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Huan Z, Li J, Luo Z, Yu Y, Li L. Hydrogel-Encapsulated Pancreatic Islet Cells as a Promising Strategy for Diabetic Cell Therapy. RESEARCH (WASHINGTON, D.C.) 2024; 7:0403. [PMID: 38966749 PMCID: PMC11221926 DOI: 10.34133/research.0403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 05/16/2024] [Indexed: 07/06/2024]
Abstract
Islet transplantation has now become a promising treatment for insulin-deficient diabetes mellitus. Compared to traditional diabetes treatments, cell therapy can restore endogenous insulin supplementation, but its large-scale clinical application is impeded by donor shortages, immune rejection, and unsuitable transplantation sites. To overcome these challenges, an increasing number of studies have attempted to transplant hydrogel-encapsulated islet cells to treat diabetes. This review mainly focuses on the strategy of hydrogel-encapsulated pancreatic islet cells for diabetic cell therapy, including different cell sources encapsulated in hydrogels, encapsulation methods, hydrogel types, and a series of accessorial manners to improve transplantation outcomes. In addition, the formation and application challenges as well as prospects are also presented.
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Affiliation(s)
- Zhikun Huan
- Department of Endocrinology, Zhongda Hospital, School of Medicine,
Southeast University, Nanjing 210009, China
| | - Jingbo Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine,
Southeast University, Nanjing 210009, China
| | - Zhiqiang Luo
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering,
Southeast University, Nanjing 210096, China
| | - Yunru Yu
- Pharmaceutical Sciences Laboratory,
Åbo Akademi University, Turku 20520, Finland
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine,
Southeast University, Nanjing 210009, China
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2
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Park H, Lee EY, You Y, Rhee M, Kim J, Hwang S, Lee P. Long-term efficacy of encapsulated xenogeneic islet transplantation: Impact of encapsulation techniques and donor genetic traits. J Diabetes Investig 2024; 15:693-703. [PMID: 38634411 PMCID: PMC11143419 DOI: 10.1111/jdi.14216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/26/2024] [Accepted: 04/01/2024] [Indexed: 04/19/2024] Open
Abstract
AIMS/INTRODUCTION To investigate the long-term efficacy of various encapsulated xenogeneic islet transplantation, and to explore the impact of different donor porcine genetic traits on islet transplantation outcomes. MATERIALS AND METHODS Donor porcine islets were obtained from wild-type, α1,3-galactosyltransferase knockout (GTKO) and GTKO with overexpression of membrane cofactor protein genotype. Naked, alginate, alginate-chitosan (AC), alginate-perfluorodecalin (A-PFD) and AC-perfluorodecalin (AC-PFD) encapsulated porcine islets were transplanted into diabetic mice. RESULTS In vitro assessments showed no differences in the viability and function of islets across encapsulation types and donor porcine islet genotypes. Xenogeneic encapsulated islet transplantation with AC-PFD capsules showed the most favorable long-term outcomes, maintaining normal blood glucose levels for 180 days. A-PFD capsules showed comparable results to AC-PFD capsules, followed by AC capsules and alginate capsules. Conversely, blood glucose levels in naked islet transplantation increased to >300 mg/dL within a week after transplantation. Naked islet transplantation outcomes showed no improvement based on donor islet genotype. However, alginate or AC capsules showed delayed increases in blood glucose levels for GTKO and GTKO with overexpression of membrane cofactor protein porcine islets compared with wild-type porcine islets. CONCLUSION The AC-PFD capsule, designed to ameliorate both hypoxia and inflammation, showed the highest long-term efficacy in xenogeneic islet transplantation. Genetic modifications of porcine islets with GTKO or GTKO with overexpression of membrane cofactor protein did not influence naked islet transplantation outcomes, but did delay graft failure when encapsulated.
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Affiliation(s)
- Heon‐Seok Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
| | - Eun Young Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
| | - Young‐Hye You
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
| | - Marie Rhee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
| | - Jong‐Min Kim
- Xenotransplantation Research CenterSeoul National University College of MedicineSeoulSouth Korea
- Present address:
Department of Animal HealthCheongju University College of Health and Medical SciencesCheongju‐siChungcheongbuk‐doSouth Korea
| | - Seong‐Soo Hwang
- Animal Biotechnology Division, National Institute of Animal ScienceRural Development AdministrationWanju‐gunJeonbuk‐doSouth Korea
| | - Poong‐Yeon Lee
- Animal Biotechnology Division, National Institute of Animal ScienceRural Development AdministrationWanju‐gunJeonbuk‐doSouth Korea
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Einstein SA, Steyn LV, Weegman BP, Suszynski TM, Sambanis A, O'Brien TD, Avgoustiniatos ES, Firpo MT, Graham ML, Janecek J, Eberly LE, Garwood M, Putnam CW, Papas KK. Hypoxia within subcutaneously implanted macroencapsulation devices limits the viability and functionality of densely loaded islets. FRONTIERS IN TRANSPLANTATION 2023; 2:1257029. [PMID: 38993891 PMCID: PMC11235299 DOI: 10.3389/frtra.2023.1257029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 10/20/2023] [Indexed: 07/13/2024]
Abstract
Introduction Subcutaneous 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. Methods Partial 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. Results In 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. Discussion Measured 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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Affiliation(s)
- Samuel A Einstein
- Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, United States
- Department of Radiology, The Pennsylvania State University, Hershey, PA, United States
| | - Leah V Steyn
- Department of Surgery, University of Arizona, Tucson, AZ, United States
| | - Bradley P Weegman
- Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, United States
- Sylvatica Biotech Inc., North Charleston, SC, United States
| | - Thomas M Suszynski
- Department of Plastic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Athanassios Sambanis
- Department of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, United States
| | - Timothy D O'Brien
- Veterinary Population Medicine Department, University of Minnesota, Saint Paul, MN, United States
- Department of Medicine, Stem Cell Institute, University of Minnesota, Minneapolis, MN, United States
| | | | - Meri T Firpo
- Department of Medicine, Stem Cell Institute, University of Minnesota, Minneapolis, MN, United States
| | - Melanie L Graham
- Veterinary Population Medicine Department, University of Minnesota, Saint Paul, MN, United States
- Department of Surgery, Preclinical Research Center, University of Minnesota, Saint Paul, MN, United States
| | - Jody Janecek
- Department of Surgery, Preclinical Research Center, University of Minnesota, Saint Paul, MN, United States
| | - Lynn E Eberly
- Division of Biostatistics, University of Minnesota, Minneapolis, MN, United States
| | - Michael Garwood
- Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, United States
| | - Charles W Putnam
- Department of Surgery, University of Arizona, Tucson, AZ, United States
| | - Klearchos K Papas
- Department of Surgery, University of Arizona, Tucson, AZ, United States
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4
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Qian Y, Li T, Zhou S, Chen X, Yang Y. A Single-Component Optogenetic Gal4-UAS System Allows Stringent Control of Gene Expression in Zebrafish and Drosophila. ACS Synth Biol 2023; 12:664-671. [PMID: 36891673 PMCID: PMC10029753 DOI: 10.1021/acssynbio.2c00410] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Indexed: 03/10/2023]
Abstract
The light-regulated Gal4-UAS system has offered new ways to control cellular activities with precise spatial and temporal resolution in zebrafish and Drosophila. However, the existing optogenetic Gal4-UAS systems suffer from having multiple protein components and a dependence on extraneous light-sensitive cofactors, which increase the technical complexity and limit the portability of these systems. To overcome these limitations, we herein describe the development of a novel optogenetic Gal4-UAS system (ltLightOn) for both zebrafish and Drosophila based on a single light-switchable transactivator, termed GAVPOLT, which dimerizes and binds to gene promoters to activate transgene expression upon blue light illumination. The ltLightOn system is independent of exogenous cofactors and exhibits a more than 2400-fold ON/OFF gene expression ratio, allowing quantitative, spatial, and temporal control of gene expression. We further demonstrate the usefulness of the ltLightOn system in regulating zebrafish embryonic development by controlling the expression of lefty1 by light. We believe that this single-component optogenetic system will be immensely useful in understanding the gene function and behavioral circuits in zebrafish and Drosophila.
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Affiliation(s)
- Yajie Qian
- Optogenetics
& Synthetic Biology Interdisciplinary Research Center, State Key
Laboratory of Bioreactor Engineering, East
China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
- Shanghai
Frontiers Science Center of Optogenetic Techniques for Cell Metabolism,
School of Pharmacy, East China University
of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
| | - Ting Li
- Optogenetics
& Synthetic Biology Interdisciplinary Research Center, State Key
Laboratory of Bioreactor Engineering, East
China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
- Shanghai
Frontiers Science Center of Optogenetic Techniques for Cell Metabolism,
School of Pharmacy, East China University
of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
| | - Siyu Zhou
- Optogenetics
& Synthetic Biology Interdisciplinary Research Center, State Key
Laboratory of Bioreactor Engineering, East
China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
- Shanghai
Frontiers Science Center of Optogenetic Techniques for Cell Metabolism,
School of Pharmacy, East China University
of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
| | - Xianjun Chen
- Optogenetics
& Synthetic Biology Interdisciplinary Research Center, State Key
Laboratory of Bioreactor Engineering, East
China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
- Shanghai
Frontiers Science Center of Optogenetic Techniques for Cell Metabolism,
School of Pharmacy, East China University
of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
| | - Yi Yang
- Optogenetics
& Synthetic Biology Interdisciplinary Research Center, State Key
Laboratory of Bioreactor Engineering, East
China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
- Shanghai
Frontiers Science Center of Optogenetic Techniques for Cell Metabolism,
School of Pharmacy, East China University
of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
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5
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Effects of Alginate Oligosaccharide on Testosterone-Induced Benign Prostatic Hyperplasia in Orchiectomized Rats. Nutrients 2023; 15:nu15030682. [PMID: 36771389 PMCID: PMC9920801 DOI: 10.3390/nu15030682] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
Benign prostatic hyperplasia (BPH) is an age-related disease of the urinary system that affects elderly men. Current treatments for BPH are associated with several adverse effects, thus highlighting the need for alternative agents. Alginate oligosaccharide (AOS), a water-soluble functional oligomer derived from brown algae, inhibits prostate cancer cell proliferation. However, the effects of AOS on BPH and the underlying molecular mechanisms remain unclear. Therefore, here, we aimed to investigate the therapeutic potential of AOS in BPH by using human benign prostatic epithelial cells (BPH-1) and a rat model of testosterone-induced BPH. Treatment with AOS inhibited in vitro and in vivo proliferation of prostatic epithelial cells and the testosterone-induced expression of androgen receptor (AR) and androgen-associated genes, such as those encoding 5α-reductase type 2 and prostate-specific antigen. Oral administration of AOS remarkably reduced the serum levels of dihydrotestosterone (DHT) and testosterone as well as the expression of proliferating cell nuclear antigen, inflammatory cytokines, and enzymes, which showed increased levels in prostatic tissues of rats with testosterone-induced BPH. Taken together, these data demonstrate that AOS suppresses testosterone-induced BPH in rats by downregulating AR and the expression of androgen-associated genes, supporting the hypothesis that AOS might be of potential use for the treatment of BPH.
