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1
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Wong JM, Pepper AR. Status of islet transplantation and innovations to sustainable outcomes: novel sites, cell sources, and drug delivery strategies. FRONTIERS IN TRANSPLANTATION 2024; 3:1485444. [PMID: 39553396 PMCID: PMC11565603 DOI: 10.3389/frtra.2024.1485444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 10/21/2024] [Indexed: 11/19/2024]
Abstract
Islet transplantation (ITx) is an effective means to restore physiologic glycemic regulation in those living with type 1 diabetes; however, there are a handful of barriers that prevent the broad application of this functionally curative procedure. The restricted cell supply, requisite for life-long toxic immunosuppression, and significant immediate and gradual graft attrition limits the procedure to only those living with brittle diabetes. While intraportal ITx is the primary clinical site, portal vein-specific factors including low oxygen tension and the instant blood-mediated inflammatory reaction are detrimental to initial engraftment and long-term function. These factors among others prevent the procedure from granting recipients long-term insulin independence. Herein, we provide an overview of the status and limitations of ITx, and novel innovations that address the shortcomings presented. Despite the marked progress highlighted in the review from as early as the initial islet tissue transplantation in 1893, ongoing efforts to improve the procedure efficacy and success are also explored. Progress in identifying unlimited cell sources, more favourable transplant sites, and novel drug delivery strategies all work to broaden ITx application and reduce adverse outcomes. Exploring combination of these approaches may uncover synergies that can further advance the field of ITx in providing sustainable functional cures. Finally, the potential of biomaterial strategies to facilitate immune evasion and local immune modulation are featured and may underpin successful application in alternative transplant sites.
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Affiliation(s)
| | - Andrew R. Pepper
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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2
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Quispe-Siccha RM, Medina-Sandoval OI, Estrada-Tinoco A, Pedroza-Pérez JA, Martínez-Tovar A, Olarte-Carrillo I, Cerón-Maldonado R, Reding-Bernal A, López-Alvarenga JC. Development of Polyvinyl Alcohol Hydrogels for Controlled Glucose Release in Biomedical Applications. Gels 2024; 10:668. [PMID: 39451320 PMCID: PMC11507832 DOI: 10.3390/gels10100668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/03/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024] Open
Abstract
Polyvinyl alcohol (PVA) hydrogels have a wide range of applications in the pharmaceutical and biomedicine fields due to their exceptional biophysical properties. The study focuses on preparing and characterizing capsule-shaped PVA hydrogels to enhance their biocompatibility and porosity for controlled glucose release and cell proliferation. The hydrogels were prepared using different concentrations (Cs) and molecular weights (MWs) of PVA, with two different lengths, A (10 mm) and B (20 mm), to control glucose release over 60 min. The preparation process involved PVA gel preparation and PVA hydrogel formation. A total of 500 µL of glucose was injected into all dehydrated hydrogels in groups A and B. Glucose release was studied by immersing the hydrogels in saline at 37 °C with stirring at 500 rpm. The SUP-B15 cell line was grown in six A1 hydrogels for biocompatibility testing. The results indicate that all hydrogels remained stable at 37 °C without degrading. Those with a higher C and MW exhibited a denser and less porous structure, lower glucose storage capacity, and higher elongation at break. Significant differences in glucose release, diffusion speed, and flux were observed, which were more evident in A1 > A4, B1 > B4, and B1 > A1 over 60 min. A1 and B1 had higher values because their higher porosity distribution allowed glucose to diffuse more easily. B1, being larger, has more glucose due to its increased length. The cell growth response and viability at 48 h in contact with the hydrogels was similar to that of the control (4.5 × 105 cells/mL, 98.5% vs. 4.8 × 105 cells/mL, 99.7% viability), thus demonstrating biocompatibility. The hydrogels effectively released glucose over 60 min, with variations based on porosity, C, MW, and length, and demonstrated good biocompatibility with the cell line.
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Affiliation(s)
- Rosa M. Quispe-Siccha
- Research and Technological Development Unit, Research Department, General Hospital of Mexico, “Dr. Eduardo Liceaga”, Mexico City 06726, Mexico
| | - Osvaldo I. Medina-Sandoval
- Interdisciplinary Biotechnology Professional Unit, National Polytechnic Institute, Mexico City 07340, Mexico; (O.I.M.-S.); (A.E.-T.); (J.A.P.-P.)
| | - Abraham Estrada-Tinoco
- Interdisciplinary Biotechnology Professional Unit, National Polytechnic Institute, Mexico City 07340, Mexico; (O.I.M.-S.); (A.E.-T.); (J.A.P.-P.)
