Biomimetic artificial islet model with vascularized microcapsule structures for durable glycemic control
doi: 10.1088/2752-5724/ad47ce
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Abstract: AbstractIslet transplantation is a promising strategy for diabetes mellitus treatment as it can recapitulate endogenous insulin secretion and provide long-term glycemic control. Islet models constructed in biomaterial scaffolds that reproduce biological characteristics of native islets is a feasible option to circumvent the dilemma of donor shortage and the requirement of chronic immunosuppression. Herein, we developed bioinspired artificial microcapsule-based islet models with microvessels for glycemic control using microfluidic electrospray strategy. Microfluidic electrospray can generate uniform hydrogel microcapsules with core-shell structure for encapsulating islet cells. The cell-laden microcapsules enabled the efficient transportation of nutrient, oxygen, and insulin; as well as the incorporation with microvessels for prompting glucose responsiveness and molecular exchange. We demonstrated by in vivo experiments that the blood glucose, food intake, and body weight of diabetic mouse models were alleviated, and the glucose tolerance was promoted after the engraftment of islet microcapsules. We further demonstrated the improved functionality of transplanted islet model in insulin secretion, immune escape, and microcirculation using standard histological and molecular analysis. These results indicated that the microcapsules with microvessels are promising artificial islet models and are valuable for treating diabetes.
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Key words:
- artificial islet model /
- microfluidics /
- vascularization /
- hydrogel /
- diabetes
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Figure 1. Schematics of biomimetic artificial islet model with vascularized microcapsule structures for durable glycemic control. (a) Fabrication of microcapsules by using microfluidic electrospray strategy. (b) Transplantation of vascularized microcapsules on the dorsal brown adipose tissue of diabetic mouse. The transplanted microcapsules secrete insulin for relieving hyperglycemia. (c) The microcapsules allow for the perfusion of nutrient and oxygen, and the release of insulin from pancreatic β cells, while hindering the attack of host immune cells.
Figure 2. Fabrication and characterization of the microcapsules based on microfluidic electrospray. (a) Schematic of the microfluidic electrospray system. (b) Bright field microscopic images of the microcapsules at (i) low and (ii) high magnifications. Scale bar is 500 μm. (c) The real-time image of the microfluidic electrospray process. (d) SEM images of a dissected microcapsule at (i) low and (ii) high magnifications. Scale bar is 200 μm in (i) and 50 μm in (ii). (e) Microcapsules loading with MIN6 cells at (i) low and (ii) high magnifications. Scale bar is 500 μm. (f) SEM images of a dissected microcapsule loading with MIN6 cells at (i) low and (ii) high magnifications. Scale bar is 200 μm in (i) and 10 μm in (ii).
Figure 3. Cell proliferation and insulin secreting function of the vascularized microcapsules. (a) HUVECs formed vasculatures in the fibrinogen matrix at day 3. (i) Vasculatures were shown in closed purple loops; blue dots indicated the branch nodes; green lines demonstrate the branches extended by cells. (ii), (iii) HUVECs and NHLFs were stained green by F-actin at top view (ii) and side view (iii). Scale bar is 200 μm in (i), and 100 μm in (ii), (iii). (b) The microcapsules with the microvessels. Cells were stained with green by Calcein AM. Scale bar is 500 μm. (c) The bright field image of the microcapsules with the microvessels. Scale bar is 500 μm. (d) Representative microscopic and Calcein AM/PI staining images of the microcapsules at day 0, 1, 2 and 3. Yellow dotted circles represent the core of the microcapsules with islet cells encapsulated. Red dotted circles represent the hydrogel shell of the microcapsules. Live cells were stained green. Dead cells were stained red. Scale bar is 200 μm. (e) Measured insulin secretion of islet cells in planar dish cultivation or encapsulated in microcapsules with or without microvessels by GSIS assays. Ctrl: the control group; MCs: the artificial islet microcapsule group; v-MCs: the vascularized artificial islet microcapsule group.
