An elastin-based vasculogenic scaffold promotes marginal islet mass engraftment and function at an extrahepatic site

Abstract

In islet transplantation, one of the major obstacles to optimal engraftment is the loss of islet natural vascularization and islet-specific extracellular matrix (ECM) during the islet isolation process. Thus, transplanted islets must re-establish nutritional and physical support through formation of new blood vessels and new ECM. To promote this critical process, we developed an elastin-based vasculogenic and ECM-promoting scaffold engineered for extrahepatic islet transplantation. The scaffold by design consisted of type I collagen (Coll) blended with 20wt% of elastin (E) shown to promote angiogenesis as well as de novo ECM deposition. The resulting "CollE" scaffolds h ad interconnected pores with a size distribution tailored to accommodate seeding of islets as well as growth of new blood vessels. In vitro, CollE scaffolds enabled prolonged culture of murine islets for up to one week while preserving their integrity, viability and function. In vivo, after only four weeks post-transplant of a marginal islet mass, CollE scaffolds demonstrated enhanced vascularization of the transplanted islets in the epididymal fat pad and promoted a prompt reversal of hyperglycemia in previously diabetic recipients. This outcome was comparable to that of kidney capsular (KC) islet transplantation, and superior to that of islets transplanted on the control collagen-only scaffolds (Coll). Crucial genes associated with angiogenesis (VEGFA, PDGFB, FGF1, and COL3A1) as well as de novo islet-specific matrix deposition (COL6A1, COL4A1, LAMA2 and FN1) were all significantly upregulated in islets on CollE scaffolds in comparison to *

White Adipose Tissue as a Site for Islet Transplantation

“…The transplant efficacy of ITx using white adipose tissue is unclear. However, some groups have successfully achieved normoglycemia using the epididymal fat pad by one donor [49,53,56] and others by more than two donors [42,50,52,55,[62][63][64][65]67]. In our experience, 200 islets can be obtained from a single mouse.…”

“…Although the epididymal fat pad has the disadvantage of systemic insulin release, it has been used for the experimental ITx studies instead of the omentum because of its ease in operability (Figure 1). Many studies have shown its usefulness in assessing various types of bioscaffold, including elastin [49], fibrin [50], poly(lactide-co-glycolide) [51][52][53][54], polyethylene glycol [13,42,[55][56][57], alginate (ALG) [58,59], and poly-l-lysine [60], much like the omentum (Table 3). Unlike in rodents, dogs, and monkeys, subcutaneous tissue in humans is composed of connective tissue and white adipose tissue.…”

Bioabsorption of Subcutaneous Nanofibrous Scaffolds Influences the Engraftment and Function of Neonatal Porcine Islets

“…The importance of extracellular matrix (ECM) components such as collagen, laminin and fibronectin for islet function has been demonstrated, signifying their critical role in organizing networks between endocrine cells, vascular endothelial cells, neural cells and immune cells [ 50 , 51 , 52 , 53 ]. These interactions facilitate the rapid signalling between the islet graft and host tissues, which enables graft survival, viability, restored insulin secretion and tissue remodelling [ 50 , 54 ]. During the enzymatic and mechanical digestion process inherent in islet isolation, the native ECM and the vasculature are disrupted [ 55 ], thus leading to a decrease in cell viability and suboptimal transplant outcomes [ 56 ].…”

Functionalised Hybrid Collagen-Elastin for Acellular Cutaneous Substitute Applications

“…Elastin may produce these effects by altering the differentiation of fibroblasts into contractile myofibroblasts [5][6][7] and promoting new elastin expression in a healing wound [8][9][10]. In addition, elastin has been shown to enhance angiogenesis [11,12]. Even though elastin has demonstrated positive effects on dermal function and regeneration, its insolubility drawbacks in three-dimensional bioscaffold construction remain underexplored.…”