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1
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Wawszczak A, Kocki J, Kołodyńska D. Alginate as a Sustainable and Biodegradable Material for Medical and Environmental Applications-The Case Studies. J Biomed Mater Res B Appl Biomater 2024; 112:1-23. [PMID: 39269132 DOI: 10.1002/jbm.b.35475] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 06/19/2024] [Accepted: 08/09/2024] [Indexed: 09/15/2024]
Abstract
Alginates are salts of alginic acid derived mainly from sea algae of the genus brown algae. They are also synthesized by some bacteria. They belong to negatively charged polysaccharides exhibiting some rheological properties. High plasticity and the ability to modify the structure are the reasons for their application in numerous industries. Moreover, when in contact with the living tissue, they do not trigger an immune response, and for this reason they are the most often tested materials for medical applications. The paper discusses the latest applications, including 3D bioprinting, drug delivery systems, and sorptive properties. Recognizing alginates as biomaterials, it emphasizes the necessity for precise processing and modification to industrialize them for specific uses. This review aims to provide a thorough understanding of the advancements in alginate research, underscoring their potential for innovative applications.
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Affiliation(s)
- Alicja Wawszczak
- Department of Inorganic Chemistry, Faculty of Chemistry, Maria Curie-Skłodowska University, Lublin, Poland
| | - Janusz Kocki
- Department of Clinical Genetics, Medical University of Lublin, Lublin, Poland
| | - Dorota Kołodyńska
- Department of Inorganic Chemistry, Faculty of Chemistry, Maria Curie-Skłodowska University, Lublin, Poland
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2
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Abbaszadeh S, Nosrati-Siahmazgi V, Musaie K, Rezaei S, Qahremani M, Xiao B, Santos HA, Shahbazi MA. Emerging strategies to bypass transplant rejection via biomaterial-assisted immunoengineering: Insights from islets and beyond. Adv Drug Deliv Rev 2023; 200:115050. [PMID: 37549847 DOI: 10.1016/j.addr.2023.115050] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/14/2023] [Accepted: 08/04/2023] [Indexed: 08/09/2023]
Abstract
Novel transplantation techniques are currently under development to preserve the function of impaired tissues or organs. While current technologies can enhance the survival of recipients, they have remained elusive to date due to graft rejection by undesired in vivo immune responses despite systemic prescription of immunosuppressants. The need for life-long immunomodulation and serious adverse effects of current medicines, the development of novel biomaterial-based immunoengineering strategies has attracted much attention lately. Immunomodulatory 3D platforms can alter immune responses locally and/or prevent transplant rejection through the protection of the graft from the attack of immune system. These new approaches aim to overcome the complexity of the long-term administration of systemic immunosuppressants, including the risks of infection, cancer incidence, and systemic toxicity. In addition, they can decrease the effective dose of the delivered drugs via direct delivery at the transplantation site. In this review, we comprehensively address the immune rejection mechanisms, followed by recent developments in biomaterial-based immunoengineering strategies to prolong transplant survival. We also compare the efficacy and safety of these new platforms with conventional agents. Finally, challenges and barriers for the clinical translation of the biomaterial-based immunoengineering transplants and prospects are discussed.
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Affiliation(s)
- Samin Abbaszadeh
- Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands
| | - Vahideh Nosrati-Siahmazgi
- Department of Pharmaceutical Biomaterials, School of Pharmacy, Zanjan University of Medical Science, 45139-56184 Zanjan, Iran
| | - Kiyan Musaie
- Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands
| | - Saman Rezaei
- Department of Pharmaceutical Biomaterials, School of Pharmacy, Zanjan University of Medical Science, 45139-56184 Zanjan, Iran
| | - Mostafa Qahremani
- Department of Pharmaceutical Biomaterials, School of Pharmacy, Zanjan University of Medical Science, 45139-56184 Zanjan, Iran
| | - Bo Xiao
- State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing 400715 China.
| | - Hélder A Santos
- Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland; W.J. Kolff Institute for Biomedical Engineering and Materials Science, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands.
| | - Mohammad-Ali Shahbazi
- Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands; W.J. Kolff Institute for Biomedical Engineering and Materials Science, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands.
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3
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Wang W, Teng Y, Xue JJ, Cai HK, Pan YB, Ye XN, Mao XL, Li SW. Nanotechnology in Kidney and Islet Transplantation: An Ongoing, Promising Field. Front Immunol 2022; 13:846032. [PMID: 35464482 PMCID: PMC9024121 DOI: 10.3389/fimmu.2022.846032] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 03/08/2022] [Indexed: 11/21/2022] Open
Abstract
Organ transplantation has evolved rapidly in recent years as a reliable option for patients with end-stage organ failure. However, organ shortage, surgical risks, acute and chronic rejection reactions and long-term immunosuppressive drug applications and their inevitable side effects remain extremely challenging problems. The application of nanotechnology in medicine has proven highly successful and has unique advantages for diagnosing and treating diseases compared to conventional methods. The combination of nanotechnology and transplantation brings a new direction of thinking to transplantation medicine. In this article, we provide an overview of the application and progress of nanotechnology in kidney and islet transplantation, including nanotechnology for renal pre-transplantation preservation, artificial biological islets, organ imaging and drug delivery.
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Affiliation(s)
- Wei Wang
- Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Ya Teng
- Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Ji-Ji Xue
- Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Hong-Kai Cai
- Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Yu-Biao Pan
- Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai, China
| | - Xing-Nan Ye
- Taizhou Hospital of Zhejiang Province, Shaoxing University, Linhai, China
| | - Xin-Li Mao
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Shao-Wei Li
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
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4
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Leal-Lopes C, Grazioli G, Mares-Guia TR, Coelho-Sampaio T, Sogayar MC. Polymerized laminin incorporation into alginate-based microcapsules reduces pericapsular overgrowth and inflammation. J Tissue Eng Regen Med 2019; 13:1912-1922. [PMID: 31348601 DOI: 10.1002/term.2942] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 07/05/2019] [Accepted: 07/11/2019] [Indexed: 11/08/2022]
Abstract
Cell encapsulation coats cells with an artificial membrane to preserve their physical and functional integrity. Different approaches try to develop more functional and biocompatible materials to avoid cell loss after transplantation due to inflammatory reaction, one of the main causes for graft failure. In this study, the LN-Biodritin biomaterial, based on alginate, chondroitin sulfate, and laminin, previously developed by our group, was further improved by replacing laminin by polylaminin, an artificial laminin polymer with anti-inflammatory properties, generating the new biomaterial polyLN-Biodritin. Capsules containing polylaminin are stable, do not induce macrophage activation in vitro, and are also able to prevent macrophage activation by encapsulated human pancreatic islets in vitro, preserving their glucose-stimulated insulin secretion potential. In addition, when empty capsules containing polylaminin were implanted into immunocompetent mice, the inflammatory response towards the implant was attenuated, when compared with capsules without polylaminin. The results indicate that polylaminin incorporation leads to lower levels of pericapsular growth on the capsules surface, lower infiltration of cells into the peritoneal cavity, and lower production of proinflammatory cytokines, both at the implant site (interleukin-12p70 (IL-12p70), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), and interferon-γ (IFN-γ)) and systemically (IL-12p70 and TNF-α). Therefore, polylaminin incorporation into the microcapsules polymer attenuates the host posttransplantation immune response against implanted microcapsules, being likely to favor maintenance of engrafted encapsulated cells.
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Affiliation(s)
- Camila Leal-Lopes
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.,Núcleo de Terapia Celular e Molecular (NUCEL), Departamento de Clínica Médica, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Gisella Grazioli
- Núcleo de Terapia Celular e Molecular (NUCEL), Departamento de Clínica Médica, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Thiago R Mares-Guia
- Núcleo de Terapia Celular e Molecular (NUCEL), Departamento de Clínica Médica, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Tatiana Coelho-Sampaio
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Mari Cleide Sogayar
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.,Núcleo de Terapia Celular e Molecular (NUCEL), Departamento de Clínica Médica, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
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5
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Correia CR, Reis RL, Mano JF. Design Principles and Multifunctionality in Cell Encapsulation Systems for Tissue Regeneration. Adv Healthc Mater 2018; 7:e1701444. [PMID: 30102458 DOI: 10.1002/adhm.201701444] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 07/16/2018] [Indexed: 12/12/2022]
Abstract
Cell encapsulation systems are being increasingly applied as multifunctional strategies to regenerate tissues. Lessons afforded with encapsulation systems aiming to treat endocrine diseases seem to be highly valuable for the tissue engineering and regenerative medicine (TERM) systems of today, in which tissue regeneration and biomaterial integration are key components. Innumerous multifunctional systems for cell compartmentalization are being proposed to meet the specific needs required in the TERM field. Herein is reviewed the variable geometries proposed to produce cell encapsulation strategies toward tissue regeneration, including spherical and fiber-shaped systems, and other complex shapes and arrangements that better mimic the highly hierarchical organization of native tissues. The application of such principles in the TERM field brings new possibilities for the development of highly complex systems, which holds tremendous promise for tissue regeneration. The complex systems aim to recreate adequate environmental signals found in native tissue (in particular during the regenerative process) to control the cellular outcome, and conferring multifunctional properties, namely the incorporation of bioactive molecules and the ability to create smart and adaptative systems in response to different stimuli. The new multifunctional properties of such systems that are being employed to fulfill the requirements of the TERM field are also discussed.
