Abstract
Cellular therapies for type-1 diabetes can leverage cell encapsulation to dispense with immunosuppression. However, encapsulated islet cells do not survive long, particularly when implanted in poorly vascularized subcutaneous sites. Here we show that the induction of neovascularization via temporary controlled inflammation through the implantation of a nylon catheter can be used to create a subcutaneous cavity that supports the transplantation and optimal function of a geometrically matching islet-encapsulation device consisting of a twisted nylon surgical thread coated with an islet-seeded alginate hydrogel. The neovascularized cavity led to the sustained reversal of diabetes, as we show in immunocompetent syngeneic, allogeneic and xenogeneic mouse models of diabetes, owing to increased oxygenation, physiological glucose responsiveness and islet survival, as indicated by a computational model of mass transport. The cavity also allowed for the in situ replacement of impaired devices, with prompt return to normoglycemia. Controlled inflammation-induced neovascularization is a scalable approach, as we show with a minipig model, and may facilitate the clinical translation of immunosuppression-free subcutaneous islet transplantation.
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Data availability
The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are available for research purposes from the corresponding authors on reasonable request. Source data for the figures are provided with this paper.
Code availability
The SHARP source code is available on GitHub (https://github.com/alexanderuernst/SHARP).
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Acknowledgements
We thank the Cornell University Animal Health Diagnostic Center for histological sectioning and staining, and the University of Alberta IsletCore (http://www.bcell.org/adi-isletcore.html) for providing human islets. Human islets were provided with the assistance of the Human Organ Procurement and Exchange (HOPE) programme, Trillium Gift of Life Network (TGLN) and other Canadian organ procurement organizations. Islet isolation was approved by the Human Research Ethics Board at the University of Alberta (Pro00013094). All donors’ families gave informed consent for the use of pancreatic tissue in research. Some schematics were created with BioRender.com. This work was partially supported by the National Institutes of Health (NIH, 1R01DK105967 to M.M.), the Novo Nordisk Company (to M.M.), the Juvenile Diabetes Research Foundation (JDRF, 2-SRA-2018-472-S-B to M.M.) and the Hartwell Foundation (to M.M.). A.U.E. was supported by the National Science Foundation Graduate Research Fellowship under grant number DGE-1650441. B.A.M.-G. was supported by the Patronato del Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ) and the Fundación para la Salud y la Educación Dr Salvador Zubirán (FunSaEd). A.M.J.S. was supported through a Canada Research Chair in Regenerative Medicine and Transplantation Surgery at the University of Alberta. A.R.P. was supported through a Canada Research Chair in Cell Therapies for Diabetes at the University of Alberta. Other study support includes the Diabetes Research Institute Foundation of Canada (DRIFCan). O2M Technologies acknowledges the support of JDRF grant 3-SRA-2020-883-M-B, NIH/NCI SBIR grants R43CA224840 and R44CA224840, and NSF SBIR grants 1819583 and 2028829.
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L.-H.W., B.A.M.-G., M.M. and A.M.J.S. conceptualized the project. L.-H.W., B.A.M.-G., M.M. and A.M.J.S. developed the methodology. L.-H.W., B.A.M.-G., A.U.E., R.L.P., A.R.P., K.O., B.E., N.V., M.K., J.A.F., A.K.D., H.-J.G. and Y.-Z.Y. conducted investigations. L.-H.W. and B.A.M.-G. performed visualization. M.M. and A.M.J.S. acquired funding. L.-H.-W. and B.A.M.-G. administered the project. L.-H.W., B.A.M.-G., M.M. and A.M.J.S. supervised the project. L.-H.W. and B.A.M.-G. wrote the original draft. L.-H.W., B.A.M.-G., A.U.E., R.L.P., A.R.P., K.O., B.E., N.V., M.K., J.A.F., A.K.D., M.M. and A.M.J.S. reviewed and edited the paper.
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A.M.J.S. serves as a consultant to ViaCyte Inc., Vertex Inc., Hemostemix Inc. and Aspect Biosystems Ltd. B.E. discloses financial interests in O2M. A.M.J.S. holds patents (US10434122B2 and CA2865122A1) for the ‘device-less’ prevascularization technique described in this paper. J.A.F. and M.M. are inventors on a patent application (US10493107B2) that covers the cell-encapsulation device described in this paper and are co-founders of Persista Bio. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Assessment of inflammatory responses promoting neovascularization.
a, Schematic representation of the experimental design to evaluate the localized inflammatory response at the unmodified (control) and vascularized site. Three time points were evaluated: 1) 1-week post-catheter implantation in the vascularized site (n = 9), 2) At implantation of the device in the vascularized site (i.e., 4-6 weeks post-catheter implantation) (n = 5), and 3) 3 days post-device implantation at both the vascularized and unmodified/non-prevascularized site (n = 4). b−f, Inflammatory assays showing tissue cytokine levels at the unmodified and modified subcutaneous site; data points represent medians and interquartile ranges. Groups are compared using Mann-Whitney U tests for independent samples and Wilcoxon matched-pairs signed rank tests, as appropriate; Data are shown as median with interquartile range.
