Self-assembling Peptide Hydrogels Research Articles

Using UV-Responsive Nanoparticles to Provide In Situ Control of Growth Factor Delivery and a More Constant Release Profile from a Hydrogel Environment.

Nanoparticles are popular delivery vehicles, but their diffusional release results in inconstant drug delivery. Here, we flatten the delivery profile into a more constant, zero-order profile. Brain-derived neurotrophic factor (BDNF) is attached to photoactive titanium dioxide nanoparticles and loaded into a nanofibrous self-assembling peptide (SAP) hydrogel. Different UV exposure conditions show three distinct profiles, including a counterintuitive decrease in release after UV exposure. We propose that the adsorption of the freed growth factor onto the hydrogel nanofibers affects release. Nanoparticles diffuse from the hydrogel readily, carrying the bound growth factor, but the freed growth factor (released from the nanoparticles by UV) instead interacts with─and is released less readily from─the hydrogel. UV shifts growth factor from nanoparticles to the hydrogel, therefore changing the diffusional release. Through midpoint UV exposure, we achieve a flattened delivery profile─unusual for diffusion─by changing in situ the amount of growth factor bound to the diffusing nanoparticles. With nanoparticle diffusion alone, we observed an increasing release profile with 36% of release in the first 6 h and 64% in the second 6 h. With midway UV exposure, this was controlled to 49 and 51%, respectively. The release of an unbound (soluble) control growth factor, glial cell-line derived neurotrophic factor (GDNF), was not affected by UV treatment, demonstrating the potential for independent control of temporal delivery profiles in a multiagent material.

Acidic and basic self-assembling peptide and peptide-graphene oxide hydrogels: characterisation and effect on encapsulated nucleus pulposus cells

Extracellular pH can have a profound effect on cell metabolism, gene and protein expression. Nucleus pulposus (NP) cells, for example, under acidic conditions accelerate the production of degradative enzymes and pro-inflammatory cytokines, leading ultimately to intervertebral disc degeneration, a major cause of back pain. Self-assembling peptide hydrogels constitute a well-established class of biomaterials that could be exploited as pH-tunable platform to investigate cell behaviour under normal and non-physiological pH. In this paper we formulated acidic (pH = 4) and basic (pH = 9) hydrogels, from the same octapeptide FEFKFEFK (F8) (F = phenyalanine, E = glutamic acid, K = lysine), to test the effect of non-physiological pH on encapsulated NP cells. Similarly, graphene oxide-containing F8 hydrogels (GO-F8) were formulated as stiffer analogues. Acidic and basic hydrogels showed peculiar morphologies and rheological properties, with all systems able to buffer within 30 minutes of exposure to cell culture media. NP cells seeded in acidic F8 hydrogels showed a more catabolic phenotype compared to basic hydrogels, with increased gene expression of degradative enzymes (MMP-3, ADAMTS-4), neurotrophic factors (NGF and BDNF) and NF-κB p65 phosphorylation. Acidic GO-F8 hydrogels also induced a catabolic response, although milder than basic counterparts and with the highest gene expression of characteristic NP-matrix components, aggrecan and collagen II. In all systems, the cellular response had a peak within 3 days of encapsulation, thereafter decreasing over 7 days, suggesting a ‘transitory’ effect of hydrogel pH on encapsulated cells. This work gives an insight on the effect of pH (and pH buffering) on encapsulated NP cells and offers new designs of low and high pH peptide hydrogels for 3D cell culture studies. Statement of significanceWe have recently shown the potential of graphene oxide - self-assembling peptide hybrid hydrogels for NP cell culture and regeneration. Alongside cell carrier, self-assembling peptide hydrogels actually provide a versatile pH-tunable platform for biological studies. In this work we decided to explore the effect of non-physiological pH (and pH buffering) on encapsulated NP cells. Our approach allows the formulation of both acidic and basic hydrogels, starting from the same peptide sequence. We showed that the initial pH of the scaffold does not affect significantly cell response to encapsulation, but the presence of GO results in lower inflammatory levels and higher NP matrix protein production. This platform could be exploited to study the effect of pH on different cell types whose behaviour can be pH-dependent.

Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review

Background: In many cases, central nervous system (CNS) injury is unchanging due to the absence of neuronal regeneration and repair capabilities. In recent years, regenerative medicine, and especially hydrogels, has reached a significant amount of attention for their promising results for the treatment of spinal cord injury (SCI) currently considered permanent. Hydrogels are categorized based on their foundation: synthetic, natural, and combination. The objective of this study was to compare the properties and efficacy of commonly used hydrogels, like collagen, and other natural peptides with synthetic self-assembling peptide hydrogels in the treatment of SCI. Methods: Articles were searched in PubMed, Scopus, Web of Science, and Embase. All studies from 1985 until January 2020 were included in the primary search. Eligible articles were included based on the following criteria: administering hydrogels (both natural and synthetic) for SCI treatment, solely focusing on spinal cord injury treatment, and published in a peer-reviewed journal. Data on axonal regeneration, revascularization, elasticity, drug delivery efficacy, and porosity were extracted. Results: A total of 24 articles were included for full-text review and data extraction. There was only one experimental study comparing collagen I (natural hydrogel) and polyethylene glycol (PEG) in an in vitro setting. The included study suggested the behavior of cells with PEG is more expectable in the injury site, which makes it a more reliable scaffold for neurites. Conclusions: There is limited research comparing and evaluating both types of natural and self-assembling peptides (SAPs) in the same animal or in vitro study, despite its importance. Although we assume that the remodeling of natural scaffolds may lead to a stable hydrogel, there was not a definitive conclusion that synthetic hydrogels are more beneficial than natural hydrogels in neuronal regeneration.

Magnetic alignment of injectable hydrogel scaffolds for spinal cord injury repair.

Injectable hydrogels for cell delivery and tissue regeneration have several advantages over pre-fabricated scaffolds that require more invasive transplantation procedures, but lack the ability to implement tunable topologies. Here, we describe an approach to create patternable and injectable scaffolds using magnetically-responsive (MR) self-assembling peptide hydrogels, and validate their efficacy to promote and align axon infiltration at the site of a spinal cord injury. In vitro experiments reveal the parameters needed to align the fibers using the application of an external magnetic field. These results indicate that applying a 100-Gauss (G) field to the peptide hydrogels during polymerization causes fiber alignment as measured by electron microscopy, even in the presence of cells. In order to mimic infiltrating axons, neural progenitor cells (NPCs) are seeded on the surface of peptide hydrogels to interrogate the effects of both magnetic alignment and embedding human mesenchymal stem cells (hMSCs) in the scaffold. NPCs infiltrate peptide hydrogels seeded with hMSCs, and exhibit increased alignment and elongation in aligned gels. In order to evaluate these injectable and patternable scaffolds in vivo, hMSC-seeded peptide hydrogels are injected at the site of a contusion spinal cord injury with and without the presence of a magnetic field to align the resulting fibrous network. Measurements of axon growth and orientation as well as inflammation and glial scar formation indicate that these metrics are improved in magnetically aligned hMSC-seeded hydrogels. The results verify that MR hydrogels can dictate the orientation of infiltrating axons, providing a viable means to control the topology of injectable scaffolds.

Antibacterial hydrogels of aromatic tripeptides.

