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Development of a novel method for measuring tissue oxygen pressure to improve the hypoxic condition in subcutaneous islet transplantation.

ABSTRACT: Subcutaneous tissue is a promising site for islet transplantation, but poor engraftment, due to hypoxia and low vascularity, hinders its prevalence. However, oxygen partial pressure (pO₂) of the subcutaneous space (SC) and other sites were reported to be equivalent in several previous reports. This contradiction may be based on accidental puncture to the indwelling micro-vessels in target tissues. We therefore developed a novel optical sensor system, instead of a conventional Clark-type needle probe, for measuring tissue pO₂ and found that pO₂ of the SC was extremely low in comparison to other sites. To verify the utility of this method, we transplanted syngeneic rat islets subcutaneously into diabetic recipients under several oxygenation conditions using an oxygen delivery device, then performed pO₂ measurement, glucose tolerance, and immunohistochemistry. The optical sensor system was validated by correlating the pO₂ values with the transplanted islet function. Interestingly, this novel technique revealed that islet viability estimated by ATP/DNA assay reduced to less than 75% by hypoxic condition at the SC, indicating that islet engraftment may substantially improve if the pO₂ levels reach those of the renal subcapsular space. Further refinements for a hypoxic condition using the present technique may contribute to improving the efficiency of subcutaneous islet transplantation.

SUBMITTER: Mitsugashira H

PROVIDER: S-EPMC9427780 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Development of a novel method for measuring tissue oxygen pressure to improve the hypoxic condition in subcutaneous islet transplantation.

Mitsugashira Hiroaki H Imura Takehiro T Inagaki Akiko A Endo Yukiko Y Katano Takumi T Saito Ryusuke R Miyagi Shigehito S Watanabe Kimiko K Kamei Takashi T Unno Michiaki M Goto Masafumi M

Scientific reports 20220830 1

Subcutaneous tissue is a promising site for islet transplantation, but poor engraftment, due to hypoxia and low vascularity, hinders its prevalence. However, oxygen partial pressure (pO<sub>2</sub>) of the subcutaneous space (SC) and other sites were reported to be equivalent in several previous reports. This contradiction may be based on accidental puncture to the indwelling micro-vessels in target tissues. We therefore developed a novel optical sensor system, instead of a conventional Clark-ty ...[more]

PMID: 36042259

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Project description:PurposeThe transplantation of pancreatic islets is a promising cell replacement therapy for type 1 diabetes. Subcutaneous islet transplantation is currently under investigation as a means to circumvent problems associated with standard intra-hepatic islet transplantation. As modifications are being developed to improve the efficacy of subcutaneous islet transplantation, it is important to have robust methods to assess engraftment. Experimentally, ATP-dependent bioluminescence imaging using luciferase reporter genes has been effective for non-invasively tracking engraftment. However, it was heretofore unknown if the bioluminescence of subcutaneously transplanted luciferase-expressing islet grafts correlates with diabetes reversal, a primary outcome of transplantation.ProceduresA retrospective analysis was conducted using data obtained from subcutaneous islet transplantations in Lewis rats. The analysis included transplantations from our laboratory in which islet donors were transgenic rats ubiquitously expressing luciferase and recipients were wild type, streptozotocin-induced diabetic rats. Data from 79 bioluminescence scans were obtained from 27 islet transplantations during the post-transplant observation period (up to 6 weeks). The bioluminescence intensity of the subcutaneously transplanted grafts, captured after the intravenous administration of luciferin, was correlated with diabetes reversal.ResultsAfter subcutaneous transplantation, islet bioluminescence decreased over time, dropping > 50 % from 1 to 3 weeks post-transplant. Bioluminescence intensity in the early post-transplant phase (1-2 weeks) correlated with the subsequent reversal of diabetes; based on optimized bioluminescence cutoff values, the bioluminescence intensity of islets at 1 and 2 weeks predicted successful transplantations. However, intensity in the late post-transplant phase (≥ 4 weeks) did not reflect transplantation outcomes.ConclusionsEarly-phase bioluminescence imaging of luciferase-expressing islets could serve as a useful tool to predict the success of subcutaneous islet transplantations by preceding changes in glucose homeostasis.

Project description:The aim of this work was to develop, characterize and test a novel 3D bioscaffold matrix which can accommodate pancreatic islets and provide them with a continuous, controlled and steady source of oxygen to prevent hypoxia-induced damage following transplantation. Hence, we made a collagen based cryogel bioscaffold which incorporated calcium peroxide (CPO) into its matrix. The optimal concentration of CPO integrated into bioscaffolds was 0.25wt.% and this generated oxygen at 0.21±0.02mM/day (day 1), 0.19±0.01mM/day (day 6), 0.13±0.03mM/day (day 14), and 0.14±0.02mM/day (day 21). Accordingly, islets seeded into cryogel-CPO bioscaffolds had a significantly higher viability and function compared to islets seeded into cryogel alone bioscaffolds or islets cultured alone on traditional cell culture plates; these findings were supported by data from quantitative computational modelling. When syngeneic islets were transplanted into the epididymal fat pad (EFP) of diabetic mice, our cryogel-0.25wt.%CPO bioscaffold improved islet function with diabetic animals re-establishing glycemic control. Mice transplanted with cryogel-0.25wt.%CPO bioscaffolds showed faster responses to intraperitoneal glucose injections and had a higher level of insulin content in their EFP compared to those transplanted with islets alone (P<0.05). Biodegradability studies predicted that our cryogel-CPO bioscaffolds will have long-lasting biostability for approximately 5 years (biodegradation rate: 16.00±0.65%/year). Long term implantation studies (i.e. 6 months) showed that our cryogel-CPO bioscaffold is biocompatible and integrated into the surrounding fat tissue with minimal adverse tissue reaction; this was further supported by no change in blood parameters (i.e. electrolyte, metabolic, chemistry and liver panels). Our novel oxygen-generating bioscaffold (i.e. cryogel-0.25wt.%CPO) therefore provides a biostable and biocompatible 3D microenvironment for islets which can facilitate islet survival and function at extra-hepatic sites of transplantation.

Dataset Information

Development of a novel method for measuring tissue oxygen pressure to improve the hypoxic condition in subcutaneous islet transplantation.

Publications

Development of a novel method for measuring tissue oxygen pressure to improve the hypoxic condition in subcutaneous islet transplantation.

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