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Dhillon J, Maguire JA, Kraeutler MJ. Stromal cell-based injection therapies for the treatment of knee osteoarthritis: A systematic review of level I randomized controlled trials. OSTEOARTHRITIS AND CARTILAGE OPEN 2025; 7:100608. [PMID: 40290651 PMCID: PMC12033899 DOI: 10.1016/j.ocarto.2025.100608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 03/27/2025] [Indexed: 04/30/2025] Open
Abstract
Objective To systematically review randomized controlled trials (RCTs) to compare clinical outcomes of stromal cell-based injection therapies versus other non-operative treatment modalities for the treatment of knee osteoarthritis (OA). Method A systematic review was performed by searching PubMed, Cochrane Library, and EMBASE to locate RCTs, published since 2019, comparing stromal cell-based injection therapies versus other non-operative modalities for the treatment of knee OA. The search terms used were: knee AND osteoarthritis AND injection AND randomized. Results Seventeen studies (all Level I evidence) were included in this review with 972 patients undergoing treatment with stromal cell-based therapy (Intervention Group) and 651 patients in the control group (Control Group). Among the 17 studies, 7 used autologous adipose-derived mesenchymal stromal cells (MSCs) (ADMSCs), 2 studies used allogeneic ADMSCs, 4 used autologous bone marrow-derived MSCs (BMMSCs), 1 used allogeneic BMMSCs, 1 used allogeneic placental MSCs, 1 used umbilical cord-derived MSCs (UCMSCs), and 1 study used autologous ADMSCs, BMMSCs, or allogeneic UCMSCs. All but 3 studies reported significantly better clinical or radiological outcomes in the Intervention Group at final follow-up. A total of 5 and 3 studies reported adverse events occurring in the Intervention and the Control groups, respectively, but they were all self-limiting. Conclusions Patients undergoing treatment of knee OA with MSCs might be expected to experience improvements in clinical and radiological outcomes in comparison to other non-operative modalities. Additional studies with mid-to long-term outcomes are needed to better determine the efficacy and safety of MSCs for the treatment of knee OA.
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Affiliation(s)
- Jaydeep Dhillon
- Samaritan Health Services, Department of Orthopedics, Corvallis, OR 97330, USA
| | - James A. Maguire
- St. Joseph's University Medical Center, Department of Orthopaedic Surgery, Paterson, NJ 07503, USA
| | - Matthew J. Kraeutler
- Texas Tech University Health Sciences Center, Department of Orthopaedic Surgery & Rehabilitation, Lubbock, TX 79430, USA
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Yi J, Byun Y, Kang SS, Shim KM, Jang K, Lee JY. Enhanced Chondrogenic Differentiation of Electrically Primed Human Mesenchymal Stem Cells for the Regeneration of Osteochondral Defects. Biomater Res 2024; 28:0109. [PMID: 39697183 PMCID: PMC11654951 DOI: 10.34133/bmr.0109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 10/12/2024] [Accepted: 10/26/2024] [Indexed: 12/20/2024] Open
Abstract
Background: Mesenchymal stem cells (MSCs) offer a promising avenue for cartilage regeneration; however, their therapeutic efficacy requires substantial improvement. Cell priming using electrical stimulation (ES) is a promising approach to augmenting the therapeutic potential of MSCs and has shown potential for various regenerative applications. This study aimed to promote the ES-mediated chondrogenic differentiation of human MSCs and facilitate the repair of injured articular cartilage. Methods: MSCs were subjected to ES under various conditions (e.g., voltage, frequency, and number of repetitions) to enhance their capability of chondrogenesis and cartilage regeneration. Chondrogenic differentiation of electrically primed MSCs (epMSCs) was assessed based on gene expression and sulfated glycosaminoglycan production, and epMSCs with hyaluronic acid were transplanted into a rat osteochondral defect model. Transcriptomic analysis was performed to determine changes in gene expression by ES. Results: epMSCs exhibited significantly increased chondrogenic gene expression and sulfated glycosaminoglycan production compared with those in unstimulated controls. Macroscopic and histological results showed that in vivo epMSC transplantation considerably enhanced cartilage regeneration. Furthermore, ES markedly altered the expression of numerous genes of MSCs, including those associated with the extracellular matrix, the Wnt signaling pathway, and cartilage development. Conclusion: ES can effectively prime MSCs to improve articular cartilage repair, offering a promising strategy for enhancing the efficacy of various MSC-based therapies.
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Affiliation(s)
- Jongdarm Yi
- School of Materials Science and Engineering,
Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Yujin Byun
- Department of Veterinary Surgery, College of Veterinary Medicine and BK21 FOUR Program,
Chonnam National University, Gwangju 61186, Republic of Korea
- Biomaterial R&BD Center,
Chonnam National University, Gwangju 61186, Republic of Korea
| | - Seong Soo Kang
- Department of Veterinary Surgery, College of Veterinary Medicine and BK21 FOUR Program,
Chonnam National University, Gwangju 61186, Republic of Korea
- Biomaterial R&BD Center,
Chonnam National University, Gwangju 61186, Republic of Korea
| | - Kyung Mi Shim
- Department of Veterinary Surgery, College of Veterinary Medicine and BK21 FOUR Program,
Chonnam National University, Gwangju 61186, Republic of Korea
- Biomaterial R&BD Center,
Chonnam National University, Gwangju 61186, Republic of Korea
| | - Kwangsik Jang
- Department of Veterinary Surgery, College of Veterinary Medicine and BK21 FOUR Program,
Chonnam National University, Gwangju 61186, Republic of Korea
- Biomaterial R&BD Center,
Chonnam National University, Gwangju 61186, Republic of Korea
| | - Jae Young Lee
- School of Materials Science and Engineering,
Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
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3
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AlOraibi S, Taurin S, Alshammary S. Advancements in Umbilical Cord Biobanking: A Comprehensive Review of Current Trends and Future Prospects. Stem Cells Cloning 2024; 17:41-58. [PMID: 39655226 PMCID: PMC11626973 DOI: 10.2147/sccaa.s481072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 11/01/2024] [Indexed: 12/12/2024] Open
Abstract
Biobanking has emerged as a transformative concept in advancing the medical field, particularly with the exponential growth of umbilical cord (UC) biobanking in recent decades. UC blood and tissue provide a rich source of primitive hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) for clinical transplantation, offering distinct advantages over alternative adult stem cell sources. However, to fully realize the therapeutic potential of UC-derived stem cells and establish a comprehensive global UC-biobanking network, it is imperative to optimize and standardize UC processing, cryopreservation methods, quality control protocols, and regulatory frameworks, alongside developing effective consent provisions. This review aims to comprehensively explore recent advancements in UC biobanking, focusing on the establishment of rigorous safety and quality control procedures, the standardization of biobanking operations, and the optimization and automation of UC processing and cryopreservation techniques. Additionally, the review examines the expanded clinical applications of UC stem cells, addresses the challenges associated with umbilical cord biobanking and UC-derived stem cell therapies, and discusses the promising role of artificial intelligence (AI) in enhancing various operational aspects of biobanking, streamlining data processing, and improving data analysis accuracy while ensuring compliance with safety and quality standards. By addressing these critical areas, this review seeks to provide insights into the future direction of UC biobanking and its potential to significantly impact regenerative medicine.
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Affiliation(s)
- Sahar AlOraibi
- Molecular Medicine Department, Princess Al Jawhara Center for Molecular Medicine, Genetics, and Hereditary Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
| | - Sebastien Taurin
- Molecular Medicine Department, Princess Al Jawhara Center for Molecular Medicine, Genetics, and Hereditary Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
| | - Sfoug Alshammary
- Molecular Medicine Department, Princess Al Jawhara Center for Molecular Medicine, Genetics, and Hereditary Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
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4
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Souza-Silva LC, Martignago CCS, Motta HG, Bonifacio M, Regina Avanzi I, Assis L, Ribeiro DA, Parisi JR, Rennó AC. A Review of Cartilage Defect Treatments Using Chitosan Hydrogels in Experimental Animal Models. Curr Pharm Biotechnol 2024; 25:1058-1072. [PMID: 37916637 DOI: 10.2174/0113892010245946230919062908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 06/08/2023] [Accepted: 06/20/2023] [Indexed: 11/03/2023]
Abstract
INTRODUCTION Chitosan (CS) is a polycationic polysaccharide comprising glucosamine and N-acetylglucosamine and constitutes a potential material for use in cartilage tissue engineering. Moreover, CS hydrogels are able to promote the expression of cartilage matrix components and reduce inflammatory and catabolic mediator production by chondrocytes. Although all the positive outcomes, no review has analyzed the effects of CS hydrogels on cartilage repair in animal models. METHODS This study aimed to review the literature to examine the effects of CS hydrogels on cartilage repair in experimental animal models. The search was done by the descriptors of the Medical Subject Headings (MeSH) defined below: "Chitosan," "hydrogel," "cartilage repair," and "in vivo." A total of 420 articles were retrieved from the databases Pubmed, Scopus, Embase, Lilacs, and Web of Science. After the eligibility analyses, this review reported 9 different papers from the beginning of 2002 through the middle of 2022. RESULTS It was found that cartilage repair was improved with the treatment of CS hydrogel, especially the one enriched with cells. In addition, CS hydrogel produced an upregulation of genes and proteins that act in the cartilage repair process, improving the biomechanical properties of gait.. CONCLUSION In conclusion, CS hydrogels were able to stimulate tissue ingrowth and accelerate the process of cartilage repair in animal studies.
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Affiliation(s)
- Lais Caroline Souza-Silva
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Santos, SP, 11015020, Brazil
| | | | - Homero Garcia Motta
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Santos, SP, 11015020, Brazil
| | - Mirian Bonifacio
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Santos, SP, 11015020, Brazil
| | - Ingrid Regina Avanzi
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Santos, SP, 11015020, Brazil
| | - Lívia Assis
- Scientific and Technological Institute, Brazil University, São Paulo, 08230-030, Brazil
| | - Daniel Araki Ribeiro
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Santos, SP, 11015020, Brazil
| | - Julia Risso Parisi
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Santos, SP, 11015020, Brazil
- Metropolitan University of Santos (UNIMES), General Francisco Glicério Avenue, 8, Santos, SP, 11045-002, Brazil
| | - Ana Claudia Rennó
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Santos, SP, 11015020, Brazil
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Sun L, Xu Y, Han Y, Cui J, Jing Z, Li D, Liu J, Xiao C, Li D, Cai B. Collagen-Based Hydrogels for Cartilage Regeneration. Orthop Surg 2023; 15:3026-3045. [PMID: 37942509 PMCID: PMC10694028 DOI: 10.1111/os.13884] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 08/13/2023] [Accepted: 08/15/2023] [Indexed: 11/10/2023] Open
Abstract
Cartilage regeneration remains difficult due to a lack of blood vessels. Degradation of the extracellular matrix (ECM) causes cartilage defects, and the ECM provides the natural environment and nutrition for cartilage regeneration. Until now, collagen hydrogels are considered to be excellent material for cartilage regeneration due to the similar structure to ECM and good biocompatibility. However, collagen hydrogels also have several drawbacks, such as low mechanical strength, limited ability to induce stem cell differentiation, and rapid degradation. Thus, there is a demanding need to optimize collagen hydrogels for cartilage regeneration. In this review, we will first briefly introduce the structure of articular cartilage and cartilage defect classification and collagen, then provide an overview of the progress made in research on collagen hydrogels with chondrocytes or stem cells, comprehensively expound the research progress and clinical applications of collagen-based hydrogels that integrate inorganic or organic materials, and finally present challenges for further clinical translation.
