Advancements in biomaterials and biofabrication for enhancing islet transplantation
Type 1 diabetes (T1D) is characterized by the degeneration of insulin-producing beta cells within pancreatic islets, resulting in impaired endogenous insulin synthesis, which necessitates exogenous insulin therapy. Although intensive insulin therapy has been effective in many patients, a subset of individuals with unstable T1D encounter challenges in maintaining optimal glycemic control through insulin injections. Pancreatic islet transplantation has emerged as a promising therapeutic alternative for such patients, offering enhanced glucose regulation, reduced risk of complications, and liberation from exogenous insulin reliance. However, impediments such as immune rejection and the need for an optimal transplantation environment limit the success of islet transplantation. Revascularization, a crucial requirement for proper islet functionality, poses a challenge in transplantation settings. Biomaterial-based biofabrication approaches have attracted considerable attention to address these challenges. Biomaterials engineered to emulate the native extracellular matrix provide a supportive environment for islet viability and functionality. This review article presents the recent advancements in biomaterials and biofabrication technologies aimed at engineering cell delivery systems to enhance the efficacy of islet transplantation. Immune protection and vascularization strategies are discussed, key biomaterials employed in islet transplantation are highlighted, and various biofabrication techniques, including electrospinning, microfabrication, and bioprinting, are explored. Furthermore, the future directions and challenges in the field of cell delivery systems for islet transplantation are discussed. The integration of appropriate biomaterials and biofabrication methods has significant potential to promote successful islet transplantation by facilitating vascularization and bolstering the immune defense mechanisms.
- Alwafi H, Alsharif AA, Wei L, et al., 2020, Incidence and prevalence of hypoglycaemia in type 1 and type 2 diabetes individuals: A systematic review and meta-analysis. Diabetes Res Clin Pract, 170: 108522.
- Shapiro AMJ, Lakey JRT, Ryan EA, et al., 2000, Islet transplantation in seven patients with Type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med, 343(4): 230–238.
- Merani S, Shapiro AMJ, 2006, Current status of pancreatic islet transplantation. Clin Sci, 110(6): 611–625.
- Shapiro AMJ, Pokrywczynska M, Ricordi C, 2017, Clinical pancreatic islet transplantation. Nat Rev Endocrinol, 13(5): 268–277.
- Vantyghem MC, de Koning EJP, Pattou F, et al., 2019, Advances in β-cell replacement therapy for the treatment of type 1 diabetes. The Lancet, 394(10205): 1274–1285.
- Jansson L, Carlsson PO, 2002, Graft vascular function after transplantation of pancreatic islets. Diabetologia, 45(6): 749–763.
- Zhang N, Su D, Qu S, et al., 2006, Sirolimus is associated with reduced islet engraftment and impaired β-cell function. Diabetes, 55(9): 2429–2436.
- Kim JE, Kim SH, Jung Y, 2016, Current status of three-dimensional printing inks for soft tissue regeneration. Tissue Eng Regen Med, 13(6): 636–646.
- Marfil‐Garza BA, Shapiro AMJ, Kin T, 2021, Clinical islet transplantation: Current progress and new frontiers. J Hepatobiliary Pancreat Sci, 28(3): 243–254.
- Schuetz C, Anazawa T, Cross SE, et al., 2018, β cell replacement therapy. Transplantation, 102(2): 215–229.
- Cantarelli E, Piemonti L, 2011, Alternative transplantation sites for pancreatic islet grafts. Curr Diab Rep, 11(5): 364–374.
- Sakata N, Tan A, Chan N, et al., 2009, Efficacy comparison between intraportal and subcapsular islet transplants in a murine diabetic model. Transplant Proc, 41(1): 346–349.
- Shi Y, Zhao YZ, Jiang Z, et al., 2022, Immune-protective formulations and process strategies for improved survival and function of transplanted islets. Front Immunol, 13, 923241.
- Yoshihara E, O’Connor C, Gasser E, et al., 2020, Immune-evasive human islet-like organoids ameliorate diabetes. Nature, 586(7830): 606–611.
