Abstract
The anterior chamber of the eye (ACE) has emerged as a promising clinical islet transplantation site because of its multiple advantages over the conventional intra-hepatic portal site. This includes reduced surgical invasiveness and increased islet graft survival rate. It also allows for enhanced accessibility and monitoring of the islets. Although the ACE is initially an immuno-privileged site, this privilege is disrupted once the islet grafts are re-vascularized. Given that the ACE is a confined space, achieving graft immune tolerance through local immunosuppressive drug delivery is therefore feasible. Here, we show that islet rejection in the ACE of mice can be significantly suppressed through local delivery of rapamycin by carefully designed sustained-release microparticles. In this 30-day study, allogeneic islet grafts with blank microparticles were completely rejected 18 days post-transplantation into mice. Importantly, allogeneic islet grafts co-injected with rapamycin releasing microparticles into a different eye of the same recipient were preserved much longer, with some grafts surviving for more than 30 days. Hence, islet allograft survival was enhanced by a localized and prolonged delivery of an immunosuppressive drug. We envisage that this procedure will relieve diabetic transplant recipients from harsh systemic immune suppression, while achieving improved glycemic control and reduced insulin dependence.
Highlights
Diabetes is a debilitating disease with high morbidity[1]
In vitro drug release in phosphate buffer saline (PBS) solution (Fig. 1b) showed rapamycin being released through a diffusion controlled manner, with a rate constant of 0.7176 (R2 = 0.97)[26]
Since the allogeneic islet rejection only occurs when the islets become vascularized, the immunosuppressive treatment has to start as early as 3 days post transplantation, and its targeted dose has to be maintained above the working concentration for a sustained duration
Summary
Diabetes is a debilitating disease with high morbidity[1]. Poor glycemic control results in long-term complications such as blood vessel damage, nerve damage, kidney failure and cardiovascular disease[2]. Low oxygen tension, sheer physical stress within the hepatic portal system and the induction of inflammation lead to significant islet graft dysfunction and loss[9,10,11,12] To compensate for this loss, a large number of islets are transplanted into a patient. The current accepted standard of islet transplantation is a minimum of 5000 isolated islet equivalents per kilogram (IEQs/kg) body weight to relieve insulin dependence[8] To achieve this number, multiple donors may be required to treat a single patient, which inadvertently strains donor adequacy. By exploiting engineered particulate drug delivery systems for islets transplanted into the ACE, we have the ability to circumvent current clinical challenges of long-term immunosuppression and low islet functional efficacy. We hypothesize that a novel engineered sustained-releasing immunosuppressive microparticle system can be co-transplanted together with islets into the ACE, to prevent graft-host immune rejection in a localized milieu
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