| | - Jorge A. Pedroza-Pérez
- Interdisciplinary Biotechnology Professional Unit, National Polytechnic Institute, Mexico City 07340, Mexico; (O.I.M.-S.); (A.E.-T.); (J.A.P.-P.)
| | - Adolfo Martínez-Tovar
- Hematology Laboratory, General Hospital of Mexico “Dr. Eduardo Liceaga”, Mexico City 06726, Mexico; (A.M.-T.); (I.O.-C.); (R.C.-M.)
| | - Irma Olarte-Carrillo
- Hematology Laboratory, General Hospital of Mexico “Dr. Eduardo Liceaga”, Mexico City 06726, Mexico; (A.M.-T.); (I.O.-C.); (R.C.-M.)
| | - Rafael Cerón-Maldonado
- Hematology Laboratory, General Hospital of Mexico “Dr. Eduardo Liceaga”, Mexico City 06726, Mexico; (A.M.-T.); (I.O.-C.); (R.C.-M.)
| | - Arturo Reding-Bernal
- Research Department, General Hospital of Mexico “Dr. Eduardo Liceaga”, Mexico City 06726, Mexico;
| | - Juan C. López-Alvarenga
- Population Health & Biostatistics, School of Medicine, University of Texas Rio Grande Valley, Edinburgh, TX 78539, USA;
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Araújo-Gomes N, Zoetebier-Liszka B, van Loo B, Becker M, Nijhuis S, Smink AM, de Haan BJ, de Vos P, Karperien M, Leijten J. Microfluidic Generation of Thin-Shelled Polyethylene Glycol-Tyramine Microgels for Non-Invasive Delivery of Immunoprotected β-Cells. Adv Healthc Mater 2024; 13:e2301552. [PMID: 37548084 DOI: 10.1002/adhm.202301552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 07/21/2023] [Indexed: 08/08/2023]
Abstract
Transplantation of microencapsulated pancreatic cells is emerging as a promising therapy to replenish β-cell mass lost from auto-immune nature of type I diabetes mellitus (T1DM). This strategy intends to use micrometer-sized microgels to provide immunoprotection to transplanted cells to avoid chronic application of immunosuppression. Clinical application of encapsulation has remained elusive due to often limited production throughputs and body's immunological reactions to implanted materials. This article presents a high-throughput fabrication of monodisperse, non-immunogenic, non-degradable, immunoprotective, semi-permeable, enzymatically-crosslinkable polyethylene glycol-tyramine (PEG-TA) microgels for β-cell microencapsulation. Monodisperse β-cell laden microgels of ≈120 µm, with a shell thickness of 20 µm are produced using an outside-in crosslinking strategy. Microencapsulated β-cells rapidly self-assemble into islet-sized spheroids. Immunoprotection of the microencapsulated is demonstrated by inability of FITC-IgG antibodies to diffuse into cell-laden microgels and NK-cell inability to kill microencapsulated β-cells. Multiplexed ELISA analysis on live blood immune reactivity confirms limited immunogenicity. Microencapsulated MIN6β1 spheroids remain glucose responsive for 28 days in vitro, and able to restore normoglycemia 5 days post-implantation in diabetic mice without notable amounts of cell death. In short, PEG-TA microgels effectively protect implanted cells from the host's immune system while being viable and functional, validating this strategy for the treatment of T1DM.