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Deng J, Yang L, Wang Z, Ouyang H, Yu H, Yuan H, Pang D. Advance of genetically modified pigs in xeno-transplantation. Front Cell Dev Biol 2022; 10:1033197. [PMID: 36299485 PMCID: PMC9590650 DOI: 10.3389/fcell.2022.1033197] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/26/2022] [Indexed: 11/13/2022] Open
Abstract
As the standard of living improves, chronic diseases and end-stage organ failure have been a regular occurrence in human beings. Organ transplantation has become one of the hopes in the fight against chronic diseases and end-stage organ failure. However, organs available for transplantation are far from sufficient to meet the demand, leading to a major organ shortage crisis. To solve this problem, researchers have turned to pigs as their target since pigs have many advantages as xenograft donors. Pigs are considered the ideal organ donor for human xenotransplantation, but direct transplantation of porcine organs to humans faces many obstacles, such as hyperacute rejection, acute humoral xenograft rejection, coagulation dysregulation, inflammatory response, coagulation dysregulation, and endogenous porcine retroviral infection. Many transgenic strategies have been developed to overcome these obstacles. This review provides an overview of current advances in genetically modified pigs for xenotransplantation. Future genetic engineering-based delivery of safe and effective organs and tissues for xenotransplantation remains our goal.
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Affiliation(s)
- Jiacheng Deng
- College of Animal Sciences, Jilin University, Changchun, China
| | - Lin Yang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Ziru Wang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Hongsheng Ouyang
- College of Animal Sciences, Jilin University, Changchun, China
- Chongqing Research Institute, Jilin University, Chongqing, China
- Chongqing Jitang Biotechnology Research Institute, Chongqing, China
| | - Hao Yu
- College of Animal Sciences, Jilin University, Changchun, China
| | - Hongming Yuan
- College of Animal Sciences, Jilin University, Changchun, China
- Chongqing Research Institute, Jilin University, Chongqing, China
- Chongqing Jitang Biotechnology Research Institute, Chongqing, China
- *Correspondence: Hongming Yuan, ; Daxin Pang,
| | - Daxin Pang
- College of Animal Sciences, Jilin University, Changchun, China
- Chongqing Research Institute, Jilin University, Chongqing, China
- Chongqing Jitang Biotechnology Research Institute, Chongqing, China
- *Correspondence: Hongming Yuan, ; Daxin Pang,
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7
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Zhou Q, Li T, Wang K, Zhang Q, Geng Z, Deng S, Cheng C, Wang Y. Current status of xenotransplantation research and the strategies for preventing xenograft rejection. Front Immunol 2022; 13:928173. [PMID: 35967435 PMCID: PMC9367636 DOI: 10.3389/fimmu.2022.928173] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 07/07/2022] [Indexed: 12/13/2022] Open
Abstract
Transplantation is often the last resort for end-stage organ failures, e.g., kidney, liver, heart, lung, and pancreas. The shortage of donor organs is the main limiting factor for successful transplantation in humans. Except living donations, other alternatives are needed, e.g., xenotransplantation of pig organs. However, immune rejection remains the major challenge to overcome in xenotransplantation. There are three different xenogeneic types of rejections, based on the responses and mechanisms involved. It includes hyperacute rejection (HAR), delayed xenograft rejection (DXR) and chronic rejection. DXR, sometimes involves acute humoral xenograft rejection (AHR) and cellular xenograft rejection (CXR), which cannot be strictly distinguished from each other in pathological process. In this review, we comprehensively discussed the mechanism of these immunological rejections and summarized the strategies for preventing them, such as generation of gene knock out donors by different genome editing tools and the use of immunosuppressive regimens. We also addressed organ-specific barriers and challenges needed to pave the way for clinical xenotransplantation. Taken together, this information will benefit the current immunological research in the field of xenotransplantation.
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Affiliation(s)
- Qiao Zhou
- Department of Rheumatology and Immunology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Ting Li
- Department of Rheumatology, Wenjiang District People’s Hospital, Chengdu, China
| | - Kaiwen Wang
- School of Medicine, Faculty of Medicine and Health, The University of Leeds, Leeds, United Kingdom
| | - Qi Zhang
- School of Medicine, University of Electronics and Technology of China, Chengdu, China
| | - Zhuowen Geng
- School of Medicine, Faculty of Medicine and Health, The University of Leeds, Leeds, United Kingdom
| | - Shaoping Deng
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
- Institute of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, Chengdu, China
| | - Chunming Cheng
- Department of Radiation Oncology, James Comprehensive Cancer Center and College of Medicine at The Ohio State University, Columbus, OH, United States
- *Correspondence: Chunming Cheng, ; Yi Wang,
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, China
- *Correspondence: Chunming Cheng, ; Yi Wang,
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Zhang Q, Gonelle-Gispert C, Li Y, Geng Z, Gerber-Lemaire S, Wang Y, Buhler L. Islet Encapsulation: New Developments for the Treatment of Type 1 Diabetes. Front Immunol 2022; 13:869984. [PMID: 35493496 PMCID: PMC9046662 DOI: 10.3389/fimmu.2022.869984] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 03/16/2022] [Indexed: 12/21/2022] Open
Abstract
Islet transplantation is a promising approach for the treatment of type 1 diabetes (T1D). Currently, clinical islet transplantation is limited by allo - and autoimmunity that may cause partial or complete loss of islet function within a short period of time, and long-term immunosuppression is required to prevent rejection. Encapsulation into semipermeable biomaterials provides a strategy that allows nutrients, oxygen and secreted hormones to diffuse through the membrane while blocking immune cells and the like out of the capsule, allowing long-term graft survival and avoiding long-term use of immunosuppression. In recent years, a variety of engineering strategies have been developed to improve the composition and properties of encapsulation materials and to explore the clinical practicality of islet cell transplantation from different sources. In particular, the encapsulation of porcine islet and the co-encapsulation of islet cells with other by-standing cells or active ingredients for promoting long-term functionality, attracted significant research efforts. Hydrogels have been widely used for cell encapsulation as well as other therapeutic applications including tissue engineering, cell carriers or drug delivery. Here, we review the current status of various hydrogel biomaterials, natural and synthetic, with particular focus on islet transplantation applications. Natural hydrophilic polymers include polysaccharides (starch, cellulose, alginic acid, hyaluronic acid, chitosan) and peptides (collagen, poly-L-lysine, poly-L-glutamic acid). Synthetic hydrophilic polymers include alcohol, acrylic acid and their derivatives [poly (acrylic acid), poly (methacrylic acid), poly(acrylamide)]. By understanding the advantages and disadvantages of materials from different sources and types, appropriate materials and encapsuling methods can be designed and selected as needed to improve the efficacy and duration of islet. Islet capsule transplantation is emerging as a promising future treatment for T1D.
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Affiliation(s)
- Qi Zhang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | | | - Yanjiao Li
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhen Geng
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, Chengdu, China
- Institute of Organ Transplantation, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chinese Academy of Sciences, Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Sandrine Gerber-Lemaire
- Group for Functionalized Biomaterials, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), EPFL SB ISIC SCI-SB-SG, Lausanne, Switzerland
- *Correspondence: Leo Buhler, ; Yi Wang, ; Sandrine Gerber-Lemaire,
| | - Yi Wang
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, Chengdu, China
- Institute of Organ Transplantation, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chinese Academy of Sciences, Sichuan Translational Medicine Research Hospital, Chengdu, China
- *Correspondence: Leo Buhler, ; Yi Wang, ; Sandrine Gerber-Lemaire,
| | - Leo Buhler
- Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, Chengdu, China
- Institute of Organ Transplantation, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chinese Academy of Sciences, Sichuan Translational Medicine Research Hospital, Chengdu, China
- *Correspondence: Leo Buhler, ; Yi Wang, ; Sandrine Gerber-Lemaire,
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Derakhshankhah H, Sajadimajd S, Jahanshahi F, Samsonchi Z, Karimi H, Hajizadeh-Saffar E, Jafari S, Razmi M, Sadegh Malvajerd S, Bahrami G, Razavi M, Izadi Z. Immunoengineering Biomaterials in Cell-Based Therapy for Type 1 Diabetes. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:1053-1066. [PMID: 34696626 DOI: 10.1089/ten.teb.2021.0134] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Type 1 diabetes (T1D) is caused by low insulin production and chronic hyperglycemia due to the destruction of pancreatic β-cells. Cell transplantation is an attractive alternative approach compared to insulin injection. However, cell therapy has been limited by major challenges including life-long requirements for immunosuppressive drugs in order to prevent host immune responses. Encapsulation of the transplanted cells can solve the problem of immune rejection, by providing a physical barrier between the transplanted cells and the recipient's immune cells. Despite current disputes in cell encapsulation approaches, thanks to recent advances in the fields of biomaterials and transplantation immunology, extensive effort has been dedicated to immunoengineering strategies in combination with encapsulation technologies to overcome the problem of the host's immune responses. The current review summarizes the most commonly used encapsulation and immunoengineering strategies combined with cell therapy which has been applied as a novel approach to improve cell replacement therapies for the management of T1D. Recent advances in the fields of biomaterial design, nanotechnology, as well as deeper knowledge about immune modulation had significantly improved cell encapsulation strategies. However, further progress requires the combined application of novel immunoengineering approaches and islet/ß-cell transplantation.
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Affiliation(s)
- Hossein Derakhshankhah
- Kermanshah University of Medical Sciences, 48464, Kermanshah, Kermanshah, Iran (the Islamic Republic of);
| | | | - Fatemeh Jahanshahi
- Iran University of Medical Sciences, 440827, Tehran, Tehran, Iran (the Islamic Republic of);
| | - Zakieh Samsonchi
- Royan Institute for Stem Cell Biology and Technology, 534061, Tehran, Iran (the Islamic Republic of);
| | - Hassan Karimi
- Royan Institute for Stem Cell Biology and Technology, 534061, Tehran, Iran (the Islamic Republic of);
| | - Ensiyeh Hajizadeh-Saffar
- Royan Institute for Stem Cell Biology and Technology, 534061, Tehran, Iran (the Islamic Republic of);
| | - Samira Jafari
- Kermanshah University of Medical Sciences, 48464, Kermanshah, Kermanshah, Iran (the Islamic Republic of);
| | - Mahdieh Razmi
- University of Tehran Institute of Biochemistry and Biophysics, 441284, Tehran, Tehran, Iran (the Islamic Republic of);
| | - Soroor Sadegh Malvajerd
- Tehran University of Medical Sciences, 48439, Tehran, Tehran, Iran (the Islamic Republic of);
| | - Gholamreza Bahrami
- Kermanshah University of Medical Sciences, 48464, Kermanshah, Kermanshah, Iran (the Islamic Republic of);
| | - Mehdi Razavi
- University of Central Florida, 6243, Orlando, Florida, United States;
| | - Zhila Izadi
- Kermanshah University of Medical Sciences, 48464, Kermanshah,Iran, Kermanshah, Iran (the Islamic Republic of), 6715847141;
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10
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Mollah MZI, Zahid HM, Mahal Z, Faruque MRI, Khandaker MU. The Usages and Potential Uses of Alginate for Healthcare Applications. Front Mol Biosci 2021; 8:719972. [PMID: 34692769 PMCID: PMC8530156 DOI: 10.3389/fmolb.2021.719972] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/07/2021] [Indexed: 01/09/2023] Open
Abstract
Due to their unique properties, alginate-based biomaterials have been extensively used to treat different diseases, and in the regeneration of diverse organs. A lot of research has been done by the different scientific community to develop biofilms for fulfilling the need for sustainable human health. The aim of this review is to hit upon a hydrogel enhancing the scope of utilization in biomedical applications. The presence of active sites in alginate hydrogels can be manipulated for managing various non-communicable diseases by encapsulating, with the bioactive component as a potential site for chemicals in developing drugs, or for delivering macromolecule nutrients. Gels are accepted for cell implantation in tissue regeneration, as they can transfer cells to the intended site. Thus, this review will accelerate advanced research avenues in tissue engineering and the potential of alginate biofilms in the healthcare sector.
