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1
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Yang SN, Shi Y, Berggren PO. The anterior chamber of the eye technology and its anatomical, optical, and immunological bases. Physiol Rev 2024; 104:881-929. [PMID: 38206586 PMCID: PMC11381035 DOI: 10.1152/physrev.00024.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 11/30/2023] [Accepted: 01/05/2024] [Indexed: 01/12/2024] Open
Abstract
The anterior chamber of the eye (ACE) is distinct in its anatomy, optics, and immunology. This guarantees that the eye perceives visual information in the context of physiology even when encountering adverse incidents like inflammation. In addition, this endows the ACE with the special nursery bed iris enriched in vasculatures and nerves. The ACE constitutes a confined space enclosing an oxygen/nutrient-rich, immune-privileged, and less stressful milieu as well as an optically transparent medium. Therefore, aside from visual perception, the ACE unexpectedly serves as an excellent transplantation site for different body parts and a unique platform for noninvasive, longitudinal, and intravital microimaging of different grafts. On the basis of these merits, the ACE technology has evolved from the prototypical through the conventional to the advanced version. Studies using this technology as a versatile biomedical research platform have led to a diverse range of basic knowledge and in-depth understanding of a variety of cells, tissues, and organs as well as artificial biomaterials, pharmaceuticals, and abiotic substances. Remarkably, the technology turns in vivo dynamic imaging of the morphological characteristics, organotypic features, developmental fates, and specific functions of intracameral grafts into reality under physiological and pathological conditions. Here we review the anatomical, optical, and immunological bases as well as technical details of the ACE technology. Moreover, we discuss major achievements obtained and potential prospective avenues for this technology.
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Affiliation(s)
- Shao-Nian Yang
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
| | - Yue Shi
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
| | - Per-Olof Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
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2
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Sun Y, Ku BJ, Moon MJ. Microstructure of the silk fibroin-based hydrogel scaffolds derived from the orb-web spider Trichonephila clavata. Appl Microsc 2024; 54:3. [PMID: 38336879 PMCID: PMC10858014 DOI: 10.1186/s42649-024-00096-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 01/12/2024] [Indexed: 02/12/2024] Open
Abstract
Due to the unique properties of the silk fibroin (SF) made from silkworm, SF-based hydrogels have recently received significant attention for various biomedical applications. However, research on the SF-based hydrogels isolated from spider silks has been rtricted due to the limited collection and preparation of naïve silk materials. Therefore, this study focused on the microstructural characteristics of hydrogel scaffolds derived from two types of woven silk glands: the major ampullate gland (MAG) and the tubuliform gland (TG), in the orb-web spider Trichonephila clavate. We compared these spider glands with those of the silk fibroin (SF) hydrogel scaffold extracted from the cocoon of the insect silkworm Bombyx mori. Our FESEM analysis revealed that the SF hydrogel has high porosity, translucency, and a loose upper structure, with attached SF fibers providing stability. The MAG hydrogel displayed even higher porosity, as well as elongated fibrous structures, and improved mechanical properties: while the TG hydrogel showed increased porosity, ridge-like or wall-like structures, and stable biocapacity formed by physical crosslinking. Due to their powerful and versatile microstructural characteristics, the MAG and TG hydrogels can become tailored substrates, very effective for tissue engineering and regenerative medicine applications.
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Affiliation(s)
- Yan Sun
- Department of Biological Sciences, Dankook University, Cheonan, 31116, Korea
| | - Bon-Jin Ku
- Department of Biological Sciences, Dankook University, Cheonan, 31116, Korea
| | - Myung-Jin Moon
- Department of Biological Sciences, Dankook University, Cheonan, 31116, Korea.
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3
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Krishtul S, Skitel Moshe M, Kovrigina I, Baruch L, Machluf M. ECM-based bioactive microencapsulation significantly improves islet function and graft performance. Acta Biomater 2023; 171:249-260. [PMID: 37708927 DOI: 10.1016/j.actbio.2023.09.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 08/17/2023] [Accepted: 09/07/2023] [Indexed: 09/16/2023]
Abstract
Microencapsulation is a promising strategy to prolong the survival and function of transplanted pancreatic islets for diabetes therapy, albeit its translation has been impeded by incoherent graft performance. The use of decellularized ECM has lately gained substantial research momentum due to its innate capacity to augment the function of cells originating from the same tissue type. In the present study, the advantages of both these approaches are leveraged in a porcine pancreatic ECM (pECM)-based microencapsulation platform, thus significantly enhancing murine pancreatic islet performance. pECM-encapsulated islets sustain high insulin secretion levels in vitro, surpassing those of islets encapsulated in conventional alginate microcapsules. Moreover, pECM-encapsulated islet cells proliferate and produce an enriched intra-islet ECM framework, displaying a distinctive structural rearrangement. The beneficial effect of pECM encapsulation is further reinforced by the temporary protection against cytokine-induced cytotoxicity. In-vivo, this platform significantly improves glucose tolerance and achieves glycemic correction in 100% of immunocompetent diabetic mice without any immunosuppression, compared to only 50% mice achieved glycemic correction by alginate encapsulation. Altogether, the results presented herein reveal that pECM-based microencapsulation offers a natural pancreatic niche that can restore the function of isolated pancreatic islets and deliver them safely, avoiding the need for immunosuppression. STATEMENT OF SIGNIFICANCE: Aiming to improve pancreatic islet transplantation outcomes in diabetic patients, we developed a microencapsulation platform based on pancreatic extracellular matrix (pECM). In these microcapsules the islets are entrapped within a pECM hydrogel that mimics the natural pancreatic microenvironment. We show that pECM encapsulation supports the islets' viability and function in culture, and provides temporal protection against cytokine-induced stress. In a diabetic mouse model, pECM encapsulation significantly improved glucose tolerance and achieved glycemic correction without any immunosuppression. These results reveal the potential of pECM encapsulation as a viable treatment for diabetes, providing a solid scientific basis for more advanced preclinical studies.
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Affiliation(s)
- Stasia Krishtul
- Faculty of Biotechnology & Food Engineering, Technion - Israel Institute of Technology, Haifa 3200003, Israel
| | - Michal Skitel Moshe
- Faculty of Biotechnology & Food Engineering, Technion - Israel Institute of Technology, Haifa 3200003, Israel
| | - Inna Kovrigina
- Faculty of Biotechnology & Food Engineering, Technion - Israel Institute of Technology, Haifa 3200003, Israel
| | - Limor Baruch
- Faculty of Biotechnology & Food Engineering, Technion - Israel Institute of Technology, Haifa 3200003, Israel
| | - Marcelle Machluf
- Faculty of Biotechnology & Food Engineering, Technion - Israel Institute of Technology, Haifa 3200003, Israel.