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Affiliation(s)
- Clara R. Correia
- 3B's Research Group – Biomaterials, Biodegradables, and BiomimeticsUniversity of MinhoHeadquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine AvePark 4805‐017 Barco Guimarães Portugal
- ICVS/3B's – PT Government Associate Laboratory Braga/Guimarães Portugal
| | - Rui L. Reis
- 3B's Research Group – Biomaterials, Biodegradables, and BiomimeticsUniversity of MinhoHeadquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine AvePark 4805‐017 Barco Guimarães Portugal
- ICVS/3B's – PT Government Associate Laboratory Braga/Guimarães Portugal
| | - João F. Mano
- 3B's Research Group – Biomaterials, Biodegradables, and BiomimeticsUniversity of MinhoHeadquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine AvePark 4805‐017 Barco Guimarães Portugal
- ICVS/3B's – PT Government Associate Laboratory Braga/Guimarães Portugal
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6
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DURUKSU G, POLAT S, KAYİŞ L, EKİMCİ GÜRCAN N, GACAR G, YAZIR Y. Improvement of the insulin secretion from beta cells encapsulated in alginate/poly-L- histidine/alginate microbeads by platelet-rich plasma. Turk J Biol 2018; 42:297-306. [PMID: 30814893 PMCID: PMC6392160 DOI: 10.3906/biy-1802-13] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Type 1 diabetes is clinically characterized as the loss of control of glucose homeostasis due to the reduced number of insulinproducing cells. Long-term glycemic control after implantation could be maintained by preserving the cell viability and tissue-specific functions during the process of microencapsulation. In this study, alginate solution was supplemented with platelet-rich plasma (PRP) to improve the viability and preserve the cell functions during the encapsulation of a beta cell line (BRIN-BD11). Cell viability was assessed and insulin secretion and insulin stimulation index were evaluated. eTh polymerization of alginate with PRP enhanced the viability up to 61% in the alginate microbeads. PRP supplementation to the alginate composition not only increased the number of viable cells by 1.95-fold, but the insulin secretion also improved by about 66%. eTh stimulation index, however, was not affected by the PRP supplementation.
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Affiliation(s)
- Gökhan DURUKSU
- Center for Stem Cell and Gene eThrapies Research and Practice, Kocaeli University
,
İzmit, Kocaeli
,
Turkey
- Department of Stem Cells, Institute of Health Sciences, Kocaeli University
,
İzmit, Kocaeli
,
Turkey
| | - Selen POLAT
- Department of Stem Cells, Institute of Health Sciences, Kocaeli University
,
İzmit, Kocaeli
,
Turkey
| | - Leyla KAYİŞ
- Department of Stem Cells, Institute of Health Sciences, Kocaeli University
,
İzmit, Kocaeli
,
Turkey
| | - Nur EKİMCİ GÜRCAN
- Department of Stem Cells, Institute of Health Sciences, Kocaeli University
,
İzmit, Kocaeli
,
Turkey
| | - Gülçin GACAR
- Center for Stem Cell and Gene eThrapies Research and Practice, Kocaeli University
,
İzmit, Kocaeli
,
Turkey
- Department of Stem Cells, Institute of Health Sciences, Kocaeli University
,
İzmit, Kocaeli
,
Turkey
| | - Yusufhan YAZIR
- Center for Stem Cell and Gene eThrapies Research and Practice, Kocaeli University
,
İzmit, Kocaeli
,
Turkey
- Department of Histology and Embryology, School of Medicine, Kocaeli University
,
İzmit, Kocaeli
,
Turkey
- Department of Stem Cells, Institute of Health Sciences, Kocaeli University
,
İzmit, Kocaeli
,
Turkey
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7
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Schubert J, Chanana M. Coating Matters: Review on Colloidal Stability of Nanoparticles with Biocompatible Coatings in Biological Media, Living Cells and Organisms. Curr Med Chem 2018; 25:4553-4586. [PMID: 29852857 PMCID: PMC7040520 DOI: 10.2174/0929867325666180601101859] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 03/13/2018] [Accepted: 04/18/2018] [Indexed: 12/21/2022]
Abstract
Within the last two decades, the field of nanomedicine has not developed as successfully as has widely been hoped for. The main reason for this is the immense complexity of the biological systems, including the physico-chemical properties of the biological fluids as well as the biochemistry and the physiology of living systems. The nanoparticles' physicochemical properties are also highly important. These differ profoundly from those of freshly synthesized particles when applied in biological/living systems as recent research in this field reveals. The physico-chemical properties of nanoparticles are predefined by their structural and functional design (core and coating material) and are highly affected by their interaction with the environment (temperature, pH, salt, proteins, cells). Since the coating material is the first part of the particle to come in contact with the environment, it does not only provide biocompatibility, but also defines the behavior (e.g. colloidal stability) and the fate (degradation, excretion, accumulation) of nanoparticles in the living systems. Hence, the coating matters, particularly for a nanoparticle system for biomedical applications, which has to fulfill its task in the complex environment of biological fluids, cells and organisms. In this review, we evaluate the performance of different coating materials for nanoparticles concerning their ability to provide colloidal stability in biological media and living systems.
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Affiliation(s)
- Jonas Schubert
- Address correspondence to these authors at the Department of Nanostructured Materials, Leibniz-Institut für Polymerforschung Dresden, Dresden, Germany and Department of Physical Chemistry II, University of Bayreuth, 95447 Bayreuth, Germany;E-mails: ;
| | - Munish Chanana
- Address correspondence to these authors at the Department of Nanostructured Materials, Leibniz-Institut für Polymerforschung Dresden, Dresden, Germany and Department of Physical Chemistry II, University of Bayreuth, 95447 Bayreuth, Germany;E-mails: ;
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8
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Krishnan R, Ko D, Foster CE, Liu W, Smink AM, de Haan B, De Vos P, Lakey JRT. Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials. Methods Mol Biol 2017; 1479:305-333. [PMID: 27738946 DOI: 10.1007/978-1-4939-6364-5_24] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Transplantation of alginate-encapsulated islets has the potential to treat patients suffering from type I diabetes, a condition characterized by an autoimmune attack against insulin-secreting beta cells. However, there are multiple immunological challenges associated with this procedure, all of which must be adequately addressed prior to translation from trials in small animal and nonhuman primate models to human clinical trials. Principal threats to graft viability include immune-mediated destruction triggered by immunogenic alginate impurities, unfavorable polymer composition and surface characteristics, and release of membrane-permeable antigens, as well as damage associated molecular patterns (DAMPs) by the encapsulated islets themselves. The lack of standardization of significant parameters of bioencapsulation device design and manufacture (i.e., purification protocols, surface-modification grafting techniques, alginate composition modifications) between labs is yet another obstacle that must be overcome before a clinically effective and applicable protocol for encapsulating islets can be implemented. Nonetheless, substantial progress is being made, as is evident from prolonged graft survival times and improved protection from immune-mediated graft destruction reported by various research groups, but also with regard to discoveries of specific pathways involved in explaining observed outcomes. Progress in the latter is essential for a comprehensive understanding of the mechanisms responsible for the varying levels of immunogenicity of certain alginate devices. Successful translation of encapsulated islet transplantation from in vitro and animal model testing to human clinical trials hinges on application of this knowledge of the pathways and interactions which comprise immune-mediated rejection. Thus, this review not only focuses on the different factors contributing to provocation of the immune reaction by encapsulated islets, but also on the defining characteristics of the response itself.
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Affiliation(s)
- Rahul Krishnan
- Department of Surgery, University of California Irvine, 333 City Blvd West, Suite 1600, Orange, CA, 92868, USA
| | - David Ko
- Department of Surgery, University of California Irvine, 333 City Blvd West, Suite 1600, Orange, CA, 92868, USA
| | - Clarence E Foster
- Department of Surgery, University of California Irvine, 333 City Blvd West, Suite 1600, Orange, CA, 92868, USA.,Department of Transplantation, University of California Irvine, Orange, CA, USA
| | - Wendy Liu
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA
| | - A M Smink
- Division of Immuno-Endocrinology, Departments of Pathology and Laboratory Medicine, University of Groningen, Groningen, The Netherlands
| | - Bart de Haan
- Division of Immuno-Endocrinology, Departments of Pathology and Laboratory Medicine, University of Groningen, Groningen, The Netherlands
| | - Paul De Vos
- Division of Immuno-Endocrinology, Departments of Pathology and Laboratory Medicine, University of Groningen, Groningen, The Netherlands
| | - Jonathan R T Lakey
- Department of Surgery, University of California Irvine, 333 City Blvd West, Suite 1600, Orange, CA, 92868, USA. .,Department of Transplantation, University of California Irvine, Orange, CA, USA. .,Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA.
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9
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Pancreatic islet macroencapsulation using microwell porous membranes. Sci Rep 2017; 7:9186. [PMID: 28835662 PMCID: PMC5569024 DOI: 10.1038/s41598-017-09647-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 07/27/2017] [Indexed: 12/21/2022] Open
Abstract
Allogeneic islet transplantation into the liver in combination with immune suppressive drug therapy is widely regarded as a potential cure for type 1 diabetes. However, the intrahepatic system is suboptimal as the concentration of drugs and nutrients there is higher compared to pancreas, which negatively affects islet function. Islet encapsulation within semipermeable membranes is a promising strategy that allows for the islet transplantation outside the suboptimal liver portal system and provides environment, where islets can perform their endocrine function. In this study, we develop a macroencapsulation device based on thin microwell membranes. The islets are seeded in separate microwells to avoid aggregation, whereas the membrane porosity is tailored to achieve sufficient transport of nutrients, glucose and insulin. The non-degradable, microwell membranes are composed of poly (ether sulfone)/polyvinylpyrrolidone and manufactured via phase separation micro molding. Our results show that the device prevents aggregation and preserves the islet’s native morphology. Moreover, the encapsulated islets maintain their glucose responsiveness and function after 7 days of culture (stimulation index above 2 for high glucose stimulation), demonstrating the potential of this novel device for islet transplantation.