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Affiliation(s)
- M. Z. I. Mollah
- Space Science Centre (ANGKASA), Universiti Kebangsaan Malaysia, Bangi, Malaysia
- Institute of Radiation and Polymer Technology, Bangladesh Atomic Energy Commission, Dhaka, Bangladesh
| | - H. M. Zahid
- Institute of Radiation and Polymer Technology, Bangladesh Atomic Energy Commission, Dhaka, Bangladesh
| | - Z. Mahal
- Institute of Radiation and Polymer Technology, Bangladesh Atomic Energy Commission, Dhaka, Bangladesh
| | | | - M. U. Khandaker
- Centre for Applied Physics and Radiation Technologies, School of Engineering and Technology, Sunway University, Selangor, Malaysia
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Wu S, Wang L, Fang Y, Huang H, You X, Wu J. Advances in Encapsulation and Delivery Strategies for Islet Transplantation. Adv Healthc Mater 2021; 10:e2100965. [PMID: 34480420 DOI: 10.1002/adhm.202100965] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/23/2021] [Indexed: 12/13/2022]
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease caused by the destruction of pancreatic β-cells in response to autoimmune reactions. Shapiro et al. conducted novel islet transplantation with a glucocorticoid-free immunosuppressive agent in 2000 and achieved great success; since then, islet transplantation has been increasingly regarded as a promising strategy for the curative treatment of T1DM. However, many unavoidable challenges, such as a lack of donors, poor revascularization, blood-mediated inflammatory reactions, hypoxia, and side effects caused by immunosuppression have severely hindered the widespread application of islet transplantation in clinics. Biomaterial-based encapsulation and delivery strategies are proposed for overcoming these obstacles, and have demonstrated remarkable improvements in islet transplantation outcomes. Herein, the major problems faced by islet transplantation are summarized and updated biomaterial-based strategies for islet transplantation, including islet encapsulation across different scales, delivery of stem cell-derived beta cells, co-delivery of islets with accessory cells and immunomodulatory molecules are highlighted.
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Affiliation(s)
- Siying Wu
- Key Laboratory of Sensing Technology and Biomedical Instrument of Guangdong Province School of Biomedical Engineering Sun Yat‐sen University Guangzhou 510006 P. R. China
| | - Liying Wang
- Key Laboratory of Sensing Technology and Biomedical Instrument of Guangdong Province School of Biomedical Engineering Sun Yat‐sen University Guangzhou 510006 P. R. China
| | - Yifen Fang
- The Affiliated TCM Hospital of Guangzhou Medical University Guangzhou 511436 P. R. China
| | - Hai Huang
- Department of Urology Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou 510120 P. R. China
| | - Xinru You
- Key Laboratory of Sensing Technology and Biomedical Instrument of Guangdong Province School of Biomedical Engineering Sun Yat‐sen University Guangzhou 510006 P. R. China
| | - Jun Wu
- Key Laboratory of Sensing Technology and Biomedical Instrument of Guangdong Province School of Biomedical Engineering Sun Yat‐sen University Guangzhou 510006 P. R. China
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12
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Tissue Engineering Strategies for Improving Beta Cell Transplantation Outcome. CURRENT TRANSPLANTATION REPORTS 2021. [DOI: 10.1007/s40472-021-00333-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Abstract
Purpose of Review
Beta cell replacement therapy as a form of islet transplantation is a promising alternative therapy with the possibility to make selected patients with type 1 diabetes (T1D) insulin independent. However, this technique faces challenges such as extensive activation of the host immune system post-transplantation, lifelong need for immunosuppression, and the scarcity of islet donor pancreas. Advancement in tissue engineering strategies can improve these challenges and allow for a more widespread application of this therapy. This review will discuss the recent development and clinical translation of tissue engineering strategies in beta cell replacement therapy.
Recent Findings
Tissue engineering offers innovative solutions for producing unlimited glucose responsive cells and fabrication of appropriate devices/scaffolds for transplantation applications. Generation of pancreatic organoids with supporting cells in biocompatible biomaterials is a powerful technique to improve the function of insulin-producing cell clusters. Fabrication of physical barriers such as encapsulation strategies can protect the cells from the host immune system and allow for graft retrieval, although this strategy still faces major challenges to fully restore physiological glucose regulation.
Summary
The three main components of tissue engineering strategies including the generation of stem cell-derived insulin-producing cells and organoids and the possibilities for therapeutic delivery of cell-seeded devices to extra-hepatic sites need to come together in order to provide safe and functional insulin-producing devices for clinical beta cell replacement therapy.
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Kuwabara R, Hu S, Smink AM, Orive G, Lakey JRT, de Vos P. Applying Immunomodulation to Promote Longevity of Immunoisolated Pancreatic Islet Grafts. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:129-140. [PMID: 33397201 DOI: 10.1089/ten.teb.2020.0326] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Islet transplantation is a promising therapy for insulin-dependent diabetes, but large-scale application is hampered by the lack of a consistent source of insulin-producing cells and need for lifelong administration of immunosuppressive drugs, which are associated with severe side effects. To avoid chronic immunosuppression, islet grafts can be enveloped in immunoisolating polymeric membranes. These immunoisolating polymeric membranes protect islet grafts from cell-mediated rejection while allowing diffusion of oxygen, nutrients, and insulin. Although clinical trials have shown the safety and feasibility of encapsulated islets to control glucose homeostasis, the strategy does up till now not support long-term graft survival. This partly can be explained by a significant loss of insulin-producing cells in the immediate period after implantation. The loss can be prevented by combining immunoisolation with immunomodulation, such as combined administration of immunomodulating cytokines or coencapsulation of immunomodulating cell types such as regulatory T cells, mesenchymal stem cells, or Sertoli cells. Also, administration of specific antibodies or apoptotic donor leucocytes is considered to create a tolerant microenvironment around immunoisolated grafts. In this review, we describe the outcomes and limitations of these approaches, as well as the recent progress in immunoisolating devices. Impact statement Immunoisolation by enveloping islets in semipermeable membranes allows for successful transplantation of islet grafts in the absence of chronic immunosuppression, but the duration of graft survival is still not permanent. The reasons for long-term final graft failure is not fully understood, but combining immunoisolation with immunomodulation of tissues or host immune system has been proposed to enhance the longevity of grafts. This article reviews the recent progress and challenges of immunoisolation, as well as the benefits and feasibility of combining encapsulation approaches with immunomodulation to promote longevity of encapsulated grafts.
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Affiliation(s)
- Rei Kuwabara
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Department of Biomaterials, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shuxian Hu
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Alexandra M Smink
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gorka Orive
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
| | - Jonathan R T Lakey
- Department of Surgery and Biomedical Engineering, University of California Irvine, Irvine, California, USA
| | - Paul de Vos
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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14
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Li T, Chen X, Qian Y, Shao J, Li X, Liu S, Zhu L, Zhao Y, Ye H, Yang Y. A synthetic BRET-based optogenetic device for pulsatile transgene expression enabling glucose homeostasis in mice. Nat Commun 2021; 12:615. [PMID: 33504786 PMCID: PMC7840992 DOI: 10.1038/s41467-021-20913-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 12/21/2020] [Indexed: 12/26/2022] Open
Abstract
Pulsing cellular dynamics in genetic circuits have been shown to provide critical capabilities to cells in stress response, signaling and development. Despite the fascinating discoveries made in the past few years, the mechanisms and functional capabilities of most pulsing systems remain unclear, and one of the critical challenges is the lack of a technology that allows pulsatile regulation of transgene expression both in vitro and in vivo. Here, we describe the development of a synthetic BRET-based transgene expression (LuminON) system based on a luminescent transcription factor, termed luminGAVPO, by fusing NanoLuc luciferase to the light-switchable transcription factor GAVPO. luminGAVPO allows pulsatile and quantitative activation of transgene expression via both chemogenetic and optogenetic approaches in mammalian cells and mice. Both the pulse amplitude and duration of transgene expression are highly tunable via adjustment of the amount of furimazine. We further demonstrated LuminON-mediated blood-glucose homeostasis in type 1 diabetic mice. We believe that the BRET-based LuminON system with the pulsatile dynamics of transgene expression provides a highly sensitive tool for precise manipulation in biological systems that has strong potential for application in diverse basic biological studies and gene- and cell-based precision therapies in the future.
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Affiliation(s)
- Ting Li
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China
- School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China
| | - Xianjun Chen
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China
- School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China
- CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yajie Qian
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China
- School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China
| | - Jiawei Shao
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai, 200241, China
| | - Xie Li
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China
- School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China
| | - Shuning Liu
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China
- School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China
| | - Linyong Zhu
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China
| | - Yuzheng Zhao
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China
- School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China
| | - Haifeng Ye
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai, 200241, China.
| | - Yi Yang
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China.
- School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China.
- CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China.