- Liang JP, Accolla RP, Soundirarajan M, et al., 2021, Engineering a macroporous oxygen-generating scaffold for enhancing islet cell transplantation within an extrahepatic site. Acta Biomater, 130: 268–280.
- Chow LW, Wang L jia, Kaufman DB, et al., 2010, Self-assembling nanostructures to deliver angiogenic factors to pancreatic islets. Biomaterials, 31(24): 6154–6161.
- Sigrist S, Mechine-Neuville A, Mandes K, et al., 2003, Influence of VEGF on the viability of encapsulated pancreatic rat islets after transplantation in diabetic mice. Cell Transplant, 12(6): 627–635.
- Zhang N, Richter A, Suriawinata J, et al., 2004, Elevated vascular endothelial growth factor production in islets improves islet graft vascularization. Diabetes, 53(4): 963–970.
- Verseijden F, Posthumus-van Sluijs SJ, van Neck JW, et al., 2012, Vascularization of prevascularized and non-prevascularized fibrin-based human adipose tissue constructs after implantation in nude mice. J Tissue Eng Regen Med, 6(3): 169–178.
- Vlahos AE, Kinney SM, Kingston BR, et al., 2020, Endothelialized collagen based pseudo-islets enables tuneable subcutaneous diabetes therapy. Biomaterials, 232: 119710.
- Gupta R, Sefton M V., 2011, Application of an endothelialized modular construct for islet transplantation in syngeneic and allogeneic immunosuppressed rat models. Tissue Eng Part A, 17(15–16): 2005–2015.
- Vlahos AE, Cober N, Sefton MV, 2017, Modular tissue engineering for the vascularization of subcutaneously transplanted pancreatic islets. Proc Natl Acad Sci, 114(35): 9337–9342.
- Stendahl JC, Kaufman DB, Stupp SI, 2009, Extracellular matrix in pancreatic islets: Relevance to scaffold design and transplantation. Cell Transplant, 18(1): 1–12.
- Place ES, Evans ND, Stevens MM, 2009, Complexity in biomaterials for tissue engineering. Nat Mater, 8(6): 457–470.
- Sandler S, Andersson A, Eizirik DL, et al., 1997, Assessment of insulin secretion in vitro from microencapsulated fetal porcine islet-like cell clusters and rat, mouse, and human pancreatic islets. Transplantation, 63(12): 1712–1718.
- Song S, Roy S, 2016, Progress and challenges in macroencapsulation approaches for type 1 diabetes (T1D) treatment: Cells, biomaterials, and devices. Biotechnol Bioeng, 113(7): 1381–1402.
- Yang K, O’Cearbhaill ED, Liu SS, et al., 2021, A therapeutic convection-enhanced macroencapsulation device for enhancing β cell viability and insulin secretion. Proc Natl Acad Sci U S A, 118(37): e2101258118.
- Goswami D, Domingo‐Lopez DA, Ward NA, et al., 2021, Design considerations for macroencapsulation devices for stem cell derived islets for the treatment of type 1 diabetes. Adv Sci, 8(16): 2100820.
- Desai T, Shea LD, 2017, Advances in islet encapsulation technologies. Nat Rev Drug Discov, 16(5): 338–350.
- White AM, Shamul JG, Xu J, et al., 2020, Engineering strategies to improve islet transplantation for type 1 diabetes therapy. ACS Biomater Sci Eng, 6(5): 2543–2562.
- Ching SH, Bansal N, Bhandari B, 2017, Alginate gel particles–A review of production techniques and physical properties. Crit Rev Food Sci Nutr, 57(6): 1133–1152.
- Zhang J, Zhu Y, Song J, et al., 2019, Rapid and long‐term glycemic regulation with a balanced charged immune‐evasive hydrogel in T1DM mice. Adv Funct Mater, 29(19): 1900140.
- Kim JH, Yoo JJ, Lee SJ, 2016, Three-dimensional cell-based bioprinting for soft tissue regeneration. Tissue Eng Regen Med, 13(6): 647–662.