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Affiliation(s)
- Lihui Sun
- Division of Bone and Joint Surgery, Center of OrthopaedicsFirst Hospital of Jilin UniversityChangchunPeople's Republic of China
| | - Yan Xu
- Division of Bone and Joint Surgery, Center of OrthopaedicsFirst Hospital of Jilin UniversityChangchunPeople's Republic of China
| | - Yu Han
- Division of Bone and Joint Surgery, Center of OrthopaedicsFirst Hospital of Jilin UniversityChangchunPeople's Republic of China
| | - Jing Cui
- Jilin Provincial Key Laboratory of Oral Biomedical Engineering, School and Hospital of StomatologyJilin UniversityChangchunChina
| | - Zheng Jing
- Division of Bone and Joint Surgery, Center of OrthopaedicsFirst Hospital of Jilin UniversityChangchunPeople's Republic of China
| | - Dongbo Li
- Division of Bone and Joint Surgery, Center of OrthopaedicsFirst Hospital of Jilin UniversityChangchunPeople's Republic of China
| | - Jianguo Liu
- Division of Bone and Joint Surgery, Center of OrthopaedicsFirst Hospital of Jilin UniversityChangchunPeople's Republic of China
| | - Chunsheng Xiao
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchunPeople's Republic of China
| | - Dongsong Li
- Division of Bone and Joint Surgery, Center of OrthopaedicsFirst Hospital of Jilin UniversityChangchunPeople's Republic of China
| | - Bo Cai
- Department of Ultrasound DiagnosisThe 964 Hospital of Chinese People's Liberation ArmyChangchunPeople's Republic of China
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Xu J, Hsu SH. Self-healing hydrogel as an injectable implant: translation in brain diseases. J Biomed Sci 2023; 30:43. [PMID: 37340481 DOI: 10.1186/s12929-023-00939-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 06/13/2023] [Indexed: 06/22/2023] Open
Abstract
Tissue engineering biomaterials are aimed to mimic natural tissue and promote new tissue formation for the treatment of impaired or diseased tissues. Highly porous biomaterial scaffolds are often used to carry cells or drugs to regenerate tissue-like structures. Meanwhile, self-healing hydrogel as a category of smart soft hydrogel with the ability to automatically repair its own structure after damage has been developed for various applications through designs of dynamic crosslinking networks. Due to flexibility, biocompatibility, and ease of functionalization, self-healing hydrogel has great potential in regenerative medicine, especially in restoring the structure and function of impaired neural tissue. Recent researchers have developed self-healing hydrogel as drug/cell carriers or tissue support matrices for targeted injection via minimally invasive surgery, which has become a promising strategy in treating brain diseases. In this review, the development history of self-healing hydrogel for biomedical applications and the design strategies according to different crosslinking (gel formation) mechanisms are summarized. The current therapeutic progress of self-healing hydrogels for brain diseases is described as well, with an emphasis on the potential therapeutic applications validated by in vivo experiments. The most recent aspect as well as the design rationale of self-healing hydrogel for different brain diseases is also addressed.
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Affiliation(s)
- Junpeng Xu
- Institute of Polymer Science and Engineering, National Taiwan University, No. 1, Sec. 4 Roosevelt Road, Taipei, 106319, Taiwan, Republic of China
| | - Shan-Hui Hsu
- Institute of Polymer Science and Engineering, National Taiwan University, No. 1, Sec. 4 Roosevelt Road, Taipei, 106319, Taiwan, Republic of China.
- Institute of Cellular and System Medicine, National Health Research Institutes, No. 35 Keyan Road, Miaoli, 350401, Taiwan, Republic of China.
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Mokhtarinia K, Rezvanian P, Masaeli E. Sustainable hydrogel-based cell therapy. SUSTAINABLE HYDROGELS 2023:443-470. [DOI: 10.1016/b978-0-323-91753-7.00009-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Song JS, Hong KT, Song KJ, Kim SJ. Repair of a large patellar cartilage defect using human umbilical cord blood-derived mesenchymal stem cells: A case report. World J Clin Cases 2022; 10:12665-12670. [PMID: 36579106 PMCID: PMC9791508 DOI: 10.12998/wjcc.v10.i34.12665] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 09/10/2022] [Accepted: 11/02/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Patellar dislocation may cause cartilage defects of various sizes. Large defects commonly require surgical treatment; however, conventional treatments are problematic.
CASE SUMMARY A 15-year-old male with a large patellar cartilage defect due to patellar dislocation was treated via human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) implantation. To our knowledge, this is the first report of this treatment for this purpose. The patient recovered well as indicated by good visual analog scale, International Knee Documentation Committee and McMaster Universities Osteoarthritis Index scores. Magnetic resonance imaging showed cartilage regeneration 18 mo postoperatively.
CONCLUSION Umbilical cord blood-derived hUCB-MSCs may be a useful treatment option for the repair of large patellar cartilage defects.
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Affiliation(s)
- Jun-Seob Song
- Department of Orthopedic Surgery, Gangnam JS Hospital, Seoul 06053, South Korea
| | - Ki-Taek Hong
- Department of Orthopedic Surgery, Gangnam JS Hospital, Seoul 06053, South Korea
| | - Ki Jeon Song
- Department of Orthopedic Surgery, Uijeongbu Street Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 11765, Gyeonggi-do, South Korea
| | - Seok Jung Kim
- Department of Orthopedic Surgery, Uijeongbu Street Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 11765, Gyeonggi-do, South Korea
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Kim M, Ahn J, Lee J, Song S, Lee S, Lee S, Kang KS. Combined Mesenchymal Stem Cells and Cartilage Acellular Matrix Injection Therapy for Osteoarthritis in Goats. Tissue Eng Regen Med 2022; 19:177-187. [PMID: 35023025 PMCID: PMC8782990 DOI: 10.1007/s13770-021-00407-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Human umbilical cord blood-derived MSCs (hUCB-MSCs) have been studied in osteoarthritis (OA) and cartilage regeneration. Our previous study demonstrated that hUCB-MSCs combined with cartilage acellular matrix injection (CAM Inj.) represent potential therapeutic agents for structural improvement and anti-inflammatory effects in a rabbit model of OA. METHODS Based on a previous study, this study has evaluated the safety and efficacy of hUCB-MSCs combined with CAM Inj. in an anterior cruciate ligament transection (ACLT) with medial meniscectomy (MMx) in a goat model. In this study, 27 goats were divided into 5 groups: normal (n = 3), OA (n = 6), OA + CAM Inj. (n = 6), OA + hUCB-MSCs (n = 6), and OA + hUCB-MSCs + CAM Inj. (n = 6). Lameness and radiographic parameters were assessed 6 months after administration, and macroscopic and histological evaluations of the goat articular cartilage were performed 6 months after intervention. RESULTS The results showed significant improvement in lameness score only in the OA + hUCB-MSCs group at 5 months after treatment (*p < 0.05), whereas the K&L score showed significant improvement only in the OA + hUCB-MSCs + CAM Inj. group 6 months after intervention (*p < 0.05). In addition, the gross findings showed significance in OA + CAM Inj. and OA + hUCB-MSCs + CAM Inj. groups 6 months after treatment (*p < 0.05 and **p < 0.01). CONCLUSION In conclusion, treatment with a combination of hUCB-MSCs and CAM Inj. reduced OA symptoms and induced effective cartilage tissue repair in a goat model. We suggest the combination of hUCB-MSCs and CAM Inj. as an alternative therapy for OA.
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Affiliation(s)
- Mijin Kim
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co. Ltd., Ace Highend Tower 8, 84, Gasan digital 1-ro, Geumcheon-gu, Seoul, 08590, Republic of Korea
| | - Jongchan Ahn
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co. Ltd., Ace Highend Tower 8, 84, Gasan digital 1-ro, Geumcheon-gu, Seoul, 08590, Republic of Korea
| | - Jusik Lee
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co. Ltd., Ace Highend Tower 8, 84, Gasan digital 1-ro, Geumcheon-gu, Seoul, 08590, Republic of Korea
| | - Seongsoo Song
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co. Ltd., Ace Highend Tower 8, 84, Gasan digital 1-ro, Geumcheon-gu, Seoul, 08590, Republic of Korea
| | - Seunghee Lee
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co. Ltd., Ace Highend Tower 8, 84, Gasan digital 1-ro, Geumcheon-gu, Seoul, 08590, Republic of Korea
| | - Seunghee Lee
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co. Ltd., Ace Highend Tower 8, 84, Gasan digital 1-ro, Geumcheon-gu, Seoul, 08590, Republic of Korea.
| | - Kyung-Sun Kang
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co. Ltd., Ace Highend Tower 8, 84, Gasan digital 1-ro, Geumcheon-gu, Seoul, 08590, Republic of Korea.
- Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
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Hu X, Xia Z, Cai K. Recent advances of 3D hydrogel culture systems for mesenchymal stem cell-based therapy and cell behavior regulation. J Mater Chem B 2022; 10:1486-1507. [DOI: 10.1039/d1tb02537f] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Mesenchymal stem cells (MSCs) have been increasingly recognized as resources for disease treatments and regenerative medicine. Meanwhile, the unique chemical and physical properties of hydrogels provide innate advantages to achieve...
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Lee NH, Na SM, Ahn HW, Kang JK, Seon JK, Song EK. Allogenic Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Are More Effective Than Bone Marrow Aspiration Concentrate for Cartilage Regeneration After High Tibial Osteotomy in Medial Unicompartmental Osteoarthritis of Knee. Arthroscopy 2021; 37:2521-2530. [PMID: 33621649 DOI: 10.1016/j.arthro.2021.02.022] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 02/08/2021] [Accepted: 02/11/2021] [Indexed: 02/02/2023]
Abstract
PURPOSE The purpose of this study was to compare the outcome of cartilage regeneration between bone marrow aspirate concentrate (BMAC) augmentation and allogeneic human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSCs) transplantation in high tibial osteotomy (HTO) with microfracture (MFX) for medial unicompartmental osteoarthritis (OA) of the knee in the young and active patient. METHODS Between January 2015 and December 2019, the patients who underwent HTO and arthroscopy with MFX combined with BMAC or allogeneic hUCB-MSCs procedure for medial unicompartmental OA with kissing lesion, which was shown full-thickness cartilage defect (≥ International Cartilage Repair Society [ICRS] grade 3B) in medial femoral cartilage and medial tibial cartilage, were include in this study. Retrospectively we compared clinical outcomes, including Hospital for Special Surgery score, Knee Society Score (KSS) pain and function, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score between BMAC and hUCB-MSCs group at minimum of 1-year follow-up. Also, second-look arthroscopy was performed simultaneously with removal of the plate after complete bone union. Cartilage regeneration was graded by the ICRS grading system at second-look arthroscopy. Radiological measurement including hip-knee-ankle (HKA) angle, posterior tibial slope angle, and correction angle were assessed. RESULTS Of 150 cases that underwent HTO with MFX combined with BMAC or allogeneic hUCB-MSCs procedure for medial unicompartmental OA, 123 cases underwent plate removal and second-look arthroscopy after a minimum of 1 year after the HTO surgery. Seventy-four cases were kissing lesion in medial femoral cartilage and medial tibial cartilage during initial HTO surgery. Finally, the BMAC group composed of 42 cases and hUCB-MSCs group composed of 32 cases were retrospectively identified in patients who had kissing lesions and second-look arthroscopies with a minimum of 1 year of follow-up. At the final follow-up of mean 18.7 months (standard deviation = 4.6 months), clinical outcomes in both groups had improved. However, there were no significant differences between the IKDC, WOMAC, or KSS pain and function scores in the 2 groups (P > .05). At second-look arthroscopy, the ICRS grade was significantly better in the hUCB-MSC group than in the BMAC group in both medial femoral and medial tibial cartilage (P = .001 for both). The average ICRS grade of the BMAC group improved from 3.9 before surgery to 2.8 after surgery. The average ICRS grade of the hUBC-MSC group improved from 3.9 before surgery to 2.0 after surgery. Radiological findings comparing postoperative HKA angle, posterior tibial slope angle, and correction angle showed no significant differences between the groups (P > .05). Therefore it was found that the postoperative correction amount did not affect the postoperative cartilage regeneration results. CONCLUSIONS We found that the hUCB-MSC procedure was more effective than the BMAC procedure for cartilage regeneration in medial unicompartmental knee OA even though the clinical outcomes improved regardless of which treatment was administered. LEVEL OF EVIDENCE Level III, retrospective comparative study.
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Affiliation(s)
- Nam-Hun Lee
- Department of Orthopaedic Surgery, Chonnam National University Medical School and Hospital, Hwasun, Republic of Korea
| | - Seung-Min Na
- Department of Orthopaedic Surgery, Chonnam National University Medical School and Hospital, Hwasun, Republic of Korea
| | - Hyeon-Wook Ahn
- Department of Orthopaedic Surgery, Chonnam National University Medical School and Hospital, Hwasun, Republic of Korea
| | - Joon-Kyoo Kang
- Department of Orthopaedic Surgery, Chonnam National University Medical School and Hospital, Hwasun, Republic of Korea
| | - Jong-Keun Seon
- Department of Orthopaedic Surgery, Chonnam National University Medical School and Hospital, Hwasun, Republic of Korea.
| | - Eun-Kyoo Song
- Department of Orthopaedic Surgery, Chonnam National University Medical School and Hospital, Hwasun, Republic of Korea
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Shamma RN, Sayed RH, Madry H, El Sayed NS, Cucchiarini M. Triblock Copolymer Bioinks in Hydrogel Three-Dimensional Printing for Regenerative Medicine: A Focus on Pluronic F127. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:451-463. [PMID: 33820451 DOI: 10.1089/ten.teb.2021.0026] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Three-dimensional (3D) bioprinting is a novel technique applied to manufacture semisolid or solid objects via deposition of successive thin layers. The widespread implementation of the 3D bioprinting technology encouraged scientists to evaluate its feasibility for applications in human regenerative medicine. 3D bioprinting gained much interest as a new strategy to prepare implantable 3D tissues or organs, tissue and organ evaluation models to test drugs, and cell/material interaction systems. The present work summarizes recent and relevant progress based on the use of hydrogels for the technology of 3D bioprinting and their emerging biomedical applications. An overview of different 3D printing techniques in addition to the nature and properties of bioinks used will be described with a focus on hydrogels as suitable bioinks for 3D printing. A comprehensive overview of triblock copolymers with emphasis on Pluronic F127 (PF127) as a bioink in 3D printing for regenerative medicine will be provided. Several biomedical applications of PF127 in tissue engineering, particularly in bone and cartilage regeneration and in vascular reconstruction, will be also discussed.
