TABLE 1.

Summary of peptide biomaterials.

Peptide name (sequence)	Polymer Used	Experimental	Results
Vascular endothelial growth factor (VEGF) (Jay and Zaltzman 2009)	Alginate microparticles crosslinked by CaCl2, ZnCl2, and SrCl2.	Development and synthesis of small alginate microparticles (<10 μm mean diameter) by using different ionic crosslinkers.	The cross-inked particles allowed the sustained release of bioactive VEGF and showed no toxicity in HUVECs
RGD peptide (Arginine-Glycine-Aspartic acid) (Chen et al., 2003)	Silk fibers	Modified silk matrices were prepared by covalent coupling of RGD peptides and compared to matrices without this coupling. An MTT assay was performed with BMSC and ACLF cell lines seeded on both matrices for 14 days.	Modification of silk fibroin fiber matrices with RGD-binding sites significantly enhanced attachment and spreading in BMSC/ACLF cells while no effect on cell proliferation was observed.
SDF1α (Shen et al., 2010)	Silk-collagen sponge	In 14 female rats weighing 200–220 g, a 6 mm portion of their Achilles tendon was removed from their left limb to implant the control scaffold (woven silk and collagen sponge + collagen gel containing PBS). The right limbs were implanted with a composite peptide scaffold (silk and collagen woven sponge + collagen gel containing SDF1α).	After 4 weeks, the SDF1α -treated tendon had increased expression of tendon repair genetic markers and endogenous SDF1α, exhibited more physiological microstructures with larger diameter collagen fibrils, and had better biomechanical properties than the control group.
CMPs KLD12:Ac-KLDLKLDLKLDL-NH2 KLD12-CMP7:Ac-KLDLKLDLKLDLGGPOGPOGPOGPOGPOGPOG-POG-NH2 (Kim et al., 2015)	Poly(l-lactide-co-caprolactone)	Hydrogel complexes were cultured in a chondrogenic medium and real-time PCR evaluation was performed to assess chondrogenic differentiation. Hydrogels were implanted into the subcutaneous dorsum of mice with in situ chondrogenesis and cartilage tissue formation analysis after 5 weeks.	CMP motifs were shown to significantly increase gene expression related to chondrogenic differentiation.
PPFLMLLKGSTR [(Li et al., 2017)] Motif sequence derived from laminin-5 α3 chain	Hyaluronic acid	A hyaluronic acid hydrogel scaffold was prepared by cross-linking with adipic dihydrazide while adding peptides using ethyl N,N-dimethylaminopropyl carbodiimide and CDI for use in spinal cord tissue restoration. The hydrogel was tested on MSCs to investigate cell viability, and SD female rats weighing 220–250 g were used for in vivo tests. The scaffolds were spinal cord-shaped, 1.5 mm thick, and a laminectomy was performed exposing the dorsal surface of the T9-10 segment.	The addition of peptide increased MSC spreading and growth while rat in vivo implantation of MSC containing HA-peptide hydrogels led to functional restoration of nerve tissue.
SDF1α (R y NR) (Muylaert et al., 2016)	Poly(l-lactide-co-caprolactone) functionalized with quadruple hydrogen bonding ureido-pyrimidinone (UPy) units	Eighteen male Sprague Dawley rats weighing between 350 and 450 g received an electrospun aortic interposition graft. Grafts were explanted on day 1 or day 7. Electrospun tubular scaffolds were engrafted in rat abdominal aortas and explanted for histological analysis after 24 h and 7 days.	Modification of poly(l-lactide-co-caprolactone) with UPy and SDF1α peptides helped retain and stimulate circulating cells to improve the cellularization of implanted vascular replacement grafts.
RGD and PQ: GGGPQGIWGQGK (Zhu et al., 2010)	Poly(ethylene glycol)	344SQ cells from KRasG12D/p53R172HΔG mice were encapsulated in hydrogels with varying concentrations of PEG-PQ [5%, 10% or 15% (w/v)] and PEG-RGDS (1, 3.5, or 7 mmol/L). Immunohistochemistry tests and quantitative RT-PC were performed to assess the response to TGF-β.	Cell-adhesive PEG-RGDs with an enzyme-degradable PEG-PQ backbone were able to induce MET in 344SQ cells to form lumenized polarized spheres and also repressed miR- 200 after TGF-β exposure with concomitant change in EMT marker gene expression.
YIGSR, RGD and REDV (Ahadian et al., 2014)	Silk fibroin scaffolds	Silk fibroin scaffolds were functionalized with peptides. Platelet adhesion and activation was assessed along with HUVEC adhesion, proliferation, and migration.	Scaffolds modified with dual peptides (YIGSR + RGD) significantly improved HUVEC proliferation and also had an increased effect on cell migration relative to scaffolds modified with only individual peptides.
