Top

06-16-2018 | Devices and technology | Review | Article

Transplantation of Macroencapsulated Insulin-Producing Cells

Journal: Current Diabetes Reports

Authors: Albert J. Hwa, Gordon C. Weir

Abstract

Purpose of Review

There is considerable interest in using macroencapsulation devices as a delivery strategy for transplanting insulin-producing cells. This review aims to summarize recent advances, to highlight remaining challenges, and to provide recommendations for the field.

Recent Findings

A variety of new device designs have been reported to improve biocompatibility and to provide protection for islet/beta cells from immune destruction while allowing continuous secretion of insulin. Some of these new approaches are in clinical trials, but more research is needed to determine how sufficient beta-cell mass can be transplanted in a clinically applicable device size, and that insulin is secreted with kinetics that will safely provide adequate controls of glucose levels.

Summary

Macroencapsulation is a potential solution to transplant beta cells without immunosuppression in diabetes patients, but new strategies must be developed to show that this approach is feasible.

Barton FB, Rickels MR, Alejandro R, Hering BJ, Wease S, Naziruddin B, et al. Improvement in outcomes of clinical islet transplantation: 1999–2010. Diabetes Care. 2012;35(7):1436–45.CrossRefPubMedPubMedCentral

Shapiro AM, Pokrywczynska M, Ricordi C. Clinical pancreatic islet transplantation. Nat Rev Endocrinol. 2017;13(5):268–77.CrossRefPubMed

Thompson DM, Meloche M, Ao Z, Paty B, Keown P, Shapiro RJ, et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation. 2011;91(3):373–8.CrossRefPubMed

Thompson DM, Begg IS, Harris C, Ao Z, Fung MA, Meloche RM, et al. Reduced progression of diabetic retinopathy after islet cell transplantation compared with intensive medical therapy. Transplantation. 2008;85(10):1400–5.CrossRefPubMed

Pagliuca FW, Millman JR, Gurtler M, Segel M, Van Dervort A, Ryu JH, et al. Generation of functional human pancreatic beta cells in vitro. Cell. 2014;159(2):428–39.CrossRefPubMedPubMedCentral

Agulnick AD, Ambruzs DM, Moorman MA, Bhoumik A, Cesario RM, Payne JK, et al. Insulin-producing endocrine cells differentiated in vitro from human embryonic stem cells function in macroencapsulation devices in vivo. Stem Cells Transl Med. 2015;4(10):1214–22.CrossRefPubMedPubMedCentral

Rezania A, Bruin JE, Arora P, Rubin A, Batushansky I, Asadi A, et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol. 2014;32(11):1121–33.CrossRefPubMed

Russ HA, Parent AV, Ringler JJ, Hennings TG, Nair GG, Shveygert M, et al. Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. EMBO J. 2015;34(13):1759–72.CrossRefPubMedPubMedCentral

Liu Z, Hu W, He T, Dai Y, Hara H, Bottino R, et al. Pig-to-primate islet xenotransplantation: past, present, and future. Cell Transplant. 2017;26(6):925–47.CrossRefPubMedPubMedCentral

10.

Chang R, Faleo G, Russ HA, Parent AV, Elledge SK, Bernards DA, et al. Nanoporous immunoprotective device for stem-cell-derived beta-cell replacement therapy. ACS Nano. 2017;11(8):7747–57.CrossRefPubMedPubMedCentral

11.

Donath MY, Boni-Schnetzler M, Ellingsgaard H, Halban PA, Ehses JA. Cytokine production by islets in health and diabetes: cellular origin, regulation and function. Trends Endocrinol Metab. 2010;21(5):261–7.CrossRefPubMed

12.

Kumagai-Braesch M, Jacobson S, Mori H, Jia X, Takahashi T, Wernerson A, et al. The TheraCyte device protects against islet allograft rejection in immunized hosts. Cell Transplant. 2013;22(7):1137–46.CrossRefPubMed

13.

Faleo G, Lee K, Nguyen V, Tang Q. Assessment of immune isolation of allogeneic mouse pancreatic progenitor cells by a macroencapsulation device. Transplantation. 2016;100(6):1211–8.CrossRefPubMedPubMedCentral

14.

Scharp DW, Swanson CJ, Olack BJ, Latta PP, Hegre OD, Doherty EJ, et al. Protection of encapsulated human islets implanted without immunosuppression in patients with type I or type II diabetes and in nondiabetic control subjects. Diabetes. 1994;43:1167–70.CrossRefPubMed

15.

• Carlsson PO, Espes D, Sedigh A, Rotem A, Zimerman B, Grinberg H, et al. Transplantation of macroencapsulated human islets within the bioartificial pancreas beta air to patients with type 1 diabetes mellitus. Am J Transplant. 2017; https://doi.org/10.1111/ajt.14642. This study shows that a macroencapsulation device with a relatively large pore size and exogenous oxygen supply can provide immune protection to allogeneic islets in non-immunosuppressed patients with T1D, but the kinetics of insulin secretion is blunted.