Self-assembled peptide hydrogels have emerged as alternatives to the conventional approaches employed in controlled drug release, wound-healing, and drug delivery, and as anti-infective agents. However, peptide hydrogels possessing antibacterial properties are less explored. In this work, we have designed three ultrashort antibacterial peptide hydrogels: Fmoc-FFH-CONH2, Fmoc-FHF-CONH2, and Fmoc-HFF-CONH2. The rheological study showed the higher storage modulus of Fmoc-FFH-CONH2 (30.43 kPa) compared to Fmoc-FHF-CONH2 and Fmoc-HFF-CONH2, which may be attributed to the enhanced aromatic interaction in Fmoc-FFH-CONH2 compared to the other two variants, resulting in more mechanical rigidity. Further, the prepared hydrogels were evaluated for their inherent antibacterial potency against Gram-positive (Staphylococcus aureus, strain MTCC 96) and Gram-negative (Pseudomonas aeruginosa, strain PA01) bacteria. Antibacterial experiments demonstrated the potency of the hydrogels in the order of Fmoc-FFH-CONH2 > Fmoc-FHF-CONH2 > Fmoc-HFF-CONH2. The antibacterial effect of the hydrogels was predominantly due to the osmotic stress and membrane disruption, which was verified by reactive oxygen species (ROS) generation and outer membrane permeabilization assays. Our findings point to the scope of using the synthesized peptide hydrogels as agents for topical applications.

Functionalized self-assembling peptide RADKPS hydrogels promote regenerative repair of degenerated intervertebral discs.

Objective: the aim of this study was to investigate whether the functionalized self-assembling peptide hydrogel RADKPS is safe and effective for regenerative repair of degenerative intervertebral discs. Methods: an in vitro degenerative model of human nucleus pulposus cells was constructed by serum starvation culture, and their proliferation, apoptosis and viability were examined after three-dimensional culture with the RADKPS hydrogel. An in vivo degenerative model of the rabbit intervertebral disc was constructed by annulus fibrosus puncture, and the degeneration of the intervertebral disc was evaluated by imaging, histology, immunohistochemistry, and biomechanics after RADKPS hydrogel intervention. Results: through in vitro cell experiments it is shown that human degenerated nucleus pulposus cells after three-dimensional culture with the RADKPS hydrogel still exhibited better proliferation, viability, and low apoptosis rate. Through in vivo animal experiments we found that rabbit degenerated intervertebral discs intervened with the RADKPS hydrogel had higher water content, better histological morphology, more extracellular matrix synthesis, and better biomechanical properties. It is demonstrated that the RADKPS hydrogel may initiate the endogenous repair process through the sustained recruitment and enrichment of nucleus pulposus progenitor cells. Conclusion: it is verified from both in vitro cellular experiments and in vivo animal experiments that the regenerative repair effect of RADKPS, a functionalized self-assembling peptide hydrogel, on degenerated intervertebral discs is safe and effective. It is shown that it would be a new therapeutic approach for the regenerative repair action of intervertebral discs.

A self-assembled peptide hydrogel for wound repair

A self-assembled peptide hydrogel for wound repair

Injectable and pH-responsive self-assembled peptide hydrogel for promoted tumor cell uptake and enhanced cancer chemotherapy.

Chemotherapy is the main treatment for cancer therapy. However, its anti-tumor efficiency is always impaired by the poor bioavailability and low tumor accumulation of chemotherapeutic drugs. The variation between the tumor microenvironment and normal tissue has been recognized as an effective tool to improve drug anti-tumor efficiency. Herein, we developed an injectable, pH-responsive, in situ self-assembled drug-peptide hydrogel (MTX-KKFKFEFEF(DA)) for highly efficient local tumor chemotherapy with few side effects. The small molecule drug, methotrexate (MTX), and pH-responsive linker, 2,3-dimethylmaleic anhydride (DA), were facilely conjugated onto the chain of the KKFKFEFEF peptide via an amidation reaction. The negatively charged drug-peptide (pH 7.4) can be activated to be positive and achieve a sol-gel phase transition under an acidic microenvironment (pH 6.5) both in vitro and in vivo, resulting in highly efficient cellular uptake and endocytosis capacities. Moreover, the in vivo anti-tumor therapeutic effect revealed that the MTX-KKFKFEFEF(DA) hydrogel exhibits long-term tumor retention time, much better tumor inhibition rate and negligible side effects after intratumoral injection into breast tumor-bearing mice. Therefore, this study reveals a versatile strategy for fabricating a pH-responsive drug-peptide hydrogel to improve the chemotherapeutic efficacy of drugs in cancer treatment.

