Objective
Islet transplantation outcomes can be improved by confining islets within a blood vessel enriched platform that concurrently prevents immune rejection. Current cell encapsulation technologies under development do not address both aspects of vascularization and immune protection, simultaneously. To this end, we present the NICHE transplantation platform, which aims at creating a locally immune protected environment enriched with blood vessels for continued sustenance of transplanted islets to achieve long-term function. The NICHE transplantation platform uses stem cells to stimulate blood vessel growth, and releases immunosuppression directly into the islet transplant bed. With this approach, the islets are housed in an immune protected, oxygen- and nutrient enriched environment, while the body is protected from the harmful effects of immunosuppressants.
In our proposed study, our objectives are to identify: 1) optimal amount of stem cells needed to stimulate blood vessel growth within the NICHE, as well as optimal transplantation window and ratio of islets-to-stem cells for improved transplant outcomes; 2) minimal curative dose of islets needed for successful engraftment to durably restore normal blood glucose levels; and 3) ideal dose of local immunosuppressants to protect islets without compromising function. The aforementioned are fundamental parameters that need to be defined to ensure the efficacy of the NICHE for long-term islet transplantation. Addressing these key aspects represents a critical step towards evaluating NICHE function in large animal models, namely diabetic nonhuman primates. The successful completion of this innovative research work will lead to clinical translation, which represents a breakthrough for millions of patients with type 1 diabetes who are dependent on daily glucose measurements and insulin injections.
Background Rationale
Islet transplantation is a viable strategy to manage type 1 diabetes without relying on administration of synthetic insulin, which is costly and requires lifelong strict adherence to repeated dosing regimen. However, in a clinical transplantation procedure, >60% of islets are destroyed within hours by the host immune response, leading to transplant failure. Further challenges include limited supply of islets from cadaveric donors, as well as dispersion and loss of islets due to lack of supportive physiological architecture after transplantation.
As an alternative approach, cell transplantation technologies have emerged to confine islets in a protective barrier, termed encapsulation. The principle of cell encapsulation is to create optimal architecture protecting transplanted islets from the host immune system attack while maintaining their function. A number of cell encapsulation technologies have made their way into clinical studies; however, achieving oxygen and nutrient sustenance via blood vessels and simultaneous immune protection still remain a challenge. Some strategies use a physical barrier to prevent immune destruction of the transplant. Although immune rejection is prevented, blood supply is hindered resulting in lack of oxygen and nutrients supply, leading to the islet death. Strategies that allow for blood supply penetration into the device instead rely on undesirable lifelong systemic immunosuppressant administration. Chronic immunosuppressants exposure to the body affects quality of life and is associated with adverse side effects, which are sometimes fatal, or could lead to susceptibility to infections and secondary diseases such as cancer.
As key immune rejection events occur at the site of transplant and surrounding microenvironment, local immunosuppressant release is a logical approach to address immune rejection of the transplanted islets. Previous approaches for local immunosuppression use hydrogels or scaffolds, which are of limited duration and do not address the oxygen deficiency within the device, thus attenuating the function of transplanted islets. Here we propose an innovative encapsulation strategy (NICHE). The NICHE simultaneously provides both extensive blood vessel supply to maintain an oxygen- and nutrient- rich environment for the transplanted islets and localized immunosuppressant release to evade the adverse effects of systemic immunosuppression.
Description of Project
Islet transplantation offers the potential of restoring the body’s natural ability to produce insulin and control diabetes without relying on pharmaceuticals. Currently, individuals receiving islet transplantation require lifelong whole-body immunosuppressants to avoid immune rejection of the transplant. These whole-body immunosuppressive regimens are associated with life-threatening adverse effects, including increased risk of infections and cancer, severely impacting their quality of life. Moreover, these immunosuppressants are oftentimes toxic to the transplanted islets. Unfortunately, transplantation eventually fails due to lack of blood vessel support for nutrients and oxygen supply to the islets or immune rejection, as whole body immunosuppressants are not fully directed to the transplant site. Given the limited donor-based supply of islets, exorbitant costs of repeated transplantations, and burden of transplant failure, a transformative therapeutic approach is urgently needed for diabetic individuals.
