Preclinical studies of antioxidant-based therapies for diabetic wound healing have yielded promising results. Redox-based therapeutics constitute a novel approach for the treatment of wounds in diabetes patients that deserve further investigation. Antioxid. Redox Signal. 27, 823-838.

There is a growing body of work dedicated to producing acellular lung scaffolds for use in regenerative medicine by decellularizing donor lungs of various species. These scaffolds typically undergo substantial matrix damage due to the harsh conditions required to remove cellular material (e.g., high pH, strong detergents), lengthy processing times, or pre-existing tissue contamination from microbial colonization. In this work, a new decellularization technique is described that maintains the global tissue architecture, key matrix components, mechanical composition and cell-seeding potential of lung tissue while effectively removing resident cellular material. Acellular lung scaffolds were produced from native porcine lungs using a combination of Triton X-100 and sodium deoxycholate (SDC) at low concentrations in 24 hours. We assessed the effect of matrix decellularization by measuring residual

Decellularized biologic scaffolds are gaining popularity over synthetic biomaterials as naturally derived materials capable of promoting improved healing. Nevertheless, the most widely used biologic material - acellular dermal matrix (ADM) - exhibits slow repopulation and remodeling, which prevents integration. Additionally, engineering control of these materials is limited because they require a natural source for their production. In the current report, we demonstrate the feasibility of using genetically engineered animals to create decellularized biologic scaffolds with favorable extracellular matrix (ECM) properties. Specifically, we utilized skin from thrombospondin (TSP)-2 KO mice to derive various decellularized products. Scanning electron microscopy and mechanical testing showed that TSP-2 KO ADM exhibited an altered structure and a reduction in elastic modulus and ultimate tensile strength, respectively. When a powdered form of KO ADM was implanted subcutaneously, it was able to promote enhanced vascularization over WT. Additionally, when implanted subcutaneously, intact slabs of KO ADM were populated by higher number of host cells when compared to WT. In vitro studies confirmed the promigratory properties of KO ADM. Specifically, degradation products released by pepsin digestion of KO ADM induced greater cell migration than WT. Moreover, cell-derived ECM from TSP-2 null fibroblasts was more permissive to fibroblast migration. Finally, ADMs were implanted in a diabetic wound model to examine their ability to accelerate wound healing. KO ADM exhibited enhanced remodeling and vascular maturation, indicative of efficient integration. Overall, we demonstrate that genetic manipulation enables engineered ECM-based materials with increased regenerative potential.

Impaired wound healing is a major complication of diabetes and can lead to the development of chronic wounds in a significant portion of diabetes patients. Despite the risks posed by impaired healing, treatment strategies for diabetic wounds remain limited due to an incomplete understanding of the underlying pathological mechanisms. Previous studies have demonstrated that overexpression of thrombospondin‐2 (TSP2), a matricellular protein released after tissue injury, is associated with significant delays in dermal healing in various mouse models. Consistently, wounds lacking TSP2 (TSP2 KO) heal faster than wounds in wild‐type mice or mice with elevated TSP2. Thus, the present study aimed to examine the role of TSP2 in delayed healing in diabetes. First, we evaluated TSP2 expression in human wounds, and found that TSP2 is elevated in wounds from diabetes patients. Then, to determine TSP2's contribution to impaired healing in diabetes, we developed a novel diabetic TSP2 KO mouse model. Though these db/db TSP2 KO mice develop obesity and hyperglycemia comparable to db/db mice, db/db TSP2 KO mice exhibit significantly improved healing. Moreover, primary fibroblasts isolated from db/db TSP2 KO mice exhibit improved migration, providing mechanistic insight into the accelerated healing in these mice. We also studied TSP2 expression in fibroblasts, the major source of TSP2 in the wound, to explore the mechanisms leading to its overexpression in diabetes. Our results showed that TSP2 expression is increased in hyperglycemia, through increased activation of the hexosamine biosynthesis pathway and subsequent O‐GlcNAc modification of transcriptional elements. Overall, the results of this study indicate for the first time that: 1) TSP2 expression is elevated in diabetes and hyperglycemia and 2) TSP2 contributes to impaired healing in diabetes. These results represent a novel role for TSP2 in diabetes complications and a novel target for improving wound healing in diabetes. Support or Funding Information NIH HL107205, NIH GM 072194, Gruber Science Fellowship This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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