A Hyaluronic Acid Demilune Scaffold and Polypyrrole-Coated Fibers Carrying Embedded Human Neural Precursor Cells and Curcumin for Surface Capping of Spinal Cord Injuries.

Tissue engineering, including cell transplantation and the application of biomaterials and bioactive molecules, represents a promising approach for regeneration following spinal cord injury (SCI). We designed a combinatorial tissue-engineered approach for the minimally invasive treatment of SCI—a hyaluronic acid (HA)-based scaffold containing polypyrrole-coated fibers (PPY) combined with the RAD16-I self-assembling peptide hydrogel (Corning® PuraMatrix™ peptide hydrogel (PM)), human induced neural progenitor cells (iNPCs), and a nanoconjugated form of curcumin (CURC). In vitro cultures demonstrated that PM preserves iNPC viability and the addition of CURC reduces apoptosis and enhances the outgrowth of Nestin-positive neurites from iNPCs, compared to non-embedded iNPCs. The treatment of spinal cord organotypic cultures also demonstrated that CURC enhances cell migration and prompts a neuron-like morphology of embedded iNPCs implanted over the tissue slices. Following sub-acute SCI by traumatic contusion in rats, the implantation of PM-embedded iNPCs and CURC with PPY fibers supported a significant increase in neuro-preservation (as measured by greater βIII-tubulin staining of neuronal fibers) and decrease in the injured area (as measured by the lack of GFAP staining). This combination therapy also restricted platelet-derived growth factor expression, indicating a reduction in fibrotic pericyte invasion. Overall, these findings support PM-embedded iNPCs with CURC placed within an HA demilune scaffold containing PPY fibers as a minimally invasive combination-based alternative to cell transplantation alone.

IPSC-derived cranial neural crest-like cells can replicate dental pulp tissue with the aid of angiogenic hydrogel

The dental pulp has irreplaceable roles in maintaining healthy teeth and its regeneration is a primary aim of regenerative endodontics. This study aimed to replicate the characteristics of dental pulp tissue by using cranial neural crest (CNC)-like cells (CNCLCs); these cells were generated by modifying several steps of a previously established method for deriving NC-like cells from induced pluripotent stem cells (iPSCs). CNC is the anterior region of the neural crest in vertebrate embryos, which contains the primordium of dental pulp cells or odontoblasts. The produced CNCLCs showed approximately 2.5–12,000-fold upregulations of major CNC marker genes. Furthermore, the CNCLCs exhibited remarkable odontoblastic differentiation ability, especially when treated with a combination of the fibroblast growth factors (FGFs) FGF4 and FGF9. The FGFs induced odontoblast marker genes by 1.7–5.0-fold, as compared to bone morphogenetic protein 4 (BMP4) treatment. In a mouse subcutaneous implant model, the CNCLCs briefly fated with FGF4 + FGF9 replicated dental pulp tissue characteristics, such as harboring odontoblast-like cells, a dentin-like layer, and vast neovascularization, induced by the angiogenic self-assembling peptide hydrogel (SAPH), SLan. SLan acts as a versatile biocompatible scaffold in the canal space. This study demonstrated a successful collaboration between regenerative medicine and SAPH technology.

Life Sciences Discovery and Technology Highlights

Life Sciences Discovery and Technology Highlights

Efficient protein incorporation and release by a jigsaw-shaped self-assembling peptide hydrogel for injured brain regeneration

During injured tissue regeneration, the extracellular matrix plays a key role in controlling and coordinating various cellular events by binding and releasing secreted proteins in addition to promoting cell adhesion. Herein, we develop a cell-adhesive fiber-forming peptide that mimics the jigsaw-shaped hydrophobic surface in the dovetail-packing motif of glycophorin A as an artificial extracellular matrix for regenerative therapy. We show that the jigsaw-shaped self-assembling peptide forms several-micrometer-long supramolecular nanofibers through a helix-to-strand transition to afford a hydrogel under physiological conditions and disperses homogeneously in the hydrogel. The molecular- and macro-scale supramolecular properties of the jigsaw-shaped self-assembling peptide hydrogel allow efficient incorporation and sustained release of vascular endothelial growth factor, and demonstrate cell transplantation-free regenerative therapeutic effects in a subacute-chronic phase mouse stroke model. This research highlights a therapeutic strategy for injured tissue regeneration using the jigsaw-shaped self-assembling peptide supramolecular hydrogel.

