Objective
If the limitations of current protocols for maintaining transplanted islet viability and function can be overcome, then they can be translated to clinic as treatment for patients. The key barriers—poor vascularization, hypoxia of transplanted islets, and immune-mediated destruction—have driven the development of innovative solutions. In our research, we have successfully achieved two key objectives in vitro:
1. Recreating the islets’ native environment: We have coaxially bioprinted islets into a core of alginate enriched with acellular extracellular matrix (ECM) derived from human pancreas tissue. This ECM preserves critical biochemical components essential for islet function. The outer shell, also enriched with this ECM, integrates pro-angiogenic factors to promote rapid vascularization and integration within host tissue.
2. Optimizing structural design for functionality: The constructs have been precisely bioprinted into an organized, porous structure to enhance nutrient delivery, meet the islets' metabolic requirements, and support glucose responsiveness.
Having accomplished these objectives in vitro, we now aim to validate the constructs’ efficacy in vivo using preclinical rodent models of diabetes. These studies will focus on evaluating the long-term viability, functionality, immune protection, and therapeutic potential of the bioprinted islets under physiological conditions. This work represents a crucial step toward scalable, reproducible pancreatic constructs that offer durable glycemic control and advanced treatment options for T1D patients.
Background Rationale
Type 1 diabetes (T1D) remains an incurable disease as the underlying causative factors are still unknown. While exogenous insulin therapy is life-saving and prevents acute metabolic decompensation, fewer than 40% of T1D patients consistently achieve recommended therapeutic goals. Many patients experience inadequate glucose control, with sustained remission of hyperglycemia being rare. Insulin therapy is further complicated by risks of hypoglycemia, and most individuals with diabetes eventually develop one or more end-organ complications over their lifetime. In recent decades, islet transplantation has emerged as a promising therapy by replacing the lost insulin-producing cells, restoring insulin secretion, achieving glucose homeostasis, and preventing some diabetes-related complications. However, the widespread clinical application of islet transplantation has been impeded by critical challenges, including poor vascularization, hypoxia of transplanted islets, immune-mediated destruction, and inconsistencies in the manufacturing process. Building on these insights, we have developed a coaxial (core and shell) bioprinting strategy that synergistically addresses these limitations. This innovative approach enables the engineering of clinically relevant pancreatic tissues by: 1) encapsulating islets within an immune-protective alginate core, 2) enriching the alginate core with native-like extracellular matrix (ECM) to provide biochemical cues essential for islet survival and function, 3) bioprinting the constructs into a highly porous and organized architecture to improve nutrient and oxygen transfer, ensuring islet viability and glucose responsiveness, and 4) supplementing the shell with ECM-derived pro-angiogenic factors to facilitate rapid vascularization and integration with recipient tissues. This bioprinting platform not only combines immune protection with supportive ECM factors but also enhances the efficacy of islet transplantation by promoting graft vascularization and integration. The strategy holds transformative potential for large-scale, reproducible biomanufacturing of high-density pancreatic constructs, paving the way for advanced, clinically relevant therapies for T1D patients.