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10
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Caddeo S, Boffito M, Sartori S. Tissue Engineering Approaches in the Design of Healthy and Pathological In Vitro Tissue Models. Front Bioeng Biotechnol 2017; 5:40. [PMID: 28798911 PMCID: PMC5526851 DOI: 10.3389/fbioe.2017.00040] [Citation(s) in RCA: 161] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 06/26/2017] [Indexed: 12/16/2022] Open
Abstract
In the tissue engineering (TE) paradigm, engineering and life sciences tools are combined to develop bioartificial substitutes for organs and tissues, which can in turn be applied in regenerative medicine, pharmaceutical, diagnostic, and basic research to elucidate fundamental aspects of cell functions in vivo or to identify mechanisms involved in aging processes and disease onset and progression. The complex three-dimensional (3D) microenvironment in which cells are organized in vivo allows the interaction between different cell types and between cells and the extracellular matrix, the composition of which varies as a function of the tissue, the degree of maturation, and health conditions. In this context, 3D in vitro models can more realistically reproduce a tissue or organ than two-dimensional (2D) models. Moreover, they can overcome the limitations of animal models and reduce the need for in vivo tests, according to the "3Rs" guiding principles for a more ethical research. The design of 3D engineered tissue models is currently in its development stage, showing high potential in overcoming the limitations of already available models. However, many issues are still opened, concerning the identification of the optimal scaffold-forming materials, cell source and biofabrication technology, and the best cell culture conditions (biochemical and physical cues) to finely replicate the native tissue and the surrounding environment. In the near future, 3D tissue-engineered models are expected to become useful tools in the preliminary testing and screening of drugs and therapies and in the investigation of the molecular mechanisms underpinning disease onset and progression. In this review, the application of TE principles to the design of in vitro 3D models will be surveyed, with a focus on the strengths and weaknesses of this emerging approach. In addition, a brief overview on the development of in vitro models of healthy and pathological bone, heart, pancreas, and liver will be presented.
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Affiliation(s)
- Silvia Caddeo
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
- Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam, Amsterdam, Netherlands
| | - Monica Boffito
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
| | - Susanna Sartori
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
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11
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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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12
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Liu Z, Hu W, He T, Dai Y, Hara H, Bottino R, Cooper DKC, Cai Z, Mou L. Pig-to-Primate Islet Xenotransplantation: Past, Present, and Future. Cell Transplant 2017; 26:925-947. [PMID: 28155815 PMCID: PMC5657750 DOI: 10.3727/096368917x694859] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 03/21/2017] [Indexed: 12/17/2022] Open
Abstract
Islet allotransplantation results in increasing success in treating type 1 diabetes, but the shortage of deceased human donor pancreata limits progress. Islet xenotransplantation, using pigs as a source of islets, is a promising approach to overcome this limitation. The greatest obstacle is the primate immune/inflammatory response to the porcine (pig) islets, which may take the form of rapid early graft rejection (the instant blood-mediated inflammatory reaction) or T-cell-mediated rejection. These problems are being resolved by the genetic engineering of the source pigs combined with improved immunosuppressive therapy. The results of pig-to-diabetic nonhuman primate islet xenotransplantation are steadily improving, with insulin independence being achieved for periods >1 year. An alternative approach is to isolate islets within a micro- or macroencapsulation device aimed at protecting them from the human recipient's immune response. Clinical trials using this approach are currently underway. This review focuses on the major aspects of pig-to-primate islet xenotransplantation and its potential for treatment of type 1 diabetes.
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Affiliation(s)
- Zhengzhao Liu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
| | - Wenbao Hu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
| | - Tian He
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
| | - Yifan Dai
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Hidetaka Hara
- Xenotransplantation Program/Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Rita Bottino
- Institute for Cellular Therapeutics, Allegheny-Singer Research Institute, Pittsburgh, PA, USA
| | - David K. C. Cooper
- Xenotransplantation Program/Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Zhiming Cai
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
| | - Lisha Mou
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
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13
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Abstract
The goal of this chapter is to provide an overview of the different purposes for which the cell microencapsulation technology can be used. These include immunoisolation of non-autologous cells used for cell therapy; immobilization of cells for localized (targeted) delivery of therapeutic products to ablate, repair, or regenerate tissue; simultaneous delivery of multiple therapeutic agents in cell therapy; spatial compartmentalization of cells in complex tissue engineering; expansion of cells in culture; and production of different probiotics and metabolites for industrial applications. For each of these applications, specific examples are provided to illustrate how the microencapsulation technology can be utilized to achieve the purpose. However, successful use of the cell microencapsulation technology for whatever purpose will ultimately depend upon careful consideration for the choice of the encapsulating polymers, the method of fabrication (cross-linking) of the microbeads, which affects the permselectivity, the biocompatibility and the mechanical strength of the microbeads as well as environmental parameters such as temperature, humidity, osmotic pressure, and storage solutions.The various applications discussed in this chapter are illustrated in the different chapters of this book and where appropriate relevant images of the microencapsulation products are provided. It is hoped that this outline of the different applications of cell microencapsulation would provide a good platform for tissue engineers, scientists, and clinicians to design novel tissue constructs and products for therapeutic and industrial applications.
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Affiliation(s)
- Emmanuel C Opara
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA. .,Virginia Tech-Wake Forest School of Biomedical Engineering & Sciences (SBES), Wake Forest School of Medicine, Winston-Salem, NC, USA.
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14
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Lavin DM, Bintz BE, Thanos CG. The Diffusive Properties of Hydrogel Microcapsules for Cell Encapsulation. Methods Mol Biol 2017; 1479:119-134. [PMID: 27738931 DOI: 10.1007/978-1-4939-6364-5_9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Hydrogel microcapsules have been used for decades to encapsulate cells and treat diseases ranging from neurodegenerative disorders to more systemic applications like Type I Diabetes. This cell encapsulation modality has been developed through more cumulative experiments than perhaps any other, owing to the relative ease of accessing the required materials, the commercial availability of droplet-generating instrumentation, and the mild microenvironment and unique permeability properties of hydrogels that are difficult to attain with alternative encapsulation systems employing thermoplastic materials. Because of their size and shape, microcapsules have an inherent advantage over macroencapsulation devices due to the more favorable surface area to volume ratio, which allows for greater efficiency in the amount of cellular cargo that is entrapped and enhanced nutrient exchange and efflux of secreted products. Unfortunately, with this significant positive benefit comes the caveat of difficult or impractical retrievability, highlighting the paradox that is particularly relevant as differentiated stem cell sources become more readily available. This chapter focuses on several techniques that can be used to evaluate the permeability and pore structure of hydrogel microcapsules, including a simplistic model for describing the diffusive behavior of alginate-polycation-alginate (APA) microcapsules with a liquid core, and an ancillary method to evaluate the ultrastructure of the APA membrane including morphometric analysis.
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Affiliation(s)
- D M Lavin
- Cytosolv, Inc., 117 Chapman St., Suite 107, Providence, RI, USA
- Brown University, Providence, RI, USA
| | - B E Bintz
- Cytosolv, Inc., 117 Chapman St., Suite 107, Providence, RI, USA
- Brown University, Providence, RI, USA
| | - C G Thanos
- Cytosolv, Inc., 117 Chapman St., Suite 107, Providence, RI, USA.
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15
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Appel AA, Ibarra V, Somo SI, Larson JC, Garson AB, Guan H, McQuilling JP, Zhong Z, Anastasio MA, Opara EC, Brey EM. Imaging of Hydrogel Microsphere Structure and Foreign Body Response Based on Endogenous X-Ray Phase Contrast. Tissue Eng Part C Methods 2016; 22:1038-1048. [PMID: 27796159 PMCID: PMC5116683 DOI: 10.1089/ten.tec.2016.0253] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 10/28/2016] [Indexed: 12/22/2022] Open
Abstract
Transplantation of functional islets encapsulated in stable biomaterials has the potential to cure Type I diabetes. However, the success of these materials requires the ability to quantitatively evaluate their stability. Imaging techniques that enable monitoring of biomaterial performance are critical to further development in the field. X-ray phase-contrast (XPC) imaging is an emerging class of X-ray techniques that have shown significant promise for imaging biomaterial and soft tissue structures. In this study, XPC imaging techniques are shown to enable three dimensional (3D) imaging and evaluation of islet volume, alginate hydrogel structure, and local soft tissue features ex vivo. Rat islets were encapsulated in sterile ultrapurified alginate systems produced using a high-throughput microfluidic system. The encapsulated islets were implanted in omentum pouches created in a rodent model of type 1 diabetes. Microbeads were imaged with XPC imaging before implantation and as whole tissue samples after explantation from the animals. XPC microcomputed tomography (μCT) was performed with systems using tube-based and synchrotron X-ray sources. Islets could be identified within alginate beads and the islet volume was quantified in the synchrotron-based μCT volumes. Omental adipose tissue could be distinguished from inflammatory regions resulting from implanted beads in harvested samples with both XPC imaging techniques. Individual beads and the local encapsulation response were observed and quantified using quantitative measurements, which showed good agreement with histology. The 3D structure of the microbeads could be characterized with XPC imaging and failed beads could also be identified. These results point to the substantial potential of XPC imaging as a tool for imaging biomaterials in small animal models and deliver a critical step toward in vivo imaging.
