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Higa K, Murata D, Azuma C, Nishida K, Nakayama K. Promotion of bone-tendon healing after ACL reconstruction using scaffold-free constructs comprising ADSCs produced by a bio-3D printer in rabbit models. J Orthop Translat 2025; 52:265-275. [PMID: 40342550 PMCID: PMC12059222 DOI: 10.1016/j.jot.2025.03.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 02/28/2025] [Accepted: 03/30/2025] [Indexed: 05/11/2025] Open
Abstract
Background/Objective: This study evaluated the impact of adipose tissue-derived mesenchymal stromal cells (ADSCs) on bone-tendon healing in rabbit anterior cruciate ligament (ACL) reconstruction. Methods Nineteen mature male Japanese White rabbits underwent bilateral ACL reconstruction. ADSC constructs were implanted in the right femoral bone tunnel of each rabbit (implant group), while the left knee served as the control group without implantation. Nine rabbits were sacrificed at 3 and 6 weeks post-surgery, while the remaining were sacrificed immediately post-surgery. Biomechanical and micro computed tomography evaluations were conducted on six rabbits, while histological observation was performed on the remaining three. Results showed: (1) The implant group exhibited a significantly greater failure load than the control group at 3 weeks post-surgery. (2) Initially, the amount of new bone in the femoral tunnel was lower in the implant group at 3 weeks but surpassed that of the control group by 6 weeks. (3) Histological analysis indicated faster bone-tendon healing in the implant group than that of the control. Conclusion These findings suggest a positive effect of ADSC constructs on bone-tendon healing post-ACL reconstruction in rabbits. However, further studies using larger animal models must confirm these effects comprehensively. The translational potential of this article The method of transplanting a scaffold-free autologous ADSC construct is a technique that can safely and reliably transplant ADSCs to the tendon-bone tunnel interface without using foreign substances. It can be applied to bone-tendon healing in ACL reconstruction surgery and other areas, such as the rotator cuff and Achilles tendon attachment site.
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Affiliation(s)
- Kotaro Higa
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 1076 Kiyuna, Ginowan, 901-2720, Japan
| | - Daiki Murata
- Center for Regenerative Medicine Research, Faculty of Medicine, Saga University, 1 Honjyo-machi, Saga, 840-8502, Japan
| | - Chinatsu Azuma
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 1076 Kiyuna, Ginowan, 901-2720, Japan
| | - Kotaro Nishida
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 1076 Kiyuna, Ginowan, 901-2720, Japan
| | - Koichi Nakayama
- Center for Regenerative Medicine Research, Faculty of Medicine, Saga University, 1 Honjyo-machi, Saga, 840-8502, Japan
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He Q, Liao Y, Wu Y, Zhang H, Long X, Zhang Y. Bioactive oligopeptides and the application in skin regeneration and rejuvenation. J Appl Biomater Funct Mater 2025; 23:22808000251330974. [PMID: 40269538 DOI: 10.1177/22808000251330974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2025] Open
Abstract
Oligopeptides, composed of 2-10 amino acid residues, are protein fragments with unique structural characteristics, including small molecular size, high biocompatibility, and modifiable functional groups. These features endow oligopeptides with excellent permeability, safety, and versatile biological activities, making them widely applicable in disease treatment, drug delivery, and skincare. In particular, oligopeptides have emerged as advanced ingredients in skincare, offering anti-aging, anti-wrinkle, and whitening effects by regulating key biological processes such as collagen synthesis, antioxidant defense, and melanin production. This review comprehensively discusses the structural properties, functional mechanisms, and diverse applications of oligopeptides and their derivatives, highlighting their potential in skin regeneration, rejuvenation, and anti-aging medicine. By providing insights into the latest advancements, this review aims to serve as a valuable reference for future research and development in oligopeptide-based therapeutics and skincare innovations.
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Affiliation(s)
- Qiulin He
- Hangzhou Singclean Medical Products Co., Ltd, Hangzhou, China
| | - Youguo Liao
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yaru Wu
- Hangzhou Singclean Medical Products Co., Ltd, Hangzhou, China
| | - Huahui Zhang
- Department of Plastic and Cosmetic, Zhejiang Hospital, Hangzhou, China
| | - Xiaohui Long
- Department of Plastic and Cosmetic, Zhejiang Hospital, Hangzhou, China
| | - Yuxiang Zhang
- Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Anjiki K, Matsumoto T, Kuroda Y, Fujita M, Hayashi S, Nakano N, Tsubosaka M, Kamenaga T, Takashima Y, Kikuchi K, Ikuta K, Onoi Y, Tachibana S, Suda Y, Wada K, Matsushita T, Kuroda R. Heterogeneous Cells as well as Adipose-Derived Stromal Cells in Stromal Vascular Fraction Contribute to Enhance Anabolic and Inhibit Catabolic Factors in Osteoarthritis. Stem Cell Rev Rep 2023; 19:2407-2419. [PMID: 37477775 DOI: 10.1007/s12015-023-10589-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/07/2023] [Indexed: 07/22/2023]
Abstract
The stromal-vascular fraction (SVF), comprising heterogeneous cell populations and adipose-derived stromal cells (ADSCs), has therapeutic potential against osteoarthritis (OA); however, the underlying mechanism remains elusive. This study aimed to investigate the therapeutic effects of heterogeneous cells in rabbit SVF on rabbit chondrocytes. Rabbit SVF and ADSCs were autografted into knees at OA onset. The SVF (1 × 105) and low-dose ADSCs (lADSC; 1 × 104) groups adjusted for their stromal cell content were compared. Animals were euthanized 8 and 12 weeks after OA onset for macroscopic and histological analyses of OA progression and synovitis. Immunohistochemical and real-time polymerase chain reaction assessments were conducted. In vitro, immune-fluorescent double staining was performed for SVF to stain macrophages with F4/80, CD86(M1), and CD163(M2). OA progression was markedly suppressed, and synovitis was reduced in the SVF groups (OARSI histological score 8 W: 6.8 ± 0.75 vs. 3.8 ± 0.75, p = 0.001; 12 W: 8.8 ± 0.4 vs. 5.4 ± 0.49, p = 0.0002). The SVF groups had higher expression of collagen II and SOX9 in cartilage and TGF-β and IL-10 in the synovium, lower expression of MMP-13, and lower macrophage M1/M2 ratio than the lADSC groups. Immunofluorescent double staining revealed a markedly higher number of M2 than that of M1 macrophages in the SVF. The therapeutic effects of SVF on chondrocytes were superior than those of lADSCs, with enhanced anabolic and inhibited catabolic factors. Heterogeneous cells, mainly M2 macrophages in the SVF, enhanced growth factor secretion and chondrocyte-protective cytokines, thus benefiting chondrocytes and knee joint homeostasis. Overall, the SVF is a safe, relatively simple, and a useful treatment option for OA.
