=9a275b521398862b09e1bd8e1cfda42d
  6. 6
    Briquez, P. S.; Clegg, L. E.; Martino, M. M.; Gabhann, F. M.; Hubbell, J. A. Design principles for therapeutic angiogenic materials Nature Reviews Materials 2016, 1, 15006 DOI: 10.1038/natrevmats.2015.6
    [ Crossref], [ CAS], Google Scholar
    6
    Design principles for therapeutic angiogenic materials
    Briquez, Priscilla S.; Clegg, Lindsay E.; Martino, Mikael M.; MacGabhann, Feilim; Hubbell, Jeffrey A.
    Nature Reviews Materials (2016), 1 (1), 15006CODEN: NRMADL; ISSN:2058-8437. (Nature Publishing Group)
    Despite extensive research, pro-angiogenic drugs have failed to translate clin., and therapeutic angiogenesis, which has potential in the treatment of various cardiovascular diseases, remains a major challenge. Physiol., angiogenesis - the process of blood-vessel growth from existing vasculature - is regulated by a complex interplay of biophys. and biochem. cues from the extracellular matrix (ECM), angiogenic factors and multiple cell types. The ECM can be regarded as the natural 3D material that regulates angiogenesis. Here, we leverage knowledge of ECM properties to derive design rules for engineering pro-angiogenic materials. We propose that pro-angiogenic materials should be biomimetic, incorporate angiogenic factors and mimic cooperative interactions between growth factors and the ECM. We highlight examples of material designs that demonstrate these principles and considerations for designing better angiogenic materials.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVert74%253D&md5=e73aeb07a9e706cde454a2d9e9072b2f
  7. 7
    Zhu, J.; Marchant, R. E. Design properties of hydrogel tissue-engineering scaffolds Expert Rev. Med. Devices 2011, 8 (5) 607– 26 DOI: 10.1586/erd.11.27
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    7
    Design properties of hydrogel tissue-engineering scaffolds
    Zhu, Junmin; Marchant, Roger E.
    Expert Review of Medical Devices (2011), 8 (5), 607-626CODEN: ERMDDX; ISSN:1743-4440. (Expert Reviews Ltd.)
    A review. This article summarizes the recent progress in the design and synthesis of hydrogels as tissue-engineering scaffolds. Hydrogels are attractive scaffolding materials owing to their highly swollen network structure, ability to encapsulate cells and bioactive mols., and efficient mass transfer. Various polymers, including natural, synthetic and natural/synthetic hybrid polymers, have been used to make hydrogels via chem. or phys. crosslinking. Recently, bioactive synthetic hydrogels have emerged as promising scaffolds because they can provide molecularly tailored biofunctions and adjustable mech. properties, as well as an extracellular matrix-like microenvironment for cell growth and tissue formation. This article addresses various strategies that have been explored to design synthetic hydrogels with extracellular matrix-mimetic bioactive properties, such as cell adhesion, proteolytic degrdn. and growth factor-binding.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1ans7jK&md5=cd78f638a3d9809f3769290d9882f9b4
  8. 8
    Lee, K.; Silva, E. A.; Mooney, D. J. Growth factor delivery-based tissue engineering: general approaches and a review of recent developments J. R. Soc., Interface 2011, 8 (55) 153– 70 DOI: 10.1098/rsif.2010.0223
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    8
    Growth factor delivery-based tissue engineering: general approaches and a review of recent developments
    Lee, Kangwon; Silva, Eduardo A.; Mooney, David J.
    Journal of the Royal Society, Interface (2011), 8 (55), 153-170CODEN: JRSICU; ISSN:1742-5689. (Royal Society)
    A review. The identification and prodn. of recombinant morphogens and growth factors that play key roles in tissue regeneration have generated much enthusiasm and numerous clin. trials, but the results of many of these trials have been largely disappointing. Interestingly, the trials that have shown benefit all contain a common denominator, the presence of a material carrier, suggesting strongly that spatio-temporal control over the location and bioactivity of factors after introduction into the body is crucial to achieve tangible therapeutic effect. Sophisticated materials systems that regulate the biol. presentation of growth factors represent an attractive new generation of therapeutic agents for the treatment of a wide variety of diseases. This review provides an overview of growth factor delivery in tissue engineering. Certain fundamental issues and design strategies relevant to the material carriers that are being actively pursued to address specific tech. objectives are discussed. Recent progress highlights the importance of materials science and engineering in growth factor delivery approaches to regenerative medicine.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlvFGhsbw%253D&md5=3299678c5d6c97fb69f6572170fb558d
  9. 9
    Zisch, A. H.; Lutolf, M. P.; Ehrbar, M.; Raeber, G. P.; Rizzi, S. C.; Davies, N.; Schmokel, H.; Bezuidenhout, D.; Djonov, V.; Zilla, P.; Hubbell, J. A. Cell-demanded release of VEGF from synthetic, biointeractive cell ingrowth matrices for vascularized tissue growth FASEB J. 2003, 17 (15) 2260– 2 DOI: 10.1096/fj.02-1041fje
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    9
    Cell-demanded release of VEGF from synthetic, biointeractive cell-ingrowth matrices for vascularized tissue growth
    Zisch, Andreas H.; Lutolf, Matthias P.; Ehrbar, Martin; Raeber, George P.; Rizzi, Simone C.; Davies, Neil; Schmoekel, Hugo; Bezuidenhout, Deon; Djonov, Valentin; Zilla, Peter; Hubbell, Jeffrey A.
    FASEB Journal (2003), 17 (15), 2260-2262, 10.1096/fj.02-1041fjeCODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)
    Local, controlled induction of angiogenesis remains a challenge that limits tissue engineering approaches to replace or restore diseased tissues. We present a new class of bioactive synthetic hydrogel matrixes based on poly(ethylene glycol) (PEG) and synthetic peptides that exploits the activity of vascular endothelial growth factor (VEGF) alongside the base matrix functionality for cellular ingrowth, i.e., induction of cell adhesion by pendant RGD-contg. peptides and provision of cell-mediated remodeling by crosslinking matrix metalloproteinase substrate peptides. By using a Michael-type addn. reaction, we incorporated variants of VEGF121 and VEGF165 covalently within the matrix, available for cells as they invade and locally remodel the material. The functionality of the matrix-conjugated VEGF was preserved and was crit. for in vitro endothelial cell survival and migration within the matrix environment. Consistent with a scheme of locally restricted availability of VEGF, grafting of these VEGF-modified hydrogel matrixes atop the chick chorioallontoic membrane evoked strong new blood vessel formation precisely at the area of graft-membrane contact. When implanted s.c. in rats, these VEGF-contg. matrixes were completely remodeled into native, vascularized tissue. This type of synthetic, biointeractive matrix with integrated angiogenic growth factor activity, presented and released only upon local cellular demand, could become highly useful in a no. of clin. healing applications of local therapeutic angiogenesis.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpvVSnsL4%253D&md5=96713a7670213b772d7ceda2457a14e3
  10. 10
    Zieris, A.; Chwalek, K.; Prokoph, S.; Levental, K. R.; Welzel, P. B.; Freudenberg, U.; Werner, C. Dual independent delivery of pro-angiogenic growth factors from starPEG-heparin hydrogels J. Controlled Release 2011, 156 (1) 28– 36 DOI: 10.1016/j.jconrel.2011.06.042
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    10
    Dual independent delivery of pro-angiogenic growth factors from starPEG-heparin hydrogels
    Zieris, A.; Chwalek, K.; Prokoph, S.; Levental, K. R.; Welzel, P. B.; Freudenberg, U.; Werner, C.
    Journal of Controlled Release (2011), 156 (1), 28-36CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
    Effective vascularization is a prerequisite for the success of various different tissue engineering concepts. While simultaneous administration of basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) has been previously demonstrated to boost angiogenesis, the combined long-term delivery of both growth factors from biomaterials is still a major challenge. In this work, two important heparin binding cytokines were delivered in parallel from a modular starPEG (multi-armed polyethylene glycol) - heparin hydrogel system to human umbilical vein endothelial cells (HUVECs) grown in culture and in a chicken embryo chorioallantoic membrane (CAM) model. As the utilized gels contain high quantities of heparin, loading and subsequent release of both growth factors (as detd. by radiolabeling studies and ELISA) occurred independently from each other. The combined delivery of FGF-2 and VEGF through starPEG-heparin hydrogels resulted in pro-angiogenic effects in vitro (study of cell survival/proliferation, morphol. and migration) and in vivo (quantification of CAM vascularization) being clearly superior over those of the administration of single factors. Consequently, the independent delivery of growth factor combinations by biohybrid starPEG-heparin matrixes allows for the precise multifactorial control of cellular processes critically detg. regeneration.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVGntrrK&md5=5068f8cbd45645de5e3f51836935809f
  11. 11
    Mammadov, R.; Mammadov, B.; Toksoz, S.; Aydin, B.; Yagci, R.; Tekinay, A. B.; Guler, M. O. Heparin Mimetic Peptide Nanofibers Promote Angiogenesis Biomacromolecules 2011, 12 (10) 3508– 3519 DOI: 10.1021/bm200957s
    [ ACS Full Text ACS Full Text], [ CAS], Google Scholar
    11
    Heparin Mimetic Peptide Nanofibers Promote Angiogenesis
    Mammadov, Rashad; Mammadov, Busra; Toksoz, Sila; Aydin, Bahri; Yagci, Ramazan; Tekinay, Ayse B.; Guler, Mustafa O.
    Biomacromolecules (2011), 12 (10), 3508-3519CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    New blood vessel formation (angiogenesis) is one of the most important processes required for functional tissue formation. Induction of angiogenesis is usually triggered by growth factors released by cells. Glycosaminoglycans (e.g., heparan sulfates) in the extracellular matrix aid in proper functioning of these growth factors. Therefore, exogenous heparin or growth factors were required for promoting angiogenesis in previous regenerative medicine studies. Here we report for the first time induction of angiogenesis by a synthetic nanofibrous peptide scaffold without the addn. of any exogenous growth factors or heparin. We designed and synthesized a self-assembling peptide amphiphile mol. that is functionalized with biol. active groups to mimic heparin. Like heparin, this mol. has the ability to interact with growth factors and effectively enhance their bioactivity. The nanofibers formed by these mols. were shown to form a 3D network mimicking the structural proteins in the extracellular matrix. Because of heparin mimicking capabilities of the peptide nanofibers, angiogenesis was induced without the addn. of exogenous growth factors in vitro. Bioactive interactions between the nanofibers and the growth factors enabled robust vascularization in vivo as well. Heparin mimetic peptide nanofibers presented here provide new opportunities for angiogenesis and tissue regeneration by avoiding the use of heparin and exogenous growth factors. The synthetic peptide nanofiber scaffolds enriched with proper chem. functional groups shown in this study can be used to induce various desired physiol. responses for tissue regeneration.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFeiu77M&md5=ab6f038642a4585e2567bfff3ed14296
  12. 12
    Laham, R. J.; Rezaee, M.; Post, M.; Sellke, F. W.; Braeckman, R. A.; Hung, D.; Simons, M. Intracoronary and Intravenous Administration of Basic Fibroblast Growth Factor: Myocardial and Tissue Distribution Drug Metab. Dispos. 1999, 27 (7) 821– 826
    [ PubMed], [ CAS], Google Scholar
    12
    Intracoronary and intravenous administration of basic fibroblast growth factor: myocardial and tissue distribution
    Laham, Roger J.; Rezaee, Mehrdad; Post, Mark; Sellke, Frank W.; Braeckman, Rene A.; Hung, David; Simons, Michael
    Drug Metabolism and Disposition (1999), 27 (7), 821-826CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)
    Therapeutic angiogenesis using various heparin-binding growth factors is a promising treatment for ischemic heart disease. Single dose intracoronary (IC) or i.v. delivery are most practical for clin. use. This study was designed to investigate the myocardial and tissue deposition of basic fibroblast growth factor (bFGF) after IC and i.v. administration in normal and chronically ischemic animals. Twenty-four Yorkshire pigs were used (12 normal and 12 ischemic animals) with IC and i.v. administration of 125I-bFGF (25 μCi) combined with cold bFGF (30 μg) and heparin (3 mg). Tissue and myocardial distribution was detd. at 1 and 24 h by measuring 125I-bFGF specific activity and by organ and light level autoradiog. The liver accounted for the majority of 125I-bFGF activity at 1 h (37.6% for IC and 42.1% for i.v. delivery), with a redn. to 2.8% for IC and 1.5% for i.v. delivery by 24 h. Total cardiac specific activity at 1 h was 0.88% for IC and 0.26% for i.v. administration and decreased to 0.05% and 0.04% at 24 h, resp. IC but not i.v. delivery resulted in higher deposition in ischemic than normal myocardium. IC delivery resulted in enhanced bFGF deposition only in myocardial territories subtended by the infused artery. The i.v. delivery compares favorably with IC delivery with a 3- to 4-fold redn. in myocardial deposition at 1 h and with similar solid organ deposition. The less invasive nature of i.v. delivery, its potential for repeat administration, and its applicability to a larger population may offset its resultant reduced myocardial deposition. Efficacy studies are ongoing.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXkt1CjsLY%253D&md5=ecf28ea32bba406f269cfd1eeb1d6fef
  13. 13
    Post, M. J.; Laham, R.; Sellke, F. W.; Simons, M. Therapeutic angiogenesis in cardiology using protein formulations Cardiovasc. Res. 2001, 49 (3) 522– 531 DOI: 10.1016/S0008-6363(00)00216-9
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    13
    Therapeutic angiogenesis in cardiology using protein formulations
    Post, M. J.; Laham, R.; Sellke, F. W.; Simons, M.
    Cardiovascular Research (2001), 49 (3), 522-531CODEN: CVREAU; ISSN:0008-6363. (Elsevier Science B.V.)
    A review with 122 refs. Therapeutic angiogenesis in cardiovascular disease aims at improving myocardial function by increasing blood flow to ischemic myocardium that is not amenable to traditional forms of revascularization. Preclin. data have provided proof of the concept that angiogenic growth factors such as fibroblast growth factor 2 (FGF-2) and vascular endothelium growth factor (VEGF) may indeed improve myocardial flow and function when administered in ways that ensure prolonged tissue exposure to these short-lived mols. Although other cytokines have been shown to enhance angiogenesis in vivo, FGF-2 and VEGF have been most widely studied and may serve as prototype proangiogenic drugs. Currently, several delivery techniques that are clin. applicable are being studied with respect to tissue distribution and retention as well as angiogenic efficacy of FGF-2 and VEGF. Although tissue distribution and retention of FGF-2 after intramyocardial injection compares favorably with other routes of administration, efficacy studies are not yet conclusive. At the same time, different protein- and gene-based formulations are being investigated. Arguments for and against protein and gene therapy are presented, showing that protein-based therapy seems to have advantages over gene therapy at the present time, although continuous efforts should be made to increase the tissue exposure time after a single administration of protein. While delivery systems and growth factor formulations are being improved, double-blind, placebo-controlled trials designed with existing animal data in mind, are needed to firmly establish the utility of therapeutic angiogenesis in cardiovascular disease.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXptlWrsA%253D%253D&md5=0a05214733e9eaf6e06d669a0cd0d13e
  14. 14
    Jain, R. K.; Au, P.; Tam, J.; Duda, D. G.; Fukumura, D. Engineering vascularized tissue Nat. Biotechnol. 2005, 23 (7) 821– 823 DOI: 10.1038/nbt0705-821
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    14
    Engineering vascularized tissue
    Jain, Rakesh K.; Au, Patrick; Tam, Josh; Duda, Dan G.; Fukumura, Dai
    Nature Biotechnology (2005), 23 (7), 821-823CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
    There is no expanded citation for this reference.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlvFehu7o%253D&md5=72877ca3f5aa081f2df72f3457f51257
  15. 15
    Simons, M.; Bonow, R. O.; Chronos, N. A.; Cohen, D. J.; Giordano, F. J.; Hammond, H. K.; Laham, R. J.; Li, W.; Pike, M.; Sellke, F. W.; Stegmann, T. J.; Udelson, J. E.; Rosengart, T. K. Clinical Trials in Coronary Angiogenesis: Issues, Problems, Consensus: An Expert Panel Summary Circulation 2000, 102 (11) e73– e86 DOI: 10.1161/01.CIR.102.11.e73
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    15
    Clinical trials in coronary angiogenesis: issues, problems, consensus: An expert panel summary
    Simons M; Bonow R O; Chronos N A; Cohen D J; Giordano F J; Hammond H K; Laham R J; Li W; Pike M; Sellke F W; Stegmann T J; Udelson J E; Rosengart T K
    Circulation (2000), 102 (11), E73-86 ISSN:.
    The rapid development of angiogenic growth factor therapy for patients with advanced ischemic heart disease over the last 5 years offers hope of a new treatment strategy based on generation of new blood supply in the diseased heart. However, as the field of therapeutic coronary angiogenesis is maturing from basic and preclinical investigations to clinical trials, many new and presently unresolved issues are coming into focus. These include in-depth understanding of the biology of angiogenesis, selection of appropriate patient populations for clinical trials, choice of therapeutic end points and means of their assessment, choice of therapeutic strategy (gene versus protein delivery), route of administration, and the side effect profile. The present article presents a summary statement of a panel of experts actively working in the field, convened by the Angiogenesis Foundation and the Angiogenesis Research Center during the 72nd meeting of the American Heart Association to define and achieve a consensus on the challenges facing development of therapeutic angiogenesis for coronary disease.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3cvls1KksA%253D%253D&md5=47cfb300b19e8c8f1717e3103172a2ed
  16. 16
    D’Andrea, L. D.; Del Gatto, A.; De Rosa, L.; Romanelli, A.; Pedone, C. Peptides Targeting Angiogenesis Related Growth Factor Receptors Curr. Pharm. Des. 2009, 15 (21) 2414– 2429 DOI: 10.2174/138161209788682235
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    16
    Peptides targeting angiogenesis related growth factor receptors
    D'Andrea, Luca D.; Del Gatto, Annarita; De Rosa, Lucia; Romanelli, Alessandra; Pedone, Carlo
    Current Pharmaceutical Design (2009), 15 (21), 2414-2429CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
    A review. Growth factors (GFs) are extracellular signaling polypeptides regulating cell proliferation, differentiation and survival. They exert a wide spectrum of biol. activities selectively binding to and activating specific membrane receptors which then transfer the message to cell interior inducing specific biochem. pathways. GFs are esp. involved in the regulation of angiogenesis, a physiol. process underlining several pathologies. Mols. able to modulate angiogenesis, interfering with the mol. recognition between a GF and its receptor, have a big pharmacol. interest. Either GF and the receptor are potential drug target. Peptides are useful mols. to develop new lead compds. disrupting protein-protein interface for pharmacol. applications. In this review the authors describe peptides targeting the receptors of the pro-angiogenic growth factors FGF, PDGF and VEGF. The biol. function and the structure of each growth factor/receptor system are discussed, as well as the mol. interaction between peptides and the receptors. Finally, the authors highlight the pharmacol. and diagnostic applications of these peptides in angiogenesis related diseases.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXos1alt7k%253D&md5=039742c8815f2284a3c950a256861011
  17. 17
    Place, E. S.; Evans, N. D.; Stevens, M. M. Complexity in biomaterials for tissue engineering Nat. Mater. 2009, 8 (6) 457– 470 DOI: 10.1038/nmat2441
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    17
    Complexity in biomaterials for tissue engineering
    Place, Elsie S.; Evans, Nicholas D.; Stevens, Molly M.
    Nature Materials (2009), 8 (6), 457-470CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
    A review. The mol. and phys. information coded within the extracellular milieu is informing the development of a new generation of biomaterials for tissue engineering. Several powerful extracellular influences have already found their way into cell-instructive scaffolds, while others remain largely unexplored. Yet for com. success tissue engineering products must be not only efficacious but also cost-effective, introducing a potential dichotomy between the need for sophistication and ease of prodn. This is spurring interest in recreating extracellular influences in simplified forms, from the redn. of biopolymers into short functional domains, to the use of basic chemistries to manipulate cell fate. In the future these exciting developments are likely to help reconcile the clin. and com. pressures on tissue engineering.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtFemsLw%253D&md5=76d460b06835fcc2db816d65618f2c20
  18. 18
    Shah, R. N.; Shah, N. A.; Del Rosario Lim, M. M.; Hsieh, C.; Nuber, G.; Stupp, S. I. Supramolecular design of self-assembling nanofibers for cartilage regeneration Proc. Natl. Acad. Sci. U. S. A. 2010, 107 (8) 3293– 3298 DOI: 10.1073/pnas.0906501107
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    18
    Supramolecular design of self-assembling nanofibers for cartilage regeneration
    Shah, Ramille N.; Shah, Nirav A.; Lim, Marc M. Del Rosario; Hsieh, Caleb; Nuber, Gordon; Stupp, Samuel I.
    Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (8), 3293-3298, S3293/1-S3293/4CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Mol. and supramol. design of bioactive biomaterials could have a significant impact on regenerative medicine. Ideal regenerative therapies should be minimally invasive, and thus the notion of self-assembling biomaterials programmed to transform from injectable liqs. to solid bioactive structures in tissue is highly attractive for clin. translation. We report here on a coassembly system of peptide amphiphile (PA) mols. designed to form nanofibers for cartilage regeneration by displaying a high d. of binding epitopes to transforming growth factor β-1 (TGFβ-1). Growth factor release studies showed that passive release of TGFβ-1 was slower from PA gels contg. the growth factor binding sites. In vitro expts. indicate these materials support the survival and promote the chondrogenic differentiation of human mesenchymal stem cells. We also show that these materials can promote regeneration of articular cartilage in a full thickness chondral defect treated with microfracture in a rabbit model with or even without the addn. of exogenous growth factor. These results demonstrate the potential of a completely synthetic bioactive biomaterial as a therapy to promote cartilage regeneration.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjtFymt7k%253D&md5=5544ae5566c3aaef434a4ea96e80d656
  19. 19
    D’Andrea, L. D.; Iaccarino, G.; Fattorusso, R.; Sorriento, D.; Carannante, C.; Capasso, D.; Trimarco, B.; Pedone, C. Targeting angiogenesis: Structural characterization and biological properties of a de novo engineered VEGF mimicking peptide Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (40) 14215– 14220 DOI: 10.1073/pnas.0505047102
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    19
    Targeting angiogenesis: Structural characterization and biological properties of a de novo engineered VEGF mimicking peptide
    D'Andrea, Luca Domenico; Iaccarino, Guido; Fattorusso, Roberto; Sorriento, Daniela; Carannante, Concetta; Capasso, Domenica; Trimarco, Bruno; Pedone, Carlo
    Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (40), 14215-14220CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Modulating angiogenesis is an attractive goal because many pathol. conditions depend on the growth of new vessels. Angiogenesis is mainly regulated by the VEGF, a mitogen specific for endothelial cells. In the last years, many efforts have been pursued to modulate the angiogenic response targeting VEGF and its receptors. Based on the x-ray structure of VEGF bound to the receptor, the authors designed a peptide, QK, reproducing a region of the VEGF binding interface: the helix region 17-25. NMR conformation anal. of QK revealed that it adopts a helical conformation in water, whereas the peptide corresponding to the α-helix region of VEGF, VEGF15, is unstructured. Biol. assays in vitro and on bovine aorta endothelial cells suggested that QK binds to the VEGF receptors and competes with VEGF. VEGF15 did not bind to the receptors indicating that the helical structure is necessary for the biol. activity. Furthermore, QK induced endothelial cells proliferation, activated cell signaling dependent on VEGF, and increased the VEGF biol. response. QK promoted capillary formation and organization in an in vitro assay on matrigel. These results suggested that the helix region 17-25 of VEGF is involved in VEGF receptor activation. The peptide designed to resemble this region shares numerous biol. properties of VEGF, thus suggesting that this region is of potential interest for biomedical applications, and mols. mimicking it could be attractive for therapeutic and diagnostic applications.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFChu7bK&md5=3c2532c688aee84b17bf208779b5adb2
  20. 20
    Rubert Perez, C. M.; Stephanopoulos, N.; Sur, S.; Lee, S. S.; Newcomb, C.; Stupp, S. I. The powerful functions of peptide-based bioactive matrices for regenerative medicine Ann. Biomed. Eng. 2015, 43 (3) 501– 14 DOI: 10.1007/s10439-014-1166-6
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    20
    The powerful functions of peptide-based bioactive matrices for regenerative medicine
    Rubert Perez Charles M; Stephanopoulos Nicholas; Sur Shantanu; Lee Sungsoo S; Newcomb Christina; Stupp Samuel I
    Annals of biomedical engineering (2015), 43 (3), 501-14 ISSN:.
    In an effort to develop bioactive matrices for regenerative medicine, peptides have been used widely to promote interactions with cells and elicit desired behaviors in vivo. This paper describes strategies that utilize peptide-based molecules as building blocks to create supramolecular nanostructures that emulate not only the architecture but also the chemistry of the extracellular matrix in mammalian biology. After initiating a desired regenerative response in vivo, the innate biodegradability of these systems allow for the natural biological processes to take over in order to promote formation of a new tissue without leaving a trace of the nonnatural components. These bioactive matrices can either bind or mimic growth factors or other protein ligands to elicit a cellular response, promote specific mechano-biological responses, and also guide the migration of cells with programmed directionality. In vivo applications discussed in this review using peptide-based matrices include the regeneration of axons after spinal cord injury, regeneration of bone, and the formation of blood vessels in ischemic muscle as a therapy in peripheral arterial disease and cardiovascular diseases.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M3ltlWitA%253D%253D&md5=17d74df96f4ba41dcf915f2af20dcc5a
  21. 21
    Webber, M. J.; Tongers, J.; Newcomb, C. J.; Marquardt, K.-T.; Bauersachs, J.; Losordo, D. W.; Stupp, S. I. Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (33) 13438– 13443 DOI: 10.1073/pnas.1016546108
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    21
    Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair
    Webber, Matthew J.; Tongers, Jorn; Newcomb, Christina J.; Marquardt, Katja-Theres; Bauersachs, Johann; Losordo, Douglas W.; Stupp, Samuel I.
    Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (33), 13438-13443, S13438/1-S13438/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    There is great demand for the development of novel therapies for ischemic cardiovascular disease, a leading cause of morbidity and mortality worldwide. We report here on the development of a completely synthetic cell-free therapy based on peptide amphiphile nanostructures designed to mimic the activity of VEGF, one of the most potent angiogenic signaling proteins. Following self-assembly of peptide amphiphiles, nanoscale filaments form that display on their surfaces a VEGF-mimetic peptide at high d. The VEGF-mimetic filaments were found to induce phosphorylation of VEGF receptors and promote proangiogenic behavior in endothelial cells, indicated by an enhancement in proliferation, survival, and migration in vitro. In a chicken embryo assay, these nanostructures elicited an angiogenic response in the host vasculature. When evaluated in a mouse hind-limb ischemia model, the nanofibers increased tissue perfusion, functional recovery, limb salvage, and treadmill endurance compared to controls, which included the VEGF-mimetic peptide alone. Immunohistol. evidence also demonstrated an increase in the d. of microcirculation in the ischemic hind limb, suggesting the mechanism of efficacy of this promising potential therapy is linked to the enhanced microcirculatory angiogenesis that results from treatment with these polyvalent VEGF-mimetic nanofibers.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtV2ms73O&md5=973461ee0d98598091803a94771e02f8
  22. 22
    Morgan, C. E.; Dombrowski, A. W.; Rubert Pérez, C. M.; Bahnson, E. S. M.; Tsihlis, N. D.; Jiang, W.; Jiang, Q.; Vercammen, J. M.; Prakash, V. S.; Pritts, T. A.; Stupp, S. I.; Kibbe, M. R. Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage ACS Nano 2016, 10 (1) 899– 909 DOI: 10.1021/acsnano.5b06025
    [ ACS Full Text ACS Full Text], [ CAS], Google Scholar
    22
    Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage
    Morgan, Courtney E.; Dombrowski, Amanda W.; Rubert Perez, Charles M.; Bahnson, Edward S. M.; Tsihlis, Nick D.; Jiang, Wulin; Jiang, Qun; Vercammen, Janet M.; Prakash, Vivek S.; Pritts, Timothy A.; Stupp, Samuel I.; Kibbe, Melina R.
    ACS Nano (2016), 10 (1), 899-909CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Noncompressible torso hemorrhage is a leading cause of mortality in civilian and battlefield trauma. We sought to develop an i.v.-injectable, tissue factor (TF)-targeted nanotherapy to stop hemorrhage. Tissue factor was chosen as a target because it is only exposed to the intravascular space upon vessel disruption. Peptide amphiphile (PA) monomers that self-assemble into nanofibers were chosen as the delivery vehicle. Three TF-binding sequences were identified (EGR, RLM, and RTL), covalently incorporated into the PA backbone, and shown to self-assemble into nanofibers by cryo-transmission electron microscopy. Both the RLM and RTL peptides bound recombinant TF in vitro. All three TF-targeted nanofibers bound to the site of punch biopsy-induced liver hemorrhage in vivo, but only RTL nanofibers reduced blood loss vs. sham (53% redn., p < 0.05). Increasing the targeting ligand d. of RTL nanofibers yielded qual. better binding to the site of injury and greater redns. in blood loss in vivo (p < 0.05). In fact, 100% RTL nanofiber reduced overall blood loss by 60% vs. sham (p < 0.05). Evaluation of the biocompatibility of the RTL nanofiber revealed that it did not induce RBC hemolysis, did not induce neutrophil or macrophage inflammation at the site of liver injury, and 70% remained intact in plasma after 30 min. In summary, these studies demonstrate successful binding of peptides to TF in vitro and successful homing of a TF-targeted PA nanofiber to the site of hemorrhage with an assocd. decrease in blood loss in vivo. Thus, this therapeutic may potentially treat noncompressible hemorrhage.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVygsb7I&md5=051be017bd4514836b74dd8e06be36db
  23. 23