16.

Evron Y, Zimermann B, Ludwig B, Barkai U, Colton CK, Weir GC, et al. Oxygen supply by photosynthesis to an implantable islet cell device. Horm Metab Res. 2015;47(1):24–30.PubMed

17.

Ludwig B, Rotem A, Schmid J, Weir GC, Colton CK, Brendel MD, et al. Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist. Proc Natl Acad Sci U S A. 2012;109(13):5022–7.CrossRefPubMedPubMedCentral

18.

Tuch BE, Keogh GW, Williams LJ, Wu W, Foster JL, Vaithilingam V, et al. Safety and viability of microencapsulated human islets transplanted into diabetic humans. Diabetes Care. 2009;32(10):1887–9.CrossRefPubMedPubMedCentral

19.

Calafiore R, Basta G, Luca G, Lemmi A, Montanucci MP, Calabrese G, et al. Microencapsulated pancreatic islet allografts into nonimmunosuppressed patients with type 1 diabetes: first two cases. Diabetes Care. 2006;29(1):137–8.CrossRefPubMed

20.

Paredes-Juarez GA, Sahasrabudhe NM, Tjoelker RS, de Haan BJ, Engelse MA, de Koning EJ, et al. DAMP production by human islets under low oxygen and nutrients in the presence or absence of an immunoisolating-capsule and necrostatin-1. Sci Rep. 2015;5:14623.CrossRefPubMedPubMedCentral

21.

Vegas AJ, Veiseh O, Doloff JC, Ma M, Tam HH, Bratlie K, et al. Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat Biotechnol. 2016;34(3):345–52.CrossRefPubMedPubMedCentral

22.

Vegas AJ, Veiseh O, Gurtler M, Millman JR, Pagliuca FW, Bader AR, et al. Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat Med. 2016;22(3):306–11.CrossRefPubMedPubMedCentral

23.

Veiseh O, Doloff JC, Ma M, Vegas AJ, Tam HH, Bader AR, et al. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nat Mater. 2015;14(6):643–51.CrossRefPubMedPubMedCentral

24.

Colton CK. Oxygen supply to encapsulated therapeutic cells. Adv Drug Deliv Rev. 2014;67-68:93–110.CrossRefPubMed

25.

Coronel MM, Geusz R, Stabler CL. Mitigating hypoxic stress on pancreatic islets via in situ oxygen generating biomaterial. Biomaterials. 2017;129:139–51.CrossRefPubMedPubMedCentral

26.

Bonner-Weir S, Orci L. New perspectives on the microvasculature of the islets of Langerhans in the rat. Diabetes. 1982;31:883–939.CrossRefPubMed

27.

Buchwald P, Tamayo-Garcia A, Manzoli V, Tomei AA, Stabler CL. Glucose-stimulated insulin release: parallel perifusion studies of free and hydrogel encapsulated human pancreatic islets. Biotechnol Bioeng. 2018;115(1):232–45.CrossRefPubMed

28.

Trivedi N, Keegan M, Steil GM, Hollister-Lock J, Hasenkamp WM, Colton CK, et al. Islets in alginate macrobeads reverse diabetes despite minimal acute insulin secretory responses. Transplantation. 2001;71(2):203–11.CrossRefPubMed

29.

Omer A, Duvivier-Kali VF, Aschenbach W, Tchipashvili V, Goodyear LJ, Weir GC. Exercise induces hypoglycemia in rats with islet transplantation. Diabetes. 2004;53(2):360–5.CrossRefPubMed

30.

Ludwig B, Reichel A, Steffen A, Zimerman B, Schally AV, Block NL, et al. Transplantation of human islets without immunosuppression. Proc Natl Acad Sci U S A. 2013;110(47):19054–8.CrossRefPubMedPubMedCentral

31.

• Korsgren O. Islet encapsulation: physiological possibilities and limitations. Diabetes. 2017;66(7):1748–54. This review provides more discussions on possible limitations of physiological insulin secretion from encapsulation insulin-producing cells.CrossRefPubMed

32.

Korsgren E, Korsgren O. Glucose effectiveness: the mouse trap in the development of novel ss-cell replacement therapies. Transplantation. 2016;100(1):111–5.CrossRefPubMed

33.

Motte E, Szepessy E, Suenens K, Stange G, Bomans M, Jacobs-Tulleneers-Thevissen D, et al. Composition and function of macroencapsulated human embryonic stem cell-derived implants: comparison with clinical human islet cell grafts. Am J Physiol Endocrinol Metab. 2014;307(9):E838–46.CrossRefPubMed

34.