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Affiliation(s)
- Rehab N Shamma
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Rabab H Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Henning Madry
- Center of Experimental Orthopaedics, Saarland University Medical Center, Homburg, Germany
| | - Nesrine S El Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Magali Cucchiarini
- Center of Experimental Orthopaedics, Saarland University Medical Center, Homburg, Germany
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13
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Wang AT, Zhao M, Feng Y, Jia H, Zhang L, Yu H, Li Z, Han Z, Han Z. Multifaceted Optimization of MSC-Based Formulation upon Sodium Iodoacetate-Induced Osteoarthritis Models by Combining Advantageous HA/PG Hydrogel and Fluorescent Tracer. Stem Cells Int 2021; 2021:1-13. [DOI: 10.1155/2021/8827212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Abstract
Owing to the boundedness of conventional remedies upon articular cartilage for self-rehabilitation and the incrementally senior citizens, the incidence of osteoarthritis (OA) is increasing worldwide. Empirical studies have revealed the advantageous and promising potentials of mesenchymal stem/stromal cells (MSCs) on the refractory OA, whereas the deficiency of systematic and detailed exploration of MSC-based therapy largely hampers the large-scale applications in regenerative medicine. Herein, we initially utilized the monosodium iodoacetate- (MIA-) induced OA rabbit models and investigated the therapeutic effect of human umbilical cord-derived UC-MSCs at serial dose gradients with the splendid hyaluronic acid and/or propylene glycol hydrogels (HA, HA/PG), respectively. Afterwards, we turned to a dual-luciferase reporter tracing system and evaluated the spatiotemporal distribution and metabolokinetics of bifluorescence expressing UC-MSCs (BF-MSCs) in OA rats. Of the aforementioned trials, we verified that the combination of HA/PG and middle-dose MSCs (
cells/ml) eventually manifested the optimal efficacy on OA rabbits. Furthermore, with the aid of the bioluminescence imaging (BLI) technology for dynamic in vitro and in vivo tracking, we intuitively delineated the spatiotemporal distribution and therapeutic process of BF-MSCs in OA rats, which substantially confirmed the reinforcement of HA/PG on BF-MSCs for OA treatment. Collectively, our data conformably demonstrated that the middle dose of UC-MSCs combined with HA/PG hydrogel was sufficient for optimal MSC-based formulation for blocking OA progression and promoting cartilage repair, which supplied overwhelming new references and enlightened MSC-based therapeutic strategies for cartilage defects.
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Affiliation(s)
- Ai-tong Wang
- Cell Products of National Engineering Center & National Stem Cell Engineering Research Center, Tianjin IMCELL Stem Cell and Gene Technology Co., Ltd., Tianjin, China
| | - Meng Zhao
- Cell Products of National Engineering Center & National Stem Cell Engineering Research Center, Tianjin IMCELL Stem Cell and Gene Technology Co., Ltd., Tianjin, China
| | - Ying Feng
- Cell Products of National Engineering Center & National Stem Cell Engineering Research Center, Tianjin IMCELL Stem Cell and Gene Technology Co., Ltd., Tianjin, China
| | - Honghong Jia
- Cell Products of National Engineering Center & National Stem Cell Engineering Research Center, Tianjin IMCELL Stem Cell and Gene Technology Co., Ltd., Tianjin, China
| | - Leisheng Zhang
- The Postdoctoral Research Station, School of Medicine, Nankai University, Tianjin, China
- Precision Medicine Division, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., Tianjin 301700, China
- State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Jiangxi Research Center of Stem Cell Engineering, Jiangxi Health-Biotech Stem Cell Technology Co., Ltd., Shangrao 334000, China
| | - Hao Yu
- Cell Products of National Engineering Center & National Stem Cell Engineering Research Center, Tianjin IMCELL Stem Cell and Gene Technology Co., Ltd., Tianjin, China
| | - Zongjin Li
- The Postdoctoral Research Station, School of Medicine, Nankai University, Tianjin, China
| | - Zhibo Han
- Cell Products of National Engineering Center & National Stem Cell Engineering Research Center, Tianjin IMCELL Stem Cell and Gene Technology Co., Ltd., Tianjin, China
- State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Zhongchao Han
- Cell Products of National Engineering Center & National Stem Cell Engineering Research Center, Tianjin IMCELL Stem Cell and Gene Technology Co., Ltd., Tianjin, China
- Precision Medicine Division, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., Tianjin 301700, China
- State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Jiangxi Research Center of Stem Cell Engineering, Jiangxi Health-Biotech Stem Cell Technology Co., Ltd., Shangrao 334000, China
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14
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Lim HC, Park YB, Ha CW, Cole BJ, Lee BK, Jeong HJ, Kim MK, Bin SI, Choi CH, Choi CH, Yoo JD, Yoon JR, Chung JY. Allogeneic Umbilical Cord Blood-Derived Mesenchymal Stem Cell Implantation Versus Microfracture for Large, Full-Thickness Cartilage Defects in Older Patients: A Multicenter Randomized Clinical Trial and Extended 5-Year Clinical Follow-up. Orthop J Sports Med 2021; 9:2325967120973052. [PMID: 33490296 PMCID: PMC7809531 DOI: 10.1177/2325967120973052] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 06/17/2020] [Indexed: 12/16/2022] Open
Abstract
Background: There is currently no optimal method for cartilage restoration in large, full-thickness cartilage defects in older patients. Purpose: To determine whether implantation of a composite of allogeneic umbilical cord blood–derived mesenchymal stem cells and 4% hyaluronate (UCB-MSC-HA) will result in reliable cartilage restoration in patients with large, full-thickness cartilage defects and whether any clinical improvements can be maintained up to 5 years postoperatively. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A randomized controlled phase 3 clinical trial was conducted for 48 weeks, and the participants then underwent extended 5-year observational follow-up. Enrolled were patients with large, full-thickness cartilage defects (International Cartilage Repair Society [ICRS] grade 4) in a single compartment of the knee joint, as confirmed by arthroscopy. The defect was treated either with UCB-MSC-HA implantation through mini-arthrotomy or with microfracture. The primary outcome was proportion of participants who improved by ≥1 grade on the ICRS Macroscopic Cartilage Repair Assessment (blinded evaluation) at 48-week arthroscopy. Secondary outcomes included histologic assessment; changes in pain visual analog scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and International Knee Documentation Committee (IKDC) score from baseline; and adverse events. Results: Among 114 randomized participants (mean age, 55.9 years; 67% female; body mass index, 26.2 kg/m2), 89 completed the phase 3 clinical trial and 73 were enrolled in the 5-year follow-up study. The mean defect size was 4.9 cm2 in the UCB-MSC-HA group and 4.0 cm2 in the microfracture group (P = .051). At 48 weeks, improvement by ≥1 ICRS grade was seen in 97.7% of the UCB-MSC-HA group versus 71.7% of the microfracture group (P = .001); the overall histologic assessment score was also superior in the UCB-MSC-HA group (P = .036). Improvement in VAS pain, WOMAC, and IKDC scores were not significantly different between the groups at 48 weeks, however the clinical results were significantly better in the UCB-MSC-HA group at 3- to 5-year follow-up (P < .05). There were no differences between the groups in adverse events. Conclusion: In older patients with symptomatic, large, full-thickness cartilage defects with or without osteoarthritis, UCB-MSC-HA implantation resulted in improved cartilage grade at second-look arthroscopy and provided more improvement in pain and function up to 5 years compared with microfracture. Registration: NCT01041001, NCT01626677 (ClinicalTrials.gov identifier).
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Affiliation(s)
- Hong-Chul Lim
- Department of Orthopedic Surgery, Korea University Guro Hospital, Korea University School of Medicine, Seoul, Republic of Korea
| | - Yong-Beom Park
- Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Chul-Won Ha
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea
| | - Brian J Cole
- Department of Orthopedics Cartilage Restoration Center, Departments of Orthopedics and Surgery, Midwest Orthopedics, Rush University Medical Center, Chicago, Illinois, USA
| | - Beom-Koo Lee
- Department of Orthopedic Surgery, Gachon University Gil Hospital, Gachon University School of Medicine, Incheon, Republic of Korea
| | - Hwa-Jae Jeong
- Department of Orthopedic Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Myung-Ku Kim
- Department of Orthopedic Surgery, Inha University Hospital, Inha University School of Medicine, Incheon, Republic of Korea
| | - Seong-Il Bin
- Department of Orthopedic Surgery, Asan Medical Center, Ulsan University School of Medicine, Seoul, Republic of Korea
| | - Chong-Hyuk Choi
- Department of Orthopedic Surgery, Gangnam Severance Hospital, Yonsei University School of Medicine, Seoul, Republic of Korea
| | - Choong Hyeok Choi
- Department of Orthopedic Surgery, Hanyang University Medical Center, Hanyang University School of Medicine, Seoul, Republic of Korea
| | - Jae-Doo Yoo
- Department of Orthopedic Surgery, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Republic of Korea
| | | | - Jung-Ro Yoon
- Department of Orthopedic Surgery, Korea University Guro Hospital, Korea University School of Medicine, Seoul, Republic of Korea.,Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea.,Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.,Department of Orthopedics Cartilage Restoration Center, Departments of Orthopedics and Surgery, Midwest Orthopedics, Rush University Medical Center, Chicago, Illinois, USA.,Department of Orthopedic Surgery, Gachon University Gil Hospital, Gachon University School of Medicine, Incheon, Republic of Korea.,Department of Orthopedic Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Department of Orthopedic Surgery, Inha University Hospital, Inha University School of Medicine, Incheon, Republic of Korea.,Department of Orthopedic Surgery, Asan Medical Center, Ulsan University School of Medicine, Seoul, Republic of Korea.,Department of Orthopedic Surgery, Gangnam Severance Hospital, Yonsei University School of Medicine, Seoul, Republic of Korea.,Department of Orthopedic Surgery, Hanyang University Medical Center, Hanyang University School of Medicine, Seoul, Republic of Korea.,Department of Orthopedic Surgery, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Republic of Korea.,Investigation performed at 10 tertiary-care hospitals in the Republic of Korea
| | - Jun-Young Chung
- Department of Orthopedic Surgery, Korea University Guro Hospital, Korea University School of Medicine, Seoul, Republic of Korea.,Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea.,Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.,Department of Orthopedics Cartilage Restoration Center, Departments of Orthopedics and Surgery, Midwest Orthopedics, Rush University Medical Center, Chicago, Illinois, USA.,Department of Orthopedic Surgery, Gachon University Gil Hospital, Gachon University School of Medicine, Incheon, Republic of Korea.,Department of Orthopedic Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Department of Orthopedic Surgery, Inha University Hospital, Inha University School of Medicine, Incheon, Republic of Korea.,Department of Orthopedic Surgery, Asan Medical Center, Ulsan University School of Medicine, Seoul, Republic of Korea.,Department of Orthopedic Surgery, Gangnam Severance Hospital, Yonsei University School of Medicine, Seoul, Republic of Korea.,Department of Orthopedic Surgery, Hanyang University Medical Center, Hanyang University School of Medicine, Seoul, Republic of Korea.,Department of Orthopedic Surgery, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Republic of Korea.,Investigation performed at 10 tertiary-care hospitals in the Republic of Korea
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15
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Kangari P, Talaei-Khozani T, Razeghian-Jahromi I, Razmkhah M. Mesenchymal stem cells: amazing remedies for bone and cartilage defects. Stem Cell Res Ther 2020; 11:492. [PMID: 33225992 PMCID: PMC7681994 DOI: 10.1186/s13287-020-02001-1] [Citation(s) in RCA: 157] [Impact Index Per Article: 31.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/27/2020] [Indexed: 12/15/2022] Open
Abstract
Skeletal disorders are among the leading debilitating factors affecting millions of people worldwide. The use of stem cells for tissue repair has raised many promises in various medical fields, including skeletal disorders. Mesenchymal stem cells (MSCs) are multipotent stromal cells with mesodermal and neural crest origin. These cells are one of the most attractive candidates in regenerative medicine, and their use could be helpful in repairing and regeneration of skeletal disorders through several mechanisms including homing, angiogenesis, differentiation, and response to inflammatory condition. The most widely studied sources of MSCs are bone marrow (BM), adipose tissue, muscle, umbilical cord (UC), umbilical cord blood (UCB), placenta (PL), Wharton's jelly (WJ), and amniotic fluid. These cells are capable of differentiating into osteoblasts, chondrocytes, adipocytes, and myocytes in vitro. MSCs obtained from various sources have diverse capabilities of secreting many different cytokines, growth factors, and chemokines. It is believed that the salutary effects of MSCs from different sources are not alike in terms of repairing or reformation of injured skeletal tissues. Accordingly, differential identification of MSCs' secretome enables us to make optimal choices in skeletal disorders considering various sources. This review discusses and compares the therapeutic abilities of MSCs from different sources for bone and cartilage diseases.
