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Self-Assembled Peptide Hydrogel for Biomedical Applications

Hong Li , Xiaodan Shi , Jieling Li

Progress in Chemistry ›› 2022, Vol. 34 ›› Issue (3) : 568 -579.

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Progress in Chemistry ›› 2022, Vol. 34 ›› Issue (3) : 568-579 DOI: 10.7536/PC210613
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Self-Assembled Peptide Hydrogel for Biomedical Applications
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Abstract

As a new type of biological material, short peptide self-assembled hydrogel holds the advantages of high biocompatibility, low immunogenicity, high water content, degradation products that can be absorbed by the body, and structure similar to natural extracellular matrix. It has broad application prospects in the fields of materials science, biomedicine and clinical medicine. In this review, we mainly introduce several commonly used methods for preparing stable and tough peptide self-assembled hydrogels, including enzyme-catalyzed hydrogelation and chemical/physical cross-linked hydrogelation and photocatalytic hydrogelation. Furthermore, some applications of peptide self-assembled hydrogels in drug delivery and anti-tumor therapy, antibacterial and wound healing, 3D bioprinting and tissue engineering are introduced. We hope that the discussion in this review can arouse more people's attention to peptide self-assembled hydrogels and promote the development of their applications in the biomedical field.

Contents

1 Introduction

2 Preparation of peptide self-assembled hydrogel

2.1 Enzyme-catalyzed hydrogelation

2.2 Chemical/physical cross-linked hydrogelation

2.3 Photocatalytic hydrogelation

3 Biomedical applications

3.1 Drug delivery and anti-tumor therapy

3.2 Antibacterial and wound healing

3.3 3D bioprinting and tissue engineering

4 Conclusion and perspective

Graphical abstract

Keywords

peptide self-assembly / hydrogel / drug delivery / antibacterial / tissue engineering

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Hong Li, Xiaodan Shi, Jieling Li. Self-Assembled Peptide Hydrogel for Biomedical Applications. Progress in Chemistry, 2022, 34(3): 568-579 DOI:10.7536/PC210613

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1 Introduction

Peptides, which are formed by dehydration condensation of several amino acids, are ubiquitous bioactive molecules in nature. As a key part of life, short peptides can form highly ordered assembly structures through molecular self-assembly process to achieve specific biological functions[1,2]. For example, driven by non-covalent intermolecular interactions (including electrostatic interactions, hydrophobic interactions, hydrogen bonding and π-π stacking), short peptide molecules can self-assemble to form a variety of nanostructures including nanotubes, nanoparticles, nanofibers and nanobelts[3⇓⇓⇓~7][8⇓⇓⇓~12]. In addition, these peptide-based nanostructures have shown great potential in drug delivery, photothermal/photoelectric conversion, photocatalysis, and optical waveguides due to the unique characteristics of peptides, such as their inherent bioendogeneity, bioactivity, biocompatibility, and biodegradability[13][14⇓~16][17⇓~19][20⇓⇓~23][24]. This review focuses on the preparation of peptide self-assembled hydrogels composed of nanofiber networks and their biological applications.
Peptide self-assembled hydrogels are a class of soft materials that typically have three-dimensional (3D) fibrous network structures that are cross-linked by physical or chemical bonds. They have high water content, porous structure, adjustable mechanical stability, good biocompatibility, excellent injectability and natural tissue-like elasticity. In addition, peptide self-assembled hydrogels are easy to achieve specific biological functions through specific modification or functionalization of amino acid side chains[25⇓⇓~28]. The above characteristics of peptide self-assembled hydrogels make them very suitable for applications in biomedical fields such as drug delivery, tissue engineering and wound healing[28⇓⇓~31][32,33][34,35]. Pochan et al. reported the use of injectable peptide self-assembling hydrogels to encapsulate curcumin for drug delivery[36]. Zhang et al. Initiatively reported that nerve cells were encapsulated in a hydrogel composed of peptide self-assembled nanofiber grids for three-dimensional culture of nerve cells[37,38]. Stupp et al. demonstrated that hydrogels formed by self-assembly of amphiphilic short peptides (PA) could be used for controlled differentiation of stem cells and cancer therapy[39,40][41,42]. Thakur et al. reported the antibacterial activity of 9-fluorenylmethoxycarbonyl (Fmoc) protected phenylalanine (Fmoc-F) and other Fmoc-modified amino acids (Fmoc-AA, Fmoc dialanine)[43]. Since the design of hydrogels with high mechanical strength and stability is of great significance for their applications in biomedical fields, in this review, several preparation methods of stable peptide-based hydrogels are mainly discussed, including enzyme-catalyzed gelation, chemical/physical cross-linking enhanced gelation, and photocatalytic gelation. Then, some representative research works on the applications of hydrogels in the fields of drug delivery and antitumor therapy, antibacterial and wound healing materials, and 3D bioprinting and tissue engineering are highlighted. It is hoped that this review will draw more attention to the importance of peptide-based self-assembling hydrogels and promote their development in biomedical applications.

