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Makarczyk MJ. Cell Therapy Approaches for Articular Cartilage Regeneration. Organogenesis 2023; 19:2278235. [PMID: 37963189 PMCID: PMC10898818 DOI: 10.1080/15476278.2023.2278235] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 10/27/2023] [Indexed: 11/16/2023] Open
Abstract
Articular cartilage is a common cartilage type found in a multitude of joints throughout the human body. However, cartilage is limited in its regenerative capacity. A range of methods have been employed to aid adults under the age of 45 with cartilage defects, but other cartilage pathologies such as osteoarthritis are limited to non-steroidal anti-inflammatory drugs and total joint arthroplasty. Cell therapies and synthetic biology can be utilized to assist not only cartilage defects but have the potential as a therapeutic approach for osteoarthritis as well. In this review, we will cover current cell therapy approaches for cartilage defect regeneration with a focus on autologous chondrocyte implantation and matrix autologous chondrocyte implantation. We will then discuss the potential of stem cells for cartilage repair in osteoarthritis and the use of synthetic biology to genetically engineer cells to promote cartilage regeneration and potentially reverse osteoarthritis.
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Affiliation(s)
- Meagan J Makarczyk
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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2
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Gomes JM, Silva SS, Fernandes EM, Lobo FC, Martín-Pastor M, Taboada P, Reis RL. Silk fibroin/cholinium gallate-based architectures as therapeutic tools. Acta Biomater 2022; 147:168-184. [PMID: 35580828 DOI: 10.1016/j.actbio.2022.05.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 05/10/2022] [Accepted: 05/10/2022] [Indexed: 12/13/2022]
Abstract
The combination of natural resources with biologically active biocompatible ionic liquids (Bio-IL) is presented as a combinatorial approach for developing tools to manage inflammatory diseases. Innovative biomedical solutions were constructed combining silk fibroin (SF) and Ch[Gallate], a Bio-IL with antioxidant and anti-inflammatory features, as freeze-dried 3D-based sponges. An evaluation of the effect of the Ch[Gallate] concentration (≤3% w/v) on the SF/Ch[Gallate] sponges was studied. Structural changes observed on the sponges revealed that the Ch[Gallate] presence positively affected the β-sheet formation while not influencing the silk native structure, which was suggested by the FTIR and solid-state NMR results, respectively. Also, it was possible to modulate their mechanical properties, antioxidant activity and stability/degradation in an aqueous environment, by changing the Ch[Gallate] concentration. The architectures showed high water uptake ability and a weight loss that follows the controlled Ch[Gallate] release rate studied for 7 days. Furthermore, the sponges supported human adipose stem cells growth and proliferation, up to 7 days. TNF-α, IL-6 (pro-inflammatory) and IL-10 (anti-inflammatory) release quantification from a human monocyte cell line revealed a decrease in the pro-inflammatory cytokines concentrations in samples containing Ch[Gallate]. These outcomes encourage the use of the developed architectures as tissue engineering solutions, potentially targeting inflammation processes. STATEMENT OF SIGNIFICANCE: Combining natural resources with active biocompatible ionic liquids (Bio-IL) is herein presented as a combinatorial approach for the development of tools to manage inflammatory diseases. We propose using silk fibroin (SF), a natural protein, with cholinium gallate, a Bio-IL, with antioxidant and anti-inflammatory properties, to construct 3D-porous sponges through a sustainable methodology. The morphological features, swelling, and stability of the architectures were controlled by Bio-IL content in the matrices. The sponges were able to support human adipose stem cells growth and proliferation, and their therapeutic effect was proved by the blockage of TNF-α from activated and differentiated THP-1 monocytes. We believe that these bio-friendly and bioactive SF/Bio-IL-based sponges are effective for targeting pathologies with associated inflammatory processes.
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Huang W, Li X, Huang C, Tang Y, Zhou Q, Chen W. LncRNAs and Rheumatoid Arthritis: From Identifying Mechanisms to Clinical Investigation. Front Immunol 2022; 12:807738. [PMID: 35087527 PMCID: PMC8786719 DOI: 10.3389/fimmu.2021.807738] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/20/2021] [Indexed: 11/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is a systemic chronic autoinflammatory disease, and the synovial hyperplasia, pannus formation, articular cartilage damage and bone matrix destruction caused by immune system abnormalities are the main features of RA. The use of Disease Modifying Anti-Rheumatic Drugs (DMARDs) has achieved great advances in the therapy of RA. Yet there are still patients facing the problem of poor response to drug therapy or drug intolerance. Current therapy methods can only moderate RA progress, but cannot stop or reverse the damage it has caused. Recent studies have reported that there are a variety of long non-coding RNAs (LncRNAs) that have been implicated in mediating many aspects of RA. Understanding the mechanism of LncRNAs in RA is therefore critical for the development of new therapy strategies and prevention strategies. In this review, we systematically elucidate the biological roles and mechanisms of action of LncRNAs and their mechanisms of action in RA. Additionally, we also highlight the potential value of LncRNAs in the clinical diagnosis and therapy of RA.
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Affiliation(s)
- Wentao Huang
- Ministry of Education (MOE) Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.,Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, China
| | - Xue Li
- Ministry of Education (MOE) Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.,Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, China
| | - Chen Huang
- Department of Minimally Invasive Interventional Radiology, Guangzhou Panyu Central, Hospital, Guangzhou, China
| | - Yukuan Tang
- Department of Minimally Invasive Interventional Radiology, Guangzhou Panyu Central, Hospital, Guangzhou, China
| | - Quan Zhou
- Department of Radiology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Wenli Chen
- Ministry of Education (MOE) Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.,Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, China
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Huynh PD, Vu NB, To XHV, Le TM. Culture and Differentiation of Human Umbilical Cord-Derived Mesenchymal Stem Cells on Growth Factor-Rich Fibrin Scaffolds to Produce Engineered Cartilages. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021:193-208. [PMID: 34739721 DOI: 10.1007/5584_2021_670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION After injuries, the cartilage healing capacity is limited owing to its nature as a particular connective tissue without blood vessels, lymphatics, or nerves. The creation of artificial cartilage tissue mimics the biological properties of native cartilage and can reduce the need for donated tissue. Fibrin is a type of biodegradable scaffold that has great potential in tissue engineering applications. It can become good material for cell adhesion and proliferation in vitro. Therefore, this study aimed to create a cartilage tissue in vitro using umbilical cord-derived mesenchymal stem cells (UCMSC) and growth factor-rich fibrin (GRF) scaffolds. METHODS UCMSCs were isolated and expanded, and platelet-rich plasma (PRP) preparations were performed following previously published protocols. PRP was activated (aPRP) by a 0.45-μm syringe filter to release growth factors inside the platelets. Each 2.105 of the UCMSCs were suspended in 2 ml of aPRP to make the mixture of MSC and PRP (MSC-PRP). Then, Ca2+ solution was added to this mixture to produce the fibril scaffold with UCMSCs inside. UCMSCs' adhesion and proliferation inside the scaffold were evaluated by observation under inverted microscopy, H-E staining, MTT assays, and scanning electron microscopy (SEM). The fibril structure containing UCMSCs was cultured, and chondrogenesis was induced using commercial chondrogenesis media for 21 days (iMSC-GRF). The differentiation in efficacy toward cartilage was evaluated based on the accumulation of aggrecan (acan), glycosaminoglycans (GAGs), and collagen type II (Col II). RESULTS The results showed that we successfully created a cartilage tissue with some characteristics that mimic the properties of natural cartilage. The engineered cartilage tissue was positive with some cartilage protein, such as acan, GAG, and Coll II. In vitro cartilage presented some natural chondrocyte-like cells. The artificial cartilage tissue was positive for CD14, CD34, CD90, CD105, and HLA-DR and negative for CD44, CD45, and CD73. CONCLUSION These results showed that using UCMSCs and growth factor-rich fibril from platelet-rich plasma was feasible to produce engineered cartilage tissue for further experiments or clinical usage.
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Affiliation(s)
- Phat Duc Huynh
- Laboratory of Stem Cell Research and Application, University of Science Ho Chi Minh City, Ho Chi Minh City, Vietnam
- Vietnam National University Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Ngoc Bich Vu
- Vietnam National University Ho Chi Minh City, Ho Chi Minh City, Vietnam.
- Stem Cell Institute, University of Science Ho Chi Minh City, Ho Chi Minh City, Vietnam.
| | - Xuan Hoang-Viet To
- Vietnam National University Ho Chi Minh City, Ho Chi Minh City, Vietnam
- Stem Cell Institute, University of Science Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Thuan Minh Le
- Laboratory of Stem Cell Research and Application, University of Science Ho Chi Minh City, Ho Chi Minh City, Vietnam
- Vietnam National University Ho Chi Minh City, Ho Chi Minh City, Vietnam
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Piñeiro-Ramil M, Sanjurjo-Rodríguez C, Rodríguez-Fernández S, Castro-Viñuelas R, Hermida-Gómez T, Blanco-García FJ, Fuentes-Boquete I, Díaz-Prado S. Generation of Mesenchymal Cell Lines Derived from Aged Donors. Int J Mol Sci 2021; 22:10667. [PMID: 34639008 PMCID: PMC8508916 DOI: 10.3390/ijms221910667] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/21/2021] [Accepted: 09/29/2021] [Indexed: 02/07/2023] Open
Abstract
Background: Mesenchymal stromal cells (MSCs) have the capacity for self-renewal and multi-differentiation, and for this reason they are considered a potential cellular source in regenerative medicine of cartilage and bone. However, research on this field is impaired by the predisposition of primary MSCs to senescence during culture expansion. Therefore, the aim of this study was to generate and characterize immortalized MSC (iMSC) lines from aged donors. Methods: Primary MSCs were immortalized by transduction of simian virus 40 large T antigen (SV40LT) and human telomerase reverse transcriptase (hTERT). Proliferation, senescence, phenotype and multi-differentiation potential of the resulting iMSC lines were analyzed. Results: MSCs proliferate faster than primary MSCs, overcome senescence and are phenotypically similar to primary MSCs. Nevertheless, their multi-differentiation potential is unbalanced towards the osteogenic lineage. There are no clear differences between osteoarthritis (OA) and non-OA iMSCs in terms of proliferation, senescence, phenotype or differentiation potential. Conclusions: Primary MSCs obtained from elderly patients can be immortalized by transduction of SV40LT and hTERT. The high osteogenic potential of iMSCs converts them into an excellent cellular source to take part in in vitro models to study bone tissue engineering.
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Affiliation(s)
- María Piñeiro-Ramil
- Grupo de Investigación en Terapia Celular y Medicina Regenerativa, Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidade da Coruña (UDC), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Servizo Galego de Saúde (SERGAS), 15006 A Coruña, Spain; (M.P.-R.); (C.S.-R.); (S.R.-F.); (R.C.-V.); (I.F.-B.)
- Centro de Investigaciones Científicas Avanzadas (CICA), Universidade da Coruña, 15071 A Coruña, Spain; (T.H.-G.); (F.J.B.-G.)
| | - Clara Sanjurjo-Rodríguez
- Grupo de Investigación en Terapia Celular y Medicina Regenerativa, Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidade da Coruña (UDC), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Servizo Galego de Saúde (SERGAS), 15006 A Coruña, Spain; (M.P.-R.); (C.S.-R.); (S.R.-F.); (R.C.-V.); (I.F.-B.)
- Centro de Investigaciones Científicas Avanzadas (CICA), Universidade da Coruña, 15071 A Coruña, Spain; (T.H.-G.); (F.J.B.-G.)
- Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain
| | - Silvia Rodríguez-Fernández
- Grupo de Investigación en Terapia Celular y Medicina Regenerativa, Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidade da Coruña (UDC), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Servizo Galego de Saúde (SERGAS), 15006 A Coruña, Spain; (M.P.-R.); (C.S.-R.); (S.R.-F.); (R.C.-V.); (I.F.-B.)
- Centro de Investigaciones Científicas Avanzadas (CICA), Universidade da Coruña, 15071 A Coruña, Spain; (T.H.-G.); (F.J.B.-G.)
| | - Rocío Castro-Viñuelas
- Grupo de Investigación en Terapia Celular y Medicina Regenerativa, Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidade da Coruña (UDC), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Servizo Galego de Saúde (SERGAS), 15006 A Coruña, Spain; (M.P.-R.); (C.S.-R.); (S.R.-F.); (R.C.-V.); (I.F.-B.)
- Centro de Investigaciones Científicas Avanzadas (CICA), Universidade da Coruña, 15071 A Coruña, Spain; (T.H.-G.); (F.J.B.-G.)
| | - Tamara Hermida-Gómez
- Centro de Investigaciones Científicas Avanzadas (CICA), Universidade da Coruña, 15071 A Coruña, Spain; (T.H.-G.); (F.J.B.-G.)
- Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario da Coruña (UDC-CHUAC), Servizo Galego de Saúde (SERGAS), 15006 A Coruña, Spain
| | - Francisco J. Blanco-García
- Centro de Investigaciones Científicas Avanzadas (CICA), Universidade da Coruña, 15071 A Coruña, Spain; (T.H.-G.); (F.J.B.-G.)
- Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario da Coruña (UDC-CHUAC), Servizo Galego de Saúde (SERGAS), 15006 A Coruña, Spain
| | - Isaac Fuentes-Boquete
- Grupo de Investigación en Terapia Celular y Medicina Regenerativa, Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidade da Coruña (UDC), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Servizo Galego de Saúde (SERGAS), 15006 A Coruña, Spain; (M.P.-R.); (C.S.-R.); (S.R.-F.); (R.C.-V.); (I.F.-B.)
- Centro de Investigaciones Científicas Avanzadas (CICA), Universidade da Coruña, 15071 A Coruña, Spain; (T.H.-G.); (F.J.B.-G.)
- Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain
| | - Silvia Díaz-Prado
- Grupo de Investigación en Terapia Celular y Medicina Regenerativa, Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidade da Coruña (UDC), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Servizo Galego de Saúde (SERGAS), 15006 A Coruña, Spain; (M.P.-R.); (C.S.-R.); (S.R.-F.); (R.C.-V.); (I.F.-B.)
- Centro de Investigaciones Científicas Avanzadas (CICA), Universidade da Coruña, 15071 A Coruña, Spain; (T.H.-G.); (F.J.B.-G.)
- Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain
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Cheng L, Suresh K S, He H, Rajput RS, Feng Q, Ramesh S, Wang Y, Krishnan S, Ostrovidov S, Camci-Unal G, Ramalingam M. 3D Printing of Micro- and Nanoscale Bone Substitutes: A Review on Technical and Translational Perspectives. Int J Nanomedicine 2021; 16:4289-4319. [PMID: 34211272 PMCID: PMC8239380 DOI: 10.2147/ijn.s311001] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/17/2021] [Indexed: 12/19/2022] Open
Abstract
Recent developments in three-dimensional (3D) printing technology offer immense potential in fabricating scaffolds and implants for various biomedical applications, especially for bone repair and regeneration. As the availability of autologous bone sources and commercial products is limited and surgical methods do not help in complete regeneration, it is necessary to develop alternative approaches for repairing large segmental bone defects. The 3D printing technology can effectively integrate different types of living cells within a 3D construct made up of conventional micro- or nanoscale biomaterials to create an artificial bone graft capable of regenerating the damaged tissues. This article reviews the developments and applications of 3D printing in bone tissue engineering and highlights the numerous conventional biomaterials and nanomaterials that have been used in the production of 3D-printed scaffolds. A comprehensive overview of the 3D printing methods such as stereolithography (SLA), selective laser sintering (SLS), fused deposition modeling (FDM), and ink-jet 3D printing, and their technical and clinical applications in bone repair and regeneration has been provided. The review is expected to be useful for readers to gain an insight into the state-of-the-art of 3D printing of bone substitutes and their translational perspectives.
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Affiliation(s)
- Lijia Cheng
- School of Basic Medicine, Chengdu University, Chengdu, 610106, People’s Republic of China
| | - Shoma Suresh K
- Biomaterials and Organ Engineering Group, Centre for Biomaterials, Cellular, and Molecular Theranostics, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Hongyan He
- School of Basic Medicine, Chengdu University, Chengdu, 610106, People’s Republic of China
| | - Ritu Singh Rajput
- Biomaterials and Organ Engineering Group, Centre for Biomaterials, Cellular, and Molecular Theranostics, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Qiyang Feng
- School of Basic Medicine, Chengdu University, Chengdu, 610106, People’s Republic of China
| | - Saravanan Ramesh
- Biomaterials and Organ Engineering Group, Centre for Biomaterials, Cellular, and Molecular Theranostics, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Yuzhuang Wang
- School of Basic Medicine, Chengdu University, Chengdu, 610106, People’s Republic of China
| | - Sasirekha Krishnan
- Biomaterials and Organ Engineering Group, Centre for Biomaterials, Cellular, and Molecular Theranostics, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Serge Ostrovidov
- Department of Radiological Sciences, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Gulden Camci-Unal
- Department of Chemical Engineering, University of Massachusetts Lowell, Lowell, MA, 01854, USA
| | - Murugan Ramalingam
- Biomaterials and Organ Engineering Group, Centre for Biomaterials, Cellular, and Molecular Theranostics, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
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Monaco G, El Haj AJ, Alini M, Stoddart MJ. Ex Vivo Systems to Study Chondrogenic Differentiation and Cartilage Integration. J Funct Morphol Kinesiol 2021; 6:E6. [PMID: 33466400 PMCID: PMC7838775 DOI: 10.3390/jfmk6010006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/18/2020] [Accepted: 12/23/2020] [Indexed: 12/21/2022] Open
Abstract
Articular cartilage injury and repair is an issue of growing importance. Although common, defects of articular cartilage present a unique clinical challenge due to its poor self-healing capacity, which is largely due to its avascular nature. There is a critical need to better study and understand cellular healing mechanisms to achieve more effective therapies for cartilage regeneration. This article aims to describe the key features of cartilage which is being modelled using tissue engineered cartilage constructs and ex vivo systems. These models have been used to investigate chondrogenic differentiation and to study the mechanisms of cartilage integration into the surrounding tissue. The review highlights the key regeneration principles of articular cartilage repair in healthy and diseased joints. Using co-culture models and novel bioreactor designs, the basis of regeneration is aligned with recent efforts for optimal therapeutic interventions.
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Affiliation(s)
- Graziana Monaco
- AO Research Institute Davos, Clavadelerstrasse 8, CH-7270 Davos Platz, Switzerland; (G.M.); (M.A.)
- School of Pharmacy & Bioengineering Research, University of Keele, Keele ST5 5BG, UK;
| | - Alicia J. El Haj
- School of Pharmacy & Bioengineering Research, University of Keele, Keele ST5 5BG, UK;
- Healthcare Technology Institute, Translational Medicine, School of Chemical Engineering, University of Birmingham, Birmingham B15 2TH, UK
| | - Mauro Alini
- AO Research Institute Davos, Clavadelerstrasse 8, CH-7270 Davos Platz, Switzerland; (G.M.); (M.A.)
| | - Martin J. Stoddart
- AO Research Institute Davos, Clavadelerstrasse 8, CH-7270 Davos Platz, Switzerland; (G.M.); (M.A.)
- School of Pharmacy & Bioengineering Research, University of Keele, Keele ST5 5BG, UK;
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Shodeinde AB, Murphy AC, Oldenkamp HF, Potdar AS, Ludolph CM, Peppas NA. Recent Advances in Smart Biomaterials for the Detection and Treatment of Autoimmune Diseases. ADVANCED FUNCTIONAL MATERIALS 2020; 30:1909556. [PMID: 33071713 PMCID: PMC7566744 DOI: 10.1002/adfm.201909556] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 01/15/2020] [Indexed: 05/07/2023]
Abstract
Autoimmune diseases are a group of debilitating illnesses that are often idiopathic in nature. The steady rise in the prevalence of these conditions warrants new approaches for diagnosis and treatment. Stimuli-responsive biomaterials also known as "smart", "intelligent" or "recognitive" biomaterials are widely studied for their applications in drug delivery, biosensing and tissue engineering due to their ability to produce thermal, optical, chemical, or structural changes upon interacting with the biological environment. This critical analysis highlights studies within the last decade that harness the recognitive capabilities of these biomaterials towards the development of novel detection and treatment options for autoimmune diseases.
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Affiliation(s)
- Aaliyah B. Shodeinde
- McKetta Department of Chemical Engineering, 200 E. Dean Keeton St. Stop C0400, Austin, TX, USA, 78712
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX, USA, 78712
| | - Andrew C. Murphy
- McKetta Department of Chemical Engineering, 200 E. Dean Keeton St. Stop C0400, Austin, TX, USA, 78712
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX, USA, 78712
| | - Heidi F. Oldenkamp
- McKetta Department of Chemical Engineering, 200 E. Dean Keeton St. Stop C0400, Austin, TX, USA, 78712
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX, USA, 78712
| | - Abhishek S. Potdar
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX, USA, 78712
| | - Catherine M. Ludolph
- McKetta Department of Chemical Engineering, 200 E. Dean Keeton St. Stop C0400, Austin, TX, USA, 78712
| | - Nicholas A. Peppas
- McKetta Department of Chemical Engineering, 200 E. Dean Keeton St. Stop C0400, Austin, TX, USA, 78712
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX, USA, 78712
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX, USA, 78712
- Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, 2409 University Ave. Stop A1900, Austin, TX, USA, 78712
- Department of Surgery and Perioperative Care, Dell Medical School, 1601 Trinity St., Bldg. B, Stop Z0800, Austin, TX, USA, 78712
- Department of Pediatrics, Dell Medical School, 1400 Barbara Jordan Blvd., Austin, TX, USA, 78723
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Kerrigan SA, McInnes IB. Reflections on ‘older’ drugs: learning new lessons in rheumatology. Nat Rev Rheumatol 2020; 16:179-183. [DOI: 10.1038/s41584-020-0375-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2020] [Indexed: 12/18/2022]
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Santos Rizzo Zuttion MS, Dias Câmara DA, Dariolli R, Takimura C, Wenceslau C, Kerkis I. In vitro heterogeneity of porcine adipose tissue-derived stem cells. Tissue Cell 2019; 58:51-60. [PMID: 31133246 DOI: 10.1016/j.tice.2019.04.001] [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: 12/26/2018] [Revised: 04/01/2019] [Accepted: 04/01/2019] [Indexed: 01/27/2023]
Abstract
Tissue-specific adult stem cells (ASC) are heterogeneous and characterized by a mix of progenitor cells that produce cells at various stages of differentiation, and ultimately different terminally differentiated cells. Understanding the heterogeneity of ASCs may lead to the development of improved protocols of cell isolation and optimized cell therapy clinical protocols. Using a combination of enzymatic and explant culture protocols, we obtained pADSC population, which is composed by two distinct morphologies: fibroblast-like cells (FLCs) and endothelial-like cells (ELCs). Both cell sub-types efficiently formed colonies, expressed CD90+/CD105+/CD44+, and differentially expressed such markers such as Nestin, Vimentin, Fibronectin, Cytokeratin, Connexin 43, CD31, CD34 and CD146 as well as the pluripotent stem cell markers Oct-4, Nanog and Sox2. Mixed populations of pADSCs did not lose their multipotentiality and the cells were able to undergo osteogenic, chondrogenic, adipogenic and myogenic differentiation. Furthermore, the mixed population spontaneously formed capillary tube structures. Our findings suggest that different subpopulations can be isolated from adipose tissue and that the ADSCs need to be better evaluated using a wide panel of different markers related to cell differentiation, which is important for stem cell therapy and regenerative medicine, particularly for advanced stem cells therapies - products that are currently under investigation or even use.
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Affiliation(s)
- Marilia Sanches Santos Rizzo Zuttion
- Laboratory of Genetics, Butantan Institute, Av. Vital Brasil, 1500 - Butantã, São Paulo, SP, 05503-900, Brazil; Federal University of São Paulo, R. Sena Madureira, 1500 - Vila Clementino, São Paulo, SP, 04021-001, Brazil.
| | - Diana Aparecida Dias Câmara
- Laboratory of Genetics, Butantan Institute, Av. Vital Brasil, 1500 - Butantã, São Paulo, SP, 05503-900, Brazil; Federal University of São Paulo, R. Sena Madureira, 1500 - Vila Clementino, São Paulo, SP, 04021-001, Brazil.
| | - Rafael Dariolli
- Heart Institute (InCor), University of São Paulo Medical School, Brazil: Av. Dr. Enéas de Carvalho Aguiar, 44 - Pinheiros, São Paulo, SP, 05403-900, Brazil.
| | - Celso Takimura
- Heart Institute (InCor), University of São Paulo Medical School, Brazil: Av. Dr. Enéas de Carvalho Aguiar, 44 - Pinheiros, São Paulo, SP, 05403-900, Brazil.
| | - Cristiane Wenceslau
- Laboratory of Genetics, Butantan Institute, Av. Vital Brasil, 1500 - Butantã, São Paulo, SP, 05503-900, Brazil.
| | - Irina Kerkis
- Laboratory of Genetics, Butantan Institute, Av. Vital Brasil, 1500 - Butantã, São Paulo, SP, 05503-900, Brazil; Federal University of São Paulo, R. Sena Madureira, 1500 - Vila Clementino, São Paulo, SP, 04021-001, Brazil.