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Affiliation(s)
- Kensuke Anjiki
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Tomoyuki Matsumoto
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
| | - Yuichi Kuroda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Masahiro Fujita
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Shinya Hayashi
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Naoki Nakano
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Masanori Tsubosaka
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Tomoyuki Kamenaga
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Yoshinori Takashima
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Kenichi Kikuchi
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Kenmei Ikuta
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Yuma Onoi
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Shotaro Tachibana
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Yoshihito Suda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Kensuke Wada
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Takehiko Matsushita
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Ryosuke Kuroda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
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Li FQ, Chen WB, Luo ZW, Chen YS, Sun YY, Su XP, Sun JM, Chen SY. Bone marrow mesenchymal stem cell-derived exosomal microRNAs target PI3K/Akt signaling pathway to promote the activation of fibroblasts. World J Stem Cells 2023; 15:248-267. [PMID: 37181002 PMCID: PMC10173806 DOI: 10.4252/wjsc.v15.i4.248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/19/2023] [Accepted: 03/23/2023] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND Fibroblast plays a major role in tendon-bone healing. Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) can activate fibroblasts and promote tendon-bone healing via the contained microRNAs (miRNAs). However, the underlying mechanism is not comprehensively understood. Herein, this study aimed to identify overlapped BMSC-derived exosomal miRNAs in three GSE datasets, and to verify their effects as well as mechanisms on fibroblasts. AIM To identify overlapped BMSC-derived exosomal miRNAs in three GSE datasets and verify their effects as well as mechanisms on fibroblasts. METHODS BMSC-derived exosomal miRNAs data (GSE71241, GSE153752, and GSE85341) were downloaded from the Gene Expression Omnibus (GEO) database. The candidate miRNAs were obtained by the intersection of three data sets. TargetScan was used to predict potential target genes for the candidate miRNAs. Functional and pathway analyses were conducted using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, respectively, by processing data with the Metascape. Highly interconnected genes in the protein-protein interaction (PPI) network were analyzed using Cytoscape software. Bromodeoxyuridine, wound healing assay, collagen contraction assay and the expression of COL I and α-smooth muscle actin positive were applied to investigate the cell proliferation, migration and collagen synthesis. Quantitative real-time reverse transcription polymerase chain reaction was applied to determine the cell fibroblastic, tenogenic, and chondrogenic potential. RESULTS Bioinformatics analyses found two BMSC-derived exosomal miRNAs, has-miR-144-3p and has-miR-23b-3p, were overlapped in three GSE datasets. PPI network analysis and functional enrichment analyses in the GO and KEGG databases indicated that both miRNAs regulated the PI3K/Akt signaling pathway by targeting phosphatase and tensin homolog (PTEN). In vitro experiments confirmed that miR-144-3p and miR-23b-3p stimulated proliferation, migration and collagen synthesis of NIH3T3 fibroblasts. Interfering with PTEN affected the phosphorylation of Akt and thus activated fibroblasts. Inhibition of PTEN also promoted the fibroblastic, tenogenic, and chondrogenic potential of NIH3T3 fibroblasts. CONCLUSION BMSC-derived exosomes promote fibroblast activation possibly through the PTEN and PI3K/Akt signaling pathways, which may serve as potential targets to further promote tendon-bone healing.
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Affiliation(s)
- Fang-Qi Li
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Wen-Bo Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Zhi-Wen Luo
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Yi-Sheng Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Ya-Ying Sun
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Xiao-Ping Su
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jun-Ming Sun
- Laboratory Animal Center, Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shi-Yi Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.
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Tian B, Zhang M, Kang X. Strategies to promote tendon-bone healing after anterior cruciate ligament reconstruction: Present and future. Front Bioeng Biotechnol 2023; 11:1104214. [PMID: 36994361 PMCID: PMC10040767 DOI: 10.3389/fbioe.2023.1104214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 03/02/2023] [Indexed: 03/16/2023] Open
Abstract
At present, anterior cruciate ligament (ACL) reconstruction still has a high failure rate. Tendon graft and bone tunnel surface angiogenesis and bony ingrowth are the main physiological processes of tendon-bone healing, and also the main reasons for the postoperative efficacy of ACL reconstruction. Poor tendon-bone healing has been also identified as one of the main causes of unsatisfactory treatment outcomes. The physiological process of tendon-bone healing is complicated because the tendon-bone junction requires the organic fusion of the tendon graft with the bone tissue. The failure of the operation is often caused by tendon dislocation or scar healing. Therefore, it is important to study the possible risk factors for tendon-bone healing and strategies to promote it. This review comprehensively analyzed the risk factors contributing to tendon-bone healing failure after ACL reconstruction. Additionally, we discuss the current strategies used to promote tendon-bone healing following ACL reconstruction.
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Yang C, Teng Y, Geng B, Xiao H, Chen C, Chen R, Yang F, Xia Y. Strategies for promoting tendon-bone healing: Current status and prospects. Front Bioeng Biotechnol 2023; 11:1118468. [PMID: 36777256 PMCID: PMC9911882 DOI: 10.3389/fbioe.2023.1118468] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 01/06/2023] [Indexed: 01/28/2023] Open
Abstract
Tendon-bone insertion (TBI) injuries are common, primarily involving the rotator cuff (RC) and anterior cruciate ligament (ACL). At present, repair surgery and reconstructive surgery are the main treatments, and the main factor determining the curative effect of surgery is postoperative tendon-bone healing, which requires the stable combination of the transplanted tendon and the bone tunnel to ensure the stability of the joint. Fibrocartilage and bone formation are the main physiological processes in the bone marrow tract. Therefore, therapeutic measures conducive to these processes are likely to be applied clinically to promote tendon-bone healing. In recent years, biomaterials and compounds, stem cells, cell factors, platelet-rich plasma, exosomes, physical therapy, and other technologies have been widely used in the study of promoting tendon-bone healing. This review provides a comprehensive summary of strategies used to promote tendon-bone healing and analyses relevant preclinical and clinical studies. The potential application value of these strategies in promoting tendon-bone healing was also discussed.