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4
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Trossmann VT, Lentz S, Scheibel T. Factors Influencing Properties of Spider Silk Coatings and Their Interactions within a Biological Environment. J Funct Biomater 2023; 14:434. [PMID: 37623678 PMCID: PMC10455157 DOI: 10.3390/jfb14080434] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/10/2023] [Accepted: 08/16/2023] [Indexed: 08/26/2023] Open
Abstract
Biomaterials are an indispensable part of biomedical research. However, although many materials display suitable application-specific properties, they provide only poor biocompatibility when implanted into a human/animal body leading to inflammation and rejection reactions. Coatings made of spider silk proteins are promising alternatives for various applications since they are biocompatible, non-toxic and anti-inflammatory. Nevertheless, the biological response toward a spider silk coating cannot be generalized. The properties of spider silk coatings are influenced by many factors, including silk source, solvent, the substrate to be coated, pre- and post-treatments and the processing technique. All these factors consequently affect the biological response of the environment and the putative application of the appropriate silk coating. Here, we summarize recently identified factors to be considered before spider silk processing as well as physicochemical characterization methods. Furthermore, we highlight important results of biological evaluations to emphasize the importance of adjustability and adaption to a specific application. Finally, we provide an experimental matrix of parameters to be considered for a specific application and a guided biological response as exemplarily tested with two different fibroblast cell lines.
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Affiliation(s)
- Vanessa T. Trossmann
- Chair of Biomaterials, Faculty of Engineering Science, University of Bayreuth, Prof.-Rüdiger-Bormann-Straße 1, 95447 Bayreuth, Germany; (V.T.T.); (S.L.)
| | - Sarah Lentz
- Chair of Biomaterials, Faculty of Engineering Science, University of Bayreuth, Prof.-Rüdiger-Bormann-Straße 1, 95447 Bayreuth, Germany; (V.T.T.); (S.L.)
| | - Thomas Scheibel
- Chair of Biomaterials, Faculty of Engineering Science, University of Bayreuth, Prof.-Rüdiger-Bormann-Straße 1, 95447 Bayreuth, Germany; (V.T.T.); (S.L.)
- Bayreuth Center for Colloids and Interfaces (BZKG), University of Bayreuth, Universitätsstraße 30, 95440 Bayreuth, Germany
- Bavarian Polymer Institute (BPI), University of Bayreuth, Universitätsstraße 30, 95440 Bayreuth, Germany
- Bayreuth Center for Molecular Biosciences (BZMB), University of Bayreuth, Universitätsstraße 30, 95440 Bayreuth, Germany
- Bayreuth Materials Center (BayMAT), University of Bayreuth, Universitätsstraße 30, 95440 Bayreuth, Germany
- Faculty of Medicine, University of Würzburg, Pleicherwall 2, 97070 Würzburg, Germany
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5
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Trossmann VT, Scheibel T. Design of Recombinant Spider Silk Proteins for Cell Type Specific Binding. Adv Healthc Mater 2023; 12:e2202660. [PMID: 36565209 PMCID: PMC11468868 DOI: 10.1002/adhm.202202660] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/19/2022] [Indexed: 12/25/2022]
Abstract
Cytophilic (cell-adhesive) materials are very important for tissue engineering and regenerative medicine. However, for engineering hierarchically organized tissue structures comprising different cell types, cell-specific attachment and guidance are decisive. In this context, materials made of recombinant spider silk proteins are promising scaffolds, since they exhibit high biocompatibility, biodegradability, and the underlying proteins can be genetically functionalized. Here, previously established spider silk variants based on the engineered Araneus diadematus fibroin 4 (eADF4(C16)) are genetically modified with cell adhesive peptide sequences from extracellular matrix proteins, including IKVAV, YIGSR, QHREDGS, and KGD. Interestingly, eADF4(C16)-KGD as one of 18 tested variants is cell-selective for C2C12 mouse myoblasts, one out of 11 tested cell lines. Co-culturing with B50 rat neuronal cells confirms the cell-specificity of eADF4(C16)-KGD material surfaces for C2C12 mouse myoblast adhesion.
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Affiliation(s)
- Vanessa Tanja Trossmann
- Chair of BiomaterialsEngineering FacultyUniversity of BayreuthProf.‐Rüdiger‐Bormann‐Straße 195447BayreuthGermany
| | - Thomas Scheibel
- Chair of BiomaterialsEngineering FacultyUniversity of BayreuthProf.‐Rüdiger‐Bormann‐Straße 195447BayreuthGermany
- Bayreuth Center for Colloids and Interfaces (BZKG)Bavarian Polymer Institute (BPI)Bayreuth Center for Molecular Biosciences (BZMB)Bayreuth Center for Material Science (BayMAT)University of BayreuthUniversitätsstraße 3095447BayreuthGermany
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6
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Bargel H, Trossmann VT, Sommer C, Scheibel T. Bioselectivity of silk protein-based materials and their bio-inspired applications. BEILSTEIN JOURNAL OF NANOTECHNOLOGY 2022; 13:902-921. [PMID: 36127898 PMCID: PMC9475208 DOI: 10.3762/bjnano.13.81] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 08/23/2022] [Indexed: 06/15/2023]
Abstract
Adhesion to material surfaces is crucial for almost all organisms regarding subsequent biological responses. Mammalian cell attachment to a surrounding biological matrix is essential for maintaining their survival and function concerning tissue formation. Conversely, the adhesion and presence of microbes interferes with important multicellular processes of tissue development. Therefore, tailoring bioselective, biologically active, and multifunctional materials for biomedical applications is a modern focus of biomaterial research. Engineering biomaterials that stimulate and interact with cell receptors to support binding and subsequent physiological responses of multicellular systems attracted much interest in the last years. Further to this, the increasing threat of multidrug resistance of pathogens against antibiotics to human health urgently requires new material concepts for preventing microbial infestation and biofilm formation. Thus, materials exhibiting microbial repellence or antimicrobial behaviour to reduce inflammation, while selectively enhancing regeneration in host tissues are of utmost interest. In this context, protein-based materials are interesting candidates due to their natural origin, biological activity, and structural properties. Silk materials, in particular those made of spider silk proteins and their recombinant counterparts, are characterized by extraordinary properties including excellent biocompatibility, slow biodegradation, low immunogenicity, and non-toxicity, making them ideally suited for tissue engineering and biomedical applications. Furthermore, recombinant production technologies allow for application-specific modification to develop adjustable, bioactive materials. The present review focusses on biological processes and surface interactions involved in the bioselective adhesion of mammalian cells and repellence of microbes on protein-based material surfaces. In addition, it highlights the importance of materials made of recombinant spider silk proteins, focussing on the progress regarding bioselectivity.
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Affiliation(s)
- Hendrik Bargel
- Department of Biomaterials, University of Bayreuth, Prof.-Rüdiger-Bormann-Str. 1, 95447 Bayreuth, Germany
| | - Vanessa T Trossmann
- Department of Biomaterials, University of Bayreuth, Prof.-Rüdiger-Bormann-Str. 1, 95447 Bayreuth, Germany
| | - Christoph Sommer
- Department of Biomaterials, University of Bayreuth, Prof.-Rüdiger-Bormann-Str. 1, 95447 Bayreuth, Germany
| | - Thomas Scheibel
- Department of Biomaterials, University of Bayreuth, Prof.-Rüdiger-Bormann-Str. 1, 95447 Bayreuth, Germany
- Bayreuth Center of Material Science and Engineering (BayMat), University of Bayreuth, Universitätsstr. 30, 95440 Bayreuth, Germany
- Bavarian Polymer Institute (BPI), University of Bayreuth, Universitätsstr. 30, 95440 Bayreuth, Germany
- Bayreuth Center of Colloids and Interfaces (BZKG), University of Bayreuth, Universitätsstr. 30, 95440 Bayreuth, Germany
- Bayreuth Center for Molecular Biosciences (BZMB), University of Bayreuth, Universitätsstr. 30, 95440 Bayreuth, Germany
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7
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Jiang L, Shen Y, Liu Y, Zhang L, Jiang W. Making human pancreatic islet organoids: Progresses on the cell origins, biomaterials and three-dimensional technologies. Theranostics 2022; 12:1537-1556. [PMID: 35198056 PMCID: PMC8825586 DOI: 10.7150/thno.66670] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 12/27/2021] [Indexed: 11/05/2022] Open
Abstract
Diabetes is one of the most socially challenging health concerns. Even though islet transplantation has shown promise for insulin-dependent diabetes, there is still no effective method for curing diabetes due to the severe shortage of transplantable donors. In recent years, organoid technology has attracted lots of attention as organoid can mirror the human organ in vivo to the maximum extent in vitro, thus bridging the gap between cellular- and tissue/organ-level biological models. Concurrently, human pancreatic islet organoids are expected to be a considerable source of islet transplantation. To construct human islet-like organoids, the seeding cells, biomaterials and three-dimensional structure are three key elements. Herein, this review summarizes current progresses about the cell origins, biomaterials and advanced technology being applied to make human islet organoids, and discusses the advantages, shortcomings, and future challenges of them as well. We hope this review can offer a cross-disciplinary perspective to build human islet organoids and provide insights for tissue engineering and regenerative medicine.
