Objective
The objective of this project is to evaluate cell-based strategies to improve the vascularization of transplanted pancreatic islets using a 3D bioprinted construct, validated based on engraftment, survival and function when transplanted into diabetic mice.
Background Rationale
Pancreatic islets in the body require a large volume of blood for their survival and function, particularly to achieve rapid regulation of blood sugar through insulin secretion. Isolating islets from donor pancreases severs this blood supply, necessitating some method to reestablish vascularization after transplantation. Current clinical practice injects the islets into the portal vein where they become lodged within the liver vasculature, and though exposed to blood, the environment is not ideal for multiple reasons that ultimately result in islet loss. A range of alternative transplantation sites such as the kidney capsule have been investigated, however, limited and slow revascularization has remained a barrier.
FluidForm Bio’s FRESH 3D bioprinting technology enables the engineering of tissue scaffolds using materials native to the body such as collagen. Using these native materials more easily allows cells to form microvessels compared to traditional scaffolds engineered from foreign synthetic materials. By allowing cells to form microvessels in tissue scaffolds containing islets, we can form a microvascular-like network around islets prior to transplanting them (pre-vascularization). Once transplanted, the patient’s own blood vessels connect to the pre-vascularized network to accelerate the rate at which islets are revascularized, minimizing early islet death and improving long-term islet health and function.
Description of Project
Current strategies to cure type 1 diabetes (T1D) by transplanting pancreatic islets into patients have had limited success, with <25% of patients achieving insulin independence after 5 years using hepatic portal vein injection into the liver. This poor success rate is due to a lack of locations in the body that can rapidly vascularize the transplanted islets to support their long-term health and function while also preventing immune rejection. FluidForm Bio’s innovative approach to islet transplantation is to bioengineer an islet-laden tissue scaffold that achieves rapid vascularization upon implantation under the skin in the subcutaneous space, which eventually could be a simple outpatient procedure. This new approach is enabled by FluidForm’s FRESH 3D bioprinting technology that uses materials native to the body such as collagen to better support islet health and promote rapid vascularization, significantly better than the foreign and synthetic materials previously used. Further, capillary-like blood vessel networks can be engineered into the device prior to transplant to potentially achieve vascularization even faster in the body. In this work, FluidForm Bio will compare islet-laden tissue scaffolds with or without pre-vascularization and assess islet survival and function, and the ability to restore normal blood sugar levels in a diabetic mouse model. By building the right environment for transplanted islets and vascular cells to thrive in, FluidForm Bio is creating a transplantation approach that is also compatible with the next-generation of cell-based therapies for T1D using gene-edited, human stem cell-derived islet-like cells that can restore euglycemia without the need for systemic immunosuppression.
Anticipated Outcome
Pre-vascularized islet and islet-only scaffolds will be implanted subcutaneously into diabetic, immunocompromised mice to study the rate at which the different conditions can return the mice back to normoglycemia. We hypothesize that our pre-vascularized islets scaffolds that have microvascular-like vessel networks at the time of implantation will improve the rate of re-vascularization of the islets after the transplant, as compared to scaffolds containing only islets. By more rapidly vascularizing the transplanted engineered tissues, we expect pre-vascularized scaffolds to return the diabetic mice’s blood sugar back to normal levels in a shorter amount of time, and with a higher rate of success than islet-only scaffolds.
Relevance to T1D
For decades researchers have transplanted encapsulated islets to protect them from the patient’s immune system. However, this encapsulation comes at the cost of vascularization around the islets, which is critical to long-term health and function. As a result, even the most successful encapsulation-based approaches see the transplanted islets lose function as the body eventually walls off the encapsulated islets with fibrotic tissue.
FluidForm Bio is developing a different approach, instead of encapsulation, we are focused on vascularization first, which will enable transplantation under the skin in the subcutaneous space. This proposal is a key step towards that goal by identifying the best combination of islets and other vascular cells to incorporate into bioprinted tissues constructs to achieve rapid, durable, and functional engraftment. Our approach is also compatible with the next-generation of cell-based therapies for T1D using stem cell-derived beta cells gene-edited to not provoke the immune system, providing a pathway to a T1D cure that is simple to deliver and does not require systemic immunosuppression.