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Affiliation(s)
- Chenhui Yang
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China,Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China,The Second School of Clinical Medical, Lanzhou University, Lanzhou, China,Department of Orthopedic, Tianshui Hand and Foot Surgery Hospital, Tianshui, China
| | - Yuanjun Teng
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China,Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China,The Second School of Clinical Medical, Lanzhou University, Lanzhou, China
| | - Bin Geng
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China,Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China,The Second School of Clinical Medical, Lanzhou University, Lanzhou, China
| | - Hefang Xiao
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China,Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China,The Second School of Clinical Medical, Lanzhou University, Lanzhou, China
| | - Changshun Chen
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China,Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China,The Second School of Clinical Medical, Lanzhou University, Lanzhou, China
| | - Rongjin Chen
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China,Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China,The Second School of Clinical Medical, Lanzhou University, Lanzhou, China
| | - Fei Yang
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China,Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China,The Second School of Clinical Medical, Lanzhou University, Lanzhou, China
| | - Yayi Xia
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China,Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China,The Second School of Clinical Medical, Lanzhou University, Lanzhou, China,*Correspondence: Yayi Xia,
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Wei B, Ji M, Lin Y, Geng R, Wang Q, Lu J. Investigation of the medium-term effect of osteoprotegerin/bone morphogenetic protein 2 combining with collagen sponges on tendon-bone healing in a rabbit. J Orthop Surg (Hong Kong) 2023; 31:10225536231163467. [PMID: 36893748 DOI: 10.1177/10225536231163467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/11/2023] Open
Abstract
BACKGROUND Osteoprotegerin (OPG) and bone morphogenetic protein-2 (BMP-2) could be administered sequentially to promote tendon-bone healing. There remain several unresolved issues in our previously published study: a) the release kinetics of OPG/BMP-2 from the OPG/BMP-2/collagen sponge (CS) combination in vitro remained unclear; b) the medium-term effect of the OPG/BMP-2/CS combination was not analyzed. Hence, we design this study to address the issues mentioned above. METHODS 30 rabbits undergoing anterior cruciate ligament reconstruction (ACLR) with an Achilles tendon autograft randomly received one of the 3 delivery at the femoral and tibial tunnels: OPG/BMP-2, OPG/BMP-2/CS combination, and nothing (blank control). At 8 and 24 weeks post-surgery, the biomechanical tests and histologic analysis were used to evaluate the tendon-bone healing. RESULTS In mechanical tests, the OPG/BMP-2/CS group showed a higher final failure load and stiffness than the other groups at 8 and 24 weeks. Additionally, the maximum stretching distance showed a decreasing trend. The mechanical failure pattern of samples shifted from a tunnel pull-away to a graft midsubstance rupture after OPG/BMP-2/CS-treated. From histological analysis, the OPG/BMP-2/CS treatment increased the amount of collagen fibers (collagen I and II) and promoted fibrocartilage attachment. CONCLUSION CS as a carrier promotes the medium-term effect of OPG and BMP-2 on tendon-bone healing at the tendon-bone interface in a rabbit ACLR model. OPG, BMP-2 and CS were already applied in several clinical practice, but a further study of clinic use of OPG/BMP-2/CS is still needed.
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Affiliation(s)
- Bing Wei
- School of Medicine, 66334Southeast University, Nanjing, China.,Department of Orthopaedic Surgery/Joint and Sports Medicine Center, Zhongda Hospital, School of Medicine, 162752Southeast University, Nanjing, China
| | - Mingliang Ji
- School of Medicine, 66334Southeast University, Nanjing, China.,Department of Orthopaedic Surgery/Joint and Sports Medicine Center, Zhongda Hospital, School of Medicine, 162752Southeast University, Nanjing, China
| | - Yucheng Lin
- School of Medicine, 66334Southeast University, Nanjing, China.,Department of Orthopaedic Surgery/Joint and Sports Medicine Center, Zhongda Hospital, School of Medicine, 162752Southeast University, Nanjing, China
| | - Rui Geng
- School of Medicine, 66334Southeast University, Nanjing, China.,Department of Orthopaedic Surgery/Joint and Sports Medicine Center, Zhongda Hospital, School of Medicine, 162752Southeast University, Nanjing, China
| | - Qing Wang
- Department of Orthopaedic Surgery, The First People's Hospital of Yongkang Affiliated to Hangzhou Medical College, Jinhua, China
| | - Jun Lu
- School of Medicine, 66334Southeast University, Nanjing, China.,Department of Orthopaedic Surgery/Joint and Sports Medicine Center, Zhongda Hospital, School of Medicine, 162752Southeast University, Nanjing, China
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The Composition of Adipose-Derived Regenerative Cells Isolated from Lipoaspirate Using a Point of Care System Does Not Depend on the Subject's Individual Age, Sex, Body Mass Index and Ethnicity. Cells 2022; 12:cells12010030. [PMID: 36611823 PMCID: PMC9818477 DOI: 10.3390/cells12010030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Uncultured, unmodified, autologous, adipose-derived regenerative cells (UA-ADRCs) are a safe and effective treatment option for various musculoskeletal pathologies. However, it is unknown whether the composition of the final cell suspension systematically varies with the subject's individual age, sex, body mass index and ethnicity. UA-ADRCs were isolated from lipoaspirate from n = 232 subjects undergoing elective lipoplasty using the Transpose RT system (InGeneron, Inc.; Houston, TX, USA). The UA-ADRCs were assessed for the number of nucleated cells, cell viability and the number of viable nucleated cells per gram of adipose tissue harvested. Cells from n = 37 subjects were further characterized using four-channel flow cytometry. The present study shows, for the first time, that key characteristics of UA-ADRCs can be independent of the subject's age, sex, BMI and ethnicity. This result has important implications for the general applicability of UA-ADRCs in regeneration of musculoskeletal tissue. Future studies must determine whether the independence of key characteristics of UA-ADRCs of the subject's individual age, sex, BMI and ethnicity only applies to the system used in the present study, or also to others of the more than 25 different experimental methods and commercially available systems used to isolate UA-ADRCs from lipoaspirate that have been described in the literature.
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Forsythe B, Chahla J, Korrapati A, Lavoie-Gagne O, Forlenza E, Diaz CC, Chung CB, Bae WC, Bach BR, Cole B, Yanke AB, Verma NN. Bone Marrow Aspirate Concentrate Augmentation May Accelerate Allograft Ligamentization in Anterior Cruciate Ligament Reconstruction: A Double-Blinded Randomized Controlled Trial. Arthroscopy 2022; 38:2255-2264. [PMID: 35042007 DOI: 10.1016/j.arthro.2022.01.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 01/03/2022] [Accepted: 01/06/2022] [Indexed: 02/02/2023]
Abstract
PURPOSE To assess the effect of bone marrow aspiration concentrate (BMAC) augmentation on clinical outcomes and magnetic resonance imaging (MRI) findings in anterior cruciate ligament (ACL) reconstruction (ACLR) with bone-patellar tendon-bone (BTB) allografts. METHODS A double-blinded, randomized controlled trial was conducted on 80 patients undergoing ACL reconstruction using BTB allografts. Patients were randomized to 2 groups: (1) bone marrow aspirate was collected from the iliac crest, concentrated, and approximately 2.5 mL was injected into the BTB allograft, or (2) a small sham incision was made at the iliac crest (control). MRI was performed at 3 months and 9 months postoperatively to determine the signal intensity ratio of the ACL graft. RESULTS Seventy-three patients were available for follow-up at 1-year postoperatively (36 BMAC, 37 control). International Knee Documentation Committee (IKDC) scores were significantly greater in the BMAC group versus the control at the 9-month postoperative period (81.6 ± 10.5 vs 74.6 ± 14.2, P = .048). There was no significant difference in the proportion of patients who met the minimal clinically important difference for IKDC between the BMAC and control groups at 9 months (89% vs 85%; P = .7). Three months postoperatively, signal intensity ratio of the inferior third of the ACL graft was significantly greater in the BMAC group versus the control group (3.2 ± 2.2 vs 2.1 ± 1.5; P = .02). CONCLUSIONS Patients who received BMAC augmentation of the BTB allograft during ACL reconstruction demonstrated greater signal intensity scores on MRI at 3 months, suggesting increased metabolic activity and remodeling, and potentially accelerated ligamentization. Additionally, patients in the BMAC group had greater patient-reported outcomes (IKDC) at 9 months postoperatively when compared with those who underwent a standard surgical procedure. There was no significant difference in the proportion of patients who met the minimal clinically important difference for IKDC between the BMAC and control groups at 9 months, suggesting limited clinical significance at this time point. LEVEL OF EVIDENCE I, randomized control trial.