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Affiliation(s)
- Alyssa A. Appel
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois
- Research Services, Edward Hines Jr. VA Hospital, Chicago, Illinois
| | - Veronica Ibarra
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois
| | - Sami I. Somo
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois
| | - Jeffery C. Larson
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois
- Research Services, Edward Hines Jr. VA Hospital, Chicago, Illinois
| | - Alfred B. Garson
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri
| | - Huifeng Guan
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri
| | | | - Zhong Zhong
- National Synchrotron Light Source, Brookhaven National Laboratory, Upton, New York
| | - Mark A. Anastasio
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri
| | - Emmanuel C. Opara
- Wake Forest Institute of Regenerative Medicine, Winston-Salem, North Carolina
| | - Eric M. Brey
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois
- Research Services, Edward Hines Jr. VA Hospital, Chicago, Illinois
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16
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Zhu HT, Lu L, Liu XY, Yu L, Lyu Y, Wang B. Treatment of diabetes with encapsulated pig islets: an update on current developments. J Zhejiang Univ Sci B 2016; 16:329-43. [PMID: 25990050 DOI: 10.1631/jzus.b1400310] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The potential use of allogeneic islet transplantation in curing type 1 diabetes mellitus has been adequately demonstrated, but its large-scale application is limited by the short supply of donor islets and the need for sustained and heavy immunosuppressive therapy. Encapsulation of pig islets was therefore suggested with a view to providing a possible alternative source of islet grafts and avoiding chronic immunosuppression and associated adverse or toxic effects. Nevertheless, several vital elements should be taken into account before this therapy becomes a clinical reality, including cell sources, encapsulation approaches, and implantation sites. This paper provides a comprehensive review of xenotransplantation of encapsulated pig islets for the treatment of type 1 diabetes mellitus, including current research findings and suggestions for future studies.
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Affiliation(s)
- Hai-tao Zhu
- Heart Center, Northwest Women's and Children's Hospital, Xi'an 710061, China; Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an 710061, China; Department of Hand Surgery, China-Japan Union Hospital, Norman Bethune Health Science Center, Jilin University, Changchun 130033, China; Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an 710061, China
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Abstract
In this article, we will review the changes that have occurred in islet transplantation at the birth of Pancreas 30 years ago. The first attempts at β-cell replacement in humans, pancreas and islet transplantation, were performed in the 1960s and 1970s. Although pancreas transplantation has been an accepted treatment for severe labile diabetes predating the emergence of the journal, allogeneic islet transplantation remains experimental. Current investigations within islet transplantation focus to improve islet function after transplantation. Improving islet viability during isolation, exploring ways to increase engraftment, and protection from the host immune system are some of the goals of these investigative efforts. The major barriers to clinical islet transplantation are shortage of human pancreas, the need for immunosuppression, and the inadequacy of the islet isolation process. It is generally accepted that islet encapsulation is an immunoisolation tool with good potential to address the first 2 of those barriers. We have therefore devoted a major part of this review to the critical factors needed to make it a clinical reality. With improved islet isolation techniques and determination of the best site of engraftment as well as improved encapsulation techniques, we hope that islet transplantation could someday achieve routine clinical use.
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Zhu H, Yu L, He Y, Lyu Y, Wang B. Microencapsulated Pig Islet Xenotransplantation as an Alternative Treatment of Diabetes. TISSUE ENGINEERING PART B-REVIEWS 2015; 21:474-89. [PMID: 26028249 DOI: 10.1089/ten.teb.2014.0499] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Haitao Zhu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
- Heart Center, Northwest Women's and Children's Hospital, Xi'an, China
| | - Liang Yu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Yayi He
- Department of Endocrinology, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Yi Lyu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an, China
| | - Bo Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an, China
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19
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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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20
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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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21
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Moshaverinia A, Chen C, Xu X, Ansari S, Zadeh HH, Schricker SR, Paine ML, Moradian-Oldak J, Khademhosseini A, Snead ML, Shi S. Regulation of the Stem Cell-Host Immune System Interplay Using Hydrogel Coencapsulation System with an Anti-Inflammatory Drug. ADVANCED FUNCTIONAL MATERIALS 2015; 25:2296-2307. [PMID: 26120294 PMCID: PMC4478611 DOI: 10.1002/adfm.201500055] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
The host immune system is known to influence mesenchymal stem cell (MSC)-mediated bone tissue regeneration. However, the therapeutic capacity of hydrogel biomaterial to modulate the interplay between MSCs and T-lymphocytes is unknown. Here it is shown that encapsulating hydrogel affects this interplay when used to encapsulate MSCs for implantation by hindering the penetration of pro-inflammatory cells and/or cytokines, leading to improved viability of the encapsulated MSCs. This combats the effects of the host pro-inflammatory T-lymphocyte-induced nuclear factor kappaB pathway, which can reduce MSC viability through the CASPASE-3 and CAS-PASE-8 associated proapoptotic cascade, resulting in the apoptosis of MSCs. To corroborate rescue of engrafted MSCs from the insult of the host immune system, the incorporation of the anti-inflammatory drug indomethacin into the encapsulating alginate hydrogel further regulates the local microenvironment and prevents pro-inflammatory cytokine-induced apoptosis. These findings suggest that the encapsulating hydrogel can regulate the MSC-host immune cell interplay and direct the fate of the implanted MSCs, leading to enhanced tissue regeneration.
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Affiliation(s)
- Alireza Moshaverinia
- Center for Craniofacial Molecular Biology (CCMB), Ostrow School of Dentistry, University of Southern California, 2250 Alcazar St, Los Angeles, CA 90033, USA
| | - Chider Chen
- School of Dental Medicine, University of Pennsylvania, 240 South 40th Street, Philadelphia, PA 19104, USA
| | - Xingtian Xu
- Center for Craniofacial Molecular Biology (CCMB), Ostrow School of Dentistry, University of Southern California, 2250 Alcazar St, Los Angeles, CA 90033, USA
| | - Sahar Ansari
- Center for Craniofacial Molecular Biology (CCMB), Ostrow School of Dentistry, University of Southern California, 2250 Alcazar St, Los Angeles, CA 90033, USA
| | - Homayoun H. Zadeh
- Center for Craniofacial Molecular Biology (CCMB), Ostrow School of Dentistry, University of Southern California, 2250 Alcazar St, Los Angeles, CA 90033, USA
| | - Scott R. Schricker
- College of Dentistry, Ohio State University, 305 W 12th Ave, Columbus, OH 43210, USA
| | - Michael L. Paine
- Center for Craniofacial Molecular Biology (CCMB), Ostrow School of Dentistry, University of Southern California, 2250 Alcazar St, Los Angeles, CA 90033, USA
| | - Janet Moradian-Oldak
- Center for Craniofacial Molecular Biology (CCMB), Ostrow School of Dentistry, University of Southern California, 2250 Alcazar St, Los Angeles, CA 90033, USA
| | - Ali Khademhosseini
- Biomaterials Innovation Research Center Harvard Medical School 65 Landsdowne St, Rm 252, Cambridge, MA 02139, USA
| | - Malcolm L. Snead
- Center for Craniofacial Molecular Biology (CCMB), Ostrow School of Dentistry, University of Southern California, 2250 Alcazar St, Los Angeles, CA 90033, USA
| | - Songtao Shi
- School of Dental Medicine, University of Pennsylvania, 240 South 40th Street, Philadelphia, PA 19104, USA
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22
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A novel multilayer immunoisolating encapsulation system overcoming protrusion of cells. Sci Rep 2014; 4:6856. [PMID: 25358640 PMCID: PMC4215319 DOI: 10.1038/srep06856] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 10/10/2014] [Indexed: 12/23/2022] Open
Abstract
Application of alginate-microencapsulated therapeutic cells is a promising approach for diseases that require a local and constant supply of therapeutic molecules. However most conventional alginate microencapsulation systems are associated with low mechanical stability and protrusion of cells which is associated with higher surface roughness and limits their clinical application. Here we have developed a novel multilayer encapsulation system that prevents cells from protruding from capsules. The system was tested using a therapeutic protein with anti-tumor activity overexpressed in mammalian cells. The cell containing core of the multilayer capsule was formed by flexible alginate, creating a cell sustaining environment. Surrounded by a poly-L-lysine layer the flexible core was enveloped in a high-G alginate matrix that is less flexible and has higher mechanical stability, which does not support cell survival. The cells in the core of the multilayer capsule did not show growth impairment and protein production was normal for periods up to 70 days in vitro. The additional alginate layer also lowered the surface roughness compared to conventional cell containing alginate-PLL capsules. Our system provides a solution for two important, often overlooked phenomena in cell encapsulation: preventing cell protrusion and improving surface roughness.