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15
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Mansour SE, Browning DJ, Wong K, Flynn HW, Bhavsar AR. The Evolving Treatment of Diabetic Retinopathy. Clin Ophthalmol 2020; 14:653-678. [PMID: 32184554 PMCID: PMC7061411 DOI: 10.2147/opth.s236637] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 02/18/2020] [Indexed: 12/13/2022] Open
Abstract
Purpose To review the current therapeutic options for the management of diabetic retinopathy (DR) and diabetic macular edema (DME) and examine the evidence for integration of laser and pharmacotherapy. Methods A review of the PubMed database was performed using the search terms diabetic retinopathy, diabetic macular edema, neovascularization, laser photocoagulation, intravitreal injection, vascular endothelial growth factor (VEGF), vitrectomy, pars plana vitreous surgery, antiangiogenic therapy. With additional cross-referencing, this yielded 835 publications of which 301 were selected based on content and relevance. Results Many recent studies have evaluated the pharmacological, laser and surgical therapeutic strategies for the treatment and prevention of DR and DME. Several newer diagnostic systems such as optical coherence tomography (OCT), microperimetry, and multifocal electroretinography (mfERG) are also assisting in further refinements in the staging and classification of DR and DME. Pharmacological therapies for both DR and DME include both systemic and ocular agents. Systemic agents that promote intensive glycemic control, control of dyslipidemia and antagonists of the renin-angiotensin system demonstrate beneficial effects for both DR and DME. Ocular therapies include anti-VEGF agents, corticosteroids and nonsteroidal anti-inflammatory drugs. Laser therapy, both as panretinal and focal or grid applications continue to be employed in management of DR and DME. Refinements in laser devices have yielded more tissue-sparing (subthreshold) modes in which many of the benefits of conventional continuous wave (CW) lasers can be obtained without the adverse side effects. Recent attempts to lessen the burden of anti-VEGF injections by integrating laser therapy have met with mixed results. Increasingly, vitreoretinal surgical techniques are employed for less advanced stages of DR and DME. The development and use of smaller gauge instrumentation and advanced anesthesia agents have been associated with a trend toward earlier surgical intervention for diabetic retinopathy. Several novel drug delivery strategies are currently being examined with the goal of decreasing the therapeutic burden of monthly intravitreal injections. These fall into one of the five categories: non-biodegradable polymeric drug delivery systems, biodegradable polymeric drug delivery systems, nanoparticle-based drug delivery systems, ocular injection devices and with sustained release refillable devices. At present, there remains no one single strategy for the management of the particular stages of DR and DME as there are many options that have not been rigorously tested through large, randomized, controlled clinical trials. Conclusion Pharmacotherapy, both ocular and systemic, will be the primary mode of intervention in the management of DR and DME in many cases when cost and treatment burden are less constrained. Conventional laser therapy has become a secondary intervention in these instances, but remains a first-line option when cost and treatment burden are more constrained. Results with subthreshold laser appear promising but will require more rigorous study to establish its role as adjunctive therapy. Evidence to support an optimal integration of the various treatment options is lacking. Central to the widespread adoption of any therapeutic regimen for DR and DME is substantiation of safety, efficacy, and cost-effectiveness by a body of sound clinical trials.
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Affiliation(s)
- Sam E Mansour
- George Washington University, Washington, DC, USA.,Virginia Retina Center, Warrenton, VA, 20186, USA
| | - David J Browning
- Charlotte Eye Ear Nose & Throat Associates, Charlotte, NC 28210, USA
| | - Keye Wong
- Retina Associates of Sarasota, Sarasota, FL 34233, USA
| | - Harry W Flynn
- Bascom Palmer Eye Institute, University of Miami Health System, Miami, FL, USA
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16
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Zhan Y, Wu Y, Chen J. Carbogen gas-challenge BOLD fMRI in assessment of liver hypoxia after portal microcapsules implantation. PLoS One 2019; 14:e0225665. [PMID: 31774857 PMCID: PMC6881018 DOI: 10.1371/journal.pone.0225665] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 11/08/2019] [Indexed: 12/15/2022] Open
Abstract
Background Hypoxia is one of the key factors affecting the survival of islet cells transplanted via the portal vein. Blood oxygen level dependent functional magnetic resonance imaging (BOLD-fMRI) is the only imaging technique that can detect the level of blood oxygen level in vivo. However, so far no study has indicated that BOLD-fMRI can be applied to monitor the liver oxygen level after islet transplantation. Objective To evaluate the value of Carbogen-challenge BOLD MRI in assessing the level of hypoxia in liver tissue after portal microcapsules implanted. Methods Fifty-one New Zealand rabbits were randomly divided into three experimental groups (15 in each group) were transplanted microencapsulated 1000 microbeads/kg (PV1 group), 3000 microbeads/kg (PV2 group), 5000 microbeads/kg (PV3 group), and 6 rabbits were injected with the same amount of saline as the control group, BOLD-fMRI was performed following carbogen breathing in each group after transplantation on 1d, 2d, 3d and 7d, T2* weighted image, R2* value and ΔR2* value parameters for the liver tissue. Pathological examinations including liver gross pathology, H&E staining and pimonidazole immunohistochemistry were performed after BOLD-fMRI. The differences of pathological results among each group were compared. The ΔR2* values and transplanted doses were analyzed. Results and conclusions ΔR2* values at the 1-3d and 7d after transplantation were significantly different in each groups (P<0.05). ΔR2* values decreased gradually with the increase of transplanted dose, and was negatively correlated with transplant dose at 3d after transplantation (r = -0.929, P <0.001). Liver histopathological examination showed that the degree of hypoxia of liver tissue increased with the increase of transplanted doses, Carbogen-challenge BOLD-fMRI can assess the degree of liver hypoxia after portal microcapsules implanted, which provided a monitoring method for early intervention.
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Affiliation(s)
- Yuefu Zhan
- Department of Radiology, Maternal and Child Health Hospital of Hainan Province, Haikou, Hainan, China
| | - Yehua Wu
- Hainan General Hospital, Haikou, China
| | - Jianqiang Chen
- Department of Radiology, Xiangya School of Medicine Affiliated Haikou Hospital, Central South University, Haikou, Hainan, China
- * E-mail:
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17
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Espona-Noguera A, Ciriza J, Cañibano-Hernández A, Orive G, Hernández RM, Saenz del Burgo L, Pedraz JL. Review of Advanced Hydrogel-Based Cell Encapsulation Systems for Insulin Delivery in Type 1 Diabetes Mellitus. Pharmaceutics 2019; 11:E597. [PMID: 31726670 PMCID: PMC6920807 DOI: 10.3390/pharmaceutics11110597] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 12/11/2022] Open
Abstract
: Type 1 Diabetes Mellitus (T1DM) is characterized by the autoimmune destruction of β-cells in the pancreatic islets. In this regard, islet transplantation aims for the replacement of the damaged β-cells through minimally invasive surgical procedures, thereby being the most suitable strategy to cure T1DM. Unfortunately, this procedure still has limitations for its widespread clinical application, including the need for long-term immunosuppression, the lack of pancreas donors and the loss of a large percentage of islets after transplantation. To overcome the aforementioned issues, islets can be encapsulated within hydrogel-like biomaterials to diminish the loss of islets, to protect the islets resulting in a reduction or elimination of immunosuppression and to enable the use of other insulin-producing cell sources. This review aims to provide an update on the different hydrogel-based encapsulation strategies of insulin-producing cells, highlighting the advantages and drawbacks for a successful clinical application.
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Affiliation(s)
- Albert Espona-Noguera
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (A.E.-N.); (J.C.); (A.C.-H.); (R.M.H.)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain
| | - Jesús Ciriza
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (A.E.-N.); (J.C.); (A.C.-H.); (R.M.H.)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain
| | - Alberto Cañibano-Hernández
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (A.E.-N.); (J.C.); (A.C.-H.); (R.M.H.)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain
| | - Gorka Orive
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (A.E.-N.); (J.C.); (A.C.-H.); (R.M.H.)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain
- University Institute for Regenerative Medicine and Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01006 Vitoria, Spain
- Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower, Singapore 169856, Singapore
| | - Rosa María Hernández
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (A.E.-N.); (J.C.); (A.C.-H.); (R.M.H.)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain
| | - Laura Saenz del Burgo
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (A.E.-N.); (J.C.); (A.C.-H.); (R.M.H.)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain
| | - Jose Luis Pedraz
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (A.E.-N.); (J.C.); (A.C.-H.); (R.M.H.)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain
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Lee KM, Kim JH, Choi ES, Kim E, Choi SK, Jeon WB. RGD-containing elastin-like polypeptide improves islet transplantation outcomes in diabetic mice. Acta Biomater 2019; 94:351-360. [PMID: 31200117 DOI: 10.1016/j.actbio.2019.06.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 05/24/2019] [Accepted: 06/10/2019] [Indexed: 12/22/2022]
Abstract
Successful islet transplantation critically depends on the isolation of healthy islets. However, the islet isolation procedure itself contributes to islet death due to the destruction of intra- and peri-islet extracellular matrices (ECMs) during digestion. We investigated whether an RGD-containing elastin-like polypeptide (REP) could function as a self-assembling matrix to replenish ECMs and protects islets from cell death. Immediately following isolation, islets were coated with REP coacervate particles via isothermal adsorption of an REP solution followed by thermal gelation. REP-coated islets displayed increased viability and insulin secretory capacity in pretransplant culture compared to untreated islets. Co-transplantation of REP-treated islets and REP beneath the renal sub-capsule in streptozotocin-induced diabetic mice restored normoglycemia and serum insulin levels. Mice that received co-transplants maintained normoglycemia for a longer period of time than those receiving untreated islets without REP. Moreover, co-transplantation sites exhibited enhanced β-cell proliferation and vascularization. Thus, the REP-based coacervation strategy improve the survival, function and therapeutic potential of transplanted islets. STATEMENT OF SIGNIFICANCE: 1). An artificial matrix polypeptide comprised of thermoresponsive elastin-like peptides and integrin-stimulatory RGD ligands (REP) to reconstitute damaged or lost matrices. 2). Through body temperature-induced coacervation, REP reconstitutes intra-islet environment and enhances islet viability and insulin secretion by activating the pro-survival and insulin signaling pathways. 3). REP-coated islets were transplanted together with the matrix polypeptide under the kidney sub-capsule of mice, it develops a new peri-insular environment, which protects the islet grafts from immune rejection thus extending islet longevity. 4). Our data suggest that in situ self-assembly of biomimetic islet environments become a new platform allowing for improved islet transplantation at extrahepatic sites.
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Affiliation(s)
- Kyeong-Min Lee
- Laboratory of Biochemistry and Cellular Engineering, Companion Diagnostics and Medical Technology Research Group, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea
| | - Jung-Hee Kim
- Laboratory of Biochemistry and Cellular Engineering, Companion Diagnostics and Medical Technology Research Group, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea
| | - Eun-Sook Choi
- Laboratory of Biochemistry and Cellular Engineering, Companion Diagnostics and Medical Technology Research Group, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea
| | - Eunjoo Kim
- Laboratory of Biochemistry and Cellular Engineering, Companion Diagnostics and Medical Technology Research Group, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea
| | - Seong-Kyoon Choi
- Core Protein Resources Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea
| | - Won Bae Jeon
- Laboratory of Biochemistry and Cellular Engineering, Companion Diagnostics and Medical Technology Research Group, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea.
