A therapeutic convection–enhanced macroencapsulation device for enhancing β cell viability and insulin secretion

Islet transplantation for type 1 diabetes treatment has been limited by the need for lifelong immunosuppression regimens. This challenge has prompted the development of macroencapsulation devices (MEDs) to immunoprotect the transplanted islets. While promising, conventional MEDs are faced with insufficient transport of oxygen, glucose, and insulin because of the reliance on passive diffusion. Hence, these devices are constrained to two-dimensional, wafer-like geometries with limited loading capacity to maintain cells within a distance of passive diffusion. We hypothesized that convective nutrient transport could extend the loading capacity while also promoting cell viability, rapid glucose equilibration, and the physiological levels of insulin secretion. Here, we showed that convective transport improves nutrient delivery throughout the device and affords a three-dimensional capsule geometry that encapsulates 9.7-fold-more cells than conventional MEDs. Transplantation of a convection-enhanced MED (ceMED) containing insulin-secreting β cells into immunocompetent, hyperglycemic rats demonstrated a rapid, vascular-independent, and glucose-stimulated insulin response, resulting in early amelioration of hyperglycemia, improved glucose tolerance, and reduced fibrosis. Finally, to address potential translational barriers, we outlined future steps necessary to optimize the ceMED design for long-term efficacy and clinical utility.

Diabetes mellitus currently burdens over 387 million people worldwide, of which 5 to ∼10% are accounted by patients with type 1 diabetes (T1D) (1). T1D is characterized by the immune destruction of insulin-secreting β cells and the loss of glycemic regulation. Although intensive insulin injection regimens and the use of glucose monitors have been shown to effectively regulate blood glucose, patients are still unable to meet glycemic control targets. In particular, those with severe hypoglycemic events and glycemic lability cannot be effectively stabilized with these technologies (2). In 2000, the Edmonton protocol was developed as a procedure that directly infuses pancreatic islets, isolated from cadaveric donors, into the portal vein of T1D patients. This procedure led to insulin independence in patients for a short period postinfusion (3, 4). However, poor long-term graft survival due to alloimmune and autoimmune rejections and engraftment inefficiency prevents sustained, therapeutic effects (5–7). Although immunosuppressants are coadministered with the transplanted cells to prevent graft rejection, 56% of patients experience partial to complete graft loss after 1 y, and only 10% of patients remain insulin independent after 5 y (4, 8). The majority of patients also experience complications from immunosuppression, including elevated risk of opportunistic infections and cancer (4, 8, 9). In addition, islet transplantation is burdened by a major islet donor shortage, since often two or more human pancreases are needed to achieve a sufficient number of islets (10).The complications of immune rejection could be overcome with macroencapsulation devices (MEDs), in which glucose-sensing, insulin-secreting cell sources like pluripotent, stem cell–derived β clusters (SC-βCs) (11), or other islet sources, are transplanted within an immune-isolating vehicle to promote cell survival and function. In MEDs, islets are housed in a single compartment that selectively permits the exchange of nutrients while obstructing host immune effectors such as cells and antibodies. Over the past few decades, MEDs have successfully restored insulin independence and normoglycemia in T1D animal models (10). However, scaling these devices for human applications has been challenging. Currently, passive diffusion-based MEDs, including Encaptra, βAir Βio-Artificial Pancreas, Cell Pouch, and MAILPAN, are being explored in phase I/II clinical trials (12–14). Nevertheless, these diffusion-based devices still suffer from limitations in the transport of glucose, insulin, and other biomolecules to the core of these devices, which compromise the survival and function of encapsulated cells. Ultimately, these devices are restricted in geometry, thickness, and cell-loading capacity.More specifically, a significant portion of encapsulated cells become nonviable immediately after transplantation because of the lack of vascularization, which results in hypoxia and limited nutrient availability. Thus, during the initial prevascularization period, which lasts ∼14-d posttransplantation, solute exchange and insulin secretion cannot occur effectively using conventional MEDs (15–17). For this reason, many encapsulated cells prematurely lose their function and eventually die. Various strategies have been developed to expediate angiogenesis around the device, especially during the initial hypoxic period after device transplantation, to reduce cell loss. Examples include prevascularization of the device, infusion of vascular endothelial growth factor, and cotransplantation of mesenchymal stem cells (15, 18–21). In another instance, βAir Βio-Artificial Pancreas incorporated a daily refillable oxygen chamber in between two islet slabs to maintain adequate oxygen supply, but the chamber is 15- to 30-fold thicker than islet layers. Despite improvements in cell viability, these strategies still cannot guarantee adequate glucose sensing and insulin release kinetics of the islets, and they further limit the available space for cell packing (22).To supply cells with enough nutrients, it has been suggested that the islet density of the MEDs should be set to 5 to ∼10% of the volume fraction (23). Consequently, a limited mass of islets must be placed within a large device to ensure optimal nutrient distribution. Otherwise, devices exhibit extreme cell loss. For instance, TheraCyte, which packs 70 to ∼216 islet equivalent (IEQ) in 4.5 μL or 1,000 IEQ in 40 μL volume, exhibited poor cell survival (19). The remaining cells were neither capable of restoring euglycemia in rodents (1,000 to ∼2,000 IEQ required) nor sustaining a therapeutic dosage needed for humans (∼500,000 islets) in a reasonably sized device (13, 24–26).To overcome these nutrient delivery challenges and improve cell-loading capacity, we designed a convection-enhanced MED (ceMED) to perfuse the device continuously. We hypothesized that convective nutrient transport in ceMED would 1) deliver more nutrients compared with diffusion-based devices, 2) increase cell survival beyond the distance limit of diffusion, 3) support a three-dimensional (3D), expanded cell layer to increase the loading capacity, 4) improve glucose sensitivity and timely insulin secretion via faster biomolecule transport, and 5) show efficacy in vivo by reducing hyperglycemia before vascularization. Overall, we demonstrated that the convective motion promotes survival of insulin-secreting β cells encapsulated at high density. We also demonstrated that it effectively captures the dynamics of glucose concentrations in the transplantation site, resulting in more appropriate insulin secretion with faster on/off responses. Finally, the ceMED showed early, vascular-independent reduction in blood glucose levels in hyperglycemic rat models several days prior to the critical 14-d posttransplantation.