多肽类水凝胶促伤口愈合机制研究进展

Research progress on mechanism of peptide hydrogels for promoting wound healing

[背景]创伤、烧伤、糖尿病及手术等引起的伤口一直威胁着人类健康,伤口治疗已经成为严重的临床挑战和经济负担.多肽类水凝胶具有良好的生物功能活性、生物相容性、生物可降解性,使其在伤口愈合不同阶段具有广阔的应用前景.[进展]本文系统综述了多肽类水凝胶在止血、炎症感染、增殖重塑等不同伤口愈合过程中的作用及机制.多肽类水凝胶通过多肽的阳离子基团、抗菌和免疫活性、自组装形成纳米纤维结构呈递药物等激活凝血过程,促进巨噬细胞从M1型转化为M2型,激活黏着斑激酶/整合素偶联激酶(FAK/ILK)、Wnt/β-连环蛋白信号通路,促进成纤细胞增殖,活化生长因子及血管内皮细胞,进而促进血管生成和胶原蛋白合成,加速伤口愈合过程.目前,部分多肽类止血、抗炎的水凝胶产品已在临床上得到应用.[展望]尽管在针对伤口愈合不同阶段的多肽类水凝胶产品研发及作用机制研究已取得突破性进展,但多肽类水凝胶机械强度不高,长期稳定性弱,具有传感完整性和按需递送的水凝胶相关研究不足,在无疤痕组织修复中的机制探索不够深入,影响其在临床上的转化应用.因此,未来在提高多肽类水凝胶机械强度、长期稳定性、对动态伤口响应性、无瘢痕伤口修复机制等方向开展深入研究,将有助于多肽类水凝胶的临床转化和应用.

[Background]Wounds caused by trauma,burns,diabetes and surgery have always posed a threat to human health,and treating these wound has become a serious clinical challenge and economic burden.The wound healing process is complex,including four stages:hemostasis,inflammation and infection,proliferation and remodeling.However,due to problems such as infection,excessive inflammation,and secondary injury,the healing process often deviates from its normal path,resulting in abnormal wound repair.Peptide hydrogels,known for their good biological functions and activities,biocompatibility,and biodegradability,have broad application prospects in different stages of wound healing.In recent years,the research and development of peptide hydrogels for different stages of wound healing and their corresponding mechanism have made breakthrough progress.Currently,while there are reviews on hydrogel dressings focusing on wound healing,there is a lack of comprehensive review on the role and mechanism of polypeptide hydrogels in different stages of wound healing.[Progress]This paper systematically reviews the roles and mechanisms of peptide hydrogels in hemostasis,inflammation and infection,and proliferation and remodeling of various wound healing processes.The positively charged amino group of polypeptide hydrogels attracts plasma fibrin,platelets and red blood cells through electrostatic action,inducing the release of physiological aggregators such as adenosine diphosphate(ADP)and thromboxane 2(TXA2),causing irreversible aggregation of platelets and promoting the formation of blood clots.At the same time,up on absorbing blood,these hydrogels expand to form a network that seals cracks in blood vessels or wounds,or they self-assemble to form a nanofiber barrier that acts as a physical hemostatic agent.Polypeptide hydrogels activate the function of the immune system through the immunomodulatory activity of the polypeptide itself or self-assemble to form a structure simulating extracellular matrix(ECM).On the other hand,polypeptide hydrogels can serve as a drug delivery platform within wound dressings,promoting the transformation of macrophages from the M1 type to the M2 type by loading anti-inflammatory drugs,thus balancing pro-inflammatory and anti-inflammatory responses.Polypeptide hydrogels affect bacterial cell membranes through their cationic,self-assembled nanostructures,causing the release of bacterial contents and thus killing bacteria.In addition,the bactericidal effects of antimicrobial peptides and the impacts of photothermal therapy(PTT)and photodynamic therapy(PDT)of photothermal substances can be synergistic by coupling with photothermal substances.By activating focal adhesion kinase/integrin linked kinase(FAK/ILK)signaling pathway and Wnt/β-catenin pathway,and by inhibiting the expression of matrix metalloproteinase-9(MMP-9),polypeptide hydrogel can promote the proliferation of human dermal fibroblast(HDF),activate growth factors and,thus promoting angiogenesis and collagen synthesis,and accelerate the wound healing process.Currently,some peptide hydrogel products for hemostasis and anti-inflammation have been applied in clinical practice.[Perspective]Although breakthrough progress has been made in the research and development of peptide hydrogels for different stages of wound healing,the issues of low mechanical strength and weak long-term stability in polypeptide hydrogels still hinder their clinical conversion applications.According to the characteristics of different types of wounds,it is necessary to make full use of the biological activity and drug delivery function of peptides to improve the wound microenvironment while solving key problems such as wound infection and excessive inflammation.The mechanisms of hydrogels for promoting wound healing still lack in-depth exploration.The application of polypeptide hydrogels in scar free tissue repair is insufficient and deserves more attention.While progress has been made in wound monitoring and responsive release of bioactive drugs at the wound site,hydrogels with sensing integrity and on-demand delivery in response to dynamic wound environments require further exploration.In the future,in-depth research aimed at improving the mechanical strength,long-term stability,dynamic wound responsiveness,and scarless wound repair mechanism of peptide hydrogels will be crucial for their clinical translation and application.