Introduction: Foreign body responses are a series of host immune cell mediated reactions that impacts the performance of implanted biomedical devices[1]. Host recognition of biomaterial surfaces initiates a series of inflammatory events that result in the collagenous encapsulation of implanted materials leading to device faliure[1]. This emphasizes the critical need for biomaterials that do not elicit foreign body responses to overcome this key barrier to long-term biomedical device function[1]. One prime example for the utility of this technology is for the development of a bioartificial pancreas (Immunoisolated insulin producing pancreatic beta cells) for the treatment of type-1 diabetes[1]. The immunoisolation of beta cells with porous biomaterials to provide an immune-barrier is a potential viable treatment strategy for type-1 diabetic patients[2]. However, clinical implementation has been challenging due to host immune responses to implant materials[1]. To address this challenge we have focused our efforts on the development of improved biomaterials for use in pancreatic beta cell transplantation. Herein we demonstrate potential of encapsulated human embryonic stem cell derived beta (SC-β) cells[3] in immunocompetent animals for the restoration of blood glucose control without immune suppression.
Methods: To enable the discovery of novel superbiocompatible biomaterials we have developed a high-throughput pipeline for the synthesis and in vivo evaluation of >1000 alginate biomaterial formulations and prototype devices. Lead formulations where used to generate optimized porous alginate hydrogel capsules fabricated with tuned geometries[2] to enhance biocompatibility and evaluated for ability to protect encapsulated SC- β cells[3] in immune competent diabetic rodents and non-human primates.
Figure 1: Development of a bioartificial pancreas for long-term immunoisolation of beta cells.
Results: We have created the first large library of hydrogels and identified a lead alginate analogue and capsule formulation that shows minimal recognition by macrophages and other immune cells and almost no visible fibrous deposition in rodents and for at least 6 months in non-human primates. Viable SC-β cells were encapsulated within novel alginate based capsule formulations. Human c-peptide and in vivo glucose responsiveness demonstrate robust and therapeutically relevant long-term glycemic control. Retrieved implants revealed viable insulin-producing cells after 174 days in immune-competent mice.
Discussion: Our results demonstrate tha the combination of tuned geometry and distribution of the chemical modification results in a unique hydrogel surface that inhibits macrophage adhesion, effectively mitigating the foreign body response to the biomaterial. Significantly our lead formulation has enabled us to achieve the first long-term glycemic correction of a diabetic, immune-competent animal model with SC-β cells encapsulated using our novel superbiocompatible chemically modified alginate formulation.
Conclusions: We report the first long term glycemic correction of a diabetic, immune-competent animal model with human SC-β cells. These results lay the groundwork for future human studies with these formulations with the goal of achieving long-term replacement therapy for type 1 diabetes.
This work was supported by the Juvenile Diabetes Research Foundation (JDRF) (Grant 17-2007-1063), the Leona M. and Harry B. Helmsley Charitable Trust Foundation (Grant 09PG-T1D027), the National Institutes of Health (Grants EB000244, EB000351, DE013023 and CA151884), the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute, and also by a generous gift from the Tayebati Family Foundation. O.V. was supported by JDRF and DOD/CDMRP postdoctoral fellowships (Grants 3-2013-178 and W81XWH-13-1-0215, respectively).
References:
[1] Dolgin, E. Encapsulate this. Nat Med 20, 9-11 (2014).
[2] Veiseh, O., et al. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nat Mater 14, 643-651 (2015).
[3] Pagliuca, F.W., et al. Generation of functional human pancreatic beta cells in vitro. Cell 159, 428-439 (2014).