    Lin, Y.-D.; Luo, C.-Y.; Hu, Y.-N.; Yeh, M.-L.; Hsueh, Y.-C.; Chang, M.-Y.; Tsai, D.-C.; Wang, J.-N.; Tang, M.-J.; Wei, E. I. H.; Springer, M. L.; Hsieh, P. C. H. Instructive Nanofiber Scaffolds with VEGF Create a Microenvironment for Arteriogenesis and Cardiac Repair Sci. Transl. Med. 2012, 4 (146) 146ra109– 146ra109 DOI: 10.1126/scitranslmed.3003841
    [ Crossref], [ PubMed], Google Scholar
    There is no corresponding record for this reference.
  24. 24
    Lee, S. S.; Hsu, E. L.; Mendoza, M.; Ghodasra, J.; Nickoli, M. S.; Ashtekar, A.; Polavarapu, M.; Babu, J.; Riaz, R. M.; Nicolas, J. D.; Nelson, D.; Hashmi, S. Z.; Kaltz, S. R.; Earhart, J. S.; Merk, B. R.; McKee, J. S.; Bairstow, S. F.; Shah, R. N.; Hsu, W. K.; Stupp, S. I. Gel Scaffolds of BMP-2-Binding Peptide Amphiphile Nanofibers for Spinal Arthrodesis Adv. Healthcare Mater. 2015, 4 (1) 131– 141 DOI: 10.1002/adhm.201400129
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    24
    Gel Scaffolds of BMP-2-Binding Peptide Amphiphile Nanofibers for Spinal Arthrodesis
    Lee, Sungsoo S.; Hsu, Erin L.; Mendoza, Marco; Ghodasra, Jason; Nickoli, Michael S.; Ashtekar, Amruta; Polavarapu, Mahesh; Babu, Jacob; Riaz, Rehan M.; Nicolas, Joseph D.; Nelson, David; Hashmi, Sohaib Z.; Kaltz, Stuart R.; Earhart, Jeffrey S.; Merk, Bradley R.; McKee, Jeff S.; Bairstow, Shawn F.; Shah, Ramille N.; Hsu, Wellington K.; Stupp, Samuel I.
    Advanced Healthcare Materials (2015), 4 (1), 131-141CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Peptide amphiphile (PA) nanofibers formed by self-assembly can be customized for specific applications in regenerative medicine through the use of mols. that display bioactive signals on their surfaces. Here, the use of PA nanofibers with binding affinity for the bone promoting growth factor BMP-2 to create a gel scaffold for osteogenesis is reported. With the objective of reducing the amt. of BMP-2 used clin. for successful arthrodesis in the spine, amts. of growth factor incorporated in the scaffolds that are 10 to 100 times lower than that those used clin. in collagen scaffolds are used. The efficacy of the bioactive PA system to promote BMP-2-induced osteogenesis in vivo is investigated in a rat posterolateral lumbar intertransverse spinal fusion model. PA nanofiber gels displaying BMP-2-binding segments exhibit superior spinal fusion rates relative to controls, effectively decreasing the required therapeutic dose of BMP-2 by 10-fold. Interestingly, a 42% fusion rate is obsd. for gels contg. the bioactive nanofibers without the use of exogenous BMP-2, suggesting the ability of the nanofiber to recruit endogenous growth factor. Results obtained here demonstrate that bioactive biomaterials with capacity to bind specific growth factors by design are great targets for regenerative medicine.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXivFWiuw%253D%253D&md5=5fd9ee59a0450282934d4ead1d0bc819
  25. 25
    Casaletto, J. B.; McClatchey, A. I. Spatial regulation of receptor tyrosine kinases in development and cancer Nat. Rev. Cancer 2012, 12 (6) 387– 400 DOI: 10.1038/nrc3277
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    25
    Spatial regulation of receptor tyrosine kinases in development and cancer
    Casaletto, Jessica B.; McClatchey, Andrea I.
    Nature Reviews Cancer (2012), 12 (6), 387-400CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
    A review. During development and tissue homeostasis, patterns of cellular organization, proliferation and movement are highly choreographed. Receptor tyrosine kinases (RTKs) have a crucial role in establishing these patterns. Individual cells and tissues exhibit tight spatial control of the RTKs that they express, enabling tissue morphogenesis and function, while preventing unwarranted cell division and migration that can contribute to tumorigenesis. Indeed, RTKs are deregulated in most human cancers and are a major focus of targeted therapeutics. A growing appreciation of the essential role of spatial RTK regulation during development prompts the realization that spatial deregulation of RTKs is likely to contribute broadly to cancer development and may affect the sensitivity and resistance of cancer to pharmacol. RTK inhibitors.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xntlyks7Y%253D&md5=87d62276b4319a41ec37befe62dde0a1
  26. 26
    Yun, Y. R.; Won, J. E.; Jeon, E.; Lee, S.; Kang, W.; Jo, H.; Jang, J. H.; Shin, U. S.; Kim, H. W. Fibroblast growth factors: biology, function, and application for tissue regeneration J. Tissue Eng. 2010, 1, 218142 DOI: 10.4061/2010/218142
    [ Crossref], Google Scholar
    There is no corresponding record for this reference.
  27. 27
    Tayalia, P.; Mooney, D. J. Controlled Growth Factor Delivery for Tissue Engineering Adv. Mater. 2009, 21 (32–33) 3269– 3285 DOI: 10.1002/adma.200900241
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    27
    Controlled Growth Factor Delivery for Tissue Engineering
    Tayalia, Prakriti; Mooney, David J.
    Advanced Materials (Weinheim, Germany) (2009), 21 (32-33), 3269-3285CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Growth factors play a crucial role in information transfer between cells and their microenvironment in tissue engineering and regeneration. They initiate their action by binding to specific receptors on the surface of target cells and the chem. identity, concn., duration, and context of these growth factors contain information that dictates cell fate. Hence, the importance of exogenous delivery of these mols. in tissue engineering is unsurprising, considering their importance for tissue regeneration. However, the short half-lives of growth factors, their relatively large size, slow tissue penetration, and their potential toxicity at high systemic levels, suggest that conventional routes of administration are unlikely to be effective. In this review, we provide an overview of the design criteria for growth factor delivery vehicles with respect to the growth factor itself and the microenvironment for delivery. We discuss various methodologies that could be adopted to achieve this localized delivery, and strategies using polymers as delivery vehicles in particular.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVOrsb7O&md5=23a290c0418cebfa7f45ed340aa4843d
  28. 28
    Turner, N.; Grose, R. Fibroblast growth factor signalling: from development to cancer Nat. Rev. Cancer 2010, 10 (2) 116– 129 DOI: 10.1038/nrc2780
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    28
    Fibroblast growth factor signalling: from development to cancer
    Turner, Nicholas; Grose, Richard
    Nature Reviews Cancer (2010), 10 (2), 116-129CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
    A review. Fibroblast growth factors (FGFs) and their receptors control a wide range of biol. functions, regulating cellular proliferation, survival, migration and differentiation. Although targeting FGF signalling as a cancer therapeutic target has lagged behind that of other receptor tyrosine kinases, there is now substantial evidence for the importance of FGF signalling in the pathogenesis of diverse tumor types, and clin. reagents that specifically target the FGFs or FGF receptors are being developed. Although FGF signalling can drive tumorigenesis, in different contexts FGF signalling can mediate tumor protective functions; the identification of the mechanisms that underlie these differential effects will be important to understand how FGF signalling can be most appropriately therapeutically targeted.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXps1Gktg%253D%253D&md5=7963bc75c149981560dffc8d91b4aaf1
  29. 29
    Murakami, M.; Sakurai, T. Role of fibroblast growth factor signaling in vascular formation and maintenance: orchestrating signaling networks as an integrated system Wires Syst. Biol. Med. 2012, 4 (6) 615– 629 DOI: 10.1002/wsbm.1190
    [ Crossref], [ PubMed], Google Scholar
    There is no corresponding record for this reference.
  30. 30
    Raballo, R.; Rhee, J.; Lyn-Cook, R.; Leckman, J. F.; Schwartz, M. L.; Vaccarino, F. M. Basic fibroblast growth factor (Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex J. Neurosci. 2000, 20 (13) 5012– 5023
    [ PubMed], [ CAS], Google Scholar
    30
    Basic fibroblast growth factor (Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex
    Raballo, Rossana; Rhee, Julianne; Lyn-Cook, Richard; Leckman, James F.; Schwartz, Michael L.; Vaccarino, Flora M.
    Journal of Neuroscience (2000), 20 (13), 5012-5023CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
    Little is known about regionally specific signals that control the no. of neuronal progenitor cells in vivo. We have previously shown that the germline mutation of the basic fibroblast growth factor (Fgf2) gene results in a redn. in the no. of cortical neurons in the adult. We show here that Fgf2 is expressed in the pseudostratified ventricular epithelium (PVE) in a dorsoventral gradient and that Fgf2 and its receptor, Fgfr-1, are downregulated by mid to late stages of neurogenesis. In Fgf2 knockout mice, the vol. and cell no. of the dorsal PVE (the cerebral cortical anlage) are substantially smaller, whereas the vol. of the basal PVE is unchanged. The dorsal PVE of Fgf2 knockout mice has a 50% decrease in founder cells and a reduced expansion of the progenitor pool over the first portion of neurogenesis. Despite this redn., the degree of apoptosis within the PVE is not changed in the Fgf2 knockouts. Cortical neuron no. was decreased by 45% in Fgf2 knockout mice by the end of neurogenesis, whereas the no. of neurons in the basal ganglia was unaffected. Microscopically, the frontal cerebral cortex of neonatal Fgf2 null mutant mice lacked large neurons in deep cortical layers. We suggest that Fgf2 is required for the generation of a specific class of cortical neurons arising from the dorsal PVE.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXksF2jt7w%253D&md5=dd80b532909defca1ae1a0462a37ae26
  31. 31
    Woodbury, M. E.; Ikezu, T. Fibroblast growth factor-2 signaling in neurogenesis and neurodegeneration J. Neuroimmune Pharmacol 2014, 9 (2) 92– 101 DOI: 10.1007/s11481-013-9501-5
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    31
    Fibroblast growth factor-2 signaling in neurogenesis and neurodegeneration
    Woodbury Maya E; Ikezu Tsuneya
    Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology (2014), 9 (2), 92-101 ISSN:.
    Fibroblast growth factor-2 (FGF2), also known as basic FGF, is a multi-functional growth factor. One of the 22-member FGF family, it signals through receptor tyrosine kinases encoding FGFR1-4. FGF2 activates FGFRs in cooperation with heparin or heparin sulfate proteoglycan to induce its pleiotropic effects in different tissues and organs, which include potent angiogenic effects and important roles in the differentiation and function of the central nervous system (CNS). FGF2 is crucial to development of the CNS, which explains its importance in adult neurogenesis. During development, high levels of FGF2 are detected from neurulation onwards. Moreover, developmental expression of FGF2 and its receptors is temporally and spatially regulated, concurring with development of specific brain regions including the hippocampus and substantia nigra pars compacta. In adult neurogenesis, FGF2 has been implicated based on its expression and regulation of neural stem and progenitor cells in the neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. FGFR1 signaling also modulates inflammatory signaling through the surface glycoprotein CD200, which regulates microglial activation. Because of its importance in adult neurogenesis and neuroinflammation, manipulation of FGF2/FGFR1 signaling has been a focus of therapeutic development for neurodegenerative disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and traumatic brain injury. Novel strategies include intranasal administration of FGF2, administration of an NCAM-derived FGFR1 agonist, and chitosan-based nanoparticles for the delivery of FGF2 in pre-clinical animal models. In this review, we highlight current research towards therapeutic interventions targeting FGF2/FGFR1 in neurodegenerative disorders.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c%252Fgt1WitQ%253D%253D&md5=b1d9f637c8d2895604f3c8e9aa98718a
  32. 32
    Kim, J. H.; Jung, Y.; Kim, S.-H.; Sun, K.; Choi, J.; Kim, H. C.; Park, Y.; Kim, S. H. The enhancement of mature vessel formation and cardiac function in infarcted hearts using dual growth factor delivery with self-assembling peptides Biomaterials 2011, 32 (26) 6080– 6088 DOI: 10.1016/j.biomaterials.2011.05.003
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    32
    The enhancement of mature vessel formation and cardiac function in infarcted hearts using dual growth factor delivery with self-assembling peptides
    Kim, Ji Hyun; Jung, Youngmee; Kim, Sang-Heon; Sun, Kyung; Choi, Jaesoon; Kim, Hee Chan; Park, Yongdoo; Kim, Soo Hyun
    Biomaterials (2011), 32 (26), 6080-6088CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    For successful treatment of myocardial infarction (MI), it is important to prevent cardiac fibrosis and maintain cardiac function by protecting cardiomyocytes and inducing angiogenesis. To establish functional and stable vessels, various growth factors, ones stimulating both endothelial cells (EC) and vascular smooth muscle cells (VSMC), are required. Self-assembling peptides form fibers (<10 nm) and provide 3-dimensional microenvironments that can recruit EC and VSMC to promote vascularization and long-term delivery of growth factors. Here we demonstrate myocardial protection of infarcted heart using dual growth factor delivery with self-assembling peptides. After coronary artery ligation in rats, growth factors (PDGF-BB and FGF-2) with self-assembling peptides were injected. There were 6 rats in each group. Hearts were harvested at 4 and 8 wk for functional and histol. anal. Infarct size and cardiomyocyte apoptosis in dual growth factors along with self-assembling peptides group were dramatically reduced compared to sham. The capillary and arterial d. of this group recovered with angiogenic synergism and cardiac functions had almost recovered. In conclusion, dual growth factors along with self-assembling peptides lead to myocardial protection, stable vessel formation, and improvement in cardiac function.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXotlChsLk%253D&md5=2759b44208b2189e8c0b59f20492e19f
  33. 33
    Tam, R. Y.; Fuehrmann, T.; Mitrousis, N.; Shoichet, M. S. Regenerative Therapies for Central Nervous System Diseases: a Biomaterials Approach Neuropsychopharmacology 2014, 39 (1) 169– 188 DOI: 10.1038/npp.2013.237
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    33
    Regenerative Therapies for Central Nervous System Diseases: a Biomaterials Approach
    Tam, Roger Y.; Fuehrmann, Tobias; Mitrousis, Nikolaos; Shoichet, Molly S.
    Neuropsychopharmacology (2014), 39 (1), 169-188CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)
    A review. The central nervous system (CNS) has a limited capacity to spontaneously regenerate following traumatic injury or disease, requiring innovative strategies to promote tissue and functional repair. Tissue regeneration strategies, such as cell and/or drug delivery, have demonstrated promising results in exptl. animal models, but have been difficult to translate clin. The efficacy of cell therapy, which involves stem cell transplantation into the CNS to replace damaged tissue, has been limited due to low cell survival and integration upon transplantation, while delivery of therapeutic mols. to the CNS using conventional methods, such as oral and i.v. administration, have been limited by diffusion across the blood-brain/spinal cord-barrier. The use of biomaterials to promote graft survival and integration as well as localized and sustained delivery of biologics to CNS injury sites is actively being pursued. This review will highlight recent advances using biomaterials as cell- and drug-delivery vehicles for CNS repair.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFymsL7E&md5=5e9870f346d2e8bc8b4baa2f964f3e45
  34. 34
    Baird, A.; Schubert, D.; Ling, N.; Guillemin, R. Receptor- and heparin-binding domains of basic fibroblast growth factor Proc. Natl. Acad. Sci. U. S. A. 1988, 85 (7) 2324– 8 DOI: 10.1073/pnas.85.7.2324
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    34
    Receptor- and heparin-binding domains of basic fibroblast growth factor
    Baird, Andrew; Schubert, David; Ling, Nicholas; Guillemin, Roger
    Proceedings of the National Academy of Sciences of the United States of America (1988), 85 (7), 2324-8CODEN: PNASA6; ISSN:0027-8424.
    Two functional domains in the primary structure of basic fibroblast growth factor (FGF) were identified on the basis of their ability to interact with the FGF receptor, bind radiolabeled heparin, and modulate the cellular response to FGF. Peptides derived from these 2 functional domains can act as partial agonists and antagonists in biol. assays of FGF activity. Peptides related to the sequences of FGF-(24-68)-NH2 and FGF-(106-115)-NH2 inhibit thymidine incorporation into 3T3 fibroblasts when they are stimulated by FGF but have no effect when the cells are treated with either platelet-derived growth factor or epidermal growth factor. They also possess partial agonist activity and can stimulate DNA synthesis when tested in the absence of exogenous FGF. The active peptides have no effect on the binding of epidermal growth factor to its receptor on A431 cells, and they can modulate the effects of FGF, but not fibronectin, on endothelial cell adhesion. The results suggest the possibility of designing specific analogs of FGF that are capable of inhibiting the biol. effects of FGF.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXktVSqt74%253D&md5=de0c889bd9652f69aa2402e9402e147c
  35. 35
    Lin, X.; Takahashi, K.; Campion, S. L.; Liu, Y.; Gustavsen, G. G.; Pena, L. A.; Zamora, P. O. Synthetic peptide F2A4-K-NS mimics fibroblast growth factor-2 in vitro and is angiogenic in vivo Int. J. Mol. Med. 2006, 17 (5) 833– 9 DOI: 10.3892/ijmm.17.5.833
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    35
    Synthetic peptide F2A4-K-NS mimics fibroblast growth factor-2 in vitro and is angiogenic in vivo
    Lin, X.; Takahashi, K.; Campion, S. L.; Liu, Y.; Gustavsen, G. G.; Pena, L. A.; Zamora, P. O.
    International Journal of Molecular Medicine (2006), 17 (5), 833-839CODEN: IJMMFG; ISSN:1107-3756. (International Journal of Molecular Medicine)
    A multi-domain synthetic peptide, F2A4-K-NS, mimicked the action of recombinant human FGF-2 (rhFGF-2) in vitro and in an in vivo model of angiogenesis. Like rhFGF-2, F2A4-K-NS was quant. shown to bind to FGF receptors in a cell-free receptor binding assay using a chimeric FGFR1 (IIIc)/Fc as monitored by surface plasmon resonance (SPR), and also shown to bind to heparin using biotinylated low-mol. wt. heparin in a similar SPR assay. In vitro, F2A4-K-NS triggered signal transduction as monitored by the stimulation of ERK1/2 phosphorylation in human umbilical cord endothelial cells. In cell based assays, it increased cell migration, cell proliferation, and gelatinase secretion; endpoints assocd. with FGF-2 stimulation. Furthermore, these in vitro effects were mediated with quantities of F2A4-K-NS that were similar to those of rhFGF-2. In vivo, F2A4-K-NS was angiogenic at doses of 40 and 400 ng/implant in a s.c. implant assay as detd. by morphol. scoring, Hb content, and histol. These results support the hypothesis that F2A4-K-NS is a mimetic of FGF-2 that can substitute for FGF-2 in vitro and in vivo. A synthetic mimetic of FGF-2, such as F2A4-K-NS, could be a useful tool in studying mechanisms of cell activation and potentially in various therapeutic applications.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xks1Cht7s%253D&md5=53813602a0d40430fc71b0ca802b5554
  36. 36
    Hartgerink, J. D.; Beniash, E.; Stupp, S. I. Peptide-amphiphile nanofibers: A versatile scaffold for the preparation of self-assembling materials Proc. Natl. Acad. Sci. U. S. A. 2002, 99 (8) 5133– 5138 DOI: 10.1073/pnas.072699999
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    36
    Peptide-amphiphile nanofibers: a versatile scaffold for the preparation of self-assembling materials
    Hartgerink, Jeffrey D.; Beniash, Elia; Stupp, Samuel I.
    Proceedings of the National Academy of Sciences of the United States of America (2002), 99 (8), 5133-5138CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Twelve derivs. of peptide-amphiphile mols., designed to self-assemble into nanofibers, are described. The scope of amino acid selection and alkyl tail modification in the peptide-amphiphile mols. are investigated, yielding nanofibers varying in morphol., surface chem., and potential bioactivity. The results demonstrate the chem. versatile nature of this supramol. system and its high potential for manufg. nanomaterials. In addn., three different modes of self-assembly resulting in nanofibers are described, including pH control, divalent ion induction, and concn.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtFKmtbc%253D&md5=c3f7e085dae93ac5a43fea1db538fdbf
  37. 37
    Zhang, S.; Greenfield, M. A.; Mata, A.; Palmer, L. C.; Bitton, R.; Mantei, J. R.; Aparicio, C.; de la Cruz, M. O.; Stupp, S. I. A self-assembly pathway to aligned monodomain gels Nat. Mater. 2010, 9 (7) 594– 601 DOI: 10.1038/nmat2778
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    37
    A self-assembly pathway to aligned monodomain gels
    Zhang, Shuming; Greenfield, Megan A.; Mata, Alvaro; Palmer, Liam C.; Bitton, Ronit; Mantei, Jason R.; Aparicio, Conrado; de la Cruz, Monica Olvera; Stupp, Samuel I.
    Nature Materials (2010), 9 (7), 594-601CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
    Aggregates of charged amphiphilic mols. have been found to access a structure at elevated temp. that templates alignment of supramol. fibrils over macroscopic scales. The thermal pathway leads to a lamellar plaque structure with fibrous texture that breaks on cooling into large arrays of aligned nanoscale fibers and forms a strongly birefringent liq. By manually dragging this liq. crystal from a pipet onto salty media, it is possible to extend this alignment over centimetres in noodle-shaped viscoelastic strings. Using this approach, the soln. of supramol. filaments can be mixed with cells at physiol. temps. to form monodomain gels of aligned cells and filaments. The nature of the self-assembly process and its biocompatibility would allow formation of cellular wires in situ that have any length and customized peptide compns. for use in biol. applications.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvVOktrY%253D&md5=d02eef3d33c9cb6b8961464f9b56a4fd
  38. 38
    Tantakitti, F.; Boekhoven, J.; Wang, X.; Kazantsev, R. V.; Yu, T.; Li, J.; Zhuang, E.; Zandi, R.; Ortony, J. H.; Newcomb, C. J.; Palmer, L. C.; Shekhawat, G. S.; de la Cruz, M. O.; Schatz, G. C.; Stupp, S. I. Energy landscapes and functions of supramolecular systems Nat. Mater. 2016, 15 (4) 469– 476 DOI: 10.1038/nmat4538
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    38
    Energy landscapes and functions of supramolecular systems
    Tantakitti, Faifan; Boekhoven, Job; Wang, Xin; Kazantsev, Roman V.; Yu, Tao; Li, Jiahe; Zhuang, Ellen; Zandi, Roya; Ortony, Julia H.; Newcomb, Christina J.; Palmer, Liam C.; Shekhawat, Gajendra S.; de la Cruz, Monica Olvera; Schatz, George C.; Stupp, Samuel I.
    Nature Materials (2016), 15 (4), 469-476CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
    By means of 2 supramol. systems, peptide amphiphiles engaged in H-bonded β-sheets, and chromophore amphiphiles driven to assemble by π-orbital overlaps, the authors showed that the min. in the energy landscapes of supramol. systems were defined by electrostatic repulsion and the ability of the dominant attractive forces to trap mols. in thermodynamically unfavorable configurations. These competing interactions could be selectively switched on and off, with the order of doing so detg. the position of the final product in the energy landscape. Within the same energy landscape, the peptide-amphiphile system formed a thermodynamically favored product characterized by long bundled fibers that promoted biol. cell adhesion and survival, and a metastable product characterized by short monodisperse fibers that interfered with adhesion and could lead to cell death. These findings suggested that, in supramol. systems, functions and energy landscapes are linked, superseding the more traditional connection between mol. design and function.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1emu7g%253D&md5=14093ed2a80d60847cd6d8948c5bace3
  39. 39
    Boekhoven, J.; Stupp, S. I. 25th Anniversary Article: Supramolecular Materials for Regenerative Medicine Adv. Mater. 2014, 26 (11) 1642– 1659 DOI: 10.1002/adma.201304606
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    39
    25th Anniversary Article: Supramolecular Materials for Regenerative Medicine
    Boekhoven, Job; Stupp, Samuel I.
    Advanced Materials (Weinheim, Germany) (2014), 26 (11), 1642-1659CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. In supramol. materials, mol. building blocks are designed to interact with one another via non-covalent interactions in order to create function. This offers the opportunity to create structures similar to those found in living systems that combine order and dynamics through the reversibility of intermol. bonds. For regenerative medicine there is a great need to develop materials that signal cells effectively, deliver or bind bioactive agents in vivo at controlled rates, have highly tunable mech. properties, but at the same time, can biodegrade safely and rapidly after fulfilling their function. These requirements make supramol. materials a great platform to develop regenerative therapies. This review illustrates the emerging science of these materials and their use in a no. of applications for regenerative medicine.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVyqt7g%253D&md5=b43a171aa07a2b6fb8e8ef9f6c25d7c8
  40. 40
    Stephanopoulos, N.; Ortony, J. H.; Stupp, S. I. Self-assembly for the synthesis of functional biomaterials Acta Mater. 2013, 61 (3) 912– 930 DOI: 10.1016/j.actamat.2012.10.046
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    40
    Self-assembly for the synthesis of functional biomaterials
    Stephanopoulos, Nicholas; Ortony, Julia H.; Stupp, Samuel I.
    Acta Materialia (2013), 61 (3), 912-930CODEN: ACMAFD; ISSN:1359-6454. (Elsevier Ltd.)
    A review. The use of self-assembly for the construction of functional biomaterials is a highly promising and exciting area of research, with great potential for the treatment of injury or disease. By using multiple noncovalent interactions, coded into the mol. design of the constituent components, self-assembly allows for the construction of complex, adaptable, and highly tunable materials with potent biol. effects. This review describes some of the seminal advances in the use of self-assembly to make novel systems for regenerative medicine and biol. Materials based on peptides, proteins, DNA, or hybrids thereof have found application in the treatment of a wide range of injuries and diseases, and this review outlines the design principles and practical applications of these systems. Most of the examples covered focus on the synthesis of hydrogels for the scaffolding or transplantation of cells, with an emphasis on the biol., mech., and structural properties of the resulting materials. In addn., we will discuss the distinct advantages conferred by self-assembly (compared with traditional covalent materials), and present some of the challenges and opportunities for the next generation of self-assembled biomaterials.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFagtrY%253D&md5=7cfe964fe6e343cb4ecd412c7164f5fd
  41. 41
    Silva, G. A.; Czeisler, C.; Niece, K. L.; Beniash, E.; Harrington, D. A.; Kessler, J. A.; Stupp, S. I. Selective differentiation of neural progenitor cells by high-epitope density nanofibers Science 2004, 303 (5662) 1352– 1355 DOI: 10.1126/science.1093783
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    41
    Selective differentiation of neural progenitor cells by high-epitope density nanofibers
    Silva, Gabriel A.; Czeisler, Catherine; Niece, Krista L.; Beniash, Elia; Harrington, Daniel A.; Kessler, John A.; Stupp, Samuel I.
    Science (Washington, DC, United States) (2004), 303 (5662), 1352-1355CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Neural progenitor cells were encapsulated in vitro within a three-dimensional network of nanofibers formed by self-assembly of peptide amphiphile mols. The self-assembly is triggered by mixing cell suspensions in media with dil. aq. solns. of the mols., and cells survive the growth of the nanofibers around them. These nanofibers were designed to present to cells the neurite-promoting laminin epitope IKVAV at nearly van der Waals d. Relative to laminin or sol. peptide, the artificial nanofiber scaffold induced very rapid differentiation of cells into neurons, while discouraging the development of astrocytes. This rapid selective differentiation is linked to the amplification of bioactive epitope presentation to cells by the nanofibers.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhsFyrtLo%253D&md5=62b424889d3e6a0ab0a70396c4dbbcb6
  42. 42
    Tysseling-Mattiace, V. M.; Sahni, V.; Niece, K. L.; Birch, D.; Czeisler, C.; Fehlings, M. G.; Stupp, S. I.; Kessler, J. A. Self-Assembling Nanofibers Inhibit Glial Scar Formation and Promote Axon Elongation after Spinal Cord Injury J. Neurosci. 2008, 28 (14) 3814– 3823 DOI: 10.1523/JNEUROSCI.0143-08.2008
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    42
    Self-assembling nanofibers inhibit glial scar formation and promote axon elongation after spinal cord injury
    Tysseling-Mattiace, Vicki M.; Sahni, Vibhu; Niece, Krista L.; Birch, Derin; Czeisler, Catherine; Fehlings, Michael G.; Stupp, Samuel I.; Kessler, John A.
    Journal of Neuroscience (2008), 28 (14), 3814-3823CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
    Peptide amphiphile (PA) mols. that self-assemble in vivo into supramol. nanofibers were used as a therapy in a mouse model of spinal cord injury (SCI). Because self-assembly of these mols. is triggered by the ionic strength of the in vivo environment, nanoscale structures can be created within the extracellular spaces of the spinal cord by simply injecting a liq. The mols. are designed to form cylindrical nanofibers that display to cells in the spinal cord the laminin epitope IKVAV at nearly van der Waals d. IKVAV PA nanofibers are known to inhibit glial differentiation of cultured neural stem cells and to promote neurite outgrowth from cultured neurons. In this work, in vivo treatment with the PA after SCI reduced astrogliosis, reduced cell death, and increased the no. of oligodendroglia at the site of injury. Furthermore, the nanofibers promoted regeneration of both descending motor fibers and ascending sensory fibers through the lesion site. Treatment with the PA also resulted in significant behavioral improvement. These observations demonstrate that it is possible to inhibit glial scar formation and to facilitate regeneration after SCI using bioactive three-dimensional nanostructures displaying high densities of neuroactive epitopes on their surfaces.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXkslSjur8%253D&md5=68d62032cd249d07e37559419e6ef286
  43. 43
    Pan, L.; North, H. A.; Sahni, V.; Jeong, S. J.; McGuire, T. L.; Berns, E. J.; Stupp, S. I.; Kessler, J. A. β1-Integrin and Integrin Linked Kinase Regulate Astrocytic Differentiation of Neural Stem Cells PLoS One 2014, 9 (8) e104335 DOI: 10.1371/journal.pone.0104335
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    43
    β1-Integrin and integrin linked kinase regulate astrocytic differentiation of neural stem cells
    Pan, Liuliu; North, Hilary A.; Sahni, Vibhu; Jeong, Su Ji; McGuire, Tammy L.; Berns, Eric J.; Stupp, Samuel I.; Kessler, John A.