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Affiliation(s)
- Parisa Kangari
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Talaei-Khozani
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Tissue Engineering Laboratory, Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Mahboobeh Razmkhah
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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16
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Chen Y, Ouyang X, Wu Y, Guo S, Xie Y, Wang G. Co-culture and Mechanical Stimulation on Mesenchymal Stem Cells and Chondrocytes for Cartilage Tissue Engineering. Curr Stem Cell Res Ther 2020; 15:54-60. [PMID: 31660820 DOI: 10.2174/1574888x14666191029104249] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 09/09/2019] [Accepted: 09/18/2019] [Indexed: 02/08/2023]
Abstract
Defects in articular cartilage injury and chronic osteoarthritis are very widespread and common, and the ability of injured cartilage to repair itself is limited. Stem cell-based cartilage tissue engineering provides a promising therapeutic option for articular cartilage damage. However, the application of the technique is limited by the number, source, proliferation, and differentiation of stem cells. The co-culture of mesenchymal stem cells and chondrocytes is available for cartilage tissue engineering, and mechanical stimulation is an important factor that should not be ignored. A combination of these two approaches, i.e., co-culture of mesenchymal stem cells and chondrocytes under mechanical stimulation, can provide sufficient quantity and quality of cells for cartilage tissue engineering, and when combined with scaffold materials and cytokines, this approach ultimately achieves the purpose of cartilage repair and reconstruction. In this review, we focus on the effects of co-culture and mechanical stimulation on mesenchymal stem cells and chondrocytes for articular cartilage tissue engineering. An in-depth understanding of the impact of co-culture and mechanical stimulation of mesenchymal stem cells and chondrocytes can facilitate the development of additional strategies for articular cartilage tissue engineering.
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Affiliation(s)
- Yawen Chen
- Key Laboratory of Biological Medicines in Universities of Shandong Province, Weifang Medical University, Weifang, 261053, China
| | - Xinli Ouyang
- Key Laboratory of Biological Medicines in Universities of Shandong Province, Weifang Medical University, Weifang, 261053, China
| | - Yide Wu
- Key Laboratory of Biological Medicines in Universities of Shandong Province, Weifang Medical University, Weifang, 261053, China
| | - Shaojia Guo
- Key Laboratory of Biological Medicines in Universities of Shandong Province, Weifang Medical University, Weifang, 261053, China
| | - Yongfang Xie
- Key Laboratory of Biological Medicines in Universities of Shandong Province, Weifang Medical University, Weifang, 261053, China
| | - Guohui Wang
- Key Laboratory of Biological Medicines in Universities of Shandong Province, Weifang Medical University, Weifang, 261053, China
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17
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Combined Transplantation of Mesenchymal Stem Cells and Endothelial Colony-Forming Cells Accelerates Refractory Diabetic Foot Ulcer Healing. Stem Cells Int 2020; 2020:8863649. [PMID: 33061991 PMCID: PMC7545465 DOI: 10.1155/2020/8863649] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/19/2020] [Accepted: 08/26/2020] [Indexed: 12/17/2022] Open
Abstract
Background This study is aimed at investigating the effect of combined transplantation of umbilical cord mesenchymal stem cells (UCMSCs) and umbilical cord blood-derived endothelial colony-forming cells (ECFCs) on diabetic foot ulcer healing and at providing a novel therapy for chronic diabetic foot ulcer. Methods We reported the treatment of refractory diabetic foot ulcers in twelve patients. Among them, five patients had two or more wounds; thus, one wound in the same patient was treated with cell injection, and other wounds were regarded as self-controls. The remaining seven patients had only one wound; therefore, the difference between the area of wound before and after treatment was estimated. The UCMSCs and ECFCs were injected into the wound along with topically applied hyaluronic acid (HA). Results In this report, we compared the healing rate of multiple separate wounds in the same foot of the same patient: one treated with cell injection combined with topically applied HA-based hydrogel and was later covered by the hydrocolloid dressings, while the self-control wounds were only treated with conventional therapy and covered by the hydrocolloid dressings. The wound underwent cell injection showed accelerated healing in comparison to control wound within the first week after treatment. In other diabetic patients with only one refractory wound, the healing rate after cell transplantation was significantly faster than that before injection. Two large wounds healed without needing skin grafts after combination therapy of cell injection and HA. After four weeks of combination treatment, wound closure was reached in six patients, and the wounds of the other six patients were significantly reduced in size. Conclusions Our study suggests that the combination of UCMSCs, ECFCs, and HA can safely synergize the accelerated healing of refractory diabetic foot ulcers.
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18
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Kabir W, Di Bella C, Jo I, Gould D, Choong PFM. Human Stem Cell Based Tissue Engineering for In Vivo Cartilage Repair: A Systematic Review. TISSUE ENGINEERING PART B-REVIEWS 2020; 27:74-93. [PMID: 32729380 DOI: 10.1089/ten.teb.2020.0155] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Pure chondral defects represent the most clinically significant articular cartilage injuries. To inform the development of clinically suitable tissue-engineering strategies for chondral repair using cells from a human patient, the combination of human stem cells (HSCs), biomaterial scaffolds, and growth factors has been widely harnessed in preclinical animal models. Due to the large heterogeneity in study designs and outcome reporting in such studies, we aimed to systematically review literature pertaining to HSC based tissue engineering strategies in animal models of chondral repair such that trends may be identified and the utility of HSCs in chondral repair can be elucidated. An extensive search strategy was carried out through PubMed, MEDLINE, and EMBASE databases to identify relevant studies. Initially the title and abstract of 787 studies were screened after which inclusion and exclusion criteria sorted 56 studies for full-text evaluation. Following full text review, a final number of 22 articles were included. Out of 22 included studies, 16 used scaffold implantation, 2 used cell pellet implantation, and 4 used intra-articular injection to administer HSCs to the region of chondral defects. HSC-containing implants outperformed scaffold-only or untreated control groups in both large and small animals for chondral regeneration. Umbilical cord mesenchymal stem cells and hyaluronic acid-containing scaffolds emerged as popular stem cell and scaffold choices, respectively. However, the short analysis timepoints post cell implantation was a key limitation in many studies. This review highlights the versatility of HSCs in achieving chondral regeneration in vivo and the enhancement of chondral repair through the selection of appropriate three-dimensional scaffolds and growth factors which are essential to support cell growth, attachment, migration, and extracellular matrix synthesis. Considerable heterogeneity exists in outcome reporting, and only one article reported biomechanical evaluation of neocartilage. Standardized outcome reporting systems that include comprehensive biomechanical testing protocols should be utilized in future in vivo studies of cartilage tissue engineering as the biomechanical quality of neocartilage is of great functional significance.
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Affiliation(s)
- Wassif Kabir
- Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.,BioFab3D, Aikenhead Centre for Medical Discovery, St. Vincent's Hospital, Fitzroy, Australia
| | - Claudia Di Bella
- BioFab3D, Aikenhead Centre for Medical Discovery, St. Vincent's Hospital, Fitzroy, Australia.,Department of Orthopaedics, St. Vincent's Hospital, Fitzroy, Victoria, Australia.,Department of Surgery, University of Melbourne, Clinical Sciences Building, St. Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Imkyeong Jo
- Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia
| | - Daniel Gould
- Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia
| | - Peter F M Choong
- BioFab3D, Aikenhead Centre for Medical Discovery, St. Vincent's Hospital, Fitzroy, Australia.,Department of Orthopaedics, St. Vincent's Hospital, Fitzroy, Victoria, Australia.,Department of Surgery, University of Melbourne, Clinical Sciences Building, St. Vincent's Hospital, Fitzroy, Victoria, Australia
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19
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Liu YYF, Lu Y, Oh S, Conduit GJ. Machine learning to predict mesenchymal stem cell efficacy for cartilage repair. PLoS Comput Biol 2020; 16:e1008275. [PMID: 33027251 PMCID: PMC7571701 DOI: 10.1371/journal.pcbi.1008275] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 10/19/2020] [Accepted: 08/20/2020] [Indexed: 12/13/2022] Open
Abstract
Inconsistent therapeutic efficacy of mesenchymal stem cells (MSCs) in regenerative medicine has been documented in many clinical trials. Precise prediction on the therapeutic outcome of a MSC therapy based on the patient's conditions would provide valuable references for clinicians to decide the treatment strategies. In this article, we performed a meta-analysis on MSC therapies for cartilage repair using machine learning. A small database was generated from published in vivo and clinical studies. The unique features of our neural network model in handling missing data and calculating prediction uncertainty enabled precise prediction of post-treatment cartilage repair scores with coefficient of determination of 0.637 ± 0.005. From this model, we identified defect area percentage, defect depth percentage, implantation cell number, body weight, tissue source, and the type of cartilage damage as critical properties that significant impact cartilage repair. A dosage of 17 - 25 million MSCs was found to achieve optimal cartilage repair. Further, critical thresholds at 6% and 64% of cartilage damage in area, and 22% and 56% in depth were predicted to significantly compromise on the efficacy of MSC therapy. This study, for the first time, demonstrated machine learning of patient-specific cartilage repair post MSC therapy. This approach can be applied to identify and investigate more critical properties involved in MSC-induced cartilage repair, and adapted for other clinical indications.
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Affiliation(s)
- Yu Yang Fredrik Liu
- Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, Cambridge, United Kingdom
- * E-mail:
| | - Yin Lu
- Bioprocessing Technology Institute, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
| | - Steve Oh
- Bioprocessing Technology Institute, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
| | - Gareth J. Conduit
- Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, Cambridge, United Kingdom
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20
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Song JS, Hong KT, Kong CG, Kim NM, Jung JY, Park HS, Kim YJ, Chang KB, Kim SJ. High tibial osteotomy with human umbilical cord blood-derived mesenchymal stem cells implantation for knee cartilage regeneration. World J Stem Cells 2020; 12:514-526. [PMID: 32742568 PMCID: PMC7360989 DOI: 10.4252/wjsc.v12.i6.514] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 04/24/2020] [Accepted: 05/12/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND High tibial osteotomy (HTO) is a well-established method for the treatment of medial compartment osteoarthritis of the knee with varus deformity. However, HTO alone cannot adequately repair the arthritic joint, necessitating cartilage regeneration therapy. Cartilage regeneration procedures with concomitant HTO are used to improve the clinical outcome in patients with varus deformity.
AIM To evaluate cartilage regeneration after implantation of allogenic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) with concomitant HTO.
METHODS Data for patients who underwent implantation of hUCB-MSCs with concomitant HTO were evaluated. The patients included in this study were over 40 years old, had a varus deformity of more than 5°, and a full-thickness International Cartilage Repair Society (ICRS) grade IV articular cartilage lesion of more than 4 cm2 in the medial compartment of the knee. All patients underwent second-look arthroscopy during hardware removal. Cartilage regeneration was evaluated macroscopically using the ICRS grading system in second-look arthroscopy. We also assessed the effects of patient characteristics, such as trochlear lesions, age, and lesion size, using patient medical records.
RESULTS A total of 125 patients were included in the study, with an average age of 58.3 ± 6.8 years (range: 43-74 years old); 95 (76%) were female and 30 (24%) were male. The average hip-knee-ankle (HKA) angle for measuring varus deformity was 7.6° ± 2.4° (range: 5.0-14.2°). In second-look arthroscopy, the status of medial femoral condyle (MFC) cartilage was as follows: 73 (58.4%) patients with ICRS grade I, 37 (29.6%) with ICRS grade II, and 15 (12%) with ICRS grade III. No patients were staged with ICRS grade IV. Additionally, the scores [except International Knee Documentation Committee (IKDC) at 1 year] of the ICRS grade I group improved more significantly than those of the ICRS grade II and III groups.
CONCLUSION Implantation of hUCB-MSCs with concomitant HTO is an effective treatment for patients with medial compartment osteoarthritis and varus deformity. Regeneration of cartilage improves the clinical outcomes for the patients.