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11
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Hawsawi YM, Al-Zahrani F, Mavromatis CH, Baghdadi MA, Saggu S, Oyouni AAA. Stem Cell Applications for Treatment of Cancer and Autoimmune Diseases: Its Promises, Obstacles, and Future Perspectives. Technol Cancer Res Treat 2019; 17:1533033818806910. [PMID: 30343639 PMCID: PMC6198389 DOI: 10.1177/1533033818806910] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Since the original discovery of stem cells, a new era of promising results has emerged in the clinical application of stem cells for the treatment of several important diseases, including cancer and autoimmune diseases. The plentiful research on stem cells during the past decades has provided significant information on the developmental, morphological, and physiological processes that govern tissue and organ formation, maintenance, and regeneration; cellular differentiation; molecular processes; and tissue homeostasis. In this review, we present the history of the use of stem cells in different clinical applications. Furthermore, we discuss the various therapeutic options for stem cells in cancer, followed by the role of stem cells in the treatment of autoimmune disorders. Additionally, we highlight the risks of and obstacles to the application of stem cells in clinical practice. Ultimately, we show future perspectives in stem cell use, with an aim to improve the clinical usefulness of stem cells.
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Affiliation(s)
- Yousef M Hawsawi
- 1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia.,2 Department of Biological Sciences, Faculty of Science and Arts, King Abdulaziz University, Rabigh, Kingdom of Saudi Arabia.,3 Department of Epidemiology and Biostatistics, King Faisal Specialist Hospital and Research Center, Jeddah, Kingdom of Saudi Arabia
| | - Faisal Al-Zahrani
- 2 Department of Biological Sciences, Faculty of Science and Arts, King Abdulaziz University, Rabigh, Kingdom of Saudi Arabia
| | - Charalampos Harris Mavromatis
- 2 Department of Biological Sciences, Faculty of Science and Arts, King Abdulaziz University, Rabigh, Kingdom of Saudi Arabia
| | - Mohammed A Baghdadi
- 1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia.,3 Department of Epidemiology and Biostatistics, King Faisal Specialist Hospital and Research Center, Jeddah, Kingdom of Saudi Arabia
| | - Shalini Saggu
- 4 Department of Biology, Faculty of Sciences, University of Tabuk, Tabuk, Kingdom of Saudi Arabia
| | - Atif Abdulwahab A Oyouni
- 4 Department of Biology, Faculty of Sciences, University of Tabuk, Tabuk, Kingdom of Saudi Arabia
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12
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Miron RJ, Zhang Y. Autologous liquid platelet rich fibrin: A novel drug delivery system. Acta Biomater 2018; 75:35-51. [PMID: 29772345 DOI: 10.1016/j.actbio.2018.05.021] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 04/24/2018] [Accepted: 05/14/2018] [Indexed: 02/07/2023]
Abstract
There is currently widespread interest within the biomaterial field to locally deliver biomolecules for bone and cartilage regeneration. Substantial work to date has focused on the potential role of these biomolecules during the healing process, and the carrier system utilized is a key factor in their effectiveness. Platelet rich fibrin (PRF) is a naturally derived fibrin scaffold that is easily obtained from peripheral blood following centrifugation. Slower centrifugation speeds have led to the commercialization of a liquid formulation (liquid-PRF) resulting in an upper plasma layer composed of liquid fibrinogen/thrombin prior to clot formation that remains in its liquid phase for approximately 15 min until injected into bodily tissues. Herein, we introduce the use of liquid PRF as an advanced local delivery system for small and large biomolecules. Potential target molecules including large (growth factors/cytokines and morphogenetic/angiogenic factors), as well as small (antibiotics, peptides, gene therapy and anti-osteoporotic) molecules are considered potential candidates for enhanced bone/cartilage tissue regeneration. Furthermore, liquid-PRF is introduced as a potential carrier system for various cell types and nano-sized particles that are capable of limiting/by-passing the immune system and minimizing potential foreign body reactions within host tissues following injection. STATEMENT OF SIGNIFICANCE There is currently widespread interest within the biomaterial field to locally deliver biomolecules for bone and cartilage regeneration. This review article focuses on the use of a liquid version of platelet rich fibrin (PRF) composed of liquid fibrinogen/thrombin as a drug delivery system. Herein, we introduce the use of liquid PRF as an advanced local delivery system for small and large biomolecules including growth factors, cytokines and morphogenetic/angiogenic factors, as well as antibiotics, peptides, gene therapy and anti-osteoporotic molecules as potential candidates for enhanced bone/cartilage tissue regeneration.
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13
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Xu XL, Li WS, Wang XJ, Du YL, Kang XQ, Hu JB, Li SJ, Ying XY, You J, Du YZ. Endogenous sialic acid-engineered micelles: a multifunctional platform for on-demand methotrexate delivery and bone repair of rheumatoid arthritis. NANOSCALE 2018; 10:2923-2935. [PMID: 29369319 DOI: 10.1039/c7nr08430g] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Rheumatoid arthritis (RA) patients have suffered from the current drug therapeutic regimen because of its high toxicity and the absence of bone regeneration for existing erosion, seriously affecting the quality of life. Herein, a sialic acid-dextran-octadecanoic acid (SA-Dex-OA) conjugate was synthesized to form micelles with a 55.06 μg mL-1 critical micelle concentration. The obtained micelles can encapsulate a disease-modifying anti-rheumatic drug, methotrexate (MTX), with 4.28% (w/w) drug content, featuring sustained drug release behavior over 48 h. In vitro and in vivo studies showed that SA-Dex-OA micelles significantly improved accumulation and transportation through a combination of SA and E-selectin receptors in inflamed cells and arthritic paws highly expressing E-selectin. MTX-loaded SA-Dex-OA micelles not only significantly inhibited the inflammatory response, but also diminished the adverse effects of MTX, as reflected by the reduced alanine aminotransferase, aspartate aminotransferase, creatinine, and urea nitrogen levels. Most importantly, the bone mineral density in rats treated with MTX-loaded SA-Dex-OA micelles was significantly higher as compared to in those treated with free MTX and Dex-OA/MTX micelles (increasing from 391.4 to 417.4 to 492.7 mg cc-1), benefiting from the effects of endogenous sialic acid in promoting MC3T3-E1 cell differentiation and mineralization. It is anticipated that SA-based micelles with bone repair activities have great potential for RA treatment and other metabolic bone diseases with serious bone erosion.
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Affiliation(s)
- Xiao-Ling Xu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
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14
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Therapeutic Benefit for Late, but Not Early, Passage Mesenchymal Stem Cells on Pain Behaviour in an Animal Model of Osteoarthritis. Stem Cells Int 2017; 2017:2905104. [PMID: 29434641 PMCID: PMC5757143 DOI: 10.1155/2017/2905104] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Accepted: 09/07/2017] [Indexed: 12/29/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) have a therapeutic potential for the treatment of osteoarthritic (OA) joint pathology and pain. The aims of this study were to determine the influence of a passage number on the effects of MSCs on pain behaviour and cartilage and bone features in a rodent model of OA. Methods Rats underwent either medial meniscal transection (MNX) or sham surgery under anaesthesia. Rats received intra-articular injection of either 1.5 × 106 late passage MSCs labelled with 10 μg/ml SiMAG, 1.5 × 106 late passage mesenchymal stem cells, the steroid Kenalog (200 μg/20 μL), 1.5 × 106 early passage MSCs, or serum-free media (SFM). Sham-operated rats received intra-articular injection of SFM. Pain behaviour was quantified until day 42 postmodel induction. Magnetic resonance imaging (MRI) was used to localise the labelled cells within the knee joint. Results Late passage MSCs and Kenalog attenuated established pain behaviour in MNX rats, but did not alter MNX-induced joint pathology at the end of the study period. Early passage MSCs exacerbated MNX-induced pain behaviour for up to one week postinjection and did not alter joint pathology. Conclusion Our data demonstrate for the first time the role of a passage number in influencing the therapeutic effects of MSCs in a model of OA pain.
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15
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A three-dimensional cell culture device for simulation of hepatic hypertension. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2017; 2017:2076-2079. [PMID: 29060305 DOI: 10.1109/embc.2017.8037262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Hepatic stellate cells (HSCs) play a crucial role in the development of liver fibrosis which is characterized by massive tissue scarring, elevated hepatic sinusoidal pressure, and portal hypertension. However, while a multitude of chemical factors have been investigated in the pathogenesis of liver fibrosis, physical factors such as elevated hydrostatic pressure and shear stress caused by blood flow in sinusoids remain unclear. In this study, we developed a three-dimensional (3D) cell culture microfluidic platform that mimics the physical environments of hepatic sinusoids to investigate the effects of elevated hydrostatic pressure on HSCs phenotypes.
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16
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Leigheb M, Bosetti M, De Consoli A, Borrone A, Cannas M, Grassi F. Chondral tissue engineering of the reumatoid knee with collagen matrix autologous chondrocytes implant. ACTA BIO-MEDICA : ATENEI PARMENSIS 2017; 88:107-113. [PMID: 29083361 PMCID: PMC6357659 DOI: 10.23750/abm.v88i4-s.6801] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 10/03/2017] [Indexed: 11/23/2022]
Abstract
Articular cartilage repair is still a challenge. To date evidence is insufficient to support a treatment over the others. Inflammatory conditions in the joint hamper the application of tissue engineering during chronic joint diseases. Most of the Matrix Autologous Chondrocyte Implantation (MACI) cases reported in literature do not deal with rheumatoid knees and do not have a long clinical-histologic follow-up. We report about a 46-year old woman who suffered of a painful focal Outerbridge 4th degree chondral lesion in the medial femoral condyle of her left rheumatoid knee. The tissue defect was filled by a Cartilage Regeneration System (CaReS®) based on a type I collagen matrix seeded by autologous in vitro expanded chondrocytes. The patient was followed up to ten years clinically and by MRI, and finally treated with a Total Knee Replacement for the increasing arthritis. Histologically, the explanted MACI tissue showed an increased cellularity with an extracellular matrix rich of collagen and glycosaminoglicanes even though the overall architecture was different from the normal cartilage pattern. The case reported suggests that the main goal of treatment for chondropathy is the long lasting control of symptoms, while permanent restoration of normal anatomy is still impossible. Mesenchymal stem cells, that develop into joint tissues, show immunosuppressive and anti-inflammatory qualities, in vitro and in vivo, indicating a potential role for tissue engineering approaches in the treatment of rheumatic diseases.
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17
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Leigheb M, Bosetti M, De Consoli A, Borrone A, Cannas M, Grassi F. Chondral tissue engineering of the reumatoid knee with collagen matrix autologous chondrocytes implant. ACTA BIO-MEDICA : ATENEI PARMENSIS 2017; 88:107-113. [PMID: 29083361 DOI: 10.23750/abm.v88i4 -s.6801] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 10/03/2017] [Indexed: 11/23/2022]
Abstract
Articular cartilage repair is still a challenge. To date evidence is insufficient to support a treatment over the others. Inflammatory conditions in the joint hamper the application of tissue engineering during chronic joint diseases. Most of the Matrix Autologous Chondrocyte Implantation (MACI) cases reported in literature do not deal with rheumatoid knees and do not have a long clinical-histologic follow-up. We report about a 46-year old woman who suffered of a painful focal Outerbridge 4th degree chondral lesion in the medial femoral condyle of her left rheumatoid knee. The tissue defect was filled by a Cartilage Regeneration System (CaReS®) based on a type I collagen matrix seeded by autologous in vitro expanded chondrocytes. The patient was followed up to ten years clinically and by MRI, and finally treated with a Total Knee Replacement for the increasing arthritis. Histologically, the explanted MACI tissue showed an increased cellularity with an extracellular matrix rich of collagen and glycosaminoglicanes even though the overall architecture was different from the normal cartilage pattern. The case reported suggests that the main goal of treatment for chondropathy is the long lasting control of symptoms, while permanent restoration of normal anatomy is still impossible. Mesenchymal stem cells, that develop into joint tissues, show immunosuppressive and anti-inflammatory qualities, in vitro and in vivo, indicating a potential role for tissue engineering approaches in the treatment of rheumatic diseases.
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18
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Alves da Silva M, Martins A, Costa-Pinto AR, Monteiro N, Faria S, Reis RL, Neves NM. Electrospun Nanofibrous Meshes Cultured With Wharton's Jelly Stem Cell: An Alternative for Cartilage Regeneration, Without the Need of Growth Factors. Biotechnol J 2017; 12. [PMID: 28902474 DOI: 10.1002/biot.201700073] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 08/28/2017] [Indexed: 12/24/2022]
Abstract
Many efforts are being directed worldwide to the treatment of OA-focal lesions. The majority of those efforts comprise either the refinement of surgical techniques or combinations of biomaterials with various autologous cells. Herein, we tested electrospun polycaprolactone (PCL) nanofibrous meshes for cartilage tissue engineering. For that, articular chondrocytes (hACs) isolated from human osteoarthritic joints and Wharton's Jelly Stem Cells (hWJSCs) are cultured on electrospun nanofiber meshes, without adding external growth factors. We observed higher glycosaminoglycans production and higher over-expression of cartilage-related genes from hWJSCs cultured with basal medium, when compared to hACs isolated from osteoarthritic joints. Moreover, the presence of sulfated proteoglycans and collagen type II is observed on both types of cell cultures. We believe that this effect is due to either the electrospun nanofibers topography or the intrinsic chondrogenic differentiation potential of hWJSCs. Therefore, we propose the electrospun nanofibrous scaffolds in combination with hWJSCs as a viable alternative to the commercial membranes used in autologous chondrogenic regeneration approaches.