2 Method for preparing peptide assembly hydrogel

2.1 Enzyme-Catalyzed Peptide Self-Assembled Hydrogel

Peptide self-assembly can provide a variety of nanoassembled structures for biological use. Controlling the structure of these assemblies "on demand" by external stimuli is important for their biomedical applications. Enzymatic triggering is one of the most commonly used external stimuli. Due to the high biocompatibility of enzymes, the hydrogels obtained by enzymatic catalysis have the advantages of homogeneity and mild reaction conditions[44⇓⇓~47]. Ulijn et al. pioneered the use of thermophiles, which thermodynamically promote the formation of peptide bonds, to catalyze the coupling of two amino acids to self-assemble into hydrogels. The main advantage of this reverse hydrolysis method is that no by-products other than water are formed[45]. They later designed a series of Fmoc-protected dipeptide amphiphiles that can be catalyzed by alkaline phosphatase (ALP)[48]. Under enzyme catalysis, these peptides can self-assemble into hydrogels with excellent antibacterial properties. Ulijn et al. also reported that self-assembling peptide nanostructures can be well controlled by changing the structural network of the enzyme (fig. 1)[49]. They found that the presence of ions significantly affects the structural network of enzymes, which in turn affects the nucleation and growth of self-assembled nanostructures, resulting in different chiral and mechanical properties of the formed hydrogels. Yang et al. Found that tyrosinase can trigger the gel-sol transition of small molecular hydrogels[44]. Ac-YYYpY-OMe (where Ac represents carboxyl, Y represents tyrosine, p represents phosphate, and OMe represents methoxy) can self-assemble into hydrogels. The hydrogel is responsive to tyrosinase and can be degraded under the catalysis of the tyrosinase. Since tyrosinase is overexpressed in malignant melanoma, this enzyme-responsive hydrogel was reported to be able to encapsulate anticancer drugs to treat malignant melanoma. Alpha-helical structures are known to be critical for the biological function of proteins and peptide-based structures. Yang et al. reported enzyme-directed peptide self-assembly to help the peptide fold into an α-helical conformation[50]. Have CRB-GDFDFpDY(CRB:chlorambucil, chlorambucil; G represents glycine, F represents phenylalanine, and Y represents tyrosine) can be converted into a CRB-GDFDFDY under the catalysis of ALP, and the sequence can further form a hydrogel with an alpha-helical conformation. Compared with the hydrogel with β-sheet conformation, the hydrogel with α-helix conformation showed better stability to protease K digestion and enhanced cellular uptake, resulting in better inhibition of cancer cells in vitro and significant inhibition of tumor tissue growth in vivo.