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19
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Espona-Noguera A, Etxebarria-Elezgarai J, Saenz Del Burgo L, Cañibano-Hernández A, Gurruchaga H, Blanco FJ, Orive G, Hernández RM, Benito-Lopez F, Ciriza J, Basabe-Desmonts L, Pedraz JL. Type 1 Diabetes Mellitus reversal via implantation of magnetically purified microencapsulated pseudoislets. Int J Pharm 2019; 560:65-77. [PMID: 30742984 DOI: 10.1016/j.ijpharm.2019.01.058] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/24/2019] [Accepted: 01/25/2019] [Indexed: 01/13/2023]
Abstract
Microencapsulation of pancreatic islets for the treatment of Type I Diabetes Mellitus (T1DM) generates a high quantity of empty microcapsules, resulting in high therapeutic graft volumes that can enhance the host's immune response. We report a 3D printed microfluidic magnetic sorting device for microcapsules purification with the objective to reduce the number of empty microcapsules prior transplantation. In this study, INS1E pseudoislets were microencapsulated within alginate (A) and alginate-poly-L-lysine-alginate (APA) microcapsules and purified through the microfluidic device. APA microcapsules demonstrated higher mechanical integrity and stability than A microcapsules, showing better pseudoislets viability and biological function. Importantly, we obtained a reduction of the graft volume of 77.5% for A microcapsules and 78.6% for APA microcapsules. After subcutaneous implantation of induced diabetic Wistar rats with magnetically purified APA microencapsulated pseudoislets, blood glucose levels were restored into normoglycemia (<200 mg/dL) for almost 17 weeks. In conclusion, our described microfluidic magnetic sorting device represents a great alternative approach for the graft volume reduction of microencapsulated pseudoislets and its application in T1DM disease.
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Affiliation(s)
- A Espona-Noguera
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - J Etxebarria-Elezgarai
- BIOMICs-microfluidics Research Group, Microfluidics Cluster UPV/EHU, University of the Basque Country, Spain
| | - L Saenz Del Burgo
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - A Cañibano-Hernández
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - H Gurruchaga
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - F J Blanco
- INIBIC-Hospital Universitario La Coruña, La Coruña, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), La Coruña, Spain
| | - G Orive
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain; University Institute for Regenerative Medicine and Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), BTI Biotechnology Institute, Vitoria-Gasteiz, Spain
| | - Rosa M Hernández
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - F Benito-Lopez
- AMMa LOAC Research Group, Microfluidics Cluster UPV/EHU, University of the Basque Country, Spain
| | - J Ciriza
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - L Basabe-Desmonts
- BIOMICs-microfluidics Research Group, Microfluidics Cluster UPV/EHU, University of the Basque Country, Spain; Basque Foundation of Science, IKERBASQUE, Spain.
| | - J L Pedraz
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain.
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20
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Hyaluronic acid enhances cell survival of encapsulated insulin-producing cells in alginate-based microcapsules. Int J Pharm 2019; 557:192-198. [PMID: 30597265 DOI: 10.1016/j.ijpharm.2018.12.062] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/13/2018] [Accepted: 12/15/2018] [Indexed: 12/18/2022]
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21
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Kuna VK, Kvarnström N, Elebring E, Holgersson SS. Isolation and Decellularization of a Whole Porcine Pancreas. J Vis Exp 2018. [PMID: 30371658 PMCID: PMC6235501 DOI: 10.3791/58302] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Tissue engineering of the whole pancreas can improve current treatments for diabetes mellitus. The ultimate goal is to tissue engineer pancreas from an allogeneic or xenogeneic source with human cells. A demonstration of methods for the efficient dissection, decellularization, and recellularization of porcine pancreas might benefit the field. Akin to human pancreases, porcine pancreases have a special anatomical arrangement with three lobes (splenic, duodenal, and connection) rounded by the duodenum and small intestine. The duodenal lobe of the pancreas connects to the duodenum by several small blood vessels. Tissue engineering of the pancreas is complicated because of its exocrine and endocrine nature. In this paper, we show a detailed protocol to dissect the whole porcine pancreas and decellularize it with detergents while saving its structure and some extracellular matrix components. To achieve complete perfusion, the aorta is chosen as inlet and the portal vein as outlet. The other blood vessels (hepatic artery, splenic vein, splenic artery, mesenteric artery and vein tree) and bile duct are ligated. To prevent the formation of thrombus, the pig is heparinized and, immediately after dissection, the organ is flushed with cold heparin. To inhibit the action of exocrine enzymes, the pancreas decellularization is set at 4 °C. The decellularization is performed by perfusion of Triton X-100, sodium deoxycholate, and deoxyribonuclease, with an intermittent and final extensive washing. With a successful decellularization, the pancreas appears white, and a histological evaluation with hematoxylin and eosin shows an absence of nuclei with a preserved extracellular matrix structure. Thus, the proposed method can be used to successfully dissect and decellularize whole porcine pancreas.
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Affiliation(s)
- Vijay Kumar Kuna
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg
| | | | - Erik Elebring
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg
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22
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Rios PD, Skoumal M, Liu J, Youngblood R, Kniazeva E, Garcia AJ, Shea LD. Evaluation of encapsulating and microporous nondegradable hydrogel scaffold designs on islet engraftment in rodent models of diabetes. Biotechnol Bioeng 2018; 115:2356-2364. [PMID: 29873059 PMCID: PMC6131066 DOI: 10.1002/bit.26741] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 05/11/2018] [Accepted: 05/22/2018] [Indexed: 02/06/2023]
Abstract
Islet transplantation is a promising therapeutic option for type 1 diabetes mellitus, yet the current delivery into the hepatic portal vasculature is limited by poor engraftment. Biomaterials have been used as a means to promote engraftment and function at extrahepatic sites, with strategies being categorized as encapsulation or microporous scaffolds that can either isolate or integrate islets with the host tissue, respectively. Although these approaches are typically studied separately using distinct material platforms, herein, we developed nondegradable polyethylene glycol (PEG)-based hydrogels for islet encapsulation or as microporous scaffolds for islet seeding to compare the initial engraftment and function of islets in syngeneic diabetic mice. Normoglycemia was restored with transplantation of islets within either encapsulating or microporous hydrogels containing 700 islet equivalents (IEQ), with transplantation on microporous hydrogels producing lower blood glucose levels at earlier times. A glucose challenge test at 1 month after transplant indicated that encapsulated islets had a delay in glucose-stimulated insulin secretion, whereas microporous hydrogels restored normoglycemia in times consistent with native pancreata. Encapsulated islets remained isolated from the host tissue, whereas the microporous scaffolds allowed for revascularization of the islets after transplant. Finally, we compared the inflammatory response after transplantation for the two systems and noted that microporous hydrogels had a substantially increased presence of neutrophils. Collectively, these findings suggest that both encapsulation and microporous PEG scaffold designs allow for stable engraftment of syngeneic islets and the ability to restore normoglycemia, yet the architecture influences islet function and responsiveness after transplantation.
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Affiliation(s)
- Peter D Rios
- Department of Biomedical Engineering, Northwestern University, Evanston, Illinois
| | - Michael Skoumal
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Jeffrey Liu
- Department of Biomedical Engineering, Northwestern University, Evanston, Illinois
- Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, Illinois
| | - Richard Youngblood
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Ekaterina Kniazeva
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
| | - Andrés J Garcia
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia
- Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia
| | - Lonnie D Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
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23
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Syed F, Bugliani M, Novelli M, Olimpico F, Suleiman M, Marselli L, Boggi U, Filipponi F, Raffa V, Krol S, Campani D, Masiello P, De Tata V, Marchetti P. Conformal coating by multilayer nano-encapsulation for the protection of human pancreatic islets: In-vitro and in-vivo studies. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2018; 14:2191-2203. [PMID: 30016718 DOI: 10.1016/j.nano.2018.06.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 06/15/2018] [Accepted: 06/28/2018] [Indexed: 01/05/2023]
Abstract
To improve the efficiency of pancreatic islet transplantation, we performed in-vitro and in-vivo experiments with isolated human pancreatic islets coated by multi-layer nano-encapsulation using differently charged polymers [chitosan and poly(sodium styrene sulfonate)] to obtain up to 9 layers. The islet coating (thickness: 104.2 ± 4.2 nm) was uniform, with ≥ 90% cell viability and well preserved beta- and alpha-cell ultrastructure. Nano-encapsulated islets maintained physiological glucose-stimulated insulin secretion by both static incubation and perifusion studies. Notably, palmitate- or cytokine-induced toxicity was significantly reduced in nano-coated islets. Xenotransplantation of nano-encapsulated islets under the kidney capsule of streptozotocin-induced C57Bl/6J diabetic mice allowed long term normal or near normal glycemia, associated with minimal infiltration of immune cell into the grafts, well preserved islet morphology and signs of re-vascularization. In summary, the multi-layer nano-encapsulation approach described in the present study provides a promising tool to effectively protect human islets both in-vitro andin-vivo conditions.
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Affiliation(s)
- Farooq Syed
- Department of Clinical and Experimental Medicine, University of Pisa, Italy.
| | - Marco Bugliani
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Michela Novelli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Francesco Olimpico
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Mara Suleiman
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Lorella Marselli
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Ugo Boggi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Franco Filipponi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | | | - Silke Krol
- NanoMed lab, Fondazione IRCCS, Istituto Neurologico "Carlo Besta", IFOM-IEO-campus, Milan, Italy; Laboratory for translational nanomedicine, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Daniela Campani
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Pellegrino Masiello
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Vincenzo De Tata
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa, Italy.
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24
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Yang J, Lou S, Kong D, Li C. Surface Engineering of Pancreatic Islets with a Heparinized StarPEG Nanocoating. J Vis Exp 2018:56879. [PMID: 29985314 PMCID: PMC6101986 DOI: 10.3791/56879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Cell surface engineering can protect implanted cells from host immune attack. It can also reshape cellular landscape to improve graft function and survival post-transplantation. This protocol aims to achieve surface engineering of pancreatic islets using an ultrathin heparin-incorporated starPEG (Hep-PEG) nanocoating. To generate the Hep-PEG nanocoating for pancreatic islet surface engineering, heparin succinimidyl succinate (Heparin-NHS) was first synthesized by modification of its carboxylate groups using N-(3-dimethylamino propyl)-N'-ethyl carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS). The Hep-PEG mixture was then formed by crosslinking of the amino end-functionalized eight-armed starPEG (starPEG-(NH2)8) and Heparin-NHS. For islet surface coating, mouse islets were isolated via collagenase digestion and gradient purification using Histopaque. Isolated islets were then treated with ice cold Hep-PEG solution for 10 min to allow covalent binding between NHS and the amine groups of islet cell membrane. Nanocoating with the Hep-PEG incurs minimal alteration to islet size and volume and heparinization of the islets with Hep-PEG may also reduce instant blood-mediated inflammatory reaction during islet transplantation. This "easy-to-adopt" approach is mild enough for surface engineering of living cells without compromising cell viability. Considering that heparin has shown binding affinity to multiple cytokines, the Hep-PEG nanocoating also provides an open platform that enables incorporation of unlimited functional biological mediators and multi-layered surfaces for living cell surface bioengineering.