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Affiliation(s)
- Marta Alves da Silva
- 3B's Research Group - Biomaterials, Biodegradables and Biomimetics, Dept. of Polymer Engineering, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, 4806-909 Taipas, Guimarães, Portugal
- ICVS/3B's Laboratório Associado PT Government Associate Laboratory, Portugal
| | - Albino Martins
- 3B's Research Group - Biomaterials, Biodegradables and Biomimetics, Dept. of Polymer Engineering, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, 4806-909 Taipas, Guimarães, Portugal
- ICVS/3B's Laboratório Associado PT Government Associate Laboratory, Portugal
| | - Ana R Costa-Pinto
- 3B's Research Group - Biomaterials, Biodegradables and Biomimetics, Dept. of Polymer Engineering, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, 4806-909 Taipas, Guimarães, Portugal
- ICVS/3B's Laboratório Associado PT Government Associate Laboratory, Portugal
| | - Nélson Monteiro
- 3B's Research Group - Biomaterials, Biodegradables and Biomimetics, Dept. of Polymer Engineering, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, 4806-909 Taipas, Guimarães, Portugal
- ICVS/3B's Laboratório Associado PT Government Associate Laboratory, Portugal
| | - Susana Faria
- Prof. S. Faria, Department of Mathematics for Science and Technology, Research CMAT, University of Minho, Guimaraes, Portugal
| | - Rui L Reis
- 3B's Research Group - Biomaterials, Biodegradables and Biomimetics, Dept. of Polymer Engineering, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, 4806-909 Taipas, Guimarães, Portugal
- ICVS/3B's Laboratório Associado PT Government Associate Laboratory, Portugal
| | - Nuno M Neves
- 3B's Research Group - Biomaterials, Biodegradables and Biomimetics, Dept. of Polymer Engineering, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, 4806-909 Taipas, Guimarães, Portugal
- ICVS/3B's Laboratório Associado PT Government Associate Laboratory, Portugal
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19
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Zeineddine HA, Frush TJ, Saleh ZM, El-Othmani MM, Saleh KJ. Applications of Tissue Engineering in Joint Arthroplasty: Current Concepts Update. Orthop Clin North Am 2017; 48:275-288. [PMID: 28577777 DOI: 10.1016/j.ocl.2017.03.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Research in tissue engineering has undoubtedly achieved significant milestones in recent years. Although it is being applied in several disciplines, tissue engineering's application is particularly advanced in orthopedic surgery and in degenerative joint diseases. The literature is full of remarkable findings and trials using tissue engineering in articular cartilage disease. With the vast and expanding knowledge, and with the variety of techniques available at hand, the authors aimed to review the current concepts and advances in the use of cell sources in articular cartilage tissue engineering.
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Affiliation(s)
- Hussein A Zeineddine
- Department of Surgery, University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637, USA
| | - Todd J Frush
- Department of Orthopaedics and Sports Medicine, Detroit Medical Center, University Health Center (UHC) 9B, 4201 Saint Antoine Street, Detroit, MI 48201-2153, USA
| | - Zeina M Saleh
- Department of Surgery, American University of Beirut Medical Center, Bliss Street, Riad El-Solh, Beirut 11072020, Lebanon
| | - Mouhanad M El-Othmani
- Department of Orthopaedics and Sports Medicine, Musculoskeletal Institute of Excellence, Detroit Medical Center, University Health Center (UHC) 9B, 4201 Saint Antoine Street, Detroit, MI 48201-2153, USA
| | - Khaled J Saleh
- Department of Orthopaedics and Sports Medicine, Detroit Medical Center, University Health Center (UHC) 9B, 4201 Saint Antoine Street, Detroit, MI 48201-2153, USA.
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20
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Peck Y, Leom LT, Low PFP, Wang DA. Establishment of an in vitro three-dimensional model for cartilage damage in rheumatoid arthritis. J Tissue Eng Regen Med 2017; 12:e237-e249. [PMID: 28079986 DOI: 10.1002/term.2399] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 11/15/2016] [Accepted: 01/09/2017] [Indexed: 11/09/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to progressive joint destruction. To further understand the process of rheumatoid cartilage damage, an in vitro model consisting of an interactive tri-culture of synovial fibroblasts (SFs), LPS-stimulated macrophages and a primary chondrocyte-based tissue-engineered construct was established. The tissue-engineered construct has a composition similar to that of human cartilage, which is rich in collagen type II and proteoglycans. Data generated from this model revealed that healthy chondrocytes were activated in the presence of SFs and macrophages. The activated chondrocytes subsequently displayed aberrant behaviours as seen in a disease state such as increased apoptosis, decreased gene expression for matrix components such as type II collagen and aggrecan, increased gene expression for tissue-degrading enzymes (MMP-1, -3, -13 and ADAMTS-4, -5), and upregulation of inflammatory mediator gene expression (TNF-α, IL-1β, IL-6 and IKBKB). Additionally, the inclusion of SFs and macrophages in the model enabled both cell types to more closely replicate an in vivo role in mediating cartilage destruction. This is evidenced by extensive matrix loss, detected in the model through immunostaining and biochemical analysis. Subsequent drug treatment with celecoxib has shown that the model was able to respond to the therapeutic effects of this drug by reversing cartilage damage. This study showed that the model was able to recapitulate certain pathological features of an RA cartilage. If properly validated, this model potentially can be used for screening new therapeutic drugs and strategies, thereby contributing to the improvement of anti-rheumatic treatment. Copyright © 2017 John Wiley & Sons, Ltd.
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Affiliation(s)
- Yvonne Peck
- Division of BioEngineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore
| | - Li Ting Leom
- Division of BioEngineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore
| | - Pei Fen Patricia Low
- Division of BioEngineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore
| | - Dong-An Wang
- Division of BioEngineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore
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21
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The LncRNA ZBED3-AS1 induces chondrogenesis of human synovial fluid mesenchymal stem cells. Biochem Biophys Res Commun 2017; 487:457-463. [PMID: 28431932 DOI: 10.1016/j.bbrc.2017.04.090] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 04/17/2017] [Indexed: 02/08/2023]
Abstract
Human synovial fluid-derived mesenchymal stem cells (SFMSCs) have great potential for cartilage induction and are promising for cell-based strategies for articular cartilage repair. Many long non-coding RNAs (lncRNAs) regulate chondrogenesis of MSCs. We hypothesized that the divergent lncRNA ZBED3-AS1, which binds locally to chromatin, could promote the expression of zbed3, a novel Axin-interacting protein that activates Wnt/β-catenin signaling, involved in chondrogenesis. However, the function of ZBED3-AS1 in SFMSCs is unclear. In this study, the expression, biological function, and roles of ZBED3-AS1 in SFMSC chondrogenesis were examined by multilineage differentiation, flow cytometry, and gain-of-function studies. We found that ZBED3-AS1 promotes chondrogenesis. Furthermore, ZBED3-AS1 could directly increase zbed3 expression. Finally, the wnt-inhibitor DKK1 could reverse the stimulatory effect of ZBED3-AS1 on chondrogenesis. These findings demonstrate the role of a new lncRNA, ZBED3-AS1, in SFMSC chondrogenesis and may improve osteoarthritis treatment.
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22
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Gari M, Alsehli H, Gari A, Abbas M, Alkaff M, Abuzinadah M, Al-Sayes F, Gari M, Dallol A, Abuzenadah AM, Gauthaman K. Derivation and differentiation of bone marrow mesenchymal stem cells from osteoarthritis patients. Tissue Eng Regen Med 2016; 13:732-739. [PMID: 30603454 DOI: 10.1007/s13770-016-0013-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 03/08/2016] [Accepted: 03/23/2016] [Indexed: 12/27/2022] Open
Abstract
Osteoarthritis (OA) of the knee is a degenerative joint disease caused by the progressive reduction of the articular cartilage surface that leads to reduced joint function. Cartilage degeneration occurs through gradual loss in extracellular matrix components including type II collagen and proteoglycan. Due to limited inherent self repair capacity of the cartilage, the use of cell-based therapies for articular cartilage regeneration is considered promising. Bone marrow mesenchymal stem cells (BM-MSCs) are multipotent cells and are highly capable of multilineage differentiation which render them valuable for regenerative medicine. In this study, BM-MSCs were isolated from OA patients and were characterized for MSC specific CD surface marker antigens using flowcytometry and their differentiation potential into adipocytes, osteocytes and chondrocytes were evaluated using histological and gene expression studies. BM-MSCs isolated from OA patients showed short spindle shaped morphology in culture and expressed positive MSC related CD markers. They also demonstrated positive staining with oil red O, alizarin red and alcian blue following differentiation into adipocytes, osteocytes and chondrocytes, respectively. In addition, chodrogenic related genes such as collagen type II alpha1, cartilage oligomeric matrix protein, fibromodulin, and SOX9 as well as osteocytic related genes such as alkaline phosphatase, core-binding factor alpha 1, osteopontin and RUNX2 runt-related transcription factor 2 were upregulated following chondrogenic and osteogenic differentiation respectively. We have successfully isolated and characterized BM-MSCs from OA patients. Although BM-MSCs has been widely studied and their potential in regenerative medicine is reported, the present study is the first report in our series of experiments on the BMSCs isolated from OA patients at King Abdulaziz University Hospital, Jeddah, Saudi Arabia.
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Affiliation(s)
- Mamdooh Gari
- 1Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- 2Stem Cell Unit, Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
- 3Sheikh Salem Bin Mahfouz Scientific Chair for Treatment of Osteoarthritis by Stem Cells, King Abdulaziz University, Jeddah, Saudi Arabia
- 4Center of Innovation in Personalized Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- 7Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589 Saudi Arabia
| | - Haneen Alsehli
- 3Sheikh Salem Bin Mahfouz Scientific Chair for Treatment of Osteoarthritis by Stem Cells, King Abdulaziz University, Jeddah, Saudi Arabia
- 4Center of Innovation in Personalized Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abdullah Gari
- 2Stem Cell Unit, Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Hematology, Faculty of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed Abbas
- 3Sheikh Salem Bin Mahfouz Scientific Chair for Treatment of Osteoarthritis by Stem Cells, King Abdulaziz University, Jeddah, Saudi Arabia
- 6Department of Orthopedic Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed Alkaff
- 3Sheikh Salem Bin Mahfouz Scientific Chair for Treatment of Osteoarthritis by Stem Cells, King Abdulaziz University, Jeddah, Saudi Arabia
- 6Department of Orthopedic Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed Abuzinadah
- 1Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- 4Center of Innovation in Personalized Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Fatin Al-Sayes
- 3Sheikh Salem Bin Mahfouz Scientific Chair for Treatment of Osteoarthritis by Stem Cells, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Hematology, Faculty of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mazin Gari
- 4Center of Innovation in Personalized Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ashraf Dallol
- 4Center of Innovation in Personalized Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Adel M Abuzenadah
- 1Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- 4Center of Innovation in Personalized Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Kalamegam Gauthaman
- 2Stem Cell Unit, Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
- 3Sheikh Salem Bin Mahfouz Scientific Chair for Treatment of Osteoarthritis by Stem Cells, King Abdulaziz University, Jeddah, Saudi Arabia
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Sun AX, Numpaisal PO, Gottardi R, Shen H, Yang G, Tuan RS. Cell and Biomimetic Scaffold-Based Approaches for Cartilage Regeneration. ACTA ACUST UNITED AC 2016. [DOI: 10.1053/j.oto.2016.06.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Kuo PL, Charng CC, Wu PC, Li PC. Shear-wave elasticity measurements of three-dimensional cell cultures for mechanobiology. J Cell Sci 2016; 130:292-302. [PMID: 27505887 PMCID: PMC5394775 DOI: 10.1242/jcs.186320] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 08/01/2016] [Indexed: 12/15/2022] Open
Abstract
Studying mechanobiology in three-dimensional (3D) cell cultures better recapitulates cell behaviors in response to various types of mechanical stimuli in vivo. Stiffening of the extracellular matrix resulting from cell remodeling potentiates many pathological conditions, including advanced cancers. However, an effective tool for measuring the spatiotemporal changes in elastic properties of such 3D cell cultures without directly contacting the samples has not been reported previously. We describe an ultrasonic shear-wave-based platform for quantitatively evaluating the spatiotemporal dynamics of the elasticity of a matrix remodeled by cells cultured in 3D environments. We used this approach to measure the elasticity changes of 3D matrices grown with highly invasive lung cancer cells and cardiac myoblasts, and to delineate the principal mechanism underlying the stiffening of matrices remodeled by these cells. The described approach can be a useful tool in fields investigating and manipulating the mechanotransduction of cells in 3D contexts, and also has potential as a drug-screening platform. Summary: Use of a non-direct-contact platform for measurement of the spatiotemporal dynamics of matrix elasticity when remodeled by cells cultured in three-dimensional contexts.