2.2 Chemical/physical crosslink hydrogel

Peptide self-assembled hydrogels used in biomedical field usually have some disadvantages such as poor elasticity and weak mechanical properties. Chemical crosslink, whether by peptide intermolecular or with other macromolecule, is believed to be an effective method for providing peptide-based hydrogels with enhance stiffness and stability. Tova et al. designed several short peptide-chromophore-peptide triblock peptides that could react with PEG-based small guest molecules to study the effect of different crosslinking reactions on the rheological properties of the resulting hydrogels[51]. They found that the viscoelasticity of hydrogels varied greatly depending on the crosslinking reaction. Palocci et al. reported the use of Genipin as a cross-linking agent for the gelation of Fmoc tripeptides[52]. Depending on the concentration of genipin, the mechanical stability of the resulting hydrogels was significantly improved. Hauser et al. prepared a disulfide-cross-linked transparent hydrogel by using a short peptide containing cysteine as an assembly motif and taking advantage of the property that cysteine can form disulfide bonds. The hydrogel was reported to have high hardness and shape fidelity, which was conducive to transplantation with tweezers during surgery[53]. Meanwhile, the hydrogel shows low allergenicity and has great application prospect in the field of wound healing.
Wang et al. developed a method of self-assembly followed by chemical cross-linking to enhance the mechanical stability of peptide hydrogels[54]. They first used acrylic acid modified short peptide Nap-FFK (NapFFK-acrylic acid, where Nap represents the naphthalene ring, F represents phenylalanine, and K represents lysine) to self-assemble to form hydrogel I. Subsequently, bienzymatic reagents (including glucose oxidase (GOx), glucose, horseradish peroxidase (HRP), acetylacetone (AcAc) and polyethylene glycol methyl methacrylate (PEGMA)) were added to the hydrogel I for chemical cross-linking after self-assembly. The crosslinking reaction is based on the following mechanism: GOx catalyzes the oxidation of glucose to gluconic acid. Subsequently, the flavin adenine dinucleotide (FAD) cofactor reduces O2 to H2O2. Then, the polymerization between PEGMA and the acrylic-modified peptide gelator was initiated by the AcAc radical generated by the HRP-catalyzed oxidation of AcAc with H2O2. The morphological characteristics show that hydrogel II has relatively smaller pore size and higher nanofiber density compared with hydrogel I, indicating that the crosslinking process contributes to the formation of polymer bridges between the nanofibers in hydrogel II. Compared with hydrogel I, the storage modulus (G ′) of hydrogel II was significantly enhanced, which confirmed that the introduction of chemical crosslinking could improve the mechanical strength and stability of the hydrogel. In addition, hydrogel II can resist more than 80% compression, while hydrogel I can not. This stable hydrogel has great potential in the fields of biocatalysis and tissue engineering scaffolds (Fig. 2).
In addition to chemical cross-linking, the supramolecular interactions between peptides and biomacromolecules can also be used to prepare stable peptide-based hydrogels. In contrast to chemical cross-linking methods, this approach allows the direct use of natural biomaterials as assembly motifs to prepare hydrogels without chemical modification or harsh chemical reactions. In addition, biomacromolecules, including proteins, peptides and polysaccharides, can be used to prepare hydrogels. Fern Fernández-Mui Muiños et al. co-assembled RAD16-I peptide with heparin to prepare a hydrogel for the culture of adipose-derived stem cells[55]. After 4 weeks of culture, the storage modulus of RAD16-I/heparin hydrogel (280 kPa) was much higher than that of the hydrogel formed by peptide self-assembly alone. It is widely accepted that injectability is a key feature of hydrogels that can be used in the biomedical field. Unfortunately, self-assembling short peptide hydrogels often lack tunable interactions between their fiber networks and thus have poor mechanical properties and injectability. Yan et al. used the electrostatic interaction between the negatively charged dipeptide Fmoc-FF and the positively charged PLL-SH (PLL stands for polylysine) to enhance the entanglement between the assembled peptide nanofibers, thereby obtaining a hydrogel with injectability[56]. The disulfide bond formed by thiol (— SH) -modified PLL (PLL-SH) also contributed to the mechanical strength of the hydrogel. They found that the hydrogel could be smoothly extruded by a 26-gauge needle (φ = 260 μm) without clogging the needle. Rheological analysis showed that the Fmoc-FF/PLL hydrogel had better rheological properties than the hydrogel formed by self-assembly of single Fmoc-FF. In addition, they found that the mechanical properties of the hydrogel could be flexibly adjusted by changing the molecular weight of the PLL. AFM images show that hydrogels formed by higher molecular weight PLLs are more prone to entanglement than hydrogels formed by lower molecular weight PLLs. These results indicate that the introduction of PLL can enhance the interaction between the nanofibers, thereby increasing the degree of crosslinking of the nanofibers to form a firm hydrogel.

2.3 Photocatalytically crosslinked hydrogel

Photoinitiation is also a common method for the preparation of peptide-based hydrogels. By changing the intensity of excitation light and exposure time, the degree of crosslinking of hydrogels can be easily regulated, thus the mechanical strength and stability of hydrogels can be regulated. Yu et al. Reported that UV-crosslinked calcitonin gene-related peptide (CGRP)/hyaluronic acid (HA) hydrogels could still maintain high bioactivity through chemical bond immobilization of CGRP, which showed great application prospects in bone tissue repair[57]. Parquette et al. Prepared a lysine dipeptide molecule modified with 7- (diethylamino) -3-coumarin carboxylic acid (7-DAC), which can self-assemble into a physically crosslinked hydrogel with a nanofiber network structure driven by electrostatic force, π-π stacking and hydrogen bonding force[58]. Furthermore, the dimerization of coumarin molecules can be initiated by irradiating the hydrogel with 365 nm ultraviolet light, so that the chemical crosslinking between nanofibers is realized, and the hydrogel with high mechanical strength and stability is obtained. Wang et al. also reported a method for preparing peptide-based hydrogels with enhanced mechanical stability by UV-initiated chemical crosslinking[59]. Their method is based on a ruthenium complex (Ru(bpy)3Cl2) that catalyzes the conversion of tyrosine to dityrosine upon light irradiation. The hydrogels were formed by self-assembly of peptides with a certain amino acid sequence.Then, Ru(bpy)3Cl2 and ammonium persulfate were added into the hydrogels, and the crosslinking reaction was triggered by white light irradiation within 2 min. The mechanical stability of cross-linked hydrogels can be improved by 104 times compared to non-cross-linked hydrogels. This enhanced mechanical stability of the hydrogel is due to the self-assembly of dihydrotyrosine-bridged peptide dimers to form a tightly entangled fibrous network structure (fig. 3).
The use of UV-catalyzed intermolecular cross-linking for the preparation of hydrogels is disadvantageous for the application of hydrogels in tissue engineering, regenerative medicine and drug delivery, such as the induction of chromosomal or genetic instability by UV irradiation. Comparatively speaking, the advantage of visible light is that it has lower biological toxicity, and it has stronger penetration ability than ultraviolet light, which can penetrate deeper into the hydrogel and improve the efficiency of hydrogel crosslinking. Kim et al. Designed a tyrosine-rich short peptide molecule YYAYY (where Y represents tyrosine and A represents alanine), and under the conditions of Ru(bpy)3Cl2 and ammonium persulfate, white light was used as the excitation light source to initiate the cross-linking between tyrosine residues, and nanogels with uniform size and good permeability were obtained[60]. Due to the chemical cross-linking between the tyrosine residues, the nanogel has high stability in various solvents and pH conditions. Lee et al. reported the preparation of stable peptide-based hydrogels by chemical crosslinking initiated by visible light[61,62]. They designed a peptide molecule with the sequence of Fmoc-FFEEK (D) GGY (where F represents phenylalanine, E represents glutamic acid, K represents lysine, D represents aspartic acid, G represents glycine, and Y represents lysine), where Y can achieve dimeric cross-linking under visible light catalysis mediated by [Ru(CO)3Cl2]2. The Fmoc-FFEEK (D) GGY molecule can self-assemble into nanofibers through the formation of an antiparallel β-sheet structure and the π-π stacking interaction between the fluorenyl group and the benzene ring, and further, the Y residue at the end of the molecule can dimerize and crosslink under the irradiation of visible light to form a hydrogel with enhanced stability. The mechanical strength of the hydrogel was characterized by rheometer, and it was found that the elastic modulus of the photocatalytically crosslinked hydrogel was nearly 2. 5 times higher than that of the uncrosslinked hydrogel. In addition, the cross-linked hydrogel immersed in deionized water could not depolymerize for at least 22 days, while the uncrosslinked hydrogel would depolymerize quickly, indicating that the cross-linked hydrogel had higher mechanical stability. The cross-linked hydrogel has great application prospect in the repair of soft tissues, ligament tissues, muscle tissues and the like.
Table 1 is a summary of methods for preparing peptide self-assembled hydrogels.