Figure 4. Transplantation of the vascularized artificial islet microcapsules and their in vivo therapeutic performances. (a) Schematic of the experimental groups. (b)-(d) Continuous monitoring of (b) blood glucose level, (c) body weight, and (d) food intake in different groups (n = 5). (e) Glucose responsiveness of diabetic mice receiving IPGTT at 28th day post transplantation (n = 5). The dotted line in (b) and (e) represents 200 mg dl-1, which is the threshold of blood glucose level for diagnosing diabetes. Statistical analyses were conducted by using Kaplan-Meier analysis. p < 0.01. Healthy: the healthy control group; DM: the diabetes group; MCs: the artificial islet microcapsule group; v-MCs: the vascularized artificial islet microcapsule group.
Figure 5. Immunohistochemical and immunofluorescence analysis results. (a) HE staining of the brown adipose tissues and transplanted grafts. (b) Immunohistochemical staining of insulin at the transplantation site. Red arrows indicate insulin-positive areas. (c) Immunofluorescence images of CD31 at the transplantation site. Yellow arrows indicate the microvessels. DM: the diabetes group; Cells: the naked cells group; MCs: the artificial islet microcapsule group; v-MCs: the vascularized artificial islet microcapsule group. Scale bars are 200 μm.
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[1] Magliano D J, Boyko E J 2021 committee IDFDAtes (IDF Diabetes Atlas)Brussels [2] Hogrebe N J, Ishahak M, Millman J R 2023 Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes Cell Stem Cell 30 530-48 doi: 10.1016/j.stem.2023.04.002 [3] Jain C, Ansarullah, Bilekova S, Lickert H 2022 Targeting pancreatic β cells for diabetes treatment Nat. Metab. 4 1097-108 doi: 10.1038/s42255-022-00618-5 [4] Rubio-Navarro A, et al 2023 A beta cell subset with enhanced insulin secretion and glucose metabolism is reduced in type 2 diabetes Nat. Cell Biol. 25 565-78 doi: 10.1038/s41556-023-01103-1 [5] Shapiro A M J, Verhoeff K 2023 A spectacular year for islet and stem cell transplantation Nat. Rev. Endocrinol. 19 68-69 doi: 10.1038/s41574-022-00790-4 [6] Chetboun M, et al 2023 Association between primary graft function and 5-year outcomes of islet allogeneic transplantation in type 1 diabetes: a retrospective, multicentre, observational cohort study in 1210 patients from the collaborative islet transplant registry Lancet Diabetes Endocrinol. 11 391-401 doi: 10.1016/s2213-8587(23)00082-7 [7] Marfil-Garza B A, et al 2022 Pancreatic islet transplantation in type 1 diabetes: 20-year experience from a single-centre cohort in Canada Lancet Diabetes Endocrinol. 10 519-32 doi: 10.1016/s2213-8587(22)00114-0 [8] Li H, Shang Y, Feng Q, Liu Y, Chen J, Dong H 2023 A novel bioartificial pancreas fabricated via islets microencapsulation in anti-adhesive core-shell microgels and macroencapsulation in a hydrogel scaffold prevascularized in vivo Bioact. Mater. 27 362-76 doi: 10.1016/j.bioactmat.2023.04.011 [9] Ernst A U, et al 2022 A predictive computational platform for optimizing the design of bioartificial pancreas devices Nat. Commun. 