To address the critical need for an improved islet transplantation approach, we developed the NICHE, an innovative technological platform akin to an immune protected bioengineered pancreas. Unlike islet transplantation technologies under development in the academic or industrial settings, the NICHE presents the key innovative feature of local immunosuppressant release. Specifically, the NICHE confines and deliver immunosuppressants in a sustained manner internally within its structure where pancreatic islets are transplanted. By limiting drug exposure to only where needed, the NICHE protects the transplanted cells from immune attack while avoiding the adverse effects of conventional whole-body immunosuppression.
Importantly, the NICHE is designed to address the limitations of the other technologies under development and with a particular focus on end-user acceptability. In this context, the NICHE is approximately 30% smaller than other macroencapsulation technologies under development without compromising islet transplantation capacity. The NICHE presents a thin, flat structure that integrates two distinct reservoirs and is designed to be implanted under the skin in the inner forearm via a minimally invasive outpatient procedure. Upon implantation, the mesenchymal stem cells in the central reservoir stimulates the growth of functional blood vessels within the NICHE, which are necessary to provide oxygen and nutrients to transplanted islets. Next, immunosuppressants are slowly and continuously released within the NICHE from the drug reservoir to create an environment protected from immune attack. Finally, islets are transplanted into the NICHE via a minimally invasive injection procedure through the skin. Clinically, the NICHE is envisioned to provide direct physician access for therapy replenishment as needed, similar to receiving an injection, in an outpatient setting.
This proposal will address key parameters fundamental for eventual clinical translation of the NICHE. Specifically, these parameters are dosage of local immunosuppressants to protect islets without compromising function, amount of stem cells needed to stimulate blood vessel growth within the NICHE, optimal transplantation window and ratio of islets-to-stem cells, and minimal curative dose of islets needed for successful engraftment to durably restore normal blood glucose levels.
Successful completion of the proposed work will result in an innovative islet transplantation platform distinct from any other under development. Achievement of our goal could profoundly impact diabetes management, providing diabetic individuals a life independent of costly pharmaceuticals, bulky insulin pumps, or the reliance on repeated, timed daily insulin injections.
Anticipated Outcome
Using our proposed approach, the neovascularized implantable cell homing and encapsulation (NICHE), we anticipate providing a pancreatic islet transplantation platform for long-term management of T1D. Exploring different transplant windows will allow us to determine the optimal timing for islet transplantation. Through the assessment of different amounts of stem cells, we expect to determine the ideal levels needed to achieve an extensive blood vessel network in the NICHE. By studying different doses of islets for transplantation we will establish the optimal amount needed for successful engraftment in the NICHE. Lastly, by investigating different doses of immunosuppressant released directly into the transplant bed, we expect to identify the ideal dosage needed to protect transplanted islets. Overall, by defining these aforementioned parameters, we will establish optimal curative conditions for the NICHE in diabetic hosts.
Based on our prior research and experience, we expect that the NICHE will provide an oxygen and nutrient rich environment with sustained local immunosuppressant release to achieve successful islet engraftment for long-term T1D management. We anticipate that our platform, once fully optimized and validated for clinical use, will significantly improve T1D management by providing a safe and simple to use platform for the transplantation of insulin producing cells.
Relevance to T1D
Type 1 diabetes (T1D) affects ~3 million people in the United States including children and adolescents and places a $15 billion annual burden on the healthcare system. T1D is caused by the autoimmune destruction of the pancreatic islets, including the insulin-producing beta cells, leading to daily dependence on insulin administration via repeated injections or the use of continuous subcutaneous pumps. Cell transplantation is emerging as a promising treatment option to replace nonfunctioning hormone secreting organs like the endocrine pancreas, or pharmaceutics such as synthetic insulin. For individuals with type I diabetes, islet transplantation aims to replace the function of the destroyed pancreatic beta cells. However, in its current approach, islet transplantation presents various limitations, including costly procedures and high rates of failures, which impedes widespread use.
As an alternative strategy, we developed the neovascularized implantable cell homing and encapsulation (NICHE) platform. The NICHE releases immunosuppressant directly into the pancreatic islets transplant bed, which is extensively enriched with blood vessels for supply of oxygen and nutrients. Our innovative platform has the potential for a breakthrough in cell transplantation, integrating an oxygen and nutrient rich environment and local immunosuppressant delivery in one device. Islets are allowed to thrive in the protective and supportive architecture, and release insulin on demand in response to the body’s needs. Importantly, by avoiding the need for whole body immunosuppression, our approach will improve the quality of life of individuals with type 1 diabetes.