3 Biological Application of Peptide Self-Assembled Hydrogel

3.1 Drug delivery and antitumor therapy

Many anticancer drugs, such as paclitaxel and doxorubicin (DOX) in chemotherapy or photosensitizers in photodynamic therapy, face the problems of low solubility, low bioavailability and easy degradation under physiological conditions. The introduction of biocompatible drug carriers is generally considered to be an effective solution to overcome the above problems. For peptide self-assembly hydrogels, their water-filled microporous structure, mild preparation conditions, responsiveness to a variety of external stimuli and good biocompatibility make them ideal drug carriers. Fatouros et al. reported that a polypeptide Ac-(RADA)4-CONH2, which can self-assemble to form a hydrogel in situ, was used as a biocompatible delivery vehicle for DOX, a chemotherapeutic agent, and curcumin (CUR), an anticancer agent, to achieve local chemotherapy of malignant brain tumors[63]. Zhao et al. Used RADA16 self-assembled hydrogel under physiological conditions as a carrier to achieve efficient loading of hydrophobic anti-tumor drug paclitaxel through the interaction between RADA16 and paclitaxel[64]. For drug delivery, it is very important to achieve controlled drug release at the lesion site and prolong the retention time of drugs at the lesion site to improve the anti-cancer efficacy of drugs. Xu et al. designed a polypeptide with a sequence of Ac-I3SLKG-NH2 (where I represents isoleucine, S represents serine, L represents leucine, K represents lysine, and G represents glycine) that was capable of self-assembling into a hydrogel with MMP-2 responsive properties (Figure 4)[65]. Because MMP-2 overexpressed by HeLa tumor cells can significantly disrupt the entanglement of the fibrous network and gradually reduce the mechanical stability of the hydrogel. Therefore, the hydrogel can serve as a sustained drug delivery platform. The anti-cancer peptide G(IIKK)3I-NH2(G3) was encapsulated into the hydrogel to achieve controlled release of G3 in a "cell demand" manner, thereby significantly inhibiting cancer cell expansion. Mo et al. Used peptide self-assembled hydrogels as reservoirs to capture cell-penetrating peptide-modified transporters (PTX-CT), which contained the antineoplastic drug paclitaxel[66]. The PTX-CT-coated hydrogel shows longer retention time in skin tissues and enhanced skin and tumor matrix permeability, and can effectively inhibit the growth of tumor tissues. Yan et al. Reported that the hydrogel formed by the co-assembly of short peptide Fmoc-FF and biomacromolecule PLL was used for the local delivery and sustained release of photosensitizer Ce6[67].
By adjusting the co-assembly ratio between Fmoc-FF and PLL, the mechanical properties of the hydrogel can be conveniently regulated, so that the hydrogel is suitable for local injection and sustained administration. They tested the sustained and controlled drug delivery properties of the hydrogel using a mouse model bearing MCF-7 tumors. Compared with free Ce6, the injectable hydrogel can act as a "reservoir" system for local delivery and sustained release of Ce6, which contributes to the long-term enrichment of Ce6 at the tumor site. Therefore, the sustained release of Ce6 is realized, and the toxic and side effects caused by drug overdose are reduced. The anti-tumor efficacy analysis also showed that Ce6 encapsulated in the hydrogel was more effective than free Ce6 in inhibiting the growth and recurrence of tumors, and caused little damage to other organs. Thus, the injectable hydrogel can be used as a delivery platform for the treatment of superficial tumors.
Multidrug resistance (MDR) is one of the main reasons for the failure of clinical treatment of cancer. Xu et al. reported that phosphotyrosine-cholesterol conjugates efficiently and selectively kill platinum-resistant ovarian cancer cells[68]. Targeting organelles by modulating the redox potential of mitochondria is a promising way to kill cancer cells and minimize acquired drug resistance. Based on this, Xu et al. Also reported another work on cancer treatment without drug resistance[69]. They covalently attached a redox modulator (e.g., triphenylphosphine (TPP)) to an oligomer-forming precursor (L-1P or D-1P) on a pair of enantiomerically phosphorylated tetrapeptides,The oligomers can then selectively self-assemble to form nanoassemblies only on the surface of tumor cells under the catalytic dephosphorylation of exo-phosphatases, such as ALP, which is overexpressed in tumor cells. These assemblies can enter the interior of tumor cells by endocytosis and can escape from lysosomes, inducing mitochondrial dysfunction to release cytochrome C, which ultimately leads to cell death. Most importantly, repeated stimulation of cancer by oligomeric precursors can unexpectedly sensitize cancer cells to the precursors without developing drug resistance. Yang et al. co-assembled negatively charged 10-hydroxycamptothecin (HCPT) -peptide amphiphiles with positively charged cisplatin to prepare nanomaterials that can penetrate cell membranes and nuclear membranes