Development of New Technologies and Bioengineering Solutions for the Advancement of Cell Replacement Therapies for Type 1 Diabetes (R43/R44)

Despite clear progress made during the last 15 years on cellular transplantation for T1D, the most recent results demonstrate a long term limited viability of engrafted islets and, as a result, limited insulin independence under different novel modalities of immunosuppressive (IS) regimens tested.  In addition, even the most innovative IS regimens required for transplant survival still have significant immediate side effects and long-term safety is uncertain. These problems together with the scarcity of donor organs and the complexity of transplants mandates a renewed emphasis on the investigation of novel methods within the field of tissue engineering for the development of a bio-artificial, cell-based hormone replacement therapy that may minimize the need of IS. To support this, it is necessary to develop/optimize novel/smart/safe biomaterials, scaffolds, bio-matrices and bio-barriers that may protect grafted cells from immune rejection and simultaneously promote appropriate vascularization/innervation with an efficient exchange of nutrients to optimize cellular long-term survival and proper function.  It is also necessary to investigate methods to use different cell sources including human progenitor cells and induced pluripotent stem cells as a valid option for cell replacement therapy.  Also, further research on the potential use of xenogeneic cells/islets is needed. Recent advances in this field as a result of support by NIDDK and the establishment of the JDRF-Helmsley Encapsulation Consortium demonstrate feasibility of these technologies mainly in rodent pre-clinical models of T1D.  However, important obstacles remain before long-term preclinical efficacy in non-human primates (NHP) and human clinical feasibility may be verified. Examples of areas that need further emphasis/development are:

• Development of encapsulation systems able to satisfy GMP standards and regulatory agency specifications including strict assurance of sterility, avoidance of bioburden, safety, and reproducibility of a product with adequate quality control measures during manufacture thus may be suitable for the clinical application of encapsulated islet technologies. System characteristics may also include: consistency, uniformity and monodispersity of hydrogels, defined number of islets per capsule, limited batch to batch variability, complete and gentle encapsulation, minimized time of islets out of culture and scalability.
• Development and optimization of novel biomaterials: highly biocompatible, stable, inert, and of a sufficient porosity to not interfere with the encapsulated cell’s physiological regulatory response to stimuli in NHP and/or human environment.
• Optimization of long-term storage methods to improve access to islet cells replacement/transplantation interventions.
• Optimization of high-throughput screening for selection of suitable encapsulation materials.
• Novel methods to test the in vivo biocompatibility of transplanted capsules/devices and the cell preparation.
• Generation of biomaterial layers with a bioactive surface capable of actively altering the localized implant environment.
• Study feasibility of pre-vascularization of devices before cell implantation to ensure better cell viability and function.
• Novel methods/technologies to ensure proper and efficient long-term oxygenation and nutrient delivery to maintain high viability and function of the encapsulated islets/cells in vivo.
• Efficient incorporation of oxygen carrying/generating agents to biomaterials/micro-nano devices.
• Non-invasive assessment of pO2 within devices and at transplant sites – at multiple time points prior to and post-transplant (hrs/days/weeks/years)
• Non-invasive evaluation of cell viability and function within encapsulation devices in vivo and in vitro (e.g., imaging technologies for this purpose).
• Devise better standardization methods to rapidly and accurately define viability and functional quality of donor islets and human stem cell-derived beta cells/islets.
• Novel biomimetic strategies for the development of immune evasive biomaterials/devices effective in a NHP/human environment with no need of systemic immunosuppression.
• Elucidation of factors/mechanisms that lead to islet exhaustion and potential interventions to ensure islets’ functional capacity.
• Development of devices/technologies to facilitate encapsulated islets implantation in extrahepatic sites including factors that may facilitate functional long-term intraperitoneal implantation.
• Optimized methods for storage and shipment of encapsulated cells/devices for transplantation.
• Methods/technologies to improve feasibility of using non-islet engineered beta/islet cells, such as human progenitor cells and induced pluripotent stem cells, as sources for T1D cell replacement therapy able to induce long-term graft acceptance/tolerance.
• Development of techniques to maintain and expand human physiologically responsive insulin-producing cells derived from stem/progenitor cells to make them suitable for cell replacement and disease modeling.
• Development of protocols for standardization of cell sources as reagents - pig cells, human stem cell derived progenitors and functional beta-like cells/islets/preps.
• Novel in vitro and in vivo pre-clinical disease models such as biomimetic/humanized that may better predict human responses to cells and material/devices.