• Robert T, De Mesmaeker I, Stange GM, Suenens KG, Ling Z, Kroon EJ, et al. Functional beta cell mass from device-encapsulated hESC-derived pancreatic endoderm achieving metabolic control. Stem Cell Rep. 2018;10(3):739–50. This report, coupled with their earlier 2014 paper, shows that the outcome of encapsulated stem cell-derived insulin-producing cell products can change based on the types of encapsulation technology. Detailed analysis of beta-cell number and the insulin content and secretion on a per-cell basis is critically important to assess the functional beta-cell mass over time.CrossRef

35.

Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol. 2008;26(4):443–52.CrossRefPubMed

36.

Maki T, Otsu I, O'Neil JJ, Dunleavy K, Mullon CJ, Solomon BA, et al. Treatment of diabetes by xenogeneic islets without immunosuppression. Use of a vascularized bioartificial pancreas. Diabetes. 1996;45:342–7.CrossRefPubMed

37.

Song S, Yeung R, Park J, Posselt AM, Desai TA, Tang Q, et al. Glucose-stimulated insulin response of silicon nanopore-immunoprotected islets under convective transport. ACS Biomater Sci Eng. 2017;3(6):1051–61.CrossRefPubMedPubMedCentral

38.

Weaver JD, Headen DM, Aquart J, Johnson CT, Shea LD, Shirwan H, et al. Vasculogenic hydrogel enhances islet survival, engraftment, and function in leading extrahepatic sites. Sci Adv. 2017;3(6):e1700184.CrossRefPubMedPubMedCentral

39.

Vlahos AE, Cober N, Sefton MV. Modular tissue engineering for the vascularization of subcutaneously transplanted pancreatic islets. Proc Natl Acad Sci U S A. 2017;114(35):9337–42.CrossRefPubMedPubMedCentral

40.

Sorenby AK, Kumagai-Braesch M, Sharma A, Hultenby KR, Wernerson AM, Tibell AB. Preimplantation of an immunoprotective device can lower the curative dose of islets to that of free islet transplantation: studies in a rodent model. Transplantation. 2008;86(2):364–6.CrossRefPubMed

41.

Rafael E, Wu GS, Hultenby K, Tibell A, Wernerson A. Improved survival of macroencapsulated islets of Langerhans by preimplantation of the immunoisolating device: a morphometric study. Cell Transplant. 2003;12(4):407–12.CrossRefPubMed

42.

An D, Chiu A, Flanders JA, Song W, Shou D, Lu YC, et al. Designing a retrievable and scalable cell encapsulation device for potential treatment of type 1 diabetes. Proc Natl Acad Sci U S A. 2018;115(2):E263–e72.CrossRefPubMed

43.

Gurlin RE, Keating MT, Li S, Lakey JR, de Feraudy S, Shergill BS, et al. Vascularization and innervation of slits within polydimethylsiloxane sheets in the subcutaneous space of athymic nude mice. J Tissue Eng 2017;8:2041731417691645.

44.

Frei AW, Li Y, Jiang K, Buchwald P, Stabler CL. Local delivery of fingolimod from three-dimensional scaffolds impacts islet graft efficacy and microenvironment in a murine diabetic model. J Tissue Eng Regen Med. 2018;12(2):393–404.CrossRefPubMed

45.

Pepper AR, Pawlick R, Gala-Lopez B, MacGillivary A, Mazzuca DM, White DJ, et al. Diabetes is reversed in a murine model by marginal mass syngeneic islet transplantation using a subcutaneous cell pouch device. Transplantation. 2015;99(11):2294–300.CrossRefPubMedPubMedCentral

46.

BL G-L, Pepper AR, Dinyari P, Malcolm AJ, Kin T, Pawlick LR, et al. Subcutaneous clinical islet transplantation in a prevascularized subcutaneous pouch—preliminary experience. CellR4. 2016;4(5):e2132.

47.

Pepper AR, Bruni A, Pawlick RL, Gala-Lopez B, Rafiei Y, Wink J, et al. Long-term function and optimization of mouse and human islet transplantation in the subcutaneous device-less site. Islets. 2016;8:1–9.CrossRef

48.

Pepper AR, Pawlick R, Bruni A, Wink J, Rafiei Y, O'Gorman D, et al. Transplantation of human pancreatic endoderm cells reverses diabetes post transplantation in a prevascularized subcutaneous site. Stem Cell Rep. 2017;8(6):1689–700.CrossRef

Be confident that your patient care is up to date

Medicine Matters is being incorporated into Springer Medicine, our new medical education platform.

Alongside the news coverage and expert commentary you have come to expect from Medicine Matters diabetes, Springer Medicine's complimentary membership also provides access to articles from renowned journals and a broad range of Continuing Medical Education programs. Create your free account »