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Affiliation(s)
- Nuno Araújo-Gomes
- Department of Developmental BioEngineering, TechMed Centre, University of Twente, Drienerlolaan 5, Enschede, 7522NB, The Netherlands
| | - Barbara Zoetebier-Liszka
- Department of Developmental BioEngineering, TechMed Centre, University of Twente, Drienerlolaan 5, Enschede, 7522NB, The Netherlands
| | - Bas van Loo
- Department of Developmental BioEngineering, TechMed Centre, University of Twente, Drienerlolaan 5, Enschede, 7522NB, The Netherlands
| | - Malin Becker
- Department of Developmental BioEngineering, TechMed Centre, University of Twente, Drienerlolaan 5, Enschede, 7522NB, The Netherlands
| | - Suzanne Nijhuis
- Department of Developmental BioEngineering, TechMed Centre, University of Twente, Drienerlolaan 5, Enschede, 7522NB, The Netherlands
| | - Alexandra M Smink
- Department of Pathology and Medical Biology, Section of Immunoendocrinology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen, 9713 GZ, The Netherlands
| | - Bart J de Haan
- Department of Pathology and Medical Biology, Section of Immunoendocrinology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen, 9713 GZ, The Netherlands
| | - Paul de Vos
- Department of Pathology and Medical Biology, Section of Immunoendocrinology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen, 9713 GZ, The Netherlands
| | - Marcel Karperien
- Department of Developmental BioEngineering, TechMed Centre, University of Twente, Drienerlolaan 5, Enschede, 7522NB, The Netherlands
| | - Jeroen Leijten
- Department of Developmental BioEngineering, TechMed Centre, University of Twente, Drienerlolaan 5, Enschede, 7522NB, The Netherlands
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Gong J, Hou L, Ching YC, Ching KY, Hai ND, Chuah CH. A review of recent advances of cellulose-based intelligent-responsive hydrogels as vehicles for controllable drug delivery system. Int J Biol Macromol 2024; 264:130525. [PMID: 38431004 DOI: 10.1016/j.ijbiomac.2024.130525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 02/17/2024] [Accepted: 02/27/2024] [Indexed: 03/05/2024]
Abstract
To realize the maximum therapeutic activity of medicine and protect the body from the adverse effects of active ingredients, drug delivery systems (DDS) featured with targeted transportation sites and controllable release have captured extensive attention over the past decades. Hydrogels with unique three-dimensional (3D) porous structures present tunable capacity, controllable degradation, various stimuli sensitivity, therapeutic agents encapsulation, and loaded drugs protection properties, which endow hydrogels with bred-in-the-bone advantages as vehicles for drug delivery. In recent years, with the impressive consciousness of the "back-to-nature" concept, biomass materials are becoming the 'rising star' as the hydrogels building blocks for controlled drug release carriers due to their biodegradability, biocompatibility, and non-toxicity properties. In particular, cellulose and its derivatives are promising candidates for fabricating hydrogels as their rich sources and high availability, and various smart cellulose-based hydrogels as targeted carriers under exogenous such as light, electric field, and magnetic field or endogenous such as pH, temperature, ionic strength, and redox gradients. In this review, we summarized the main synthetic strategies of smart cellulose-based hydrogels including physical and chemical cross-linking, and illustrated the detailed intelligent-responsive mechanism of hydrogels in DDS under external stimulus. Additionally, the ongoing development and challenges of cellulose-based hydrogels in the biomedical field are also presented.
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Affiliation(s)
- Jingwei Gong
- Department of Chemical Engineering, Faculty of Engineering, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Leilei Hou
- Department of Catalytic Chemistry and Engineering, State key-laboratory of fine chemicals, Dalian University of Technology, Dalian 116034, People's Republic of China
| | - Yern Chee Ching
- Department of Chemical Engineering, Faculty of Engineering, University of Malaya, Kuala Lumpur 50603, Malaysia.
| | - Kuan Yong Ching
- University of Reading Malaysia, Kota Ilmu, Persiaran Graduan, Educity, 79200 Nusajaya, Johor, Malaysia
| | - Nguyen Dai Hai
- Institute of Chemical Technology, Vietnam Academy of Science and Technology, Department of Biomaterials & Bioengineering, Ho Chi Minh City, Viet Nam
| | - Cheng Hock Chuah
- Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia
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Bai X, Wang D, Wang B, Zhang X, Bai Y, Zhang X, Tian R, Li C, Yi Q, Cheng Y, He S. Staphylococcal protein A-modified hydrogel facilitates in situ immunomodulation by capturing anti-HMGB1 for islet grafts. Acta Biomater 2023; 166:95-108. [PMID: 37150280 DOI: 10.1016/j.actbio.2023.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 04/28/2023] [Accepted: 05/02/2023] [Indexed: 05/09/2023]
Abstract
Islet transplantation is regarded as the most promising therapy for type 1 diabetes. However, both hypoxia and immune attack impair the grafted islets after transplantation, eventually failing the islet graft. Although many studies showed that biomaterials with nanoscale pores, like hydrogels, could protect islets from immune cells, the pores on biomaterials inhibited vascular endothelial cells (VECs) to creep in, which resulted in poor revascularization. Thus, a hydrogel device that can facilitate in situ immune modulations without the cost of poor revascularization should be put forward. Accordingly, we designed a spA-modified hydrogel capturing anti-HMGB1 mAB (mAB-spA Gel): the Staphylococcus aureus protein A (spA) was conjugated on the network of hydrogel to capture anti-HMGB1mAB which can inactivate immune cells, while the pore sizes of the hydrogel were more than 100μm which allows vascular endothelial cells (VECs) to creep in. In this study, we screened the optimal spA concentration in mAB-spA Gel according to the physical properties and antibody binding capability, then demonstrated that it could facilitate in situ immunomodulation without decreasing the vessel reconstruction in vitro. Further, we transplanted islet graft in vivo and showed that the survival of islets was elongated. In conclusion, mAB-spA Gel provided an alternative islet encapsulation strategy for type 1 diabetes. STATEMENT OF SIGNIFICANCE: Although various studies have shown that the backbone of the hydrogels can isolate islets grafts from immune cells and the survival of the islets can be prolonged by this way, it is also reported that when the pore size of the backbone is too small the revascularization will be adversely affected. According to this point, it is hard to adjust hydrogel's pore size to protect the islets from the immune attack while allowing endothelial vascular cells to creep in. To solve this dilemma, we designed an immunomodulatory hydrogel inhibiting the activation of T cells by immunosuppressive IgGs instead of the backbone network, so the hydrogel can prolong the survival of islets without the sacrifice of revascularization.