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Affiliation(s)
- Lai Jiang
- Department of Biological Repositories, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Yiru Shen
- College of Life Sciences, Wuhan University, Wuhan 430071, China
| | - Yajing Liu
- Asia Regenerative Medicine Ltd., Shenzhen 518110, China
| | - Lei Zhang
- Asia Regenerative Medicine Ltd., Shenzhen 518110, China
| | - Wei Jiang
- Department of Biological Repositories, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Human Genetics Resource Preservation Center of Wuhan University, Wuhan 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China
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8
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Kharbikar BN, Chendke GS, Desai TA. Modulating the foreign body response of implants for diabetes treatment. Adv Drug Deliv Rev 2021; 174:87-113. [PMID: 33484736 PMCID: PMC8217111 DOI: 10.1016/j.addr.2021.01.011] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/30/2020] [Accepted: 01/10/2021] [Indexed: 02/06/2023]
Abstract
Diabetes Mellitus is a group of diseases characterized by high blood glucose levels due to patients' inability to produce sufficient insulin. Current interventions often require implants that can detect and correct high blood glucose levels with minimal patient intervention. However, these implantable technologies have not reached their full potential in vivo due to the foreign body response and subsequent development of fibrosis. Therefore, for long-term function of implants, modulating the initial immune response is crucial in preventing the activation and progression of the immune cascade. This review discusses the different molecular mechanisms and cellular interactions involved in the activation and progression of foreign body response (FBR) and fibrosis, specifically for implants used in diabetes. We also highlight the various strategies and techniques that have been used for immunomodulation and prevention of fibrosis. We investigate how these general strategies have been applied to implants used for the treatment of diabetes, offering insights on how these devices can be further modified to circumvent FBR and fibrosis.
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Affiliation(s)
- Bhushan N Kharbikar
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Gauree S Chendke
- University of California Berkeley - University of California San Francisco Graduate Program in Bioengineering, San Francisco, CA 94143, USA
| | - Tejal A Desai
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; University of California Berkeley - University of California San Francisco Graduate Program in Bioengineering, San Francisco, CA 94143, USA; Department of Bioengineering, University of California, Berkeley, CA 94720, USA.
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9
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Withanage S, Savin A, Nikolaeva V, Kiseleva A, Dukhinova M, Krivoshapkin P, Krivoshapkina E. Native Spider Silk-Based Antimicrobial Hydrogels for Biomedical Applications. Polymers (Basel) 2021; 13:1796. [PMID: 34072375 PMCID: PMC8198725 DOI: 10.3390/polym13111796] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/25/2021] [Accepted: 05/27/2021] [Indexed: 01/25/2023] Open
Abstract
Novel antimicrobial natural polymeric hybrid hydrogels based on hyaluronic acid (HA) and spider silk (Ss) were prepared using the chemical crosslinking method. The effects of the component ratios on the hydrogel characteristics were observed parallel to the primary physicochemical characterization of the hydrogels with scanning electron microscopic imaging, Fourier-transform infrared spectroscopy, and contact angle measurements, which confirmed the successful crosslinking, regular porous structure, exact composition, and hydrophilic properties of hyaluronic acid/spider silk-based hydrogels. Further characterizations of the hydrogels were performed with the swelling degree, enzymatic degradability, viscosity, conductivity, and shrinking ability tests. The hyaluronic acid/spider silk-based hydrogels do not show drastic cytotoxicity over human postnatal fibroblasts (HPF). Hydrogels show extraordinary antimicrobial ability on both gram-negative and gram-positive bacteria. These hydrogels could be an excellent alternative that aids in overcoming antimicrobial drug resistance, which is considered to be one of the major global problems in the biomedical industry. Hyaluronic acid/spider silk-based hydrogels are a promising material for collaborated antimicrobial and anti-inflammatory drug delivery systems for external use. The rheological properties of the hydrogels show shear-thinning properties, which suggest that the hydrogels could be applied in 3D printing, such as in the 3D printing of antimicrobial surgical meshes.
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Affiliation(s)
| | | | | | | | | | | | - Elena Krivoshapkina
- SCAMT Institute, ITMO University, Lomonosova str. 9, 191002 Saint Petersburg, Russia; (S.W.); (A.S.); (V.N.); (A.K.); (M.D.); (P.K.)
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10
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Laporte C, Tubbs E, Pierron M, Gallego A, Moisan A, Lamarche F, Lozano T, Hernandez A, Cottet-Rousselle C, Gauchez AS, Persoons V, Bottausci F, Fontelaye C, Boizot F, Lablanche S, Rivera F. Improved human islets’ viability and functionality with mesenchymal stem cells and arg-gly-asp tripeptides supplementation of alginate micro-encapsulated islets in vitro. Biochem Biophys Res Commun 2020; 528:650-657. [DOI: 10.1016/j.bbrc.2020.05.107] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 05/15/2020] [Indexed: 12/19/2022]
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11
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Pancreatic islets seeded in a novel bioscaffold forms an organoid to rescue insulin production and reverse hyperglycemia in models of type 1 diabetes. Sci Rep 2020; 10:4362. [PMID: 32152396 PMCID: PMC7062832 DOI: 10.1038/s41598-020-60947-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 02/11/2020] [Indexed: 01/10/2023] Open
Abstract
Therapeutic approaches to combat type 1 diabetes (T1D) include donor pancreas transplantation, exogenous insulin administration and immunosuppressive therapies. However, these clinical applications are limited due to insufficient tissue compatible donors, side effects of exogenous insulin administration and/or increased onset of opportunistic infections attributable to induced global immunosuppression. An alternative approach to alleviate disease states is to utilize insulin-producing pancreatic islets seeded in a bioscaffold for implantation into diabetic recipients. The present studies now report that a newly developed cationic polymer biomaterial serves as an efficient bioscaffold for delivery of donor syngeneic pancreatic islet cells to reverse hyperglycemia in murine streptozotocin induced- or non-obese diabetic mouse models of T1D. Intraperitoneal implantation of pancreatic islets seeded within the copolymer bioscaffold supports long-term cell viability, response to extracellular signaling cues and ability to produce soluble factors into the microenvironment. Elevated insulin levels were measured in recipient diabetic mice upon implantation of the islet-seeded biomaterial coupled with reduced blood glucose levels, collectively resulting in increased survival and stabilization of metabolic indices. Importantly, the implanted islet-seeded biomaterial assembled into a solid organoid substructure that reorganized the extracellular matrix compartment and recruited endothelial progenitors for neovascularization. This allowed survival of the graft long-term in vivo and access to the blood for monitoring glucose levels. These results highlight the novelty, simplicity and effectiveness of this biomaterial for tissue regeneration and in vivo restoration of organ functions.
