Bioactive extracellular matrix scaffolds engineered with proangiogenic proteoglycan mimetics and loaded with endothelial progenitor cells promote neovascularization and diabetic wound healing

Abstract

Diabetic ischemic wound treatment remains a critical clinical challenge. Neovascularization plays a significant role in wound healing during all stages of the tissue repair process. Strategies that enhance angiogenesis and neovascularization and improve ischemic pathology may promote the healing of poor wounds, particularly diabetic wounds in highly ischemic conditions. We previously identified a cyclic peptide LXW7 that specifically binds to integrin αvβ3 on endothelial progenitor cells (EPCs) and endothelial cells (ECs), activates vascular endothelial growth factor (VEGF) receptors, and promotes EC growth and maturation. In this study, we designed and synthesized a multi-functional pro-angiogenic molecule by grafting LXW7 and collagen-binding peptides (SILY) to a dermatan sulfate (DS) glycosaminoglycan backbone, named LXW7-DS-SILY, and further employed this multi-functional molecule to functionalize collagen-based extracellular matrix (ECM) scaffolds. We confirmed that LXW7-DS-SILY modification significantly promoted EPC attachment and growth on the ECM scaffolds in vitro and supported EPC survival in vivo in the ischemic environment. When applied in an established Zucker Diabetic Fatty (ZDF) rat ischemic skin flap model, LXW7-DS-SILY-functionalized ECM scaffolds loaded with EPCs significantly improved wound healing, enhanced neovascularization and modulated collagen fibrillogenesis in the ischemic environment. Altogether, this study provides a promising novel treatment to accelerate diabetic ischemic wound healing, thereby reducing limb amputation and mortality of diabetic patients.

Mechanically active small intestinal submucosa hydrogel for accelerating chronic wound healing

“…Neovascularization is responsible for the transport of inflammatory cells, nutrients, chemokines, and cytokines, as well as the removal of waste, which plays a pivotal role in fast wound healing. 29 Here, both SIS-PAAm and SIS-PNIPAm hydrogel promoted the migration of HUVECs (Fig. 2C) with a significantly higher relative migration area (Fig.…”

Bioengineering approaches for nerve graft revascularization: Current concepts and future directions

“…We further demonstrated that LXW7 can support both endogenous and exogenous EC binding and enhanced EC proliferation and functionality (Hao et al, 2023; Hao, Fan, et al, 2020; He et al, 2022). In one study, we engineered biomaterial scaffolds with LXW7 and loaded the scaffold with exogenous EPCs and showed that this approach significantly promotes neovascularization and diabetic wound healing in a Zucker Diabetic Fatty (ZDF) rat ischemic skin flap model (He et al, 2022). In another recent study, we applied LXW7 to functionalize the biomaterial scaffold and showed that this technology effectively regulates endogenous EC and EPC adhesion and promotes vascularized bone regeneration for both adult and fetal birth defects (Hao et al, 2023).…”

Phase-change composite filled natural nanotubes in hydrogel promote wound healing under photothermally triggered drug release

“…Collagen proteins, including type Ⅰ and Ⅲ, are the primary constituents in dermal extracellular matrix [ 53 ]. Previous studies revealed that early abundant deposition of collagen III would accelerate wound healing and result in scarless skin [ 53 , 54 ]. Masson staining was done to visualize the total collagen proteins [ 6 ].…”