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Affiliation(s)
- Xue Bai
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China; Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Dan Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China
| | - Bin Wang
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Xiao Zhang
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China; Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yan Bai
- School of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Xinying Zhang
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China; Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Ruoyuan Tian
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China; Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Caihua Li
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China; Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Qiying Yi
- Laboratory Animal Center, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yao Cheng
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Sirong He
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China; Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China.
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Peighami R, Mehrnia M, Yazdian F, Sheikhpour M. Biocompatibility evaluation of polyethersulfone-pyrolytic carbon composite membrane in artificial pancreas. Biointerphases 2023; 18:021003. [PMID: 36944533 DOI: 10.1116/6.0002155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023] Open
Abstract
Polyethersulfone (PES) membranes are widely used in medical devices, especially intravascular devices such as intravascular bioartificial pancreases. In the current work, the pure PES and PES-pyrolytic carbon (PyC) composite membranes were synthesized and permeability studies were conducted. In addition, the cytocompatibility and hemocompatibility of the pure PES and PES-PyC membranes were investigated. These materials were characterized using peripheral blood mononuclear cell (PBMC) activation, platelet activation, platelet adhesion, ß-cell viability and proliferation, and ß-cell response to hyperglycemia. The results showed that platelet activation decreased from 87.3% to 27.8%. Any alteration in the morphology of sticking platelets was prevented, and the number of attached platelets decreased by modification with PyC. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay corroborated that PBMC activation was encouraged by the PyC-modified PES membrane surface. It can be concluded that PES-modified membranes show higher hemocompatibility than pure PES membranes. ß-cells cultured on all the three membranes displayed a lower rate of proliferation although the cells on the PES-PyC (0.1 wt. %) membrane indicated a slightly higher viability and proliferation than those on the pure PES and PES-PyC (0.05 wt. %) membranes. It shows that the PES-PyC (0.1 wt. %) membrane possesses superior cytocompatibility over the other membranes.
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Affiliation(s)
- Reza Peighami
- Department of Life Science Engineering, Faculty of New Science and Technology, University of Tehran, Tehran 1439956191, Iran
| | - Mohamadreza Mehrnia
- School of Chemical Engineering, College of Engineering, University of Tehran, Tehran 1417614411, Iran
| | - Fatemeh Yazdian
- Department of Life Science Engineering, Faculty of New Science and Technology, University of Tehran, Tehran 1439956191, Iran
| | - Mojgan Sheikhpour
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran 1316943551, Iran
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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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Fuchs S, Ernst AU, Wang LH, Shariati K, Wang X, Liu Q, Ma M. Hydrogels in Emerging Technologies for Type 1 Diabetes. Chem Rev 2020; 121:11458-11526. [DOI: 10.1021/acs.chemrev.0c01062] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Stephanie Fuchs
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Alexander U. Ernst
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Long-Hai Wang
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Kaavian Shariati
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Xi Wang
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Qingsheng Liu
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Minglin Ma
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
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Regenerative Medicine in Diabetes. Biomedicines 2020; 8:biomedicines8120537. [PMID: 33255837 PMCID: PMC7761045 DOI: 10.3390/biomedicines8120537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 12/03/2022] Open
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Massaro M, Cavallaro G, Colletti CG, D'Azzo G, Guernelli S, Lazzara G, Pieraccini S, Riela S. Halloysite nanotubes for efficient loading, stabilization and controlled release of insulin. J Colloid Interface Sci 2018; 524:156-164. [PMID: 29649624 DOI: 10.1016/j.jcis.2018.04.025] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 03/29/2018] [Accepted: 04/05/2018] [Indexed: 12/11/2022]
Abstract
HYPOTHESIS Oral insulin administration is not actually effective due to insulin rapid degradation, inactivation and digestion by proteolytic enzymes which results in low bioavailability. Moreover insulin is poorly permeable and lack of lipophilicity. These limits can be overcome by the loading of protein in some nanostructured carrier such as halloysite nanotubes (HNTs). EXPERIMENTS Herein we propose an easy strategy to obtain HNT hybrid materials for the delivery of insulin. We report a detailed description on the thermal behavior and stability of insulin loaded and released from the HNTs hybrid by the combination of several techniques. FINDINGS Release experiments of insulin from the HNTs revealed the efficacy of the nanocarrier. Circular Dichroism data evidenced that the released insulin exhibits its native-like secondary structure confirming the suitability of HNT/insulin as delivery system for at least three months. The loaded nanotubes were filled into chitosan matrix with the aim to prepare bionanocomposite films that can be used for transdermal delivery. This work puts forward an efficient strategy to prepare halloysite based nanocarriers containing insulin that could be employed in several biomedical applications. The detailed description of the prepared HNT/insulin hybrid represents a fundamental point for designing advanced delivery systems.