    PLoS One (2014), 9 (8), e104335/1-e104335/12, 12 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Astrogliosis with glial scar formation after damage to the nervous system is a major impediment to axonal regeneration and functional recovery. The present study examd. the role of β1-integrin signaling in regulating astrocytic differentiation of neural stem cells. In the adult spinal cord β1-integrin is expressed predominantly in the ependymal region where ependymal stem cells (ESCs) reside. β1-Integrin signaling suppressed astrocytic differentiation of both cultured ESCs and subventricular zone (SVZ) progenitor cells. Conditional knockout of β1-integrin enhanced astrogliogenesis both by cultured ESCs and by SVZ progenitor cells. Previous studies have shown that injection into the injured spinal cord of a self-assembling peptide amphiphile that displays an IKVAV epitope (IKVAV-PA) limits glial scar formation and enhances functional recovery. Here we find that injection of IKVAV-PA induced high levels of β1-integrin in ESCs in vivo, and that conditional knockout of β1-integrin abolished the astroglial suppressive effects of IKVAV-PA in vitro. Injection into an injured spinal cord of PAs expressing two other epitopes known to interact with β1-integrin, a Tenascin C epitope and the fibronectin epitope RGD, improved functional recovery comparable to the effects of IKVAV-PA. Finally we found that the effects of β1-integrin signaling on astrogliosis are mediated by integrin linked kinase (ILK). These observations demonstrate an important role for β1-integrin/ILK signaling in regulating astrogliosis from ESCs and suggest ILK as a potential target for limiting glial scar formation after nervous system injury.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1aks73J&md5=d2d8caf7a3128a08e6a8efbb42c02c23
  44. 44
    Huang, Z.; Sargeant, T. D.; Hulvat, J. F.; Mata, A.; Bringas, P.; Koh, C. Y.; Stupp, S. I.; Snead, M. L. Bioactive Nanofibers Instruct Cells to Proliferate and Differentiate During Enamel Regeneration J. Bone Miner. Res. 2008, 23 (12) 1995– 2006 DOI: 10.1359/jbmr.080705
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    44
    Bioactive nanofibers instruct cells to proliferate and differentiate during enamel regeneration
    Huang, Zhan; Sargeant, Timothy D.; Hulvat, James F.; Mata, Alvaro; Bringas, Pablo, Jr.; Koh, Chung-Yan; Stupp, Samuel I.; Snead, Malcolm L.
    Journal of Bone and Mineral Research (2008), 23 (12), 1995-2006CODEN: JBMREJ; ISSN:0884-0431. (American Society for Bone and Mineral Research)
    During tooth development, ectoderm-derived ameloblast cells create enamel by synthesizing a complex protein mixt. serving to control cell to matrix interactions and the habit of hydroxyapatite crystallites. Using an in vitro cell and organ culture system, we studied the effect of artificial bioactive nanostructures on ameloblasts with the long-term goal of developing cell-based strategies for tooth regeneration. We used branched peptide amphiphile mols. contg. the peptide motif Arg-Gly-Asp, or "RGD" (abbreviated BRGD-PA), known to self-assemble in physiol. environments into nanofibers that display on their surfaces high densities of this biol. signal. Ameloblast-like cells (line LS8) and primary enamel organ epithelial (EOE) cells were cultured within PA hydrogels, and the PA was injected into the enamel organ epithelia of mouse embryonic incisors. The expression of amelogenin, ameloblastin, integrin α5, and integrin α6 was detected by quant. real-time PCR and immunodetection techniques. We performed cell proliferation assay using BrdU labeling and a biomineralization assay using Alizarin red S staining with quant. Ca2+ measurements. In the cell culture model, ameloblast-like cells (LS8) and primary EOE cells responded to the BRGD-PA nanostructures with enhanced proliferation and greater amelogenin, ameloblastin, and integrin expression levels. At the site of injection of the BRGD-PA in the organ culture model, we obsd. EOE cell proliferation with differentiation into ameloblasts as evidenced by their expression of enamel specific proteins. Ultrastructural anal. showed the nanofibers within the forming extracellular matrix, in contact with the EOE cells engaged in enamel formation and regeneration. This study shows that BRGD-PA nanofibers present with enamel proteins participate in integrin-mediated cell binding to the matrix with delivery of instructive signals for enamel formation.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosVyltrs%253D&md5=f9c4486b62c03e5b8c2e7840de9050b2
  45. 45
    Mata, A.; Geng, Y. B.; Henrikson, K. J.; Aparicio, C.; Stock, S. R.; Satcher, R. L.; Stupp, S. I. Bone regeneration mediated by biomimetic mineralization of a nanofiber matrix Biomaterials 2010, 31 (23) 6004– 6012 DOI: 10.1016/j.biomaterials.2010.04.013
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    45
    Bone regeneration mediated by biomimetic mineralization of a nanofiber matrix
    Mata, Alvaro; Geng, Yanbiao; Henrikson, Karl J.; Aparicio, Conrado; Stock, Stuart R.; Satcher, Robert L.; Stupp, Samuel I.
    Biomaterials (2010), 31 (23), 6004-6012CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    Rapid bone regeneration within a three-dimensional defect without the use of bone grafts, exogenous growth factors, or cells remains a major challenge. We report here on the use of self-assembling peptide nanostructured gels to promote bone regeneration that have the capacity to mineralize in biomimetic fashion. The main mol. design was the use of phosphoserine residues in the sequence of a peptide amphiphile known to nucleate hydroxyapatite crystals on the surfaces of nanofibers. We tested the system in a rat femoral crit.-size defect by placing pre-assembled nanofiber gels in a 5 mm gap and analyzed bone formation with micro-computed tomog. and histol. We found within 4 wk significantly higher bone formation relative to controls lacking phosphorylated residues and comparable bone formation to that obsd. in animals treated with a clin. used allogenic bone matrix.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnslamt7g%253D&md5=31b506ca096d15e5545c810d5ddf4424
  46. 46
    Lee, S. S.; Huang, B. J.; Kaltz, S. R.; Sur, S.; Newcomb, C. J.; Stock, S. R.; Shah, R. N.; Stupp, S. I. Bone regeneration with low dose BMP-2 amplified by biomimetic supramolecular nanofibers within collagen scaffolds Biomaterials 2013, 34 (2) 452– 459 DOI: 10.1016/j.biomaterials.2012.10.005
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    46
    Bone regeneration with low dose BMP-2 amplified by biomimetic supramolecular nanofibers within collagen scaffolds
    Lee, Sungsoo S.; Huang, Brian J.; Kaltz, Stuart R.; Sur, Shantanu; Newcomb, Christina J.; Stock, Stuart R.; Shah, Ramille N.; Stupp, Samuel I.
    Biomaterials (2013), 34 (2), 452-459CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    Bone morphogenetic protein-2 (BMP-2) is a potent osteoinductive cytokine that plays a crit. role during bone regeneration and repair. In the extracellular environment, sulfated polysaccharides anchored covalently to glycoproteins such as syndecan and also non-covalently to fibronectin fibers have been shown to bind BMP-2 through a heparin-binding domain and regulate its bioactivity. We report here on a synthetic biomimetic strategy that emulates biol. BMP-2 signaling through the use of peptide amphiphile nanofibers designed to bind heparin. The supramol. nanofibers, which integrate the biol. role of syndecan and fibronectin, were allowed to form gel networks within the pores of an absorbable collagen scaffold by simply infiltrating dil. solns. of the peptide amphiphile, heparan sulfate, and BMP-2. The hybrid biomaterial enhanced significantly bone regeneration in a rat crit.-size femoral defect model using BMP-2 amts. that are one order of magnitude lower than required for healing in this animal model. Using micro-computed tomog., we also showed that the hybrid scaffold was more effective at bridging within the gap relative to a conventional scaffold of the type used clin. based on collagen and BMP-2. Histol. evaluation also revealed the presence of more mature bone in the new ossified tissue when the low dose of BMP-2 was delivered using the biomimetic supramol. system. These results demonstrate how molecularly designed materials that mimic features of the extracellular environment can amplify the regenerative capacity of growth factors.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFGjtLvI&md5=cf9ef30ed6ca1efff6fe8211dc4fb40e
  47. 47
    Chow, L. W.; Bitton, R.; Webber, M. J.; Carvajal, D.; Shull, K. R.; Sharma, A. K.; Stupp, S. I. A bioactive self-assembled membrane to promote angiogenesis Biomaterials 2011, 32 (6) 1574– 1582 DOI: 10.1016/j.biomaterials.2010.10.048
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    47
    A bioactive self-assembled membrane to promote angiogenesis
    Chow, Lesley W.; Bitton, Ronit; Webber, Matthew J.; Carvajal, Daniel; Shull, Kenneth R.; Sharma, Arun K.; Stupp, Samuel I.
    Biomaterials (2011), 32 (6), 1574-1582CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    We report here on a bioactive hierarchically structured membrane formed by self-assembly. The membrane is formed with hyaluronic acid and peptide amphiphiles with binding affinity for heparin, and its hierarchical structure contains both an amorphous zone and a layer of fibrils oriented perpendicular to the membrane plane. The design of bioactivity is based on the potential ability to bind and slowly release heparin-binding growth factors. Human mesenchymal stem cells (hMSCs) seeded on these membranes attached and remained viable. Basic fibroblast growth factor (FGF2) and vascular endothelial growth factor (VEGF) were incorporated within the membrane structure prior to self-assembly and released into media over a prolonged period of time (14 days). Using the chicken chorioallantoic membrane (CAM) assay, we also found that these membranes induced a significant and rapid enhancement of angiogenesis relative to controls.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1SqtrbL&md5=c97eabb880fb0ccf9559b8169e447c1b
  48. 48
    Rajangam, K.; Arnold, M. S.; Rocco, M. A.; Stupp, S. I. Peptide amphiphile nanostructure-heparin interactions and their relationship to bioactivity Biomaterials 2008, 29 (23) 3298– 3305 DOI: 10.1016/j.biomaterials.2008.04.008
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    48
    Peptide amphiphile nanostructure-heparin interactions and their relationship to bioactivity
    Rajangam, Kanya; Arnold, Michael S.; Rocco, Mark A.; Stupp, Samuel I.
    Biomaterials (2008), 29 (23), 3298-3305CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    Heparin-protein interactions are important in many physiol. processes including angiogenesis, the growth of new blood vessels from existing ones. We have previously developed a highly angiogenic self-assembling gel, wherein the self-assembly process is triggered by the interactions between heparin and peptide amphiphiles (PAs) with a consensus heparin binding sequence. In this report, this consensus sequence was scrambled and incorporated into a new peptide amphiphile in order to study its importance in heparin interaction and bioactivity. Heparin was able to trigger gel formation of the scrambled peptide amphiphile (SPA). Furthermore, the affinity of the scrambled mol. for heparin was unchanged as shown by isothermal titrn. calorimetry and high Foerster resonance emission transfer efficiency. However, both the mobile fraction and the dissocn. rate const. of heparin, using fluorescence recovery after photobleaching, were markedly higher in its interaction with the scrambled mol. implying a weaker assocn. Importantly, the scrambled peptide amphiphile-heparin gel had significantly less angiogenic bioactivity as shown by decreased tubule formation of sandwiched endothelial cells. Hence, we believe that the presence of the consensus sequence stabilizes the interaction with heparin and is important for the bioactivity of these new materials.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmsFahs7s%253D&md5=1741cca2aaba33c5806bc9785f2e59ad
  49. 49
    Shah, R. N.; Shah, N. A.; Lim, M. M. D.; Hsieh, C.; Nuber, G.; Stupp, S. I. Supramolecular design of self-assembling nanofibers for cartilage regeneration Proc. Natl. Acad. Sci. U. S. A. 2010, 107 (8) 3293– 3298 DOI: 10.1073/pnas.0906501107
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    49
    Supramolecular design of self-assembling nanofibers for cartilage regeneration
    Shah, Ramille N.; Shah, Nirav A.; Lim, Marc M. Del Rosario; Hsieh, Caleb; Nuber, Gordon; Stupp, Samuel I.
    Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (8), 3293-3298, S3293/1-S3293/4CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Mol. and supramol. design of bioactive biomaterials could have a significant impact on regenerative medicine. Ideal regenerative therapies should be minimally invasive, and thus the notion of self-assembling biomaterials programmed to transform from injectable liqs. to solid bioactive structures in tissue is highly attractive for clin. translation. We report here on a coassembly system of peptide amphiphile (PA) mols. designed to form nanofibers for cartilage regeneration by displaying a high d. of binding epitopes to transforming growth factor β-1 (TGFβ-1). Growth factor release studies showed that passive release of TGFβ-1 was slower from PA gels contg. the growth factor binding sites. In vitro expts. indicate these materials support the survival and promote the chondrogenic differentiation of human mesenchymal stem cells. We also show that these materials can promote regeneration of articular cartilage in a full thickness chondral defect treated with microfracture in a rabbit model with or even without the addn. of exogenous growth factor. These results demonstrate the potential of a completely synthetic bioactive biomaterial as a therapy to promote cartilage regeneration.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjtFymt7k%253D&md5=5544ae5566c3aaef434a4ea96e80d656
  50. 50
    Newcomb, C. J.; Sur, S.; Ortony, J. H.; Lee, O. S.; Matson, J. B.; Boekhoven, J.; Yu, J. M.; Schatz, G. C.; Stupp, S. I. Cell death versus cell survival instructed by supramolecular cohesion of nanostructures Nat. Commun. 2014, 5, 3321 DOI: 10.1038/ncomms4321
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    50
    Cell death versus cell survival instructed by supramolecular cohesion of nanostructures
    Newcomb Christina J; Sur Shantanu; Ortony Julia H; Matson John B; Boekhoven Job; Yu Jeong Min; Lee One-Sun; Schatz George C; Stupp Samuel I
    Nature communications (2014), 5 (), 3321 ISSN:.
    Many naturally occurring peptides containing cationic and hydrophobic domains have evolved to interact with mammalian cell membranes and have been incorporated into materials for non-viral gene delivery, cancer therapy or treatment of microbial infections. Their electrostatic attraction to the negatively charged cell surface and hydrophobic interactions with the membrane lipids enable intracellular delivery or cell lysis. Although the effects of hydrophobicity and cationic charge of soluble molecules on the cell membrane are well known, the interactions between materials with these molecular features and cells remain poorly understood. Here we report that varying the cohesive forces within nanofibres of supramolecular materials with nearly identical cationic and hydrophobic structure instruct cell death or cell survival. Weak intermolecular bonds promote cell death through disruption of lipid membranes, while materials reinforced by hydrogen bonds support cell viability. These findings provide new strategies to design biomaterials that interact with the cell membrane.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cvlsFOqtg%253D%253D&md5=3baf11f7a1278e14392fb71219011d05
  51. 51
    Pashuck, E. T.; Stupp, S. I. Direct Observation of Morphological Tranformation from Twisted Ribbons into Helical Ribbons J. Am. Chem. Soc. 2010, 132 (26) 8819– 8821 DOI: 10.1021/ja100613w
    [ ACS Full Text ACS Full Text], [ CAS], Google Scholar
    51
    Direct Observation of Morphological Transformation from Twisted Ribbons into Helical Ribbons
    Pashuck, E. Thomas; Stupp, Samuel I.
    Journal of the American Chemical Society (2010), 132 (26), 8819-8821CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The authors report on the direct observation of a nanostructural transformation from a twisted ribbon to a helical ribbon in supramol. assemblies of peptide amphiphiles. Using cryogenic electron microscopy, a peptide amphiphile mol., H3C(CH2)14CO-(Phe)3-(Glu)3-OH, contg. arom. residues was found to first assemble into short twisted ribbons in the time range of seconds, which then elongate in the time scale of minutes, and finally transform into helical ribbons over the course of weeks. By synthesizing an analogous mol., H3C(CH2)14CO-(Ala)3-(Glu)3-OH, without the arom. side groups, it was found that a cylindrical nanostructure is formed that does not undergo any transitions during the same time period. The study of metastable states in peptide aggregation can contribute to our understanding of amyloid-related diseases, such as Alzheimer's disease.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnsFyhs7Y%253D&md5=ba5ca9ea5b90bb8b5938c3c8914c4e64
  52. 52
    Hamley, I. W.; Dehsorkhi, A.; Castelletto, V.; Furzeland, S.; Atkins, D.; Seitsonen, J.; Ruokolainen, J. Reversible helical unwinding transition of a self-assembling peptide amphiphile Soft Matter 2013, 9 (39) 9290– 9293 DOI: 10.1039/c3sm51725j
    [ Crossref], [ CAS], Google Scholar
    52
    Reversible helical unwinding transition of a self-assembling peptide amphiphile
    Hamley, Ian W.; Dehsorkhi, Ashkan; Castelletto, Valeria; Furzeland, Steve; Atkins, Derek; Seitsonen, Jani; Ruokolainen, Janne
    Soft Matter (2013), 9 (39), 9290-9293CODEN: SMOABF; ISSN:1744-683X. (Royal Society of Chemistry)
    A designed peptide amphiphile C16-KKFFVLK self-assembles into nanotubes and helical ribbons in aq. soln. at room temp. A remarkable unwinding transition, leading to twisted tapes, is obsd. on heating. Nanotubes and ribbons re-form on cooling.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVKgsrbI&md5=b28b225d3881d1823a738b83b7b8ff1d
  53. 53
    Springer, B. A.; Pantoliano, M. W.; Barbera, F. A.; Gunyuzlu, P. L.; Thompson, L. D.; Herblin, W. F.; Rosenfeld, S. A.; Book, G. W. Identification and concerted function of two receptor binding surfaces on basic fibroblast growth factor required for mitogenesis J. Biol. Chem. 1994, 269 (43) 26879– 26884
    [ PubMed], [ CAS], Google Scholar
    53
    Identification and concerted function of two receptor binding surfaces on basic fibroblast growth factor required for mitogenesis
    Springer, Barry A.; Pantoliano, Michael W.; Barbera, Frank A.; Gunyuzlu, Michael W.; Barbera, Frank A.; Gunyuzlu, Paul L.; Thompson, Leo D.; Herblin, William F.; Rosenfelds, Stuart A.; Book, Glen W.
    Journal of Biological Chemistry (1994), 269 (43), 26879-84CODEN: JBCHA3; ISSN:0021-9258.
    Members of the fibroblast growth factor (FGF) family promote angiogenesis and would repair, modulate early developmental events and survival of neurons, and have been assocd. with the pathogenesis of various diseases. FGFs interact with specific FGF receptors (FGFRs) and heparan sulfate proteoglycans on cell surface to mediate mitogenesis. Using protein structure-based site-directed mutagenesis of basic FGF (bFGF), the authors have identified two FGFR binding sites on bFGF which act in concert to initiate signal transduction. Both FGFR binding surfaces are distinct from the heparan sulfate proteoglycan binding domain. The primary, higher affinity, binding interaction comprises a cluster of solvent exposed hydrophobic amino acids (Tyr-24, Tyr-103, Leu-140, and Met-142), and two polar residues (Arg-44 and Asn-101). The hydrophobic contacts dominate the primary binding interaction and provide ∼75% of the binding affinity. The secondary FGFR binding site of bFGF has an ∼250-fold lower affinity and is composed of amino acids Lys-110, Tyr-111, and Trp-114 in a surface-exposed type I β-turn (formerly known as the putative receptor binding loop). Binding of FGFR to both bFGF surfaces in a stoichiometry of 2FGFR:1bFGF is required for growth factor mediated cell proliferation. This represents a mechanism for the fibroblast growth factor/receptor family in which FGF facilities FGFR dimerization and subsequent signal transduction events as a monomeric ligand.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmt1ahtr0%253D&md5=75051de6a18f2bb7d94010633b912576
  54. 54
    Greenfield, N. J. Using circular dichroism spectra to estimate protein secondary structure Nat. Protoc 2007, 1 (6) 2876– 2890 DOI: 10.1038/nprot.2006.202
    [ Crossref], Google Scholar
    There is no corresponding record for this reference.
  55. 55
    Mohammadi, M.; Olsen, S. K.; Ibrahimi, O. A. Structural basis for fibroblast growth factor receptor activation Cytokine Growth Factor Rev. 2005, 16 (2) 107– 37 DOI: 10.1016/j.cytogfr.2005.01.008
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    55
    Structural basis for fibroblast growth factor receptor activation
    Mohammadi, Moosa; Olsen, Shaun K.; Ibrahimi, Omar A.
    Cytokine & Growth Factor Reviews (2005), 16 (2), 107-137CODEN: CGFRFB; ISSN:1359-6101. (Elsevier B.V.)
    A review. FGF signaling plays a ubiquitous role in human biol. as a regulator of embryonic development, homeostasis and regenerative processes. In addn., aberrant FGF signaling leads to diverse human pathologies including skeletal, olfactory, and metabolic disorders as well as cancer. FGFs execute their pleiotropic biol. actions by binding, dimerizing and activating cell surface FGF receptors (FGFRs). Proper regulation of FGF-FGFR binding specificity is essential for the regulation of FGF signaling and is achieved through primary sequence variations among the 18 FGFs and seven FGFRs. The severity of human skeletal syndromes arising from mutations that violate FGF-FGFR specificity is a testament to the importance of maintaining precision in FGF-FGFR specificity. The discovery that heparin/heparan sulfate (HS) proteoglycans are required for FGF signaling led to numerous models for FGFR dimerization and heralded one of the most controversial issues in FGF signaling. Recent crystallog. analyses have led to two fundamentally different models for FGFR dimerization. These models differ in both the stoichiometry and minimal length of heparin required for dimerization, the quaternary arrangement of FGF, FGFR and heparin in the dimer, and in the mechanism of 1:1 FGF-FGFR recognition and specificity. In this review, we provide an overview of recent structural and biochem. studies used to differentiate between the two crystallog. models. Interestingly, the structural and biophys. analyses of naturally occurring pathogenic FGFR mutations have provided the most compelling and unbiased evidences for the correct mechanisms for FGF-FGFR dimerization and binding specificity. The structural analyses of different FGF-FGFR complexes have also shed light on the intricate mechanisms detg. FGF-FGFR binding specificity and promiscuity and also provide a plausible explanation for the mol. basis of a large no. craniosynostosis mutations.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjvVOns7g%253D&md5=746ae413058ad52c77d77a553003746c
  56. 56
    Schlessinger, J.; Plotnikov, A. N.; Ibrahimi, O. A.; Eliseenkova, A. V.; Yeh, B. K.; Yayon, A.; Linhardt, R. J.; Mohammadi, M. Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization Mol. Cell 2000, 6 (3) 743– 50 DOI: 10.1016/S1097-2765(00)00073-3
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    56
    Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization
    Schlessinger, Joseph; Plotnikov, Alexander N.; Ibrahimi, Omar A.; Eliseenkova, Anna V.; Yeh, Brian K.; Yayon, Avner; Linhardt, Robert J.; Mohammadi, Moosa
    Molecular Cell (2000), 6 (3), 743-750CODEN: MOCEFL; ISSN:1097-2765. (Cell Press)
    The crystal structure of a dimeric 2:2:2 FGF:FGFR:heparin ternary complex at 3 Å resoln. has been detd. Within each 1:1 FGF:FGFR complex, heparin makes numerous contacts with both FGF and FGFR, thereby augmenting FGF-FGFR binding. Heparin also interacts with FGFR in the adjoining 1:1 FGF:FGFR complex to promote FGFR dimerization. The 6-O-sulfate group of heparin plays a pivotal role in mediating both interactions. The unexpected stoichiometry of heparin binding in the structure led the authors to propose a revised model for FGFR dimerization. Biochem. data in support of this model are also presented. This model provides a structural basis for FGFR activation by small mol. heparin analogs and may facilitate the design of heparin mimetics capable of modulating FGF signaling.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXntVyhsbg%253D&md5=0aaacc2d5377dba261ff8b3f080debf9
  57. 57
    Lin, Y. Y.; Qiao, Y.; Tang, P. F.; Li, Z. B.; Huang, J. B. Controllable self-assembled laminated nanoribbons from dipeptide-amphiphile bearing azobenzene moiety Soft Matter 2011, 7 (6) 2762– 2769 DOI: 10.1039/c0sm01050b
    [ Crossref], [ CAS], Google Scholar
    57
    Controllable self-assembled laminated nanoribbons from dipeptide-amphiphile bearing azobenzene moiety
    Lin, Yiyang; Qiao, Yan; Tang, Peifeng; Li, Zhibo; Huang, Jianbin
    Soft Matter (2011), 7 (6), 2762-2769CODEN: SMOABF; ISSN:1744-683X. (Royal Society of Chemistry)
    Artificial peptide self-assembly is an appealing research subject which has been demonstrated to be a reliable approach to create hierarchical nanostructures and biomaterials. In this paper, a dipeptide-amphiphile incorporated with an azobenzene moiety is synthesized, which are found to self-assemble into well-defined laminated nanoribbons as well as macroscopic hydrogel. The nanoribbons are formed by nanofibers aligning in nearly lamellar arrays. The driving force of dipeptide self-assembly is proposed to be a synergic effect of hydrophobic interaction, arom. packing, and hydrogen bond. The addn. of NaCl is found to promote hydrogelation and nanoribbon formation. Finally photoisomerization of the azobenzene group is utilized to rationally control dipeptide self-assembly and hydrogel formation by remote light input.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXivFSqu7s%253D&md5=a62efea6bdd1feae4999643334cac108
  58. 58
    Miravet, J. F.; Escuder, B.; Segarra-Maset, M. D.; Tena-Solsona, M.; Hamley, I. W.; Dehsorkhi, A.; Castelletto, V. Self-assembly of a peptide amphiphile: transition from nanotape fibrils to micelles Soft Matter 2013, 9 (13) 3558– 3564 DOI: 10.1039/c3sm27899a
    [ Crossref], [ CAS], Google Scholar
    58
    Self-assembly of a peptide amphiphile: transition from nanotape fibrils to micelles
    Miravet, Juan F.; Escuder, Beatriu; Segarra-Maset, Maria Dolores; Tena-Solsona, Marta; Hamley, Ian W.; Dehsorkhi, Ashkan; Castelletto, Valeria
    Soft Matter (2013), 9 (13), 3558-3564CODEN: SMOABF; ISSN:1744-683X. (Royal Society of Chemistry)
    A thermal transition is obsd. in the peptide amphiphile C16-KTTKS (TFA salt) from nanotapes at 20 °C to micelles at higher temp. (the transition temp. depending on concn.). The formation of extended nanotapes by the acetate salt of this peptide amphiphile, which incorporates a pentapeptide from type I procollagen, has been studied previously. Here, proton NMR and SAXS provide evidence for the TFA salt spherical micelles at high temp. The phase behavior, with a Krafft temp. sepg. insol. aggregates (extended nanotapes) at low temp. from the high temp. micellar phase resembles that for conventional surfactants, however this has not previously been reported for peptide amphiphiles.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsFGktLs%253D&md5=b630532dc18e507d260c2ab264c370b0
  59. 59
    Goetz, R.; Mohammadi, M. Exploring mechanisms of FGF signalling through the lens of structural biology Nat. Rev. Mol. Cell Biol. 2013, 14 (3) 166– 180 DOI: 10.1038/nrm3528
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    59
    Exploring mechanisms of FGF signalling through the lens of structural biology
    Goetz, Regina; Mohammadi, Moosa
    Nature Reviews Molecular Cell Biology (2013), 14 (3), 166-180CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
    A review. Fibroblast growth factors (FGFs) mediate a broad range of functions in both the developing and adult organism. The accumulated wealth of structural information on the FGF signaling pathway has begun to unveil the underlying mol. mechanisms that modulate this system to generate a myriad of distinct biol. outputs in development, tissue homeostasis and metab. At the ligand and receptor level, these mechanisms include alternative splicing of the ligand (FGF8 subfamily) and the receptor (FGFR1-FGFR3), ligand homodimerization (FGF9 subfamily), site-specific proteolytic cleavage of the ligand (FGF23), and interaction of the ligand and the receptor with heparan sulfate cofactor and Klotho co-receptor.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitlentr8%253D&md5=5dcac124dcc9f836f3e304bc081ef8f6
  60. 60
    Nowak, S. J.; Corces, V. G. Phosphorylation of histone H3: a balancing act between chromosome condensation and transcriptional activation Trends Genet. 2004, 20 (4) 214– 220 DOI: 10.1016/j.tig.2004.02.007
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    60
    Phosphorylation of histone H3: a balancing act between chromosome condensation and transcriptional activation
    Nowak, Scott J.; Corces, Victor G.
    Trends in Genetics (2004), 20 (4), 214-220CODEN: TRGEE2; ISSN:0168-9525. (Elsevier Science Ltd.)
    A review. In recent years, the covalent modification of histone tails has emerged as a crucial step in controlling the transcription of eukaryotic genes. Phosphorylation of the serine 10 residue of the N-terminal tail of histone H3 is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addn., this modification is important during interphase because it enables the transcription of an increasing no. of genes that are activated as a consequence of a variety of cell-signaling events. The location of the serine 10 residue in close proximity to other modifiable amino acids in the histone H3 tail enables the possibility of an interaction between phosphorylation of serine 10 and methylation and/or acetylation of lysine 9 and lysine 14. Finally, the finding that the histone H3.3 variant, which has a conserved N-terminal tail, can replace histone H3 at sites of active transcription, adds a new layer of complexity and possibilities to the regulation of transcription through changes in chromatin structure.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXisVGitbs%253D&md5=94633792527752aed6bd9388aafbf74e
  61. 61
    Esser, J. S.; Rahner, S.; Deckler, M.; Bode, C.; Patterson, C.; Moser, M. Fibroblast Growth Factor Signaling Pathway in Endothelial Cells Is Activated by BMPER to Promote Angiogenesis Arterioscler., Thromb., Vasc. Biol. 2015, 35 (2) 358– 367 DOI: 10.1161/ATVBAHA.114.304345
    [ Crossref], [ PubMed], [ CAS], Google Scholar
    61
    Fibroblast Growth Factor Signaling Pathway in Endothelial Cells Is Activated by BMPER to Promote Angiogenesis
    Esser, Jennifer S.; Rahner, Susanne; Deckler, Meike; Bode, Christoph; Patterson, Cam; Moser, Martin
    Arteriosclerosis, Thrombosis, and Vascular Biology (2015), 35 (2), 358-367CODEN: ATVBFA; ISSN:1079-5642. (Lippincott Williams & Wilkins)
    OBJECTIVE-: Previously, we have identified bone morphogenetic protein endothelial cell precursor-derived regulator (BMPER) to increase the angiogenic activity of endothelial cells in a concn.-dependent manner. In this project, we now investigate how BMPER acts in concert with key mols. of angiogenesis to promote blood vessel formation. APPROACH AND RESULTS-: To assess the effect of BMPER on angiogenesis-related signaling pathways, we performed an angiogenesis antibody array with BMPER-stimulated endothelial cells. We detected increased basic fibroblast growth factor (bFGF/FGF-2) expression after BMPER stimulation and decreased expression of thrombospondin-1. Addnl., FGF receptor-1 expression, phosphorylation, FGF signaling pathway activity, and cell survival were increased. Consistently, silencing of BMPER by small interfering RNA decreased bFGF and FGF receptor-1 expression and increased thrombospondin-1 expression and cell apoptosis. Next, we investigated the interaction of BMPER and the FGF signaling pathway in endothelial cell function. BMPER stimulation increased endothelial cell angiogenic activity in migration, Matrigel, and spheroid assays. To block FGF signaling, an anti-bFGF antibody was used, which effectively inhibited the proangiogenic BMPER effect. Accordingly, BMPER-silenced endothelial cells under bFGF stimulation showed decreased angiogenic activity compared with bFGF control. We confirmed these findings in vivo by s.c. Matrigel injections with and without bFGF in C57BL/6_Bmper mice. Aortic ring assays of C57BL/6_Bmper mice confirmed a specific effect for bFGF but not for vascular endothelial growth factor. CONCLUSIONS-: Taken together, the proangiogenic BMPER effect in endothelial cells is mediated by inhibition of antiangiogenic thrombospondin-1 and enhanced expression and activation of the FGF signaling pathway that is crucial in the promotion of angiogenesis.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFyru78%253D&md5=1825f856e76784dc918bea02bf94dab7

