Development and evaluation of self-assembled biomaterials to maximise the function of conformal encapsulation of pancreatic islets in type 1 diabetes

摘要

T1D is an autoimmune disease that affects over three million Americans. In T1D, beta cells within pancreatic islets are selectively destroyed by autoimmune responses. Beta cells are responsible for secreting insulin, which regulates glucose metabolism and homeostasis. Patients with T1D become dependent on exogenous insulin injections and are susceptible to acute and chronic complications, which can be life-threatening. Islet transplantation completely eliminates complications of type-1 diabetes (T1D) and can restore insulin secretion and glucose homeostasis, but requires life-long immunosuppression and graft survival is limited. Islet encapsulation may allow transplantation without immunosuppression but it failed in the past three decades. Here we combine a recently developed encapsulation techniques (conformal coating, CC) and new nanotechnology strategies to create an encapsulation platform for islets transplantation without immunosuppression and with enhanced cells survival. In particular I have previously developed PEG-PPS (polyethylene glycol-polypropylene sulfide) amphiphilic block copolymers (Fig. 1) that carry and deliver hydrophobic drugs, in vitro and in vivo, including dexamethasone (DEXA) and cyclosporine-A (CsA). DEXA and CsA are approved by the FDA for utilization in islet transplantation and their synergistic effect with islet encapsulation has been proven. Additionally, I showed that PEG-PPS block copolymers are non-immunogenic and non-toxic. To increase the stability of amphiphilic block copolymers upon oxidation, I recently developed and patented a new family of block copolymers made of PEG-OES (polyethylene glycol-oligoethylene sulfide). The combination of hydrophobicity and crystallinity of PEG-OES blocks drives self-assembling into highly stable linear-fibrils (nano-fibers, Fig. 2A). I found that also PEG-OES nano-fibers allow rapid and stable incorporation of CsA and DEXA without the need for chemical conjugation. The nanofibers and their cargo can be incorporated within CC capsules of the islet before transplantation (Fig. 2B) without compromising GSIR functionality of enclosed human islets. Like PEG-PPS micelles, PEG-OES nano-fibers are able of slowly releasing CsA and DEXA by diffusion, oxidation or reduction in vivo, providing sustained local immunomodulation in the encapsulated graft. PEG-OES nano-fibers are also used here as carriers of perfluorocarbons (PFCs) to increase oxygen diffusivity in the encapsulated islets (Fig. 2). PFCs can dissolve significant quantities of O2 with higher affinity than hemoglobin. PFCs are hydrophobic and therefore they can be incorporated into the hydrophobic core of PEG-OES nano-fibers, promoting the transport of O2 into the CC islets and avoiding any systemic toxicity. The work presented here is intended to improve the existing CC technology to allow its translation into human clinical trials, balancing nutrient transport and immunoisolation of CC capsules through PEG-OES nanocarriers.