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Affiliation(s)
- Marina Massaro
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy
| | - Giuseppe Cavallaro
- Dipartimento di Fisica e Chimica (DiFC), University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy
| | - Carmelo G Colletti
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy
| | - Giuseppe D'Azzo
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy
| | - Susanna Guernelli
- Dipartimento di Chimica "Giacomo Ciamician", University of Bologna, Via S. Giacomo 11, 40126 Bologna, Italy
| | - Giuseppe Lazzara
- Dipartimento di Fisica e Chimica (DiFC), University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy
| | - Silvia Pieraccini
- Dipartimento di Chimica "Giacomo Ciamician", University of Bologna, Via S. Giacomo 11, 40126 Bologna, Italy
| | - Serena Riela
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy.
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Preparation, characterization and performance studies of polyethersulfone (PES) - pyrolytic carbon (PyC) composite membranes. JOURNAL OF POLYMER RESEARCH 2017. [DOI: 10.1007/s10965-016-1180-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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13
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Takahashi Y, Takebe T, Taniguchi H. Engineering pancreatic tissues from stem cells towards therapy. Regen Ther 2016; 3:15-23. [PMID: 31245468 PMCID: PMC6581807 DOI: 10.1016/j.reth.2016.01.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 12/17/2015] [Accepted: 01/20/2016] [Indexed: 12/20/2022] Open
Abstract
Pancreatic islet transplantation is performed as a potential treatment for type 1 diabetes mellitus. However, this approach is significantly limited due to the critical shortage of islet sources. Recently, a number of publications have developed protocols for directed β-cell differentiation of pluripotent cells, such as embryonic stem (ES) or induced pluripotent stem (iPS) cells. Decades of studies have led to the development of modified protocols that recapitulate molecular developmental cues by combining various growth factors and small molecules with improved efficiency. However, the later step of pancreatic differentiation into functional β-cells has yet to be satisfactory in vitro, highlighting alternative approach by recapitulating spatiotemporal multicellular interaction in three-dimensional (3D) culture. Here, we summarize recent progress in the directed differentiation into pancreatic β-cells with a focus on both two-dimensional (2D) and 3D differentiation settings. We also discuss the potential transplantation strategies in combination with current bioengineering approaches towards diabetes therapy.
Transplantation of stem cell derived pancreatic progenitors is a possible approach for generating mature β-cell in vivo. Promise of 3-D (or 4-D) culture has started to be explored by reconstituting pancreatic tissue structures. Self-condensation culture is a basic technique of integrating multiple heterotypic lineages including vasculatures. Bioengineering approach has been combined for developing effective transplant strategies.