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Affiliation(s)
- Brian Forsythe
- Department of Sports Medicine, Midwest Orthopaedics at Rush, Chicago, Illinois, U.S.A..
| | - Jorge Chahla
- Department of Sports Medicine, Midwest Orthopaedics at Rush, Chicago, Illinois, U.S.A
| | - Avinaash Korrapati
- Department of Sports Medicine, Midwest Orthopaedics at Rush, Chicago, Illinois, U.S.A
| | - Ophelie Lavoie-Gagne
- Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, Massachusetts, U.S.A
| | - Enrico Forlenza
- Department of Sports Medicine, Midwest Orthopaedics at Rush, Chicago, Illinois, U.S.A
| | - Connor C Diaz
- Department of Sports Medicine, Midwest Orthopaedics at Rush, Chicago, Illinois, U.S.A
| | - Christine B Chung
- Department of Radiology, University of California, San Diego, California, U.S.A
| | - Won C Bae
- Department of Radiology, University of California, San Diego, California, U.S.A
| | - Bernard R Bach
- Department of Sports Medicine, Midwest Orthopaedics at Rush, Chicago, Illinois, U.S.A
| | - Brian Cole
- Department of Sports Medicine, Midwest Orthopaedics at Rush, Chicago, Illinois, U.S.A
| | - Adam B Yanke
- Department of Sports Medicine, Midwest Orthopaedics at Rush, Chicago, Illinois, U.S.A
| | - Nikhil N Verma
- Department of Sports Medicine, Midwest Orthopaedics at Rush, Chicago, Illinois, U.S.A
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Hayashi K, Fang X, Ueda H, Miwa A, Naka T, Tsuchiya H. Bone Regeneration Using Autologous Adipose-Derived Stem Cell Spheroid Complex. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.3014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Bone defects require reconstruction using various biomaterials or non-biological materials. Stem cell spheroids can be used for scaffold-free approaches for osteogenesis. We set up a culture method for creating an optimal osteogenic adipose-derived stem cell (ADSC) spheroid complex
by measuring the expression of protein in a sequential series of culture media. After culturing ADSC spheroids for 24 hours in DMEM, the spheroids were cultured in ascorbic acid-containing medium for five days followed by osteoblast differentiation medium. One day after exchanging to osteoblast
differentiation medium, spheroids were collected and cultured for four days to obtain a spheroid complex. Each culture period was determined by analyzing the expression of collagen type I, alkaline phosphatase and integrin α5 to maximize the activity of ADSC spheroids. The expression
of collagen type I increased significantly in ascorbic acid-containing medium (p < 0.05) compared with control medium on day five, suggesting that culturing spheroids in ascorbic acid increases collagen synthesis. RNA was extracted from ADSC spheroids after 1, 3, 5, and 7 days in
each medium and RT-PCR was performed to measure integrin α5 expression. The expression was transiently high on the first day of osteoblast differentiation culture and then gradually decreased. Osteoblast differentiation medium enhanced cell adhesion in spheroids. An in vivo
study confirmed the osteogenic potential of the ADSC spheroid complex created by the established protocol. The ADSC spheroid complex stimulated bone regeneration and will be applied to the treatment of large bone defects.
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Affiliation(s)
- Katsuhiro Hayashi
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, 920-8641, Japan
| | - Xang Fang
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, 920-8641, Japan
| | - Hiroshi Ueda
- Shibuya Corporation, Ko-58 Mameda-Honmachi, Kanazawa, Ishikawa, 920-8681, Japan
| | - Akihiro Miwa
- Shibuya Corporation, Ko-58 Mameda-Honmachi, Kanazawa, Ishikawa, 920-8681, Japan
| | - Toshiaki Naka
- Shibuya Corporation, Ko-58 Mameda-Honmachi, Kanazawa, Ishikawa, 920-8681, Japan
| | - Hiroyuki Tsuchiya
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, 920-8641, Japan
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11
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Yao S, Yung PSH, Lui PPY. Tackling the Challenges of Graft Healing After Anterior Cruciate Ligament Reconstruction-Thinking From the Endpoint. Front Bioeng Biotechnol 2022; 9:756930. [PMID: 35004636 PMCID: PMC8727521 DOI: 10.3389/fbioe.2021.756930] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 11/09/2021] [Indexed: 12/30/2022] Open
Abstract
Anterior cruciate ligament (ACL) tear is common in sports and accidents, and accounts for over 50% of all knee injuries. ACL reconstruction (ACLR) is commonly indicated to restore the knee stability, prevent anterior–posterior translation, and reduce the risk of developing post-traumatic osteoarthritis. However, the outcome of biological graft healing is not satisfactory with graft failure after ACLR. Tendon graft-to-bone tunnel healing and graft mid-substance remodeling are two key challenges of biological graft healing after ACLR. Mounting evidence supports excessive inflammation due to ACL injury and ACLR, and tendon graft-to-bone tunnel motion negatively influences these two key processes. To tackle the problem of biological graft healing, we believe that an inductive approach should be adopted, starting from the endpoint that we expected after ACLR, even though the results may not be achievable at present, followed by developing clinically practical strategies to achieve this ultimate goal. We believe that mineralization of tunnel graft and ligamentization of graft mid-substance to restore the ultrastructure and anatomy of the original ACL are the ultimate targets of ACLR. Hence, strategies that are osteoinductive, angiogenic, or anti-inflammatory should drive graft healing toward the targets. This paper reviews pre-clinical and clinical literature supporting this claim and the role of inflammation in negatively influencing graft healing. The practical considerations when developing a biological therapy to promote ACLR for future clinical translation are also discussed.