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Affiliation(s)
- Jun-Seob Song
- Department of Orthopedic Surgery, Gangnam JS Hospital, Seoul 06053, South Korea
| | - Ki-Taek Hong
- Department of Orthopedic Surgery, Gangnam JS Hospital, Seoul 06053, South Korea
| | - Chae-Gwan Kong
- Department of Orthopedic Surgery, College of Medicine, The Catholic University of Korea, Uijeongbu-si 11765, South Korea
| | - Na-Min Kim
- Department of Orthopedic Surgery, Gangnam JS Hospital, Seoul 06053, South Korea
| | - Jae-Yub Jung
- Department of Orthopedic Surgery, Gangnam JS Hospital, Seoul 06053, South Korea
| | - Han-Soo Park
- Department of Orthopedic Surgery, Gangnam JS Hospital, Seoul 06053, South Korea
| | - Young Ju Kim
- Department of Nursing Education & Administration, Uijeongbu St. Mary’s Hospital, The Catholic University of Korea, Uijeongbu-si 11765, South Korea
| | - Ki Bong Chang
- Department of Orthopedic Surgery, College of Medicine, The Catholic University of Korea, Uijeongbu-si 11765, South Korea
| | - Seok Jung Kim
- Department of Orthopedic Surgery, College of Medicine, The Catholic University of Korea, Uijeongbu-si 11765, South Korea
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21
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Wang AT, Zhang QF, Wang NX, Yu CY, Liu RM, Luo Y, Zhao YJ, Xiao JH. Cocktail of Hyaluronic Acid and Human Amniotic Mesenchymal Cells Effectively Repairs Cartilage Injuries in Sodium Iodoacetate-Induced Osteoarthritis Rats. Front Bioeng Biotechnol 2020; 8:87. [PMID: 32211385 PMCID: PMC7068044 DOI: 10.3389/fbioe.2020.00087] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 01/30/2020] [Indexed: 12/17/2022] Open
Abstract
Osteoarthritis (OA) is one of the most common refractory degenerative articular cartilage diseases. Human amniotic mesenchymal cells (hAMSCs) have emerged as a promising stem cell source for cartilage repair, and hyaluronic acid (HA) has proven to be a versatile regulator for stem cell transplantation. Herein, an effective and straightforward intra-articular injection therapy using a cocktail of hAMSCs and HA was developed to treat knee OA in a rat model. The injured cartilage was remarkably regenerated, yielding results comparable to normal cartilage levels after 56 days of treatment. Both hAMSCs and HA were indispensable organic components in this therapy, in which HA could synergistically enhance the effects of hAMSCs on cartilage repair. The regenerative mechanism was attributed to the fact that the addition of HA comprehensively enhances the activities of hAMSCs, including chondrogenic differentiation, proliferation, colonization, and regenerative modulation. This cocktail paves a new avenue for injection therapy to treat OA, holding the potential to realize rapid clinical translation.
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Affiliation(s)
- Ai-Tong Wang
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Qing-Fang Zhang
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Nuo-Xin Wang
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Chang-Yin Yu
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Ru-Ming Liu
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yi Luo
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yu-Jie Zhao
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jian-Hui Xiao
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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22
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Implantation of allogenic umbilical cord blood-derived mesenchymal stem cells improves knee osteoarthritis outcomes: Two-year follow-up. Regen Ther 2020; 14:32-39. [PMID: 31988992 PMCID: PMC6965506 DOI: 10.1016/j.reth.2019.10.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 09/20/2019] [Accepted: 10/22/2019] [Indexed: 12/12/2022] Open
Abstract
Introduction Clinical outcomes after the implantation of allogenic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in osteoarthritic knees have been rarely reported. Our study aimed to investigate clinical outcomes of osteoarthritic patients who underwent hUCB-MSC implantation. Methods In this case series (level of evidence: 4), from January 2014 to December 2015, 128 patients with full-thickness cartilage lesions (International Cartilage Repair Society grade 4 and Kellgren–Lawrence grade ≤3) who underwent hUCB-MSC implantation were retrospectively evaluated with a minimum of 2-year follow-up. After removing the sclerotic subchondral bone with an arthroscopic burr, 4-mm-diameter holes were created at 2-mm intervals, and hyaluronic acid and hUCB-MSCs were subsequently mixed and implanted in the holes and other articular defect sites. Clinical outcomes were evaluated preoperatively, 1 year postoperatively, and 2 years postoperatively (minimum) using visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and International Knee Documentation Committee (IKDC) scores. To assess clinical outcomes, patients were divided into two or three groups according to the lesion size, lesion location, number of lesions, body mass index, and age; statistical analyses were performed using these data. Results The mean (±standard deviation) VAS, WOMAC, and IKDC scores at 1 and 2 years after surgery including hUCB-MSC implantation improved significantly compared to the preoperative scores (P < 0.001). There were significant differences in the lesion location (P < 0.05). Medial femoral condyle lesions resulted in worse outcomes compared with lateral femoral condyle and trochlea lesions. No adverse reactions or postoperative complications were noted. Conclusions Implantation of hUCB-MSCs is effective for treating knee osteoarthritis based on a follow-up lasting a minimum of 2 years.
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Key Words
- ACI, autologous chondrocyte implantation
- AT-MSCs, adipose tissue-derived MSCs
- Allogenic
- BM-MSCs, bone marrow-derived MSCs
- BMI, body mass index
- HA, hyaluronic acid
- Human umbilical cord blood
- IKDC, International Knee Documentation Committee
- KL, Kellgren–Lawrence
- Knee osteoarthritis
- LFC, lateral femoral condyle
- MFC, medial femoral condyle
- MRI, magnetic resonance imaging
- Mesenchymal stem cells
- OA, osteoarthritis
- OAT, osteochondral autologous transplantation
- VAS, visual analog scale
- WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index
- hUCB-MSCs, human umbilical cord blood-derived mesenchymal stem cells
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Harris DT, Israel S. What will Become of the Taxpayer Investment in Public Cord Blood Stem Cell Banking? Curr Stem Cell Res Ther 2019; 14:367-372. [PMID: 30806326 DOI: 10.2174/1574888x14666190222184155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 11/08/2018] [Accepted: 02/04/2019] [Indexed: 11/22/2022]
Abstract
Cord Blood (CB) is a unique and readily available source of hematopoietic stem cells for transplantation. CB also contains other types of stem cells, including endothelial stem cells and mesenchymal stem cells, that may prove useful in non-traditional clinical uses. Genetic and molecular analyses have demonstrated that CB stem cells lie somewhere between mature stem cells like those found in Bone Marrow (BM), and fetal stem cells. After 25 years of clinical experience, CB is now used in the same fashion as BM for all typical malignant and genetic diseases treated by bone marrow transplant. Due to the establishment of CB banks in the US and abroad, more than 35,000 CB transplants have been performed over the past 25 years. An average of 700-800 CB transplants are performed annually. In addition, CB is now used more frequently for regenerative medicine and tissue engineering applications. At first glance, it seems that everything could not be better with the public cord blood banks and the use of their samples in the clinic. However, a recent report by the Rand Corp. reviewed the US national cord blood stem cell banking program and detailed many ongoing problems. However, some details were omitted from the report that would shed some light on the causes of many of the problems. This paper will summarize the status of the public cord blood stem cell banking program in the US, detail the problems associated with the program that could jeopardize its existence and suggest possible solutions to resolve these issues.
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Affiliation(s)
- David T Harris
- AHSC Biorepository Professor of Immunobiology and Medicine University of Arizona and Scientific Director, Celebration Stem Cell Centre Gilbert, AZ, United States
| | - Scott Israel
- Laboratory Director and Quality Control Director Celebration Stem Cell Centre Gilbert, AZ, United States
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24
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Cell-to-Cell Culture Inhibits Dedifferentiation of Chondrocytes and Induces Differentiation of Human Umbilical Cord-Derived Mesenchymal Stem Cells. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5871698. [PMID: 31828107 PMCID: PMC6885164 DOI: 10.1155/2019/5871698] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 09/13/2019] [Accepted: 10/08/2019] [Indexed: 12/28/2022]
Abstract
Background Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) possess great promise as a therapeutic to repair damaged cartilage. Direct intra-articular injection of mesenchymal stem cells has been shown to reduce cartilage damage and is advantageous as surgical implantation and associated side effects can be avoided using this approach. However, the efficacy of stem cell-based therapy for cartilage repair depends highly on the direct interactions of these stem cells with chondrocytes in the joint. In this study, we have carried out an in vitro cell-to-cell contact coculture study with human articular chondrocytes (hACs) and hUC-MSCs, with the goal of this study being to evaluate interactions between hACs and hUC-MSCs. Methods Low-density monolayer cultures of hUC-MSCs and hACs were mixed at a ratio of 1 : 1 in direct cell-to-cell contact groups. Results were analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence. Results A mixed coculture of hUC-MSCs and hACs was found to exhibit synergistic interactions with enhanced differentiation of hUC-MSCs and reduced dedifferentiation of chondrocytes. Mixed cultures after 21 days were found to exhibit sufficient chondrogenic induction. Conclusions The results from this study suggest the presence of mutual effects between hUC-MSCs and hACs even culture at low density and provide further support for the use of intra-articular injection strategies for cartilage defect treatment.
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25
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Zheng P, Hu X, Lou Y, Tang K. A Rabbit Model of Osteochondral Regeneration Using Three-Dimensional Printed Polycaprolactone-Hydroxyapatite Scaffolds Coated with Umbilical Cord Blood Mesenchymal Stem Cells and Chondrocytes. Med Sci Monit 2019; 25:7361-7369. [PMID: 31570688 PMCID: PMC6784681 DOI: 10.12659/msm.915441] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 06/01/2019] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND This study aimed to investigate a rabbit model of osteochondral regeneration using three-dimensional (3-D) printed polycaprolactone-hydroxyapatite (PCL-HA) scaffolds coated with umbilical cord blood mesenchymal stem cells (UCB-MSCs) and chondrocytes. MATERIAL AND METHODS Nine female New Zealand white rabbits were included in the study. The 3-D PCL-HA scaffolds were prepared using fused deposition modeling 3-D printing technology. Seeding cells were prepared by co-culture of rabbit UCB-MSCs and chondrocytes with a ratio of 3: 1. A total of 4×10⁶ cells were seeded on 3-D PCL-HA scaffolds and implanted into rabbits with femoral trochlear defects. After 8 weeks of in vivo implantation, 12 specimens were sampled and examined using histology and scanning electron microscopy (SEM). The International Cartilage Repair Society (ICRS) macroscopic scores and histological results were recorded and compared with those of the unseeded PCL-HA scaffolds. RESULTS Mean ICRS scores for the UCB-MSCs and chondrocyte-seeded PCL-HA scaffolds (group A) were significantly higher than the normal unseeded control (NC) PCL-HA scaffold group (group B) (P<0.05). Histology with safranin-O and fast-green staining showed that the UCB chondrocyte-seeded PCL-HA scaffolds significantly promoted bone and cartilage regeneration. CONCLUSIONS In a rabbit model of osteochondral regeneration using 3-D printed PCL-HA scaffolds, the UCB chondrocyte-seeded PCL-HA scaffold promoted articular cartilage repair when compared with the control or non-seeded PCL-HA scaffolds.
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26
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Song JS, Hong KT, Kim NM, Jung JY, Park HS, Kim YC, Shetty AA, Kim SJ. Allogenic umbilical cord blood-derived mesenchymal stem cells implantation for the treatment of juvenile osteochondritis dissecans of the knee. J Clin Orthop Trauma 2019; 10:S20-S25. [PMID: 31700204 PMCID: PMC6823810 DOI: 10.1016/j.jcot.2019.03.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 03/29/2019] [Accepted: 03/30/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Osteochondritis dissecans (OCD) is a pathologic condition accompanied by the gradual destruction of subchondral bone and defects in the overlying articular cartilage.This case series reports the results of allogenic human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) implantation for the treatment of osteochondral defect in two cases of juvenile osteochondritis dissecans. CASE PRESENTATION Two patients with osteochondral defect of the knee recovered from the disease enough to begin major exercise 1 year after hUCB-MSCs implantation. The IKDC, VAS, and Tegner score of the two patients showed an excellent improvement and concurrent arthroscopy was performed; cartilage regeneration of ICRS grade 1 similar to normal was observed. The modified two-dimensional MOCART scores increased in both cases over time. CONCLUSION This is the first case series detailing the results of treating juvenile OCD lesions using hUCB-MSCs. This could be an option for treating juvenile OCD.
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Affiliation(s)
- Jun-Seob Song
- Department of Orthopaedic Surgery, Seoul JS Hospital, Seoul, Republic of Korea
| | - Ki-Taek Hong
- Department of Orthopaedic Surgery, Seoul JS Hospital, Seoul, Republic of Korea
| | - Na-Min Kim
- Department of Orthopaedic Surgery, Seoul JS Hospital, Seoul, Republic of Korea
| | - Jae-Yub Jung
- Department of Orthopaedic Surgery, Seoul JS Hospital, Seoul, Republic of Korea
| | - Han-Soo Park
- Department of Orthopaedic Surgery, Seoul JS Hospital, Seoul, Republic of Korea
| | - Yoo-Chang Kim
- Department of Orthopaedic Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Asode Ananthram Shetty
- Canterbury Christ Church University, Faculty of Health and Social Sciences, 30 Pembroke Court, Chatham Maritime, Kent, ME4 4UF, United Kingdom
| | - Seok Jung Kim
- Department of Orthopaedic Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea,Corresponding author. Department of Orthopedic Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 271, Cheonbo-Ro, Uijeongbu-si, Gyeonggi-do, 11765, Republic of Korea.
