Large-Scale Nanofiber Manufacturing| Anisotropic structure of nanofiber hydrogel accelerates diabetic woundhealing via triadic synergy ofimmune-angiogenic-neurogenic microenvironments

Professor Wang Xiumei from Tsinghua University: Anisotropic Nanofiber Hydrogel Structure Effectively Regulates Immune-Angiogenic-Neurogenic Triple Microenvironment to Accelerate Diabetic Wound Healing

Diabetic wounds are chronic and difficult-to-heal wounds whose complex inhibitory microenvironment is dominated by hyperglycemia, hypoxia, and persistent inflammation, leading to various cellular dysfunctions. The wound healing process involves multiple complex and overlapping stages including hemostasis, inflammation, proliferation, and remodeling. However, due to microenvironment imbalance, these stages are often disrupted in diabetic wounds, resulting in impaired healing. Currently, with the rapid development of tissue engineering, designing bioactive materials loaded with instructive signals to effectively regulate multicellular functions and remodel multidimensional microenvironments has become a promising strategy for diabetic wound repair.

Recently, Professor Wang Xiumei from Tsinghua University published her latest research titled "Anisotropic structure of nanofiber hydrogel accelerates diabetic wound healing via triadic synergy of immune-angiogenic-neurogenic microenvironments" in Bioactive Materials. Using liquid-receiving electrospinning technology, the researchers successfully prepared multilevel aligned nanofiber fibrin hydrogel (AFG). This hydrogel possesses anisotropic structural signals that significantly enhance mechanosensitivity of adherent cells, thereby regulating various cellular functions including shape-induced macrophage phenotype polarization, Schwann cell morphological maturation, fibroblast-oriented extracellular matrix deposition, and enhanced endothelial cell vascularization.To further regulate interactions between multiple microenvironments, the researchers loaded this aligned nanofiber hydrogel with vascular endothelial growth factor (VEGF)-mimetic peptide (KLT) through peptide molecular self-assembly technology as bioactive signals to coordinate the interactions of immune, angiogenic, and neurogenic triple microenvironments. The functionalized aligned nanofiber hydrogel (AFGKLT) effectively optimized multidimensional microenvironments and accelerated healing of chronic diabetic wounds, providing new insights for applications of anisotropic materials in wound healing.

Figure 1: Preparation process and mechanism of action of AFGKLT hydrogel.

Figure 2: Physical property characterization of AFGKLT nanofiber hydrogel.

Experimental results showed that the aligned fiber hydrogel prepared by liquid electrospinning technology had uniform fiber diameter of about 200 nm and highly aligned fiber arrangement. This aligned fiber structure not only significantly improved peptide grafting efficiency but also optimized sustained release performance of peptides, ensuring continuous and stable release of bioactive signals. Additionally, AFGKLT hydrogel exhibited excellent physical properties with significantly enhanced water content and hydrophilicity, more similar to natural extracellular matrix, providing an ideal microenvironment for cells to support adhesion and functional performance.

Figure 3: AFGKLT regulates behaviors of multiple cell types.

In vitro experiments demonstrated that the functionalized aligned fiber hydrogel (AFGKLT) effectively regulated multicellular behaviors through synergistic delivery of aligned physical structure and bioactive peptides, promoting recruitment and vascularization of vascular endothelial cells, anti-inflammatory polarization of macrophages, maturation of Schwann cells, as well as migration and oriented cytoskeleton extension of fibroblasts. The researchers innovatively combined physical structure of hydrogel with bioactive signals to achieve synergistic regulation of multicellular functions.

Figure 4: AFGKLT hydrogel accelerates diabetic wound healing by optimizing wound microenvironment.

In diabetic rat skin wound repair experiments, the AFGKLT hydrogel treatment group showed significant wound healing effects with wound healing rate reaching 92.5% after 4 weeks. Histological analysis further proved that AFGKLT hydrogel optimized skin regeneration microenvironment by remodeling inflammation-angiogenesis-neurogenesis triple microenvironment in chronic diabetic wounds, promoting ordered collagen accumulation and hair follicle regeneration, ultimately accelerating healing of chronic diabetic wounds. This study highlights that anisotropic materials can achieve multidimensional microenvironment remodeling through multicellular behavior regulation for chronic diabetic wound repair, providing new perspectives for applications of anisotropic materials in wound healing.