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Affiliation(s)
- Jingyi Yang
- Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science & Peking Union Medical College
| | - Shaofeng Lou
- Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science & Peking Union Medical College
| | - Deling Kong
- Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science & Peking Union Medical College
| | - Chen Li
- Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science & Peking Union Medical College;
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25
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Yang KC, Yanai G, Yang SY, Canning P, Satou Y, Kawagoe M, Sumi S. Low-adhesive ethylene vinyl alcohol-based packaging to xenogeneic islet encapsulation for type 1 diabetes treatment. Biotechnol Bioeng 2018; 115:2341-2355. [PMID: 29777589 DOI: 10.1002/bit.26730] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 03/17/2018] [Accepted: 05/16/2018] [Indexed: 01/16/2023]
Abstract
Transplantation of encapsulated porcine islets is proposed to treat type 1 diabetes. However, the envelopment of fibrous tissue and the infiltration of immune cells impair islet function and eventually cause implant failure. It is known that hemodialysis using an ethylene vinyl alcohol (EVOH) membrane results in minor tissue responses. Therefore, we hypothesized that using a low-adhesive EVOH membrane for encapsulation may prevent host cell accumulation and fibrous capsule formation. In this study, rat islets suspended in chitosan gel were encapsulated in bags made from highly porous EVOH membranes, and their in vitro insulin secretion function as well as in vivo performance was evaluated. The results showed that the EVOH bag did not affect islet survival or glucose-stimulated insulin secretion. Whereas naked islets were dysfunctional after 7 days of culture in vitro, islets within the EVOH bag produced insulin continuously for 30 days. Streptozotocin-induced diabetic mice were given islets-chitosan gel-EVOH implants intraperitoneally (650-800 islets equivalent) and exhibited lower blood glucose levels and regained body weight during a 4-week observation period. The transplanted mice had higher levels of serum insulin and C-peptide, with an improved blood glucose disappearance rate. Retrieved implants had minor tissue adhesion, and histology showed a limited number of mononuclear cells and fibroblasts surrounding the implants. No invasion of host cells into the EVOH bags was noticed, and the encapsulated islets were intact and positive for insulin-glucagon immunostaining. In conclusion, an EVOH bag can protect encapsulated islets, limit fibrous capsule formation, and extend graft function.
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Affiliation(s)
- Kai-Chiang Yang
- Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.,School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Goichi Yanai
- Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Sin-Yu Yang
- Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Priyadarshini Canning
- Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Yoshio Satou
- Molding Component Business Department, Kuraray Co., Ltd, Tokyo, Japan
| | - Masako Kawagoe
- Molding Component Business Department, Kuraray Co., Ltd, Tokyo, Japan
| | - Shoichiro Sumi
- Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
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26
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Lew B, Kim IY, Choi H, Kim K. Sustained exenatide delivery via intracapsular microspheres for improved survival and function of microencapsulated porcine islets. Drug Deliv Transl Res 2018; 8:857-862. [DOI: 10.1007/s13346-018-0484-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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27
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Zhu H, Li W, Liu Z, Li W, Chen N, Lu L, Zhang W, Wang Z, Wang B, Pan K, Zhang X, Chen G. Selection of Implantation Sites for Transplantation of Encapsulated Pancreatic Islets. TISSUE ENGINEERING PART B-REVIEWS 2018; 24:191-214. [PMID: 29048258 DOI: 10.1089/ten.teb.2017.0311] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pancreatic islet transplantation has been validated as a valuable therapy for type 1 diabetes mellitus patients with exhausted insulin treatment. However, this therapy remains limited by the shortage of donor and the requirement of lifelong immunosuppression. Islet encapsulation, as an available bioartificial pancreas (BAP), represents a promising approach to enable protecting islet grafts without or with minimal immunosuppression and possibly expanding the donor pool. To develop a clinically implantable BAP, some key aspects need to be taken into account: encapsulation material, capsule design, and implant site. Among them, the implant site exerts an important influence on the engraftment, stability, and biocompatibility of implanted BAP. Currently, an optimal site for encapsulated islet transplantation may include sufficient capacity to host large graft volumes, portal drainage, ease of access using safe and reproducible procedure, adequate blood/oxygen supply, minimal immune/inflammatory reaction, pliable for noninvasive imaging and biopsy, and potential of local microenvironment manipulation or bioengineering. Varying degrees of success have been confirmed with the utilization of liver or extrahepatic sites in an experimental or preclinical setting. However, the ideal implant site remains to be further engineered or selected for the widespread application of encapsulated islet transplantation.
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Affiliation(s)
- Haitao Zhu
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China .,2 Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University , Xi'an, China
| | - Wenjing Li
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Zhongwei Liu
- 3 Department of Cardiology, Shaanxi Provincial People's Hospital , Xi'an, China
| | - Wenliang Li
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Niuniu Chen
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Linlin Lu
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Wei Zhang
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Zhen Wang
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Bo Wang
- 2 Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University , Xi'an, China .,4 Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University , Xi'an, China
| | - Kaili Pan
- 5 Department of Pediatrics (No. 2 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Xiaoge Zhang
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Guoqiang Chen
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
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28
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Abstract
Review of emerging advances and persisting challenges in the engineering and translation of islet encapsulation technologies.
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Affiliation(s)
| | - Long-Hai Wang
- Department of Biological and Environmental Engineering
- Cornell University
- Ithaca
- USA
| | - Minglin Ma
- Department of Biological and Environmental Engineering
- Cornell University
- Ithaca
- USA
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29
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Chen X, Luo J, Wu M, Pan Z, Xie Y, Wang H, Chen B, Zhu H. Study on Association of Pentraxin 3 and Diabetic Nephropathy in a Rat Model. J Diabetes Res 2018; 2018:8968573. [PMID: 29725602 PMCID: PMC5872604 DOI: 10.1155/2018/8968573] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 12/08/2017] [Accepted: 12/24/2017] [Indexed: 01/04/2023] Open
Abstract
Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. Compared with other therapies for diabetic patients, islet transplantation can effectively prevent and reverse diabetes-induced microvascular disease, such as diabetic retinopathy and nephropathy. PTX3 is the only long pentraxin that can be detected in renal tissue. In this study, we investigated the expression of PTX3 when early DN was reversed after islet transplantation. Methods. Diabetes was induced in rats by injecting streptozotocin (STZ). Twelve weeks later, the diabetic rats were divided into 2 groups: the islet transplantation group (IT) and the diabetic nephropathy group (DN). Renal injury, renal function, and the expression of PTX3 in the plasma and the kidneys were assessed with urinalysis, immunohistochemical staining, and Western blot, respectively. Results. The expression of PTX3 in the kidney was significantly decreased in the DN group but increased in the IT group because of the reversal of DN. Conclusions. Our data showed that the level of PTX3 in renal tissue is closely related to renal injury in DN. This may be used to quantify the extent of renal injury in DN, provide a potential early indicator of renal tubular injury in early DN patients, and assess DN clinical progression.
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Affiliation(s)
- Xuehai Chen
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Jiao Luo
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Minmin Wu
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Zhuo Pan
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Yue Xie
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Hongwei Wang
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Bicheng Chen
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Zhejiang Provincial Top Key Discipline in Surgery, Wenzhou Key Laboratory of Surgery, Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Hong Zhu
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
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30
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Elebring E, Kuna VK, Kvarnström N, Sumitran-Holgersson S. Cold-perfusion decellularization of whole-organ porcine pancreas supports human fetal pancreatic cell attachment and expression of endocrine and exocrine markers. J Tissue Eng 2017; 8:2041731417738145. [PMID: 29118967 PMCID: PMC5669317 DOI: 10.1177/2041731417738145] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 09/29/2017] [Indexed: 12/23/2022] Open
Abstract
Despite progress in the field of decellularization and recellularization, the outcome for pancreas has not been adequate. This might be due to the challenging dual nature of pancreas with both endocrine and exocrine tissues. We aimed to develop a novel and efficient cold-perfusion method for decellularization of porcine pancreas and recellularize acellular scaffolds with human fetal pancreatic stem cells. Decellularization of whole porcine pancreas at 4°C with sodium deoxycholate, Triton X-100 and DNase efficiently removed cellular material, while preserving the extracellular matrix structure. Furthermore, recellularization of acellular pieces with human fetal pancreatic stem cells for 14 days showed attached and proliferating cells. Both endocrine (C-peptide and PDX1) and exocrine (glucagon and α-amylase) markers were expressed in recellularized tissues. Thus, cold-perfusion can successfully decellularize porcine pancreas, which when recellularized with human fetal pancreatic stem cells shows relevant endocrine and exocrine phenotypes. Decellularized pancreas is a promising biomaterial and might translate to clinical relevance for treatment of diabetes.
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Affiliation(s)
- Erik Elebring
- Laboratory for Transplantation and Regenerative Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Vijay K Kuna
- Laboratory for Transplantation and Regenerative Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Niclas Kvarnström
- The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Suchitra Sumitran-Holgersson
- Laboratory for Transplantation and Regenerative Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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31
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Montanari E, Meier RPH, Mahou R, Seebach JD, Wandrey C, Gerber-Lemaire S, Buhler LH, Gonelle-Gispert C. Multipotent mesenchymal stromal cells enhance insulin secretion from human islets via N-cadherin interaction and prolong function of transplanted encapsulated islets in mice. Stem Cell Res Ther 2017; 8:199. [PMID: 28962589 PMCID: PMC5622460 DOI: 10.1186/s13287-017-0646-7] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 06/13/2017] [Accepted: 08/14/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Multipotent mesenchymal stromal cells (MSC) enhance viability and function of islets of Langerhans. We aimed to examine the interactions between human MSC and human islets of Langerhans that influence the function of islets. METHODS Human MSC and human islets (or pseudoislets, obtained after digestion and reaggregation of islet cells) were cocultured with or without cellular contact and glucose-stimulated insulin secretion assays were performed to assess cell function. The expression of several adhesion molecules, notably ICAM-1 and N-cadherin on islets and MSC, was investigated by qPCR. The role of N-cadherin was analyzed by adding an anti-N-cadherin antibody in islets cultured with or without MSC for 24 h followed by insulin measurements in static incubation assays. Islets and MSC were coencapsulated in new hydrogel microspheres composed of calcium alginate and covalently crosslinked polyethylene glycol. Encapsulated cells were transplanted intraperitoneally in streptozotocin-induced diabetic mice and glycemia was monitored. Islet function was evaluated by the intraperitoneal glucose tolerance test. RESULTS In vitro, free islets and pseudoislets cocultured in contact with MSC showed a significantly increased insulin secretion when compared to islets or pseudoislets cultured alone or cocultured without cell-to-cell contact with MSC (p < 0.05). The expression of ICAM-1 and N-cadherin was present on islets and MSC. Blocking N-cadherin prevented the enhanced insulin secretion by islets cultured in contact with MSC whereas it did not affect insulin secretion by islets cultured alone. Upon transplantation in diabetic mice, islets microencapsulated together with MSC showed significantly prolonged normoglycemia when compared with islets alone (median 69 and 39 days, respectively, p < 0.01). The intraperitoneal glucose tolerance test revealed an improved glycemic response in mice treated with islets microencapsulated together with MSC compared to mice transplanted with islets alone (p < 0.001). CONCLUSIONS MSC improve survival and function of islets of Langerhans by cell-to-cell contact mediated by the adhesion molecule N-cadherin.