RDG and GHK Ada-Ahx-GGRGD and Ada-Ahx-GGGHK (Shin et al., 2017)	Poly(hydroxyethyl methacrylate)	Cryogels were synthesized by vinyl addition polymerization in aqueous solution and functionalized with peptide and tested with PC-12 rat pheochromocytoma cells and NIH 3T3 mouse embryonic fibroblast cells.	Poly(hydroxyethyl methacrylate) synthetic cryogels functionalized with peptides provided a controllable/stable charge and high specific activity in the tested cell lines in addition to showing a synergistic effect on cell proliferation in 3T3 and PC-12 cells.
OH-CATH30 (OH30) (Essa et al., 2020)	Carboxymethyl chitosan nanoparticles	Nanoparticles were synthesized from carboxymethyl chitosan and loaded with CATH30 antimicrobial peptides. OH30 release behavior of nanoparticles in simulated wound fluid (SWF) was assessed along with antibacterial activity. Cell migration assays were performed on the HaCaT cell line. Evaluation and measurement of wound healing was carried out in female mice of 6 weeks of age and average weight 20–25 g. Injured with a skin biopsy punch (ID = 7 mm).	Wound healing in the OH-CATH30 group was significantly accelerated compared to the administration of CMCS or OH30 alone. Expression of anti-inflammatory cytokines was increased along with an improvement in cell migration. No effects on keratinocyte metabolism and proliferation were observed.
GRGDYP, GRGDSP KHIFSDDSSE (Almany and Seliktar, 2005)	Alginate	Peptide-coupled calcium alginate hydrogels were synthesized by partial oxidation with periodate followed by reductive amination. Adhesion tests were performed on C2C12-type mouse skeletal myoblast cells and human dental (RP89) stem cells.	While C2C12 myoblasts adhered to both functionalized and control gels, RP89 cells only adhered to alginate gels with the highest concentrations of peptide.
RGD (phenol2-poly(ethylene glycol)-RGD) (Almany and Seliktar, 2005)	Hyaluronic acid-tyramine	Horseradish peroxidase and hydrogen peroxide were used to simultaneously crosslink the HA gel and incorporate phenol-containing peptides. The gel was subcutaneously injected in a 6- to 9-week-old mouse model along with HUVECs and human fibroblasts.	HUVECs cultured on or within the RGD-modified hydrogels showed adhesion behavior that led to enhanced cell proliferation, migration, and formation of a capillary-like network. When HUVECs and human fibroblasts (HFF1) were encapsulated together in the RGD-modified hydrogel, functional vasculature was demonstrated within the cell-laden gel after 2 weeks in subcutaneous tissue.
YIGSR QK: VEGF (Song et al., 2019)	Poly(ethylene glycol) and gelatin	Poly(ethylene glycol) and gelatin hydrogels were functionalized with peptides and tested on human umbilical vein endothelial cells containing 2% fetal bovine protein (FBS) and growth factors with the exception of serum VEGF. VEGFR2/KDR phosphorylation, gene expression and immunofluorescence assays were carried out.	The inclusion of QK, a VEGF-mimetic peptide, led to a strong biological response to in vitro gels in HUVEC cells, as measured by an increase in phosphorylated VEGFR2 and a change in cell morphology.
CGGRGDS (Gentsch et al., 2011)	Poly(lactide-co-glycolide)	The synthesis of nanofiber meshes was carried out in a one-step process resulting in surface biofunctionalization with peptide segments. The fiber surface was assayed with photoelectron spectroscopy (XPS) and adhesion data were collected by mapping forces at the apex of fibers on a grid. L929 murine fluorescent renal fibroblasts were used for adhesion and migration tests.	Bioavailability and bioactivity of peptides on fiber surfaces was demonstrated, resulting in meshes promoting increased fibroblast adhesion and migration compared to pure PLGA meshes.
Peptide amphiphiles (PAs) YIGSR KKKKK MMP-2-sensitive sequences GTAGLIGQ (Bhatt et al., 2013)	Polycaprolactone	Polycaprolactone nanofibers were electrospun along with peptide amphiphiles. SEM and TEM were used to characterize the morphology of the nanofibers and confirm the coating of PA on the surface of the ePCL nanofibers. Nanofibers were tested on HUVECs and human aortic smooth muscle cells (AoSMC) to assess cellular adhesion and proliferation.	The hybrid nanomatrix of self-assembling PA-coated ePCL nanofibers provided stimulative mechanical strength and topographic structure, promoting endothelial cell-specific increased adhesion and proliferation while limiting smooth muscle cell proliferation.