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12
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Johansson U, Shalaly ND, Hjelm LC, Ria M, Berggren PO, Hedhammar M. Integration of Primary Endocrine Cells and Supportive Cells Using Functionalized Silk Promotes the Formation of Prevascularized Islet-like Clusters. ACS Biomater Sci Eng 2020; 6:1186-1195. [PMID: 33464872 DOI: 10.1021/acsbiomaterials.9b01573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Pancreatic islet transplantation has not yet succeeded as an overall treatment for type 1 diabetes because of limited access to donor islets, as well as low efficacy and poor reproducibility of the current procedure. Herein, a method to create islets-like composite clusters (coclusters) from dispersed endocrine cells and supportive cells is described, attempting to improve compatibility with the recipient and more efficiently make use of the donor-derived material. To mimic the extracellular matrix environment, recombinant spider silk functionalized with cell binding motifs are used as 3D support for the coclusters. A cell binding motif derived from fibronectin (FN) was found superior in promoting cell adherence, while a plain RGD-motif incorporated in the repetitive part of the silk protein (2R) increased the mobility and cluster formation of endocrine cells. Self-assembly of a mixture of FN/2R silk is utilized to integrate endocrine cells together with endothelial and mesenchymal cells into islet-like coclusters. Both xenogenic and allogenic versions of these coclusters were found to be viable and were able to respond to dynamic glucose stimulation with insulin release. Moreover, the endothelial cells were found to be colocalized with the endocrine cells, showing that the silk combined with supportive cells may promote vascularization. This method to engineer combined islet-like coclusters allows donor-derived endocrine cells to be surrounded by supportive cells from the recipient, which have the potential to further promote engraftment in the host and considerably reduce risk of rejection.
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Affiliation(s)
- Ulrika Johansson
- Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, SE-106 91 Stockholm, Sweden.,Linnæus Center of Biomaterials Chemistry, Linnæus University, Kalmar, Sweden.,Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Nancy Dekki Shalaly
- Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, SE-106 91 Stockholm, Sweden
| | - Linnea Charlotta Hjelm
- Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, SE-106 91 Stockholm, Sweden
| | - Massimiliano Ria
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, S-17176 Stockholm, Sweden
| | - Per-Olof Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, S-17176 Stockholm, Sweden
| | - My Hedhammar
- Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, SE-106 91 Stockholm, Sweden
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13
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Peng CA, Kozubowski L, Marcotte WR. Advances in Plant-Derived Scaffold Proteins. FRONTIERS IN PLANT SCIENCE 2020; 11:122. [PMID: 32161608 PMCID: PMC7052361 DOI: 10.3389/fpls.2020.00122] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 01/27/2020] [Indexed: 05/13/2023]
Abstract
Scaffold proteins form critical biomatrices that support cell adhesion and proliferation for regenerative medicine and drug screening. The increasing demand for such applications urges solutions for cost effective and sustainable supplies of hypoallergenic and biocompatible scaffold proteins. Here, we summarize recent efforts in obtaining plant-derived biosynthetic spider silk analogue and the extracellular matrix protein, collagen. Both proteins are composed of a large number of tandem block repeats, which makes production in bacterial hosts challenging. Furthermore, post-translational modification of collagen is essential for its function which requires co-transformation of multiple copies of human prolyl 4-hydroxylase. We discuss our perspectives on how the GAANTRY system could potentially assist the production of native-sized spider dragline silk proteins and prolyl hydroxylated collagen. The potential of recombinant scaffold proteins in drug delivery and drug discovery is also addressed.
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14
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Nilebäck L, Widhe M, Seijsing J, Bysell H, Sharma PK, Hedhammar M. Bioactive Silk Coatings Reduce the Adhesion of Staphylococcus aureus while Supporting Growth of Osteoblast-like Cells. ACS APPLIED MATERIALS & INTERFACES 2019; 11:24999-25007. [PMID: 31241302 DOI: 10.1021/acsami.9b05531] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Orthopedic and dental implants are associated with a substantial risk of failure due to biomaterial-associated infections and poor osseointegration. To prevent such outcomes, a coating can be applied on the implant to ideally both reduce the risk of bacterial adhesion and support establishment of osteoblasts. We present a strategy to construct dual-functional silk coatings with such properties. Silk coatings were made from a recombinant partial spider silk protein either alone (silkwt) or fused with a cell-binding motif derived from fibronectin (FN-silk). The biofilm-dispersal enzyme Dispersin B (DspB) and two peptidoglycan degrading endolysins, PlySs2 and SAL-1, were produced recombinantly. A sortase recognition tag (SrtTag) was included to allow site-specific conjugation of each enzyme onto silkwt and FN-silk coatings using an engineered variant of the transpeptidase Sortase A (SrtA*). To evaluate bacterial adhesion on the samples, Staphylococcus aureus was incubated on the coatings and subsequently subjected to live/dead staining. Fluorescence microscopy revealed a reduced number of bacteria on all silk coatings containing enzymes. Moreover, the bacteria were mobile to a higher degree, indicating a negative influence on the bacterial adhesion. The capability to support mammalian cell interactions was assessed by cultivation of the osteosarcoma cell line U-2 OS on dual-functional surfaces, prepared by conjugating the enzymes onto FN-silk coatings. U-2 OS cells could adhere to silk coatings with enzymes and showed high spreading and viability, demonstrating good cell compatibility.
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Affiliation(s)
- Linnea Nilebäck
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health , AlbaNova University Center, KTH Royal Institute of Technology , SE-106 91 Stockholm , Sweden
| | - Mona Widhe
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health , AlbaNova University Center, KTH Royal Institute of Technology , SE-106 91 Stockholm , Sweden
| | - Johan Seijsing
- Department of Molecular Biosciences, The Wenner-Gren Institute , Stockholm University , SE-106 91 Stockholm , Sweden
| | - Helena Bysell
- RISE Research Institutes of Sweden , SE-11486 Stockholm , Sweden
| | - Prashant K Sharma
- Department of Biomedical Engineering , University of Groningen and University Medical Center of Groningen , NL-9713AV Groningen , The Netherlands
| | - My Hedhammar
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health , AlbaNova University Center, KTH Royal Institute of Technology , SE-106 91 Stockholm , Sweden
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16
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Xu L, Guo Y, Huang Y, Xu Y, Lu Y, Wang Z. Hydrogel materials for the application of islet transplantation. J Biomater Appl 2019; 33:1252-1264. [PMID: 30791850 DOI: 10.1177/0885328219831391] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Type 1 diabetes mellitus is a serious disease comprising approximately 10% of all diabetes cases, and the global incidence of type 1 diabetes mellitus is steadily rising without any promise of a cure in the near future. Although islet transplantation has proven to be an effective means of treating type 1 diabetes mellitus and promoting insulin independence in patients, its widespread implementation has been severely constrained by instances of post-transplantation islet cell death, rejection, and severe adverse immune responses. Islet encapsulation is an active area of research aimed at shielding implanted islets from immunological rejection and inflammation while still allowing for effective insulin and nutrient exchange with donor cells. Given their promising physical and chemical properties, hydrogels have been a major subject of focus in the field of islet transplantation and encapsulation technology, offering promising advances towards immunologically privileged islet implants. The present review therefore summarizes the current state of research regarding the use of hydrogels in the context of islet transplantation, including both natural molecular hydrogels and artificial polymer hydrogels, with the goal of understanding the current strengths and weaknesses of this treatment strategy.