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23
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Spasojevic M, Paredes-Juarez GA, Vorenkamp J, de Haan BJ, Schouten AJ, de Vos P. Reduction of the inflammatory responses against alginate-poly-L-lysine microcapsules by anti-biofouling surfaces of PEG-b-PLL diblock copolymers. PLoS One 2014; 9:e109837. [PMID: 25347191 PMCID: PMC4209974 DOI: 10.1371/journal.pone.0109837] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2014] [Accepted: 09/03/2014] [Indexed: 01/12/2023] Open
Abstract
Large-scale application of alginate-poly-L-lysine (alginate-PLL) capsules used for microencapsulation of living cells is hampered by varying degrees of success, caused by tissue responses against the capsules in the host. A major cause is proinflammatory PLL which is applied at the surface to provide semipermeable properties and immunoprotection. In this study, we investigated whether application of poly(ethylene glycol)-block-poly(L-lysine hydrochloride) diblock copolymers (PEG-b-PLL) can reduce the responses against PLL on alginate-matrices. The application of PEG-b-PLL was studied in two manners: (i) as a substitute for PLL or (ii) as an anti-biofouling layer on top of a proinflammatory, but immunoprotective, semipermeable alginate-PLL100 membrane. Transmission FTIR was applied to monitor the binding of PEG-b-PLL. When applied as a substitute for PLL, strong host responses in mice were observed. These responses were caused by insufficient binding of the PLL block of the diblock copolymers confirmed by FTIR. When PEG-b-PLL was applied as an anti-biofouling layer on top of PLL100 the responses in mice were severely reduced. Building an effective anti-biofouling layer required 50 hours as confirmed by FTIR, immunocytochemistry and XPS. Our study provides new insight in the binding requirements of polyamino acids necessary to provide an immunoprotective membrane. Furthermore, we present a relatively simple method to mask proinflammatory components on the surface of microcapsules to reduce host responses. Finally, but most importantly, our study illustrates the importance of combining physicochemical and biological methods to understand the complex interactions at the capsules' surface that determine the success or failure of microcapsules applicable for cell-encapsulation.
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Affiliation(s)
- Milica Spasojevic
- Department of Polymer Chemistry, Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands
- Departments of Pathology and Laboratory Medicine, section of Medical Biology, division of immunoendocrinology, University of Groningen, Groningen, The Netherlands
| | - Genaro A. Paredes-Juarez
- Departments of Pathology and Laboratory Medicine, section of Medical Biology, division of immunoendocrinology, University of Groningen, Groningen, The Netherlands
| | - Joop Vorenkamp
- Department of Polymer Chemistry, Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands
| | - Bart J. de Haan
- Departments of Pathology and Laboratory Medicine, section of Medical Biology, division of immunoendocrinology, University of Groningen, Groningen, The Netherlands
| | - Arend Jan Schouten
- Department of Polymer Chemistry, Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands
| | - Paul de Vos
- Departments of Pathology and Laboratory Medicine, section of Medical Biology, division of immunoendocrinology, University of Groningen, Groningen, The Netherlands
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24
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Orlando G, Gianello P, Salvatori M, Stratta RJ, Soker S, Ricordi C, Domínguez-Bendala J. Cell replacement strategies aimed at reconstitution of the β-cell compartment in type 1 diabetes. Diabetes 2014; 63:1433-44. [PMID: 24757193 DOI: 10.2337/db13-1742] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Emerging technologies in regenerative medicine have the potential to restore the β-cell compartment in diabetic patients, thereby overcoming the inadequacies of current treatment strategies and organ supply. Novel approaches include: 1) Encapsulation technology that protects islet transplants from host immune surveillance; 2) stem cell therapies and cellular reprogramming, which seek to regenerate the depleted β-cell compartment; and 3) whole-organ bioengineering, which capitalizes on the innate properties of the pancreas extracellular matrix to drive cellular repopulation. Collaborative efforts across these subfields of regenerative medicine seek to ultimately produce a bioengineered pancreas capable of restoring endocrine function in patients with insulin-dependent diabetes.
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25
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Akilbekova D, Philiph R, Graham A, Bratlie KM. Macrophage reprogramming: Influence of latex beads with various functional groups on macrophage phenotype and phagocytic uptakein vitro. J Biomed Mater Res A 2014; 103:262-8. [DOI: 10.1002/jbm.a.35169] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Revised: 02/19/2014] [Accepted: 03/13/2014] [Indexed: 01/05/2023]
Affiliation(s)
- Dana Akilbekova
- Department of Materials Science & Engineering; Iowa State University; Ames Iowa 50011
| | - Rachel Philiph
- Department of Materials Science & Engineering; Iowa State University; Ames Iowa 50011
| | - Austin Graham
- Department of Materials Science & Engineering; Iowa State University; Ames Iowa 50011
| | - Kaitlin M. Bratlie
- Department of Materials Science & Engineering; Iowa State University; Ames Iowa 50011
- Department of Chemical & Biological Engineering; Iowa State University; Ames Iowa 50011
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26
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Scharp DW, Marchetti P. Encapsulated islets for diabetes therapy: history, current progress, and critical issues requiring solution. Adv Drug Deliv Rev 2014; 67-68:35-73. [PMID: 23916992 DOI: 10.1016/j.addr.2013.07.018] [Citation(s) in RCA: 226] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Revised: 07/10/2013] [Accepted: 07/22/2013] [Indexed: 02/07/2023]
Abstract
Insulin therapy became a reality in 1921 dramatically saving lives of people with diabetes, but not protecting them from long-term complications. Clinically successful free islet implants began in 1989 but require life long immunosuppression. Several encapsulated islet approaches have been ongoing for over 30 years without defining a clinically relevant product. Macro-devices encapsulating islet mass in a single device have shown long-term success in large animals but human trials have been limited by critical challenges. Micro-capsules using alginate or similar hydrogels encapsulate individual islets with many hundreds of promising rodent results published, but a low incidence of successful translation to large animal and human results. Reduction of encapsulated islet mass for clinical transplantation is in progress. This review covers the status of both early and current studies including the presentation of corporate efforts involved. It concludes by defining the critical items requiring solution to enable a successful clinical diabetes therapy.
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Fu HX, Li H, Wu LL, Zhao YZ, Xu YY, Zhu YL, Xue SL, Wang DW, Liu CY, Yang SL, Li XK. Preparation and microscopy examination of alginate-poly-l-lysine-alginate microcapsules. Drug Dev Ind Pharm 2014; 40:1523-9. [DOI: 10.3109/03639045.2013.836212] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Araújo-Filho I, Rêgo ACM, Azevedo ÍM, Carvalho MDF, Medeiros AC. Ileal interposition and viability of pancreatic islets transplanted into intramuscular site of diabetic rats. J INVEST SURG 2014; 27:191-6. [PMID: 24377965 DOI: 10.3109/08941939.2013.870622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Assuming that ileal stimulation by food may increase incretin secretion, we aimed to investigate whether ileal interposition obtains adequate pancreatic islet viability and function after intramuscular islet transplantation in diabetic rats. METHODS We investigated four groups of eight Wistar rats: ileal interposition + islet transplantation, islet transplantation, ileal interposition, and diabetic control. All rats were subjected to streptozotocin-induced diabetes. We used the C-peptide/glucose ratio and islet image to investigate beta cell mass, and plasma glucagon like peptide-1 (GLP-1) measure. RESULTS Ileal interposition was effective in preserving function and increasing islet mass in animals with islets transplanted into alginate microcapsules. The plasma GLP-1 level in the diabetic control rats was a basal concentration (4.1 ± 1.2 pM). GLP-1 level after ileal interposition + islet transplantation (12.3 ± 3.3 pM) was significantly higher (p < .05) than in the islet transplantation group (8.2 ± 2.4 pM) and ileal interposition group rats (7.6 ± 1.8 pM). CONCLUSIONS Ileal interposition positively influenced beta cell viability after intramuscular transplantation of pancreatic islets in diabetic rats.
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Affiliation(s)
- Irami Araújo-Filho
- Department of Surgery, Federal University of Rio Grande do Norte, Natal , Brazil
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Gattás-Asfura KM, Stabler CL. Bioorthogonal layer-by-layer encapsulation of pancreatic islets via hyperbranched polymers. ACS APPLIED MATERIALS & INTERFACES 2013; 5:9964-74. [PMID: 24063764 PMCID: PMC3856945 DOI: 10.1021/am401981g] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Encapsulation of viable tissues via layer-by-layer polymer assembly provides a versatile platform for cell surface engineering, with nanoscale control over the capsule properties. Herein, we report the development of a hyperbranched polymer-based, ultrathin capsule architecture expressing bioorthogonal functionality and tailored physiochemical properties. Random carbodiimide-based condensation of 3,5-dicarboxyphenyl glycineamide on alginate yielded a highly branched polysaccharide with multiple, spatially restricted, and readily functionalizable terminal carboxylate moieties. Poly(ethylene glycol) (PEG) was utilized to link azido end groups to the structured alginate. Together with a phosphine-functionalized poly(amidoamine) dendrimer, nanoscale layer-by-layer coatings, covalently stabilized via Staudinger ligation, were assembled onto solid surfaces and pancreatic islets. The effects of electrostatic and/or bioorthogonal covalent interlayer interactions on the resulting coating efficiency and stability, as well as pancreatic islet viability and function, were studied. These hyperbranched polymers provide a flexible platform for the formation of covalently stabilized, ultrathin coatings on viable cells and tissues. In addition, the hyperbranched nature of the polymers presents a highly functionalized surface capable of bioorthogonal conjugation of additional bioactive or labeling motifs.