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Key Words
- 2D, two-dimensional
- 3D, three-dimensional
- BMP, bone morphogenic protein
- Diabetes
- ES, embryonic stem
- FGF, fibroblast growth factors
- Heterotypic cellular interaction
- IBMIR, instant blood-mediated reaction
- ILV, indolactam V
- Ngn3, neurogenin 3
- PEG, polyethylene glycol
- PI3K, phosphatidylinositol-3 kinase
- PIPAAm, poly-N-isopropylacrylamide
- PVA, polyvinyl alcohol
- Pancreas
- Pdx1, pancreatic and duodenal homeobox 1
- Ptf1a, pancreatic transcription factor 1a
- Regenerative medicine
- VEGF, vascular endothelial growth factor
- Vascularization
- iPS, induced pluripotent stem
- iPS/ES cell
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Affiliation(s)
- Yoshinobu Takahashi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan
| | - Takanori Takebe
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan.,Advanced Medical Research Center, Yokohama City University, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan.,PRESTO, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi, Saitama, 332-0012, Japan.,Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH, 45229- 3039, USA
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan.,Advanced Medical Research Center, Yokohama City University, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan
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14
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Yang HK, Yoon KH. Current status of encapsulated islet transplantation. J Diabetes Complications 2015; 29:737-43. [PMID: 25881917 DOI: 10.1016/j.jdiacomp.2015.03.017] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 03/10/2015] [Accepted: 03/11/2015] [Indexed: 02/07/2023]
Abstract
Islet transplantation is a treatment modality for diabetes mellitus that can maintain insulin levels within a physiologically appropriate range. However, wider clinical application is limited by insufficient donor numbers and a need for lifelong immunosuppression. Despite various clinical and preclinical trials, there is no single standard immunosuppressive regimen that can suppress acute and chronic immune reactions with lower toxicity to grafted islets. One of the strategies for overcoming lifelong immunosuppression is the incorporation of encapsulation technology, which can provide a physical immune barrier by keeping out high molecular weight immune system components, while still allowing low molecular weight oxygen, insulin and nutrients to pass through. Encapsulated islet transplantation approaches that have been studied so far include macroencapsulation, microencapsulation, conformal coating and nanoencapsulation. Herein we will review the basic concepts of islet encapsulation technique, earlier works to recent progress related to clinical studies and corporate investigations on encapsulated islet transplantation.
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MESH Headings
- Animals
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/surgery
- Diabetes Mellitus, Type 1/therapy
- Diabetes Mellitus, Type 2/immunology
- Diabetes Mellitus, Type 2/surgery
- Diabetes Mellitus, Type 2/therapy
- Graft Enhancement, Immunologic/adverse effects
- Graft Enhancement, Immunologic/methods
- Graft Enhancement, Immunologic/trends
- Humans
- Injections, Intraperitoneal
- Islets of Langerhans Transplantation/adverse effects
- Islets of Langerhans Transplantation/immunology
- Islets of Langerhans Transplantation/methods
- Islets of Langerhans Transplantation/trends
- Microtechnology
- Nanotechnology/trends
- Pancreas, Artificial/adverse effects
- Pancreas, Artificial/trends
- Surface Properties
- Transplantation, Heterologous/adverse effects
- Transplantation, Heterologous/methods
- Transplantation, Heterologous/trends
- Transplantation, Heterotopic/adverse effects
- Transplantation, Heterotopic/methods
- Transplantation, Heterotopic/trends
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Affiliation(s)
- Hae Kyung Yang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kun-Ho Yoon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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15
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Shyong YJ, Tsai CC, Lin RF, Soung HS, Hsieh HC, Hsueh YS, Chang KC, Lin FH. Insulin-loaded hydroxyapatite combined with macrophage activity to deliver insulin for diabetes mellitus. J Mater Chem B 2015; 3:2331-2340. [DOI: 10.1039/c4tb01639d] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
InsHAP is engulfed by macrophages and the lysosome/endosome hybrid is broken down by osmosis, which facilitates delivery of insulin into the bloodstream.
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Affiliation(s)
- Yen-Jye Shyong
- Institute of Biomedical Engineering
- National Taiwan University
- Taipei 10617
- Taiwan
| | - Cheng-Chia Tsai
- Department of Neurosurgery
- Mackay Memorial Hospital
- Taipei City 10449
- Taiwan
- Graduate Institute of Injury Prevention and Control
| | - Rui-Feng Lin
- Department of Neurosurgery
- Mackay Memorial Hospital
- Taipei City 10449
- Taiwan
| | - Hung-Sheng Soung
- Department of Psychiatry
- Yuan-Shan br. of Taipei Veteran General Hospital
- Taiwan, ROC
| | - Hui-Chen Hsieh
- Institute of Biomedical Engineering
- National Taiwan University
- Taipei 10617
- Taiwan
| | - Yu-Sheng Hsueh
- Institute of Biomedical Engineering
- National Taiwan University
- Taipei 10617
- Taiwan
| | - Kuo-Chi Chang
- Department of Chemical Engineering and Biotechnology
- National Taipei University of Technology
- Taipei
- Taiwan
| | - Feng-Huei Lin
- Institute of Biomedical Engineering
- National Taiwan University
- Taipei 10617
- Taiwan
- Division of Medical Engineering
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16
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Iuamoto LR, Meyer A, Chaib E, D’Albuquerque LAC. Review of experimental attempts of islet allotransplantation in rodents: Parameters involved and viability of the procedure. World J Gastroenterol 2014; 20:13512-13520. [PMID: 25309081 PMCID: PMC4188902 DOI: 10.3748/wjg.v20.i37.13512] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Revised: 05/03/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
The purpose of the present study was to organize the parameters involved in experimental allotransplantation in rodents to elaborate the most suitable model to supply the scarcity of islet donors. We used the PubMed database to systematically search for published articles containing the keywords “rodent islet transplantation” to review. We included studies that involved allotransplantation experiments with rodents’ islets, and we reviewed the reference lists from the eligible publications that were retrieved. We excluded articles related to isotransplantation, autotransplantation and xenotransplantation, i.e., transplantation in other species. A total of 25 studies related to allotransplantation were selected for systematic review based on their relevance and updated data. Allotransplantation in rodents is promising and continues to develop. Survival rates of allografts have increased with the discovery of new immunosuppressive drugs and the use of different graft sites. These successes suggest that islet transplantation is a promising method to overcome the scarcity of islet donors and advance the treatment options for type 1 diabetes.