to achieve dual-synergistic nuclear delivery of anticancer drugs[70]. These nanomaterials showed improved inhibitory ability against cancer cells, including drug-resistant cancer cells, and promoted the effect of synergistic tumor therapy in vivo. In another work, Yang et al. Designed and synthesized a peptide molecule with the sequence of NBD-GFFpY-ss-ERGD (where G represents glycine, F represents phenylalanine, Y represents tyrosine, E represents glutamic acid, R represents arginine, and D represents aspartic acid)[71]. In PBS buffer, the molecule can be self-assembled into nanoparticles under the action of phosphatase, and then transformed into nanofibers under the action of glutathione. Because the concentrations of phosphatase and glutathione in hepatoma cells are higher than those in normal cells, the peptide molecules they designed can also achieve the above morphological transformation in hepatoma cells (HepG2 and QGY7703). Peptide molecules first assemble around liver cancer cells to form nanoparticles, and then form nanofibers in the cells. Due to the high concentration of intracellular phosphatase and glutathione, the uptake rate of NBD-GFFpY-ss-ERGD in liver cancer cells is much higher than that in normal cells, so the molecule can selectively kill liver cancer cells and improve the performance of tumor diagnosis and treatment.
It is well known that the immune system plays an important role in suppressing tumors and other immune-related diseases. However, free antigens often exhibit poor immunogenicity[72,73]. Therefore, there is an urgent need for immune adjuvants with good biocompatibility and biodegradability to enhance the immunogenicity of antigens. In addition to the commonly used nanoparticles, polymeric micelles and polymeric hydrogels, self-assembled peptide nanomaterials have attracted wide attention in the field of immune adjuvant preparation due to their low production cost, high stability and activity[74,75][76,77][78⇓~80]. By covalently linking ovalbumin (OVA) to peptide Q11, Collier et al. prepared a peptide-based vaccine that can elicit a robust immune response[81]. Li et al. prepared Q11-based anti-tumor vaccines containing B-cell epitopes and found that these vaccines were able to induce the production of large amounts of antibodies that specifically recognize human breast tumor cells[82]. Yang et al. Found that the humoral immune response can be optimized by using short peptide self-assembled hydrogel as a non-covalently linked immune adjuvant[83]. They embedded OVA in peptide hydrogel by co-assembly method, and found that compared with free OVA, OVA co-assembled in peptide hydrogel could induce a large number of antibody production and secretion of related cytokines by enhancing antigen uptake, thereby inducing dendritic cell maturation, prolonging lymph node accumulation and promoting germinal center formation. Yang and Zhao et al. Also reported that MUC1 antigen was covalently linked to a peptide Nap-GDFDFDYDK (wherein Nap represents a naphthalene ring, G represents glycine, F represents phenylalanine, Y represents tyrosine, and K represents lysine) to prepare an anti-tumor vaccine capable of eliciting humoral and cellular immune responses[84]. However, there are few reports of peptides as antigens to directly elicit immune responses. Yan et al. innovatively reported the work of directly activating T immune cells with peptide self-assembled hydrogels (fig. 5)[56]. The hydrogel they used was made by co-assembly of aromatic short peptide Fmoc-FF and polypeptide PLL-SH. The hydrogel has an alpha-helix secondary structure, which is similar to the conformation of the natural fiber antigen, so that the hydrogel has application potential in cancer immunotherapy. They therefore established a C57BL/6 tumor-bearing (B16) mouse model to confirm their speculation. The in vitro/in vivo cytotoxicity and degradation experiments proved that the hydrogel had excellent biocompatibility and degradability. Tumor growth in mice injected subcutaneously with the hydrogel was significantly inhibited compared to mice not injected with the hydrogel. To confirm that the growth inhibition of the tumor was caused by the hydrogel-induced immune response, they further analyzed the peripheral blood mononuclear cells (PBMCs) of normal and xenografted mice with flow cytometry.
The results showed that the mice treated with the Fmoc-FF/PLL-SH hydrogel exhibited a higher level of CD3 + T cell expression compared to the mice not treated with the hydrogel, indicating that the hydrogel has the ability to activate therapeutic anti-tumor immunity. In addition, the ratio of CD4 + T/CD8 + T in mice treated with the hydrogel was higher than that in mice not treated with the hydrogel, which is further evidence that the hydrogel can elicit an effective immune response because the ratio of CD4 + T/CD8 + T can indicate the level of antigen-specific activation of T cells. The above results indicate that the injectable hydrogel with specific structure and highly stable helical conformation has great potential in the development of new anti-tumor vaccines.