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Affiliation(s)
- Kerim M Gattás-Asfura
- Diabetes Research Institute, University of Miami , Miami, Florida 33136 United States
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Spasojevic M, Bhujbal S, Paredes G, de Haan BJ, Schouten AJ, de Vos P. Considerations in binding diblock copolymers on hydrophilic alginate beads for providing an immunoprotective membrane. J Biomed Mater Res A 2013; 102:1887-96. [PMID: 23853069 PMCID: PMC4232034 DOI: 10.1002/jbm.a.34863] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Revised: 06/13/2013] [Accepted: 06/28/2013] [Indexed: 01/14/2023]
Abstract
Alginate-based microcapsules are being proposed for treatment of many types of diseases. A major obstacle however in the successes is that these capsules are having large lab-to-lab variations. To make the process more reproducible, we propose to cover the surface of alginate capsules with diblock polymers that can form polymer brushes. In the present study, we describe the stepwise considerations for successful application of diblock copolymer of polyethylene glycol (PEG) and poly-l-lysine (PLL) on the surface of alginate beads. Special procedures had to be designed as alginate beads are hydrophilic and most protocols are designed for hydrophobic biomaterials. The successful attachment of diblock copolymer and the presence of PEG blocks on the surface of the capsules were studied by fluorescence microscopy. Longer time periods, that is, 30–60 min, are required to achieve saturation of the surface. The block lengths influenced the strength of the capsules. Shorter PLL blocks resulted in less stable capsules. Adequate permeability of the capsules was achieved with poly(ethylene glycol)-block-poly(l-lysine hydrochloride) (PEG454-b-PLL100) diblock copolymers. The capsules were a barrier for immunoglobulin G. The PEG454-b-PLL100 capsules have similar mechanical properties as PLL capsules. Minor immune activation of nuclear factor κB in THP-1 monocytes was observed with both PLL and PEG454-b-PLL100 capsules prepared from purified alginate. Our results show that we can successfully apply block copolymers on the surface of hydrophilic alginate beads without interfering with the physicochemical properties.
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Affiliation(s)
- Milica Spasojevic
- Department of Polymer Chemistry, Zernike Institute for Advanced Materials, University of Groningen, 9747, AG Groningen, the Netherlands; Departments of Pathology and Laboratory Medicine, Section of Medical Biology, Division of Immunoendocrinology, University of Groningen, Hanzeplein 1, 9700, RB Groningen, The Netherlands
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Pareta R, Sanders B, Babbar P, Soker T, Booth C, McQuilling J, Sivanandane S, Stratta RJ, Orlando G, Opara EC. Immunoisolation: where regenerative medicine meets solid organ transplantation. Expert Rev Clin Immunol 2013; 8:685-92. [PMID: 23078065 DOI: 10.1586/eci.12.64] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Immunoisolation refers to an immunological strategy in which nonself antigens present on an allograft or xenograft are not allowed to come in contact with the host immune system, and it is implemented to prevent allorecognition and avoid immunosuppression. In this setting, the two most promising technologies, encapsulation of pancreatic islets (EPI) and immunocloaking (IC), are used. In the case of EPI, islets are inserted in capsules that, allow exchange of oxygen, nutrients and other molecules. In the case of IC, a natural nanofilm is injected prior to renal transplantation within the vasculature of the graft with the intent to pave the inner surface of the vascular lumen and camouflage the antigens located on the membrane of endothelia cells. Significant progress achieved in experimental models is leading EPI and IC to clinical translation.
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Affiliation(s)
- Rajesh Pareta
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA
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Dang TT, Thai AV, Cohen J, Slosberg JE, Siniakowicz K, Doloff JC, Ma M, Hollister-Lock J, Tang KM, Gu Z, Cheng H, Weir GC, Langer R, Anderson DG. Enhanced function of immuno-isolated islets in diabetes therapy by co-encapsulation with an anti-inflammatory drug. Biomaterials 2013; 34:5792-801. [PMID: 23660251 DOI: 10.1016/j.biomaterials.2013.04.016] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 04/06/2013] [Indexed: 12/12/2022]
Abstract
Immuno-isolation of islets has the potential to enable the replacement of pancreatic function in diabetic patients. However, host response to the encapsulated islets frequently leads to fibrotic overgrowth with subsequent impairment of the transplanted grafts. Here, we identified and incorporated anti-inflammatory agents into islet-containing microcapsules to address this challenge. In vivo subcutaneous screening of 16 small molecule anti-inflammatory drugs was performed to identify promising compounds that could minimize the formation of fibrotic cell layers. Using parallel non-invasive fluorescent and bioluminescent imaging, we identified dexamethasone and curcumin as the most effective drugs in inhibiting the activities of inflammatory proteases and reactive oxygen species in the host response to subcutaneously injected biomaterials. Next, we demonstrated that co-encapsulating curcumin with pancreatic rat islets in alginate microcapsules reduced fibrotic overgrowth and improved glycemic control in a mouse model of chemically-induced type I diabetes. These results showed that localized administration of anti-inflammatory drug can improve the longevity of encapsulated islets and may facilitate the translation of this technology toward a long-term cure for type I diabetes.
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Affiliation(s)
- Tram T Dang
- Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
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Lieder R, Petersen PH, Sigurjónsson ÓE. Endotoxins-the invisible companion in biomaterials research. TISSUE ENGINEERING PART B-REVIEWS 2013; 19:391-402. [PMID: 23350734 DOI: 10.1089/ten.teb.2012.0636] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Metal implants and polymeric devices for the application in the clinical treatment of orthopedic tissue injuries are increasingly coated with bioactive biomaterials derived from natural substances to induce desirable biological effects. Many metals and polymers used in biomaterials research show high affinity for endotoxins, which are abundant in the environment. Endotoxin contamination is indicated in the pathology of periodontitis and aseptic implant loosening, but may also affect the evaluation of a biomaterial's bioactivity by inducing strong inflammatory reactions. In this review, we discuss the high affinity of three commonly used implant biomaterials for endotoxins and how the contamination can affect the outcome of the orthopedic fixation. The chemical nature of bacterial endotoxins and some of the clinical health implications are described, as this knowledge is critically important to tackle the issues associated with the measurement and removal of endotoxins from medical devices. Commonly used methods for endotoxin testing and removal from natural substances are examined and the lack of standard guidelines for the in vitro evaluation of biomaterials is discussed.
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Affiliation(s)
- Ramona Lieder
- The Blood Bank, Landspitali University Hospital, Reykjavik, Iceland
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34
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Dufrane D, Gianello P. Macro- or microencapsulation of pig islets to cure type 1 diabetes. World J Gastroenterol 2012; 18:6885-93. [PMID: 23322985 PMCID: PMC3531671 DOI: 10.3748/wjg.v18.i47.6885] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Revised: 06/14/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
Although allogeneic islet transplantation can successfully cure type 1 diabetes, it has limited applicability. For example, organs are in short supply; several human pancreas donors are often needed to treat one diabetic recipient; the intrahepatic site may not be the most appropriate site for islet implantation; and immunosuppressive regimens, which are associated with side effects, are often required to prolong survival of the islet graft. An alternative source of insulin-producing cells would therefore be of major interest. Pigs represent a possible alternative source of beta cells. Grafting of pig islets may appear difficult because of the immunologic species barrier, but pig islets have been shown to function in primates for at least 6 mo with clinically incompatible immunosuppression. Therefore, a bioartificial pancreas made of encapsulated pig islets may resolve issues associated with islet allotransplantation. Although several groups have shown that encapsulated pig islets are functional in small-animal models, less is known about the use of bioartificial pancreases in large-animal models. In this review, we summarize current knowledge of encapsulated pig islets, to determine obstacles to implantation in humans and possible solutions to overcome these obstacles.
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Canaple L, Rehor A, Hunkeler D. Improving cell encapsulation through size control. JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION 2012; 13:783-96. [PMID: 12296444 DOI: 10.1163/156856202760197410] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Capsules based on the polyelectrolyte complexation between the polyanions sodium alginate and sodium cellulose sulphate with the polycation poly(methylene-co-guanidine) hydrochloride in the presence of calcium chloride have previously shown important advantages for cell encapsulation. However, in vivo long-term applications require capsule features that are well suited for the functionality of encapsulated cells. These should be targeted to the site of implantation with an appropriate size, a relative stability, and suitable diffusion properties. This study shows the effect of capsule size reduction, from 1 mm to 400 microm, on capsule quality control, mechanical stability, diffusion properties, and in vitro activities of the encapsulated cells. Following a controlled preparation, it was determined that the capsule mechanical stability was largely dependent on the volume ratio of the capsule over the membrane. The molecule diffusion time was related to the surface/volume ratio of the capsule even for the capsules exhibiting an identical cut-off towards the proteins and the dextran molecules. Finally, the in vitro cellular activities, for both primary cultures of rat islets and murine hepatocytes, were improved for cells encapsulated into the 400 microm capsules compared with those in the 1 mm capsules. All of these findings suggest that the smaller capsules present better properties for future clinical applications, at the same time widening the choice of implantation site, and strengthen the notion that slight changes in the capsular morphological parameters can largely influence the graft function in vivo.
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Affiliation(s)
- Laurence Canaple
- Laboratory of Polyelectrolytes and Biomacromolecules, Swiss Federal Institute of Technology, Lausanne.
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Martinez CJ, Kim JW, Ye C, Ortiz I, Rowat AC, Marquez M, Weitz D. A Microfluidic Approach to Encapsulate Living Cells in Uniform Alginate Hydrogel Microparticles. Macromol Biosci 2012; 12:946-51. [DOI: 10.1002/mabi.201100351] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2011] [Revised: 11/18/2011] [Indexed: 11/09/2022]
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Thirumalai S, Mobed-Miremadi M, Sridhar-Keralapura M. Effect of therapeutic ultrasound on acoustically sensitive microcapsules. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2012; 2011:7207-10. [PMID: 22256001 DOI: 10.1109/iembs.2011.6091821] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
In the area of therapeutic ultrasound activated drug delivery, difficulties exist in designing a carrier that responds to ultrasound for triggering and imaging but also provides adequate treatment potential. In this paper, we report on a novel acoustically sensitive microcapsule reservoir that can be activated with therapeutic ultrasound for payload release and can be potentially tracked using imaging. It is being designed for increased longevity and is not planned for the circulation. Here, we describe its unique formulation and demonstrate effects of therapeutic ultrasound on it at 1 MHz using a combined optical-acoustic setup on a microscope. We see membrane bulging and damage for small and large capsules with both continuous and pulsed ultrasound. We also show some preliminary work on understanding the mechanism behind these effects. The reservoirs show potential for future ultrasound activated release and imaging while being patent in form and function over several weeks.