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Affiliation(s)
- Liancheng Xu
- Suqian First Hospital, Suqian, Jiangsu, China
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Yibing Guo
- Research center of clinical medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Yan Huang
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- Research center of clinical medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Yang Xu
- Research center of clinical medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Yuhua Lu
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- Research center of clinical medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Zhiwei Wang
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
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Abstract
Diabetes develops due to deficient functional β cell mass, insulin resistance, or both. Yet, various challenges in understanding the mechanisms underlying diabetes development in vivo remain to be overcome owing to the lack of appropriate intravital imaging technologies. To meet these challenges, we have exploited the anterior chamber of the eye (ACE) as a novel imaging site to understand diabetes basics and clinics in vivo. We have developed a technology platform transplanting pancreatic islets into the ACE where they later on can be imaged non-invasively for long time. It turns out that the ACE serves as an optimal imaging site and provides implanted islets with an oxygen-rich milieu and an immune-privileged niche where they undergo optimal engraftment, rich vascularization and dense innervation, preserve organotypic features and live with satisfactory viability and functionality. The ACE technology has led to a series of significant observations. It enables in vivo microscopy of islet cytoarchitecture, function and viability in the physiological context and intravital imaging of a variety of pathological events such as autoimmune insulitis, defects in β cell function and mass and insulin resistance during diabetes development in a real-time manner. Furthermore, application of the ACE technology in humanized mice and non-human primates verifies translational and clinical values of the technology. In this article, we describe the ACE technology in detail, review accumulated knowledge gained by means of the ACE technology and delineate prospective avenues for the ACE technology.
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18
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Kumar M, Gupta P, Bhattacharjee S, Nandi SK, Mandal BB. Immunomodulatory injectable silk hydrogels maintaining functional islets and promoting anti-inflammatory M2 macrophage polarization. Biomaterials 2018; 187:1-17. [DOI: 10.1016/j.biomaterials.2018.09.037] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/28/2018] [Accepted: 09/23/2018] [Indexed: 02/08/2023]
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Magaz A, Faroni A, Gough JE, Reid AJ, Li X, Blaker JJ. Bioactive Silk-Based Nerve Guidance Conduits for Augmenting Peripheral Nerve Repair. Adv Healthc Mater 2018; 7:e1800308. [PMID: 30260575 DOI: 10.1002/adhm.201800308] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 05/22/2018] [Indexed: 02/03/2023]
Abstract
Repair of peripheral nerve injuries depends upon complex biology stemming from the manifold and challenging injury-healing processes of the peripheral nervous system. While surgical treatment options are available, they tend to be characterized by poor clinical outcomes for the injured patients. This is particularly apparent in the clinical management of a nerve gap whereby nerve autograft remains the best clinical option despite numerous limitations; in addition, effective repair becomes progressively more difficult with larger gaps. Nerve conduit strategies based on tissue engineering approaches and the use of silk as scaffolding material have attracted much attention in recent years to overcome these limitations and meet the clinical demand of large gap nerve repair. This review examines the scientific advances made with silk-based conduits for peripheral nerve repair. The focus is on enhancing bioactivity of the conduits in terms of physical guidance cues, inner wall and lumen modification, and imbuing novel conductive functionalities.
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Affiliation(s)
- Adrián Magaz
- Bio‐Active Materials GroupSchool of MaterialsMSS TowerThe University of Manchester Manchester M13 9PL UK
- Institute of Materials Research and Engineering (IMRE)Agency for Science Technology and Research (A*STAR) 2 Fusionopolis, Way, Innovis #08‐03 Singapore 138634 Singapore
| | - Alessandro Faroni
- Blond McIndoe LaboratoriesDivision of Cell Matrix Biology and Regenerative MedicineSchool of Biological SciencesFaculty of Biology, Medicine and HealthThe University of ManchesterManchester Academic Health Science Centre Manchester M13 9PL UK
| | - Julie E. Gough
- School of MaterialsThe University of Manchester Manchester M13 9PL UK
| | - Adam J. Reid
- Blond McIndoe LaboratoriesDivision of Cell Matrix Biology and Regenerative MedicineSchool of Biological SciencesFaculty of Biology, Medicine and HealthThe University of ManchesterManchester Academic Health Science Centre Manchester M13 9PL UK
- Department of Plastic Surgery and BurnsWythenshawe HospitalManchester University NHS Foundation TrustManchester Academic Health Science Centre Manchester M23 9LT UK
| | - Xu Li
- Institute of Materials Research and Engineering (IMRE)Agency for Science Technology and Research (A*STAR) 2 Fusionopolis, Way, Innovis #08‐03 Singapore 138634 Singapore
| | - Jonny J. Blaker
- Bio‐Active Materials GroupSchool of MaterialsMSS TowerThe University of Manchester Manchester M13 9PL UK
- School of MaterialsThe University of Manchester Manchester M13 9PL UK
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20
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Tran SH, Wilson CG, Seib FP. A Review of the Emerging Role of Silk for the Treatment of the Eye. Pharm Res 2018; 35:248. [PMID: 30397820 PMCID: PMC6223815 DOI: 10.1007/s11095-018-2534-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 10/23/2018] [Indexed: 12/12/2022]
Abstract
Silk is a remarkable biopolymer with a long history of medical use. Silk fabrications have a robust track record for load-bearing applications, including surgical threads and meshes, which are clinically approved for use in humans. The progression of top-down and bottom-up engineering approaches using silk as the basis of a drug delivery or cell-loaded matrix helped to re-ignite interest in this ancient material. This review comprehensively summarises the current applications of silk for tissue engineering and drug delivery, with specific reference to the eye. Additionally, the review also covers emerging trends for the use of silk as a biologically active biopolymer for the treatment of eye disorders. The review concludes with future capabilities of silk to contribute to advanced, electronically-enhanced ocular drug delivery concepts.
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Affiliation(s)
- Simon H Tran
- 37D Biosystems, Inc., 2372 Morse Avenue, Suite 433, Irvine, California, 92614, USA
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, UK
| | - Clive G Wilson
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, UK
| | - F Philipp Seib
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, UK.
- Max Bergmann Center of Biomaterials Dresden, Leibniz Institute of Polymer Research Dresden, Hohe Strasse 6, 01069, Dresden, Germany.