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Affiliation(s)
- Shiyi Yao
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Patrick Shu Hang Yung
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Pauline Po Yee Lui
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
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Rodríguez-Merchán EC. Anterior Cruciate Ligament Reconstruction: Is Biological Augmentation Beneficial? Int J Mol Sci 2021; 22:12566. [PMID: 34830448 PMCID: PMC8625610 DOI: 10.3390/ijms222212566] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/17/2021] [Accepted: 11/19/2021] [Indexed: 12/28/2022] Open
Abstract
Surgical reconstruction in anterior cruciate ligament (ACL) ruptures has proven to be a highly effective technique that usually provides satisfactory results. However, despite the majority of patients recovering their function after this procedure, ACL reconstruction (ACLR) is still imperfect. To improve these results, various biological augmentation (BA) techniques have been employed mostly in animal models. They include: (1) growth factors (bone morphogenetic protein, epidermal growth factor, granulocyte colony-stimulating factor, basic fibroblast growth factor, transforming growth factor-β, hepatocyte growth factor, vascular endothelial growth factor, and platelet concentrates such as platelet-rich plasma, fibrin clot, and autologous conditioned serum), (2) mesenchymal stem cells, (3) autologous tissue, (4) various pharmaceuticals (matrix metalloproteinase-inhibitor alpha-2-macroglobulin bisphosphonates), (5) biophysical/environmental methods (hyperbaric oxygen, low-intensity pulsed ultrasound, extracorporeal shockwave therapy), (6) biomaterials (fixation methods, biological coatings, biosynthetic bone substitutes, osteoconductive materials), and (7) gene therapy. All of them have shown good results in experimental studies; however, the clinical studies on BA published so far are highly heterogeneous and have a low degree of evidence. The most widely used technique to date is platelet-rich plasma. My position is that orthopedic surgeons must be very cautious when considering using PRP or other BA methods in ACLR.
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Affiliation(s)
- Emerito Carlos Rodríguez-Merchán
- Department of Orthopedic Surgery, La Paz University Hospital—IdiPaz, 28046 Madrid, Spain;
- Osteoarticular Surgery Research, Hospital La Paz Institute for Health Research—IdiPAZ (La Paz University Hospital—Autonomous University of Madrid), 28046 Madrid, Spain
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13
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Tie K, Cai J, Qin J, Xiao H, Shangguan Y, Wang H, Chen L. Nanog/NFATc1/Osterix signaling pathway-mediated promotion of bone formation at the tendon-bone interface after ACL reconstruction with De-BMSCs transplantation. Stem Cell Res Ther 2021; 12:576. [PMID: 34775995 PMCID: PMC8591902 DOI: 10.1186/s13287-021-02643-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 10/25/2021] [Indexed: 11/10/2022] Open
Abstract
Background Bone formation plays an important role in early tendon–bone healing after anterior cruciate ligament reconstruction (ACLR). Dedifferentiated osteogenic bone marrow mesenchymal stem cells (De-BMSCs) have enhanced osteogenic potential. This study aimed to investigate the effect of De-BMSCs transplantation on the promotion of bone formation at the tendon–bone interface after ACLR and to further explore the molecular mechanism of the enhanced osteogenic potential of De-BMSCs. Methods BMSCs from the femurs and tibias of New Zealand white rabbits were subjected to osteogenic induction and then cultured in medium without osteogenic factors; the obtained cell population was termed De-BMSCs. De-BMSCs were induced to undergo osteo-, chondro- and adipo-differentiation in vitro to examine the characteristics of primitive stem cells. An ACLR model with a semitendinosus tendon was established in rabbits, and the animals were divided into a control group, BMSCs group, and De-BMSCs group. At 12 weeks after surgery, the rabbits in each group were sacrificed to evaluate tendon–bone healing by histologic staining, micro-computed tomography (micro-CT) examination, and biomechanical testing. During osteogenic differentiation of De-BMSCs, an siRNA targeting nuclear factor of activated T-cells 1 (NFATc1) was used to verify the molecular mechanism of the enhanced osteogenic potential of De-BMSCs. Results De-BMSCs exhibited some properties similar to BMSCs, including multiple differentiation potential and cell surface markers. Bone formation at the tendon–bone interface in the De-BMSCs group was significantly increased, and biomechanical strength was significantly improved. During the osteogenic differentiation of De-BMSCs, the expression of Nanog and NFATc1 was synergistically increased, which promoted the interaction of NFATc1 and Osterix, resulting in increased expression of osteoblast marker genes such as COL1A, OCN, and OPN. Conclusions De-BMSCs transplantation could promote bone formation at the tendon–bone interface after ACLR and improve the biomechanical strength of the reconstruction. The Nanog/NFATc1/Osterix signaling pathway mediated the enhanced osteogenic differentiation efficiency of De-BMSCs. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02643-9.
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Affiliation(s)
- Kai Tie
- Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Jinghang Cai
- Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Jun Qin
- Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Hao Xiao
- Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yangfan Shangguan
- Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Hui Wang
- Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, 430071, China.
| | - Liaobin Chen
- Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
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Matsumoto T, Sato Y, Kobayashi T, Suzuki K, Kimura A, Soma T, Ito E, Kikuchi T, Kobayashi S, Harato K, Niki Y, Matsumoto M, Nakamura M, Miyamoto T. Adipose-Derived Stem Cell Sheets Improve Early Biomechanical Graft Strength in Rabbits After Anterior Cruciate Ligament Reconstruction. Am J Sports Med 2021; 49:3508-3518. [PMID: 34643475 DOI: 10.1177/03635465211041582] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Although various reconstruction techniques are available for anterior cruciate ligament (ACL) injuries, a long recovery time is required before patients return to sports activities, as the reconstructed ACL requires time to regain strength. To date, several studies have reported use of mesenchymal stem cells in orthopaedic surgery; however, no studies have used adipose-derived stem cell (ADSC) sheets in ACL reconstruction (ACLR). HYPOTHESIS ADSC sheet transplantation can improve biomechanical strength of the autograft used in ACLR. STUDY DESIGN Controlled laboratory study. METHODS A total of 68 healthy Japanese white rabbits underwent unilateral ACLR with a semitendinosus tendon autograft after random enrollment into a control group (no sheet; n = 34) and a sheet group (ADSC sheet; n = 34). At 2, 4, 8, 16, and 24 weeks after surgery, rabbits in each group were sacrificed to evaluate tendon-bone healing using histological staining, micro-computed tomography, and biomechanical testing. At 24 weeks, scanning transmission electron microscopy of the graft midsubstance was performed. RESULTS The ultimate failure load for the control and sheet groups, respectively, was as follows: 17.2 ± 5.5 versus 37.3 ± 10.3 (P = .01) at 2 weeks, 28.6 ± 1.9 versus 47.4 ± 10.4 (P = .003) at 4 weeks, 53.0 ± 14.3 versus 48.1 ± 9.3 (P = .59) at 8 weeks, 66.2 ± 9.3 versus 95.2 ± 43.1 (P = .24) at 16 weeks, and 66.7 ± 27.3 versus 85.3 ± 29.5 (P = .39) at 24 weeks. The histological score was also significantly higher in the sheet group compared with the control group at early stages up to 8 weeks. On micro-computed tomography, relative to the control group, the bone tunnel area was significantly narrower in the sheet group at 4 weeks, and the bone volume/tissue volume of the tendon-bone interface was significantly greater at 24 weeks. Scanning transmission electron microscopy at 24 weeks indicated that the mean collagen fiber diameter in the midsubstance was significantly greater, as was the occupation ratio of collagen fibers per field of view, in the sheet group. CONCLUSION ADSC sheets improved biomechanical strength, prevented bone tunnel enlargement, and promoted tendon-bone interface healing and graft midsubstance healing in an in vivo rabbit model. CLINICAL RELEVANCE ADSC sheets may be useful for early tendon-bone healing and graft maturation in ACLR.