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Zhang W, He X. Microencapsulating and Banking Living Cells for Cell-Based Medicine. JOURNAL OF HEALTHCARE ENGINEERING 2011; 2:427-446. [PMID: 22180835 DOI: 10.1260/2040-2295.2.4.427] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
A major challenge to the eventual success of the emerging cell-based medicine such as tissue engineering, regenerative medicine, and cell transplantation is the limited availability of the desired cell sources. This challenge can be addressed by cell microencapsulation to overcome the undesired immune response (i.e., to achieve immunoisolation) so that non-autologous cells can be used to treat human diseases, and by cell/tissue preservation to bank living cells for wide distribution to end users so that they are readily available when needed in the future. This review summarizes the status quo of research in both cell microencapsulation and banking the microencapsulated cells. It is concluded with a brief outlook of future research directions in this important field.
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Affiliation(s)
- Wujie Zhang
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210
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Vaithilingam V, Quayum N, Joglekar MV, Jensen J, Hardikar AA, Oberholzer J, Guillemin GJ, Tuch BE. Effect of alginate encapsulation on the cellular transcriptome of human islets. Biomaterials 2011; 32:8416-25. [PMID: 21889795 DOI: 10.1016/j.biomaterials.2011.06.044] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2011] [Accepted: 06/20/2011] [Indexed: 10/17/2022]
Abstract
Encapsulation of human islets may prevent their immune rejection when transplanted into diabetic recipients. To assist in understanding why clinical outcomes with encapsulated islets were not ideal, we examined the effect of encapsulation on their global gene (mRNA) and selected miRNAs (non-coding (nc)RNA) expression. For functional studies, encapsulated islets were transplanted into peritoneal cavity of diabetic NOD-SCID mice. Genomics analysis and transplantation studies demonstrate that islet origin and isolation centres are a major source of variation in islet quality. In contrast, tissue culture and the encapsulation process had only a minimal effect, and did not affect islet viability. Microarray analysis showed that as few as 29 genes were up-regulated and 2 genes down-regulated (cut-off threshold 0.1) by encapsulation. Ingenuity analysis showed that up-regulated genes were involved mostly in inflammation, especially chemotaxis, and vascularisation. However, protein expression of these factors was not altered by encapsulation, raising doubts about the biosignificance of the gene changes. Encapsulation had no effect on levels of islet miRNAs. In vivo studies indicate differences among the centres in the quality of the islets isolated. We conclude that microencapsulation of human islets with barium alginate has little effect on their transcriptome.
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Dang TT, Bratlie KM, Bogatyrev SR, Chen XY, Langer R, Anderson DG. Spatiotemporal effects of a controlled-release anti-inflammatory drug on the cellular dynamics of host response. Biomaterials 2011; 32:4464-70. [PMID: 21429573 DOI: 10.1016/j.biomaterials.2011.02.048] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2011] [Accepted: 02/12/2011] [Indexed: 10/18/2022]
Abstract
In general, biomaterials induce a non-specific host response when implanted in the body. This reaction has the potential to interfere with the function of the implanted materials. One method for controlling the host response is through local, controlled-release of anti-inflammatory agents. Herein, we investigate the spatial and temporal effects of an anti-inflammatory drug on the cellular dynamics of the innate immune response to subcutaneously implanted poly(lactic-co-glycolic) microparticles. Noninvasive fluorescence imaging was used to investigate the influence of dexamethasone drug loading and release kinetics on the local and systemic inhibition of inflammatory cellular activities. Temporal monitoring of host response showed that inhibition of inflammatory proteases in the early phase was correlated with decreased cellular infiltration in the later phase of the foreign body response. We believe that using controlled-release anti-inflammatory platforms to modulate early cellular dynamics will be useful in reducing the foreign body response to implanted biomaterials and medical devices.
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Affiliation(s)
- Tram T Dang
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, 02139, USA
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Stiegler P, Matzi V, Pierer E, Hauser O, Schaffellner S, Renner H, Greilberger J, Aigner R, Maier A, Lackner C, Iberer F, Smolle-Jüttner FM, Tscheliessnigg K, Stadlbauer V. Creation of a prevascularized site for cell transplantation in rats. Xenotransplantation 2011; 17:379-90. [PMID: 20955294 DOI: 10.1111/j.1399-3089.2010.00606.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Transplanted cells, especially islet cells, are likely to become apoptotic due to local hypoxia leading to graft dysfunction. Isolated pancreatic islet cells depend on the diffusion of oxygen from the surrounding tissue; therefore, access to sufficient oxygen supply is beneficial, particularly when microcapsules are used for immunoisolation in xenotransplantation. The aim of this study was to create a prevascularized site for cell transplantation in rats and test its effectiveness with microencapsulated HEK293 cells. METHODS The combination of implantation of a foam dressing, vacuum-assisted wound closure (foam+VAC) and hyperbaric oxygenation (HBO) was used in 40 Sprague-Dawley rats. Blood flow and vascular endothelial growth factor (VEGF) levels were determined. Sodium cellulose sulphate (SCS)-microencapsulated HEK293 cells were xenotransplanted into the foam dressing in rats pre-treated with HBO, and angiogenesis and apoptosis were assessed. RESULTS Vessel ingrowth and VEGF levels increased depending on the duration of HBO treatment. The area containing the foam was perfused significantly better in the experimental groups when compared to controls. Only a small amount of apoptosis occurs in SCS-microencapsulated HEK293 cells after xenotransplantation. CONCLUSION As ischemia-damaged cells are likely to undergo cell death or loose functionality due to hypoxia, therefore leading to graft dysfunction, the combination foam+VAC and HBO might be a promising method to create a prevascularized site to achieve better results in xenogeneic cell transplantation.
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Affiliation(s)
- Philipp Stiegler
- Department of Surgery, Division of Transplantation Surgery, Medical University Graz, Graz, Austria.
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Daoud J, Rosenberg L, Tabrizian M. Pancreatic Islet Culture and Preservation Strategies: Advances, Challenges, and Future Outlook. Cell Transplant 2010; 19:1523-35. [DOI: 10.3727/096368910x515872] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Postisolation islet survival is a critical step for achieving successful and efficient islet transplantation. This involves the optimization of islet culture in order to prolong survival and functionality in vitro. Many studies have focused on different strategies to culture pancreatic islets in vitro through manipulation of culture media, surface modified substrates, and the use of various techniques such as encapsulation, embedding, scaffold, and bioreactor culture strategies. This review aims to present and discuss the different methodologies employed to optimize pancreatic islet culture in vitro as well as address their respective advantages and drawbacks.
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Affiliation(s)
- Jamal Daoud
- Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, QC, Canada
| | - Lawrence Rosenberg
- Department of Surgery, Faculty of Medicine, McGill University, Montreal, QC, Canada
| | - Maryam Tabrizian
- Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, QC, Canada
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Vaithilingam V, Oberholzer J, Guillemin GJ, Tuch BE. Beneficial effects of desferrioxamine on encapsulated human islets--in vitro and in vivo study. Am J Transplant 2010; 10:1961-9. [PMID: 20645943 DOI: 10.1111/j.1600-6143.2010.03209.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
As many as 2000 IEQs (islet equivalent) of encapsulated human islets are required to normalize glucose levels in diabetic mice. To reduce this number, encapsulated islets were exposed to 100 μM desferrioxamine (DFO) prior to transplantation. Cell viability, glucose-induced insulin secretion, VEGF (Vascular endothelial growth factor), HIF-1α (Hypoxia inducible factor-1 alpha), caspase-3 and caspase-8 levels were assessed after exposure to DFO for 12, 24 or 72 h. Subsequently, 1000, 750 or 500 encapsulated IEQs were infused into peritoneal cavity of diabetic mice after 24 h exposure to DFO. Neither viability nor function in vitro was affected by DFO, and levels of caspase-3 and caspase-8 were unchanged. DFO significantly enhanced VEGF secretion by 1.6- and 2.5-fold at 24 and 72 h, respectively, with a concomitant increase in HIF-1α levels. Euglycemia was achieved in 100% mice receiving 1000 preconditioned IEQs, as compared to only 36% receiving unconditioned IEQs (p < 0.001). Similarly, with 750 IEQ, euglycemia was achieved in 50% mice receiving preconditioned islets as compared to 10% receiving unconditioned islets (p = 0.049). Mice receiving preconditioned islets had lower glucose levels than those receiving unconditioned islets. In summary, DFO treatment enhances HIF-1α and VEGF expression in encapsulated human islets and improves their ability to function when transplanted.
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Affiliation(s)
- V Vaithilingam
- Department of Pharmacology, University of New South Wales, Sydney, Australia
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Abstract
Clinical islet transplantation (CIT), the infusion of allogeneic islets within the liver, has the potential to provide precise and sustainable control of blood glucose levels for the treatment of type 1 diabetes. The success and long-term outcomes of CIT, however, are limited by obstacles such as a nonoptimal transplantation site and severe inflammatory and immunological responses to the transplant. Tissue engineering strategies are poised to combat these challenges. In this review, emerging methods for engineering an optimal islet transplantation site, as well as novel approaches for improving islet cell encapsulation, are discussed.