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21
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Gharravi AM, Jafar A, Ebrahimi M, Mahmodi A, Pourhashemi E, Haseli N, Talaie N, Hajiasgarli P. Current status of stem cell therapy, scaffolds for the treatment of diabetes mellitus. Diabetes Metab Syndr 2018; 12:1133-1139. [PMID: 30168429 DOI: 10.1016/j.dsx.2018.06.021] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 06/25/2018] [Indexed: 12/24/2022]
Abstract
Diabetes mellitus (DM) remains the 7th leading cause of death in the world. Daily insulin injection is one component of a treatment plan for people with Diabetes mellitus type 1 (T1DM) that restores normal or near-normal blood sugar levels. However, Insulin treatment depends upon a variety of individual factors and leads to poor and drastic glycemic control. The need for an effective cell replacement strategy will be the aim of future clinical trials. Therefore, the aim of this systematic review is to outline the latest advances in scaffolding and stem cell therapy as a non-pharmacologic treatment for T1DM. It also emphasizes on some pancreas differentiation protocols and the clinical trials associated with stem cell therapy regarding T1DM in vitro and in vivo.
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Affiliation(s)
- Anneh Mohammad Gharravi
- Stem Cells and Tissue Engineering Research Center, Shahroud University of Medical Sciences, Shahroud, Iran.
| | - Alireza Jafar
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Mehrdad Ebrahimi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Ahmad Mahmodi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Erfan Pourhashemi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Nasrin Haseli
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Niloofar Talaie
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Parinaz Hajiasgarli
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
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22
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Liebsch C, Bucan V, Menger B, Köhne F, Waldmann KH, Vaslaitis D, Vogt PM, Strauss S, Kuhbier JW. Preliminary investigations of spider silk in wounds in vivo — Implications for an innovative wound dressing. Burns 2018; 44:1829-1838. [DOI: 10.1016/j.burns.2018.03.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 03/13/2018] [Accepted: 03/22/2018] [Indexed: 12/20/2022]
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23
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Perez-Basterrechea M, Esteban MM, Vega JA, Obaya AJ. Tissue-engineering approaches in pancreatic islet transplantation. Biotechnol Bioeng 2018; 115:3009-3029. [PMID: 30144310 DOI: 10.1002/bit.26821] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/08/2018] [Accepted: 08/14/2018] [Indexed: 12/15/2022]
Abstract
Pancreatic islet transplantation is a promising alternative to whole-pancreas transplantation as a treatment of type 1 diabetes mellitus. This technique has been extensively developed during the past few years, with the main purpose of minimizing the complications arising from the standard protocols used in organ transplantation. By using a variety of strategies used in tissue engineering and regenerative medicine, pancreatic islets have been successfully introduced in host patients with different outcomes in terms of islet survival and functionality, as well as the desired normoglycemic control. Here, we describe and discuss those strategies to transplant islets together with different scaffolds, in combination with various cell types and diffusible factors, and always with the aim of reducing host immune response and achieving islet survival, regardless of the site of transplantation.
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Affiliation(s)
- Marcos Perez-Basterrechea
- Unidad de Terapia Celular y Medicina Regenerativa, Servicio de Hematología y Hemoterapia, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.,Plataforma de Terapias Avanzadas, Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Manuel M Esteban
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
| | - Jose A Vega
- Departamento de Morfología y Biología Celular, Universidad de Oviedo, Oviedo, Spain.,Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - Alvaro J Obaya
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
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24
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Thatikonda N, Nilebäck L, Kempe A, Widhe M, Hedhammar M. Bioactivation of Spider Silk with Basic Fibroblast Growth Factor for in Vitro Cell Culture: A Step toward Creation of Artificial ECM. ACS Biomater Sci Eng 2018; 4:3384-3396. [DOI: 10.1021/acsbiomaterials.8b00844] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Naresh Thatikonda
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, 114 28, Sweden
| | - Linnea Nilebäck
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, 114 28, Sweden
| | - Adam Kempe
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, 114 28, Sweden
| | - Mona Widhe
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, 114 28, Sweden
| | - My Hedhammar
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, 114 28, Sweden
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25
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Chouhan D, Thatikonda N, Nilebäck L, Widhe M, Hedhammar M, Mandal BB. Recombinant Spider Silk Functionalized Silkworm Silk Matrices as Potential Bioactive Wound Dressings and Skin Grafts. ACS APPLIED MATERIALS & INTERFACES 2018; 10:23560-23572. [PMID: 29940099 DOI: 10.1021/acsami.8b05853] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Silk is considered to be a potential biomaterial for a wide number of biomedical applications. Silk fibroin (SF) can be retrieved in sufficient quantities from the cocoons produced by silkworms. While it is easy to formulate into scaffolds with favorable mechanical properties, the natural SF does not contain bioactive functions. Spider silk proteins, on the contrary, can be produced in fusion with bioactive protein domains, but the recombinant procedures are expensive, and large-scale production is challenging. We combine the two types of silk to fabricate affordable, functional tissue-engineered constructs for wound-healing applications. Nanofibrous mats and microporous scaffolds made of natural silkworm SF are used as a bulk material that are top-coated with the recombinant spider silk protein (4RepCT) in fusion with a cell-binding motif, antimicrobial peptides, and a growth factor. For this, the inherent silk properties are utilized to form interactions between the two silk types by self-assembly. The intended function, that is, improved cell adhesion, antimicrobial activity, and growth factor stimulation, could be demonstrated for the obtained functionalized silk mats. As a skin prototype, SF scaffolds coated with functionalized silk are cocultured with multiple cell types to demonstrate formation of a bilayered tissue construct with a keratinized epidermal layer under in vitro conditions. The encouraging results support this strategy of fabrication of an affordable bioactive SF-spider silk-based biomaterial for wound dressings and skin substitutes.
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Affiliation(s)
- Dimple Chouhan
- Biomaterial and Tissue Engineering Laboratory, Department of Biosciences and Bioengineering , Indian Institute of Technology Guwahati , Guwahati 781039 , Assam , India
| | - Naresh Thatikonda
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health , KTH Royal Institute of Technology, AlbaNova University Center , 106 91 Stockholm , Sweden
| | - Linnea Nilebäck
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health , KTH Royal Institute of Technology, AlbaNova University Center , 106 91 Stockholm , Sweden
| | - Mona Widhe
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health , KTH Royal Institute of Technology, AlbaNova University Center , 106 91 Stockholm , Sweden
| | - My Hedhammar
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health , KTH Royal Institute of Technology, AlbaNova University Center , 106 91 Stockholm , Sweden
| | - Biman B Mandal
- Biomaterial and Tissue Engineering Laboratory, Department of Biosciences and Bioengineering , Indian Institute of Technology Guwahati , Guwahati 781039 , Assam , India
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Aigner TB, DeSimone E, Scheibel T. Biomedical Applications of Recombinant Silk-Based Materials. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2018; 30:e1704636. [PMID: 29436028 DOI: 10.1002/adma.201704636] [Citation(s) in RCA: 183] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 10/26/2017] [Indexed: 05/18/2023]
Abstract
Silk is mostly known as a luxurious textile, which originates from silkworms first cultivated in China. A deeper look into the variety of silk reveals that it can be used for much more, in nature and by humanity. For medical purposes, natural silks were recognized early as a potential biomaterial for surgical threads or wound dressings; however, as biomedical engineering advances, the demand for high-performance, naturally derived biomaterials becomes more pressing and stringent. A common problem of natural materials is their large batch-to-batch variation, the quantity available, their potentially high immunogenicity, and their fast biodegradation. Some of these common problems also apply to silk; therefore, recombinant approaches for producing silk proteins have been developed. There are several research groups which study and utilize various recombinantly produced silk proteins, and many of these have also investigated their products for biomedical applications. This review gives a critical overview over of the results for applications of recombinant silk proteins in biomedical engineering.
