Objective
The objective for this 3-year project is to achieve the following milestones: (i) translate the oxygen-generating materials and cell factories to work directly within the FRESH 3D bioprinting process, (ii) build and validate 2-component combinations of collagen scaffolds with either oxygen-generating materials or immune-modulating cell factories to establish the ability to integrate capabilities, and (iii) build and validate 3-component combinations of collagen scaffolds, oxygen-generating materials, and cell factories into constructs that provide therapeutic efficacy in a rigorous diabetic preclinical model by supporting islet viability, guiding robust vascularization and function, and avoiding systemic immunosuppression.
Background Rationale
Decades of research has shown that rapid re-vascularization of islet grafts is critical for the durable success of transplantation because hypoxia exposure from the moment of transplantation broadly impacts implant outcomes. While it is unclear if islets exposed to hypoxia can recover function when re-oxygenated, incremental increases in oxygen concentration can result in significant improvements. The OxySite oxygen-generating materials developed by the Stabler lab will provide this capability over the short-term as host vascularization grows into the scaffolds. To achieve islet survival longer-term, the surrounding extracellular matrix (ECM) is critical for cell support (mitigation of anoikis), as well as promoting robust vascularization, and biomaterials and growth factors can promote islet survival and function. Freeform reversible embedding of suspended hydrogels (FRESH) 3D bioprinting developed by the Feinberg lab creates functional tissues and computationally-generated multiscale vasculature with distinct 3D control of the ECM and cells. Further, the Feinberg lab has already published on using FRESH with PDMS-based materials and encapsulated cell spheroids, building confidence that OxySite and cell factories can be readily integrated in this process as additional “bioinks”. Finally, integration of cell factories capable of modulating local immune responses represents a clinically viable solution towards dampening or even eliminating the need for systemic immunosuppression.
Description of Project
This proposal seeks to combine technologies from the Feinberg, Stabler and Veiseh laboratories in order to develop advanced bioengineered tissue scaffolds for cell therapy in T1D. Specifically, we are focused on using 3D bioprinting to integrate oxygen-generating materials, pro-angiogenic extracellular matrix (ECM) scaffolds, and immune modulatory cells to enable islet engraftment and function within the subcutaneous space. This will address three critical capabilities needed for the successful engraftment of beta cells by providing (i) oxygen generation within the scaffold to ensure short-term viability, (ii) pro-angiogenic ECM scaffolds to accelerate vascular ingrowth for long-term viability and function, and (iii) cytokine producing cell factories for local immune modulation and prevention of graft rejection. Furthermore, we will address key advanced manufacturing capabilities needed for clinical translation by integrating all three innovative approaches within a single and scalable, biofabrication process. If successful, this will serve as the foundation to move forward with more advanced pre-clinical models and potentially lead to clinical translation of a bioengineered tissue construct that can restore normal insulin production for T1D patients.
Anticipated Outcome
We anticipate being able to 3D bioprint a bioengineered tissue construct that contains islets, immune modulatory cell factories and OxySite to support viability during rapid vascularization and engraftment in vivo. These centimeter scale volumetric constructs. These constructs will be validated using a combination of in vitro assays and in vivo pre-clinical animal models.
Relevance to T1D
The relevance of the bioengineered islet tissue construct we are developing is to provide an improved therapeutic device for islet transplantation into Type I diabetics. The synergistic integration of technologies from JDRF-funded Feinberg, Stabler and Veiseh labs will enable rapid vascularization of implanted islets that maintain high viability, robustly engraft for maximum insulin secretion, and immune tolerance for long-term survival without the need for systemic immunosuppression.