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Development of a Bioartificial Vascular Pancreas.

ABSTRACT: Transplantation of pancreatic islets has been shown to be effective, in some patients, for the long-term treatment of type 1 diabetes. However, transplantation of islets into either the portal vein or the subcutaneous space can be limited by insufficient oxygen transfer, leading to islet loss. Furthermore, oxygen diffusion limitations can be magnified when islet numbers are increased dramatically, as in translating from rodent studies to human-scale treatments. To address these limitations, an islet transplantation approach using an acellular vascular graft as a vascular scaffold has been developed, termed the BioVascular Pancreas (BVP). To create the BVP, islets are seeded as an outer coating on the surface of an acellular vascular graft, using fibrin as a hydrogel carrier. The BVP can then be anastomosed as an arterial (or arteriovenous) graft, which allows fully oxygenated arterial blood with a pO₂ of roughly 100 mmHg to flow through the graft lumen and thereby supply oxygen to the islets. In silico simulations and in vitro bioreactor experiments show that the BVP design provides adequate survivability for islets and helps avoid islet hypoxia. When implanted as end-to-end abdominal aorta grafts in nude rats, BVPs were able to restore near-normoglycemia durably for 90 days and developed robust microvascular infiltration from the host. Furthermore, pilot implantations in pigs were performed, which demonstrated the scalability of the technology. Given the potential benefits provided by the BVP, this tissue design may eventually serve as a solution for transplantation of pancreatic islets to treat or cure type 1 diabetes.

SUBMITTER: Han EX

PROVIDER: S-EPMC8243137 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Although sites for clinical or experimental islet transplantation are well established, pancreatic islet survival and function in these locations remain unsatisfactory. A possible factor that might account for this outcome is local hypoxia caused by the limited blood supply. Here, we modified a prevascularized tissue-engineered chamber (TEC) that facilitated the viability and function of the seeded islets in vivo by providing a microvascular network prior to transplantation. TECs were created, filled with Growth Factor-Matrigel™ (Matrigel™) and then implanted into the groins of mice with streptozotocin-induced diabetes. The degree of microvascularization in each TECs was analyzed by histology, real-time PCR, and Western blotting. Three hundred syngeneic islets were seeded into each chamber on days 0, 14, and 28 post-chamber implantation, and 300, 200, or 100 syngeneic islets were seeded into additional chambers on day 28 post-implantation, respectively. Furthermore, allogeneic or xenogeneic islet transplantation is a potential solution for organ shortage. The feasibility of TECs as transplantation sites for islet allografts or xenografts and treatment with anti-CD45RB and/or anti-CD40L (MR-1) was therefore explored. A highly developed microvascularized network was established in each TEC on day 28 post-implantation. Normalization of blood glucose levels in diabetic mice was negatively correlated with the duration of prevascularization and the number of seeded syngeneic islets. Combined treatment with anti-CD45RB and MR-1 resulted in long-term survival of the grafts following allotransplantation (5/5, 100%) and xenotransplantation (16/20, 80%). Flow cytometry demonstrated that the frequency of CD4+Foxp3-Treg and CD4+IL-4+-Th2 cells increased significantly after tolerogenic xenograft transplantation, while the number of CD4+IFN-γ-Th1 cells decreased. These findings demonstrate that highly developed microvascularized constructs can facilitate the survival of transplanted islets in a TECs, implying its potential application as artificial pancreas in the future.

Project description:IntroductionWe have recently reported about a novel technique for the generation of bioartificial vascular grafts based on the use of a compacted fibrin matrix. In this study, we evaluated the effects of a dehydration process on the biomechanical properties of compacted fibrin tubes and whether it allows for their long-term storage.Materials and methodsFibrin was precipitated from fresh frozen plasma by means of cryoprecipitation and simultaneously with a thrombin solution applied in a high-speed rotating casting mold. Subsequent dehydration of the fibrin tubes (29/38) was performed in dry air with a dilator inside the tube to prevent the collapse of the lumen. Dehydrated fibrin tubes were stored for six (n=9) and 12 months (n=10) at room temperature. Comparative analysis was done on initially generated and dehydrated fibrin tubes before and after storage to evaluate the effects of the dehydration process and storage on the biomechanical properties and structure of the tubes.ResultsThirty-eight fibrin tubes were generated by high-speed rotation-molding from 142±3 mg fibrinogen with an inner diameter of 5.8±0.1 mm and a length of 100 mm. A centrifugal force of nearly 900×g compacted applied fibrin, while fluid was pressed out of the matrix and drained from the mold via holes resulting in a 16-fold compaction of the fibrin matrix. Dehydration was characterized by shrinkage of the tubes to a diameter of 3.2±0.2 mm, while the length remained at 100 mm equivalent to a further two-fold compaction. The biomechanical strength of the dehydrated fibrin tubes significantly increased to values comparable to that of native ovine carotid arteries and maintained during the first 6 months of storage. After 12 months of storage, only five of 10 tubes were intact, and only one showed maintained biomechanical strength.DiscussionCompaction of a fibrin matrix in high-speed rotation-moulding and subsequent dehydration enables for the construction of small-caliber fibrin grafts. Over and above, the dehydration process allows their storage and stockpiling as a prerequisite for clinical use.

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Development of a Bioartificial Vascular Pancreas.

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