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Affiliation(s)
| | - Elise DeSimone
- University Bayreuth, Lehrstuhl Biomaterialien, Universitätsstr. 30, 95447, Bayreuth, Germany
| | - Thomas Scheibel
- Bayreuther Zentrum für Kolloide und Grenzflächen (BZKG), Bayreuther Zentrum für Bio-Makromoleküle (bio-mac), Bayreuther Zentrum für Molekulare Biowissenschaften (BZMB), Bayreuther Materialzentrum (BayMAT), Bayerisches Polymerinstitut (BPI), University Bayreuth, Universitätsstr. 30, 95447, Bayreuth, Germany
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Shih H, Liu HY, Lin CC. Improving gelation efficiency and cytocompatibility of visible light polymerized thiol-norbornene hydrogels via addition of soluble tyrosine. Biomater Sci 2018; 5:589-599. [PMID: 28174779 DOI: 10.1039/c6bm00778c] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hydrogels immobilized with biomimetic peptides have been used widely for tissue engineering and drug delivery applications. Photopolymerization has been among the most commonly used techniques to fabricate peptide-immobilized hydrogels as it offers rapid and robust peptide immobilization within a crosslinked hydrogel network. Both chain-growth and step-growth photopolymerizations can be used to immobilize peptides within covalently crosslinked hydrogels. A previously developed visible light mediated step-growth thiol-norbornene gelation scheme has demonstrated efficient crosslinking of hydrogels composed of an inert poly(ethylene glycol)-norbornene (PEGNB) macromer and a small molecular weight bis-thiol linker, such as dithiothreitol (DTT). Compared with conventional visible light mediated chain-polymerizations where multiple initiator components are required, step-growth photopolymerized thiol-norbornene hydrogels are more cytocompatible for the in situ encapsulation of radical sensitive cells (e.g., pancreatic β-cells). This contribution explored visible light based crosslinking of various bis-cysteine containing peptides with macromer 8-arm PEGNB to form biomimetic hydrogels suitable for in situ cell encapsulation. It was found that the addition of soluble tyrosine during polymerization not only significantly accelerated gelation, but also improved the crosslinking efficiency of PEG-peptide hydrogels as evidenced by a decreased gel point and enhanced gel modulus. In addition, soluble tyrosine drastically enhanced the cytocompatibility of the resulting PEG-peptide hydrogels, as demonstrated by in situ encapsulation and culture of pancreatic MIN6 β-cells. This visible light based thiol-norbornene crosslinking mechanism provides an attractive gelation method for preparing cytocompatible PEG-peptide hydrogels for tissue engineering applications.
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Affiliation(s)
- Han Shih
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA
| | - Hung-Yi Liu
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA
| | - Chien-Chi Lin
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA and Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA.
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Deptuch T, Dams-Kozlowska H. Silk Materials Functionalized via Genetic Engineering for Biomedical Applications. MATERIALS (BASEL, SWITZERLAND) 2017; 10:E1417. [PMID: 29231863 PMCID: PMC5744352 DOI: 10.3390/ma10121417] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 12/04/2017] [Accepted: 12/06/2017] [Indexed: 12/21/2022]
Abstract
The great mechanical properties, biocompatibility and biodegradability of silk-based materials make them applicable to the biomedical field. Genetic engineering enables the construction of synthetic equivalents of natural silks. Knowledge about the relationship between the structure and function of silk proteins enables the design of bioengineered silks that can serve as the foundation of new biomaterials. Furthermore, in order to better address the needs of modern biomedicine, genetic engineering can be used to obtain silk-based materials with new functionalities. Sequences encoding new peptides or domains can be added to the sequences encoding the silk proteins. The expression of one cDNA fragment indicates that each silk molecule is related to a functional fragment. This review summarizes the proposed genetic functionalization of silk-based materials that can be potentially useful for biomedical applications.
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Affiliation(s)
- Tomasz Deptuch
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 61-688 Poznan, Poland.
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-688 Poznan, Poland.
| | - Hanna Dams-Kozlowska
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 61-688 Poznan, Poland.
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-688 Poznan, Poland.
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29
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Dholakia S, Royston E, Quiroga I, Sinha S, Reddy S, Gilbert J, Friend PJ. The rise and potential fall of pancreas transplantation. Br Med Bull 2017; 124:171-179. [PMID: 29088319 DOI: 10.1093/bmb/ldx039] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 10/04/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND The aim of this review is to bring pancreatic transplantation out of the specialist realm, informing practitioners about this important procedure, so that they feel better equipped to refer suitable patients for transplantation and manage, counsel and support when encountering them within their own speciality. SOURCES OF DATA Narrative review conducted in May 2017. OVID interface searching EMBASE and MEDLINE databases, using Timeframe: Inception to June 1, 2017. Articles were assessed for clinical relevance and most up to date content with articles written in english as the only inclusion criteria. Other sources, used included conference proceedings/presentations, unpublished data from our institution (Oxford Transplant Centre). AREAS OF AGREEMENT Pancreas transplantation has evolved from an experimental procedure to the gold standard of care for patients with type 1 diabetes and uraemia. Currently, it remains the most effective method of establishing and maintaining euglycemia over the longer term, halting and potentially reversing many of the secondary complications associated with diabetes. Significant improvements to quality of life and better life expectancy make it in the longer term, a lifesaving procedure compared to waiting candidates. AREAS OF CONTROVERSY The future of solid organ pancreas transplantation remains uncertain, with extensive comorbidity and advances in alternative therapies makes the long-term growth of the procedure questionable. GROWING POINTS AND AREAS TIMELY FOR DEVELOPING RESEARCH Therapies to alleviate problems associated with ischaemia reperfusion injury, graft pancreatitis and more effective monitoring methods for detecting and treating organ rejection are the key areas of growth.