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Affiliation(s)
- Po-Ling Kuo
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan.,Department of Electrical Engineering, National Taiwan University, Taipei 10617, Taiwan.,Department of Rehabilitation, National Taiwan University Hospital, Taipei 10002, Taiwan
| | - Ching-Che Charng
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan
| | - Po-Chen Wu
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan
| | - Pai-Chi Li
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan .,Department of Electrical Engineering, National Taiwan University, Taipei 10617, Taiwan
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25
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Utilization of nanoparticle technology in rheumatoid arthritis treatment. Biomed Pharmacother 2016; 80:30-41. [PMID: 27133037 DOI: 10.1016/j.biopha.2016.03.004] [Citation(s) in RCA: 124] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 03/03/2016] [Accepted: 03/03/2016] [Indexed: 02/06/2023] Open
Abstract
Rheumatoid arthritis (RA) is one of the common and severe autoimmune diseases related to joints. This chronic autoimmune inflammatory disease, leads to functional limitation and reduced quality of life, since as there is bone and cartilage destruction, joint swelling and pain. Current advances and new treatment approaches have considerably postponed disease progression and improved the quality of life for many patients. In spite of major advances in therapeutic options, restrictions on the routes of administration and the necessity for frequent and long-term dosing often result in systemic adverse effects and patient non-compliance. Unlike usual drugs, nanoparticle systems are planned to deliver therapeutic agents especially to inflamed synovium, so avoiding systemic and unpleasant effects. The present review discusses about some of the most successful drugs in RA therapy and their side effects and also focuses on key design parameters of RA-targeted nanotechnology-based strategies for improving RA therapies.
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Overcoming translational challenges - The delivery of mechanical stimuli in vivo. Int J Biochem Cell Biol 2015; 69:162-72. [PMID: 26482595 DOI: 10.1016/j.biocel.2015.10.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 10/11/2015] [Accepted: 10/12/2015] [Indexed: 01/22/2023]
Abstract
Despite major medical advances, non-union bone fractures and skeletal defects continue to place significant burden on the patient, the clinicians and the healthcare system as a whole. Current bone substitute approaches are still limited in effectiveness and to date no adequate bone substitute material has been developed for routine clinical application. Tissue engineering presents a novel approach to tackling this clinical burden and developing an acceptable solution for the treatment of skeletal defects. Over the past three decades the field has evolved to appreciate the key biological, material and physical parameters influencing the development of a cell-based tissue engineered therapy and to create associated technologies to exploit such parameters. In recent years a number of therapies have started progressing along the pre-clinical pipeline to build a case for regulatory approval and ultimately clinical adoption. However, little emphasis has been given to the translational challenges faced when moving from "bench-to-bedside". One particular challenge lies in the delivery of functional mechanical stimuli to implanted cell populations to activate and promote osteogenic activities. This review introduces novel bio-magnetic approaches to overcoming this challenge.
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Magalhães J, Lebourg M, Deplaine H, Gómez Ribelles JL, Blanco FJ. Effect of the Physicochemical Properties of Pure or Chitosan-Coated Poly(L-Lactic Acid)Scaffolds on the Chondrogenic Differentiation of Mesenchymal Stem Cells from Osteoarthritic Patients. Tissue Eng Part A 2015; 21:716-28. [DOI: 10.1089/ten.tea.2014.0133] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Joana Magalhães
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain
- Grupo de Bioingeniería Tisular y Terapia Celular (GBTTC-CHUAC), Servicio de Reumatología. Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), A Coruña, Spain
| | - Myriam Lebourg
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain
- Centro de Biomateriales e Ingeniería Tisular, Universidad Politécnica de Valencia. Valencia, Spain
| | - Harmony Deplaine
- Centro de Biomateriales e Ingeniería Tisular, Universidad Politécnica de Valencia. Valencia, Spain
| | - José Luis Gómez Ribelles
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain
- Centro de Biomateriales e Ingeniería Tisular, Universidad Politécnica de Valencia. Valencia, Spain
| | - Francisco J. Blanco
- Grupo de Bioingeniería Tisular y Terapia Celular (GBTTC-CHUAC), Servicio de Reumatología. Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), A Coruña, Spain
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Makris EA, Gomoll AH, Malizos KN, Hu JC, Athanasiou KA. Repair and tissue engineering techniques for articular cartilage. Nat Rev Rheumatol 2015; 11:21-34. [PMID: 25247412 PMCID: PMC4629810 DOI: 10.1038/nrrheum.2014.157] [Citation(s) in RCA: 867] [Impact Index Per Article: 86.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chondral and osteochondral lesions due to injury or other pathology commonly result in the development of osteoarthritis, eventually leading to progressive total joint destruction. Although current progress suggests that biologic agents can delay the advancement of deterioration, such drugs are incapable of promoting tissue restoration. The limited ability of articular cartilage to regenerate renders joint arthroplasty an unavoidable surgical intervention. This Review describes current, widely used clinical repair techniques for resurfacing articular cartilage defects; short-term and long-term clinical outcomes of these techniques are discussed. Also reviewed is a developmental pipeline of acellular and cellular regenerative products and techniques that could revolutionize joint care over the next decade by promoting the development of functional articular cartilage. Acellular products typically consist of collagen or hyaluronic-acid-based materials, whereas cellular techniques use either primary cells or stem cells, with or without scaffolds. Central to these efforts is the prominent role that tissue engineering has in translating biological technology into clinical products; therefore, concomitant regulatory processes are also discussed.
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Affiliation(s)
- Eleftherios A Makris
- Department of Biomedical Engineering, University of California Davis, One Shields Avenue, Davis, CA 95616, USA
| | - Andreas H Gomoll
- Department of Orthopaedic Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Konstantinos N Malizos
- Department of Orthopaedic Surgery and Musculoskeletal Trauma, University of Thessaly, Biopolis, Larisa 41110, Greece
| | - Jerry C Hu
- Department of Biomedical Engineering, University of California Davis, One Shields Avenue, Davis, CA 95616, USA
| | - Kyriacos A Athanasiou
- Department of Orthopaedic Surgery, University of California Davis, One Shields Avenue, Davis, CA 95616, USA
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Baghaban Eslaminejad M, Malakooty Poor E. Mesenchymal stem cells as a potent cell source for articular cartilage regeneration. World J Stem Cells 2014; 6:344-354. [PMID: 25126383 PMCID: PMC4131275 DOI: 10.4252/wjsc.v6.i3.344] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 12/07/2013] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Since articular cartilage possesses only a weak capacity for repair, its regeneration potential is considered one of the most important challenges for orthopedic surgeons. The treatment options, such as marrow stimulation techniques, fail to induce a repair tissue with the same functional and mechanical properties of native hyaline cartilage. Osteochondral transplantation is considered an effective treatment option but is associated with some disadvantages, including donor-site morbidity, tissue supply limitation, unsuitable mechanical properties and thickness of the obtained tissue. Although autologous chondrocyte implantation results in reasonable repair, it requires a two-step surgical procedure. Moreover, chondrocytes expanded in culture gradually undergo dedifferentiation, so lose morphological features and specialized functions. In the search for alternative cells, scientists have found mesenchymal stem cells (MSCs) to be an appropriate cellular material for articular cartilage repair. These cells were originally isolated from bone marrow samples and further investigations have revealed the presence of the cells in many other tissues. Furthermore, chondrogenic differentiation is an inherent property of MSCs noticed at the time of the cell discovery. MSCs are known to exhibit homing potential to the damaged site at which they differentiate into the tissue cells or secrete a wide spectrum of bioactive factors with regenerative properties. Moreover, these cells possess a considerable immunomodulatory potential that make them the general donor for therapeutic applications. All of these topics will be discussed in this review.
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Sidney LE, Kirkham GR, Buttery LD. Comparison of osteogenic differentiation of embryonic stem cells and primary osteoblasts revealed by responses to IL-1β, TNF-α, and IFN-γ. Stem Cells Dev 2014; 23:605-17. [PMID: 24192281 DOI: 10.1089/scd.2013.0336] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
There are well-established approaches for osteogenic differentiation of embryonic stem cells (ESCs), but few show direct comparison with primary osteoblasts or demonstrate differences in response to external factors. Here, we show comparative analysis of in vitro osteogenic differentiation of mouse ESC (osteo-mESC) and mouse primary osteoblasts. Both cell types formed mineralized bone nodules and produced osteogenic extracellular matrix, based on immunostaining for osteopontin and osteocalcin. However, there were marked differences in the morphology of osteo-mESCs and levels of mRNA expression for osteogenic genes. In response to the addition of proinflammatory cytokines interleukin-1β, tumor necrosis factor-α, and interferon-γ to the culture medium, primary osteoblasts showed increased production of nitric oxide (NO) and prostaglandin E2 (PGE2) at early time points and decreases in cell viability. In contrast, osteo-mESCs maintained viability and did not produce NO and PGE2 until day 21. The formation of bone nodules by primary osteoblasts was reduced markedly after cytokine stimulation but was unaffected in osteo-mESCs. Cell sorting of osteo-mESCs by cadherin-11 (cad-11) showed clear osteogenesis of cad-11(+) cells compared to unsorted osteo-mESCs and cad-11(-) cells. Moreover, the cad-11(+) cells showed a significant response to cytokines, similar to primary osteoblasts. Overall, these results show that while osteo-mESC cultures, without specific cell sorting, show characteristics of osteoblasts, there are also marked differences, notably in their responses to cytokine stimuli. These findings are relevant to understanding the differentiation of stem cells and especially developing in vitro models of disease, testing new drugs, and developing cell therapies.
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Affiliation(s)
- Laura E Sidney
- Division of Drug Delivery and Tissue Engineering, School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham , Nottingham, United Kingdom
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Sun YP, Zheng YH, Liu WJ, Zheng YL, Zhang ZG. Synovium fragment-derived cells exhibit characteristics similar to those of dissociated multipotent cells in synovial fluid of the temporomandibular joint. PLoS One 2014; 9:e101896. [PMID: 25003199 PMCID: PMC4087006 DOI: 10.1371/journal.pone.0101896] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 06/12/2014] [Indexed: 01/22/2023] Open
Abstract
Multipotent mesenchymal stem cells (MSCs) found in the synovial fluid (SFMSCs) of the tempromandibular joint (TMJ) remain poorly understood. During TMJ arthrocentesis, we discovered that synovial fluid collected from some patients with TMJ disorders contained not only SFMSCs but also synovium fragments (SFs). In this study, we attempted to characterize both the SFMSCs and SF-derived cells (SFCs) in order to further understand the role of MSCs in the synovial fluid of the TMJ. The SFs were membranous and translucent and consisted of several cell layers, indicating that their origin was only from the intima. SFCs were obtained by digestion of the SFs and subsequently expanded in vitro. SFMSCs were enriched by centrifugation of the synovial fluid and expanded in vitro. SFCs and SFMSCs displayed a similar fibroblast-like, spindle-shaped morphology, and we observed that some SFMSCs grew out of small tissue masses in culture. Flow cytometric analysis showed that both groups of cells expressed similar surface markers, including CD90, CD44, CD105, and CD73. However, both were negative for Stro-1, CD146, CD45, CD34, CD11b, CD19, and HLA-DR. Immunofluorescent staining showed that both SFs and SFMSCs expressed vascular cell adhesion molecule 1. Both SFCs and SFMSCs could be induced to differentiate down osteogenic, chondrogenic, adipogenic, and neurogenic lineages in vitro. Together, our results indicate that the intima is the most likely tissue origin of SFMSCs in the TMJ. Moreover, the SFs are composed of only intima and thus offer an improved source of synovium-derived MSCs compared to synovium specimens obtained by surgery, which contain both intima and subintima.