3.2 Antibacterial and wound healing

Antimicrobial peptide-based hydrogels are usually assembled from peptides with intrinsic antimicrobial activity, called antimicrobial peptides (AMPs), which are currently the focus of biomedical applications, such as wound dressings. Singh et al. Found that the hydrogel formed by the assembly of α/γ hybrid peptides had broad-spectrum antibacterial activity against Gram-negative and Gram-positive bacteria[85]. Banerjee et al. Designed a series of peptides and covalently attached long fatty acyl chains to the C-termini of these peptides to prepare hydrogels with antibacterial activity against Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (Escherichia coli)[86]. Li et al. prepared supramolecular hydrogels with pH-responsive and antibacterial properties using cationic PA modified with lysine residues[87].
However, most of AMPs are disordered in aqueous solution, and it is difficult to form hydrogels through self-assembly process. Promoting the gelation of AMPs by enzymatic catalysis to enhance the cross-linking of peptide molecular aggregates seems to be an effective method for the preparation of antibacterial hydrogels. Under the enzymatic catalysis of lysyl oxidase (LO) and plasma amine oxidase (PAO), Xu et al. realized the self-assembly gelation of antimicrobial peptide A9K2 (Fig. 6)[88]. They found that the two enzymes could convert peptides without assembly ability into structural units with self-assembly ability or induce the connection between peptide molecular aggregates, leading to the formation of fibrous hydrogels. The antibacterial activity of the enzyme-catalyzed A9K2 hydrogel was first characterized by the survival of bacteria (Bacillus subtilis 168) cultured with or without the hydrogel, with SYTO 9 and PI as bacterial live/dead indicators. The results showed that the bacteria cultured on the surface of the hydrogel showed red fluorescence, indicating that the bacteria were dead. However, the bacteria in the culture dish without hydrogel showed strong green fluorescence, indicating that the bacteria still had a high survival rate. The above experiments show that the hydrogel has high antibacterial activity. At the same time, Xu et al also detected the release level of LDH, which can be used as an indicator of cell death, to evaluate the cytotoxicity of hydrogels. When NIH 3T3 and HEK293 cells were cultured on the surface of A9K2 hydrogel, almost no LDH release was detected, indicating that the hydrogel formed by A9K2 self-assembly has low cytotoxicity to mammalian cells. In order to evaluate the selectivity of hydrogels for mammalian cells, Xu et al. Also carried out co-culture experiments of Bacillus subtilis 168 with NIH 3T3 cells. They found that in the absence of enzymatic hydrogels, the introduction of bacteria led to massive cell death in mammals, while in the presence of hydrogels, NIH 3T3 cells co-cultured with bacteria could proliferate well on the gel surface.However, no obvious morphological change was observed, which indicated that the A9K2 hydrogel had high selectivity for cells and could effectively prevent bacterial contamination, showing a broad application prospect in regenerative medicine, drug delivery and other fields. Wang et al subsequently designed an amphiphilic peptide I4K2, which can self-assemble into fibrous hydrogels through the catalytic crosslinking of PAO and show high antibacterial ability[89]. The hydrogel shows extremely high antibacterial activity against both G+ and G- bacteria, while the toxicity to cells is very low. In addition, the hydrogel can also be used as a drug carrier for sustained release of drugs. These advantages make enzymatic I4K2 hydrogels promising candidates for biomedical applications.
The excellent antibacterial activity of peptide self-assembled hydrogels makes them promising in the field of wound healing. In addition to having antibacterial ability, peptide-based hydrogels are widely used as wound dressings due to their high air permeability and ability to provide a suitable aqueous environment and to be used as drug delivery vehicles, thereby promoting rapid wound closure and healing and reducing scar formation. Hartgerink et al. Found that multidomain peptide (MDP) hydrogels accelerated full-thickness wound healing in diabetic mice[90]. By supporting the growth of cells involved in the wound healing process, MDP hydrogels can accelerate the rate of granulation tissue formation, re-epithelialization, vascularization, and innervation to promote wound healing. Hauser et al. Reported that the use of ultra-short aliphatic peptide self-assembled hydrogels could accelerate the healing of burn wounds[91]. They designed two short peptide hydrogels to investigate their ability to accelerate wound healing compared to standard beauty patches. They found that both hydrogels had a stronger self-dissolving debridement effect than Meipi, and that both hydrogels could also promote epithelial and dermal regeneration, reaching 86.2% and 92.9% wound closure rates, respectively, far more effective than Meipi, whose burn recovery rate was only 62.8%. Tekinay et al. reported the effect of heparin-mimicking peptide nanofiber hydrogels on burn wound healing (fig. 7)[92].
Bioactive hydrogel scaffolds have been reported to be able to promote angiogenesis through their affinity for basic growth factors. Compared with the non-bioactive peptide hydrogel and the commercially available wound dressing 3MTMTegadermTM, the wounds treated with the heparin-mimicking peptide hydrogel are characterized by highly ordered and collagen-rich granulation tissue layers, high-density neovascularization structures, faster epithelial regeneration and skin appendage development, and minimal crusting.The bioactive hydrogel can be used as an efficient wound dressing scaffold to promote wound healing.