Cited By

This article is cited by 11 publications.

  1. Christopher M. Serrano, Ronit Freeman, Jacqueline Godbe, Jacob A. Lewis, Samuel I. Stupp. DNA-Peptide Amphiphile Nanofibers Enhance Aptamer Function. ACS Applied Bio Materials 2019, 2 (7) , 2955-2963. DOI: 10.1021/acsabm.9b00310.
  2. Yuna Shang, Dengke Zhi, Guowei Feng, Zhongyan Wang, Duo Mao, Shuang Guo, Ruihua Liu, Lulu Liu, Shuhao Zhang, Shenghuan Sun, Kai Wang, Deling Kong, Jie Gao, Zhimou Yang. Supramolecular Nanofibers with Superior Bioactivity to Insulin-Like Growth Factor-I. Nano Letters 2019, 19 (3) , 1560-1569. DOI: 10.1021/acs.nanolett.8b04406.
  3. Alexandra N. Edelbrock, Zaida Àlvarez, Dina Simkin, Timmy Fyrner, Stacey M. Chin, Kohei Sato, Evangelos Kiskinis, Samuel I. Stupp. Supramolecular Nanostructure Activates TrkB Receptor Signaling of Neuronal Cells by Mimicking Brain-Derived Neurotrophic Factor. Nano Letters 2018, 18 (10) , 6237-6247. DOI: 10.1021/acs.nanolett.8b02317.
  4. Biplab Sarkar, Peter K. Nguyen, William Gao, Akhil Dondapati, Zain Siddiqui, Vivek A. Kumar. Angiogenic Self-Assembling Peptide Scaffolds for Functional Tissue Regeneration. Biomacromolecules 2018, 19 (9) , 3597-3611. DOI: 10.1021/acs.biomac.8b01137.
  5. Xiaoyuan Zhang, Coucong Gong, Ozioma Udochukwu Akakuru, Zhiqiang Su, Aiguo Wu, Gang Wei. The design and biomedical applications of self-assembled two-dimensional organic biomaterials. Chemical Society Reviews 2019, 48 (23) , 5564-5595. DOI: 10.1039/C8CS01003J.
  6. Jiaju Lu, Xiaoqing Yan, Xun Sun, Xuezhen Shen, Heyong Yin, Chenhao Wang, Yifan Liu, Changfeng Lu, Haitao Fu, Shuhui Yang, Yu Wang, Xiaodan Sun, Lingyun Zhao, Shibi Lu, Antonios G. Mikos, Jiang Peng, Xiumei Wang. Synergistic effects of dual-presenting VEGF- and BDNF-mimetic peptide epitopes from self-assembling peptide hydrogels on peripheral nerve regeneration. Nanoscale 2019, 11 (42) , 19943-19958. DOI: 10.1039/C9NR04521J.
  7. Katsuhiro Hosoyama, Caitlin Lazurko, Marcelo Muñoz, Christopher D. McTiernan, Emilio I. Alarcon. Peptide-Based Functional Biomaterials for Soft-Tissue Repair. Frontiers in Bioengineering and Biotechnology 2019, 7 DOI: 10.3389/fbioe.2019.00205.
  8. Angela W. Xie, William L. Murphy. Engineered biomaterials to mitigate growth factor cost in cell biomanufacturing. Current Opinion in Biomedical Engineering 2019, 10, 1-10. DOI: 10.1016/j.cobme.2018.12.004.
  9. Alexandra Brito, Yousef M. Abul-Haija, Diana Soares da Costa, Ramon Novoa-Carballal, Rui L. Reis, Rein V. Ulijn, Ricardo A. Pires, Iva Pashkuleva. Minimalistic supramolecular proteoglycan mimics by co-assembly of aromatic peptide and carbohydrate amphiphiles. Chemical Science 2019, 10 (8) , 2385-2390. DOI: 10.1039/C8SC04361B.
  10. Kiara F. Bruggeman, Richard J. Williams, David R. Nisbet. Dynamic and Responsive Growth Factor Delivery from Electrospun and Hydrogel Tissue Engineering Materials. Advanced Healthcare Materials 2018, 7 (1) , 1700836. DOI: 10.1002/adhm.201700836.
  11. Fumitaka Ishiwari, Yoshiaki Shoji, Takanori Fukushima. Supramolecular scaffolds enabling the controlled assembly of functional molecular units. Chemical Science 2018, 9 (8) , 2028-2041. DOI: 10.1039/C7SC04340F.

  • Abstract

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 1

    Figure 1. Nanostructure characterization of the FGF2-PAs. (A) Cryo-TEM (left), conventional TEM (middle), and AFM (right) images of FGF2-PA nanoribbons (in the cryo-TEM images, areas revealing helical turns along the nanoribbon are highlighted by white arrows). (B) Cryo-TEM (left), conventional TEM (middle), and AFM (right) images of mutant FGF2-PA nanoribbons (in the cryo-TEM images, areas where ribbons do not fold into helical structures are highlighted by white arrows).

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 2

    Figure 2. CD and TEM analysis of FGF2-PA and mutant FGF2-PA nanostructures. (A) CD spectra of FGF2-PA (blue line), mutant FGF2-PA (orange line), FGF-2 mimetic peptide (green line), and K3-PA backbone at 1 mM in 25 mM HEPES at pH 7.4 buffer after annealing. Inset: close-up of the β-sheet region for FGF2-PA, mutant FGF2-PA, and FGF-2 mimetic peptide, showing the weakness in β-sheet signal compared to that of the K3-PA backbone PA. (B) Proposed conformations of the FGF-2 peptide, FGF2-PA, and mutant FGF2-PA (length scale on the left side). (C and D) Banding pattern analysis of the section of a UA stained FGF2-PA nanoribbon and a mutant FGF2-PA nanoribbon (white double-headed arrows). The graphs on the right show that the low gray values (gray bars) correspond to the darker areas (UA deposition) in the TEM images and that the higher gray values correspond to the lighter areas.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 3

    Figure 3. Cell proliferation, migration, and viability assays. (A) HUVEC proliferation after 16 h of incubation with FGF2-PA (blue bars), mutant FGF2-PA (orange bars), and FGF-2 mimetic peptide at 750 and 500 nM with native FGF-2 protein at 1.50 and 0.150 nM as positive controls. (B) Fluorescent images of cells after being incubated with FGF2-PA and mutant FGF2-PA for 16 h stained with calcein AM and ethidium homodimer-1. (C) Graph showing >90% metabolic activity for HUVECS incubated with 750 and 500 nM of FGF2-PA, mutant FGF2-PA, and FGF-2 mimetic peptide. (D) Graph showing significant migration of HUVECs using the chemotaxis chamber setup with starved cells incubated with FGF2-PA, mutant FGF2-PA, and FGF-2 mimetic peptide at 750 and 500 nM and with native FGF-2 protein at 3.00, 1.50, and 0.150 nM (*P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001, with starvation media used as a negative control).

