Towards an additive manufactured macroencapsulation device for islet cell replacement therapy
Levey, Ruth E.
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Islet encapsulation devices can induce a Foreign Body Response (FBR) and the formation of a hardened avascular fibrotic capsule. This FBR is heightened when the device features a smooth surface as fibrous tissue is unable to adhere to the device, causing friction and thus instigating a substantial immunological reaction causing implant failure. In this thesis we examine whether additive manufactured multiscale porous topographies can promote optimal tissue integration and vascularisation for the purpose of long-term functional islet macroencapsulation devices. Devices exhibiting progressively more complex surface topographies (quantity of pores, microtexture and macrotexture) were implanted subcutaneously in a rodent model. Upon explant, analysis of the fibrous capsule, angiogenic and macrophage response were performed. To determine whether this macroencapsulation device can support syngeneic islet survival and function, intra-peritoneal delivery of islets encapsulated within multiscale porosity macroencapsulation devices was performed in an STZ-induced diabetes rodent model. To validate scalability and functionality, devices were implanted in an STZ-induced diabetes pig model for two weeks before the blood glucose levels were measured in response to the infusion of insulin through the device. SEM and MicroCT imaging demonstrated no tissue attachment and a noticeable void between the smooth surface devices and surrounding tissue. A significant increase in capsule thickness, vessel density and maturity were associated with complex surface topographies with no difference in macrophage populations. Moreover, macroencapsulated syngeneic islets maintained glucose responsiveness and function for up to 8 weeks. Bioavailability was equal when the same dose of insulin is delivered via the device vs subcutaneously in a diabetic pig model. The additive manufactured multiscale porous topographies we developed on silicone macroencapsulation devices increased tissue integration, vascularity and supported extended islet function in vivo. Our findings demonstrated clinical scalability and large animal functionality with the ability to resolve diffusion limitations of current macroencapsulation devices. We aim to continue the translation of the multiscale porosity macroencapsulation device and improve the outcomes of people with Type 1 diabetes through the development of viable, long term implants.