13 6031 doi: 10.1038/s41467-022-33760-5 [10] Wang X, et al 2021 A nanofibrous encapsulation device for safe delivery of insulin-producing cells to treat type 1 diabetes Sci. Transl. Med. 13 eabb4601 doi: 10.1126/scitranslmed.abb4601 [11] Zhang H, Liu Y, Chen G, Wang H, Chen C, Li M, Lu P, Zhao Y 2020 Immunotherapeutic silk inverse opal particles for post-surgical tumor treatment Sci. Bull. 65 380-8 doi: 10.1016/j.scib.2019.10.023 [12] Liu Y, Huang Q, Wang J, Fu F, Ren J, Zhao Y 2017 Microfluidic generation of egg-derived protein microcarriers for 3D cell culture and drug delivery Sci. Bull. 62 1283-90 doi: 10.1016/j.scib.2017.09.006 [13] Zhang B, Cheng Y, Wang H, Ye B, Shang L, Zhao Y, Gu Z 2015 Multifunctional inverse opal particles for drug delivery and monitoring Nanoscale 7 10590-4 doi: 10.1039/c5nr02324f [14] Yang L, Liu Y, Sun L, Zhao C, Chen G, Zhao Y 2021 Biomass microcapsules with stem cell encapsulation for bone repair Nanomicro Lett. 14 4 doi: 10.1007/s40820-021-00747-8 [15] Zhao C, Yu Y, Zhang X, Wu X, Ren J, Zhao Y 2019 Biomimetic intestinal barrier based on microfluidic encapsulated sucralfate microcapsules Sci. Bull. 64 1418-25 doi: 10.1016/j.scib.2019.07.020 [16] Zhao C, Cai L, Nie M, Shang L, Wang Y, Zhao Y 2021 Cheerios effect inspired microbubbles as suspended and adhered oral delivery systems Adv. Sci. 8 2004184 doi: 10.1002/advs.202004184 [17] Li Y, Yan D, Fu F, Liu Y, Zhang B, Wang J, Shang L, Gu Z, Zhao Y 2017 Composite core-shell microparticles from microfluidics for synergistic drug delivery Sci. China Mater. 60 543-53 doi: 10.1007/s40843-016-5151-6 [18] Zhu Y, Sun L, Fu X, Liu J, Liang Z, Tan H, Li W, Zhao Y 2021 Engineering microcapsules to construct vascularized human brain organoids Chem. Eng. J. 424 130427 doi: 10.1016/j.cej.2021.130427 [19] Yao W, Che J, Zhao C, Zhang X, Zhou H, Bai F 2023 Treatment of Alzheimer’s disease by microcapsule regulates neurotransmitter release via microfluidic technology Eng. Regen. 4 183-92 doi: 10.1016/j.engreg.2023.02.005 [20] Wang H, Liu Y, Chen Z, Sun L, Zhao Y 2020 Anisotropic structural color particles from colloidal phase separation Sci. Adv. 6 eaay1438 doi: 10.1126/sciadv.aay1438 [21] Cai L, Zhao C, Chen H, Fan L, Zhao Y, Qian X, Chai R 2022 Suctioncupinspired adhesive micromotors for drug delivery Adv. Sci. 9 2103384 doi: 10.1002/advs.202103384 [22] Heinrich M A, Uboldi I, Kuninty P R, Ankone M J K, van Baarlen J, Zhang Y S, Jain K, Prakash J 2023 Microarchitectural mimicking of stroma-induced vasculature compression in pancreatic tumors using a 3D engineered model Bioact. Mater. 22 18-33 doi: 10.1016/j.bioactmat.2022.09.015 [23] Shang L, Shangguan F, Cheng Y, Lu J, Xie Z, Zhao Y, Gu Z 2013 Microfluidic generation of magnetoresponsive Janus photonic crystal particles Nanoscale 5 9553-7 doi: 10.1039/c3nr03218c [24] Liu Y, Sun L, Zhang H, Shang L, Zhao Y 2021 Microfluidics for drug development: from synthesis to evaluation Chem. Rev. 121 7468-529 doi: 10.1021/acs.chemrev.0c01289 [25] Shang L, Yu Y, Gao W, Wang Y, Qu L, Zhao Z, Chai R, Zhao Y 2018 Bioinspired anisotropic wettability surfaces from dynamic Ferrofluid assembled templates Adv. Funct. Mater. 