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 4

    Figure 4. Effect of FGF2-PA on activation of cell signaling. (A) Western blot analysis shows upregulation of the pFGFR1 receptor, pERK1/2 proliferation signaling pathway, and pH3 proliferation marker promoted by FGF2-PA at 750 and 500 nM, native FGF-2 protein at 3.00, 1.50, and 0.150 nM and starvation conditions. Mutant FGF2-PA and FGF-2 mimetic peptide at 750 and 500 nM failed to induce any significant FGF-2 signaling. (B) Bar graph presenting quantitative analysis of the Western blot data using densitometry (intensity values normalized to GADPH). (*P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001, with starvation media used as a negative control). (C) Confocal images of vinculin staining (red), nuclei (DAPI, blue), and phosphorylated FGFR1 (green).

    High Resolution Image
    Download MS PowerPoint Slide

  • References

    ARTICLE SECTIONS
    Jump To

    This article references 61 other publications.

    1. 1
      Barrientos, S.; Stojadinovic, O.; Golinko, M. S.; Brem, H.; Tomic-Canic, M. Growth factors and cytokines in wound healing Wound Repair Regen 2008, 16 (5) 585– 601 DOI: 10.1111/j.1524-475X.2008.00410.x
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      1
      Growth factors and cytokines in wound healing
      Barrientos Stephan; Stojadinovic Olivera; Golinko Michael S; Brem Harold; Tomic-Canic Marjana
      Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society (2008), 16 (5), 585-601 ISSN:.
      Wound healing is an evolutionarily conserved, complex, multicellular process that, in skin, aims at barrier restoration. This process involves the coordinated efforts of several cell types including keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. The migration, infiltration, proliferation, and differentiation of these cells will culminate in an inflammatory response, the formation of new tissue and ultimately wound closure. This complex process is executed and regulated by an equally complex signaling network involving numerous growth factors, cytokines and chemokines. Of particular importance is the epidermal growth factor (EGF) family, transforming growth factor beta (TGF-beta) family, fibroblast growth factor (FGF) family, vascular endothelial growth factor (VEGF), granulocyte macrophage colony stimulating factor (GM-CSF), platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), interleukin (IL) family, and tumor necrosis factor-alpha family. Currently, patients are treated by three growth factors: PDGF-BB, bFGF, and GM-CSF. Only PDGF-BB has successfully completed randomized clinical trials in the Unites States. With gene therapy now in clinical trial and the discovery of biodegradable polymers, fibrin mesh, and human collagen serving as potential delivery systems other growth factors may soon be available to patients. This review will focus on the specific roles of these growth factors and cytokines during the wound healing process.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1M%252FlslGktQ%253D%253D&md5=7792cfbb76f359dab3ba2a5935a9c567
    2. 2
      Behm, B.; Babilas, P.; Landthaler, M.; Schreml, S. Cytokines, chemokines and growth factors in wound healing J. Eur. Acad. Dermatol Venereol 2012, 26 (7) 812– 20 DOI: 10.1111/j.1468-3083.2011.04415.x
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      2
      Cytokines, chemokines and growth factors in wound healing
      Behm, B.; Babilas, P.; Landthaler, M.; Schreml, S.
      Journal of the European Academy of Dermatology and Venereology (2012), 26 (7), 812-820CODEN: JEAVEQ; ISSN:1468-3083. (Wiley-Blackwell)
      A review. In wound healing, a variety of mediators have been identified throughout the years. The mediators discussed here comprise growth factors, cytokines and chemokines. These mediators act via multiple (specific) receptors to facilitate wound closure. As research in the last years has led to many new findings, there is a need to give an overview on what is known, and on what might possibly play a role as a mol. target for future wound therapy. This review aims to keep the reader up to date with selected important and novel findings regarding growth factors, cytokines and chemokines in wound healing.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVKjtLnF&md5=fb4320634f5e4e6eb80e84967a5f4e59
    3. 3
      Pashuck, E. T.; Stevens, M. M. Designing Regenerative Biomaterial Therapies for the Clinic Sci. Transl. Med. 2012, 4 (160) 160sr4 DOI: 10.1126/scitranslmed.3002717
      [ Crossref], [ PubMed], Google Scholar
      There is no corresponding record for this reference.
    4. 4
      Pashuck, E. T.; Stevens, M. M. Designing regenerative biomaterial therapies for the clinic Sci. Transl. Med. 2012, 4 (160) 160sr4 DOI: 10.1126/scitranslmed.3002717
      [ Crossref], [ PubMed], Google Scholar
      There is no corresponding record for this reference.
    5. 5
      Belair, D. G.; Le, N. N.; Murphy, W. L. Design of growth factor sequestering biomaterials Chem. Commun. 2014, 50 (99) 15651– 15668 DOI: 10.1039/C4CC04317K
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      5
      Design of growth factor sequestering biomaterials
      Belair, David G.; Le, Ngoc Nhi; Murphy, William L.
      Chemical Communications (Cambridge, United Kingdom) (2014), 50 (99), 15651-15668CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      A review. Growth factors (GFs) are major regulatory proteins that can govern cell fate, migration, and organization. Numerous aspects of the cell milieu can modulate cell responses to GFs, and GF regulation is often achieved by the native extracellular matrix (ECM). For example, the ECM can sequester GFs and thereby control GF bioavailability. In addn., GFs can exert distinct effects depending on whether they are sequestered in soln., at two-dimensional interfaces, or within three-dimensional matrixes. Understanding how the context of GF sequestering impacts cell function in the native ECM can instruct the design of sol. or insol. GF sequestering moieties, which can then be used in a variety of bioengineering applications. This Feature Article provides an overview of the natural mechanisms of GF sequestering in the cell milieu, and reviews the recent bioengineering approaches that have sequestered GFs to modulate cell function. Results to date demonstrate that the cell response to GF sequestering depends on the affinity of the sequestering interaction, the spatial proximity of sequestering in relation to cells, the source of the GF (supplemented or endogenous), and the phase of the sequestering moiety (sol. or insol.). We highlight the importance of context for the future design of biomaterials that can leverage endogenous mols. in the cell milieu and mitigate the need for supplemented factors.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlOltr%252FJ&md5=9a275b521398862b09e1bd8e1cfda42d
    6. 6
      Briquez, P. S.; Clegg, L. E.; Martino, M. M.; Gabhann, F. M.; Hubbell, J. A. Design principles for therapeutic angiogenic materials Nature Reviews Materials 2016, 1, 15006 DOI: 10.1038/natrevmats.2015.6
      [ Crossref], [ CAS], Google Scholar
      6
      Design principles for therapeutic angiogenic materials
      Briquez, Priscilla S.; Clegg, Lindsay E.; Martino, Mikael M.; MacGabhann, Feilim; Hubbell, Jeffrey A.
      Nature Reviews Materials (2016), 1 (1), 15006CODEN: NRMADL; ISSN:2058-8437. (Nature Publishing Group)
      Despite extensive research, pro-angiogenic drugs have failed to translate clin., and therapeutic angiogenesis, which has potential in the treatment of various cardiovascular diseases, remains a major challenge. Physiol., angiogenesis - the process of blood-vessel growth from existing vasculature - is regulated by a complex interplay of biophys. and biochem. cues from the extracellular matrix (ECM), angiogenic factors and multiple cell types. The ECM can be regarded as the natural 3D material that regulates angiogenesis. Here, we leverage knowledge of ECM properties to derive design rules for engineering pro-angiogenic materials. We propose that pro-angiogenic materials should be biomimetic, incorporate angiogenic factors and mimic cooperative interactions between growth factors and the ECM. We highlight examples of material designs that demonstrate these principles and considerations for designing better angiogenic materials.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVert74%253D&md5=e73aeb07a9e706cde454a2d9e9072b2f
    7. 7
      Zhu, J.; Marchant, R. E. Design properties of hydrogel tissue-engineering scaffolds Expert Rev. Med. Devices 2011, 8 (5) 607– 26 DOI: 10.1586/erd.11.27
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      7
      Design properties of hydrogel tissue-engineering scaffolds
      Zhu, Junmin; Marchant, Roger E.
      Expert Review of Medical Devices (2011), 8 (5), 607-626CODEN: ERMDDX; ISSN:1743-4440. (Expert Reviews Ltd.)
      A review. This article summarizes the recent progress in the design and synthesis of hydrogels as tissue-engineering scaffolds. Hydrogels are attractive scaffolding materials owing to their highly swollen network structure, ability to encapsulate cells and bioactive mols., and efficient mass transfer. Various polymers, including natural, synthetic and natural/synthetic hybrid polymers, have been used to make hydrogels via chem. or phys. crosslinking. Recently, bioactive synthetic hydrogels have emerged as promising scaffolds because they can provide molecularly tailored biofunctions and adjustable mech. properties, as well as an extracellular matrix-like microenvironment for cell growth and tissue formation. This article addresses various strategies that have been explored to design synthetic hydrogels with extracellular matrix-mimetic bioactive properties, such as cell adhesion, proteolytic degrdn. and growth factor-binding.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1ans7jK&md5=cd78f638a3d9809f3769290d9882f9b4
    8. 8
      Lee, K.; Silva, E. A.; Mooney, D. J. Growth factor delivery-based tissue engineering: general approaches and a review of recent developments J. R. Soc., Interface 2011, 8 (55) 153– 70 DOI: 10.1098/rsif.2010.0223
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      8
      Growth factor delivery-based tissue engineering: general approaches and a review of recent developments
      Lee, Kangwon; Silva, Eduardo A.; Mooney, David J.
      Journal of the Royal Society, Interface (2011), 8 (55), 153-170CODEN: JRSICU; ISSN:1742-5689. (Royal Society)
      A review. The identification and prodn. of recombinant morphogens and growth factors that play key roles in tissue regeneration have generated much enthusiasm and numerous clin. trials, but the results of many of these trials have been largely disappointing. Interestingly, the trials that have shown benefit all contain a common denominator, the presence of a material carrier, suggesting strongly that spatio-temporal control over the location and bioactivity of factors after introduction into the body is crucial to achieve tangible therapeutic effect. Sophisticated materials systems that regulate the biol. presentation of growth factors represent an attractive new generation of therapeutic agents for the treatment of a wide variety of diseases. This review provides an overview of growth factor delivery in tissue engineering. Certain fundamental issues and design strategies relevant to the material carriers that are being actively pursued to address specific tech. objectives are discussed. Recent progress highlights the importance of materials science and engineering in growth factor delivery approaches to regenerative medicine.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlvFGhsbw%253D&md5=3299678c5d6c97fb69f6572170fb558d
    9. 9
      Zisch, A. H.; Lutolf, M. P.; Ehrbar, M.; Raeber, G. P.; Rizzi, S. C.; Davies, N.; Schmokel, H.; Bezuidenhout, D.; Djonov, V.; Zilla, P.; Hubbell, J. A. Cell-demanded release of VEGF from synthetic, biointeractive cell ingrowth matrices for vascularized tissue growth FASEB J. 2003, 17 (15) 2260– 2 DOI: 10.1096/fj.02-1041fje
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      9
      Cell-demanded release of VEGF from synthetic, biointeractive cell-ingrowth matrices for vascularized tissue growth
      Zisch, Andreas H.; Lutolf, Matthias P.; Ehrbar, Martin; Raeber, George P.; Rizzi, Simone C.; Davies, Neil; Schmoekel, Hugo; Bezuidenhout, Deon; Djonov, Valentin; Zilla, Peter; Hubbell, Jeffrey A.
      FASEB Journal (2003), 17 (15), 2260-2262, 10.1096/fj.02-1041fjeCODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)
      Local, controlled induction of angiogenesis remains a challenge that limits tissue engineering approaches to replace or restore diseased tissues. We present a new class of bioactive synthetic hydrogel matrixes based on poly(ethylene glycol) (PEG) and synthetic peptides that exploits the activity of vascular endothelial growth factor (VEGF) alongside the base matrix functionality for cellular ingrowth, i.e., induction of cell adhesion by pendant RGD-contg. peptides and provision of cell-mediated remodeling by crosslinking matrix metalloproteinase substrate peptides. By using a Michael-type addn. reaction, we incorporated variants of VEGF121 and VEGF165 covalently within the matrix, available for cells as they invade and locally remodel the material. The functionality of the matrix-conjugated VEGF was preserved and was crit. for in vitro endothelial cell survival and migration within the matrix environment. Consistent with a scheme of locally restricted availability of VEGF, grafting of these VEGF-modified hydrogel matrixes atop the chick chorioallontoic membrane evoked strong new blood vessel formation precisely at the area of graft-membrane contact. When implanted s.c. in rats, these VEGF-contg. matrixes were completely remodeled into native, vascularized tissue. This type of synthetic, biointeractive matrix with integrated angiogenic growth factor activity, presented and released only upon local cellular demand, could become highly useful in a no. of clin. healing applications of local therapeutic angiogenesis.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpvVSnsL4%253D&md5=96713a7670213b772d7ceda2457a14e3
    10. 10
      Zieris, A.; Chwalek, K.; Prokoph, S.; Levental, K. R.; Welzel, P. B.; Freudenberg, U.; Werner, C. Dual independent delivery of pro-angiogenic growth factors from starPEG-heparin hydrogels J. Controlled Release 2011, 156 (1) 28– 36 DOI: 10.1016/j.jconrel.2011.06.042
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      10
      Dual independent delivery of pro-angiogenic growth factors from starPEG-heparin hydrogels
      Zieris, A.; Chwalek, K.; Prokoph, S.; Levental, K. R.; Welzel, P. B.; Freudenberg, U.; Werner, C.
      Journal of Controlled Release (2011), 156 (1), 28-36CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
      Effective vascularization is a prerequisite for the success of various different tissue engineering concepts. While simultaneous administration of basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) has been previously demonstrated to boost angiogenesis, the combined long-term delivery of both growth factors from biomaterials is still a major challenge. In this work, two important heparin binding cytokines were delivered in parallel from a modular starPEG (multi-armed polyethylene glycol) - heparin hydrogel system to human umbilical vein endothelial cells (HUVECs) grown in culture and in a chicken embryo chorioallantoic membrane (CAM) model. As the utilized gels contain high quantities of heparin, loading and subsequent release of both growth factors (as detd. by radiolabeling studies and ELISA) occurred independently from each other. The combined delivery of FGF-2 and VEGF through starPEG-heparin hydrogels resulted in pro-angiogenic effects in vitro (study of cell survival/proliferation, morphol. and migration) and in vivo (quantification of CAM vascularization) being clearly superior over those of the administration of single factors. Consequently, the independent delivery of growth factor combinations by biohybrid starPEG-heparin matrixes allows for the precise multifactorial control of cellular processes critically detg. regeneration.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVGntrrK&md5=5068f8cbd45645de5e3f51836935809f
    11. 11
      Mammadov, R.; Mammadov, B.; Toksoz, S.; Aydin, B.; Yagci, R.; Tekinay, A. B.; Guler, M. O. Heparin Mimetic Peptide Nanofibers Promote Angiogenesis Biomacromolecules 2011, 12 (10) 3508– 3519 DOI: 10.1021/bm200957s
      [ ACS Full Text ACS Full Text], [ CAS], Google Scholar
      11
      Heparin Mimetic Peptide Nanofibers Promote Angiogenesis
      Mammadov, Rashad; Mammadov, Busra; Toksoz, Sila; Aydin, Bahri; Yagci, Ramazan; Tekinay, Ayse B.; Guler, Mustafa O.
      Biomacromolecules (2011), 12 (10), 3508-3519CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      New blood vessel formation (angiogenesis) is one of the most important processes required for functional tissue formation. Induction of angiogenesis is usually triggered by growth factors released by cells. Glycosaminoglycans (e.g., heparan sulfates) in the extracellular matrix aid in proper functioning of these growth factors. Therefore, exogenous heparin or growth factors were required for promoting angiogenesis in previous regenerative medicine studies. Here we report for the first time induction of angiogenesis by a synthetic nanofibrous peptide scaffold without the addn. of any exogenous growth factors or heparin. We designed and synthesized a self-assembling peptide amphiphile mol. that is functionalized with biol. active groups to mimic heparin. Like heparin, this mol. has the ability to interact with growth factors and effectively enhance their bioactivity. The nanofibers formed by these mols. were shown to form a 3D network mimicking the structural proteins in the extracellular matrix. Because of heparin mimicking capabilities of the peptide nanofibers, angiogenesis was induced without the addn. of exogenous growth factors in vitro. Bioactive interactions between the nanofibers and the growth factors enabled robust vascularization in vivo as well. Heparin mimetic peptide nanofibers presented here provide new opportunities for angiogenesis and tissue regeneration by avoiding the use of heparin and exogenous growth factors. The synthetic peptide nanofiber scaffolds enriched with proper chem. functional groups shown in this study can be used to induce various desired physiol. responses for tissue regeneration.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFeiu77M&md5=ab6f038642a4585e2567bfff3ed14296
    12. 12
      Laham, R. J.; Rezaee, M.; Post, M.; Sellke, F. W.; Braeckman, R. A.; Hung, D.; Simons, M. Intracoronary and Intravenous Administration of Basic Fibroblast Growth Factor: Myocardial and Tissue Distribution Drug Metab. Dispos. 1999, 27 (7) 821– 826
      [ PubMed], [ CAS], Google Scholar
      12
      Intracoronary and intravenous administration of basic fibroblast growth factor: myocardial and tissue distribution
      Laham, Roger J.; Rezaee, Mehrdad; Post, Mark; Sellke, Frank W.; Braeckman, Rene A.; Hung, David; Simons, Michael
      Drug Metabolism and Disposition (1999), 27 (7), 821-826CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)
      Therapeutic angiogenesis using various heparin-binding growth factors is a promising treatment for ischemic heart disease. Single dose intracoronary (IC) or i.v. delivery are most practical for clin. use. This study was designed to investigate the myocardial and tissue deposition of basic fibroblast growth factor (bFGF) after IC and i.v. administration in normal and chronically ischemic animals. Twenty-four Yorkshire pigs were used (12 normal and 12 ischemic animals) with IC and i.v. administration of 125I-bFGF (25 μCi) combined with cold bFGF (30 μg) and heparin (3 mg). Tissue and myocardial distribution was detd. at 1 and 24 h by measuring 125I-bFGF specific activity and by organ and light level autoradiog. The liver accounted for the majority of 125I-bFGF activity at 1 h (37.6% for IC and 42.1% for i.v. delivery), with a redn. to 2.8% for IC and 1.5% for i.v. delivery by 24 h. Total cardiac specific activity at 1 h was 0.88% for IC and 0.26% for i.v. administration and decreased to 0.05% and 0.04% at 24 h, resp. IC but not i.v. delivery resulted in higher deposition in ischemic than normal myocardium. IC delivery resulted in enhanced bFGF deposition only in myocardial territories subtended by the infused artery. The i.v. delivery compares favorably with IC delivery with a 3- to 4-fold redn. in myocardial deposition at 1 h and with similar solid organ deposition. The less invasive nature of i.v. delivery, its potential for repeat administration, and its applicability to a larger population may offset its resultant reduced myocardial deposition. Efficacy studies are ongoing.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXkt1CjsLY%253D&md5=ecf28ea32bba406f269cfd1eeb1d6fef
    13. 13
      Post, M. J.; Laham, R.; Sellke, F. W.; Simons, M. Therapeutic angiogenesis in cardiology using protein formulations Cardiovasc. Res. 2001, 49 (3) 522– 531 DOI: 10.1016/S0008-6363(00)00216-9
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      13
      Therapeutic angiogenesis in cardiology using protein formulations
      Post, M. J.; Laham, R.; Sellke, F. W.; Simons, M.
      Cardiovascular Research (2001), 49 (3), 522-531CODEN: CVREAU; ISSN:0008-6363. (Elsevier Science B.V.)
      A review with 122 refs. Therapeutic angiogenesis in cardiovascular disease aims at improving myocardial function by increasing blood flow to ischemic myocardium that is not amenable to traditional forms of revascularization. Preclin. data have provided proof of the concept that angiogenic growth factors such as fibroblast growth factor 2 (FGF-2) and vascular endothelium growth factor (VEGF) may indeed improve myocardial flow and function when administered in ways that ensure prolonged tissue exposure to these short-lived mols. Although other cytokines have been shown to enhance angiogenesis in vivo, FGF-2 and VEGF have been most widely studied and may serve as prototype proangiogenic drugs. Currently, several delivery techniques that are clin. applicable are being studied with respect to tissue distribution and retention as well as angiogenic efficacy of FGF-2 and VEGF. Although tissue distribution and retention of FGF-2 after intramyocardial injection compares favorably with other routes of administration, efficacy studies are not yet conclusive. At the same time, different protein- and gene-based formulations are being investigated. Arguments for and against protein and gene therapy are presented, showing that protein-based therapy seems to have advantages over gene therapy at the present time, although continuous efforts should be made to increase the tissue exposure time after a single administration of protein. While delivery systems and growth factor formulations are being improved, double-blind, placebo-controlled trials designed with existing animal data in mind, are needed to firmly establish the utility of therapeutic angiogenesis in cardiovascular disease.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXptlWrsA%253D%253D&md5=0a05214733e9eaf6e06d669a0cd0d13e
    14. 14
      Jain, R. K.; Au, P.; Tam, J.; Duda, D. G.; Fukumura, D. Engineering vascularized tissue Nat. Biotechnol. 2005, 23 (7) 821– 823 DOI: 10.1038/nbt0705-821
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      14
      Engineering vascularized tissue
      Jain, Rakesh K.; Au, Patrick; Tam, Josh; Duda, Dan G.; Fukumura, Dai
      Nature Biotechnology (2005), 23 (7), 821-823CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
      There is no expanded citation for this reference.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlvFehu7o%253D&md5=72877ca3f5aa081f2df72f3457f51257
    15. 15
      Simons, M.; Bonow, R. O.; Chronos, N. A.; Cohen, D. J.; Giordano, F. J.; Hammond, H. K.; Laham, R. J.; Li, W.; Pike, M.; Sellke, F. W.; Stegmann, T. J.; Udelson, J. E.; Rosengart, T. K. Clinical Trials in Coronary Angiogenesis: Issues, Problems, Consensus: An Expert Panel Summary Circulation 2000, 102 (11) e73– e86 DOI: 10.1161/01.CIR.102.11.e73
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      15
      Clinical trials in coronary angiogenesis: issues, problems, consensus: An expert panel summary
      Simons M; Bonow R O; Chronos N A; Cohen D J; Giordano F J; Hammond H K; Laham R J; Li W; Pike M; Sellke F W; Stegmann T J; Udelson J E; Rosengart T K
      Circulation (2000), 102 (11), E73-86 ISSN:.
      The rapid development of angiogenic growth factor therapy for patients with advanced ischemic heart disease over the last 5 years offers hope of a new treatment strategy based on generation of new blood supply in the diseased heart. However, as the field of therapeutic coronary angiogenesis is maturing from basic and preclinical investigations to clinical trials, many new and presently unresolved issues are coming into focus. These include in-depth understanding of the biology of angiogenesis, selection of appropriate patient populations for clinical trials, choice of therapeutic end points and means of their assessment, choice of therapeutic strategy (gene versus protein delivery), route of administration, and the side effect profile. The present article presents a summary statement of a panel of experts actively working in the field, convened by the Angiogenesis Foundation and the Angiogenesis Research Center during the 72nd meeting of the American Heart Association to define and achieve a consensus on the challenges facing development of therapeutic angiogenesis for coronary disease.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3cvls1KksA%253D%253D&md5=47cfb300b19e8c8f1717e3103172a2ed
    16. 16
      D’Andrea, L. D.; Del Gatto, A.; De Rosa, L.; Romanelli, A.; Pedone, C. Peptides Targeting Angiogenesis Related Growth Factor Receptors Curr. Pharm. Des. 2009, 15 (21) 2414– 2429 DOI: 10.2174/138161209788682235
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      16
      Peptides targeting angiogenesis related growth factor receptors
      D'Andrea, Luca D.; Del Gatto, Annarita; De Rosa, Lucia; Romanelli, Alessandra; Pedone, Carlo
      Current Pharmaceutical Design (2009), 15 (21), 2414-2429CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