Derived from the laminin B1: TS(CDPGYIGSRAS)8 Derived from fibronectin: TS(CDPGYIGSRAS)8 and (TGRGDSPAS)8 (Gouveia et al., 2014)	Silk fibroin	Tests of resistance to breakage of WT and recombinant silk fibers were carried out along with an in vivo long-term safety evaluation where four sponges of 5 mm in diameter and 2.5 mm in thickness were implanted in the paravertebral muscle in male SD rats with a body weight of 200–280 g and 8 weeks of age. Cell adhesion migration assays were performed on Balb/c 3T3 mouse fibroblasts.	Recombinant silk fibroin films incorporating only the L- or H-chain-independent TS sequence (CDPGYIGSRAS)8 showing significantly increased adhesive activities in mouse endothelial and smooth muscle cells in addition to high migration activities of endothelial cells.
Angiopoietin-1 derived peptide: QHREDGS (Reis et al., 2012)	Chitosan-collagen	Conjugation of QHREDGS to chitosan was carried out using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDC) chemistry, then an evaluation of peptide conjugation efficiency was made. Subsequently, the chitosan and collagen hydrogel was synthesized and SEM, degradation, and rheological tests were carried out. An MI mouse model was used in adult male C57 Black-6 mice.	Subcutaneous injection of peptide-functionalized hydrogel in rats had the ability to localize to the injection site and retain cells, with CM contractile apparatus identified after 7 days.
Laminin peptide (YIGSR) (Itoh et al. 2005)	Chitosan and Hydroxyapatite	Chitosan tubes from crab tendon coated with hydroxyapatite were functionalized with YIGSR peptide. In male Sprague-Dawley (SD) rats weighing 180 g, the right sciatic nerve of each rat was exposed and a 10 mm long section was excised. The synthesized tube was grafted onto the nerve and electrophysiological and histological evaluations were carried out.	YIGSR-conjugated tube transplantation resulted in regenerated nerve tissue attached to thin layers of epineurium-like structure formed on the surface of the inner tube, enhancing axonal nerve regeneration and promoting proximal nerve stump and bridge sprouting.
Laminin peptide AG73: RKR-LQVQLSIRT (Monteiro et al., 2015)	Chitosan	The preparation of a chitosan membrane was carried out with the peptide CGGRKRLQVQLSIRT. Human newborn foreskin keratinocytes were used for adhesion and propagation tests. In 8-week-old 22–26 g BALB/c Slc-nu male nude mice, the fasciae of the abdominal muscles was exposed and an AG73 chitosan membrane was placed.	The AG73 peptide-conjugated chitosan membrane promotes cell adhesion and propagation in vitro, with 80% of human keratinocytes adhering to membranes within 2 h. In vivo, application of the membrane established a stratified epidermis-like structure in the fascia.
Polyglutamate (p(Glu)) Polylysine (p(Lys)) (Eckhart et al., 2019)	Graphene oxide	Synthesis of NCA monomers was carried out to carry out the electrophilic synthesis of CG (ECG), later the synthesis of the peptides was carried out by means of encapping. Subsequently, dispersions of CG and p(Lys)long–G (0.5 mg mL−1 in deionized water) were prepared and their pH was adjusted. Cell culture was carried out on PCL12 cells, a cell line that was isolated from a rat pheochromocytoma.	Functionalization of graphene oxide with conductive and biocompatible peptides was carried out to make three-dimensional mechanically robust constructions. The conductivity and bioactivity of these Pep-G materials was demonstrated by electrically stimulated PC12 cells cultured on a p(Lys) long-G pellet showing enhanced neurite adhesion and growth.
VEGF15: Ac-KVKFMDVYQRSYCHP-amide QK: Ac-KLTWQELYQLKYKGI-amide (Leslie-Barbick et al., 2011)	Poly(ethylene glycol)	The synthesis of hydrogels based on polyethylene glycol was carried out by preparing and purifying different combinations of this material with the peptides QK, RGDS and VGEF. The bioactivity assay was carried out in human umbilical vein endothelial cells and finally the in vivo assay was performed in Flk1-myr::mCherry transgenic mice.	In response to the QK-peptide functionalized hydrogel, endothelial cells formed tubule structures and established cellular connections. In vivo results showed a more complete coverage of the host microvasculature within the hydrogel, as well as improvement in the points of contact, branching, and density of blood vessels.
OA-GL12 GLLSGINAEWPC (Kumbar et al., 2008)	Not applicable	Peptides were synthesized through Fmoc-SPPS and tested in keratinocytes (HaCaT), human skin fibroblasts (HSF), human umbilical vein endothelial cells (HUVEC), and murine macrophages. In adult male mice weighing 22–25 g, full-thickness skin wound models were made after 7 days of acclimatization.	Peptide treatment resulted in an improvement in wound healing. The secretion of tumor necrosis factor (TNF) and transforming growth factor β1 (TGF-β1) in the murine macrophage cell line was decreased. Histological analysis indicated that mice treated with OA-GL12 (10 nM) displayed increased regeneration of neo-epidermis and restoration of the dermis.