- Kong X, Chen L, Li B, et al., 2021, Applications of oxidized alginate in regenerative medicine. J Mater Chem B, 9(12): 2785–2801.
- Volpatti LR, Bochenek MA, Facklam AL, et al., 2023, Partially oxidized alginate as a biodegradable carrier for glucose‐responsive insulin delivery and islet cell replacement therapy. Adv Healthc Mater, 12(2): 2201822.
- Cen L, Liu W, Cui L, et al., 2008, Collagen tissue engineering: development of novel biomaterials and applications. Pediatr Res, 63(5): 492–496.
- Parenteau-Bareil R, Gauvin R, Berthod F, 2010, Collagen-based biomaterials for tissue engineering applications. Materials (Basel), 3(3): 1863–1887.
- Rosenblatt J, Devereux B, Wallace DG, 1993, Dynamic rheological studies of hydrophobic interactions in injectable collagen biomaterials. J Appl Polym Sci, 50(6): 953–963.
- Rosenblatt J, Rhee W, Wallace D, 1989, The effect of collagen fiber size distribution on the release rate of proteins from collagen matrices by diffusion. J Control Release, 9(3): 195–203.
- Lee BR, Hwang JW, Choi YY, et al., 2012, In situ formation and collagen-alginate composite encapsulation of pancreatic islet spheroids. Biomaterials, 33(3): 837–845.
- Lee SJ, Yoo JJ, Atala A, 2018, Biomaterials and tissue engineering, in Clinical Regenerative Medicine in Urology, Springer Singapore, Singapore, 17–51.
- Riopel M, 2014, Collagen matrix support of pancreatic islet survival and function. Front Biosci, 19(1): 77.
- Yang K, Lee M, Jones PA, et al., 2020, A 3D culture platform enables development of zinc-binding prodrugs for targeted proliferation of β cells. Sci Adv, 6(47): eabc3207.
- He C, Ji H, Qian Y, et al., 2019, Heparin-based and heparin-inspired hydrogels: size-effect, gelation and biomedical applications. J Mater Chem B, 7(8): 1186–1208.
- Cabric S, Sanchez J, Johansson U, et al., 2010, Anchoring of vascular endothelial growth factor to surface-immobilized heparin on pancreatic islets: Implications for stimulating islet angiogenesis. Tissue Eng Part A, 16(3): 961–970.
- Uzunalli G, Tumtas Y, Delibasi T, et al., 2015, Improving pancreatic islet in vitro functionality and transplantation efficiency by using heparin mimetic peptide nanofiber gels. Acta Biomater, 22: 8–18.
- Davis NE, Beenken-Rothkopf LN, Mirsoian A, et al., 2012, Enhanced function of pancreatic islets co-encapsulated with ECM proteins and mesenchymal stromal cells in a silk hydrogel. Biomaterials, 33(28): 6691–6697.
- Hamilton DC, Shih HH, Schubert RA, et al., 2017, A silk-based encapsulation platform for pancreatic islet transplantation improves islet function in vivo. J Tissue Eng Regen Med, 11(3): 887–895.
- Kumar M, Gupta P, Bhattacharjee S, et al., 2018, Immunomodulatory injectable silk hydrogels maintaining functional islets and promoting anti-inflammatory M2 macrophage polarization. Biomaterials, 187: 1–17.
- Chendke GS, Faleo G, Juang C, et al., 2019, Supporting survival of transplanted stem‐cell‐derived insulin‐producing cells in an encapsulation device augmented with controlled release of amino acids. Adv Biosyst, 3(9): 1900086.
- Kumar M, Nandi SK, Kaplan DL, et al., 2017, Localized immunomodulatory silk macrocapsules for islet-like spheroid formation and sustained insulin production. ACS Biomater Sci Eng, 3(10): 2443–2456.
- Mao D, Zhu M, Zhang X, et al., 2017, A macroporous heparin-releasing silk fibroin scaffold improves islet transplantation outcome by promoting islet revascularisation and survival. Acta Biomater, 59: 210–220.