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Affiliation(s)
- Yang-peng Sun
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, People's Republic of China
| | - You-hua Zheng
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, People's Republic of China
| | - Wen-jing Liu
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, People's Republic of China
| | - Yu-liang Zheng
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, People's Republic of China
| | - Zhi-guang Zhang
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, People's Republic of China
- * E-mail:
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Markides H, Kehoe O, Morris RH, El Haj AJ. Whole body tracking of superparamagnetic iron oxide nanoparticle-labelled cells--a rheumatoid arthritis mouse model. Stem Cell Res Ther 2013; 4:126. [PMID: 24406201 PMCID: PMC3854718 DOI: 10.1186/scrt337] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Accepted: 10/11/2013] [Indexed: 12/29/2022] Open
Abstract
Introduction The application of mesenchymal stem cells (MSCs) in treating rheumatoid arthritis (RA) has been made possible by the immunosuppressive and differentiation abilities of these cells. A non-invasive means of assessing cell integration and bio-distribution is fundamental in evaluating the risks and success of this therapy, thereby enabling clinical translation. This paper defines the use of superparamagnetic iron oxide nanoparticles (SPIONs) in conjunction with magnetic resonance imaging (MRI) to image and track MSCs in vivo within a murine model of RA. Methods Murine MSCs (mMSCs) were isolated, expanded and labelled with SiMAG, a commercially available particle. In vitro MRI visibility thresholds were investigated by labelling mMSCs with SiMAG with concentrations ranging from 0 to 10 μg/ml and resuspending varying cell doses (103 to 5 × 105 cells) in 2 mg/ml collagen prior to MR-imaging. Similarly, in vivo detection thresholds were identified by implanting 3 × 105 mMSCs labelled with 0 to 10 μg/ml SiMAG within the synovial cavity of a mouse and MR-imaging. Upon RA induction, 300,000 mMSCs labelled with SiMAG (10 μg/ml) were implanted via intra-articular injection and joint swelling monitored as an indication of RA development over seven days. Furthermore, the effect of SiMAG on cell viability, proliferation and differentiation was investigated. Results A minimum particle concentration of 1 μg/ml (300,000 cells) and cell dose of 100,000 cells (5 and 10 μg/ml) were identified as the in vitro MRI detection threshold. Cell viability, proliferation and differentiation capabilities were not affected, with labelled populations undergoing successful differentiation down osteogenic and adipogenic lineages. A significant decrease (P < 0.01) in joint swelling was measured in groups containing SiMAG-labelled and unlabelled mMSCs implying that the presence of SPIONs does not affect the immunomodulating properties of the cells. In vivo MRI scans demonstrated good contrast and the identification of SiMAG-labelled populations within the synovial joint up to 7 days post implantation. This was further confirmed using histological analysis. Conclusions We have been able to monitor and track the migration of stem cell populations within the rheumatic joint in a non-invasive manner. This manuscript goes further to highlight the key characteristics (biocompatible and the ability to create significant contrast at realistic doses within a clinical relevant system) demonstrated by SiMAG that should be incorporated into the design of a new clinically approved tracking agent.
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Ullah M, Eucker J, Sittinger M, Ringe J. Mesenchymal stem cells and their chondrogenic differentiated and dedifferentiated progeny express chemokine receptor CCR9 and chemotactically migrate toward CCL25 or serum. Stem Cell Res Ther 2013; 4:99. [PMID: 23958031 PMCID: PMC3854782 DOI: 10.1186/scrt310] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 06/10/2013] [Accepted: 08/12/2013] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Guided migration of chondrogenically differentiated cells has not been well studied, even though it may be critical for growth, repair, and regenerative processes. The chemokine CCL25 is believed to play a critical role in the directional migration of leukocytes and stem cells. To investigate the motility effect of serum- or CCL25-mediated chemotaxis on chondrogenically differentiated cells, mesenchymal stem cells (MSCs) were induced to chondrogenic lineage cells. METHODS MSC-derived chondrogenically differentiated cells were characterized for morphology, histology, immunohistochemistry, quantitative polymerase chain reaction (qPCR), surface profile, and serum- or CCL25-mediated cell migration. Additionally, the chemokine receptor, CCR9, was examined in different states of MSCs. RESULTS The chondrogenic differentiated state of MSCs was positive for collagen type II and Alcian blue staining, and showed significantly upregulated expression of COL2A1and SOX9, and downregulated expression of CD44, CD73, CD90, CD105 and CD166, in contrast to the undifferentiated and dedifferentiated states of MSCs. For the chondrogenic differentiated, undifferentiated, and dedifferentiated states of MSCs, the serum-mediated chemotaxis was in a percentage ratio of 33%:84%:85%, and CCL25-mediated chemotaxis was in percentage ratio of 12%:14%:13%, respectively. On the protein level, CCR9, receptor of CCL25, was expressed in the form of extracellular and intracellular domains. On the gene level, qPCR confirmed the expression of CCR9 in different states of MSCs. CONCLUSIONS CCL25 is an effective cue to guide migration in a directional way. In CCL25-mediated chemotaxis, the cell-migration rate was almost the same for different states of MSCs. In serum-mediated chemotaxis, the cell-migration rate of chondrogenically differentiated cells was significantly lower than that in undifferentiated or dedifferentiated cells. Current knowledge of the surface CD profile and cell migration could be beneficial for regenerative cellular therapies.
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Affiliation(s)
- Mujib Ullah
- Tissue Engineering Laboratory & Berlin-Brandenburg Center for Regenerative Therapies, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Jan Eucker
- Department of Hematology and Oncology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Michael Sittinger
- Tissue Engineering Laboratory & Berlin-Brandenburg Center for Regenerative Therapies, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Jochen Ringe
- Tissue Engineering Laboratory & Berlin-Brandenburg Center for Regenerative Therapies, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
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Saha S, Kirkham J, Wood D, Curran S, Yang XB. Informing future cartilage repair strategies: a comparative study of three different human cell types for cartilage tissue engineering. Cell Tissue Res 2013; 352:495-507. [PMID: 23474783 PMCID: PMC3663993 DOI: 10.1007/s00441-013-1586-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Accepted: 02/07/2013] [Indexed: 01/22/2023]
Abstract
A major clinical need exists for cartilage repair and regeneration. Despite many different strategies having been pursued, the identification of an optimised cell type and of pre-treatment conditions remains a challenge. This study compares the cartilage-like tissue generated by human bone marrow stromal cells (HBMSCs) and human neonatal and adult chondrocytes cultured on three-dimensional (3D) scaffolds under various conditions in vitro and in vivo with the aim of informing future cartilage repair strategies based upon tissue-engineering approaches. After 3 weeks in vitro culture, all three cell types showed cartilage-like tissue formation on 3D poly (lactide-co-glycolide) acid scaffolds only when cultured in chondrogenic medium. After 6 weeks of chondro-induction, neonatal chondrocyte constructs revealed the most cartilage-like tissue formation with a prominent superficial zone-like layer, a middle zone-like structure and the thinnest fibrous capsule. HBMSC constructs had the thickest fibrous capsule formation. Under basal culture conditions, neonatal articular chondrocytes failed to form any tissue, whereas HBMSCs and adult chondrocytes showed thick fibrous capsule formation at 6 weeks. After in vivo implantation, all groups generated more compact tissues compared with in vitro constructs. Pre-culturing in chondrogenic media for 1 week before implantation reduced fibrous tissue formation in all cell constructs at week 3. After 6 weeks, only the adult chondrocyte group pre-cultured in chondrogenic media was able to maintain a more chondrogenic/less fibrocartilaginous phenotype. Thus, pre-culture under chondrogenic conditions is required to maintain a long-term chondrogenic phenotype, with adult chondrocytes being a more promising cell source than HBMSCs for articular cartilage tissue engineering.
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Affiliation(s)
- Sushmita Saha
- Biomaterials and Tissue Engineering Group, Leeds Dental Institute, University of Leeds, Leeds, LS2 9LU, UK
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Duda GN, Eniwumide JO, Sittinger M. Constraints to Articular Cartilage Regeneration. Regen Med 2013. [DOI: 10.1007/978-94-007-5690-8_41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Ullah M, Hamouda H, Stich S, Sittinger M, Ringe J. A reliable protocol for the isolation of viable, chondrogenically differentiated human mesenchymal stem cells from high-density pellet cultures. Biores Open Access 2012; 1:297-305. [PMID: 23514965 PMCID: PMC3559221 DOI: 10.1089/biores.2012.0279] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Administration of chondrogenically differentiated mesenchymal stem cells (MSC) is discussed as a promising approach for the regenerative treatment of injured or diseased cartilage. The high-density pellet culture is the standard culture for chondrogenic differentiation, but cells in pellets secrete extracellular matrix (ECM) that they become entrapped in. Protocols for cell isolation from pellets often result in cell damage and dedifferentiation towards less differentiated MSC. Therefore, our aim was to develop a reliable protocol for the isolation of viable, chondrogenically differentiated MSC from high-density pellet cultures. Human bone marrow MSC were chondrogenically stimulated with transforming growth factor-β3, and the cartilaginous structure of the pellets was verified by alcian blue staining of cartilage proteoglycans, antibody staining of cartilage collagen type II, and quantitative real-time reverse-transcription polymerase chain reaction of the marker genes COL2A1 and SOX9. Trypsin and collagenases II and P were tested alone or in combination, and for different concentrations and times, to find a protocol for optimized pellet digestion. Whereas trypsin was not able to release viable cells, 90-min digestion with 300 U of collagenase II, 20 U of collagenase P, and 2 mM CaCl2 worked quite well and resulted in about 2.5×10(5) cells/pellet. The protocol was further optimized for the separation of released cells and ECM from each other. Cells were alcian blue and collagen type II positive and expressed COL2A1 and SOX9, verifying a chondrogenic character. However, they had different morphological shapes. The ECM was also uniformly alcian blue and collagen type II positive but showed different organizational and structural forms. To conclude, our protocol allows the reliable isolation of a defined number of viable, chondrogenically differentiated MSC from high-density pellet cultures. Such cells, as well as the ECM components, are of interest as research tools and for cartilage tissue engineering.
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Affiliation(s)
- Mujib Ullah
- Tissue Engineering Laboratory and Berlin-Brandenburg Center for Regenerative Therapies, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Houda Hamouda
- AG Glycodesign and Glycoanalytics, Institute of Laboratory Medicine, Clinical Chemistry, and Pathobiochemistry; Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Stefan Stich
- Tissue Engineering Laboratory and Berlin-Brandenburg Center for Regenerative Therapies, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Sittinger
- Tissue Engineering Laboratory and Berlin-Brandenburg Center for Regenerative Therapies, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Jochen Ringe
- Tissue Engineering Laboratory and Berlin-Brandenburg Center for Regenerative Therapies, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
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Mamidi MK, Singh G, Husin JM, Nathan KG, Sasidharan G, Zakaria Z, Bhonde R, Majumdar AS, Das AK. Impact of passing mesenchymal stem cells through smaller bore size needles for subsequent use in patients for clinical or cosmetic indications. J Transl Med 2012; 10:229. [PMID: 23171323 PMCID: PMC3543333 DOI: 10.1186/1479-5876-10-229] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Accepted: 10/18/2012] [Indexed: 12/21/2022] Open
Abstract
Background Numerous preclinical and clinical studies have investigated the regenerative potential and the trophic support of mesenchymal stem cells (MSCs) following their injection into a target organ. Clinicians favor the use of smallest bore needles possible for delivering MSCs into vascular organs like heart, liver and spleen. There has been a concern that small needle bore sizes may be detrimental to the health of these cells and reduce the survival and plasticity of MSCs. Methods In this report, we aimed to investigate the smallest possible bore size needle which would support the safe delivery of MSCs into various tissues for different clinical or cosmetic applications. To accomplish this we injected cells via needle sizes 24, 25 and 26 G attached to 1 ml syringe in the laboratory and collected the cells aseptically. Control cells were ejected via 1 ml syringe without any needle. Thereafter, the needle ejected cells were cultured and characterized for their morphology, attachment, viability, phenotypic expression, differentiation potential, cryopreservation and in vivo migration abilities. In the second phase of the study, cells were injected via 26 G needle attached to 1 ml syringe for 10 times. Results Similar phenotypic and functional characteristics were observed between ejected and control group of cells. MSCs maintained their cellular and functional properties after single and multiple injections. Conclusions This study proves that 26 G bore size needles can be safely used to inject MSCs for clinical/therapeutics purposes.
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Affiliation(s)
- Murali Krishna Mamidi
- Stempeutics Research Malaysia Sdn. Bhd, Technology Park Malaysia, 57000 Kuala Lumpur, Malaysia
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Abstract
Joint destruction occurs in both osteoarthritis and rheumatoid arthritis. Even in the era of biologic agents, this destruction can be delayed but not averted. As cartilage has limited ability to self-regenerate, joint arthroplasty is required. Here, we outline current tissue engineering procedures (including autologous chondrocyte implantation and in situ mesenchymal stem cell recruitment) that are routinely applied for the regenerative treatment of injured or early osteoarthritic cartilage. Potential future regenerative therapies, including administration of multipotent or pluripotent stem cells, are also discussed. In the future, cell-free, material-based (for cartilage lesions) or cell-free, factor-based (for osteoarthritic cartilage) therapies to facilitate the recruitment of repair cells and improve cartilage metabolism are likely to become more important. Moreover, delivery of anti-inflammatory factors or immunomodulatory cells could be a regenerative treatment option for rheumatoid arthritis. Tissue engineering faces a crucial phase to translate products into clinical routine and the regulatory framework for cell-based products in particular is an important issue.