Extended Data Fig. 2 Evaluation of glucose-responsive insulin kinetics of encapsulated islets in perifusion simulation model.
a,b, Model settings for the perifusion simulation with non-encapsulated (a) and encapsulated (b) islets. The variable ci|j denotes the concentration species i in subdomain j. Top images show the 3-dimensional model; bottom images show the boundary conditions applied in the simulation on a representative 2-dimensional cross section. c–g, Settings and results of the in silico dynamic perifusion simulation to compare glucose-stimulated insulin secretion kinetics in non-encapsulated and encapsulated islets. (c) Inlet glucose concentration settings of the perifusion simulation, featuring three 60 min glucose regimens: an initial low-concentration (2.8 mM) phase, followed by a high-concentration (16.7 mM) phase, and finally a return to the low concentration (2.8 mM) regime; inset plots show the continuous transition of glucose concentration between regimens occurring over 2 min. Schematic showing the in silico representation of the perifusion test. Non-encapsulated (left) and encapsulated (right) islets were positioned in flowing media and exposed to the variable glucose regime, producing a simulated insulin outflux. (d) Glucose concentration (as a volume-average) in islets over time during the in silico perfusion test. (e) Surface plots of the glucose concentration in the perifusion system at 120 and 150 min with non-encapsulated (left) and encapsulated (right) islets. (f) Outlet flux (normalized by IEQ) of insulin over time during the in silico perifusion test. (g) Surface plots of insulin concentration in the perifusion system at 120 and 150 min with non-encapsulated (left) and encapsulated (right) islets.
Extended Data Fig. 3 Model physics and boundary conditions.
a, Schematic of a two-dimensional representation of the geometry dimensions applied in simulations of rat islet-containing devices. b, Mathematical representation of the external and internal boundary conditions. c, Values of the external boundary oxygen tension applied in simulations (based on the average value from EPR oxygen measurements) for devices at the unmodified and vascularized site, respectively.
Extended Data Fig. 4 Effect of vascularization on oxygenation outcomes.
a, Distribution of EPR oxygen measurements in the unmodified and vascularized sites (this figure is a copy of Fig. 2m); mean ± SD. b, Probability density functions of the best-fit normal distributions to the absolute pO2 measurements at the unmodified and vascularized sites shown in a. c–f, Results from Monte Carlo simulations of the rat islet device where the external boundary pO2, pext, was treated as a random variable described by the normal distributions shown in b. Mean pO2 (c and d) and net necrotic fraction within rat islets (e and f) in devices in the unmodified and vascularized sites. Data was compared in bar graphs (c and e) and in relation to the simulated value of pext (d and f). c and e: ****p < 0.0001 (two-sided Mann-Whitney U test); mean ± SD.
Extended Data Fig. 5 Glucose tolerance tests of mice with impaired encapsulation devices.
Blood glucose data from two animals (taken from Fig. 4g) showing hyperglycaemia and impaired glucose responsiveness.
Extended Data Fig. 6 In situ device replacement at the vascularized site.
a,b, Schematic showing the process of device replacement. Following device retrieval, the sharp end of the customized PE tube is inserted to maintain patency of the vascularized subcutaneous pocket. Once the PE tube is in place, a new device is inserted through the expanded funnel-shaped side of the customized PE tube. Following device implantation, the PE tube is completely removed. c, BG measurements of one mouse experiencing partial graft attrition of the initial transplantation, device replacement, and retrieval.
Supplementary information
Supplementary Information
Supplementary methods, figures, tables, references and video captions.
Supplementary Video 1
Glucose and insulin concentrations over time in the in silico perifusion test of non-encapsulated (free) and encapsulated islets.
Supplementary Video 2
Representative facile retrieval of a rat islet device in a mouse.
Supplementary Video 3
Transplantation and retrieval (4 months after transplantation) of a human islet device.
Supplementary Video 4
Surgical procedures for device implantation and retrieval (1 month after implantation) in minipigs.
Supplementary Video 5
Surgical procedure showing the implantation of a 12-cm long catheter into the subcutaneous space in a minipig.
Supplementary Video 6
Mechanical tests showing robustness of a potentially scalable encapsulation device under bending and compression.
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Wang, LH., Marfil-Garza, B.A., Ernst, A.U. et al. Inflammation-induced subcutaneous neovascularization for the long-term survival of encapsulated islets without immunosuppression. Nat. Biomed. Eng (2023). https://doi.org/10.1038/s41551-023-01145-8
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DOI: https://doi.org/10.1038/s41551-023-01145-8