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27
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Park YB, Ha CW, Kim JA, Kim S, Park YG. Comparison of Undifferentiated Versus Chondrogenic Predifferentiated Mesenchymal Stem Cells Derived From Human Umbilical Cord Blood for Cartilage Repair in a Rat Model. Am J Sports Med 2019; 47:451-461. [PMID: 30640523 DOI: 10.1177/0363546518815151] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have gained much interest as a promising cell source for regenerative medicine owing to the noninvasive collection, availability, high expansion capacity, and low immunogenicity. However, few in vivo studies have reported the use of hUCB-MSCs on cartilage repair. Moreover, little study has been conducted on the effects of chondrogenic predifferentiation of hUCB-MSCs on cartilage repair. PURPOSE To compare the effectiveness of transplanting undifferentiated versus chondrogenic predifferentiated mesenchymal stem cells (MSCs) for treating osteochondral defects. STUDY DESIGN Controlled laboratory study. METHODS Critical-sized osteochondral defects were created in the trochlear grooves of rat femurs. In 20 rats, a composite of chondrogenic predifferentiated hUCB-MSCs (chondro-MSCs) and 4% hyaluronic acid (HA) hydrogel was transplanted into defects in the right knees, whereas undifferentiated hUCB-MSCs (undiff-MSCs) and 4% HA hydrogel were transplanted into the left knees. In the control groups, 4% HA hydrogel without MSCs was transplanted into defects in the right knees, and the defects in the left knees were left untreated in 20 rats. The cartilage repair was evaluated at 8 and 16 weeks after surgery. RESULTS Transplanting undiff-MSCs resulted in overall superior cartilage repair as compared with chondro-MSCs, HA alone, or no treatment. The articular surfaces of the defect sites in the undiff-MSC group were relatively smoother than those of the other treatments. The undiff-MSC group showed cellular morphology and arrangement similar to surrounding normal articular cartilage tissue at 16 weeks, both of which were also better than those of the other groups. In addition, the undiff-MSC group showed coloration similar to surrounding normal articular cartilage tissue at 16 weeks in safranin O and type II collagen immunohistochemical staining. The histological scores also revealed that cartilage repair with undiff-MSCs was better than that with chondro-MSCs, HA alone, or no treatment ( P < .05 in all). CONCLUSION This study demonstrated that treatment with undiff-MSCs resulted in more favorable cartilage repair than that with chondro-MSCs in a rat model. These findings indicate that chondrogenic predifferentiation of MSCs before transplantation does not enhance cartilage repair. CLINICAL RELEVANCE The results of this study support the use of undifferentiated MSCs, rather than chondrogenic predifferentiated MSCs, as a stem cell therapy strategy for cartilage repair.
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Affiliation(s)
- Yong-Beom Park
- Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Chul-Won Ha
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea
| | - Jin-A Kim
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea
| | - Seongchan Kim
- Department of Orthopedic Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Republic of Korea
| | - Yong-Geun Park
- Department of Orthopedic Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Republic of Korea
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28
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Ha CW, Park YB, Kim SH, Lee HJ. Intra-articular Mesenchymal Stem Cells in Osteoarthritis of the Knee: A Systematic Review of Clinical Outcomes and Evidence of Cartilage Repair. Arthroscopy 2019; 35:277-288.e2. [PMID: 30455086 DOI: 10.1016/j.arthro.2018.07.028] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 07/10/2018] [Accepted: 07/12/2018] [Indexed: 02/07/2023]
Abstract
PURPOSE To provide a systematic review of the clinical literature reporting the efficacy of mesenchymal stem cells (MSCs) in terms of clinical outcomes including pain and function and cartilage repair in patients with osteoarthritis. METHODS We systematically reviewed any studies investigating clinical outcomes and cartilage repair after the clinical application of cell populations containing MSCs in human subjects with knee osteoarthritis through MEDLINE, EMBASE, the Cochrane Library, CINAHL, Web of Science, and Scopus. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Studies with a level of evidence of IV or V were excluded. Methodological quality was assessed using the Modified Coleman Methodology Score. Clinical outcomes were assessed using clinical scores, and cartilage repair was assessed using magnetic resonance imaging and second-look arthroscopy findings. RESULTS A total of 17 studies that met the criteria of 50 full-text studies were included in this review, with 6 randomized controlled trials, 8 prospective observational studies, and 3 retrospective case-control studies. Among 17 studies, 8 studies used bone marrow-derived MSCs, 6 used adipose tissue-derived stromal vascular fraction, 2 used adipose tissue-derived MSCs, and 1 used umbilical cord blood-derived MSCs. All studies except 2 reported significantly better clinical outcomes in the MSC group or improved clinical outcomes at final follow-up. In terms of cartilage repair, 9 of 11 studies reported improvement of the cartilage state on magnetic resonance imaging, and 6 of 7 studies reported repaired tissue on second-look arthroscopy. The mean Modified Coleman Methodology Score was 55.5 ± 15.5 (range, 28-74). CONCLUSIONS Intra-articular MSCs provide improvements in pain and function in knee osteoarthritis at short-term follow-up (<28 months) in many cases. Some efficacy has been shown of MSCs for cartilage repair in osteoarthritis; however, the evidence of efficacy of intra-articular MSCs on both clinical outcomes and cartilage repair remains limited. LEVEL OF EVIDENCE Level III; systematic review of level I, II, and III studies.
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Affiliation(s)
- Chul-Won Ha
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yong-Beom Park
- Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul 06973, Republic of Korea.
| | - Seong Hwan Kim
- Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul 06973, Republic of Korea
| | - Han-Jun Lee
- Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul 06973, Republic of Korea
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29
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Jiao J, Huang J, Zhang Z. Hydrogels based on chitosan in tissue regeneration: How do they work? A mini review. J Appl Polym Sci 2018. [DOI: 10.1002/app.47235] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Jiao Jiao
- Neuropsychiatric Institute; Medical School of Southeast University; Nanjing Jiangsu 210009 China
- Department of Neurology; Affiliated ZhongDa Hospital; Nanjing Jiangsu 210009 China
| | - Jinjian Huang
- Lab for Trauma and Surgical Infections, Department of Surgery; Jinling Hospital; Nanjing Jiangsu 210002 China
| | - Zhijun Zhang
- Neuropsychiatric Institute; Medical School of Southeast University; Nanjing Jiangsu 210009 China
- Department of Neurology; Affiliated ZhongDa Hospital; Nanjing Jiangsu 210009 China
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30
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Rim YA, Nam Y, Ju JH. Application of Cord Blood and Cord Blood-Derived Induced Pluripotent Stem Cells for Cartilage Regeneration. Cell Transplant 2018; 28:529-537. [PMID: 30251563 PMCID: PMC7103603 DOI: 10.1177/0963689718794864] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Regeneration of articular cartilage is of great interest in cartilage tissue engineering
since articular cartilage has a low regenerative capacity. Due to the difficulty in
obtaining healthy cartilage for transplantation, there is a need to develop an alternative
and effective regeneration therapy to treat degenerative or damaged joint diseases. Stem
cells including various adult stem cells and pluripotent stem cells are now actively used
in tissue engineering. Here, we provide an overview of the current status of cord blood
cells and induced pluripotent stem cells derived from these cells in cartilage
regeneration. The abilities of these cells to undergo chondrogenic differentiation are
also described. Finally, the technical challenges of articular cartilage regeneration and
future directions are discussed.
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Affiliation(s)
- Yeri Alice Rim
- 1 CiSTEM Laboratory, Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yoojun Nam
- 1 CiSTEM Laboratory, Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ji Hyeon Ju
- 1 CiSTEM Laboratory, Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,2 Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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31
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Comparative efficacy of stem cells and secretome in articular cartilage regeneration: a systematic review and meta-analysis. Cell Tissue Res 2018; 375:329-344. [PMID: 30084022 DOI: 10.1007/s00441-018-2884-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 07/04/2018] [Indexed: 12/17/2022]
Abstract
Articular cartilage defect remains the most challenging joint disease due to limited intrinsic healing capacity of the cartilage that most often progresses to osteoarthritis. In recent years, stem cell therapy has evolved as therapeutic strategies for articular cartilage regeneration. However, a number of studies have shown that therapeutic efficacy of stem cell transplantation is attributed to multiple secreted factors that modulate the surrounding milieu to evoke reparative processes. This systematic review and meta-analysis aim to evaluate and compare the therapeutic efficacy of stem cell and secretome in articular cartilage regeneration in animal models. We systematically searched the PubMed, CINAHL, Cochrane Library, Ovid Medline and Scopus databases until August 2017 using search terms related to stem cells, cartilage regeneration and animals. A random effect meta-analysis of the included studies was performed to assess the treatment effects on new cartilage formation on an absolute score of 0-100% scale. Subgroup analyses were also performed by sorting studies independently based on similar characteristics. The pooled analysis of 59 studies that utilized stem cells significantly improved new cartilage formation by 25.99% as compared with control. Similarly, the secretome also significantly increased cartilage regeneration by 26.08% in comparison to the control. Subgroup analyses revealed no significant difference in the effect of stem cells in new cartilage formation. However, there was a significant decline in the effect of stem cells in articular cartilage regeneration during long-term follow-up, suggesting that the duration of follow-up is a predictor of new cartilage formation. Secretome has shown a similar effect to stem cells in new cartilage formation. The risk of bias assessment showed poor reporting for most studies thereby limiting the actual risk of bias assessment. The present study suggests that both stem cells and secretome interventions improve cartilage regeneration in animal trials. Graphical abstract ᅟ.
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32
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Park YB, Ha CW, Rhim JH, Lee HJ. Stem Cell Therapy for Articular Cartilage Repair: Review of the Entity of Cell Populations Used and the Result of the Clinical Application of Each Entity. Am J Sports Med 2018; 46:2540-2552. [PMID: 29023156 DOI: 10.1177/0363546517729152] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Following successful preclinical studies, stem cell therapy is emerging as a candidate for the treatment of articular cartilage lesions. Because stem cell therapy for cartilage repair in humans is at an early phase, confusion and errors are found in the literature regarding use of the term stem cell therapy in this field. PURPOSE To provide an overview of the outcomes of cartilage repair, elucidating the various cell populations used, and thus reduce confusion with regard to using the term stem cell therapy. STUDY DESIGN Systematic review. METHODS The authors systematically reviewed any studies on clinical application of mesenchymal stem cells (MSCs) in human subjects. A comprehensive search was performed in MEDLINE, EMBASE, the Cochrane Library, CINAHL, Web of Science, and Scopus for human studies that evaluated articular cartilage repair with cell populations containing MSCs. These studies were classified as using bone marrow-derived MSCs, adipose tissue-derived MSCs, peripheral blood-derived MSCs, synovium-derived MSCs, and umbilical cord blood-derived MSCs according to the entity of cell population used. RESULTS Forty-six clinical studies were identified to focus on cartilage repair with MSCs: 20 studies with bone marrow-derived MSCs, 21 studies with adipose tissue-derived MSCs, 3 studies with peripheral blood-derived MSCs, 1 study with synovium-derived MSCs, and 1 study with umbilical cord blood-derived MSCs. All clinical studies reported that cartilage treated with MSCs showed favorable clinical outcomes in terms of clinical scores or cartilage repair evaluated by MRI. However, most studies were limited to case reports and case series. Among these 46 clinical studies, 18 studies erroneously referred to adipose tissue-derived stromal vascular fractions as "adipose-derived MSCs," 2 studies referred to peripheral blood-derived progenitor cells as "peripheral blood-derived MSCs," and 1 study referred to bone marrow aspirate concentrate as "bone marrow-derived MSCs." CONCLUSION Limited evidence is available regarding clinical benefit of stem cell therapy for articular cartilage repair. Because the literature contains substantial errors in describing the therapeutic cells used, researchers need to be alert and observant of proper terms, especially regarding whether the cells used were stem cells or cell populations containing a small portion of stem cells, to prevent confusion in understanding the results of a given stem cell-based therapy.
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Affiliation(s)
- Yong-Beom Park
- Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Dongjak-gu, Seoul, Republic of Korea
| | - Chul-Won Ha
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Republic of Korea.,Stem Cell & Regenerative Medicine Research Institute, Samsung Medical Center, Gangnam-gu, Seoul, Republic of Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Gangnam-gu, Seoul, Republic of Korea
| | - Ji Heon Rhim
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Republic of Korea
| | - Han-Jun Lee
- Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Dongjak-gu, Seoul, Republic of Korea
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33
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Iturriaga L, Hernáez-Moya R, Erezuma I, Dolatshahi-Pirouz A, Orive G. Advances in stem cell therapy for cartilage regeneration in osteoarthritis. Expert Opin Biol Ther 2018; 18:883-896. [PMID: 30020816 DOI: 10.1080/14712598.2018.1502266] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Osteoarthritis (OA) is a progressive joint disease that compromises the structural integrity of cartilage tissue. Conventional treatments based on medication or surgery are nowadays inefficient and cell-based therapy has emerged as one of the most promising methods for cartilage regeneration. The first therapy developed for cartilage defects was autologous chondrocyte implantation, but in the last few decades stem cells (SCs) from different sources have been proposed as a possible alternative for OA. AREAS COVERED SC sources and available delivery procedures (scaffolds/hydrogels) are presented, along with the main issues arisen in this regard. Thereafter, preclinical and clinical trials performed in recent years are reviewed in order to take a glance toward the potential benefits that such therapies could deliver to the patients. EXPERT OPINION SCs have proven their potential and safety for OA treatment. Nevertheless, there are still many questions to be resolved before their widespread used in clinical practice, such as the treatment mechanism, the best cell source, the most appropriate processing method, the most effective dose and delivery procedure, and their efficacy. In this sense, long-term follow-up and larger randomized controlled trials utilizing standardized and established outcome scores are mandatory to make objective conclusions.