      A review. Growth factors (GFs) are extracellular signaling polypeptides regulating cell proliferation, differentiation and survival. They exert a wide spectrum of biol. activities selectively binding to and activating specific membrane receptors which then transfer the message to cell interior inducing specific biochem. pathways. GFs are esp. involved in the regulation of angiogenesis, a physiol. process underlining several pathologies. Mols. able to modulate angiogenesis, interfering with the mol. recognition between a GF and its receptor, have a big pharmacol. interest. Either GF and the receptor are potential drug target. Peptides are useful mols. to develop new lead compds. disrupting protein-protein interface for pharmacol. applications. In this review the authors describe peptides targeting the receptors of the pro-angiogenic growth factors FGF, PDGF and VEGF. The biol. function and the structure of each growth factor/receptor system are discussed, as well as the mol. interaction between peptides and the receptors. Finally, the authors highlight the pharmacol. and diagnostic applications of these peptides in angiogenesis related diseases.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXos1alt7k%253D&md5=039742c8815f2284a3c950a256861011
    17. 17
      Place, E. S.; Evans, N. D.; Stevens, M. M. Complexity in biomaterials for tissue engineering Nat. Mater. 2009, 8 (6) 457– 470 DOI: 10.1038/nmat2441
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      17
      Complexity in biomaterials for tissue engineering
      Place, Elsie S.; Evans, Nicholas D.; Stevens, Molly M.
      Nature Materials (2009), 8 (6), 457-470CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
      A review. The mol. and phys. information coded within the extracellular milieu is informing the development of a new generation of biomaterials for tissue engineering. Several powerful extracellular influences have already found their way into cell-instructive scaffolds, while others remain largely unexplored. Yet for com. success tissue engineering products must be not only efficacious but also cost-effective, introducing a potential dichotomy between the need for sophistication and ease of prodn. This is spurring interest in recreating extracellular influences in simplified forms, from the redn. of biopolymers into short functional domains, to the use of basic chemistries to manipulate cell fate. In the future these exciting developments are likely to help reconcile the clin. and com. pressures on tissue engineering.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtFemsLw%253D&md5=76d460b06835fcc2db816d65618f2c20
    18. 18
      Shah, R. N.; Shah, N. A.; Del Rosario Lim, M. M.; Hsieh, C.; Nuber, G.; Stupp, S. I. Supramolecular design of self-assembling nanofibers for cartilage regeneration Proc. Natl. Acad. Sci. U. S. A. 2010, 107 (8) 3293– 3298 DOI: 10.1073/pnas.0906501107
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      18
      Supramolecular design of self-assembling nanofibers for cartilage regeneration
      Shah, Ramille N.; Shah, Nirav A.; Lim, Marc M. Del Rosario; Hsieh, Caleb; Nuber, Gordon; Stupp, Samuel I.
      Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (8), 3293-3298, S3293/1-S3293/4CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Mol. and supramol. design of bioactive biomaterials could have a significant impact on regenerative medicine. Ideal regenerative therapies should be minimally invasive, and thus the notion of self-assembling biomaterials programmed to transform from injectable liqs. to solid bioactive structures in tissue is highly attractive for clin. translation. We report here on a coassembly system of peptide amphiphile (PA) mols. designed to form nanofibers for cartilage regeneration by displaying a high d. of binding epitopes to transforming growth factor β-1 (TGFβ-1). Growth factor release studies showed that passive release of TGFβ-1 was slower from PA gels contg. the growth factor binding sites. In vitro expts. indicate these materials support the survival and promote the chondrogenic differentiation of human mesenchymal stem cells. We also show that these materials can promote regeneration of articular cartilage in a full thickness chondral defect treated with microfracture in a rabbit model with or even without the addn. of exogenous growth factor. These results demonstrate the potential of a completely synthetic bioactive biomaterial as a therapy to promote cartilage regeneration.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjtFymt7k%253D&md5=5544ae5566c3aaef434a4ea96e80d656
    19. 19
      D’Andrea, L. D.; Iaccarino, G.; Fattorusso, R.; Sorriento, D.; Carannante, C.; Capasso, D.; Trimarco, B.; Pedone, C. Targeting angiogenesis: Structural characterization and biological properties of a de novo engineered VEGF mimicking peptide Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (40) 14215– 14220 DOI: 10.1073/pnas.0505047102
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      19
      Targeting angiogenesis: Structural characterization and biological properties of a de novo engineered VEGF mimicking peptide
      D'Andrea, Luca Domenico; Iaccarino, Guido; Fattorusso, Roberto; Sorriento, Daniela; Carannante, Concetta; Capasso, Domenica; Trimarco, Bruno; Pedone, Carlo
      Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (40), 14215-14220CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Modulating angiogenesis is an attractive goal because many pathol. conditions depend on the growth of new vessels. Angiogenesis is mainly regulated by the VEGF, a mitogen specific for endothelial cells. In the last years, many efforts have been pursued to modulate the angiogenic response targeting VEGF and its receptors. Based on the x-ray structure of VEGF bound to the receptor, the authors designed a peptide, QK, reproducing a region of the VEGF binding interface: the helix region 17-25. NMR conformation anal. of QK revealed that it adopts a helical conformation in water, whereas the peptide corresponding to the α-helix region of VEGF, VEGF15, is unstructured. Biol. assays in vitro and on bovine aorta endothelial cells suggested that QK binds to the VEGF receptors and competes with VEGF. VEGF15 did not bind to the receptors indicating that the helical structure is necessary for the biol. activity. Furthermore, QK induced endothelial cells proliferation, activated cell signaling dependent on VEGF, and increased the VEGF biol. response. QK promoted capillary formation and organization in an in vitro assay on matrigel. These results suggested that the helix region 17-25 of VEGF is involved in VEGF receptor activation. The peptide designed to resemble this region shares numerous biol. properties of VEGF, thus suggesting that this region is of potential interest for biomedical applications, and mols. mimicking it could be attractive for therapeutic and diagnostic applications.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFChu7bK&md5=3c2532c688aee84b17bf208779b5adb2
    20. 20
      Rubert Perez, C. M.; Stephanopoulos, N.; Sur, S.; Lee, S. S.; Newcomb, C.; Stupp, S. I. The powerful functions of peptide-based bioactive matrices for regenerative medicine Ann. Biomed. Eng. 2015, 43 (3) 501– 14 DOI: 10.1007/s10439-014-1166-6
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      20
      The powerful functions of peptide-based bioactive matrices for regenerative medicine
      Rubert Perez Charles M; Stephanopoulos Nicholas; Sur Shantanu; Lee Sungsoo S; Newcomb Christina; Stupp Samuel I
      Annals of biomedical engineering (2015), 43 (3), 501-14 ISSN:.
      In an effort to develop bioactive matrices for regenerative medicine, peptides have been used widely to promote interactions with cells and elicit desired behaviors in vivo. This paper describes strategies that utilize peptide-based molecules as building blocks to create supramolecular nanostructures that emulate not only the architecture but also the chemistry of the extracellular matrix in mammalian biology. After initiating a desired regenerative response in vivo, the innate biodegradability of these systems allow for the natural biological processes to take over in order to promote formation of a new tissue without leaving a trace of the nonnatural components. These bioactive matrices can either bind or mimic growth factors or other protein ligands to elicit a cellular response, promote specific mechano-biological responses, and also guide the migration of cells with programmed directionality. In vivo applications discussed in this review using peptide-based matrices include the regeneration of axons after spinal cord injury, regeneration of bone, and the formation of blood vessels in ischemic muscle as a therapy in peripheral arterial disease and cardiovascular diseases.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M3ltlWitA%253D%253D&md5=17d74df96f4ba41dcf915f2af20dcc5a
    21. 21
      Webber, M. J.; Tongers, J.; Newcomb, C. J.; Marquardt, K.-T.; Bauersachs, J.; Losordo, D. W.; Stupp, S. I. Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (33) 13438– 13443 DOI: 10.1073/pnas.1016546108
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      21
      Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair
      Webber, Matthew J.; Tongers, Jorn; Newcomb, Christina J.; Marquardt, Katja-Theres; Bauersachs, Johann; Losordo, Douglas W.; Stupp, Samuel I.
      Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (33), 13438-13443, S13438/1-S13438/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      There is great demand for the development of novel therapies for ischemic cardiovascular disease, a leading cause of morbidity and mortality worldwide. We report here on the development of a completely synthetic cell-free therapy based on peptide amphiphile nanostructures designed to mimic the activity of VEGF, one of the most potent angiogenic signaling proteins. Following self-assembly of peptide amphiphiles, nanoscale filaments form that display on their surfaces a VEGF-mimetic peptide at high d. The VEGF-mimetic filaments were found to induce phosphorylation of VEGF receptors and promote proangiogenic behavior in endothelial cells, indicated by an enhancement in proliferation, survival, and migration in vitro. In a chicken embryo assay, these nanostructures elicited an angiogenic response in the host vasculature. When evaluated in a mouse hind-limb ischemia model, the nanofibers increased tissue perfusion, functional recovery, limb salvage, and treadmill endurance compared to controls, which included the VEGF-mimetic peptide alone. Immunohistol. evidence also demonstrated an increase in the d. of microcirculation in the ischemic hind limb, suggesting the mechanism of efficacy of this promising potential therapy is linked to the enhanced microcirculatory angiogenesis that results from treatment with these polyvalent VEGF-mimetic nanofibers.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtV2ms73O&md5=973461ee0d98598091803a94771e02f8
    22. 22
      Morgan, C. E.; Dombrowski, A. W.; Rubert Pérez, C. M.; Bahnson, E. S. M.; Tsihlis, N. D.; Jiang, W.; Jiang, Q.; Vercammen, J. M.; Prakash, V. S.; Pritts, T. A.; Stupp, S. I.; Kibbe, M. R. Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage ACS Nano 2016, 10 (1) 899– 909 DOI: 10.1021/acsnano.5b06025
      [ ACS Full Text ACS Full Text], [ CAS], Google Scholar
      22
      Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage
      Morgan, Courtney E.; Dombrowski, Amanda W.; Rubert Perez, Charles M.; Bahnson, Edward S. M.; Tsihlis, Nick D.; Jiang, Wulin; Jiang, Qun; Vercammen, Janet M.; Prakash, Vivek S.; Pritts, Timothy A.; Stupp, Samuel I.; Kibbe, Melina R.
      ACS Nano (2016), 10 (1), 899-909CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Noncompressible torso hemorrhage is a leading cause of mortality in civilian and battlefield trauma. We sought to develop an i.v.-injectable, tissue factor (TF)-targeted nanotherapy to stop hemorrhage. Tissue factor was chosen as a target because it is only exposed to the intravascular space upon vessel disruption. Peptide amphiphile (PA) monomers that self-assemble into nanofibers were chosen as the delivery vehicle. Three TF-binding sequences were identified (EGR, RLM, and RTL), covalently incorporated into the PA backbone, and shown to self-assemble into nanofibers by cryo-transmission electron microscopy. Both the RLM and RTL peptides bound recombinant TF in vitro. All three TF-targeted nanofibers bound to the site of punch biopsy-induced liver hemorrhage in vivo, but only RTL nanofibers reduced blood loss vs. sham (53% redn., p < 0.05). Increasing the targeting ligand d. of RTL nanofibers yielded qual. better binding to the site of injury and greater redns. in blood loss in vivo (p < 0.05). In fact, 100% RTL nanofiber reduced overall blood loss by 60% vs. sham (p < 0.05). Evaluation of the biocompatibility of the RTL nanofiber revealed that it did not induce RBC hemolysis, did not induce neutrophil or macrophage inflammation at the site of liver injury, and 70% remained intact in plasma after 30 min. In summary, these studies demonstrate successful binding of peptides to TF in vitro and successful homing of a TF-targeted PA nanofiber to the site of hemorrhage with an assocd. decrease in blood loss in vivo. Thus, this therapeutic may potentially treat noncompressible hemorrhage.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVygsb7I&md5=051be017bd4514836b74dd8e06be36db
    23. 23
      Lin, Y.-D.; Luo, C.-Y.; Hu, Y.-N.; Yeh, M.-L.; Hsueh, Y.-C.; Chang, M.-Y.; Tsai, D.-C.; Wang, J.-N.; Tang, M.-J.; Wei, E. I. H.; Springer, M. L.; Hsieh, P. C. H. Instructive Nanofiber Scaffolds with VEGF Create a Microenvironment for Arteriogenesis and Cardiac Repair Sci. Transl. Med. 2012, 4 (146) 146ra109– 146ra109 DOI: 10.1126/scitranslmed.3003841
      [ Crossref], [ PubMed], Google Scholar
      There is no corresponding record for this reference.
    24. 24
      Lee, S. S.; Hsu, E. L.; Mendoza, M.; Ghodasra, J.; Nickoli, M. S.; Ashtekar, A.; Polavarapu, M.; Babu, J.; Riaz, R. M.; Nicolas, J. D.; Nelson, D.; Hashmi, S. Z.; Kaltz, S. R.; Earhart, J. S.; Merk, B. R.; McKee, J. S.; Bairstow, S. F.; Shah, R. N.; Hsu, W. K.; Stupp, S. I. Gel Scaffolds of BMP-2-Binding Peptide Amphiphile Nanofibers for Spinal Arthrodesis Adv. Healthcare Mater. 2015, 4 (1) 131– 141 DOI: 10.1002/adhm.201400129
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      24
      Gel Scaffolds of BMP-2-Binding Peptide Amphiphile Nanofibers for Spinal Arthrodesis
      Lee, Sungsoo S.; Hsu, Erin L.; Mendoza, Marco; Ghodasra, Jason; Nickoli, Michael S.; Ashtekar, Amruta; Polavarapu, Mahesh; Babu, Jacob; Riaz, Rehan M.; Nicolas, Joseph D.; Nelson, David; Hashmi, Sohaib Z.; Kaltz, Stuart R.; Earhart, Jeffrey S.; Merk, Bradley R.; McKee, Jeff S.; Bairstow, Shawn F.; Shah, Ramille N.; Hsu, Wellington K.; Stupp, Samuel I.
      Advanced Healthcare Materials (2015), 4 (1), 131-141CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Peptide amphiphile (PA) nanofibers formed by self-assembly can be customized for specific applications in regenerative medicine through the use of mols. that display bioactive signals on their surfaces. Here, the use of PA nanofibers with binding affinity for the bone promoting growth factor BMP-2 to create a gel scaffold for osteogenesis is reported. With the objective of reducing the amt. of BMP-2 used clin. for successful arthrodesis in the spine, amts. of growth factor incorporated in the scaffolds that are 10 to 100 times lower than that those used clin. in collagen scaffolds are used. The efficacy of the bioactive PA system to promote BMP-2-induced osteogenesis in vivo is investigated in a rat posterolateral lumbar intertransverse spinal fusion model. PA nanofiber gels displaying BMP-2-binding segments exhibit superior spinal fusion rates relative to controls, effectively decreasing the required therapeutic dose of BMP-2 by 10-fold. Interestingly, a 42% fusion rate is obsd. for gels contg. the bioactive nanofibers without the use of exogenous BMP-2, suggesting the ability of the nanofiber to recruit endogenous growth factor. Results obtained here demonstrate that bioactive biomaterials with capacity to bind specific growth factors by design are great targets for regenerative medicine.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXivFWiuw%253D%253D&md5=5fd9ee59a0450282934d4ead1d0bc819
    25. 25
      Casaletto, J. B.; McClatchey, A. I. Spatial regulation of receptor tyrosine kinases in development and cancer Nat. Rev. Cancer 2012, 12 (6) 387– 400 DOI: 10.1038/nrc3277
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      25
      Spatial regulation of receptor tyrosine kinases in development and cancer
      Casaletto, Jessica B.; McClatchey, Andrea I.
      Nature Reviews Cancer (2012), 12 (6), 387-400CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
      A review. During development and tissue homeostasis, patterns of cellular organization, proliferation and movement are highly choreographed. Receptor tyrosine kinases (RTKs) have a crucial role in establishing these patterns. Individual cells and tissues exhibit tight spatial control of the RTKs that they express, enabling tissue morphogenesis and function, while preventing unwarranted cell division and migration that can contribute to tumorigenesis. Indeed, RTKs are deregulated in most human cancers and are a major focus of targeted therapeutics. A growing appreciation of the essential role of spatial RTK regulation during development prompts the realization that spatial deregulation of RTKs is likely to contribute broadly to cancer development and may affect the sensitivity and resistance of cancer to pharmacol. RTK inhibitors.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xntlyks7Y%253D&md5=87d62276b4319a41ec37befe62dde0a1
    26. 26
      Yun, Y. R.; Won, J. E.; Jeon, E.; Lee, S.; Kang, W.; Jo, H.; Jang, J. H.; Shin, U. S.; Kim, H. W. Fibroblast growth factors: biology, function, and application for tissue regeneration J. Tissue Eng. 2010, 1, 218142 DOI: 10.4061/2010/218142
      [ Crossref], Google Scholar
      There is no corresponding record for this reference.
    27. 27
      Tayalia, P.; Mooney, D. J. Controlled Growth Factor Delivery for Tissue Engineering Adv. Mater. 2009, 21 (32–33) 3269– 3285 DOI: 10.1002/adma.200900241
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      27
      Controlled Growth Factor Delivery for Tissue Engineering
      Tayalia, Prakriti; Mooney, David J.
      Advanced Materials (Weinheim, Germany) (2009), 21 (32-33), 3269-3285CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Growth factors play a crucial role in information transfer between cells and their microenvironment in tissue engineering and regeneration. They initiate their action by binding to specific receptors on the surface of target cells and the chem. identity, concn., duration, and context of these growth factors contain information that dictates cell fate. Hence, the importance of exogenous delivery of these mols. in tissue engineering is unsurprising, considering their importance for tissue regeneration. However, the short half-lives of growth factors, their relatively large size, slow tissue penetration, and their potential toxicity at high systemic levels, suggest that conventional routes of administration are unlikely to be effective. In this review, we provide an overview of the design criteria for growth factor delivery vehicles with respect to the growth factor itself and the microenvironment for delivery. We discuss various methodologies that could be adopted to achieve this localized delivery, and strategies using polymers as delivery vehicles in particular.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVOrsb7O&md5=23a290c0418cebfa7f45ed340aa4843d
    28. 28
      Turner, N.; Grose, R. Fibroblast growth factor signalling: from development to cancer Nat. Rev. Cancer 2010, 10 (2) 116– 129 DOI: 10.1038/nrc2780
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      28
      Fibroblast growth factor signalling: from development to cancer
      Turner, Nicholas; Grose, Richard
      Nature Reviews Cancer (2010), 10 (2), 116-129CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
      A review. Fibroblast growth factors (FGFs) and their receptors control a wide range of biol. functions, regulating cellular proliferation, survival, migration and differentiation. Although targeting FGF signalling as a cancer therapeutic target has lagged behind that of other receptor tyrosine kinases, there is now substantial evidence for the importance of FGF signalling in the pathogenesis of diverse tumor types, and clin. reagents that specifically target the FGFs or FGF receptors are being developed. Although FGF signalling can drive tumorigenesis, in different contexts FGF signalling can mediate tumor protective functions; the identification of the mechanisms that underlie these differential effects will be important to understand how FGF signalling can be most appropriately therapeutically targeted.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXps1Gktg%253D%253D&md5=7963bc75c149981560dffc8d91b4aaf1
    29. 29
      Murakami, M.; Sakurai, T. Role of fibroblast growth factor signaling in vascular formation and maintenance: orchestrating signaling networks as an integrated system Wires Syst. Biol. Med. 2012, 4 (6) 615– 629 DOI: 10.1002/wsbm.1190
      [ Crossref], [ PubMed], Google Scholar
      There is no corresponding record for this reference.
    30. 30
      Raballo, R.; Rhee, J.; Lyn-Cook, R.; Leckman, J. F.; Schwartz, M. L.; Vaccarino, F. M. Basic fibroblast growth factor (Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex J. Neurosci. 2000, 20 (13) 5012– 5023
      [ PubMed], [ CAS], Google Scholar
      30
      Basic fibroblast growth factor (Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex
      Raballo, Rossana; Rhee, Julianne; Lyn-Cook, Richard; Leckman, James F.; Schwartz, Michael L.; Vaccarino, Flora M.
      Journal of Neuroscience (2000), 20 (13), 5012-5023CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
      Little is known about regionally specific signals that control the no. of neuronal progenitor cells in vivo. We have previously shown that the germline mutation of the basic fibroblast growth factor (Fgf2) gene results in a redn. in the no. of cortical neurons in the adult. We show here that Fgf2 is expressed in the pseudostratified ventricular epithelium (PVE) in a dorsoventral gradient and that Fgf2 and its receptor, Fgfr-1, are downregulated by mid to late stages of neurogenesis. In Fgf2 knockout mice, the vol. and cell no. of the dorsal PVE (the cerebral cortical anlage) are substantially smaller, whereas the vol. of the basal PVE is unchanged. The dorsal PVE of Fgf2 knockout mice has a 50% decrease in founder cells and a reduced expansion of the progenitor pool over the first portion of neurogenesis. Despite this redn., the degree of apoptosis within the PVE is not changed in the Fgf2 knockouts. Cortical neuron no. was decreased by 45% in Fgf2 knockout mice by the end of neurogenesis, whereas the no. of neurons in the basal ganglia was unaffected. Microscopically, the frontal cerebral cortex of neonatal Fgf2 null mutant mice lacked large neurons in deep cortical layers. We suggest that Fgf2 is required for the generation of a specific class of cortical neurons arising from the dorsal PVE.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXksF2jt7w%253D&md5=dd80b532909defca1ae1a0462a37ae26
    31. 31
      Woodbury, M. E.; Ikezu, T. Fibroblast growth factor-2 signaling in neurogenesis and neurodegeneration J. Neuroimmune Pharmacol 2014, 9 (2) 92– 101 DOI: 10.1007/s11481-013-9501-5
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      31
      Fibroblast growth factor-2 signaling in neurogenesis and neurodegeneration
      Woodbury Maya E; Ikezu Tsuneya
      Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology (2014), 9 (2), 92-101 ISSN:.
      Fibroblast growth factor-2 (FGF2), also known as basic FGF, is a multi-functional growth factor. One of the 22-member FGF family, it signals through receptor tyrosine kinases encoding FGFR1-4. FGF2 activates FGFRs in cooperation with heparin or heparin sulfate proteoglycan to induce its pleiotropic effects in different tissues and organs, which include potent angiogenic effects and important roles in the differentiation and function of the central nervous system (CNS). FGF2 is crucial to development of the CNS, which explains its importance in adult neurogenesis. During development, high levels of FGF2 are detected from neurulation onwards. Moreover, developmental expression of FGF2 and its receptors is temporally and spatially regulated, concurring with development of specific brain regions including the hippocampus and substantia nigra pars compacta. In adult neurogenesis, FGF2 has been implicated based on its expression and regulation of neural stem and progenitor cells in the neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. FGFR1 signaling also modulates inflammatory signaling through the surface glycoprotein CD200, which regulates microglial activation. Because of its importance in adult neurogenesis and neuroinflammation, manipulation of FGF2/FGFR1 signaling has been a focus of therapeutic development for neurodegenerative disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and traumatic brain injury. Novel strategies include intranasal administration of FGF2, administration of an NCAM-derived FGFR1 agonist, and chitosan-based nanoparticles for the delivery of FGF2 in pre-clinical animal models. In this review, we highlight current research towards therapeutic interventions targeting FGF2/FGFR1 in neurodegenerative disorders.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c%252Fgt1WitQ%253D%253D&md5=b1d9f637c8d2895604f3c8e9aa98718a
    32. 32
      Kim, J. H.; Jung, Y.; Kim, S.-H.; Sun, K.; Choi, J.; Kim, H. C.; Park, Y.; Kim, S. H. The enhancement of mature vessel formation and cardiac function in infarcted hearts using dual growth factor delivery with self-assembling peptides Biomaterials 2011, 32 (26) 6080– 6088 DOI: 10.1016/j.biomaterials.2011.05.003
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      32
      The enhancement of mature vessel formation and cardiac function in infarcted hearts using dual growth factor delivery with self-assembling peptides
      Kim, Ji Hyun; Jung, Youngmee; Kim, Sang-Heon; Sun, Kyung; Choi, Jaesoon; Kim, Hee Chan; Park, Yongdoo; Kim, Soo Hyun
      Biomaterials (2011), 32 (26), 6080-6088CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      For successful treatment of myocardial infarction (MI), it is important to prevent cardiac fibrosis and maintain cardiac function by protecting cardiomyocytes and inducing angiogenesis. To establish functional and stable vessels, various growth factors, ones stimulating both endothelial cells (EC) and vascular smooth muscle cells (VSMC), are required. Self-assembling peptides form fibers (<10 nm) and provide 3-dimensional microenvironments that can recruit EC and VSMC to promote vascularization and long-term delivery of growth factors. Here we demonstrate myocardial protection of infarcted heart using dual growth factor delivery with self-assembling peptides. After coronary artery ligation in rats, growth factors (PDGF-BB and FGF-2) with self-assembling peptides were injected. There were 6 rats in each group. Hearts were harvested at 4 and 8 wk for functional and histol. anal. Infarct size and cardiomyocyte apoptosis in dual growth factors along with self-assembling peptides group were dramatically reduced compared to sham. The capillary and arterial d. of this group recovered with angiogenic synergism and cardiac functions had almost recovered. In conclusion, dual growth factors along with self-assembling peptides lead to myocardial protection, stable vessel formation, and improvement in cardiac function.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXotlChsLk%253D&md5=2759b44208b2189e8c0b59f20492e19f