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Park SI, Lee HR, Kim S, Ahn MW, Do SH. Time-sequential modulation in expression of growth factors from platelet-rich plasma (PRP) on the chondrocyte cultures. Mol Cell Biochem 2011; 361:9-17. [PMID: 21956670 DOI: 10.1007/s11010-011-1081-1] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2011] [Accepted: 09/16/2011] [Indexed: 12/21/2022]
Abstract
Platelets are involved in hemostasis, wound healing, and tumor growth. Autologous blood products are commonly used to facilitate healing in a variety of clinical surgery applications. Recently, it was shown that platelet-rich plasma (PRP) has more specific growth factors that participate in the healing process. This study investigated the expression of PRP growth factors and evaluated their potential role in the cartilage regeneration using primary isolated chondrocytes. PRP obtained from New Zealand White rabbit by low speed centrifugation. Extracted PRPs contained 6-10 × 10(6) platelet/μl and concentration of platelets was slightly variable. Primary isolated chondrocytes from the same rabbits were cultured and treated with 0.1-20% PRP. The cells were collected and examined by reverse transcription-polymerase chain reaction and cytochemical staining. The expression of sex determining region Y-box 9, transforming growth factor-beta, vascular endothelial growth factor, and chondromdulin-I was increased in chondrocyte cultures with 10% PRP by time-dependent manner. To maintain the integrity of the cartilage, the proteoglycan contents were also up-regulated from the mRNA of aggrecan and positive Safranin-O staining in PRP concentration- and time-dependent manner. PRP provides crucial growth factors related to chondrocyte proliferation and differentiation through time-sequential modulation. Controlled in vivo trials for cartilage regeneration are needed.
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Affiliation(s)
- Se-Il Park
- Department of Orthopedic Surgery, College of Medicine, Yeungnam University, Daegu, Korea
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Bahney C, Lujan T, Hsu C, Bottlang M, West J, Johnstone B. Visible light photoinitiation of mesenchymal stem cell-laden bioresponsive hydrogels. Eur Cell Mater 2011; 22:43-55; discussion 55. [PMID: 21761391 PMCID: PMC5050040 DOI: 10.22203/ecm.v022a04] [Citation(s) in RCA: 154] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Biological activity can be added to synthetic scaffolds by incorporating functional peptide sequences that provide enzyme-mediated degradation sites, facilitate cellular adhesion or stimulate signaling pathways. Poly(ethylene glycol) diacrylate is a popular synthetic base for tissue engineering scaffolds because it creates a hydrophilic environment that can be chemically manipulated to add this biological functionality. Furthermore, the acrylate groups allow for encapsulation of cells using photopolymerization under physiological conditions. One complication with the addition of these peptides is that aromatic amino acids absorb light at 285 nm and compete with the ultraviolet (UV)-sensitive photoinitiators such as IrgacureTM 2959 (I2959), the most commonly used initiator for cytocompatible photoencapsulation of cells into synthetic scaffolds. In this study we define non-toxic conditions for photoencapsulation of human mesenchymal stem cells (hMSC) in PEGDA scaffolds using a visible light photoinitiator system composed of eosin Y, triethanolamine and 1-vinyl-2-pyrrolidinone. This visible light photoinitiator produced hydrogel scaffolds with an increased viability of encapsulated hMSCs and a more tightly crosslinked network in one-third the time of UV polymerization with I2959.
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Affiliation(s)
- C.S. Bahney
- Department of Orthopaedics and Rehabilitation, Oregon Health & Science University (OHSU), Portland, OR, USA,Department of Cell and Developmental Biology, Oregon Health & Science University (OHSU), Portland, OR, USA
| | - T.J. Lujan
- Biomechanics Laboratory, Legacy Research & Technology Center, Portland, OR, USA
| | - C.W. Hsu
- Department of Bioengineering, Rice University, Houson, TX, USA
| | - M. Bottlang
- Biomechanics Laboratory, Legacy Research & Technology Center, Portland, OR, USA
| | - J.L. West
- Department of Bioengineering, Rice University, Houson, TX, USA
| | - B. Johnstone
- Department of Orthopaedics and Rehabilitation, Oregon Health & Science University (OHSU), Portland, OR, USA,Department of Cell and Developmental Biology, Oregon Health & Science University (OHSU), Portland, OR, USA,Address for correspondence: Brian Johnstone, Oregon Health & Science University, Department of Orthopaedics & Rehabilitation, OP31, 3181 Sam Jackson Park Road, Portland OR 97239, USA,
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Cox G, McGonagle D, Boxall SA, Buckley CT, Jones E, Giannoudis PV. The use of the reamer-irrigator-aspirator to harvest mesenchymal stem cells. ACTA ACUST UNITED AC 2011; 93:517-24. [PMID: 21464493 DOI: 10.1302/0301-620x.93b4.25506] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The scarcity of mesenchymal stem cells (MSCs) in iliac crest bone marrow aspirate (ICBMA), and the expense and time in culturing cells, has led to the search for alternative harvest sites. The reamer-irrigation-aspirator (RIA) provides continuous irrigation and suction during reaming of long bones. The aspirated contents pass via a filter, trapping bony fragments, before moving into a 'waste' bag from which MSCs have been previously isolated. We examined the liquid and solid phases, performed a novel digestion of the solid phase, and made a comparative assessment in terms of number, phenotype and differentiation capacity with matched ICBMA. The solid fraction from the filtrate was digested for 60 minutes at 37° C with collagenase. Enumeration was performed via the colony-forming unit fibroblast (CFU-F) assay. Passage (P2) cells were differentiated towards osteogenic, adipogenic and chondrogenic lineages, and their phenotypes assessed using flow cytometry (CD33, CD34, CD45, CD73, CD90, and CD105). MSCs from the RIA phases were able to differentiate at least as well as those from ICBMA, and all fractions had phenotypes consistent with other established sources. The median number of colonies for the three groups was: ICBMA = 8.5 (2 to 86), RIA-liquid = 19.5 (4 to 90), RIA-solid = 109 (67 to 200) per 200 μl. The mean total yield of cells for the three groups was: ICBMA = 920 (0 to 4275), RIA-liquid = 114,983 (16,500 to 477,750), RIA-solid = 12,785 (7210 to 28 475). The RIA filtrate contains large numbers of MSCs that could potentially be extracted without enzymatic digestion and used for bone repair without prior cell expansion.
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Affiliation(s)
- G Cox
- Department of Trauma and Orthopaedics, Academic Unit, Clarendon Wing, Leeds Teaching Hospitals NHS Trust, Great George Street, Leeds LS1 3EX, UK
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Andreas K, Zehbe R, Kazubek M, Grzeschik K, Sternberg N, Bäumler H, Schubert H, Sittinger M, Ringe J. Biodegradable insulin-loaded PLGA microspheres fabricated by three different emulsification techniques: investigation for cartilage tissue engineering. Acta Biomater 2011; 7:1485-95. [PMID: 21168535 DOI: 10.1016/j.actbio.2010.12.014] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2010] [Revised: 11/17/2010] [Accepted: 12/13/2010] [Indexed: 01/02/2023]
Abstract
Growth, differentiation and migration factors facilitate the engineering of tissues but need to be administered with defined gradients over a prolonged period of time. In this study insulin as a growth factor for cartilage tissue engineering and a biodegradable PLGA delivery device were used. The aim was to investigate comparatively three different microencapsulation techniques, solid-in-oil-in-water (s/o/w), water-in-oil-in-water (w/o/w) and oil-in-oil-in-water (o/o/w), for the fabrication of insulin-loaded PLGA microspheres with regard to protein loading efficiency, release and degradation kinetics, biological activity of the released protein and phagocytosis of the microspheres. Insulin-loaded PLGA microspheres prepared by all three emulsification techniques had smooth and spherical surfaces with a negative zeta potential. The preparation technique did not affect particle degradation nor induce phagocytosis by human leukocytes. The delivery of structurally intact and biologically active insulin from the microspheres was shown using circular dichroism spectroscopy and a MCF7 cell-based proliferation assay. However, the insulin loading efficiency (w/o/w about 80%, s/o/w 60%, and o/o/w 25%) and the insulin release kinetics were influenced by the microencapsulation technique. The results demonstrate that the w/o/w microspheres are most appropriate, providing a high encapsulation efficiency and low initial burst release, and thus these were finally used for cartilage tissue engineering. Insulin released from w/o/w PLGA microspheres stimulated the formation of cartilage considerably in chondrocyte high density pellet cultures, as determined by increased secretion of proteoglycans and collagen type II. Our results should encourage further studies applying protein-loaded PLGA microspheres in combination with cell transplants or cell-free in situ tissue engineering implants to regenerate cartilage.
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Affiliation(s)
- Kristin Andreas
- Berlin-Brandenburg Center for Regenerative Therapies, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
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Krause CD, Izotova LS, Ren G, Yuan ZR, Shi Y, Chen CC, Ron Y, Pestka S. Efficient co-expression of bicistronic proteins in mesenchymal stem cells by development and optimization of a multifunctional plasmid. Stem Cell Res Ther 2011; 2:15. [PMID: 21401924 PMCID: PMC3226286 DOI: 10.1186/scrt56] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2010] [Accepted: 03/14/2011] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Local synthesis of interferon within B16 tumors mediates anti-tumor effects. Based on reports that stem cells are recruited to tumors, and because systemic administration of interferon causes dose-limiting undesirable side effects, we wanted to improve the anti-tumor effects of interferon while simultaneously minimizing its systemic side effects by employing mesenchymal stem cells (MSCs) as tumor-localized ectopic producers of interferon. Many vectors exist to fulfill this purpose, but their transfection efficiency and resulting expression levels vary considerably. METHODS To follow both the recruitment to tumors and the synthesis of interferon by MSCs, we designed a bicistronic vector system that permits fluorescent visualization of vector-transfected and interferon-producing MSCs. We used Mu-IFNαA cDNA as the first cistron and the cherry fluorescent protein cDNA as the second cistron, whose translation requires the internal ribosome entry sequence (IRES) from the encephalomyocarditis virus 5' untranslated region. Observing inconsistent expression of these cistrons in various vectors and cell lines, especially compared with a control plasmid pmaxGFP, we optimized the expression of this bicistronic message by mutating pcDNA3 to facilitate exchange of the promoter and polyadenylation segments controlling both the gene of interest and the eukaryotic antibiotic resistance gene as well as the eukaryotic antibiotic resistance gene itself, and effectively compare the effects of these exchanges, creating plasmid pc3.5. RESULTS Murine MSCs stably and ectopically expressing Mu-IFNαA inhibited the establishment of tumors in homogeneic C57/BL6 mice. Mu-IFNαA expressed from the bicistronic message is fully biologically active, but is expressed at only two-thirds of the level observed from a monocistronic message. Cap-dependent translation is threefold more efficient than IRES-driven translation in 293T, B16, and MSC cell lines. Both efficient expression and good transfection efficiency require strong expression of the gene of interest and a chimeric intron. High doses of Mu-IFNαA within tumors inhibited tumor establishment but may not inhibit tumor growth. CONCLUSIONS Our modified vector and its derived plasmids will find use in stem cell therapeutics, gene expression, mRNA regulation, and transcription regulation. Local release of Mu-IFNαA within tumors may differently affect tumor establishment and tumor growth.
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Affiliation(s)
- Christopher D Krause
- Department of Molecular Genetics, Microbiology, and Immunology, RWJMS-UMDNJ, 675 Hoes Lane West, Piscataway, NJ 08854, USA
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Toghraie FS, Chenari N, Gholipour MA, Faghih Z, Torabinejad S, Dehghani S, Ghaderi A. Treatment of osteoarthritis with infrapatellar fat pad derived mesenchymal stem cells in Rabbit. Knee 2011; 18:71-75. [PMID: 20591677 DOI: 10.1016/j.knee.2010.03.001] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2010] [Revised: 02/20/2010] [Accepted: 03/07/2010] [Indexed: 02/02/2023]
Abstract
Osteoarthritis (OA) is a progressively debilitating disease that affects mostly cartilage, with associated changes in the bone. Increasing incidence of OA and the aging population coupled with insufficient therapeutic choices has led to focus on the potential of stem cells as a novel strategy for cartilage repair. In this study, we used scaffold free mesenchymal stem cells obtained from infrapatellar fat pad in an experimental animal model of OA by direct intraarticular injection. Mesenchymal stem cells isolated from a 2.8kg White New Zealand rabbit. The cells were expanded and grown in vitro. OA was induced by unilaterally anterior cruciate ligament transection of knee joints. Twelve weeks after operation, a single dose of 1 million cells suspended in 1ml of medium was delivered to the injured knee by direct intraarticular injection. Control group received 1ml of medium without cells. The knees were examined after sixteen and twenty weeks from the surgery. Repairing was investigated radiologically, grossly and histologically using haematoxylin and eosin, Safranin-O and toluidine blue staining. Radiological assessment confirmed development of OA changes after 12 weeks. Rabbits receiving mesenchymal stem cells showed lower degree of cartilage degeneration, osteophyte formation, and Subchondral sclerosis than control group at 20 week after surgery. The quality of cartilage was significantly better in cell-treated group compared with control group after 20 weeks. In conclusion, infrapatellar fat pad derived mesenchymal stem cells could be the promising cell sources for the treatment of OA.