3.3 3D printing and tissue engineering

3D printing extends our ability to prepare structurally complex scaffolds that can be used for tissue engineering. Peptide-based hydrogels are ideal for 3D printing bioinks due to their good biocompatibility, adjustable gelation process for extrusion printing, easy chemical modification and similarity to natural cell microenvironment. Domingos et al. Used their own designed peptides that can self-assemble into hydrogels under physiological conditions as ink for 3D bioprinting[93]. Based on the commercial extrusion AM system, they can directly print EpH4 cell suspensions containing peptide gelators to construct a variety of biomimetic structures. After printing, the cells encapsulated in the hydrogel could still maintain high activity and began to proliferate after 7 days of culture. Wang et al. reported a novel hydrogel with interpenetrating network structure formed by macromolecule-supramolecular polymer double network (PS-DN gel) for cartilage regeneration[94]. The polymer network is composed of polyacrylamide, and the supramolecular polymer network is composed of nanofibers formed by peptide self-assembly. When loaded, the peptide self-assembled fibers can act as sacrificial bonds to efficiently dissipate energy. Due to the ability of peptides to self-assemble quickly and accurately, hydrogels achieve rapid recovery when the applied mechanical load is withdrawn. The mechanical properties of the hydrogel were characterized, and the hydrogel was found to exhibit similar energy dissipation, strain hardening, and stress relaxation behaviors as articular cartilage. In addition, the mechanical properties of the hydrogel can be controlled by changing the molecular ratio. This new type of biomaterial has important application prospects in the repair and regeneration of cartilage and other load-bearing tissues. Jiang et al. Also reported an interpenetrating double-network hydrogel formed by a covalent polymer network and a peptide self-assembled supramolecular network for cartilage tissue repair[95]. The hydrogel has a high Young's modulus of 209 kPa, a compression limit of nearly 70%, a toughness of about 47 kJ·m-3, and can achieve rapid repair within seconds. Using rabbit cartilage damage as a model, Jiang et al. Investigated the ability of the hydrogel to promote cartilage repair[96]. After 12 weeks of in vivo experiments, they found that the hydrogel could significantly promote the repair of cartilage defects. Hauser et al. reported the use of ultrashort peptide self-assembled hydrogels as printable scaffolds for 3D cell culture (fig. 8). They found that the lysine-containing hexapeptide could rapidly self-assemble into an extremely hard hydrogel with a storage modulus of up to 40 kPa, which exhibited high shape fidelity in PBS and could be extruded through a 25 G needle to form an array of hydrogel droplets. Human H1 embryonic stem cells seeded on a peptide hydrogel droplet array can proliferate into 3D spheres and express a variety of pluripotent nuclear transcription factors and surface biomarkers, indicating that the hydrogel has potential applications in tissue engineering and drug screening. The printable hydrogel can also be used to build multicellular structures. They then seeded human umbilical vein endothelial cells, fibroblasts and keratinocytes on specific areas of the hydrogel droplet array to study multicellular culture. After 7 days of co-culture, a biomimetic structure with multiple cells and regions was successfully obtained, which can be used as an in vitro model of skin.
Tissue engineering is regarded as one of the most promising applications of peptide self-assembled hydrogels due to the high similarity between peptide self-assembled hydrogels and human tissues. Peptide self-assembled hydrogels are regarded as ideal scaffolds for tissue engineering, mainly due to the following advantages of the hydrogels: high water content environment can protect cells and drugs from inactivation, can promote the transport of nutrients to cells, can be modified by cell adhesion ligands, can be injected in vivo and has good biocompatibility[97]. Zhang et al. Successfully realized the three-dimensional cell culture of neural stem cells by using peptide self-assembled hydrogel as a scaffold and encapsulating neural stem cells into the hydrogel scaffold with serum medium[37]. These neural stem cells encapsulated in the hydrogel can differentiate into progenitor cells, neurons, astrocytes, and oligodendrocytes, and can survive for at least 5 months. Chen et al. reported work on peptide (EFK8) -carbon nanotube (SWNT) hybrid hydrogels for tissue and 3D tumor engineering (fig. 9)[98]. The introduction of SWNTs into the hydrogel can enhance the attachment, proliferation and migration of NIH-3T3 cells, and can promote the morphological change of A549 lung cancer cells from spherical to spreading state. Li et al. reported the work of co-assembling hydrogels with NapFF and silk fibroin (SF) for tissue engineering[99]. NapFF can not only self-assemble into supramolecular hydrogels, but also trigger the transition of SF molecules from random coil conformation to β-sheet structure through hydrophobic and hydrogen bonding interactions, thus enabling the rapid formation of hydrogels. Furthermore, they co-assembled NapFF modified with RGD fragments (NapFFRGD) with silk fibroin to form hydrogels to promote cell adhesion. HUVEC cells seeded on the gel surface showed improved cell adhesion and spreading characteristics, demonstrating the excellent cell compatibility of the hydrogel. Since vascularization plays an important role in tissue regeneration, they next investigated the potential use of RGD-functionalized gels to support microvasculature formation. They planted HUVECs on the surface of RGD-functionalized hydrogel loaded with VEGF, which is the main regulator of angiogenesis, and found that HUVECs could form tubular network structures within 72 H. In addition, they evaluated the ability of the VEGF-loaded hydrogel to assist microvessel formation in vivo by implanting the hydrogel subcutaneously into the dorsal side of mice. More capillaries were observed in mice injected with VEGF hydrogel than in mice not injected with hydrogel, and capillary density increased with time. Immunohistochemical experiments confirmed that the vessels formed in the vicinity of the implanted RGD-functionalized hydrogels were composed of endothelial cells. These results demonstrate the potential application of hydrogel in tissue engineering.