    33. 33
      Tam, R. Y.; Fuehrmann, T.; Mitrousis, N.; Shoichet, M. S. Regenerative Therapies for Central Nervous System Diseases: a Biomaterials Approach Neuropsychopharmacology 2014, 39 (1) 169– 188 DOI: 10.1038/npp.2013.237
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      33
      Regenerative Therapies for Central Nervous System Diseases: a Biomaterials Approach
      Tam, Roger Y.; Fuehrmann, Tobias; Mitrousis, Nikolaos; Shoichet, Molly S.
      Neuropsychopharmacology (2014), 39 (1), 169-188CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)
      A review. The central nervous system (CNS) has a limited capacity to spontaneously regenerate following traumatic injury or disease, requiring innovative strategies to promote tissue and functional repair. Tissue regeneration strategies, such as cell and/or drug delivery, have demonstrated promising results in exptl. animal models, but have been difficult to translate clin. The efficacy of cell therapy, which involves stem cell transplantation into the CNS to replace damaged tissue, has been limited due to low cell survival and integration upon transplantation, while delivery of therapeutic mols. to the CNS using conventional methods, such as oral and i.v. administration, have been limited by diffusion across the blood-brain/spinal cord-barrier. The use of biomaterials to promote graft survival and integration as well as localized and sustained delivery of biologics to CNS injury sites is actively being pursued. This review will highlight recent advances using biomaterials as cell- and drug-delivery vehicles for CNS repair.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFymsL7E&md5=5e9870f346d2e8bc8b4baa2f964f3e45
    34. 34
      Baird, A.; Schubert, D.; Ling, N.; Guillemin, R. Receptor- and heparin-binding domains of basic fibroblast growth factor Proc. Natl. Acad. Sci. U. S. A. 1988, 85 (7) 2324– 8 DOI: 10.1073/pnas.85.7.2324
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      34
      Receptor- and heparin-binding domains of basic fibroblast growth factor
      Baird, Andrew; Schubert, David; Ling, Nicholas; Guillemin, Roger
      Proceedings of the National Academy of Sciences of the United States of America (1988), 85 (7), 2324-8CODEN: PNASA6; ISSN:0027-8424.
      Two functional domains in the primary structure of basic fibroblast growth factor (FGF) were identified on the basis of their ability to interact with the FGF receptor, bind radiolabeled heparin, and modulate the cellular response to FGF. Peptides derived from these 2 functional domains can act as partial agonists and antagonists in biol. assays of FGF activity. Peptides related to the sequences of FGF-(24-68)-NH2 and FGF-(106-115)-NH2 inhibit thymidine incorporation into 3T3 fibroblasts when they are stimulated by FGF but have no effect when the cells are treated with either platelet-derived growth factor or epidermal growth factor. They also possess partial agonist activity and can stimulate DNA synthesis when tested in the absence of exogenous FGF. The active peptides have no effect on the binding of epidermal growth factor to its receptor on A431 cells, and they can modulate the effects of FGF, but not fibronectin, on endothelial cell adhesion. The results suggest the possibility of designing specific analogs of FGF that are capable of inhibiting the biol. effects of FGF.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXktVSqt74%253D&md5=de0c889bd9652f69aa2402e9402e147c
    35. 35
      Lin, X.; Takahashi, K.; Campion, S. L.; Liu, Y.; Gustavsen, G. G.; Pena, L. A.; Zamora, P. O. Synthetic peptide F2A4-K-NS mimics fibroblast growth factor-2 in vitro and is angiogenic in vivo Int. J. Mol. Med. 2006, 17 (5) 833– 9 DOI: 10.3892/ijmm.17.5.833
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      35
      Synthetic peptide F2A4-K-NS mimics fibroblast growth factor-2 in vitro and is angiogenic in vivo
      Lin, X.; Takahashi, K.; Campion, S. L.; Liu, Y.; Gustavsen, G. G.; Pena, L. A.; Zamora, P. O.
      International Journal of Molecular Medicine (2006), 17 (5), 833-839CODEN: IJMMFG; ISSN:1107-3756. (International Journal of Molecular Medicine)
      A multi-domain synthetic peptide, F2A4-K-NS, mimicked the action of recombinant human FGF-2 (rhFGF-2) in vitro and in an in vivo model of angiogenesis. Like rhFGF-2, F2A4-K-NS was quant. shown to bind to FGF receptors in a cell-free receptor binding assay using a chimeric FGFR1 (IIIc)/Fc as monitored by surface plasmon resonance (SPR), and also shown to bind to heparin using biotinylated low-mol. wt. heparin in a similar SPR assay. In vitro, F2A4-K-NS triggered signal transduction as monitored by the stimulation of ERK1/2 phosphorylation in human umbilical cord endothelial cells. In cell based assays, it increased cell migration, cell proliferation, and gelatinase secretion; endpoints assocd. with FGF-2 stimulation. Furthermore, these in vitro effects were mediated with quantities of F2A4-K-NS that were similar to those of rhFGF-2. In vivo, F2A4-K-NS was angiogenic at doses of 40 and 400 ng/implant in a s.c. implant assay as detd. by morphol. scoring, Hb content, and histol. These results support the hypothesis that F2A4-K-NS is a mimetic of FGF-2 that can substitute for FGF-2 in vitro and in vivo. A synthetic mimetic of FGF-2, such as F2A4-K-NS, could be a useful tool in studying mechanisms of cell activation and potentially in various therapeutic applications.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xks1Cht7s%253D&md5=53813602a0d40430fc71b0ca802b5554
    36. 36
      Hartgerink, J. D.; Beniash, E.; Stupp, S. I. Peptide-amphiphile nanofibers: A versatile scaffold for the preparation of self-assembling materials Proc. Natl. Acad. Sci. U. S. A. 2002, 99 (8) 5133– 5138 DOI: 10.1073/pnas.072699999
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      36
      Peptide-amphiphile nanofibers: a versatile scaffold for the preparation of self-assembling materials
      Hartgerink, Jeffrey D.; Beniash, Elia; Stupp, Samuel I.
      Proceedings of the National Academy of Sciences of the United States of America (2002), 99 (8), 5133-5138CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Twelve derivs. of peptide-amphiphile mols., designed to self-assemble into nanofibers, are described. The scope of amino acid selection and alkyl tail modification in the peptide-amphiphile mols. are investigated, yielding nanofibers varying in morphol., surface chem., and potential bioactivity. The results demonstrate the chem. versatile nature of this supramol. system and its high potential for manufg. nanomaterials. In addn., three different modes of self-assembly resulting in nanofibers are described, including pH control, divalent ion induction, and concn.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtFKmtbc%253D&md5=c3f7e085dae93ac5a43fea1db538fdbf
    37. 37
      Zhang, S.; Greenfield, M. A.; Mata, A.; Palmer, L. C.; Bitton, R.; Mantei, J. R.; Aparicio, C.; de la Cruz, M. O.; Stupp, S. I. A self-assembly pathway to aligned monodomain gels Nat. Mater. 2010, 9 (7) 594– 601 DOI: 10.1038/nmat2778
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      37
      A self-assembly pathway to aligned monodomain gels
      Zhang, Shuming; Greenfield, Megan A.; Mata, Alvaro; Palmer, Liam C.; Bitton, Ronit; Mantei, Jason R.; Aparicio, Conrado; de la Cruz, Monica Olvera; Stupp, Samuel I.
      Nature Materials (2010), 9 (7), 594-601CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
      Aggregates of charged amphiphilic mols. have been found to access a structure at elevated temp. that templates alignment of supramol. fibrils over macroscopic scales. The thermal pathway leads to a lamellar plaque structure with fibrous texture that breaks on cooling into large arrays of aligned nanoscale fibers and forms a strongly birefringent liq. By manually dragging this liq. crystal from a pipet onto salty media, it is possible to extend this alignment over centimetres in noodle-shaped viscoelastic strings. Using this approach, the soln. of supramol. filaments can be mixed with cells at physiol. temps. to form monodomain gels of aligned cells and filaments. The nature of the self-assembly process and its biocompatibility would allow formation of cellular wires in situ that have any length and customized peptide compns. for use in biol. applications.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvVOktrY%253D&md5=d02eef3d33c9cb6b8961464f9b56a4fd
    38. 38
      Tantakitti, F.; Boekhoven, J.; Wang, X.; Kazantsev, R. V.; Yu, T.; Li, J.; Zhuang, E.; Zandi, R.; Ortony, J. H.; Newcomb, C. J.; Palmer, L. C.; Shekhawat, G. S.; de la Cruz, M. O.; Schatz, G. C.; Stupp, S. I. Energy landscapes and functions of supramolecular systems Nat. Mater. 2016, 15 (4) 469– 476 DOI: 10.1038/nmat4538
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      38
      Energy landscapes and functions of supramolecular systems
      Tantakitti, Faifan; Boekhoven, Job; Wang, Xin; Kazantsev, Roman V.; Yu, Tao; Li, Jiahe; Zhuang, Ellen; Zandi, Roya; Ortony, Julia H.; Newcomb, Christina J.; Palmer, Liam C.; Shekhawat, Gajendra S.; de la Cruz, Monica Olvera; Schatz, George C.; Stupp, Samuel I.
      Nature Materials (2016), 15 (4), 469-476CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
      By means of 2 supramol. systems, peptide amphiphiles engaged in H-bonded β-sheets, and chromophore amphiphiles driven to assemble by π-orbital overlaps, the authors showed that the min. in the energy landscapes of supramol. systems were defined by electrostatic repulsion and the ability of the dominant attractive forces to trap mols. in thermodynamically unfavorable configurations. These competing interactions could be selectively switched on and off, with the order of doing so detg. the position of the final product in the energy landscape. Within the same energy landscape, the peptide-amphiphile system formed a thermodynamically favored product characterized by long bundled fibers that promoted biol. cell adhesion and survival, and a metastable product characterized by short monodisperse fibers that interfered with adhesion and could lead to cell death. These findings suggested that, in supramol. systems, functions and energy landscapes are linked, superseding the more traditional connection between mol. design and function.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1emu7g%253D&md5=14093ed2a80d60847cd6d8948c5bace3
    39. 39
      Boekhoven, J.; Stupp, S. I. 25th Anniversary Article: Supramolecular Materials for Regenerative Medicine Adv. Mater. 2014, 26 (11) 1642– 1659 DOI: 10.1002/adma.201304606
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      39
      25th Anniversary Article: Supramolecular Materials for Regenerative Medicine
      Boekhoven, Job; Stupp, Samuel I.
      Advanced Materials (Weinheim, Germany) (2014), 26 (11), 1642-1659CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. In supramol. materials, mol. building blocks are designed to interact with one another via non-covalent interactions in order to create function. This offers the opportunity to create structures similar to those found in living systems that combine order and dynamics through the reversibility of intermol. bonds. For regenerative medicine there is a great need to develop materials that signal cells effectively, deliver or bind bioactive agents in vivo at controlled rates, have highly tunable mech. properties, but at the same time, can biodegrade safely and rapidly after fulfilling their function. These requirements make supramol. materials a great platform to develop regenerative therapies. This review illustrates the emerging science of these materials and their use in a no. of applications for regenerative medicine.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVyqt7g%253D&md5=b43a171aa07a2b6fb8e8ef9f6c25d7c8
    40. 40
      Stephanopoulos, N.; Ortony, J. H.; Stupp, S. I. Self-assembly for the synthesis of functional biomaterials Acta Mater. 2013, 61 (3) 912– 930 DOI: 10.1016/j.actamat.2012.10.046
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      40
      Self-assembly for the synthesis of functional biomaterials
      Stephanopoulos, Nicholas; Ortony, Julia H.; Stupp, Samuel I.
      Acta Materialia (2013), 61 (3), 912-930CODEN: ACMAFD; ISSN:1359-6454. (Elsevier Ltd.)
      A review. The use of self-assembly for the construction of functional biomaterials is a highly promising and exciting area of research, with great potential for the treatment of injury or disease. By using multiple noncovalent interactions, coded into the mol. design of the constituent components, self-assembly allows for the construction of complex, adaptable, and highly tunable materials with potent biol. effects. This review describes some of the seminal advances in the use of self-assembly to make novel systems for regenerative medicine and biol. Materials based on peptides, proteins, DNA, or hybrids thereof have found application in the treatment of a wide range of injuries and diseases, and this review outlines the design principles and practical applications of these systems. Most of the examples covered focus on the synthesis of hydrogels for the scaffolding or transplantation of cells, with an emphasis on the biol., mech., and structural properties of the resulting materials. In addn., we will discuss the distinct advantages conferred by self-assembly (compared with traditional covalent materials), and present some of the challenges and opportunities for the next generation of self-assembled biomaterials.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFagtrY%253D&md5=7cfe964fe6e343cb4ecd412c7164f5fd
    41. 41
      Silva, G. A.; Czeisler, C.; Niece, K. L.; Beniash, E.; Harrington, D. A.; Kessler, J. A.; Stupp, S. I. Selective differentiation of neural progenitor cells by high-epitope density nanofibers Science 2004, 303 (5662) 1352– 1355 DOI: 10.1126/science.1093783
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      41
      Selective differentiation of neural progenitor cells by high-epitope density nanofibers
      Silva, Gabriel A.; Czeisler, Catherine; Niece, Krista L.; Beniash, Elia; Harrington, Daniel A.; Kessler, John A.; Stupp, Samuel I.
      Science (Washington, DC, United States) (2004), 303 (5662), 1352-1355CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Neural progenitor cells were encapsulated in vitro within a three-dimensional network of nanofibers formed by self-assembly of peptide amphiphile mols. The self-assembly is triggered by mixing cell suspensions in media with dil. aq. solns. of the mols., and cells survive the growth of the nanofibers around them. These nanofibers were designed to present to cells the neurite-promoting laminin epitope IKVAV at nearly van der Waals d. Relative to laminin or sol. peptide, the artificial nanofiber scaffold induced very rapid differentiation of cells into neurons, while discouraging the development of astrocytes. This rapid selective differentiation is linked to the amplification of bioactive epitope presentation to cells by the nanofibers.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhsFyrtLo%253D&md5=62b424889d3e6a0ab0a70396c4dbbcb6
    42. 42
      Tysseling-Mattiace, V. M.; Sahni, V.; Niece, K. L.; Birch, D.; Czeisler, C.; Fehlings, M. G.; Stupp, S. I.; Kessler, J. A. Self-Assembling Nanofibers Inhibit Glial Scar Formation and Promote Axon Elongation after Spinal Cord Injury J. Neurosci. 2008, 28 (14) 3814– 3823 DOI: 10.1523/JNEUROSCI.0143-08.2008
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      42
      Self-assembling nanofibers inhibit glial scar formation and promote axon elongation after spinal cord injury
      Tysseling-Mattiace, Vicki M.; Sahni, Vibhu; Niece, Krista L.; Birch, Derin; Czeisler, Catherine; Fehlings, Michael G.; Stupp, Samuel I.; Kessler, John A.
      Journal of Neuroscience (2008), 28 (14), 3814-3823CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
      Peptide amphiphile (PA) mols. that self-assemble in vivo into supramol. nanofibers were used as a therapy in a mouse model of spinal cord injury (SCI). Because self-assembly of these mols. is triggered by the ionic strength of the in vivo environment, nanoscale structures can be created within the extracellular spaces of the spinal cord by simply injecting a liq. The mols. are designed to form cylindrical nanofibers that display to cells in the spinal cord the laminin epitope IKVAV at nearly van der Waals d. IKVAV PA nanofibers are known to inhibit glial differentiation of cultured neural stem cells and to promote neurite outgrowth from cultured neurons. In this work, in vivo treatment with the PA after SCI reduced astrogliosis, reduced cell death, and increased the no. of oligodendroglia at the site of injury. Furthermore, the nanofibers promoted regeneration of both descending motor fibers and ascending sensory fibers through the lesion site. Treatment with the PA also resulted in significant behavioral improvement. These observations demonstrate that it is possible to inhibit glial scar formation and to facilitate regeneration after SCI using bioactive three-dimensional nanostructures displaying high densities of neuroactive epitopes on their surfaces.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXkslSjur8%253D&md5=68d62032cd249d07e37559419e6ef286
    43. 43
      Pan, L.; North, H. A.; Sahni, V.; Jeong, S. J.; McGuire, T. L.; Berns, E. J.; Stupp, S. I.; Kessler, J. A. β1-Integrin and Integrin Linked Kinase Regulate Astrocytic Differentiation of Neural Stem Cells PLoS One 2014, 9 (8) e104335 DOI: 10.1371/journal.pone.0104335
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      43
      β1-Integrin and integrin linked kinase regulate astrocytic differentiation of neural stem cells
      Pan, Liuliu; North, Hilary A.; Sahni, Vibhu; Jeong, Su Ji; McGuire, Tammy L.; Berns, Eric J.; Stupp, Samuel I.; Kessler, John A.
      PLoS One (2014), 9 (8), e104335/1-e104335/12, 12 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Astrogliosis with glial scar formation after damage to the nervous system is a major impediment to axonal regeneration and functional recovery. The present study examd. the role of β1-integrin signaling in regulating astrocytic differentiation of neural stem cells. In the adult spinal cord β1-integrin is expressed predominantly in the ependymal region where ependymal stem cells (ESCs) reside. β1-Integrin signaling suppressed astrocytic differentiation of both cultured ESCs and subventricular zone (SVZ) progenitor cells. Conditional knockout of β1-integrin enhanced astrogliogenesis both by cultured ESCs and by SVZ progenitor cells. Previous studies have shown that injection into the injured spinal cord of a self-assembling peptide amphiphile that displays an IKVAV epitope (IKVAV-PA) limits glial scar formation and enhances functional recovery. Here we find that injection of IKVAV-PA induced high levels of β1-integrin in ESCs in vivo, and that conditional knockout of β1-integrin abolished the astroglial suppressive effects of IKVAV-PA in vitro. Injection into an injured spinal cord of PAs expressing two other epitopes known to interact with β1-integrin, a Tenascin C epitope and the fibronectin epitope RGD, improved functional recovery comparable to the effects of IKVAV-PA. Finally we found that the effects of β1-integrin signaling on astrogliosis are mediated by integrin linked kinase (ILK). These observations demonstrate an important role for β1-integrin/ILK signaling in regulating astrogliosis from ESCs and suggest ILK as a potential target for limiting glial scar formation after nervous system injury.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1aks73J&md5=d2d8caf7a3128a08e6a8efbb42c02c23
    44. 44
      Huang, Z.; Sargeant, T. D.; Hulvat, J. F.; Mata, A.; Bringas, P.; Koh, C. Y.; Stupp, S. I.; Snead, M. L. Bioactive Nanofibers Instruct Cells to Proliferate and Differentiate During Enamel Regeneration J. Bone Miner. Res. 2008, 23 (12) 1995– 2006 DOI: 10.1359/jbmr.080705
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      44
      Bioactive nanofibers instruct cells to proliferate and differentiate during enamel regeneration
      Huang, Zhan; Sargeant, Timothy D.; Hulvat, James F.; Mata, Alvaro; Bringas, Pablo, Jr.; Koh, Chung-Yan; Stupp, Samuel I.; Snead, Malcolm L.
      Journal of Bone and Mineral Research (2008), 23 (12), 1995-2006CODEN: JBMREJ; ISSN:0884-0431. (American Society for Bone and Mineral Research)
      During tooth development, ectoderm-derived ameloblast cells create enamel by synthesizing a complex protein mixt. serving to control cell to matrix interactions and the habit of hydroxyapatite crystallites. Using an in vitro cell and organ culture system, we studied the effect of artificial bioactive nanostructures on ameloblasts with the long-term goal of developing cell-based strategies for tooth regeneration. We used branched peptide amphiphile mols. contg. the peptide motif Arg-Gly-Asp, or "RGD" (abbreviated BRGD-PA), known to self-assemble in physiol. environments into nanofibers that display on their surfaces high densities of this biol. signal. Ameloblast-like cells (line LS8) and primary enamel organ epithelial (EOE) cells were cultured within PA hydrogels, and the PA was injected into the enamel organ epithelia of mouse embryonic incisors. The expression of amelogenin, ameloblastin, integrin α5, and integrin α6 was detected by quant. real-time PCR and immunodetection techniques. We performed cell proliferation assay using BrdU labeling and a biomineralization assay using Alizarin red S staining with quant. Ca2+ measurements. In the cell culture model, ameloblast-like cells (LS8) and primary EOE cells responded to the BRGD-PA nanostructures with enhanced proliferation and greater amelogenin, ameloblastin, and integrin expression levels. At the site of injection of the BRGD-PA in the organ culture model, we obsd. EOE cell proliferation with differentiation into ameloblasts as evidenced by their expression of enamel specific proteins. Ultrastructural anal. showed the nanofibers within the forming extracellular matrix, in contact with the EOE cells engaged in enamel formation and regeneration. This study shows that BRGD-PA nanofibers present with enamel proteins participate in integrin-mediated cell binding to the matrix with delivery of instructive signals for enamel formation.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosVyltrs%253D&md5=f9c4486b62c03e5b8c2e7840de9050b2
    45. 45
      Mata, A.; Geng, Y. B.; Henrikson, K. J.; Aparicio, C.; Stock, S. R.; Satcher, R. L.; Stupp, S. I. Bone regeneration mediated by biomimetic mineralization of a nanofiber matrix Biomaterials 2010, 31 (23) 6004– 6012 DOI: 10.1016/j.biomaterials.2010.04.013
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      45
      Bone regeneration mediated by biomimetic mineralization of a nanofiber matrix
      Mata, Alvaro; Geng, Yanbiao; Henrikson, Karl J.; Aparicio, Conrado; Stock, Stuart R.; Satcher, Robert L.; Stupp, Samuel I.
      Biomaterials (2010), 31 (23), 6004-6012CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      Rapid bone regeneration within a three-dimensional defect without the use of bone grafts, exogenous growth factors, or cells remains a major challenge. We report here on the use of self-assembling peptide nanostructured gels to promote bone regeneration that have the capacity to mineralize in biomimetic fashion. The main mol. design was the use of phosphoserine residues in the sequence of a peptide amphiphile known to nucleate hydroxyapatite crystals on the surfaces of nanofibers. We tested the system in a rat femoral crit.-size defect by placing pre-assembled nanofiber gels in a 5 mm gap and analyzed bone formation with micro-computed tomog. and histol. We found within 4 wk significantly higher bone formation relative to controls lacking phosphorylated residues and comparable bone formation to that obsd. in animals treated with a clin. used allogenic bone matrix.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnslamt7g%253D&md5=31b506ca096d15e5545c810d5ddf4424
    46. 46
      Lee, S. S.; Huang, B. J.; Kaltz, S. R.; Sur, S.; Newcomb, C. J.; Stock, S. R.; Shah, R. N.; Stupp, S. I. Bone regeneration with low dose BMP-2 amplified by biomimetic supramolecular nanofibers within collagen scaffolds Biomaterials 2013, 34 (2) 452– 459 DOI: 10.1016/j.biomaterials.2012.10.005
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      46
      Bone regeneration with low dose BMP-2 amplified by biomimetic supramolecular nanofibers within collagen scaffolds
      Lee, Sungsoo S.; Huang, Brian J.; Kaltz, Stuart R.; Sur, Shantanu; Newcomb, Christina J.; Stock, Stuart R.; Shah, Ramille N.; Stupp, Samuel I.
      Biomaterials (2013), 34 (2), 452-459CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      Bone morphogenetic protein-2 (BMP-2) is a potent osteoinductive cytokine that plays a crit. role during bone regeneration and repair. In the extracellular environment, sulfated polysaccharides anchored covalently to glycoproteins such as syndecan and also non-covalently to fibronectin fibers have been shown to bind BMP-2 through a heparin-binding domain and regulate its bioactivity. We report here on a synthetic biomimetic strategy that emulates biol. BMP-2 signaling through the use of peptide amphiphile nanofibers designed to bind heparin. The supramol. nanofibers, which integrate the biol. role of syndecan and fibronectin, were allowed to form gel networks within the pores of an absorbable collagen scaffold by simply infiltrating dil. solns. of the peptide amphiphile, heparan sulfate, and BMP-2. The hybrid biomaterial enhanced significantly bone regeneration in a rat crit.-size femoral defect model using BMP-2 amts. that are one order of magnitude lower than required for healing in this animal model. Using micro-computed tomog., we also showed that the hybrid scaffold was more effective at bridging within the gap relative to a conventional scaffold of the type used clin. based on collagen and BMP-2. Histol. evaluation also revealed the presence of more mature bone in the new ossified tissue when the low dose of BMP-2 was delivered using the biomimetic supramol. system. These results demonstrate how molecularly designed materials that mimic features of the extracellular environment can amplify the regenerative capacity of growth factors.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFGjtLvI&md5=cf9ef30ed6ca1efff6fe8211dc4fb40e