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Affiliation(s)
- Leire Iturriaga
- a NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy , University of the Basque Country UPV/EHU , Vitoria-Gasteiz , Spain.,b Biomedical Research Networking Centre in Bioengineering , Biomaterials and Nanomedicine (CIBER-BBN) , Vitoria-Gasteiz , Spain
| | - Raquel Hernáez-Moya
- a NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy , University of the Basque Country UPV/EHU , Vitoria-Gasteiz , Spain.,b Biomedical Research Networking Centre in Bioengineering , Biomaterials and Nanomedicine (CIBER-BBN) , Vitoria-Gasteiz , Spain
| | - Itsasne Erezuma
- a NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy , University of the Basque Country UPV/EHU , Vitoria-Gasteiz , Spain.,b Biomedical Research Networking Centre in Bioengineering , Biomaterials and Nanomedicine (CIBER-BBN) , Vitoria-Gasteiz , Spain
| | - Alireza Dolatshahi-Pirouz
- c DTU Nanotech, Center for Intestinal Absorption and Transport of Biopharmaceutical , Technical University of Denmark , Lyngby , Denmark
| | - Gorka Orive
- a NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy , University of the Basque Country UPV/EHU , Vitoria-Gasteiz , Spain.,b Biomedical Research Networking Centre in Bioengineering , Biomaterials and Nanomedicine (CIBER-BBN) , Vitoria-Gasteiz , Spain.,d University Institute for Regenerative Medicine and Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua) , Vitoria , Spain
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McIntyre JA, Jones IA, Danilkovich A, Vangsness CT. The Placenta: Applications in Orthopaedic Sports Medicine. Am J Sports Med 2018; 46:234-247. [PMID: 28375638 DOI: 10.1177/0363546517697682] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Placenta has a long history of use for treating burns and wounds. It is a rich source of collagen and other extracellular matrix proteins, tissue reparative growth factors, and stem cells, including mesenchymal stem cells (MSCs). Recent data show its therapeutic potential for orthopaedic sports medicine indications. PURPOSE To provide orthopaedic surgeons with an anatomic description of the placenta, to characterize its cellular composition, and to review the literature reporting the use of placenta-derived cells and placental tissue allografts for orthopaedic sports medicine indications in animal models and in humans. STUDY DESIGN Systematic review. METHODS Using a total of 63 keyword combinations, the PubMed and MEDLINE databases were searched for published articles describing the use of placental cells and/or tissue for orthopaedic sports medicine indications. Information was collected on placental tissue type, indications, animal model, study design, treatment regimen, safety, and efficacy outcomes. Results were categorized by indication and subcategorized by animal model. RESULTS Outcomes for 29 animal studies and 6 human studies reporting the use of placenta-derived therapeutics were generally positive; however, the placental tissue source, clinical indication, and administration route were highly variable across these studies. Fourteen animal studies described the use of placental tissue for tendon injuries, 13 studies for osteoarthritis or articular cartilage injuries, 3 for ligament injuries, and 1 for synovitis. Both placenta-derived culture-expanded cells (epithelial cells or MSCs) and placental tissue allografts were used in animal studies. In all human studies, commercial placental allografts were used. Five of 6 human studies examined the treatment of foot and ankle pathological conditions, and 1 studied the treatment of knee osteoarthritis. CONCLUSION A review of the small number of reported studies revealed a high degree of variability in placental cell types, placental tissue preparation, routes of administration, and treatment regimens, which prohibits making any definitive conclusions. Currently, the clinical use of placenta is limited to only commercial placental tissue allografts, as there are no placenta-derived biological drugs approved for the treatment of orthopaedic sports medicine conditions in the United States. However, this review shows that the application of placental cells or tissue allografts appears to be safe and has potential to improve outcomes for orthopaedic sports medicine indications.
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Affiliation(s)
- James Alexander McIntyre
- School of Medicine & Health Sciences, George Washington University, Washington, District of Columbia, USA
| | - Ian A Jones
- Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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Sánchez-Téllez DA, Téllez-Jurado L, Rodríguez-Lorenzo LM. Hydrogels for Cartilage Regeneration, from Polysaccharides to Hybrids. Polymers (Basel) 2017; 9:E671. [PMID: 30965974 PMCID: PMC6418920 DOI: 10.3390/polym9120671] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Revised: 11/24/2017] [Accepted: 11/29/2017] [Indexed: 12/12/2022] Open
Abstract
The aims of this paper are: (1) to review the current state of the art in the field of cartilage substitution and regeneration; (2) to examine the patented biomaterials being used in preclinical and clinical stages; (3) to explore the potential of polymeric hydrogels for these applications and the reasons that hinder their clinical success. The studies about hydrogels used as potential biomaterials selected for this review are divided into the two major trends in tissue engineering: (1) the use of cell-free biomaterials; and (2) the use of cell seeded biomaterials. Preparation techniques and resulting hydrogel properties are also reviewed. More recent proposals, based on the combination of different polymers and the hybridization process to improve the properties of these materials, are also reviewed. The combination of elements such as scaffolds (cellular solids), matrices (hydrogel-based), growth factors and mechanical stimuli is needed to optimize properties of the required materials in order to facilitate tissue formation, cartilage regeneration and final clinical application. Polymer combinations and hybrids are the most promising materials for this application. Hybrid scaffolds may maximize cell growth and local tissue integration by forming cartilage-like tissue with biomimetic features.
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Affiliation(s)
- Daniela Anahí Sánchez-Téllez
- Instituto Politécnico Nacional-ESIQIE, Depto. Ing. en Metalurgia y Materiales, UPALM-Zacatenco, Mexico City 07738, Mexico.
- Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Av. Monforte de Lemos 3-5, Pabellón 11, Planta 0, 28029 Madrid, Spain.
| | - Lucía Téllez-Jurado
- Instituto Politécnico Nacional-ESIQIE, Depto. Ing. en Metalurgia y Materiales, UPALM-Zacatenco, Mexico City 07738, Mexico.
| | - Luís María Rodríguez-Lorenzo
- Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Av. Monforte de Lemos 3-5, Pabellón 11, Planta 0, 28029 Madrid, Spain.
- Department Polymeric Nanomaterials and Biomaterials, ICTP-CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.
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Sandell LJ. JOR Virtual Issue on stem cells in orthopaedics. J Orthop Res 2017; 35:2593-2594. [PMID: 29228506 DOI: 10.1002/jor.23803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Linda J Sandell
- Editor in Chief, Journal of Orthopaedic Research, Mildred B. Simon Professor, Department of Orthopaedic Surgery, Professor, Departments of Cell Biology and Physiology and Biomedical Engineering, Musculoskeletal Research Center, Washington University School of Medicine
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Hypoxia Is a Critical Parameter for Chondrogenic Differentiation of Human Umbilical Cord Blood Mesenchymal Stem Cells in Type I/III Collagen Sponges. Int J Mol Sci 2017; 18:ijms18091933. [PMID: 28885597 PMCID: PMC5618582 DOI: 10.3390/ijms18091933] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 08/29/2017] [Accepted: 09/01/2017] [Indexed: 12/18/2022] Open
Abstract
Umbilical cord blood (UCB) is an attractive alternative to bone marrow for isolation of mesenchymal stem cells (MSCs) to treat articular cartilage defects. Here, we set out to determine the growth factors (bone morphogenetic protein 2 (BMP-2) and transforming growth factor-β (TGF-β1)) and oxygen tension effects during chondrogenesis of human UCB-MSCs for cartilage engineering. Chondrogenic differentiation was induced using 3D cultures in type I/III collagen sponges with chondrogenic factors in normoxia (21% O₂) or hypoxia (<5% O₂) for 7, 14 and 21 days. Our results show that UCB-MSCs can be committed to chondrogenesis in the presence of BMP-2+TGF-β1. Normoxia induced the highest levels of chondrocyte-specific markers. However, hypoxia exerted more benefit by decreasing collagen X and matrix metalloproteinase-13 (MMP13) expression, two chondrocyte hypertrophy markers. However, a better chondrogenesis was obtained by switching oxygen conditions, with seven days in normoxia followed by 14 days in hypoxia, since these conditions avoid hypertrophy of hUCB-MSC-derived chondrocytes while maintaining the expression of chondrocyte-specific markers observed in normoxia. Our study demonstrates that oxygen tension is a key factor for chondrogenesis and suggests that UBC-MSCs 3D-culture should begin in normoxia to obtain a more efficient chondrocyte differentiation before placing them in hypoxia for chondrocyte phenotype stabilization. UCB-MSCs are therefore a reliable source for cartilage engineering.
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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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Park YB, Ha CW, Kim JA, Han WJ, Rhim JH, Lee HJ, Kim KJ, Park YG, Chung JY. Single-stage cell-based cartilage repair in a rabbit model: cell tracking and in vivo chondrogenesis of human umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid hydrogel composite. Osteoarthritis Cartilage 2017; 25:570-580. [PMID: 27789339 DOI: 10.1016/j.joca.2016.10.012] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Revised: 09/26/2016] [Accepted: 10/15/2016] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have gained popularity as a promising cell source for regenerative medicine, but limited in vivo studies have reported cartilage repair. In addition, the roles of MSCs in cartilage repair are not well-understood. The purpose of this study was to investigate the feasibility of transplanting hUCB-MSCs and hyaluronic acid (HA) hydrogel composite to repair articular cartilage defects in a rabbit model and determine whether the transplanted cells persisted or disappeared from the defect site. DESIGN Osteochondral defects were created in the trochlear grooves of the knees. The hUCB-MSCs and HA composite was transplanted into the defect of experimental knees. Control knees were transplanted by HA or left untreated. Animals were sacrificed at 8 and 16 weeks post-transplantation and additionally at 2 and 4 weeks to evaluate the fate of transplanted cells. The repair tissues were evaluated by gross, histological and immunohistochemical analysis. RESULTS Transplanting hUCB-MSCs and HA composite resulted in overall superior cartilage repair tissue with better quality than HA alone or no treatment. Cellular architecture and collagen arrangement at 16 weeks were similar to those of surrounding normal articular cartilage tissue. Histological scores also revealed that cartilage repair in experimental knees was better than that in control knees. Immunohistochemical analysis with anti-human nuclear antibody confirmed that the transplanted MSCs disappeared gradually over time. CONCLUSION Transplanting hUCB-MSCs and HA composite promote cartilage repair and interactions between hUCB-MSCs and host cells initiated by paracrine action may play an important role in cartilage repair.
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Affiliation(s)
- Y B Park
- Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, South Korea.
| | - C W Ha
- Department of Orthopedic Surgery, Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea.
| | - J A Kim
- Department of Orthopedic Surgery, Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
| | - W J Han
- Department of Orthopedic Surgery, Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
| | - J H Rhim
- Department of Orthopedic Surgery, Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
| | - H J Lee
- Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, South Korea.
| | - K J Kim
- Department of Orthopedic Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, South Korea.
| | - Y G Park
- Department of Orthopedic Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, South Korea.
| | - J Y Chung
- Department of Orthopedic Surgery, Ajou University Hospital, Ajou University School of Medicine, Suwon, South Korea.
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Park YB, Ha CW, Lee CH, Park YG. Restoration of a large osteochondral defect of the knee using a composite of umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid hydrogel: a case report with a 5-year follow-up. BMC Musculoskelet Disord 2017; 18:59. [PMID: 28148266 PMCID: PMC5288855 DOI: 10.1186/s12891-017-1422-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 01/19/2017] [Indexed: 02/06/2023] Open
Abstract
Background The treatment of articular cartilage defects is a therapeutic challenge for orthopaedic surgeons. Furthermore, large osteochondral defects needs restoration of the underlying bone for sufficient biomechanical characteristics as well as the overlying cartilage. Case presentation A symptomatic large osteochondral defect in the knee joint was restored using a composite of umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) 0.5 x 107/ml and 4% hyaluronic acid (HA) hydrogel. Significant improvements in pain and function of the knee joint were identified by the evaluation at 12 months after surgery. A hyaline-like cartilage completely filled the defect and was congruent with the surrounding normal cartilage as revealed by magnetic resonance imaging (MRI), a second-look arthroscopy and histological assessment. The improved clinical outcomes maintained until 5.5 years. MRI also showed the maintenance of the restored bony and cartilaginous tissues. Conclusion This case report suggests that the composite of allogeneic UCB-MSCs and HA hydrogel can be considered a safe and effective treatment option for large osteochondral defects of the knee.
