Functionalized Peptide Hydrogels: Enabling Dynamic 1 Stage-Adaptive Modulation for Wound Healing 2

Qi Peng¹Gui-hua Miao¹Xi-kun Ma¹Xiu-zhen Zhang^2*

• ¹West China Hospital of Sichuan University West China Institute of Orthopedics, Chengdu, China
• ²West China Hospital of Sichuan University State Key Laboratory of Biotherapy, Chengdu, China

43 Abstract 44 Functionalized peptide hydrogels represent an emerging class of 45 intelligent wound dressings that dynamically coordinate the multifaceted 46 process of wound healing through stage-specific bioactivities. By 47 leveraging programmable molecular designs, these hydrogels actively 48 engage with key healing phases—hemostasis, antibiosis, inflammation 49 resolution, angiogenesis, and tissue remodeling—enabling spatiotemporal 50 control over cellular behaviors and molecular cues. For instance, 51 antimicrobial peptides (e.g., EPL, LL37, TCP-25) not only eradicate 52 pathogens but also modulate macrophage polarization to mitigate excessive 53 inflammation. Angiogenic factors (e.g., VEGF, SDF-1) are sustainably 54 released to promote vascularization, while MMP-responsive components 55 facilitate ECM remodeling by balancing collagen deposition and 56 degradation. Additionally, integrin-binding motifs (e.g., RGD) enhance 57 cell adhesion and migration, further accelerating re-epithelialization. With 58 inherent self-healing, injectability, and microenvironmental responsiveness 59 (e.g., to pH, enzymes, or ROS), these hydrogels adapt to dynamic wound 60 conditions, offering synergistic therapeutic outcomes. Future directions 61 include designing multi-stimuli-responsive systems, personalized peptide 62 sequences, and advanced delivery platforms (e.g., 3D-printed scaffolds, 63 cell/exosome-loaded hydrogels) to advance clinical translation in precision 64 wound management and regenerative medicine.