3D Bioprinting of Vascularized Implantable Pancreas Construct for a Functional Cure for Diabetes
Abstract
Type 1 diabetes mellitus (T1D) is among the most common forms of chronic and disabling disease that severely impact the lives of service members, veterans, and civilians. T1D results from the destruction of beta cells in the pancreatic islets, leading to loss of insulin production and resultant hyperglycemia. Treatment of T1D is a challenging problem due to a lack of appropriate therapeutic options to restore or replace beta cell function. Current treatment for T1D includes taking insulin (2-4 injections per day). A pancreatic islet transplantation offers a potential cure for T1D to restore glycemic control and eliminate the need for insulin injection. However, the shortage of healthy donor organs and the use of lifelong immune suppression often complicate these procedures. Three-dimensional (3D) bioprinting of engineered pancreatic tissue construct using insulin-producing cells has emerged as an alternative approach for T1D treatments. The 3D bioprinting technology shows promise for directly creating 3D tissue-like complex living structures through the precise placement of cell-laden hydrogels in a layer-by-layer fashion. However, the current 3D bioprinting approach has shown disappointing results to date, including low cell survival and failure to achieve normal tissue function. One potential reason for these is delayed vascularization and insufficient blood supply to clinically relevant size tissues following implantation to the body. To overcome this vascularization challenge, we previously developed a 3D pre-vascularized scaffold using a digital light processing (DLP) printer platform. Using this platform, we were successful in engineering the vascularized scaffold that integrates geometrically controlled and durable vascular channels. We demonstrated that the vascular channels within the scaffold could be directly connected to the host vasculature surgically and achieve immediate and continuous blood flow. The vascularized scaffold could provide sufficient oxygen and nutrients to the cells, resulting in maintaining cell viability. In this application, we propose an innovative platform technology of bioprinting a transplantable prevascularized pancreatic islet tissue that is capable of establishing direct surgical anastomosis with host vasculature and providing immediate blood perfusion for tissue survival, integration, and function in vivo. We hypothesize that direct and immediate blood supply to pancreatic islet cells within a tissue construct through the robust vascular channels will support long-term cell survival and function. Two specific aims have been developed to achieve the goal of this proposal. 1) Specific Aim 1: Develop a 3D vascularized pancreatic tissue construct. 2) Specific Aim 2: In vivo feasibility testing of using the vascularized pancreatic tissue construct. In Specific Aim 1, we will develop the 3D vascularized pancreatic tissue construct using the DLP system and human pancreatic islet cells. The design of the construct will be optimized in terms of vascular channel geometry, bioink formulation and concentration, and cell concentration to maximize cell survival and long-term insulin production. The blood perfusion, cell survival, tissue formation, and insulin production will be evaluated for up to 4 weeks in vitro. In Specific Aim 2, the construct will be surgically connected to the host vessels in rats. Blood perfusion, oxygen saturation, cell survival, and tissue functionality will be evaluated. The most innovative concept and technology utilized in this proposal is the unique strategy to engineer a transplantable vascularized pancreatic tissue construct that allows for direct surgical vascular connection, thereby providing immediate and continuous blood perfusion with the host vasculature to achieve long-term tissue survival and function. To our knowledge, this is the first study demonstrating that the implantation of vascularized pancreas tissue construct is possible, thus overcoming the un
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110105
Entities
People
- Ji Hyun Kim
Organizations
- United States Army
- Wake Forest University