- Öberg-Welsh C, 2001, Long-term culture in matrigel enhances the insulin secretion of fetal porcine islet-like cell clusters in vitro. Pancreas, 22(2): 157–163.
- Aisenbrey EA, Murphy WL, 2020, Synthetic alternatives to Matrigel. Nat Rev Mater, 5(7): 539–551.
- Foster GA, García AJ, 2017, Bio-synthetic materials for immunomodulation of islet transplants. Adv Drug Deliv Rev, 114: 266–271.
- Dufour JM, Rajotte R V, Zimmerman M, et al., 2005, Development of an ectopic site for islet transplantation, using biodegradable scaffolds. Tissue Eng, 11(9–10): 1323–1331.
- Blomeier H, Zhang X, Rives C, et al., 2006, Polymer scaffolds as synthetic microenvironments for extrahepatic islet transplantation. Transplantation, 82(4): 452–459.
- Guo C, Zhang T, Tang J, et al., 2023, Construction of PLGA porous microsphere-based artificial pancreatic islets assisted by the cell centrifugation perfusion technique. ACS Omega, 8(17): 15288–15897.
- Vanaei S, Parizi MS, Vanaei S, et al., 2021, An overview on materials and techniques in 3D bioprinting toward biomedical application. Eng Regen, 2: 1–18.
- Singh S, Prakash C, Singh M, et al., 2019, Poly-lactic- Acid: Potential material for bio-printing applications, in Biomanufacturing. Springer International Publishing, Cham, 69–87.
- Huang H, Shang Y, Li H, et al., 2022, Co-transplantation of islets-laden microgels and biodegradable O 2 -generating microspheres for diabetes treatment. ACS Appl Mater Interfaces, 14(34): 38448–38458.
- Hoveizi E, Tavakol S, 2019, Therapeutic potential of human mesenchymal stem cells derived beta cell precursors on a nanofibrous scaffold: An approach to treat diabetes mellitus. J Cell Physiol, 234(7): 10196–10204.
- Liu XY, Nothias JM, Scavone A, et al., 2010, Biocompatibility investigation of polyethylene glycol and alginate-poly-l-lysine for islet encapsulation. ASAIO J, 56(3): 241–245.
- De Toni T, Stock AA, Devaux F, et al., 2022, Parallel evaluation of polyethylene glycol conformal coating and alginate microencapsulation as immunoisolation strategies for pancreatic islet transplantation. Front Bioeng Biotechnol, 10, 886483.
- Teramura Y, Kaneda Y, Iwata H, 2007, Islet-encapsulation in ultra-thin layer-by-layer membranes of poly(vinyl alcohol) anchored to poly(ethylene glycol)-lipids in the cell membrane. Biomaterials, 28(32): 4818–4825.
- Weaver JD, Headen DM, Hunckler MD, et al., 2018, Design of a vascularized synthetic poly(ethylene glycol) macroencapsulation device for islet transplantation. Biomaterials, 172: 54–65.
- Stock AA, Gonzalez GC, Pete SI, et al., 2022, Performance of islets of Langerhans conformally coated via an emulsion cross-linking method in diabetic rodents and nonhuman primates. Sci Adv, 8(26): eabm3145.
- Gunatillake PA, Adhikari R, 2003, Biodegradable synthetic polymers for tissue engineering. Eur Cell Mater, 5: 1–16; discussion 16.
- Kim BS, Das S, Jang J, et al., 2020, Decellularized extracellular matrix-based bioinks for engineering tissue- and organ-specific microenvironments. Chem Rev, 120(19): 10608– 10661.
- Pati F, Jang J, Ha DH, et al., 2014, Printing three-dimensional tissue analogues with decellularized extracellular matrix bioink. Nat Commun, 5(1), 3935.
- Kim J, Shim IK, Hwang DG, et al., 2019, 3D cell printing of islet-laden pancreatic tissue-derived extracellular matrix bioink constructs for enhancing pancreatic functions. J Mater Chem B, 7(10): 1773–1781.