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Affiliation(s)
- Yong-Beom Park
- Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Dongjak-gu, Seoul, 06973, South Korea
| | - Chul-Won Ha
- Department of Orthopaedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea. .,Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea. .,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea.
| | - Choong-Hee Lee
- Department of Orthopaedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Yong-Geun Park
- Department of Orthopedic Surgery, Jeju National University Hospital, Jeju National University School of Medicine, 15 Aran 13-gil, Jeju-si, 63241, South Korea
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Abstract
Tissue engineering aims to repair the damaged tissue by transplantation of cells or introducing bioactive factors in a biocompatible scaffold. In recent years, biodegradable polymer scaffolds mimicking the extracellular matrix have been developed to promote the cell proliferation and extracellular matrix deposition. The biodegradable polymer scaffolds thus act as templates for tissue repair and regeneration. This article reviews the updated information regarding various types of natural and synthetic biodegradable polymers as well as their functions, physico-chemical properties, and degradation mechanisms in the development of biodegradable scaffolds for tissue engineering applications, including their combination with 3D printing.
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Affiliation(s)
- Shan-Hui Hsu
- Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan, ROC.
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Park YB, Ha CW, Kim JA, Rhim JH, Park YG, Chung JY, Lee HJ. Effect of Transplanting Various Concentrations of a Composite of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells and Hyaluronic Acid Hydrogel on Articular Cartilage Repair in a Rabbit Model. PLoS One 2016; 11:e0165446. [PMID: 27824874 PMCID: PMC5100912 DOI: 10.1371/journal.pone.0165446] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 10/12/2016] [Indexed: 02/06/2023] Open
Abstract
Background Mesenchymal stem cells (MSCs) are known to have therapeutic potential for cartilage repair. However, the optimal concentration of MSCs for cartilage repair remains unclear. Therefore, we aimed to explore the feasibility of cartilage repair by human umbilical cord blood-derived MSCs (hUCB-MSCs) and to determine the optimal concentrations of the MSCs in a rabbit model. Methods Osteochondral defects were created in the trochlear groove of femur in 55 rabbits. Four experimental groups (11 rabbits/group) were treated by transplanting the composite of hUCB-MSCs and HA with various MSCs concentrations (0.1, 0.5, 1.0, and 1.5 x 107 cells/ml). One control group was left untreated. At 4, 8, and 16 weeks post-transplantation, the degree of cartilage repair was evaluated grossly and histologically. Findings Overall, transplanting hUCB-MSCs and HA hydrogel resulted in cartilage repair tissue with better quality than the control without transplantation (P = 0.015 in 0.1, P = 0.004 in 0.5, P = 0.004 in 1.0, P = 0.132 in 1.5 x 107 cells/ml). Interestingly, high cell concentration of hUCB-MSCs (1.5×107 cells/ml) was inferior to low cell concentrations (0.1, 0.5, and 1.0 x 107 cells/ml) in cartilage repair (P = 0.394,P = 0.041, P = 0.699, respectively). The 0.5 x 107 cells/ml group showed the highest cartilage repair score at 4, 8 and 16 weeks post transplantation, and followed by 0.1x107 cells/ml group or 1.0 x 107 cell/ml group. Conclusions The results of this study suggest that transplantation of the composite of hUCB-MSCs and HA is beneficial for cartilage repair. In addition, this study shows that optimal MSC concentration needs to be determined for better cartilage repair.
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Affiliation(s)
- Yong-Beom Park
- Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Dongjak-gu, Seoul 06973, South Korea
| | - Chul-Won Ha
- Department of Orthopaedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, South Korea
- Stem Cell & Regenerative Medicine Research Institute, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, South Korea
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
- * E-mail: ,
| | - Jin-A Kim
- Department of Orthopaedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, South Korea
- Stem Cell & Regenerative Medicine Research Institute, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, South Korea
| | - Ji-Heon Rhim
- Department of Orthopaedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, South Korea
- Stem Cell & Regenerative Medicine Research Institute, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, South Korea
| | - Yong-Geun Park
- Department of Orthopedic Surgery, Jeju National University Hospital, Jeju National University School of Medicine, 15 Aran 13-gil, Jeju-si 63241, South Korea
| | - Jun Young Chung
- Department of Orthopaedic Surgery, Ajou University Hospital, Ajou University School of Medicine, 164 World cup-ro, Yeongtong-gu, Suwon 16499, South Korea
| | - Han-Jun Lee
- Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Dongjak-gu, Seoul 06973, South Korea
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Park Y, Ha C, Lee C, Yoon YC, Park Y. Cartilage Regeneration in Osteoarthritic Patients by a Composite of Allogeneic Umbilical Cord Blood-Derived Mesenchymal Stem Cells and Hyaluronate Hydrogel: Results from a Clinical Trial for Safety and Proof-of-Concept with 7 Years of Extended Follow-Up. Stem Cells Transl Med 2016; 6:613-621. [PMID: 28191757 PMCID: PMC5442809 DOI: 10.5966/sctm.2016-0157] [Citation(s) in RCA: 289] [Impact Index Per Article: 32.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 07/28/2016] [Indexed: 12/11/2022] Open
Abstract
Few methods are available to regenerate articular cartilage defects in patients with osteoarthritis. We aimed to assess the safety and efficacy of articular cartilage regeneration by a novel medicinal product composed of allogeneic human umbilical cord blood‐derived mesenchymal stem cells (hUCB‐MSCs). Patients with Kellgren‐Lawrence grade 3 osteoarthritis and International Cartilage Repair Society (ICRS) grade 4 cartilage defects were enrolled in this clinical trial. The stem cell‐based medicinal product (a composite of culture‐expanded allogeneic hUCB‐MSCs and hyaluronic acid hydrogel [Cartistem]) was applied to the lesion site. Safety was assessed by the World Health Organization common toxicity criteria. The primary efficacy outcome was ICRS cartilage repair assessed by arthroscopy at 12 weeks. The secondary efficacy outcome was visual analog scale (VAS) score for pain on walking. During a 7‐year extended follow‐up, we evaluated safety, VAS score, International Knee Documentation Committee (IKDC) subjective score, magnetic resonance imaging (MRI) findings, and histological evaluations. Seven participants were enrolled. Maturing repair tissue was observed at the 12‐week arthroscopic evaluation. The VAS and IKDC scores were improved at 24 weeks. The improved clinical outcomes were stable over 7 years of follow‐up. The histological findings at 1 year showed hyaline‐like cartilage. MRI at 3 years showed persistence of the regenerated cartilage. Only five mild to moderate treatment‐emergent adverse events were observed. There were no cases of osteogenesis or tumorigenesis over 7 years. The application of this novel stem cell‐based medicinal product appears to be safe and effective for the regeneration of durable articular cartilage in osteoarthritic knees. Stem Cells Translational Medicine2017;6:613–621
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Affiliation(s)
- Yong‐Beom Park
- Department of Orthopedic Surgery, Chung‐Ang University Hospital, Chung‐Ang University College of Medicine, Seoul, Republic of Korea
| | - Chul‐Won Ha
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Stem Cell & Regenerative Medicine Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea
| | - Choong‐Hee Lee
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Young Cheol Yoon
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yong‐Geun Park
- Department of Orthopedic Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Republic of Korea
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Chondrogenic commitment of human umbilical cord blood-derived mesenchymal stem cells in collagen matrices for cartilage engineering. Sci Rep 2016; 6:32786. [PMID: 27604951 PMCID: PMC5015060 DOI: 10.1038/srep32786] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 08/12/2016] [Indexed: 12/12/2022] Open
Abstract
Umbilical cord blood (UCB) is a promising alternative source of mesenchymal stem cells (MSCs), because UCB-MSCs are abundant and harvesting them is a painless non-invasive procedure. Potential clinical applications of UCB-MSCs have been identified, but their ability for chondrogenic differentiation has not yet been fully evaluated. The aim of our work was to characterize and determine the chondrogenic differentiation potential of human UCB-MSCs (hUCB-MSCs) for cartilage tissue engineering using an approach combining 3D culture in type I/III collagen sponges and chondrogenic factors. Our results showed that UCB-MSCs have a high proliferative capacity. These cells differentiated easily into an osteoblast lineage but not into an adipocyte lineage. Furthermore, BMP-2 and TGF-β1 potentiated chondrogenic differentiation, as revealed by a strong increase in mature chondrocyte-specific mRNA (COL2A1, COL2B, ACAN) and protein (type II collagen) markers. Although growth factors increased the transcription of hypertrophic chondrocyte markers such as COL10A1 and MMP13, the cells present in the neo-tissue maintained their phenotype and did not progress to terminal differentiation and mineralization of the extracellular matrix after subcutaneous implantation in nude mice. Our study demonstrates that our culture model has efficient chondrogenic differentiation, and that hUCB-MSCs can be a reliable source for cartilage tissue engineering.
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Abstract
Among the surgical options for large full-thickness chondral injuries, cell-based therapy has been practiced and its satisfactory outcomes have been reported. One area that appears promising is cell-based therapies utilizing stem cells. Various tissues within the human body contain mesenchymal stem cells (MSCs) from where these can be harvested. These include bone marrow, adipose, synovium, peripheral blood, and umbilical cord. In this article, both preclinical animal studies and clinical studies dealing with the use of MSCs for cartilage repair of the knee are reviewed. Majority of the clinical papers have shown promising results; however, there are a limited number of studies of high evidence level. Clinical significance of the stem cell therapy as compared to other surgical options as well as optimization of the procedure in terms of cell type and delivery method is still to be determined.
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Affiliation(s)
- Shinichi Yoshiya
- Department of Orthopaedic Surgery, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
| | - Aman Dhawan
- Sports Medicine, Penn State Hershey Bone and Joint Institute, Hershey, PA, 17033-0850, USA.
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Ha CW, Park YB, Chung JY, Park YG. Cartilage Repair Using Composites of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells and Hyaluronic Acid Hydrogel in a Minipig Model. Stem Cells Transl Med 2015; 4:1044-51. [PMID: 26240434 DOI: 10.5966/sctm.2014-0264] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Accepted: 06/17/2015] [Indexed: 12/27/2022] Open
Abstract
UNLABELLED The cartilage regeneration potential of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) with a hyaluronic acid (HA) hydrogel composite has shown remarkable results in rat and rabbit models. The purpose of the present study was to confirm the consistent regenerative potential in a pig model using three different cell lines. A full-thickness chondral injury was intentionally created in the trochlear groove of each knee in 6 minipigs. Three weeks later, an osteochondral defect, 5 mm wide by 10 mm deep, was created, followed by an 8-mm-wide and 5-mm-deep reaming. A mixture (1.5 ml) of hUCB-MSCs (0.5×10(7) cells per milliliter) and 4% HA hydrogel composite was then transplanted into the defect on the right knee. Each cell line was used in two minipigs. The osteochondral defect created in the same manner on the left knee was untreated to act as the control. At 12 weeks postoperatively, the pigs were sacrificed, and the degree of subsequent cartilage regeneration was evaluated by gross and histological analysis. The transplanted knee resulted in superior and more complete hyaline cartilage regeneration compared with the control knee. The cellular characteristics (e.g., cellular proliferation and chondrogenic differentiation capacity) of the hUCB-MSCs influenced the degree of cartilage regeneration potential. This evidence of consistent cartilage regeneration using composites of hUCB-MSCs and HA hydrogel in a large animal model could be a stepping stone to a human clinical trial in the future. SIGNIFICANCE To date, several studies have investigated the chondrogenic potential of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs); however, the preclinical studies are still limited in numbers with various results. In parallel, in the past several years, the cartilage regeneration potential of hUCB-MSCs with a hyaluronic acid (HA) hydrogel composite have been investigated and remarkable results in rat and rabbit models have been attained. (These experimental results are currently in preparation for publication.) Before applying the cartilage regeneration technique in a human clinical trial, it seemed necessary to confirm the consistent result in a larger animal model. At 12 weeks postoperatively, the minipigs were sacrificed, and the degree of subsequent cartilage regeneration was evaluated by gross and histological analysis. The transplanted knee resulted in superior and more complete hyaline cartilage regeneration compared with the control knee. This evidence of consistent cartilage regeneration with composites of hUCB-MSCs and HA hydrogel in a large animal model could be a stepping stone to a human clinical trial in the future.
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Affiliation(s)
- Chul-Won Ha
- Department of Orthopedic Surgery, Stem Cell and Regenerative Medicine Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Orthopedic Surgery, Ajou University Hospital, Ajou University School of Medicine, Seoul, Republic of Korea; Department of Orthopedic Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju-do, Republic of Korea
| | - Yong-Beom Park
- Department of Orthopedic Surgery, Stem Cell and Regenerative Medicine Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Orthopedic Surgery, Ajou University Hospital, Ajou University School of Medicine, Seoul, Republic of Korea; Department of Orthopedic Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju-do, Republic of Korea
| | - Jun-Young Chung
- Department of Orthopedic Surgery, Stem Cell and Regenerative Medicine Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Orthopedic Surgery, Ajou University Hospital, Ajou University School of Medicine, Seoul, Republic of Korea; Department of Orthopedic Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju-do, Republic of Korea
| | - Yong-Geun Park
- Department of Orthopedic Surgery, Stem Cell and Regenerative Medicine Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Orthopedic Surgery, Ajou University Hospital, Ajou University School of Medicine, Seoul, Republic of Korea; Department of Orthopedic Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju-do, Republic of Korea
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