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Affiliation(s)
- Tatsuaki Matsumoto
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Yuiko Sato
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan; Department of Advanced Therapy for Musculoskeletal Disorders II, School of Medicine, Keio University, Tokyo, Japan; Department of Musculoskeletal Reconstruction and Regeneration Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Tami Kobayashi
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan; Department of Advanced Therapy for Musculoskeletal Disorders II, School of Medicine, Keio University, Tokyo, Japan; Department of Musculoskeletal Reconstruction and Regeneration Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Kunika Suzuki
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan; Regenerative Medicine iPS Gateway Center, Tokyo, Japan
| | - Atsushi Kimura
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Tomoya Soma
- Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Eri Ito
- Institute for Integrated Sports Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Toshiyuki Kikuchi
- Department of Clinical Research, National Hospital Organization Murayama Medical Center, Tokyo, Japan
| | - Shu Kobayashi
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Kengo Harato
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Yasuo Niki
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Morio Matsumoto
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Masaya Nakamura
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Takeshi Miyamoto
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan; Department of Advanced Therapy for Musculoskeletal Disorders II, School of Medicine, Keio University, Tokyo, Japan; Department of Musculoskeletal Reconstruction and Regeneration Surgery, School of Medicine, Keio University, Tokyo, Japan; Department of Orthopedic Surgery, Kumamoto University, Kumamoto, Japan
- Investigation performed at Keio University, Tokyo, Japan
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15
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He S, Qin T. [Research progress of interfacial tissue engineering in rotator cuff repair]. ZHONGGUO XIU FU CHONG JIAN WAI KE ZA ZHI = ZHONGGUO XIUFU CHONGJIAN WAIKE ZAZHI = CHINESE JOURNAL OF REPARATIVE AND RECONSTRUCTIVE SURGERY 2021; 35:1341-1351. [PMID: 34651491 DOI: 10.7507/1002-1892.202104064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Objective To summarize the research progress of interfacial tissue engineering in rotator cuff repair. Methods The recent literature at home and abroad concerning interfacial tissue engineering in rotator cuff repair was analysed and summarized. Results Interfacial tissue engineering is to reconstruct complex and hierarchical interfacial tissues through a variety of methods to repair or regenerate damaged joints of different tissues. Interfacial tissue engineering in rotator cuff repair mainly includes seed cells, growth factors, biomaterials, oxygen concentration, and mechanical stimulation. Conclusion The best strategy for rotator cuff healing and regeneration requires not only the use of biomaterials with gradient changes, but also the combination of seed cells, growth factors, and specific culture conditions (such as oxygen concentration and mechanical stimulation). However, the clinical transformation of the relevant treatment is still a very slow process.
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Affiliation(s)
- Shukun He
- Laboratory of Stem Cells and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China
| | - Tingwu Qin
- Laboratory of Stem Cells and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China
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16
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Zhao X, Zhou Y, Li J, Zhang C, Wang J. Opportunities and challenges of hydrogel microspheres for tendon-bone healing after anterior cruciate ligament reconstruction. J Biomed Mater Res B Appl Biomater 2021; 110:289-301. [PMID: 34418286 DOI: 10.1002/jbm.b.34925] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/28/2021] [Accepted: 08/01/2021] [Indexed: 01/31/2023]
Abstract
Poor angiogenesis and bony ingrowth are the major factors causing unsatisfactory healing between the tendon graft and the bone tunnel surface. Exogenous biological factors, biomaterials, and cells have been considered as new strategies to promote healing quality in recent years. However, it remains challenging for their clinical use because of insufficient in-situ retention time and release efficiency. Increasing attention has been paid to the hydrogel microspheres (HMPs) as potential drug-loading deliveries in biomedicine due to their minimally invasive manner, extended drug retention time, and high loading efficiency. In this review, the healing mechanism between the tendon graft and the bone tunnel is introduced, which is followed by a brief summarization of current methods applied for enhancement of the healing quality. Then, the preclinical studies focusing on HMPs as novel drug carriers are summarized to address the aforementioned concerns in the treatment of tendon-bone healing. Of note, the challenges and perspectives of HMPs in clinical conversion are also outlooked. Collectively, this review may inspire researchers and clinicians to develop clinical available HMPs in orthopedics such as sports medicine from both material and biomedical aspects.
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Affiliation(s)
- Xibang Zhao
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yuanyuan Zhou
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jianting Li
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Chao Zhang
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jiali Wang
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, China
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Application of Stem Cell Therapy for ACL Graft Regeneration. Stem Cells Int 2021; 2021:6641818. [PMID: 34381504 PMCID: PMC8352687 DOI: 10.1155/2021/6641818] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/19/2021] [Accepted: 06/30/2021] [Indexed: 02/07/2023] Open
Abstract
Graft regeneration after anterior cruciate ligament (ACL) reconstruction surgery is a complex three-stage process, which usually takes a long duration and often results in fibrous scar tissue formation that exerts a detrimental impact on the patients' prognosis. Hence, as a regeneration technique, stem cell transplantation has attracted increasing attention. Several different stem cell types have been utilized in animal experiments, and almost all of these have shown good capacity in improving tendon-bone regeneration. Various differentiation inducers have been widely applied together with stem cells to enhance specific lineage differentiation, such as recombinant gene transfection, growth factors, and biomaterials. Among the various different types of stem cells, bone marrow-derived mesenchymal stem cells (BMSCs) have been investigated the most, while ligament stem progenitor cells (LDSCs) have demonstrated the best potential in generating tendon/ligament lineage cells. In the clinic, 4 relevant completed trials have been reported, but only one trial with BMSCs showed improved outcomes, while 5 relevant trials are still in progress. This review describes the process of ACL graft regeneration after implantation and summarizes the current application of stem cells from bench to bedside, as well as discusses future perspectives in this field.
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Xu Y, Zhang WX, Wang LN, Ming YQ, Li YL, Ni GX. Stem cell therapies in tendon-bone healing. World J Stem Cells 2021; 13:753-775. [PMID: 34367476 PMCID: PMC8316867 DOI: 10.4252/wjsc.v13.i7.753] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 05/08/2021] [Accepted: 06/23/2021] [Indexed: 02/06/2023] Open
Abstract
Tendon-bone insertion injuries such as rotator cuff and anterior cruciate ligament injuries are currently highly common and severe. The key method of treating this kind of injury is the reconstruction operation. The success of this reconstructive process depends on the ability of the graft to incorporate into the bone. Recently, there has been substantial discussion about how to enhance the integration of tendon and bone through biological methods. Stem cells like bone marrow mesenchymal stem cells (MSCs), tendon stem/progenitor cells, synovium-derived MSCs, adipose-derived stem cells, or periosteum-derived periosteal stem cells can self-regenerate and potentially differentiate into different cell types, which have been widely used in tissue repair and regeneration. Thus, we concentrate in this review on the current circumstances of tendon-bone healing using stem cell therapy.
