A scalable device-less biomaterial approach for subcutaneous islet transplantation

Abstract

In this study methacrylic acid copolymer coated tubes generated a robust vascular 15 response in the subcutaneous space, which was critical to support islet transplantation in a 16 streptozotocin-induced diabetic mouse model. More importantly, the subcutaneous pre-17 vascularization approach using this copolymer coating was scalable into a larger allogeneic rat 18 model and returned animals to normoglycemia for up to 70 days. This platform highlights the 19 potential of a scalable biomaterial approach for pre-vascularization of the subcutaneous space 20 in larger animal models. 21 22 23 24 25 26 27 28 29 30 31 32 33 Abstract: 36The subcutaneous space has been shown to be a suitable site for islet transplantation, however 37 an abundance of islets is required to achieve normoglycemia, often requiring multiple donors. 38The loss of islets is due to the hypoxic conditions islets experience during revascularization, 39 resulting in apoptosis. Therefore, to reduce the therapeutic dosage required to achieve 40 normoglycemia, pre-vascularization of the subcutaneous space has been pursued. In this study, 41we highlight a biomaterial-based approach using a methacrylic acid copolymer coating to 42 generate a robust pre-vascularized subcutaneous cavity for islet transplantation. We also 43 devised a simple, but not-trivial, procedure for filling the cavity with an islet suspension in 44 collagen. We show that the pre-vascularized site can support a marginal mass of islets to 45 rapidly return streptozotocin-induced diabetic SCID/bg mice to normoglycemia. Furthermore, 46immunocompetent Sprague Daley rats remained normoglycemia for up to 70 days until they 47 experienced graft destabilization as they outgrew their implants. This work highlights 48 methacrylic acid-based biomaterials as a suitable pre-vascularization strategy for the 49 subcutaneous space that is scalable and doesn't require exogenous cells or growth factors. 50 51 52 53 54 55 56 57 58 59 60 3 61 1.0 -Introduction: 62The subcutaneous space is currently being pursued as an alternative transplant site for 63 pancreatic islets, because it can support a large transplant volume (assuming a large area is 64 feasible), is minimally invasive, and is accessible for graft retrieval in the event of 65 complications 1,2 . However, the subcutaneous site is poorly vascularized and must be modified to 66 support the engraftment of pancreatic islets. There have been various successful approaches 67 for subcutaneously delivering pancreatic islets, such as delivering them within biomaterials 3 , 68 with cells 1,4 , or in large macro devices 5,6 . These approaches all support islet engraftment; 69 however, many require an excess of islets to achieve normoglycemia. 70Alternative strategies to subcutaneously deliver pancreatic islets have been pursued, 71 using a two-step approach to first prepare a cavity within the subcutaneous space, followed by 72 islet transplantation into the preformed cavity 2,5,7 . These approaches focus primarily on reducing 73 the initial inflammatory re...

In vivo vascularization and islet function in a microwell device for pancreatic islet transplantation

“…However, this difference was no longer observed after 28 days of implantation at both sites. Regression of blood vessels, in absence of transplanted islets, has also been observed by others [22].…”