Engineering Vascularized Islet Macroencapsulation Devices: An in vitro Platform to Study Oxygen Transport in Perfused Immobilized Pancreatic Beta Cell Cultures

Fernandez, Stephanie A.; Champion, Kurtis S.; Danielczak, Lisa; Gasparrini, Marco; Paraskevas, Steven; Leask, Richard L.; Hoesli, Corinne A.

doi:10.3389/fbioe.2022.884071

Cited by 5 publications

(2 citation statements)

References 36 publications

(40 reference statements)

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“…Our data and conclusions should not be taken as a blanket condemnation of this technology. Transplanting cells inside a TEG offers essential advantages (68,70,140,141): it localizes the graft within the device, the cells are therefore more amenable to in vivo assessments and, if need be, can be retrieved. Previous efforts (142) to develop a tissue-engineered islet graft (or bioartificial pancreas) have struggled to achieve clinical translation (58,61,63,(143)(144)(145), but with recent developments in stem cell and xenogeneic islet technologies (87,(146)(147)(148)(149)(150)(151)(152)(153)(154)(155) and the promise of scalable alternative β-cell sources (142, 151, 156, 157), there is a renewed interest in-and progress towarddeveloping a functional insulin-producing, cell-containing TEG for diabetes treatment (87,(158)(159)(160)(161).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia within subcutaneously implanted macroencapsulation devices limits the viability and functionality of densely loaded islets

Einstein,

Steyn,

Weegman

et al. 2023

Front. Transplant.

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IntroductionSubcutaneous macroencapsulation devices circumvent disadvantages of intraportal islet therapy. However, a curative dose of islets within reasonably sized devices requires dense cell packing. We measured internal PO2 of implanted devices, mathematically modeled oxygen availability within devices and tested the predictions with implanted devices containing densely packed human islets.MethodsPartial pressure of oxygen (PO2) within implanted empty devices was measured by noninvasive 19F-MRS. A mathematical model was constructed, predicting internal PO2, viability and functionality of densely packed islets as a function of external PO2. Finally, viability was measured by oxygen consumption rate (OCR) in day 7 explants loaded at various islet densities.ResultsIn empty devices, PO2 was 12 mmHg or lower, despite successful external vascularization. Devices loaded with human islets implanted for 7 days, then explanted and assessed by OCR confirmed trends proffered by the model but viability was substantially lower than predicted. Co-localization of insulin and caspase-3 immunostaining suggested that apoptosis contributed to loss of beta cells.DiscussionMeasured PO2 within empty devices declined during the first few days post-transplant then modestly increased with neovascularization around the device. Viability of islets is inversely related to islet density within devices.

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Section: Discussionmentioning

confidence: 99%

Hypoxia within subcutaneously implanted macroencapsulation devices limits the viability and functionality of densely loaded islets

Einstein,

Steyn,

Weegman

et al. 2023

Front. Transplant.

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“…As insulin therapy and islet encapsulation devices in T1D are among the most well developed and explored applications in this field, 33 we aimed to use insulin as a representative therapy. Other groups have previously investigated therapy transport from implantable encapsulation devices such as the ceMED 43 and Fernandez et al vascularized 46,47 devices which also incorporate effects of convective flow. However, these studies do not take into account the impacts of the FBR on insulin release.…”

Section: Introductionmentioning

confidence: 99%

Exploring therapy transport from implantable medical devices using experimentally informed computational methods

Trask,

Ward,

Tarpey

et al. 2024

Biomater. Sci.

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In vitro oxygen imaging of acellular and cell-loaded beta cell replacement devices

Kotecha,

Wang,

Hameed

et al. 2023

Sci Rep

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Type 1 diabetes (T1D) is an autoimmune disease that leads to the loss of insulin-producing beta cells. Bioartificial pancreas (BAP) or beta cell replacement strategies have shown promise in curing T1D and providing long-term insulin independence. Hypoxia (low oxygen concentration) that may occur in the BAP devices due to cell oxygen consumption at the early stages after implantation damages the cells, in addition to imposing limitations to device dimensions when translating promising results from rodents to humans. Finding ways to provide cells with sufficient oxygenation remains the major challenge in realizing BAP devices’ full potential. Therefore, in vitro oxygen imaging assessment of BAP devices is crucial for predicting the devices’ in vivo efficiency. Electron paramagnetic resonance oxygen imaging (EPROI, also known as electron MRI or eMRI) is a unique imaging technique that delivers absolute partial pressure of oxygen (pO2) maps and has been used for cancer hypoxia research for decades. However, its applicability for assessing BAP devices has not been explored. EPROI utilizes low magnetic fields in the mT range, static gradients, and the linear relationship between the spin–lattice relaxation rate (R1) of oxygen-sensitive spin probes such as trityl OX071 and pO2 to generate oxygen maps in tissues. With the support of the Juvenile Diabetes Research Foundation (JDRF), an academic-industry partnership consortium, the “Oxygen Measurement Core” was established at O2M to perform oxygen imaging assessment of BAP devices originated from core members’ laboratories. This article aims to establish the protocols and demonstrate a few examples of in vitro oxygen imaging of BAP devices using EPROI. All pO2 measurements were performed using a recently introduced 720 MHz/25 mT preclinical oxygen imager instrument, JIVA-25™. We began by performing pO2 calibration of the biomaterials used in BAPs at 25 mT magnetic field since no such data exist. We compared the EPROI pO2 measurement with a single-point probe for a few selected materials. We also performed trityl OX071 toxicity studies with fibroblasts, as well as insulin-producing cells (beta TC6, MIN6, and human islet cells). Finally, we performed proof-of-concept in vitro pO2 imaging of five BAP devices that varied in size, shape, and biomaterials. We demonstrated that EPROI is compatible with commonly used biomaterials and that trityl OX071 is nontoxic to cells. A comparison of the EPROI with a fluorescent-based point oxygen probe in selected biomaterials showed higher accuracy of EPROI. The imaging of typically heterogenous BAP devices demonstrated the utility of obtaining oxygen maps over single-point measurements. In summary, we present EPROI as a quality control tool for developing efficient cell transplantation devices and artificial tissue grafts. Although the focus of this work is encapsulation systems for diabetes, the techniques developed in this project are easily transferable to other biomaterials, tissue grafts, and cell therapy devices used in the field of tissue engineering and regenerative medicine (TERM). In summary, EPROI is a unique noninvasive tool to experimentally study oxygen distribution in cell transplantation devices and artificial tissues, which can revolutionize the treatment of degenerative diseases like T1D.

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Engineering Vascularized Islet Macroencapsulation Devices: An in vitro Platform to Study Oxygen Transport in Perfused Immobilized Pancreatic Beta Cell Cultures

Cited by 5 publications

References 36 publications

Hypoxia within subcutaneously implanted macroencapsulation devices limits the viability and functionality of densely loaded islets

Hypoxia within subcutaneously implanted macroencapsulation devices limits the viability and functionality of densely loaded islets

Exploring therapy transport from implantable medical devices using experimentally informed computational methods

In vitro oxygen imaging of acellular and cell-loaded beta cell replacement devices

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