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Affiliation(s)
- Yue Xu
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Wan-Xia Zhang
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Li-Na Wang
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Yue-Qing Ming
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Yu-Lin Li
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Guo-Xin Ni
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China.
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Combination of chondrocytes and chondrons improves extracellular matrix production to promote the repairs of defective knee cartilage in rabbits. J Orthop Translat 2021; 28:47-54. [PMID: 33717981 PMCID: PMC7906883 DOI: 10.1016/j.jot.2021.01.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 12/12/2020] [Accepted: 01/13/2021] [Indexed: 12/02/2022] Open
Abstract
Background Chondrons are composed of chondrocytes and the surrounding pericellular matrix (PCM) and function to enhance chondrocyte-mediated cartilage tissue engineering. This study aimed at investigating the potential effect of combined chondrocytes with chondrons on the production of proteoglycan and collagen-II (Col-2) and the repair of defective knee cartilage in rabbits. Methods Chondrocytes and chondrons were isolated from the knee cartilage of rabbits, and cultured alone or co-cultured for varying periods in vitro. Their morphology was characterized by histology. The levels of aggrecan (AGG), Col-2 and glycosaminoglycan (GAG) expression were quantified by qRT-PCR, Alcian blue-based precipitation and ELISA. The effect of combined chondrocytes with chondrons in alginate spheres on the repair of defective knee cartilage was examined in rabbits. Results The isolated chondrocytes and chondrons displayed unique morphology and began to proliferate on day 3 and 6 post culture, respectively, accompanied by completely degenerated PCM on day 6 post culture. Evidently, chondrocytes had stronger proliferation capacity than chondrons. Longitudinal analyses indicated that culture of chondrons, but not chondrocytes, increased AGG mRNA transcripts and GAG levels with time and Col-2 mRNA transcripts only on day 3 post culture. Compared with chondrocytes or chondrons alone, co-culture of chondrocytes and chondrons significantly up-regulated AGG and Col-2 expression and GAG production, particularly at a ratio of 1:1. Implantation with chondrocytes and chondrons at 1:1 significantly promoted the repair of defective knee cartilage in rabbits, accompanied by reduced the Wakiteni scores with time. Conclusion Combined chondrons with chondrocytes promoted the production of extracellular matrix and the repair of defective knee cartilage in rabbits. The translational potential of this article This study explores that the combination of chondrons and chondrocytes may be new therapeutic strategy for cartilage tissue engineering and repair of defective cartilage.
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He X, Li Y, Guo J, Xu J, Zu H, Huang L, Tim-Yun Ong M, Shu-Hang Yung P, Qin L. Biomaterials developed for facilitating healing outcome after anterior cruciate ligament reconstruction: Efficacy, surgical protocols, and assessments using preclinical animal models. Biomaterials 2020; 269:120625. [PMID: 33395579 DOI: 10.1016/j.biomaterials.2020.120625] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 12/16/2020] [Accepted: 12/18/2020] [Indexed: 12/17/2022]
Abstract
Anterior cruciate ligament (ACL) reconstruction is the recommended treatment for ACL tear in the American Academy of Orthopaedic Surgeons (AAOS) guideline. However, not a small number of cases failed because of the tunnel bone resorption, unsatisfactory bone-tendon integration, and graft degeneration. The biomaterials developed and designed for improving ACL reconstruction have been investigated for decades. According to the Food and Drug Administration (FDA) and the International Organization for Standardization (ISO) regulations, animal studies should be performed to prove the safety and bioeffect of materials before clinical trials. In this review, we first evaluated available biomaterials that can enhance the healing outcome after ACL reconstruction in animals and then discussed the animal models and assessments for testing applied materials. Furthermore, we identified the relevance and knowledge gaps between animal experimental studies and clinical expectations. Critical analyses and suggestions for future research were also provided to design the animal study connecting basic research and requirements for future clinical translation.
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Affiliation(s)
- Xuan He
- Musculoskeletal Research Laboratory of Department of Orthopaedics & Traumatology and Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory of Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Ye Li
- Musculoskeletal Research Laboratory of Department of Orthopaedics & Traumatology and Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory of Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Jiaxin Guo
- Musculoskeletal Research Laboratory of Department of Orthopaedics & Traumatology and Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory of Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Jiankun Xu
- Musculoskeletal Research Laboratory of Department of Orthopaedics & Traumatology and Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory of Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Haiyue Zu
- Musculoskeletal Research Laboratory of Department of Orthopaedics & Traumatology and Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory of Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Le Huang
- Musculoskeletal Research Laboratory of Department of Orthopaedics & Traumatology and Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory of Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Michael Tim-Yun Ong
- Musculoskeletal Research Laboratory of Department of Orthopaedics & Traumatology and Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory of Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Patrick Shu-Hang Yung
- Musculoskeletal Research Laboratory of Department of Orthopaedics & Traumatology and Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory of Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Ling Qin
- Musculoskeletal Research Laboratory of Department of Orthopaedics & Traumatology and Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory of Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
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Mengsteab PY, Otsuka T, McClinton A, Shemshaki NS, Shah S, Kan HM, Obopilwe E, Vella AT, Nair LS, Laurencin CT. Mechanically superior matrices promote osteointegration and regeneration of anterior cruciate ligament tissue in rabbits. Proc Natl Acad Sci U S A 2020; 117:28655-28666. [PMID: 33144508 PMCID: PMC7682397 DOI: 10.1073/pnas.2012347117] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The gold standard treatment for anterior cruciate ligament (ACL) reconstruction is the use of tendon autografts and allografts. Limiting factors for this treatment include donor site morbidity, potential disease transmission, and variable graft quality. To address these limitations, we previously developed an off-the-shelf alternative, a poly(l-lactic) acid (PLLA) bioengineered ACL matrix, and demonstrated its feasibility to regenerate ACL tissue. This study aims to 1) accelerate the rate of regeneration using the bioengineered ACL matrix by supplementation with bone marrow aspirate concentrate (BMAC) and growth factors (BMP-2, FGF-2, and FGF-8) and 2) increase matrix strength retention. Histological evaluation showed robust tissue regeneration in all groups. The presence of cuboidal cells reminiscent of ACL fibroblasts and chondrocytes surrounded by an extracellular matrix rich in anionic macromolecules was up-regulated in the BMAC group. This was not observed in previous studies and is indicative of enhanced regeneration. Additionally, intraarticular treatment with FGF-2 and FGF-8 was found to suppress joint inflammation. To increase matrix strength retention, we incorporated nondegradable fibers, polyethylene terephthalate (PET), into the PLLA bioengineered ACL matrix to fabricate a "tiger graft." The tiger graft demonstrated the greatest peak loads among the experimental groups and the highest to date in a rabbit model. Moreover, the tiger graft showed superior osteointegration, making it an ideal bioengineered ACL matrix. The results of this study illustrate the beneficial effect bioactive factors and PET incorporation have on ACL regeneration and signal a promising step toward the clinical translation of a functional bioengineered ACL matrix.