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17
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Liu F, Tian W, Yang Y, Zhang Q, Zhu M, Yang L, Yang L, Li J, Liu J, Wu P, Yang K, Wang X, Shen Y, Qi Z. Optimal method for short-term or long-term islet preservation: comparison of islet culture, cold preservation and cryopreservation. J Artif Organs 2014; 17:337-43. [PMID: 24944122 DOI: 10.1007/s10047-014-0777-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 05/28/2014] [Indexed: 11/30/2022]
Abstract
Islet preservation plays an important role for the success of islet transplantation. To determine the optimal method for islet preservation, we compared the outcomes of islet culture, cold preservation, and cryopreservation in this study. Isolated rat islets were divided into three groups: 37 °C group (conventional culture at 37 °C in RPMI-1640 medium), 4 °C group (cold preservation at 4 °C in University of Wisconsin (UW) solution), and -80 °C group (cryopreservation at -80 °C with dimethyl sulfoxide (DMSO)). Recovery rate, Calcein-AM/PI double staining, insulin release, mRNA level of hypoxia-inducible factor-1α (HIF-1α), and protein level of Bax in islets were examined after short-term (1 day) or long-term (7 days) preservation. After either short-term or long-term preservation, 4 °C group showed higher recovery rate of the islets number, lower percentage of PI positive area, better insulin release ability, and lower expression levels of HIF-1α and Bax in comparison to the 37 or -80 °C group. Meanwhile, islets in 37 °C group showed better function, and down-regulation of HIF-1α and Bax than those in -80 °C group on day 1; however, worse function of islets, up-regulated HIF-1α and Bax in 37 °C group were observed in comparison to -80 °C group on day 7. These results suggest that cold preservation at 4 °C in UW solution is the optimal method in comparison to the conventional culture at 37 °C or cryopreservation at -80 °C for short-term or long-term islet preservation. Furthermore, the potential mechanism may relate to, at least in part, apoptosis induced by the HIF-1α.
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Affiliation(s)
- Fei Liu
- Department of Histology and Embryology, School of Medicine, Nankai University, 94 Weijin Road, Nankai District, Tianjin, 300071, China
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18
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Krishnan R, Alexander M, Robles L, Foster CE, Lakey JRT. Islet and stem cell encapsulation for clinical transplantation. Rev Diabet Stud 2014; 11:84-101. [PMID: 25148368 DOI: 10.1900/rds.2014.11.84] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Over the last decade, improvements in islet isolation techniques have made islet transplantation an option for a certain subset of patients with long-standing diabetes. Although islet transplants have shown improved graft function, adequate function beyond the second year has not yet been demonstrated, and patients still require immunosuppression to prevent rejection. Since allogeneic islet transplants have experienced some success, the next step is to improve graft function while eliminating the need for systemic immunosuppressive therapy. Biomaterial encapsulation offers a strategy to avoid the need for toxic immunosuppression while increasing the chances of graft function and survival. Encapsulation entails coating cells or tissue in a semipermeable biocompatible material that allows for the passage of nutrients, oxygen, and hormones while blocking immune cells and regulatory substances from recognizing and destroying the cell, thus avoiding the need for systemic immunosuppressive therapy. Despite advances in encapsulation technology, these developments have not yet been meaningfully translated into clinical islet transplantation, for which several factors are to blame, including graft hypoxia, host inflammatory response, fibrosis, improper choice of biomaterial type, lack of standard guidelines, and post-transplantation device failure. Several new approaches, such as the use of porcine islets, stem cells, development of prevascularized implants, islet nanocoating, and multilayer encapsulation, continue to generate intense scientific interest in this rapidly expanding field. This review provides a comprehensive update on islet and stem cell encapsulation as a treatment modality in type 1 diabetes, including a historical outlook as well as current and future research avenues.