Novel self-assembling peptide hydrogel with pH-tunable assembly microstructure, gel mechanics and the entrapment of curcumin

Insight is provided into the mechanism of peptide gelation, a self-assembled process of particular interest, due to its wide existence in natural events and broad applications in food and biomaterials field, but hard to control as minor alterations in the peptide sequence. Here, we design a family of pentapeptides and control their self-assembly behaviors, from micro- and nanoparticles to nanofibers and hydrogels. Furthermore, based on the thermodynamics, the gelation kinetics and the ionization status of terminal groups, the peptide assembly goes through five stages as varying the pH value and the assembly structures are highly dependent on the charging status of the terminal groups. The gelation rules of these peptides are further investigated. Besides, we also load hydrophobic functional molecule (curcumin) into different self-assembly nanostructures with high encapsulation efficiency and remarkable thermal and light protection on curcumin. These peptides assemblies with tunable structures, encapsulation ability and photothermal stabilization could become promising candidates for hydrophobic function factor delivery in food industry.

Efficacy and histopathological effects of self-assembling peptides RADA16 and IEIK13 in neurosurgical hemostasis

There is a continued need for effective hemostatic agents that are safe for neurosurgical use. Self-assembling peptide hydrogels have been suggested as novel hemostatic agents. They offer some advantages for neurosurgical hemostasis (e.g., transparency), but their efficacy and safety for neurosurgery have not been established. In this paper, the efficacy and safety of two self-assembling peptides, RADA16 and IEIK13, are explored for hemostasis of oozing bleeding on the rat cerebral cortex (n = 56). Chronic safety was evaluated by neuropathological evaluation at one, four, and twelve weeks after craniotomy (n = 32). An inactive control and oxidized cellulose served as comparators. Mean time-to-hemostasis was significantly shorter for RADA16 and IEIK13 compared to controls, while safety evaluation yielded similar results. Histopathological response consisted primarily of macrophage infiltration at the lesion site in all groups. This study confirms the hemostatic potential and safety of RADA16 and IEIK13 for hemostasis in the rat brain.

Short and simple peptide-based pH-sensitive hydrogel for antitumor drug delivery

Since self-assembled peptide hydrogels can solve the problems such as low solubility, poor selectivity and serious adverse effects of traditional chemotherapy drugs, they have been widely used as carrier materials for drug delivery. In this study, we developed a novel and injectable drug delivery platform for the antitumor drug doxorubicin (DOX) using a pH-responsive ionic-complementary octapeptide FOE. This octapeptide could self-assemble into stable hydrogel under neutral conditions, while disassemble under the tumor microenvironment. Especially, at pH 5.8, its micromorphology displayed a transition from nanofibers to nanospheres with the change of secondary structure, which enhanced cellular uptake of DOX. In addition, FOE hydrogel serves as a smart drug reservoir by localized injection to achieve sustained drug release and improve antitumor efficacy. This octapeptide opens up new avenues for promoting the clinical translation of anticancer drugs on account of excellent injectable properties and economic benefits of simple and short sequence.

Multicomponent Peptide Hydrogels as an Innovative Platform for Cell-Based Tissue Engineering in the Dental Pulp.