28 1705802 doi: 10.1002/adfm.201705802 [26] Zhao X, Bian F, Sun L, Cai L, Li L, Zhao Y 2020 Microfluidic generation of nanomaterials for biomedical applications Small 16 1901943 doi: 10.1002/smll.201901943 [27] Zhang Y S, Khademhosseini A 2017 Advances in engineering hydrogels Science 356 eaaf3627 doi: 10.1126/science.aaf3627 [28] Yang S, Wang F, Han H, Santos H A, Zhang Y, Zhang H, Wei J, Cai Z 2023 Fabricated technology of biomedical micro-nano hydrogel Biomed. Technol. 2 31-48 doi: 10.1016/j.bmt.2022.11.012 [29] Li N, Chen H, Xu D, Zhao Y 2024 Bio-inspired hierarchical particles for bioassays Biomed. Technol. 6 17-25 doi: 10.1016/j.bmt.2023.09.003 [30] Chen F, Li X, Yu Y, Li Q, Lin H, Xu L, Shum H C 2023 Phase-separation facilitated one-step fabrication of multiscale heterogeneous two-aqueous-phase gel Nat. Commun. 14 2793 doi: 10.1038/s41467-023-38394-9 [31] Sun J, Li J, Huan Z, Pandol S J, Liu D, Shang L, Li L 2023 Mesenchymal stem cellladen composite β cell porous microgel for diabetes treatment Adv. Funct. Mater. 33 2211897 doi: 10.1002/adfm.202211897 [32] Li J, et al 2022 Porous microcarriers with pancreatic β cell aggregates loading for diabetic care Chem. Eng. J. 436 135174 doi: 10.1016/j.cej.2022.135174 [33] Liu X, Yu Y, Liu D, Li J, Sun J, Wei Q, Zhao Y, Pandol S J, Li L 2022 Porous microcapsules encapsulating β cells generated by microfluidic electrospray technology for diabetes treatment npg Asia Mater. 14 39 doi: 10.1038/s41427-022-00385-5 [34] Zhang H, Chen G, Yu Y, Guo J, Tan Q, Zhao Y 2020 Microfluidic printing of slippery textiles for medical drainage around wounds Adv. Sci. 7 2000789 doi: 10.1002/advs.202000789 [35] Wang X, Yu Y, Yang C, Shao C, Shi K, Shang L, Ye F, Zhao Y 2021 Microfluidic 3D printing responsive scaffolds with biomimetic enrichment channels for bone regeneration Adv. Funct. Mater. 31 2105190 doi: 10.1002/adfm.202105190 [36] Chen G, Yu Y, Fu X, Wang G, Wang Z, Wu X, Ren J, Zhao Y 2022 Microfluidic encapsulated manganese organic frameworks as enzyme mimetics for inflammatory bowel disease treatment J. Colloid Interface Sci. 607 1382-90 doi: 10.1016/j.jcis.2021.09.016 [37] Fan L, Zhang X, Wang L, Song Y, Yi K, Wang X, Zhang H, Li L, Zhao Y 2024 Bioinspired porous microneedles dwelled stem cells for diabetic wound treatment Adv. Funct. Mater. 2316742 doi: 10.1002/adfm.202316742 [38] Zhu Y, Zhang X, Sun L, Wang Y, Zhao Y 2023 Engineering human brain assembloids by microfluidics Adv. Mater. 35 2210083 doi: 10.1002/adma.202210083 [39] Yan Y, et al 2019 Vascularized 3D printed scaffolds for promoting bone regeneration Biomaterials 190-191 97-110 doi: 10.1016/j.biomaterials.2018.10.033 [40] Li G, et al 2020 Construction of dual-biofunctionalized chitosan/collagen scaffolds for simultaneous neovascularization and nerve regeneration Research 2020 2603048 doi: 10.34133/2020/2603048 [41] Cai L, Li N, Zhang Y, Gu H, Zhu Y 2023 Microfluidics-derived microcarrier systems for oral delivery Biomed. Technol. 1 30-38 doi: 10.1016/j.bmt.2022.11.001 [42] Zhuge W, Liu H, Wang W, Wang J 2022 Microfluidic bioscaffolds for regenerative engineering Eng. Regen. 3 110-20 doi: 10.1016/j.engreg.2021.12.003 [43] Kepple J D, Barra J M, Young M E, Hunter C S, Tse H M 2022 Islet transplantation into brown adipose tissue can delay immune rejection JCI Insight 7 e152800 doi: 10.1172/jci.insight.152800 -
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