Support for Small Business Innovation Research (SBIR) to Development and Testing of New Technologies and Bioengineering Solutions for the Advancement of Cell Replacement Therapies for Type 1 Diabetes (R43/R44 Clinical Trial Not Allowed)

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, because of support by NIDDK/NIH and other funding agencies, 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: Delivery Technologies and Implantation Strategies Development of bio-barrier/encapsulation systems able to satisfy GMP standards and regulatory agency specifications with adequate quality control measures during manufacture that may be suitable for clinical application of the cell replacement delivery device. 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 a NHP and/or human environment. Optimization of longer-term culture and long-term storage methods to improve access to islet cells replacement/transplantation interventions. Optimization of high-throughput screening for selection of suitable implantable device materials. Novel methods to test the in vivo biocompatibility of transplanted capsules/devices and the cell preparations. Generation of biomaterial layers with a bioactive surface capable of actively altering the localized implant environment. Novel biomimetic and immuno-engineering strategies for the development of immune evasive biomaterials/devices effective with no need of systemic immunosuppression Study feasibility of pre-vascularization of devices before implantation to ensure better cell viability and function. Agents incorporated in implantable devices to enhance vascularization at the tissue/device interface during the healing process after implantation. Novel methods/technologies to ensure proper and efficient long-term oxygenation and nutrient delivery to maintain high viability and function of the implanted islets/cells in vivo. Efficient incorporation of oxygen carrying/generating agents to biomaterials/micro-nano devices. Development of devices/technologies to facilitate implantation in extrahepatic site. Development of retrievable technologies for ex-vivo assessment of functional properties and if needed for safety reasons. Non-invasive assessment of pO2 within devices and at transplant sites Cell Sources and Functional Testing Characterization of oxygenation, viability and potency of islets or human stem cell derived (beta-cells/islets) within encapsulation devices in vitro and/or in vivo. Non-invasive evaluation of cell viability and function within encapsulation devices in vitro and in vitro (e.g., imaging technologies for this purpose). Devise better standardization methods to define viability and functional quality of donor islets and human stem cell-derived beta cells/islets rapidly and accurately. Novel biomimetic and immuno-engineering strategies for the development of immune evasive biomaterials/devices effective in an NHP/human environment with no need of systemic immunosuppression. Bio-immuno-engineering of islets/cells to make them resistant to allo/autoimmune rejection without the need of systemic immunosuppression Elucidation of factors/mechanisms that lead to islet/cell exhaustion and potential interventions to ensure functional capacity. Optimized methods for storage and shipment of cells/devices for transplantation. Methods/technologies to improve feasibility of using engineered beta/islet cells, such as human progenitor cells and induced pluripotent stem cells, as sources for cell replacement with long-term graft acceptance/tolerance. Cell products should demonstrate stability in terms of the phenotype, functional capability, and viability when implanted. Development of techniques to maintain and expand human islets and 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. Non-invasive assessment of vascularization and blood flow around implanted encapsulation devices, especially in conjunction with functional (oxygen) measurements Pre-clinical Assessment Novel in vitro and in vivo pre-clinical disease models such as biomimetic/humanized that may inform feasibility of clinical transplantation. Studies to evaluate the feasibility of co-transplantation with other cell types that may improve long term viability and functional capability of the islets/cells. Development and testing of bioengineering strategies that may improve islet/cell viability and resistance to allo/autoimmune rejection and control tumorigenesis after implantation. See Section VIII. Other Information for award authorities and regulations. Section II. Award Information Funding Instrument Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity. Application Types Allowed New (Phase I, Fast-Track) Renewal (Phase II) New (Phase II SBIR, Direct Phase II) The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for the FOA. Clinical Trial? Not Allowed: Only accepting applications that do not propose clinical trials Need help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards The NIDDK intends to commit $3,000,000 in FY 2022 to fund 3-8 awards. Award Budget Budgets up to $300,000 total costs per project for Phase I and up to $2,000,000 total costs per project for Phase II may be requested. Award Project Period Durations up to 1 year for Phase I and up to 2 years for Phase II may be requested.