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Affiliation(s)
- Jaime A Giraldo
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida, USA
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45
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Calcium phosphate cement chamber as an immunoisolative device for bioartificial pancreas: in vitro and preliminary in vivo study. Pancreas 2010; 39:444-51. [PMID: 20084047 DOI: 10.1097/mpa.0b013e3181be2f95] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES This study examined a calcium phosphate cement (CPC) chamber as an immunoisolative device to facilitate the use of xenogeneic cell sources without immunosuppression for the bioartificial pancreas (BAP). METHODS Mouse insulinoma cells were encapsulated in agarose gel and then enclosed in a CPC chamber to create a BAP. Bioartificial pancreas were evaluated by cell viability, live-dead cell ratio, and cytokine-mediated cytotoxicity assay and implanted into the peritoneal cavity of diabetic rats. Nonfasting blood glucose and serum insulin levels were analyzed perioperatively; BAPs were also retrieved for histological examination. RESULTS Insulinoma cells enclosed in the CPC chamber had normal viability, cell survival, and insulin secretion that was even cultured in media with cytokines. The nonfasting blood glucose level of rats was decreased from 460 +/- 50 to 132 +/- 43 mg/dL and maintained euglycemia for 22 days; serum insulin level was increased from 0.34 +/- 0.11 to 1.43 +/- 0.30 microg/dL after operation. Histological examination revealed the fibrous tissue envelopment, and immune-related cells that competed for oxygen resulting in hypoxia could be attributed to the dysfunction of BAPs. CONCLUSIONS This study proved the feasibility for using a CPC chamber as an immunoisolative device for the BAP. An alternative implanted site should be considered to extend the functional longevity of BAPs in further study.
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Yang XD, Li HM, Chen M, Zou XH, Zhu LY, Wei CJ, Chen GQ. Enhanced insulin production from murine islet beta cells incubated on poly(3-hydroxybutyrate-co-3-hydroxyhexanoate). J Biomed Mater Res A 2010; 92:548-55. [PMID: 19235213 DOI: 10.1002/jbm.a.32379] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Islet transplantation represents an important alternative for the treatment of diabetes. However, the selection of suitable materials is critical for the success of such an implantation application. In this study, cellular migration, aggregation, and insulin production of a murine islet beta-cell line, NIT-1 cells on microbially produced polyesters poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx), poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P3HB4HB) or polylactic acid (PLA) films were investigated. Spherical islet-like structures were only detected on PHBHHx films after 48 h cultivation. To understand the mechanism underlying the formation of cell aggregates, NIT-1-GFP, a stable transfectant of the green fluorescent protein was used in a time-lapse imaging study. Cell aggregation began on PHBHHx at 2 h, and became obvious at 4 h. Furthermore, cells on PHBHHx displayed higher metabolic activities measured by MTT assay than that on tissue culture plate. More importantly, insulin gene expression as well as extracellular secretion was upregulated after growth on PHBHHx for 72 h. Thus, PHBHHx can be a strong candidate for islet transplantation.
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Affiliation(s)
- Xiao-Di Yang
- Multidisciplinary Research Center, Shantou University, Shantou, Guangdong 515063, China
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de Vos P, Spasojevic M, Faas MM. Treatment of diabetes with encapsulated islets. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2010; 670:38-53. [PMID: 20384217 DOI: 10.1007/978-1-4419-5786-3_5] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
Cell encapsulation has been proposed for the treatment of a wide variety of diseases since it allows for transplantation of cells in the absence of undesired immunosuppression. The technology has been proposed to be a solution for the treatment of diabetes since it potentially allows a mandatory minute-to-minute regulation of glucose levels without side-effects. Encapsulation is based on the principle that transplanted tissue is protected for the host immune system by a semipermeable capsule. Many different concepts of capsules have been tested. During the past two decades three major approaches of encapsulation have been studied. These include (i) intravascular macrocapsules, which are anastomosed to the vascular system as AV shunt, (ii) extravascular macrocapsules, which are mostly diffusion chambers transplanted at different sites and (iii) extravascular microcapsules transplanted in the peritoneal cavity. The advantages and pitfalls of the three approaches are discussed and compared in view of applicability in clinical islet transplantation.
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Affiliation(s)
- Paul de Vos
- Department of Pathology and Laboratory Medicine, Section of Immunoendocrinology, University of Groningen. Hanzeplein 1, 9700 RB Groningen, The Netherlands.
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Giovagnoli S, Blasi P, Luca G, Fallarino F, Calvitti M, Mancuso F, Ricci M, Basta G, Becchetti E, Rossi C, Calafiore R. Bioactive long-term release from biodegradable microspheres preserves implanted ALG-PLO-ALG microcapsules from in vivo response to purified alginate. Pharm Res 2009; 27:285-95. [PMID: 20043193 DOI: 10.1007/s11095-009-0017-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2009] [Accepted: 11/24/2009] [Indexed: 12/24/2022]
Abstract
PURPOSE To assess whether prevention of unexpected in vivo adverse inflammatory and immune responses to biohybrid organ grafts for the treatment of Type I Diabetes Mellitus (T1DM) is possible by superoxide dismutase and ketoprofen controlled release. METHODS Superoxide dismutase and ketoprofen-loaded polyester microspheres were prepared by W/O/W and O/W methods, embodied into purified alginate-poly-L-ornithine-alginate microcapsules and intraperitoneally implanted into CD1 mice. The microspheres were characterized for morphology, size, encapsulation efficiency, enzyme activity and in vitro release. Purified alginate contaminants were assayed, and the obtained microcapsules were investigated for size and morphology before and after implantation over 30 days. Cell pericapsular overgrowth and expression were evaluated by optical microscopy and flow cytometry. RESULTS Superoxide dismutase and ketoprofen sustained release reduced cell pericapsular overgrowth in comparison to the control. Superoxide dismutase release allowed preserving the microcapsules over 30 days. Ketoprofen-loaded microspheres showed some effect in the immediate post-grafting period. A higher macrophage and T-cell expression was observed for the control group. CONCLUSIONS Microspheres containing superoxide dismutase and ketoprofen may represent novel tools to limit or prevent unpredictable adverse in vivo response to alginate, thus contributing to improve cell transplantation success rates in T1DM treatment.
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Affiliation(s)
- Stefano Giovagnoli
- Dipartimento di Chimica e Tecnologia del Farmaco, Faculty of Pharmacy, University of Perugia, Via del Liceo 1, Perugia, 06123, Italy.
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Breger JC, Lyle DB, Shallcross JC, Langone JJ, Wang NS. Defining critical inflammatory parameters for endotoxin impurity in manufactured alginate microcapsules. J Biomed Mater Res B Appl Biomater 2009; 91:755-765. [PMID: 19585560 DOI: 10.1002/jbm.b.31452] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Since current purification methods cannot completely remove all traces of endotoxin in biomaterials intended for use in implantable or blood-contacting devices, acceptable levels of endotoxin contamination that will not cause a significant inflammatory reaction need to be defined. Inflammatory reactions to biomaterials may include production of high concentrations of potentially harmful nitric oxide (NO) generated by macrophages. Nitrite accumulation was measured from RAW264.7 cells treated with either lipopolysaccharide (LPS) free in solution or defined quantities of LPS incorporated into alginate in the absence or presence of murine interferon-gamma (mrIFN-gamma). In the absence of IFN-gamma, significant NO production by RAW 264.7 cells occurred for LPS levels down to 0.018 EU/mL. In the presence of mrIFN-gamma, the lowest concentration of LPS tested in solution (0.006 EU/mL) elicited a significant increase in NO production. In the absence or presence of mrIFN-gamma, five times the concentration of LPS incorporated into alginate as compared to LPS free in solution was necessary to elicit a similar NO response by RAW264.7. These results demonstrate that very low concentrations of endotoxin can elicit significant NO responses from macrophages, particularly when inflammatory cytokines are present. Biomaterials may sequester endotoxin, resulting in lower inflammatory reactions that otherwise might be expected.
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Affiliation(s)
- Joyce C Breger
- Department of Chemical and Biomolecular Engineering, University of Maryland, College Park, Maryland 20742.,Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, FDA, Silver Spring, Maryland 20993-002
| | - Daniel B Lyle
- Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, FDA, Silver Spring, Maryland 20993-002
| | - Jonathan C Shallcross
- Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, FDA, Silver Spring, Maryland 20993-002
| | - John J Langone
- Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, FDA, Silver Spring, Maryland 20993-002
| | - Nam Sun Wang
- Department of Chemical and Biomolecular Engineering, University of Maryland, College Park, Maryland 20742
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Abstract
Allogeneic islet transplantation faces difficulties because (1) organ shortage is recurrent; (2) several pancreas donors are often needed to treat one diabetic recipient; and (3) the intrahepatic site of islet implantation may not be the most appropriate site. Another source of insulin-producing cells, therefore, would be of major interest, and pigs represent a possible and serious source for obtaining such cells. Pig islet grafts may seem difficult because of the species barrier, but recent reports demonstrate that pig islets may function in primates for at least 6 months. Pig islet xenotransplantation, however, must still overcome several hurdles before becoming clinically applicable. The actual consensus is to produce more preclinical data in the pig-to-primate model as a necessary requirement to envisage any pig-to-human transplantation of islets; therefore, a summary of the actual acquired knowledge of pig islet transplantation in primates seemed useful and is summarized in this overview.
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