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Affiliation(s)
- Elisa Montanari
- Department of Surgery, Geneva University Hospitals and Medical Faculty, 1211, Geneva, Switzerland
| | - Raphael P H Meier
- Department of Surgery, Geneva University Hospitals and Medical Faculty, 1211, Geneva, Switzerland
| | - Redouan Mahou
- Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada.,Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland
| | - Jörg D Seebach
- Division of Immunology and Allergy, Geneva University Hospitals and Medical Faculty, 1211, Geneva, Switzerland
| | - Christine Wandrey
- Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland
| | - Sandrine Gerber-Lemaire
- Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland
| | - Leo H Buhler
- Department of Surgery, Geneva University Hospitals and Medical Faculty, 1211, Geneva, Switzerland
| | - Carmen Gonelle-Gispert
- Department of Surgery, Geneva University Hospitals and Medical Faculty, 1211, Geneva, Switzerland.
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Tunable injectable alginate-based hydrogel for cell therapy in Type 1 Diabetes Mellitus. Int J Biol Macromol 2017; 107:1261-1269. [PMID: 28962846 DOI: 10.1016/j.ijbiomac.2017.09.103] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 09/11/2017] [Accepted: 09/26/2017] [Indexed: 02/07/2023]
Abstract
Islet transplantation has the potential of reestablishing naturally-regulated insulin production in Type 1 diabetic patients. Nevertheless, this procedure is limited due to the low islet survival after transplantation and the lifelong immunosuppression to avoid rejection. Islet embedding within a biocompatible matrix provides mechanical protection and a physical barrier against the immune system thus, increasing islet survival. Alginate is the preferred biomaterial used for embedding insulin-producing cells because of its biocompatibility, low toxicity and ease of gelation. However, alginate gelation is poorly controlled, affecting its physicochemical properties as an injectable biomaterial. Including different concentrations of the phosphate salt Na2HPO4 in alginate hydrogels, we can modulate their gelation time, tuning their physicochemical properties like stiffness and porosity while maintaining an appropriate injectability. Moreover, these hydrogels showed good biocompatibility when embedding a rat insulinoma cell line, especially at low Na2HPO4 concentrations, indicating that these hydrogels have potential as injectable biomaterials for Type 1 Diabetes Mellitus treatment.
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Abstract
Transplantation of pancreatic islets encapsulated within immuno-protective microcapsules is a strategy that has the potential to overcome graft rejection without the need for toxic immunosuppressive medication. However, despite promising preclinical studies, clinical trials using encapsulated islets have lacked long-term efficacy, and although generally considered clinically safe, have not been encouraging overall. One of the major factors limiting the long-term function of encapsulated islets is the host's immunological reaction to the transplanted graft which is often manifested as pericapsular fibrotic overgrowth (PFO). PFO forms a barrier on the capsule surface that prevents the ingress of oxygen and nutrients leading to islet cell starvation, hypoxia and death. The mechanism of PFO formation is still not elucidated fully and studies using a pig model have tried to understand the host immune response to empty alginate microcapsules. In this review, the varied strategies to overcome or reduce PFO are discussed, including alginate purification, altering microcapsule geometry, modifying alginate chemical composition, co-encapsulation with immunomodulatory cells, administration of pharmacological agents, and alternative transplantation sites. Nanoencapsulation technologies, such as conformal and layer-by-layer coating technologies, as well as nanofiber, thin-film nanoporous devices, and silicone based NanoGland devices are also addressed. Finally, this review outlines recent progress in imaging technologies to track encapsulated cells, as well as promising perspectives concerning the production of insulin-producing cells from stem cells for encapsulation.
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Affiliation(s)
- Vijayaganapathy Vaithilingam
- Materials Science and Engineering, Commonwealth Scientific and Industrial Research Organization (CSIRO), North Ryde, New South Wales, Australia
| | - Sumeet Bal
- Materials Science and Engineering, Commonwealth Scientific and Industrial Research Organization (CSIRO), North Ryde, New South Wales, Australia
| | - Bernard E Tuch
- School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia
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Xue S, Yin J, Shao J, Yu Y, Yang L, Wang Y, Xie M, Fussenegger M, Ye H. A Synthetic-Biology-Inspired Therapeutic Strategy for Targeting and Treating Hepatogenous Diabetes. Mol Ther 2017; 25:443-455. [PMID: 28153094 DOI: 10.1016/j.ymthe.2016.11.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 11/11/2016] [Accepted: 11/15/2016] [Indexed: 12/31/2022] Open
Abstract
Hepatogenous diabetes is a complex disease that is typified by the simultaneous presence of type 2 diabetes and many forms of liver disease. The chief pathogenic determinant in this pathophysiological network is insulin resistance (IR), an asymptomatic disease state in which impaired insulin signaling in target tissues initiates a variety of organ dysfunctions. However, pharmacotherapies targeting IR remain limited and are generally inapplicable for liver disease patients. Oleanolic acid (OA) is a plant-derived triterpenoid that is frequently used in Chinese medicine as a safe but slow-acting treatment in many liver disorders. Here, we utilized the congruent pharmacological activities of OA and glucagon-like-peptide 1 (GLP-1) in relieving IR and improving liver and pancreas functions and used a synthetic-biology-inspired design principle to engineer a therapeutic gene circuit that enables a concerted action of both drugs. In particular, OA-triggered short human GLP-1 (shGLP-1) expression in hepatogenous diabetic mice rapidly and simultaneously attenuated many disease-specific metabolic failures, whereas OA or shGLP-1 monotherapy failed to achieve corresponding therapeutic effects. Collectively, this work shows that rationally engineered synthetic gene circuits are capable of treating multifactorial diseases in a synergistic manner by multiplexing the targeting efficacies of single therapeutics.
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Affiliation(s)
- Shuai Xue
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China
| | - Jianli Yin
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China
| | - Jiawei Shao
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China
| | - Yuanhuan Yu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China
| | - Linfeng Yang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China
| | - Yidan Wang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China
| | - Mingqi Xie
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China; Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland
| | - Martin Fussenegger
- Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland
| | - Haifeng Ye
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.
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Lou S, Zhang X, Zhang J, Deng J, Kong D, Li C. Pancreatic islet surface bioengineering with a heparin-incorporated starPEG nanofilm. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2017; 78:24-31. [PMID: 28575981 DOI: 10.1016/j.msec.2017.03.295] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 03/28/2017] [Accepted: 03/31/2017] [Indexed: 01/06/2023]
Abstract
Cell surface engineering could protect implanted cells from host immune rejections while modify the cellular landscape for better post-transplantation graft function and survival. Islet transplantation is considered the most promising therapeutic option with the potential to cure diabetes. Current approach to improve clinical efficacy of pancreatic islet transplantation is alginate encapsulation. However, disappointing outcomes have been reported in clinical trials due to larger islet size resulted by encapsulation and alginate-elicited host immune responses. We have developed an ultrathin nanofilm of starPEG with incorporated heparin (Hep-PEG) that binds covalently to the amine groups of islet surface membrane via its N-hydroxysuccinimide groups. The Hep-PEG nanocoating elicited minimal alteration on islet volume in culture. Hep-PEG-coated islets exhibited robust islet viability accompanied by uncompromised islet insulin secretory function. Instant blood-mediated inflammatory reaction was also reduced by Hep-PEG islet coating, accompanied by enhanced intra-islet revascularization. In addition, despite its semi-permeability, Hep-PEG islet coating promoted the survival of islets exposed to pro-inflammatory cytokines. Considering that inflammation and hypoxia are primary causes of immediate cell loss for cell therapy, the Hep-PEG nanofilm represents a viable approach for cell surface engineering which would improve the clinical outcome of cell therapies.
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Affiliation(s)
- Shaofeng Lou
- Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Xiuyuan Zhang
- Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science& Peking Union Medical College, Tianjin 300192, China
| | - Jimin Zhang
- Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Juan Deng
- Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science& Peking Union Medical College, Tianjin 300192, China
| | - Deling Kong
- Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China; Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science& Peking Union Medical College, Tianjin 300192, China.
| | - Chen Li
- Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science& Peking Union Medical College, Tianjin 300192, China.
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Cell based therapeutics in type 1 diabetes mellitus. Int J Pharm 2017; 521:346-356. [DOI: 10.1016/j.ijpharm.2017.02.063] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 02/21/2017] [Accepted: 02/22/2017] [Indexed: 12/21/2022]
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Einstein SA, Weegman BP, Firpo MT, Papas KK, Garwood M. Development and Validation of Noninvasive Magnetic Resonance Relaxometry for the In Vivo Assessment of Tissue-Engineered Graft Oxygenation. Tissue Eng Part C Methods 2016; 22:1009-1017. [PMID: 27758135 PMCID: PMC5116663 DOI: 10.1089/ten.tec.2016.0106] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 09/26/2016] [Indexed: 11/12/2022] Open
Abstract
Techniques to monitor the oxygen partial pressure (pO2) within implanted tissue-engineered grafts (TEGs) are critically necessary for TEG development, but current methods are invasive and inaccurate. In this study, we developed an accurate and noninvasive technique to monitor TEG pO2 utilizing proton (1H) or fluorine (19F) magnetic resonance spectroscopy (MRS) relaxometry. The value of the spin-lattice relaxation rate constant (R1) of some biocompatible compounds is sensitive to dissolved oxygen (and temperature), while insensitive to other external factors. Through this physical mechanism, MRS can measure the pO2 of implanted TEGs. We evaluated six potential MRS pO2 probes and measured their oxygen and temperature sensitivities and their intrinsic R1 values at 16.4 T. Acellular TEGs were constructed by emulsifying porcine plasma with perfluoro-15-crown-5-ether, injecting the emulsion into a macroencapsulation device, and cross-linking the plasma with a thrombin solution. A multiparametric calibration equation containing R1, pO2, and temperature was empirically generated from MRS data and validated with fiber optic (FO) probes in vitro. TEGs were then implanted in a dorsal subcutaneous pocket in a murine model and evaluated with MRS up to 29 days postimplantation. R1 measurements from the TEGs were converted to pO2 values using the established calibration equation and these in vivo pO2 measurements were simultaneously validated with FO probes. Additionally, MRS was used to detect increased pO2 within implanted TEGs that received supplemental oxygen delivery. Finally, based on a comparison of our MRS data with previously reported data, ultra-high-field (16.4 T) is shown to have an advantage for measuring hypoxia with 19F MRS. Results from this study show MRS relaxometry to be a precise, accurate, and noninvasive technique to monitor TEG pO2 in vitro and in vivo.