- Damodaran RG, Vermette P, 2018, Decellularized pancreas as a native extracellular matrix scaffold for pancreatic islet seeding and culture. J Tissue Eng Regen Med, 12(5): 1230–1237.
- Sackett SD, Tremmel DM, Ma F, et al., 2018, Extracellular matrix scaffold and hydrogel derived from decellularized and delipidized human pancreas. Sci Rep, 8(1): 10452.
- Berkova Z, Zacharovova K, Patikova A, et al., 2022, Decellularized pancreatic tail as matrix for pancreatic islet transplantation into the greater omentum in rats. J Funct Biomater, 13(4): 171.
- Jun I, Han HS, Edwards J, et al., 2018, Electrospun fibrous scaffolds for tissue engineering: Viewpoints on architecture and fabrication. Int J Mol Sci, 19(3): 745.
- Zaszczyńska A, Niemczyk-Soczynska B, Sajkiewicz P, 2022, A comprehensive review of electrospun fibers, 3D-printed scaffolds, and hydrogels for cancer therapies. Polymers (Basel), 14(23): 5278.
- Buitinga M, Truckenmüller R, Engelse MA, et al., 2013, Microwell scaffolds for the extrahepatic transplantation of islets of langerhans. PLoS One, 8(5): e64772.
- Liu Q, Wang X, Chiu A, et al., 2021, A zwitterionic polyurethane nanoporous device with low foreign‐body response for islet encapsulation. Adv Mater, 33(39): 2102852.
- Mridha AR, Dargaville TR, Dalton PD, et al., 2022, Prevascularized retrievable hybrid implant to enhance function of subcutaneous encapsulated islets. Tissue Eng Part A, 28(5–6): 212–224.
- Rodríguez-Comas J, Ramón-Azcón J, 2022, Islet-on-a-chip for the study of pancreatic β-cell function. Vitr Model, 1(1): 41–57.
- Jun Y, Lee J, Choi S, et al., 2019, In vivo–mimicking microfluidic perfusion culture of pancreatic islet spheroids. Sci Adv, 5(11): eaax4520.
- Patel SN, Ishahak M, Chaimov D, et al., 2021, Organoid microphysiological system preserves pancreatic islet function within 3D matrix. Sci Adv, 7(7).
- Bauer S, Wennberg Huldt C, Kanebratt KP, et al., 2017, Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model. Sci Rep, 7(1): 14620.
- Abadpour S, Aizenshtadt A, Olsen PA, et al., 2020, Pancreas-on-a-chip technology for transplantation applications. Curr Diab Rep, 20(12): 72.
- Billiet T, Vandenhaute M, Schelfhout J, et al., 2012, A review of trends and limitations in hydrogel-rapid prototyping for tissue engineering. Biomaterials, 33(26): 6020–6041.
- Kim D, Kang D, Kim D, et al., 2023, Volumetric bioprinting strategies for creating large-scale tissues and organs. MRS Bull, 48: 657–667.
- Kim J, Kang K, Drogemuller CJ, et al., 2019, Bioprinting an artificial pancreas for Type 1 diabetes. Curr Diab Rep, 19(8): 53.
- Duin S, Schütz K, Ahlfeld T, et al., 2019, 3D bioprinting of functional islets of Langerhans in an alginate/methylcellulose hydrogel blend. Adv Healthc Mater, 8(7): 1801631.
- Liu X, Carter SD, Renes MJ, et al., 2019, Development of a coaxial 3D printing platform for biofabrication of implantable islet‐containing constructs. Adv Healthc Mater, 8(7): 1801181.
- Gungor-Ozkerim PS, Inci I, Zhang YS, et al., 2018, Bioinks for 3D bioprinting: An overview. Biomater Sci, 6(5): 915–946.
- Marchioli G, van Gurp L, van Krieken PP, et al., 2015, Fabrication of three-dimensional bioplotted hydrogel scaffolds for islets of Langerhans transplantation. Biofabrication, 7(2): 025009.
- Sun W, Starly B, Daly AC, et al., 2020, The bioprinting roadmap. Biofabrication, 12(2): 022002.