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Affiliation(s)
- S Dholakia
- Oxford Transplant Centre, Nuffield Department of Surgical Science, University of Oxford, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK
| | - E Royston
- Oxford Transplant Centre, Nuffield Department of Surgical Science, University of Oxford, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK
| | - I Quiroga
- Oxford Transplant Centre, Nuffield Department of Surgical Science, University of Oxford, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK
| | - S Sinha
- Oxford Transplant Centre, Nuffield Department of Surgical Science, University of Oxford, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK
| | - S Reddy
- Oxford Transplant Centre, Nuffield Department of Surgical Science, University of Oxford, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK
| | - J Gilbert
- Oxford Transplant Centre, Nuffield Department of Surgical Science, University of Oxford, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK
| | - P J Friend
- Oxford Transplant Centre, Nuffield Department of Surgical Science, University of Oxford, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK
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Nilebäck L, Hedin J, Widhe M, Floderus LS, Krona A, Bysell H, Hedhammar M. Self-Assembly of Recombinant Silk as a Strategy for Chemical-Free Formation of Bioactive Coatings: A Real-Time Study. Biomacromolecules 2017; 18:846-854. [DOI: 10.1021/acs.biomac.6b01721] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Linnea Nilebäck
- KTH Royal Institute of Technology, School of Biotechnology, AlbaNova University Center, SE-106 91 Stockholm, Sweden
| | - Jesper Hedin
- SP Technical Research Institute of Technology, SP Chemistry, Materials and Surfaces, Drottning Kristinas väg 45, SE-114 86 Stockholm, Sweden
| | - Mona Widhe
- KTH Royal Institute of Technology, School of Biotechnology, AlbaNova University Center, SE-106 91 Stockholm, Sweden
| | - Lotta S. Floderus
- KTH Royal Institute of Technology, School of Biotechnology, AlbaNova University Center, SE-106 91 Stockholm, Sweden
| | - Annika Krona
- SP Technical Research Institute of Technology, SP Food and Bioscience, Soft Materials Science, Box 5401, SE-402 29 Gothenburg, Sweden
| | - Helena Bysell
- SP Technical Research Institute of Technology, SP Chemistry, Materials and Surfaces, Drottning Kristinas väg 45, SE-114 86 Stockholm, Sweden
| | - My Hedhammar
- KTH Royal Institute of Technology, School of Biotechnology, AlbaNova University Center, SE-106 91 Stockholm, Sweden
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31
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Howell DW, Duran CL, Tsai SP, Bondos SE, Bayless KJ. Functionalization of Ultrabithorax Materials with Vascular Endothelial Growth Factor Enhances Angiogenic Activity. Biomacromolecules 2016; 17:3558-3569. [DOI: 10.1021/acs.biomac.6b01068] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- David W. Howell
- Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, College Station, Texas 77843, United States
| | - Camille L. Duran
- Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, College Station, Texas 77843, United States
| | - Shang-Pu Tsai
- Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, College Station, Texas 77843, United States
| | - Sarah E. Bondos
- Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, College Station, Texas 77843, United States
- Department
of Biochemistry and Cell Biology, Rice University, Houston, Texas 77005, United States
| | - Kayla J. Bayless
- Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, College Station, Texas 77843, United States
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Barkai U, Rotem A, de Vos P. Survival of encapsulated islets: More than a membrane story. World J Transplant 2016; 6:69-90. [PMID: 27011906 PMCID: PMC4801806 DOI: 10.5500/wjt.v6.i1.69] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/02/2015] [Accepted: 12/20/2015] [Indexed: 02/05/2023] Open
Abstract
At present, proven clinical treatments but no cures are available for diabetes, a global epidemic with a huge economic burden. Transplantation of islets of Langerhans by their infusion into vascularized organs is an experimental clinical protocol, the first approach to attain cure. However, it is associated with lifelong use of immunosuppressants. To overcome the need for immunosuppression, islets are encapsulated and separated from the host immune system by a permselective membrane. The lead material for this application is alginate which was tested in many animal models and a few clinical trials. This review discusses all aspects related to the function of transplanted encapsulated islets such as the basic requirements from a permselective membrane (e.g., allowable hydrodynamic radii, implications of the thickness of the membrane and relative electrical charge). Another aspect involves adequate oxygen supply, which is essential for survival/performance of transplanted islets, especially when using large retrievable macro-capsules implanted in poorly oxygenated sites like the subcutis. Notably, islets can survive under low oxygen tension and are physiologically active at > 40 Torr. Surprisingly, when densely crowded, islets are fully functional under hyperoxic pressure of up to 500 Torr (> 300% of atmospheric oxygen tension). The review also addresses an additional category of requirements for optimal performance of transplanted islets, named auxiliary technologies. These include control of inflammation, apoptosis, angiogenesis, and the intra-capsular environment. The review highlights that curing diabetes with a functional bio-artificial pancreas requires optimizing all of these aspects, and that significant advances have already been made in many of them.
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Llacua A, de Haan BJ, Smink SA, de Vos P. Extracellular matrix components supporting human islet function in alginate-based immunoprotective microcapsules for treatment of diabetes. J Biomed Mater Res A 2016; 104:1788-96. [PMID: 26990360 DOI: 10.1002/jbm.a.35706] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 02/16/2016] [Accepted: 03/02/2016] [Indexed: 02/06/2023]
Abstract
In the pancreas, extracellular matrix (ECM) components play an import role in providing mechanical and physiological support, and also contribute to the function of islets. These ECM-connections are damaged during islet-isolation from the pancreas and are not fully recovered after encapsulation and transplantation. To promote the functional survival of human pancreatic islets, we tested different ECMs molecules in alginate-encapsulated human islets. These were laminin derived recognition sequences, IKVAV, RGD, LRE, PDSGR, collagen I sequence DGEA (0.01 - 1.0 mM), and collagen IV (50 - 200 µg/mL). Interaction with RGD and PDSGR promoted islet viability and glucose induced insulin secretion (GIIS) when it was applied at concentrations ranging from 0.01 - 1.0 mM (p < 0.05). Also the laminin sequence LRE contributed to enhanced GIIS but only at higher concentrations of 1 mM (p < 0.05). Collagen IV also had beneficial effects but only at 50 µg/ml and no further improvement was observed at higher concentrations. IKVAV and DGEA had no effects on human islets. Synergistic effects were observed by adding Collagen(IV)-RGD, Collagen(IV)-LRE, and Collagen(IV)-PDSGR to encapsulated human islets. Our results demonstrate the potential of specific ECM components in support of functional survival of human encapsulated and free islet grafts. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1788-1796, 2016.
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Affiliation(s)
- Alberto Llacua
- Department of Pathology and Medical Biology, Immunoendocrinology, University of Groningen, Hanzeplein 1, Groningen, RB, 9700, The Netherlands
| | - Bart J de Haan
- Department of Pathology and Medical Biology, Immunoendocrinology, University of Groningen, Hanzeplein 1, Groningen, RB, 9700, The Netherlands
| | - Sandra A Smink
- Department of Pathology and Medical Biology, Immunoendocrinology, University of Groningen, Hanzeplein 1, Groningen, RB, 9700, The Netherlands
| | - Paul de Vos
- Department of Pathology and Medical Biology, Immunoendocrinology, University of Groningen, Hanzeplein 1, Groningen, RB, 9700, The Netherlands
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Shalaly ND, Ria M, Johansson U, Åvall K, Berggren PO, Hedhammar M. Silk matrices promote formation of insulin-secreting islet-like clusters. Biomaterials 2016; 90:50-61. [PMID: 26986856 DOI: 10.1016/j.biomaterials.2016.03.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 02/26/2016] [Accepted: 03/01/2016] [Indexed: 11/29/2022]
Abstract
Ex vivo expansion of endocrine cells constitutes an interesting alternative to be able to match the unmet need of transplantable pancreatic islets. However, endocrine cells become fragile once removed from their extracellular matrix (ECM) and typically become senescent and loose insulin expression during conventional 2D culture. Herein we develop a protocol where 3D silk matrices functionalized with ECM-derived motifs are used for generation of insulin-secreting islet-like clusters from mouse and human primary cells. The obtained clusters were shown to attain an islet-like spheroid shape and to maintain functional insulin release upon glucose stimulation in vitro. Furthermore, in vivo imaging of transplanted murine clusters showed engraftment with increasing vessel formation during time. There was no sign of cell death and the clusters maintained or increased in size throughout the period, thus suggesting a suitable cluster size for transplantation.
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Affiliation(s)
- Nancy Dekki Shalaly
- Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden
| | - Massimiliano Ria
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, S-17176 Stockholm, Sweden
| | - Ulrika Johansson
- Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden
| | - Karin Åvall
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, S-17176 Stockholm, Sweden
| | - Per-Olof Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, S-17176 Stockholm, Sweden
| | - My Hedhammar
- Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden; Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, S-750 07 Uppsala, Sweden.
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