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Affiliation(s)
- Rahul Krishnan
- Department of Surgery, University of California Irvine, Orange, CA 92868, USA
| | - Michael Alexander
- Department of Surgery, University of California Irvine, Orange, CA 92868, USA
| | - Lourdes Robles
- Department of Surgery, University of California Irvine, Orange, CA 92868, USA
| | - Clarence E Foster
- Department of Surgery, University of California Irvine, Orange, CA 92868, USA
| | - Jonathan R T Lakey
- Department of Surgery, University of California Irvine, Orange, CA 92868, USA
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19
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Yoshimatsu G, Sakata N, Tsuchiya H, Ishida M, Motoi F, Egawa S, Sumi S, Goto M, Unno M. Development of polyvinyl alcohol bioartificial pancreas with rat islets and mesenchymal stem cells. Transplant Proc 2014; 45:1875-80. [PMID: 23769061 DOI: 10.1016/j.transproceed.2013.01.043] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Accepted: 01/15/2013] [Indexed: 12/30/2022]
Abstract
To improve the function of the polyvinyl alcohol (PVA) bioartificial pancreas, we focused on bone marrow-derived mesenchymal stem cells (MSCs). We examined whether the function of PVA-encapsulated rat islets could be improved by coencapsulation with syngeneic MSCs. We macroencapsulated 1,500 rat islet equivalents (IEQ) with or without 1 × 10(6) MSCs with the use of 3% PVA solution before implantation intraperitoneally into diabetic BALB/c mice. We evaluated the function of the device in vitro (the residual rate, viability, and insulin-releasing function of the islets) and in vivo assessments (blood glucose and serum C-peptide changes after transplantation and glucose tolerance test). Although cultured islets also were destroyed, the shapes of the islets cocultured with MSCs were preserved but not different from encapsulated islets without MSCs. At 96 hours after culture the residual rates of islet recovery among those cocultured with versus without MSCs were 66% versus 39.5%, respectively, (P = .03). On the other hand, there was no significant difference between encapsulated islets with versus without MSCs. Furthermore, the stimulation index of the islets was improved by coculture with MSCs (2.6 ± 0.6 vs 1.4 ± 0.1; P = .03), but no beneficial effects were observed between islets encapsulated with versus without MSCs. The viability of islets cocultured with MSCs was significantly better than that without MSCs (84.2 ± 2.5 vs 73.3 ± 0.9; P = .037), but MSCs did not improve the viability of encapsulated islets. There were no significant differences in blood glucose or serum C-peptide between islets encapsulated with versus without MSCs. The histologic findings showed many degenerative islets and MSCs soon after transplantation. In conclusion, further studies are necessary to develop a novel PVA bioartificial pancreas that can be used with MSCs.
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Affiliation(s)
- G Yoshimatsu
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Japan
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21
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Yang KC, Wu CC, Yang SH, Chiu CC, Sumi S, Lee HS. Investigating the suspension culture on aggregation and function of mouse pancreatic β-cells. J Biomed Mater Res A 2013; 101:2273-82. [PMID: 23348877 DOI: 10.1002/jbm.a.34547] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2012] [Revised: 10/23/2012] [Accepted: 11/27/2012] [Indexed: 01/21/2023]
Abstract
The integrity and hierarchical structure of islet influence β-cells physiology dramatically. A culture substrate which can maintain or improve β-cells aggregation shall benefit cell therapy for diabetics. In this study, nontreated, type IV collagen, Lipidure, and ultralow attachment dishes were used to culture a murine β-cell line, MIN-6. The formation and biological performances of pseudoislets were investigated. Results showed that β-cells formed loose and irregular aggregates on nontreated dishes. Oppositely, pseudoislets formed on other three substrates. Most pseudoislets on Lipidure and type IV collagen dishes had a diameter between 100-150 μm with high survival rate, while large pseudoislets (>250 μm) with seriously central necrosis were found on ultralow attachment dishes. Western blot analysis revealed that pseudoislets had relatively higher connexin 36 protein productions relative to single cells. The glucose-stimulated insulin secretion test showed pseudoislets on type IV collagen have high stimulation index. Monolayers from TCPS dishes and pseudoislets from type IV collagen or Lipidure dishes were further transplanted into diabetic mice. Animals received both single cells and pseudoislets had decreasing blood glucose level and regained body weight. Histologic examination revealed that all implants successfully engrafted with positive insulin staining. Interestingly, the area under curve for the intraperitoneal glucose tolerance test showed pseudoislets had superior glucose disappearance rate. This study reveals that isolated islets or insulin-producing cells can be cultured on type IV collagen or Lipidure dishes to improve/maintain integrity prior to transplantation.
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Affiliation(s)
- Kai-Chiang Yang
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
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