- Chen S, Luo J, Shen L, et al., 2022, 3D printing mini-capsule device for islet delivery to treat Type 1 diabetes. ACS Appl Mater Interfaces, 14(20): 23139–23151.
- Clua‐Ferré L, De Chiara F, Rodríguez‐Comas J, et al., 2022, Collagen‐tannic acid spheroids for β‐cell encapsulation fabricated using a 3D bioprinter. Adv Mater Technol, 7(7): 2101696.
- Hwang DG, Jo Y, Kim M, et al., 2022, A 3D bioprinted hybrid encapsulation system for delivery of human pluripotent stem cell-derived pancreatic islet-like aggregates. Biofabrication, 14(1): 014101.
- Scheiner KC, Coulter F, Maas-Bakker RF, et al., 2020, Vascular endothelial growth factor–releasing microspheres based on poly(ε-caprolactone-PEG-ε- caprolactone)-b-poly(L-lactide) multiblock copolymers incorporated in a three-dimensional printed poly(dimethylsiloxane) cell macroencapsulation device. J Pharm Sci, 109(1): 863–870.
- Wang X, 2019, Advanced polymers for three-dimensional (3D) organ bioprinting. Micromachines, 10(12): 814.
- Wang D, Guo Y, Zhu J, et al., 2022, Hyaluronic acid methacrylate/pancreatic extracellular matrix as a potential 3D printing bioink for constructing islet organoids. Acta Biomater, 165: 86–101.
- Fu B, Shen J, Chen Y, et al., 2021, Narrative review of gene modification: Applications in three-dimensional (3D) bioprinting. Ann Transl Med, 9(19):1502.
- Hogrebe NJ, Augsornworawat P, Maxwell KG, et al., 2020, Targeting the cytoskeleton to direct pancreatic differentiation of human pluripotent stem cells. Nat Biotechnol, 38(4): 460–470.
- Pagliuca FW, Millman JR, Gürtler M, et al., 2014, Generation of functional human pancreatic β cells in vitro. Cell, 159(2): 428–439.
- Rezania A, Bruin JE, Arora P, et al., 2014, Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol, 32(11): 1121–1133.
- Nair GG, Liu JS, Russ HA, et al., 2019, Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived β cells. Nat Cell Biol, 21(2): 263–274.
- Penney J, Ralvenius WT, Tsai LH, 2020, Modeling Alzheimer’s disease with iPSC-derived brain cells. Mol Psychiatry, 25(1): 148–167.
- Turinetto V, Orlando L, Giachino C, 2017, Induced pluripotent stem cells: Advances in the quest for genetic stability during reprogramming process. Int J Mol Sci, 18(9): 1952.
- Mirmalek-Sani SH, Orlando G, McQuilling JP, et al., 2013, Porcine pancreas extracellular matrix as a platform for endocrine pancreas bioengineering. Biomaterials, 34(22): 5488–5495.
- Napierala H, Hillebrandt KH, Haep N, et al., 2017, Engineering an endocrine neo-pancreas by repopulation of a decellularized rat pancreas with islets of Langerhans. Sci Rep, 7(1): 41777.
- Chaimov D, Baruch L, Krishtul S, et al., 2017, Innovative encapsulation platform based on pancreatic extracellular matrix achieve substantial insulin delivery. J Control Release, 257: 91–101.
- Jiang K, Chaimov D, Patel SN, et al., 2019, 3-D physiomimetic extracellular matrix hydrogels provide a supportive microenvironment for rodent and human islet culture. Biomaterials, 198: 37–48.
- Zhu Y, Wang D, Yao X, et al., 2021, Biomimetic hybrid scaffold of electrospun silk fibroin and pancreatic decellularized extracellular matrix for islet survival. J Biomater Sci Polym Ed, 32(2): 151–165.
- Ahn CB, Lee JH, Kim JH, et al., 2022, Development of a 3D subcutaneous construct containing insulin-producing beta cells using bioprinting. Bio-Design Manuf, 5(2): 265–276.