In light of the increasing levels of antibiotic resistance, nanomaterials and novel biologics are urgently required to manage bacterial infections. To date, commercially available self-assembling peptide hydrogels have not been studied extensively for their ability to inhibit micro-organisms relevant to tissue engineering sites such as dental root canals. In this work, we assess the biocompatibility of dental pulp stem/stromal cells with commercially available multicomponent peptide hydrogels. We also determine the effects of dental pulp stem/stromal cell (DPSC) culture in hydrogels on growth factor/cytokine expression. Furthermore, to investigate novel aspects of self-assembling peptide hydrogels, we determine their antimicrobial activity against the oral pathogens Staphylococcus aureus, Enterococcus faecalis, and Fusobacterium nucleatum. We show that self-assembling peptide hydrogels and hydrogels functionalized with the adhesion motif Arg-Gly-Asp (RGD) are biocompatible with DPSCs, and that cells grown in 3D hydrogel cultures produce a discrete secretome compared with 2D-cultured cells. Furthermore, we show that soluble peptides and assembled hydrogels have antimicrobial effects against oral pathogens. Given their antibacterial activity against oral pathogens, biocompatibility with dental pulp stem/stromal cells and enhancement of an angiogenic secretome, multicomponent peptide hydrogels hold promise for translational use.

Repair of Peripheral Nerve Injury Using Hydrogels Based on Self-Assembled Peptides.

Peripheral nerve injury often occurs in young adults and is characterized by complex regeneration mechanisms, poor prognosis, and slow recovery, which not only creates psychological obstacles for the patients but also causes a significant burden on society, making it a fundamental problem in clinical medicine. Various steps are needed to promote regeneration of the peripheral nerve. As a bioremediation material, self-assembled peptide (SAP) hydrogels have attracted international attention. They can not only be designed with different characteristics but also be applied in the repair of peripheral nerve injury by promoting cell proliferation or drug-loaded sustained release. SAP hydrogels are widely used in tissue engineering and have become the focus of research. They have extensive application prospects and are of great potential biological value. In this paper, the application of SAP hydrogel in peripheral nerve injury repair is reviewed, and the latest progress in peptide composites and fabrication techniques are discussed.

Paracrine study of adipose tissue-derived mesenchymal stem cells (ADMSCs) in a self-assembling nano-polypeptide hydrogel environment

Abstract To research the paracrine role of adipose tissue-derived mesenchymal stem cells (ADMSCs) in promoting angiogenesis under the three-dimensional culture conditions consisting of a functionalized self-assembling peptide nanofiber hydrogel. ADMSCs were isolated, extracted, and then identified. Three kinds of peptides (RADAI-16, RGD, and KLT) were prepared, and a functionalized self-assembling peptide nanofiber hydrogel was produced by mixing RADAI-16, RGD, and KLT in a volume ratio 2:1:1. AFM was used to observe RADAI-16, RGD, KLT, and the functionalized self-assembling peptide nanofiber hydrogel. Then, ADMSCs were cultured under three-dimensional conditions consisting of the peptide nanofiber hydrogel, and AFM was used to observe cell migration. The ADMSCs in the common culture group (37°C, 5% CO2 cell culture box) and hypoxic culture group (37°C, 10% CO2, and 1% O2 hypoxic culture box) acted as controls. ADMSCs were three-dimensionally cultured in situ for 1 day, and then the concentrations of HGF and VEGF in the supernatant were determined by ELISA. Cells were extracted from the peptide nanofiber hydrogel, and HO-1 expression was detected by western blotting. ADMSCs have high expression levels of CD29, CD90, and CDl05 and low expression levels of CD34 and CD45. In addition, they can differentiate into adipocytes and osteocytes. The diameters of the fibers of RADAI-16, RGD, KLT, and the functionalized self-assembling peptide hydrogel are 17.34 ± 1.82, 15.50 ± 1.41, 13.77 ± 1.18, and 20.26 ± 1.25 nm, respectively. AFM indicated that cells in the functionalized self-assembling peptide nanofiber hydrogel migrated farther than those in RADAI-16. The concentrations of HGF under common, hypoxic, and three-dimensional culture conditions were 47.31 ± 6.75, 247.86 ± 17.59, and 297.25 ± 17.95 pg/mL, respectively, while the concentrations of VEGF were 218.30 ± 3.03, 267.13 ± 4.27, and 289.14 ± 3.11 pg/mL, respectively. Both HGF and VEGF were expressed more in the presence of the functionalized self-assembling peptide nanofiber hydrogel than in its absence (P < 0.05). Using western blotting, ADMSCs cultured under hypoxic and three-dimensional conditions were found to have high expression levels of HO-1. Culturing ADMSCs under three-dimensional conditions consisting of functionalized self-assembling peptide nanofiber hydrogels can promote their paracrine role in angiogenesis, such as HGF and VEGF, and hypoxia is one of the important elements.