    47. 47
      Chow, L. W.; Bitton, R.; Webber, M. J.; Carvajal, D.; Shull, K. R.; Sharma, A. K.; Stupp, S. I. A bioactive self-assembled membrane to promote angiogenesis Biomaterials 2011, 32 (6) 1574– 1582 DOI: 10.1016/j.biomaterials.2010.10.048
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      47
      A bioactive self-assembled membrane to promote angiogenesis
      Chow, Lesley W.; Bitton, Ronit; Webber, Matthew J.; Carvajal, Daniel; Shull, Kenneth R.; Sharma, Arun K.; Stupp, Samuel I.
      Biomaterials (2011), 32 (6), 1574-1582CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      We report here on a bioactive hierarchically structured membrane formed by self-assembly. The membrane is formed with hyaluronic acid and peptide amphiphiles with binding affinity for heparin, and its hierarchical structure contains both an amorphous zone and a layer of fibrils oriented perpendicular to the membrane plane. The design of bioactivity is based on the potential ability to bind and slowly release heparin-binding growth factors. Human mesenchymal stem cells (hMSCs) seeded on these membranes attached and remained viable. Basic fibroblast growth factor (FGF2) and vascular endothelial growth factor (VEGF) were incorporated within the membrane structure prior to self-assembly and released into media over a prolonged period of time (14 days). Using the chicken chorioallantoic membrane (CAM) assay, we also found that these membranes induced a significant and rapid enhancement of angiogenesis relative to controls.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1SqtrbL&md5=c97eabb880fb0ccf9559b8169e447c1b
    48. 48
      Rajangam, K.; Arnold, M. S.; Rocco, M. A.; Stupp, S. I. Peptide amphiphile nanostructure-heparin interactions and their relationship to bioactivity Biomaterials 2008, 29 (23) 3298– 3305 DOI: 10.1016/j.biomaterials.2008.04.008
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      48
      Peptide amphiphile nanostructure-heparin interactions and their relationship to bioactivity
      Rajangam, Kanya; Arnold, Michael S.; Rocco, Mark A.; Stupp, Samuel I.
      Biomaterials (2008), 29 (23), 3298-3305CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      Heparin-protein interactions are important in many physiol. processes including angiogenesis, the growth of new blood vessels from existing ones. We have previously developed a highly angiogenic self-assembling gel, wherein the self-assembly process is triggered by the interactions between heparin and peptide amphiphiles (PAs) with a consensus heparin binding sequence. In this report, this consensus sequence was scrambled and incorporated into a new peptide amphiphile in order to study its importance in heparin interaction and bioactivity. Heparin was able to trigger gel formation of the scrambled peptide amphiphile (SPA). Furthermore, the affinity of the scrambled mol. for heparin was unchanged as shown by isothermal titrn. calorimetry and high Foerster resonance emission transfer efficiency. However, both the mobile fraction and the dissocn. rate const. of heparin, using fluorescence recovery after photobleaching, were markedly higher in its interaction with the scrambled mol. implying a weaker assocn. Importantly, the scrambled peptide amphiphile-heparin gel had significantly less angiogenic bioactivity as shown by decreased tubule formation of sandwiched endothelial cells. Hence, we believe that the presence of the consensus sequence stabilizes the interaction with heparin and is important for the bioactivity of these new materials.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmsFahs7s%253D&md5=1741cca2aaba33c5806bc9785f2e59ad
    49. 49
      Shah, R. N.; Shah, N. A.; Lim, M. M. D.; Hsieh, C.; Nuber, G.; Stupp, S. I. Supramolecular design of self-assembling nanofibers for cartilage regeneration Proc. Natl. Acad. Sci. U. S. A. 2010, 107 (8) 3293– 3298 DOI: 10.1073/pnas.0906501107
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      49
      Supramolecular design of self-assembling nanofibers for cartilage regeneration
      Shah, Ramille N.; Shah, Nirav A.; Lim, Marc M. Del Rosario; Hsieh, Caleb; Nuber, Gordon; Stupp, Samuel I.
      Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (8), 3293-3298, S3293/1-S3293/4CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Mol. and supramol. design of bioactive biomaterials could have a significant impact on regenerative medicine. Ideal regenerative therapies should be minimally invasive, and thus the notion of self-assembling biomaterials programmed to transform from injectable liqs. to solid bioactive structures in tissue is highly attractive for clin. translation. We report here on a coassembly system of peptide amphiphile (PA) mols. designed to form nanofibers for cartilage regeneration by displaying a high d. of binding epitopes to transforming growth factor β-1 (TGFβ-1). Growth factor release studies showed that passive release of TGFβ-1 was slower from PA gels contg. the growth factor binding sites. In vitro expts. indicate these materials support the survival and promote the chondrogenic differentiation of human mesenchymal stem cells. We also show that these materials can promote regeneration of articular cartilage in a full thickness chondral defect treated with microfracture in a rabbit model with or even without the addn. of exogenous growth factor. These results demonstrate the potential of a completely synthetic bioactive biomaterial as a therapy to promote cartilage regeneration.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjtFymt7k%253D&md5=5544ae5566c3aaef434a4ea96e80d656
    50. 50
      Newcomb, C. J.; Sur, S.; Ortony, J. H.; Lee, O. S.; Matson, J. B.; Boekhoven, J.; Yu, J. M.; Schatz, G. C.; Stupp, S. I. Cell death versus cell survival instructed by supramolecular cohesion of nanostructures Nat. Commun. 2014, 5, 3321 DOI: 10.1038/ncomms4321
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      50
      Cell death versus cell survival instructed by supramolecular cohesion of nanostructures
      Newcomb Christina J; Sur Shantanu; Ortony Julia H; Matson John B; Boekhoven Job; Yu Jeong Min; Lee One-Sun; Schatz George C; Stupp Samuel I
      Nature communications (2014), 5 (), 3321 ISSN:.
      Many naturally occurring peptides containing cationic and hydrophobic domains have evolved to interact with mammalian cell membranes and have been incorporated into materials for non-viral gene delivery, cancer therapy or treatment of microbial infections. Their electrostatic attraction to the negatively charged cell surface and hydrophobic interactions with the membrane lipids enable intracellular delivery or cell lysis. Although the effects of hydrophobicity and cationic charge of soluble molecules on the cell membrane are well known, the interactions between materials with these molecular features and cells remain poorly understood. Here we report that varying the cohesive forces within nanofibres of supramolecular materials with nearly identical cationic and hydrophobic structure instruct cell death or cell survival. Weak intermolecular bonds promote cell death through disruption of lipid membranes, while materials reinforced by hydrogen bonds support cell viability. These findings provide new strategies to design biomaterials that interact with the cell membrane.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cvlsFOqtg%253D%253D&md5=3baf11f7a1278e14392fb71219011d05
    51. 51
      Pashuck, E. T.; Stupp, S. I. Direct Observation of Morphological Tranformation from Twisted Ribbons into Helical Ribbons J. Am. Chem. Soc. 2010, 132 (26) 8819– 8821 DOI: 10.1021/ja100613w
      [ ACS Full Text ACS Full Text], [ CAS], Google Scholar
      51
      Direct Observation of Morphological Transformation from Twisted Ribbons into Helical Ribbons
      Pashuck, E. Thomas; Stupp, Samuel I.
      Journal of the American Chemical Society (2010), 132 (26), 8819-8821CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The authors report on the direct observation of a nanostructural transformation from a twisted ribbon to a helical ribbon in supramol. assemblies of peptide amphiphiles. Using cryogenic electron microscopy, a peptide amphiphile mol., H3C(CH2)14CO-(Phe)3-(Glu)3-OH, contg. arom. residues was found to first assemble into short twisted ribbons in the time range of seconds, which then elongate in the time scale of minutes, and finally transform into helical ribbons over the course of weeks. By synthesizing an analogous mol., H3C(CH2)14CO-(Ala)3-(Glu)3-OH, without the arom. side groups, it was found that a cylindrical nanostructure is formed that does not undergo any transitions during the same time period. The study of metastable states in peptide aggregation can contribute to our understanding of amyloid-related diseases, such as Alzheimer's disease.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnsFyhs7Y%253D&md5=ba5ca9ea5b90bb8b5938c3c8914c4e64
    52. 52
      Hamley, I. W.; Dehsorkhi, A.; Castelletto, V.; Furzeland, S.; Atkins, D.; Seitsonen, J.; Ruokolainen, J. Reversible helical unwinding transition of a self-assembling peptide amphiphile Soft Matter 2013, 9 (39) 9290– 9293 DOI: 10.1039/c3sm51725j
      [ Crossref], [ CAS], Google Scholar
      52
      Reversible helical unwinding transition of a self-assembling peptide amphiphile
      Hamley, Ian W.; Dehsorkhi, Ashkan; Castelletto, Valeria; Furzeland, Steve; Atkins, Derek; Seitsonen, Jani; Ruokolainen, Janne
      Soft Matter (2013), 9 (39), 9290-9293CODEN: SMOABF; ISSN:1744-683X. (Royal Society of Chemistry)
      A designed peptide amphiphile C16-KKFFVLK self-assembles into nanotubes and helical ribbons in aq. soln. at room temp. A remarkable unwinding transition, leading to twisted tapes, is obsd. on heating. Nanotubes and ribbons re-form on cooling.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVKgsrbI&md5=b28b225d3881d1823a738b83b7b8ff1d
    53. 53
      Springer, B. A.; Pantoliano, M. W.; Barbera, F. A.; Gunyuzlu, P. L.; Thompson, L. D.; Herblin, W. F.; Rosenfeld, S. A.; Book, G. W. Identification and concerted function of two receptor binding surfaces on basic fibroblast growth factor required for mitogenesis J. Biol. Chem. 1994, 269 (43) 26879– 26884
      [ PubMed], [ CAS], Google Scholar
      53
      Identification and concerted function of two receptor binding surfaces on basic fibroblast growth factor required for mitogenesis
      Springer, Barry A.; Pantoliano, Michael W.; Barbera, Frank A.; Gunyuzlu, Michael W.; Barbera, Frank A.; Gunyuzlu, Paul L.; Thompson, Leo D.; Herblin, William F.; Rosenfelds, Stuart A.; Book, Glen W.
      Journal of Biological Chemistry (1994), 269 (43), 26879-84CODEN: JBCHA3; ISSN:0021-9258.
      Members of the fibroblast growth factor (FGF) family promote angiogenesis and would repair, modulate early developmental events and survival of neurons, and have been assocd. with the pathogenesis of various diseases. FGFs interact with specific FGF receptors (FGFRs) and heparan sulfate proteoglycans on cell surface to mediate mitogenesis. Using protein structure-based site-directed mutagenesis of basic FGF (bFGF), the authors have identified two FGFR binding sites on bFGF which act in concert to initiate signal transduction. Both FGFR binding surfaces are distinct from the heparan sulfate proteoglycan binding domain. The primary, higher affinity, binding interaction comprises a cluster of solvent exposed hydrophobic amino acids (Tyr-24, Tyr-103, Leu-140, and Met-142), and two polar residues (Arg-44 and Asn-101). The hydrophobic contacts dominate the primary binding interaction and provide ∼75% of the binding affinity. The secondary FGFR binding site of bFGF has an ∼250-fold lower affinity and is composed of amino acids Lys-110, Tyr-111, and Trp-114 in a surface-exposed type I β-turn (formerly known as the putative receptor binding loop). Binding of FGFR to both bFGF surfaces in a stoichiometry of 2FGFR:1bFGF is required for growth factor mediated cell proliferation. This represents a mechanism for the fibroblast growth factor/receptor family in which FGF facilities FGFR dimerization and subsequent signal transduction events as a monomeric ligand.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmt1ahtr0%253D&md5=75051de6a18f2bb7d94010633b912576
    54. 54
      Greenfield, N. J. Using circular dichroism spectra to estimate protein secondary structure Nat. Protoc 2007, 1 (6) 2876– 2890 DOI: 10.1038/nprot.2006.202
      [ Crossref], Google Scholar
      There is no corresponding record for this reference.
    55. 55
      Mohammadi, M.; Olsen, S. K.; Ibrahimi, O. A. Structural basis for fibroblast growth factor receptor activation Cytokine Growth Factor Rev. 2005, 16 (2) 107– 37 DOI: 10.1016/j.cytogfr.2005.01.008
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      55
      Structural basis for fibroblast growth factor receptor activation
      Mohammadi, Moosa; Olsen, Shaun K.; Ibrahimi, Omar A.
      Cytokine & Growth Factor Reviews (2005), 16 (2), 107-137CODEN: CGFRFB; ISSN:1359-6101. (Elsevier B.V.)
      A review. FGF signaling plays a ubiquitous role in human biol. as a regulator of embryonic development, homeostasis and regenerative processes. In addn., aberrant FGF signaling leads to diverse human pathologies including skeletal, olfactory, and metabolic disorders as well as cancer. FGFs execute their pleiotropic biol. actions by binding, dimerizing and activating cell surface FGF receptors (FGFRs). Proper regulation of FGF-FGFR binding specificity is essential for the regulation of FGF signaling and is achieved through primary sequence variations among the 18 FGFs and seven FGFRs. The severity of human skeletal syndromes arising from mutations that violate FGF-FGFR specificity is a testament to the importance of maintaining precision in FGF-FGFR specificity. The discovery that heparin/heparan sulfate (HS) proteoglycans are required for FGF signaling led to numerous models for FGFR dimerization and heralded one of the most controversial issues in FGF signaling. Recent crystallog. analyses have led to two fundamentally different models for FGFR dimerization. These models differ in both the stoichiometry and minimal length of heparin required for dimerization, the quaternary arrangement of FGF, FGFR and heparin in the dimer, and in the mechanism of 1:1 FGF-FGFR recognition and specificity. In this review, we provide an overview of recent structural and biochem. studies used to differentiate between the two crystallog. models. Interestingly, the structural and biophys. analyses of naturally occurring pathogenic FGFR mutations have provided the most compelling and unbiased evidences for the correct mechanisms for FGF-FGFR dimerization and binding specificity. The structural analyses of different FGF-FGFR complexes have also shed light on the intricate mechanisms detg. FGF-FGFR binding specificity and promiscuity and also provide a plausible explanation for the mol. basis of a large no. craniosynostosis mutations.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjvVOns7g%253D&md5=746ae413058ad52c77d77a553003746c
    56. 56
      Schlessinger, J.; Plotnikov, A. N.; Ibrahimi, O. A.; Eliseenkova, A. V.; Yeh, B. K.; Yayon, A.; Linhardt, R. J.; Mohammadi, M. Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization Mol. Cell 2000, 6 (3) 743– 50 DOI: 10.1016/S1097-2765(00)00073-3
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      56
      Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization
      Schlessinger, Joseph; Plotnikov, Alexander N.; Ibrahimi, Omar A.; Eliseenkova, Anna V.; Yeh, Brian K.; Yayon, Avner; Linhardt, Robert J.; Mohammadi, Moosa
      Molecular Cell (2000), 6 (3), 743-750CODEN: MOCEFL; ISSN:1097-2765. (Cell Press)
      The crystal structure of a dimeric 2:2:2 FGF:FGFR:heparin ternary complex at 3 Å resoln. has been detd. Within each 1:1 FGF:FGFR complex, heparin makes numerous contacts with both FGF and FGFR, thereby augmenting FGF-FGFR binding. Heparin also interacts with FGFR in the adjoining 1:1 FGF:FGFR complex to promote FGFR dimerization. The 6-O-sulfate group of heparin plays a pivotal role in mediating both interactions. The unexpected stoichiometry of heparin binding in the structure led the authors to propose a revised model for FGFR dimerization. Biochem. data in support of this model are also presented. This model provides a structural basis for FGFR activation by small mol. heparin analogs and may facilitate the design of heparin mimetics capable of modulating FGF signaling.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXntVyhsbg%253D&md5=0aaacc2d5377dba261ff8b3f080debf9
    57. 57
      Lin, Y. Y.; Qiao, Y.; Tang, P. F.; Li, Z. B.; Huang, J. B. Controllable self-assembled laminated nanoribbons from dipeptide-amphiphile bearing azobenzene moiety Soft Matter 2011, 7 (6) 2762– 2769 DOI: 10.1039/c0sm01050b
      [ Crossref], [ CAS], Google Scholar
      57
      Controllable self-assembled laminated nanoribbons from dipeptide-amphiphile bearing azobenzene moiety
      Lin, Yiyang; Qiao, Yan; Tang, Peifeng; Li, Zhibo; Huang, Jianbin
      Soft Matter (2011), 7 (6), 2762-2769CODEN: SMOABF; ISSN:1744-683X. (Royal Society of Chemistry)
      Artificial peptide self-assembly is an appealing research subject which has been demonstrated to be a reliable approach to create hierarchical nanostructures and biomaterials. In this paper, a dipeptide-amphiphile incorporated with an azobenzene moiety is synthesized, which are found to self-assemble into well-defined laminated nanoribbons as well as macroscopic hydrogel. The nanoribbons are formed by nanofibers aligning in nearly lamellar arrays. The driving force of dipeptide self-assembly is proposed to be a synergic effect of hydrophobic interaction, arom. packing, and hydrogen bond. The addn. of NaCl is found to promote hydrogelation and nanoribbon formation. Finally photoisomerization of the azobenzene group is utilized to rationally control dipeptide self-assembly and hydrogel formation by remote light input.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXivFSqu7s%253D&md5=a62efea6bdd1feae4999643334cac108
    58. 58
      Miravet, J. F.; Escuder, B.; Segarra-Maset, M. D.; Tena-Solsona, M.; Hamley, I. W.; Dehsorkhi, A.; Castelletto, V. Self-assembly of a peptide amphiphile: transition from nanotape fibrils to micelles Soft Matter 2013, 9 (13) 3558– 3564 DOI: 10.1039/c3sm27899a
      [ Crossref], [ CAS], Google Scholar
      58
      Self-assembly of a peptide amphiphile: transition from nanotape fibrils to micelles
      Miravet, Juan F.; Escuder, Beatriu; Segarra-Maset, Maria Dolores; Tena-Solsona, Marta; Hamley, Ian W.; Dehsorkhi, Ashkan; Castelletto, Valeria
      Soft Matter (2013), 9 (13), 3558-3564CODEN: SMOABF; ISSN:1744-683X. (Royal Society of Chemistry)
      A thermal transition is obsd. in the peptide amphiphile C16-KTTKS (TFA salt) from nanotapes at 20 °C to micelles at higher temp. (the transition temp. depending on concn.). The formation of extended nanotapes by the acetate salt of this peptide amphiphile, which incorporates a pentapeptide from type I procollagen, has been studied previously. Here, proton NMR and SAXS provide evidence for the TFA salt spherical micelles at high temp. The phase behavior, with a Krafft temp. sepg. insol. aggregates (extended nanotapes) at low temp. from the high temp. micellar phase resembles that for conventional surfactants, however this has not previously been reported for peptide amphiphiles.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsFGktLs%253D&md5=b630532dc18e507d260c2ab264c370b0
    59. 59
      Goetz, R.; Mohammadi, M. Exploring mechanisms of FGF signalling through the lens of structural biology Nat. Rev. Mol. Cell Biol. 2013, 14 (3) 166– 180 DOI: 10.1038/nrm3528
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      59
      Exploring mechanisms of FGF signalling through the lens of structural biology
      Goetz, Regina; Mohammadi, Moosa
      Nature Reviews Molecular Cell Biology (2013), 14 (3), 166-180CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
      A review. Fibroblast growth factors (FGFs) mediate a broad range of functions in both the developing and adult organism. The accumulated wealth of structural information on the FGF signaling pathway has begun to unveil the underlying mol. mechanisms that modulate this system to generate a myriad of distinct biol. outputs in development, tissue homeostasis and metab. At the ligand and receptor level, these mechanisms include alternative splicing of the ligand (FGF8 subfamily) and the receptor (FGFR1-FGFR3), ligand homodimerization (FGF9 subfamily), site-specific proteolytic cleavage of the ligand (FGF23), and interaction of the ligand and the receptor with heparan sulfate cofactor and Klotho co-receptor.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitlentr8%253D&md5=5dcac124dcc9f836f3e304bc081ef8f6
    60. 60
      Nowak, S. J.; Corces, V. G. Phosphorylation of histone H3: a balancing act between chromosome condensation and transcriptional activation Trends Genet. 2004, 20 (4) 214– 220 DOI: 10.1016/j.tig.2004.02.007
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      60
      Phosphorylation of histone H3: a balancing act between chromosome condensation and transcriptional activation
      Nowak, Scott J.; Corces, Victor G.
      Trends in Genetics (2004), 20 (4), 214-220CODEN: TRGEE2; ISSN:0168-9525. (Elsevier Science Ltd.)
      A review. In recent years, the covalent modification of histone tails has emerged as a crucial step in controlling the transcription of eukaryotic genes. Phosphorylation of the serine 10 residue of the N-terminal tail of histone H3 is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addn., this modification is important during interphase because it enables the transcription of an increasing no. of genes that are activated as a consequence of a variety of cell-signaling events. The location of the serine 10 residue in close proximity to other modifiable amino acids in the histone H3 tail enables the possibility of an interaction between phosphorylation of serine 10 and methylation and/or acetylation of lysine 9 and lysine 14. Finally, the finding that the histone H3.3 variant, which has a conserved N-terminal tail, can replace histone H3 at sites of active transcription, adds a new layer of complexity and possibilities to the regulation of transcription through changes in chromatin structure.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXisVGitbs%253D&md5=94633792527752aed6bd9388aafbf74e
    61. 61
      Esser, J. S.; Rahner, S.; Deckler, M.; Bode, C.; Patterson, C.; Moser, M. Fibroblast Growth Factor Signaling Pathway in Endothelial Cells Is Activated by BMPER to Promote Angiogenesis Arterioscler., Thromb., Vasc. Biol. 2015, 35 (2) 358– 367 DOI: 10.1161/ATVBAHA.114.304345
      [ Crossref], [ PubMed], [ CAS], Google Scholar
      61
      Fibroblast Growth Factor Signaling Pathway in Endothelial Cells Is Activated by BMPER to Promote Angiogenesis
      Esser, Jennifer S.; Rahner, Susanne; Deckler, Meike; Bode, Christoph; Patterson, Cam; Moser, Martin
      Arteriosclerosis, Thrombosis, and Vascular Biology (2015), 35 (2), 358-367CODEN: ATVBFA; ISSN:1079-5642. (Lippincott Williams & Wilkins)
      OBJECTIVE-: Previously, we have identified bone morphogenetic protein endothelial cell precursor-derived regulator (BMPER) to increase the angiogenic activity of endothelial cells in a concn.-dependent manner. In this project, we now investigate how BMPER acts in concert with key mols. of angiogenesis to promote blood vessel formation. APPROACH AND RESULTS-: To assess the effect of BMPER on angiogenesis-related signaling pathways, we performed an angiogenesis antibody array with BMPER-stimulated endothelial cells. We detected increased basic fibroblast growth factor (bFGF/FGF-2) expression after BMPER stimulation and decreased expression of thrombospondin-1. Addnl., FGF receptor-1 expression, phosphorylation, FGF signaling pathway activity, and cell survival were increased. Consistently, silencing of BMPER by small interfering RNA decreased bFGF and FGF receptor-1 expression and increased thrombospondin-1 expression and cell apoptosis. Next, we investigated the interaction of BMPER and the FGF signaling pathway in endothelial cell function. BMPER stimulation increased endothelial cell angiogenic activity in migration, Matrigel, and spheroid assays. To block FGF signaling, an anti-bFGF antibody was used, which effectively inhibited the proangiogenic BMPER effect. Accordingly, BMPER-silenced endothelial cells under bFGF stimulation showed decreased angiogenic activity compared with bFGF control. We confirmed these findings in vivo by s.c. Matrigel injections with and without bFGF in C57BL/6_Bmper mice. Aortic ring assays of C57BL/6_Bmper mice confirmed a specific effect for bFGF but not for vascular endothelial growth factor. CONCLUSIONS-: Taken together, the proangiogenic BMPER effect in endothelial cells is mediated by inhibition of antiangiogenic thrombospondin-1 and enhanced expression and activation of the FGF signaling pathway that is crucial in the promotion of angiogenesis.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFyru78%253D&md5=1825f856e76784dc918bea02bf94dab7

  • Supporting Information

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsbiomaterials.7b00347.

    • PA chemical structures and characterization as well as additional TEM and SEM micrographs, CD spectra, proliferation, and cell viability studies (PDF)

    Terms & Conditions

    Electronic Supporting Information files are available without a subscription to ACS Web Editions. The American Chemical Society holds a copyright ownership interest in any copyrightable Supporting Information. Files available from the ACS website may be downloaded for personal use only. Users are not otherwise permitted to reproduce, republish, redistribute, or sell any Supporting Information from the ACS website, either in whole or in part, in either machine-readable form or any other form without permission from the American Chemical Society. For permission to reproduce, republish and redistribute this material, requesters must process their own requests via the RightsLink permission system. Information about how to use the RightsLink permission system can be found at http://pubs.acs.org/page/copyright/permissions.html.

PDF [ 6MB]

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

STEP 1:
Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

OOPS

You have to login with your ACS ID befor you can login with your Mendeley account.

MENDELEY PAIRING EXPIRED
Your Mendeley pairing has expired. Please reconnect

This website uses cookies to improve your user experience. By continuing to use the site, you are accepting our use of cookies. Read the ACS privacy policy.

CONTINUE