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Affiliation(s)
- F S Toghraie
- Faculty of Vet Medicine, Shiraz University, Iran
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Ma D, Yao H, Tian W, Chen F, Liu Y, Mao T, Ren L. Enhancing bone formation by transplantation of a scaffold-free tissue-engineered periosteum in a rabbit model. Clin Oral Implants Res 2011; 22:1193-1199. [PMID: 21303418 DOI: 10.1111/j.1600-0501.2010.02091.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVES The periosteum plays an important role in bone regeneration. However, the harvesting of autogenous periosteum is associated with disadvantages such as donor site morbidity and limited donor sources. This study uses an osteogenic predifferentiated cell sheet to fabricate a scaffold-free tissue-engineered periosteum (TEP). MATERIAL AND METHODS We generated an osteogenic predifferentiated cell sheet from rabbit bone marrow stromal cells (BMSCs) using a continuous culture system and harvested it using a scraping technique. Then, the in vitro characterization of the sheet was investigated using microscopy investigation, quantitative analysis of alkaline phosphatase (ALP) activity, and RT-PCR. Next, we demonstrated the in vivo osteogenic potential of the engineered sheet in ectopic sites together with a porous β-tricalcium phosphate ceramic. Finally, we evaluated its efficiency in treating delayed fracture healing after wrapping the cell sheet around the mandible in a rabbit model. RESULTS The engineered periosteum showed sporadic mineralized nodules, elevated ALP activity, and up-regulated gene expression of osteogenic markers. After implantation in the subcutaneous pockets of the donor rabbits, the in vivo bone-forming capability of the engineered periosteum was confirmed by histological examinations. Additionally, when wrapping the engineered periosteum around a mandibular fracture gap, we observed improved bone healing and reduced amounts of fibrous tissue at the fracture site. CONCLUSION The osteogenic predifferentiated BMSC sheet can act as a scaffold-free TEP to facilitate bone regeneration. Hence, our study provides a promising strategy for enhancing bone regeneration in clinical settings.
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Affiliation(s)
- Dongyang Ma
- Department of Oral and Maxillofacial Surgery, Lanzhou General Hospital, Lanzhou Command of PLA, Gansu, ChinaDepartment of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Shaanxi, ChinaRege Lab of Tissue Engineering, Department of Bioscience, Faculty of Life Science, Northwest University, Shaanxi, ChinaDepartment of Orthodontics, School of Stomatology, Lanzhou University, Gansu, China
| | - Hong Yao
- Department of Oral and Maxillofacial Surgery, Lanzhou General Hospital, Lanzhou Command of PLA, Gansu, ChinaDepartment of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Shaanxi, ChinaRege Lab of Tissue Engineering, Department of Bioscience, Faculty of Life Science, Northwest University, Shaanxi, ChinaDepartment of Orthodontics, School of Stomatology, Lanzhou University, Gansu, China
| | - Wenyan Tian
- Department of Oral and Maxillofacial Surgery, Lanzhou General Hospital, Lanzhou Command of PLA, Gansu, ChinaDepartment of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Shaanxi, ChinaRege Lab of Tissue Engineering, Department of Bioscience, Faculty of Life Science, Northwest University, Shaanxi, ChinaDepartment of Orthodontics, School of Stomatology, Lanzhou University, Gansu, China
| | - Fulin Chen
- Department of Oral and Maxillofacial Surgery, Lanzhou General Hospital, Lanzhou Command of PLA, Gansu, ChinaDepartment of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Shaanxi, ChinaRege Lab of Tissue Engineering, Department of Bioscience, Faculty of Life Science, Northwest University, Shaanxi, ChinaDepartment of Orthodontics, School of Stomatology, Lanzhou University, Gansu, China
| | - Yanpu Liu
- Department of Oral and Maxillofacial Surgery, Lanzhou General Hospital, Lanzhou Command of PLA, Gansu, ChinaDepartment of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Shaanxi, ChinaRege Lab of Tissue Engineering, Department of Bioscience, Faculty of Life Science, Northwest University, Shaanxi, ChinaDepartment of Orthodontics, School of Stomatology, Lanzhou University, Gansu, China
| | - Tianqiu Mao
- Department of Oral and Maxillofacial Surgery, Lanzhou General Hospital, Lanzhou Command of PLA, Gansu, ChinaDepartment of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Shaanxi, ChinaRege Lab of Tissue Engineering, Department of Bioscience, Faculty of Life Science, Northwest University, Shaanxi, ChinaDepartment of Orthodontics, School of Stomatology, Lanzhou University, Gansu, China
| | - Liling Ren
- Department of Oral and Maxillofacial Surgery, Lanzhou General Hospital, Lanzhou Command of PLA, Gansu, ChinaDepartment of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Shaanxi, ChinaRege Lab of Tissue Engineering, Department of Bioscience, Faculty of Life Science, Northwest University, Shaanxi, ChinaDepartment of Orthodontics, School of Stomatology, Lanzhou University, Gansu, China
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Chanda D, Kumar S, Ponnazhagan S. Therapeutic potential of adult bone marrow-derived mesenchymal stem cells in diseases of the skeleton. J Cell Biochem 2011; 111:249-57. [PMID: 20506559 DOI: 10.1002/jcb.22701] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mesenchymal stem cells (MSCs) are the most popular among the adult stem cells in tissue engineering and regenerative medicine. Since their discovery and functional characterization in the late 1960s and early 1970s, MSCs or MSC-like cells have been obtained from various mesodermal and non-mesodermal tissues, although majority of the therapeutic applications involved bone marrow-derived MSCs. Based on its mesenchymal origin, it was predicted earlier that MSCs only can differentiate into mesengenic lineages like bone, cartilage, fat or muscle. However, varied isolation and cell culturing methods identified subsets of MSCs in the bone marrow which not only differentiated into mesenchymal lineages, but also into ectodermal and endodermal derivatives. Although, true pluripotent status is yet to be established, MSCs have been successfully used in bone and cartilage regeneration in osteoporotic fracture and arthritis, respectively, and in the repair of cardiac tissue following myocardial infarction. Immunosuppressive properties of MSCs extend utility of MSCs to reduce complications of graft versus host disease and rheumatoid arthritis. Homing of MSCs to sites of tissue injury, including tumor, is well established. In addition to their ability in tissue regeneration, MSCs can be genetically engineered ex vivo for delivery of therapeutic molecule(s) to the sites of injury or tumorigenesis as cell therapy vehicles. MSCs tend to lose surface receptors for trafficking and have been reported to develop sarcoma in long-term culture. In this article, we reviewed the current status of MSCs with special emphasis to therapeutic application in bone-related diseases.
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Affiliation(s)
- Diptiman Chanda
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0007, USA
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Lodi D, Iannitti T, Palmieri B. Stem cells in clinical practice: applications and warnings. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2011; 30:9. [PMID: 21241480 PMCID: PMC3033847 DOI: 10.1186/1756-9966-30-9] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/26/2010] [Accepted: 01/17/2011] [Indexed: 12/11/2022]
Abstract
Stem cells are a relevant source of information about cellular differentiation, molecular processes and tissue homeostasis, but also one of the most putative biological tools to treat degenerative diseases. This review focuses on human stem cells clinical and experimental applications. Our aim is to take a correct view of the available stem cell subtypes and their rational use in the medical area, with a specific focus on their therapeutic benefits and side effects. We have reviewed the main clinical trials dividing them basing on their clinical applications, and taking into account the ethical issue associated with the stem cell therapy.
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Affiliation(s)
- Daniele Lodi
- Department of Nephrology, Dialysis and Transplantation, University of Modena and Reggio Emilia Medical School, Modena, Italy
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Constraints to Articular Cartilage Regeneration. Regen Med 2011. [DOI: 10.1007/978-90-481-9075-1_37] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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da Silva MA, Martins A, Teixeira AA, Reis RL, Neves NM. Impact of biological agents and tissue engineering approaches on the treatment of rheumatic diseases. TISSUE ENGINEERING PART B-REVIEWS 2010; 16:331-9. [PMID: 20025434 DOI: 10.1089/ten.teb.2009.0536] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The treatment of rheumatic diseases has been the focus of many clinical studies aiming to achieve the best combination of drugs for symptom reduction. Although improved understanding of the pathophysiology of rheumatic diseases has led to the identification of effective therapeutic strategies, its cure remains unknown. Biological agents are a breakthrough in the treatment of these diseases. They proved to be more effective than the other conventional therapies in refractory inflammatory rheumatic diseases. Among them, tumor necrosis factor inhibitors are widely used, namely Etanercept, Infliximab, or Adalimumab, alone or in combination with disease-modifying antirheumatic drugs. Nevertheless, severe adverse effects have been detected in patients with history of recurrent infections, including cardiac failure or malignancy. Currently, most of the available therapies for rheumatic diseases do not have sufficient tissue specificity. Consequently, high drug doses must be administrated systemically, leading to adverse side effects associated with its possible toxicity. Drug delivery systems, by its targeted nature, are excellent solutions to overcome this problem. In this review, we will describe the state-of-the-art in clinical studies on the treatment of rheumatic diseases, emphasizing the use of biological agents and target drug delivery systems. Some alternative novel strategies of regenerative medicine and its implications for rheumatic diseases will also be discussed.
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Dehne T, Schenk R, Perka C, Morawietz L, Pruss A, Sittinger M, Kaps C, Ringe J. Gene expression profiling of primary human articular chondrocytes in high-density micromasses reveals patterns of recovery, maintenance, re- and dedifferentiation. Gene 2010; 462:8-17. [PMID: 20433912 DOI: 10.1016/j.gene.2010.04.006] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2009] [Revised: 03/07/2010] [Accepted: 04/16/2010] [Indexed: 12/13/2022]
Abstract
The high-density micromass culture has been widely applied to study chondrocyte cell physiology and pathophysiological mechanisms. Since an integrated image has not been established so far, we analyzed the phenotypic alterations of human articular chondrocytes in this model on the broad molecular level. Freshly isolated chondrocytes were assembled as micromasses and maintained up to 6 weeks in medium containing human serum. Formation of cartilaginous extracellular matrix (ECM) was evaluated by histological and immunohistochemical staining. At 0, 3 and 6 weeks, chondrocyte micromasses were subjected to gene expression analysis using oligonucleotide microarrays and real-time RT-PCR. Micromasses developed a cartilaginous ECM rich in proteoglycans and type II collagen. On gene expression level, time-dependent expression patterns was observed. The induction of genes associated with cartilage-specific ECM (COL2A1 and COL11A1) and developmental signaling (GDF5, GDF10, ID1, ID4 and FGFR1-3) indicated redifferentiation within the first 3 weeks. The repression of genes related to stress response (HSPA1A and HSPA4), apoptotic events (HYOU1, NFKBIA and TRAF1), and degradation (MMP1, MMP10 and MMP12) suggested a recovery of chondrocytes. Constant expression of other chondrogenic (ACAN, FN1 and MGP) and hypertrophic markers (COL10A1, ALPL, PTHR1 and PTHR2) indicated a pattern of phenotypic maintenance. Simultaneously, the expression of chondrogenic growth (BMP6, TGFA, FGF1 and FGF2) and transcription factors (SOX9, EGR1, HES1 and TGIF1), and other cartilage ECM-related genes (COMP and PRG4) was consistently repressed and expression of collagens related to dedifferentiation (COL1A1 and COL3A1) was steadily induced indicating a progressing loss of cartilage phenotype. Likewise, a steady increase of genes associated with proliferation (GAS6, SERPINF1, VEGFB and VEGFC) and apoptosis (DRAM, DPAK1, HSPB, GPX1, NGFRAP1 and TIA1) was observed. Sequence and interplay of identified expression patterns suggest that chondrocyte micromass cultures maintain a differentiated phenotype up to 3 weeks in vitro and might be useful for studying chondrocyte biology, pathophysiology and differentiation. Cultivation longer than 6 weeks leads to progressing dedifferentiation of chondrocytes that should be considered on long-term evaluations.
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Affiliation(s)
- Tilo Dehne
- Tissue Engineering Laboratory and Berlin-Brandenburg Center for Regenerative Therapies, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Tucholskystrasse 2, 10117 Berlin, Germany.
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