A Bionic Nano-Band-Aid Constructed by the Three-Stage Self-Assembly of Peptides for Rapid Liver Hemostasis.

Critical challenges remain in trauma emergency and surgical procedures involving liver bleeding, particularly in perforating wounds that cannot be pressed and large wounds that cannot be sewn. Self-assembling peptide hydrogels are particularly attractive due to their intrinsic biocompatibility and programmability. Herein, we develop a nano-band-aid (NBA) through a three-stage self-assembly strategy of two functionalized peptides, which were first coassembled into nanofibers and then woven to a meshlike network driven by Ca2+. Then, catalyzed by blood coagulation factor XIIIa (FXIIIa), NBA underwent a third stage, self-assembly into a densely compacted physical barrier to stop and control the bleeding. As expected, NBA rapidly and efficiently stopped the bleeding in rat liver scratches while effectively reducing the inflammation around the wound and promoting the wound healing. This bionic self-assembly strategy will provide a clinically potential peptide-based treatment for fatal liver bleeding and reinvigorate efforts to develop self-assembling peptide hydrogels as hemostatic agents.

Injectable self-assembling peptide nanofiber hydrogel as a bioactive 3D platform to promote chronic wound tissue regeneration

Chronic wounds remain a worldwide clinical challenge, and bioactive materials that can promote skin regeneration are required. Self-assembling peptide (SAP) hydrogels have shown great potential in tissue repair, but their regenerative efficacy and possible mechanism in chronic wound healing are unclear. Here, we report an SAP (KGH) that enhances extracellular matrix (ECM) remodeling and angiogenesis, thereby promoting chronic wound healing in diabetic mice. In vivo, the KGH hydrogel was retained in wounds up to 7 days after injection, and it was effective in speeding up wound closure by ∼20% compared to the control groups and enhancing angiogenesis (e.g., VEGFA, CD31+ capillaries), cell proliferation (e.g., PCNA+ cells), formation of granulation tissue (e.g., α-SMA), and ECM deposition/remodeling (e.g., collagen I, fibronectin). In vitro, the KGH hydrogel created a 3D microenvironment for skin cells, maintained the sustained growth of cell spheroids, and increased the secretion of ECM proteins (e.g., laminin) and growth factors (e.g., PDGFB, VEGFA, and TGF-β) in skin keratinocytes compared to the conventional 2D culture. Mechanistically, the KGH hydrogel might promote wound tissue regeneration by activating the Rho/ROCK and TGF-β/MEK/MAPK pathways. As a type of designed material, SAP can be further re-engineered with biological motifs, therapeutic reagents, or stem cells to enhance skin regeneration. This study highlights that SAP hydrogels are a promising material platform for advanced chronic wound healing and might have translational potential in future clinical applications. Statement of significanceChronic wounds are a common and serious health issue worldwide, and bioactive dressing materials are required to address this issue. SAP hydrogels have shown certain tissue repair potential, but their regenerative efficacy and underlying mechanism in chronic wound healing remain elusive. Herein, we report that SAP hydrogels create a native 3D microenvironment that can remarkably stimulate angiogenesis and ECM remodeling in diabetic wounds. Mechanistically, the SAP hydrogel promoted ECM proteins and GFs secretion in skin cells through the activation of the Rho/ROCK and TGF-ß/MEK/MAPK pathways. Additionally, SAP can be readily engineered with various bioactive motifs or therapeutic drugs/cells. This work highlights SAP hydrogels as a promising biomaterial platform for chronic wound healing and the regeneration of many other tissues.