Adipose-Derived Stromal Cell-Sheets Sandwiched, Book-Shaped Acellular Dermal Matrix Capable of Sustained Release of Basic Fibroblast Growth Factor Promote Diabetic Wound Healing.

Xin Shi,Chengjie Li,Xing Li,Yaowu Chen,Liyuan Jiang,Hongbin Lu,Xin Zhao,Can Chen,Yusheng He,Jun Liu,Yanpeng Cao,Xiaoren Liu,Wei Shi,Bei Chen,Xiying Li

doi:10.3389/fcell.2021.646967

Abstract

The management of diabetic wounds is a therapeutic challenge in clinical settings. Current tissue engineering strategies for diabetic wound healing are insufficient, owing to the lack of an appropriate scaffold that can load a large number of stem cells and induce the interaction of stem cells to form granulation tissue. Herein we fabricated a book-shaped decellularized dermal matrix (BDDM), which shows a high resemblance to native dermal tissue in terms of its histology, microstructure, and ingredients, is non-cytotoxic and low-immunogenic, and allows adipose-derived stromal cell (ASC) attachment and proliferation. Then, a collagen-binding domain (CBD) capable of binding collagen was fused into basic fibroblast growth factor (bFGF) to synthetize a recombinant growth factor (termed as CBD–bFGF). After that, CBD–bFGF was tethered onto the collagen fibers of BDDM to improve its endothelial inducibility. Finally, a functional scaffold (CBD–bFGF/BDDM) was fabricated. In vitro and in vivo experiments demonstrated that CBD–bFGF/BDDM can release tethered bFGF with a sustained release profile, steadily inducing the interaction of stem cells down to endothelial differentiation. ASCs were cultured to form a cell sheet and then sandwiched by CBD–bFGF/BDDM, thus enlarging the number of stem cells loaded into the scaffold. Using a rat model, the ASC sheets sandwiched with CBD–bFGF/BDDM (ASCs/CBD–bFGF/BDDM) were capable of enhancing the formation of granulation tissue, promoting angiogenesis, and facilitating collagen deposition and remodeling. Therefore, the findings of this study demonstrate that ASCs/CBD–bFGF/BDDM could be applicable for diabetic wound healing.

Highlights

As a worldwide health concern, diabetes affects approximately 420 million people (American Diabetes and Association, 2013; Cho et al, 2019; Li et al, 2020)
Immunogenicity of collagen-binding domain (CBD)–basic fibroblast growth factor (bFGF)/bookshaped decellularized dermal matrix (BDDM) After RAW 264.7 cells were cultured with tissue culture polystyrene (TCP), CBD– bFGF/BDDM, and LPS, the supernatants of the TCP and CBD– bFGF/BDDM groups showed similar levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), and both of these groups showed significantly lower expression levels than those in the LPS group (Figure 5F). These results indicated that CBD– bFGF/BDDM is a biomaterial with low immunogenicity
adipose-derived stromal cell (ASC)/CBD–bFGF/BDDM Stimulates Angiogenesis in Diabetic Wounds Considering that CBD–bFGF/BDDM showed superior endothelial inducibility in vitro, we evaluated new blood vessel formation at the wound site at day 7 post-wounding to explore the efficacy of ASCs/CBD–bFGF/BDDM on the stimulation of angiogenesis

Summary

Introduction

As a worldwide health concern, diabetes affects approximately 420 million people (American Diabetes and Association, 2013; Cho et al, 2019; Li et al, 2020). Diabetic foot ulcers (DFUs), a major complication of diabetes mellitus and a type of chronic wound, occur in 15–25% of patients with diabetes (Shrestha et al, 2013; Liu et al, 2017; Atosona and Larbie, 2019; Grennan, 2019). The current standard of treatment includes debridement of the wound, infection control, and application of various wound dressings to facilitate healing (Brem et al, 2004; Wu et al, 2007). In many patients, these curative treatments are not efficient in facilitating rapid wound healing; non-healing diabetic ulcers cause an extremely heavy burden on their families and the healthcare system (2013; Zhang et al, 2020). It is urgent to develop an affordable and efficacious treatment strategy

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