Development of a Bioartificial Vascular Pancreas

Abstract

Transplantation of pancreatic islets has been shown to be effective, in some patients, for the long-term treatment of type 1 diabetes. However, transplantation of islets into either the portal vein or the subcutaneous space can be limited by insufficient oxygen transfer, leading to islet loss. Furthermore, oxygen diffusion limitations can be magnified when islet numbers are increased dramatically, as in translating from rodent studies to human-scale treatments. To address these limitations, an islet transplantation approach using an acellular vascular graft as a vascular scaffold has been developed, termed the BioVascular Pancreas (BVP). To create the BVP, islets are seeded as an outer coating on the surface of an acellular vascular graft, using fibrin as a hydrogel carrier. The BVP can then be anastomosed as an arterial (or arteriovenous) graft, which allows fully oxygenated arterial blood with a pO2 of roughly 100 mmHg to flow through the graft lumen and thereby supply oxygen to the islets. In silico simulations and in vitro bioreactor experiments show that the BVP design provides adequate survivability for islets and helps avoid islet hypoxia. When implanted as end-to-end abdominal aorta grafts in nude rats, BVPs were able to restore near-normoglycemia durably for 90 days and developed robust microvascular infiltration from the host. Furthermore, pilot implantations in pigs were performed, which demonstrated the scalability of the technology. Given the potential benefits provided by the BVP, this tissue design may eventually serve as a solution for transplantation of pancreatic islets to treat or cure type 1 diabetes.

Expanding tubular microvessels on stiff substrates with endothelial cells and pericytes from the same adult tissue

“…It can be used in tissue vascularization, which is a core question in tissue engineering. 57 For example, intensive efforts have been made to fabricate vascularized tissue and organ models, such as the vascularized pancreas, 58 , 59 adipose tissue, 60 bladder, 61 islet, 62 skin, 63 and so on. The model presented in this study can be further improved and applied in these ex vivo settings in the future.…”

Mathematical and Computational Modeling of Poroelastic Cell Scaffolds Used in the Design of an Implantable Bioartificial Pancreas

“…In particular, we mention here an excellent study by Buchwald [8] that informed our own work in terms of advection-reaction-diffusion models for oxygen concentration, where an advection-reaction-diffusion model and the parameters were provided. These parameters and a simplified oxygen concentration and consumption computational model was recently utilized in a study of a simplified bioartificial pancreas without membrane encapsulation, consisting of an acellular tubular graft "lined" with pancreatic islets coated on the outer surface using a hydrogel carrier [9]. In a similar set-up, the work in [10] investigated an in vitro cylindrical perfusion system to study oxygen effects on islet-like clusters immobilized in alginate hydrogel.…”

Toward 3D-bioprinting of an endocrine pancreas: A building-block concept for bioartificial insulin-secreting tissue

“…Especially in terms of oxygen and nutrient diffusion the variable size of human islets 4 needs to be considered to avoid function loss and central core necrosis. 3,43 We addressed this requirement by performing simulations of diffusion gradients and metabolic activity of human islets. The intention was to enable different boundary conditions for variations of parametric scaffold architecture applicability, thus avoiding iterative experimental designs of a macroscopic device from bench to bedside.…”