4 Conclusions and outlook

Peptide self-assembled hydrogels have been extensively studied in the past decade as matrices for biomedical applications. This review focuses on the recent progress in triggering the gelation of peptide molecules to form stable hydrogels. The potential applications of peptide self-assembled hydrogels in the fields of drug delivery and antitumor therapy, antibacterial and wound healing materials, and 3D bioprinting and tissue engineering are also presented. Although peptide-based hydrogels have achieved encouraging results in the above fields so far, their relatively low mechanical strength, long-term stability and similarity to extracellular matrix are still urgent problems to be solved before the final clinical trials. Peptide-based hydrogels with enhanced stability can be obtained by rationally designing the peptide molecular structure to enhance intermolecular forces, such as hydrophobic interactions, hydrogen bonding, and π-π stacking, or by introducing chemical cross-linkers, catalytic enzymes, or coordination ions. Considering the complexity of biological systems, it is difficult to prepare hydrogels that meet all the requirements of biological applications with only one type of hydrogel. The rational design of hydrogels for biomedical applications should combine biocompatible components, such as peptides, with a variety of biologically functional molecules and other synthetic macromolecules that can adjust the properties of hydrogels, so that they have suitable strength and shear thinning properties to meet the needs of their biological and medical applications. In addition, for tissue engineering, natural tissues or organs are generally composed of cells according to a certain spatial distribution and arrangement. How to realize the growth of cells in vitro according to the cell arrangement of target tissues or organs is a long-term research difficulty in tissue engineering. As a three-dimensional scaffold for cell growth, peptide self-assembled hydrogel is a key factor in guiding cell arrangement and organ functionalization in vitro. How to construct peptide self-assembled hydrogels with orientation structure and mechanical gradient to guide the directional arrangement and growth of cells has also become a research hotspot in the field of biomedicine. Through rational design, we believe that peptide-based hydrogels will bring great benefits to all of us in the future.

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Funding

National Natural Science Foundation of China(22072155)

National Natural Science Foundation of China(21703169)

Scientific Research Plan of Shaanxi Province of China(2021KJXX-39)

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