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Affiliation(s)
- Samuel A. Einstein
- Department of Radiology, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, Minnesota
| | - Bradley P. Weegman
- Department of Radiology, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, Minnesota
| | - Meri T. Firpo
- Department of Medicine, Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota
| | | | - Michael Garwood
- Department of Radiology, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, Minnesota
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38
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Kaviani M, Azarpira N. Insight into microenvironment remodeling in pancreatic endocrine tissue engineering: Biological and biomaterial approaches. Tissue Eng Regen Med 2016; 13:475-484. [PMID: 30603429 PMCID: PMC6170842 DOI: 10.1007/s13770-016-0014-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 02/03/2016] [Accepted: 02/05/2016] [Indexed: 01/04/2023] Open
Abstract
The treatment of diabetes mellitus, as a chronic and complicated disease, is a valuable purpose. Islet transplantation can provide metabolic stability and insulin independence in type 1 diabetes patients. Diet and insulin therapy are only diabetes controllers and cannot remove all of the diabetes complications. Moreover, islet transplantation is more promising treatment than whole pancreas transplantation because of lesser invasive surgical procedure and morbidity and mortality. According to the importance of extracellular matrix for islet viability and function, microenvironment remodeling of pancreatic endocrine tissue can lead to more success in diabetes treatment by pancreatic islets. Production of bioengineered pancreas and remodeling of pancreas extracellular matrix provide essential microenvironment for re-vascularization, re-innervation and signaling cascades triggering. Therefore, islets show better viability and function in these conditions. Researchers conduct various scaffolds with different biomaterials for the improvement of islet viability, function and transplantation outcome. The attention to normal pancreas anatomy, embryology and histology is critical to understand the pancreatic Langerhans islets niche and finally to achieve efficient engineered structure. Therefore, in the present study, the status and components of the islets niche is mentioned and fundamental issues related to the tissue engineering of this structure is considered. The purpose of this review article is summarization of recent progress in the endocrine pancreas tissue engineering and biomaterials and biological aspects of it.
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Affiliation(s)
- Maryam Kaviani
- Transplant Research Center, Shiraz University of Medical Sciences, Mohamad Rasulallah Research Tower, Khalili street, Shiraz, 7193635899 Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Mohamad Rasulallah Research Tower, Khalili street, Shiraz, 7193635899 Iran
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39
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Synthetic biology — application-oriented cell engineering. Curr Opin Biotechnol 2016; 40:139-148. [DOI: 10.1016/j.copbio.2016.04.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 04/02/2016] [Accepted: 04/05/2016] [Indexed: 01/01/2023]
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40
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Matsumoto S, Tomiya M, Sawamoto O. Current status and future of clinical islet xenotransplantation. J Diabetes 2016; 8:483-93. [PMID: 26987992 DOI: 10.1111/1753-0407.12395] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 02/18/2016] [Accepted: 03/04/2016] [Indexed: 12/11/2022] Open
Abstract
β-Cell replacement therapy, including allogeneic pancreas and islet transplantation, can normalize HbA1c levels in unstable type 1 diabetic (T1D) patients, but a donor shortage is a serious issue. To overcome this problem, xenotransplantation is an attractive option. In fact, islet transplantation from porcine pancreata was performed in the 1990s, which opened the door for islet xenotransplantation, but the possibility of porcine endogenous retrovirus (PERV) infection was raised, which has restricted progress in this field. The International Xenotransplantation Association published a consensus statement on conditions for undertaking clinical trials of porcine islet products in T1D to restart islet xenotransplantation safely. Clinical porcine islet xenotransplantation was restarted under comprehensive regulations in New Zealand. In addition, newly emerged gene-editing technologies have activated the xenotransplantation field. Islet xenotransplantation is becoming a clinical reality, with the results of recent studies showing promise to advance this field.
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Affiliation(s)
- Shinichi Matsumoto
- Research and Development Center, Otsuka Pharmaceutical Factory, Inc, Naruto, Japan
- Islet Transplantation Project National Institute for Global Health and Medicine, Tokyo, Japan
| | - Masayuki Tomiya
- Department of Regenerative Medicine, Otsuka Pharmaceutical Factory, Naruto, Japan
| | - Osamu Sawamoto
- Department of Regenerative Medicine, Otsuka Pharmaceutical Factory, Naruto, Japan
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Barkai U, Rotem A, de Vos P. Survival of encapsulated islets: More than a membrane story. World J Transplant 2016; 6:69-90. [PMID: 27011906 PMCID: PMC4801806 DOI: 10.5500/wjt.v6.i1.69] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/02/2015] [Accepted: 12/20/2015] [Indexed: 02/05/2023] Open
Abstract
At present, proven clinical treatments but no cures are available for diabetes, a global epidemic with a huge economic burden. Transplantation of islets of Langerhans by their infusion into vascularized organs is an experimental clinical protocol, the first approach to attain cure. However, it is associated with lifelong use of immunosuppressants. To overcome the need for immunosuppression, islets are encapsulated and separated from the host immune system by a permselective membrane. The lead material for this application is alginate which was tested in many animal models and a few clinical trials. This review discusses all aspects related to the function of transplanted encapsulated islets such as the basic requirements from a permselective membrane (e.g., allowable hydrodynamic radii, implications of the thickness of the membrane and relative electrical charge). Another aspect involves adequate oxygen supply, which is essential for survival/performance of transplanted islets, especially when using large retrievable macro-capsules implanted in poorly oxygenated sites like the subcutis. Notably, islets can survive under low oxygen tension and are physiologically active at > 40 Torr. Surprisingly, when densely crowded, islets are fully functional under hyperoxic pressure of up to 500 Torr (> 300% of atmospheric oxygen tension). The review also addresses an additional category of requirements for optimal performance of transplanted islets, named auxiliary technologies. These include control of inflammation, apoptosis, angiogenesis, and the intra-capsular environment. The review highlights that curing diabetes with a functional bio-artificial pancreas requires optimizing all of these aspects, and that significant advances have already been made in many of them.
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Szekalska M, Puciłowska A, Szymańska E, Ciosek P, Winnicka K. Alginate: Current Use and Future Perspectives in Pharmaceutical and Biomedical Applications. INT J POLYM SCI 2016; 2016:1-17. [DOI: 10.1155/2016/7697031] [Citation(s) in RCA: 247] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025] Open
Abstract
Over the last decades, alginates, natural multifunctional polymers, have increasingly drawn attention as attractive compounds in the biomedical and pharmaceutical fields due to their unique physicochemical properties and versatile biological activities. The focus of the paper is to describe biological and pharmacological activity of alginates and to discuss the present use and future possibilities of alginates as a tool in drug formulation. The recent technological advancements with using alginates, issues related to alginates suitability as matrix for three-dimensional tissue cultures, adjuvants of antibiotics, and antiviral agents in cell transplantation in diabetes or neurodegenerative diseases treatment, and an update on the antimicrobial and antiviral therapy of the alginate based drugs are also highlighted.
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Affiliation(s)
- Marta Szekalska
- Department of Pharmaceutical Technology, Medical University of Białystok, Mickiewicza 2c, 15-222 Białystok, Poland
| | - Agata Puciłowska
- Department of Pharmaceutical Technology, Medical University of Białystok, Mickiewicza 2c, 15-222 Białystok, Poland
| | - Emilia Szymańska
- Department of Pharmaceutical Technology, Medical University of Białystok, Mickiewicza 2c, 15-222 Białystok, Poland
| | - Patrycja Ciosek
- Department of Microbioanalytics, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
| | - Katarzyna Winnicka
- Department of Pharmaceutical Technology, Medical University of Białystok, Mickiewicza 2c, 15-222 Białystok, Poland
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VEGF-conjugated alginate hydrogel prompt angiogenesis and improve pancreatic islet engraftment and function in type 1 diabetes. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2015; 59:958-964. [PMID: 26652453 DOI: 10.1016/j.msec.2015.11.009] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 10/08/2015] [Accepted: 11/03/2015] [Indexed: 02/06/2023]
Abstract
Type 1 diabetes was a life-long disease that affected numerous people around the world. Insulin therapy has its limitations that may involve hyperglycemia and heavy burden of patient by repeated dose. Islet transplantation emerged as a promising approach to reach periodical reverse of diabetes, however, transplanted islets suffer from foreign body reaction and lack of nutrition and oxygen supply, especially in the blood-vessel-shortage subcutaneous site which was preferred by patient and surgeon. In this study, we designed and synthesized a vascular endothelial growth factor (VEGF) conjugated alginate material to encapsulate the transplanted islets via 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS) reaction, and successful conjugation was confirmed by Nuclear Magnetic Resonance H1 spectrum. The best VEGF concentration (100ng/ml) was determined by the combined studies of the mechanical property and endothelial cell growth assay. In vivo study, conjugated VEGF on alginate exhibited sustained promoting angiogenesis property after subcutaneous transplantation by histology study and islets encapsulated in this material achieved long term therapeutic effect (up to 50days) in the diabetic mice model. In conclusion, this study establishes a simple biomaterial strategy for islet transplantation to enhance islet survival and function, which could be a feasible therapeutic alternative for type 1 diabetes.
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Synthetic Biology--Toward Therapeutic Solutions. J Mol Biol 2015; 428:945-62. [PMID: 26334368 DOI: 10.1016/j.jmb.2015.08.020] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 08/18/2015] [Accepted: 08/19/2015] [Indexed: 02/07/2023]
Abstract
Higher multicellular organisms have evolved sophisticated intracellular and intercellular biological networks that enable cell growth and survival to fulfill an organism's needs. Although such networks allow the assembly of complex tissues and even provide healing and protective capabilities, malfunctioning cells can have severe consequences for an organism's survival. In humans, such events can result in severe disorders and diseases, including metabolic and immunological disorders, as well as cancer. Dominating the therapeutic frontier for these potentially lethal disorders, cell and gene therapies aim to relieve or eliminate patient suffering by restoring the function of damaged, diseased, and aging cells and tissues via the introduction of healthy cells or alternative genes. However, despite recent success, these efforts have yet to achieve sufficient therapeutic effects, and further work is needed to ensure the safe and precise control of transgene expression and cellular processes. In this review, we describe the biological tools and devices that are at the forefront of synthetic biology and discuss their potential to advance the specificity, efficiency, and safety of the current generation of cell and gene therapies, including how they can be used to confer curative effects that far surpass those of conventional therapeutics. We also highlight the current therapeutic delivery tools and the current limitations that hamper their use in human applications.
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Abstract
INTRODUCTION Islet transplantation can treat the most severe cases of type 1 diabetes but it currently requires deceased donor pancreata as an islet source and chronic immunosuppression to prevent rejection and recurrence of autoimmunity. Stem cell-derived insulin-producing cells may address the shortage of organ donors, whereas cell encapsulation may reduce or eliminate the requirement for immunosuppression, minimizing the risks associated with the islet transplantation procedure, and potentially prolonging graft survival. AREAS COVERED This review focuses on the design principles for immunoisolation devices and on stem cell differentiation into insulin-producing cell products. The reader will gain understanding of the different types of immunoisolation devices and the key parameters that affect the outcome of the encapsulated graft. Progresses in stem cell differentiation towards mature endocrine islet cells, including the most recent clinical trials and the challenges associated with the application of immunoisolation devices designed for primary islets to stem-cell products, are also discussed. EXPERT OPINION Recent advancements in the field of stem cell-derived islet cell products and immunoisolation strategies hold great promise for type 1 diabetes. However, a combination product including both cells and an immunoisolation strategy still needs to be optimized and tested for safety and efficacy.
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Affiliation(s)
- Alice Anna Tomei
- University of Miami Miller School of Medicine, Diabetes Research Institute , 1450 NW 10th Avenue, Miami, FL 33136 , USA +1 305 243 3469 ;
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Ludwig B, Ludwig S. Transplantable bioartificial pancreas devices: current status and future prospects. Langenbecks Arch Surg 2015; 400:531-40. [DOI: 10.1007/s00423-015-1314-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 06/04/2015] [Indexed: 02/08/2023]
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