Description of Project
Diabetes is a severe disease that affects millions of Americans and results in billions of dollars in healthcare costs annually. In type 1 diabetes (T1D), the immune system mistakenly attacks and destroys islets—small clusters of cells in the pancreas responsible for producing insulin, the hormone essential for regulating blood sugar. Islet transplantation offers a promising approach to restoring physiological function, providing an alternative to complete pancreas transplantation or artificial pancreas systems. However, its widespread use has been limited by several key challenges, including the lack of long-term efficacy, a shortage of donor islets, inadequate vascularization, relative hypoxia of transplanted islets, and immune system-mediated destruction. Our team has successfully developed and fabricated a novel bioprinted human islet construct to address these barriers. Using an innovative coaxial bioprinting strategy, we have encapsulated islets in an immune-protective alginate core enriched with extracellular matrix (ECM) derived from human pancreas tissue. This ECM preserves essential biochemical components needed for islet function and creates a supportive, native-like environment for the islets. The shell of the construct is further supplemented with pro-angiogenic factors to promote rapid vascularization and integration with the recipient's tissues. To ensure optimal functionality, the construct is bioprinted into a highly porous design, enabling efficient nutrient delivery and glucose responsiveness. We are now moving forward to test these bioprinted constructs in diabetic mouse models. These preclinical studies aim to evaluate their long-term viability, functionality, immune protection, and potential for reversing diabetes. This research represents a critical step toward creating a bioengineered solution capable of providing durable glycemic control with minimal dependence on external immunosuppression. Moreover, the construct is designed for ease of implantation and retrieval, laying the groundwork for a cost-effective treatment that could revolutionize care for diabetic patients. By addressing the current limitations of islet transplantation, we are working toward establishing an advanced and practical therapeutic option for individuals living with T1D.
Anticipated Outcome
Building on a solid foundation of strong prior data from our team, we are confident in the success of our research strategy. The use of extracellular matrix (ECM)-based technology is supported by a robust body of evidence demonstrating that ECM scaffolds enhance cell viability, function, and longevity, making them an ideal platform for cell therapy. Notably, our group at Wake Forest pioneered the development of ECM scaffolds derived from both pig and human pancreas, which have been shown to sustain islet function in vitro, modulate immune responses, and guide the differentiation of stem cells into pancreas-specific lineages. By combining this ECM technology with cutting-edge 3D bioprinting methods, we can precisely fabricate larger, highly organized pancreatic tissue constructs. This approach enables efficient nutrient and oxygen diffusion, providing islets with a rich culture environment to maintain their health and functionality. These bioprinted constructs have already been validated in vitro, demonstrating high compatibility and improved function. The next phase of our research will involve evaluating the constructs in vivo using preclinical diabetic mouse models. We anticipate successfully producing a high-density, ordered, and porous pancreatic construct capable of delivering immune protection for islets, along with critical biochemical factors to sustain their health and function. Importantly, the constructs are expected to significantly enhance therapeutic efficacy by accelerating graft vascularization and integration within recipient tissues. This innovative bioprinting platform represents a transformative step toward reproducible and scalable solutions for pancreatic tissue engineering and advanced diabetes therapies.
Relevance to T1D
In type 1 diabetes (T1D), the pancreas is unable to produce sufficient insulin, the hormone that regulates blood sugar levels. Insulin is produced by beta cells, which reside within the pancreas. For reasons not yet fully understood, the immune system mistakenly attacks and destroys these beta cells. While insulin therapy remains the standard treatment, fewer than 40% of patients achieve their therapeutic goals, leaving many inadequately controlled. This often leads to long-term complications that cannot be fully prevented by insulin injections alone. Over the past decade, islet transplantation has emerged as a promising therapy by replacing the lost insulin-producing cells. However, current approaches face significant challenges, including limited long-term efficacy and durability. To address these limitations, our team has successfully developed a functional human bioprinted islet construct. This advanced construct has been designed to recreate the islets’ natural environment, providing a scaffold made from the extracellular matrix (ECM) of human pancreatic tissue. This ECM acts as the cells’ native 3D framework, essential for their survival and functionality. The islets have been precisely 3D bioprinted into a highly ordered and porous structure to ensure adequate oxygen and nutrient supply. This innovative design promotes rapid vascularization and integration within the recipient's tissue, improving the viability and glucose responsiveness of the transplanted islets. We are now preparing to test these bioprinted islet constructs in preclinical animal models to evaluate their function, immune protection, and long-term stability. These studies will allow us to fine-tune the construct design and validate its potential as a transformative solution for beta cell replacement in T1D. By overcoming current challenges, this research represents a significant step toward a new generation of treatments that could improve the lives of countless individuals with T1D.