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Affiliation(s)
- Paulos Y Mengsteab
- Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health, Farmington, CT 06030
- Raymond and Beverly Sackler Center for Biological, Physical and Engineering Sciences, University of Connecticut Health, Farmington, CT 06030
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269
| | - Takayoshi Otsuka
- Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health, Farmington, CT 06030
- Raymond and Beverly Sackler Center for Biological, Physical and Engineering Sciences, University of Connecticut Health, Farmington, CT 06030
| | - Aneesah McClinton
- Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health, Farmington, CT 06030
- Raymond and Beverly Sackler Center for Biological, Physical and Engineering Sciences, University of Connecticut Health, Farmington, CT 06030
- Department of Surgery, University of Connecticut School of Medicine, Farmington, CT, 06030
| | - Nikoo Saveh Shemshaki
- Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health, Farmington, CT 06030
- Raymond and Beverly Sackler Center for Biological, Physical and Engineering Sciences, University of Connecticut Health, Farmington, CT 06030
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269
| | - Shiv Shah
- Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health, Farmington, CT 06030
- Raymond and Beverly Sackler Center for Biological, Physical and Engineering Sciences, University of Connecticut Health, Farmington, CT 06030
- Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, CT 06269
| | - Ho-Man Kan
- Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health, Farmington, CT 06030
- Raymond and Beverly Sackler Center for Biological, Physical and Engineering Sciences, University of Connecticut Health, Farmington, CT 06030
| | - Elifho Obopilwe
- Department of Orthopedic Surgery, University of Connecticut Health, Farmington, CT 06030
| | - Anthony T Vella
- Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06030
| | - Lakshmi S Nair
- Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health, Farmington, CT 06030
- Raymond and Beverly Sackler Center for Biological, Physical and Engineering Sciences, University of Connecticut Health, Farmington, CT 06030
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269
- Department of Orthopedic Surgery, University of Connecticut Health, Farmington, CT 06030
- Department of Materials Science and Engineering, University of Connecticut, Storrs, CT 06269
| | - Cato T Laurencin
- Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health, Farmington, CT 06030;
- Raymond and Beverly Sackler Center for Biological, Physical and Engineering Sciences, University of Connecticut Health, Farmington, CT 06030
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269
- Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, CT 06269
- Department of Orthopedic Surgery, University of Connecticut Health, Farmington, CT 06030
- Department of Materials Science and Engineering, University of Connecticut, Storrs, CT 06269
- Department of Reconstructive Sciences, University of Connecticut Health Center, Farmington, CT 06030
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Takagi T, Kabata T, Hayashi K, Fang X, Kajino Y, Inoue D, Ohmori T, Ueno T, Yoshitani J, Ueoka K, Yamamuro Y, Tsuchiya H. Periodic injections of adipose-derived stem cell sheets attenuate osteoarthritis progression in an experimental rabbit model. BMC Musculoskelet Disord 2020; 21:691. [PMID: 33076883 PMCID: PMC7574575 DOI: 10.1186/s12891-020-03718-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 10/13/2020] [Indexed: 12/05/2022] Open
Abstract
Background Subcutaneous adipose tissue represents an abundant source of multipotent adult stem cells named as Adipose-derived stem cells (ADSCs). With a cell sheet approach, ADSCs survive longer, and can be delivered in large quantities. We investigated whether intra-articular ADSC sheets attenuated osteoarthritis (OA) progression in a rabbit anterior cruciate ligament transection (ACLT) model. Methods Fabricating medium containing ascorbate-2-phosphate was used to enhance collagen protein secretion by the ADSCs to make ADSC sheets. At 4 weeks after ACLT, autologous ADSC sheets were injected intra-articularly into the right knee (ADSC sheets group), and autologous cell death sheets treated by liquid nitrogen were injected into the left knee (control group). Subsequent injections were administered once weekly. Femoral condyles were compared macroscopically and histologically. Results Macroscopically, OA progression was significantly milder in the ADSC sheets than in the control groups. Histologically, control knees showed obvious erosions in the medial and lateral condyles, while cartilage was retained predominantly in the ADSC sheets group. Immunohistochemically, MMP-1, MMP-13, ADAMTS-4 were less expressive in the ADSC sheets than in the control groups. Conclusions Periodic ADSC sheets injections inhibited articular cartilage degeneration without inducing any adverse effects. A large quantity of autologous ADSCs delivered by cell sheets homed to the synovium and protected chondrocytes.
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Affiliation(s)
- Tomoharu Takagi
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa university, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Tamon Kabata
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa university, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.
| | - Katsuhiro Hayashi
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa university, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Xiang Fang
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa university, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Yoshitomo Kajino
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa university, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Daisuke Inoue
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa university, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Takaaki Ohmori
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa university, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Takuro Ueno
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa university, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Junya Yoshitani
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa university, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Ken Ueoka
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa university, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Yuki Yamamuro
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa university, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Hiroyuki Tsuchiya
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa university, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
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23
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Alentorn-Geli E, Seijas R, Martínez-De la Torre A, Cuscó X, Steinbacher G, Álvarez-Díaz P, Barastegui D, Navarro J, Serra-Renom JM, Nishishinya B, Català J, Laiz P, García-Balletbó M, Cugat R. Effects of autologous adipose-derived regenerative stem cells administered at the time of anterior cruciate ligament reconstruction on knee function and graft healing. J Orthop Surg (Hong Kong) 2020; 27:2309499019867580. [PMID: 31470759 DOI: 10.1177/2309499019867580] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
PURPOSE To compare the healing and clinical outcomes of anterior cruciate ligament (ACL) reconstruction between patients with or without intraoperative administration of adipose-derived regenerative stem cells (ADRC). METHODS Between 2013 and 2014, the outcomes of 20 soccer players undergoing ACL reconstruction using bone-patellar tendon-bone autograft infiltrated with ADRC at the end of the procedure were compared to a historical, matched cohort of 19 soccer players undergoing the same procedure without ADRC. Outcomes were obtained at baseline, and 6 and 12 months postop for IKDC (International Knee Documentation Committee), Lysholm, and Lequesne, and at 2, 4, 6, and 12 months postop for VAS (visual analogue scale) for pain and graft maturation to evaluate the ligamentization process (magnetic resonance imaging (MRI)-based). RESULTS Both groups significantly improved the IKDC (p < 0.001 in both groups), Lysholm (p < 0.001 in both groups), Lequesne index (p < 0.001 in both groups), VAS for pain (p = 0.002 for the ADRC and p < 0.001 for the control group), and MRI scores (p < 0.001 in both groups) in the 12 months postop compared to baseline scores. However, there were no significant differences in the improvement of the outcomes between groups across time (p > 0.05). All patients returned to sports after surgery, but 8 (40%) patients in the ADRC and 13 (68.4%) patients in the control group had lower Tegner activity score at 12 months postop. CONCLUSIONS Patients receiving ADRC at the time of ACL reconstruction significantly improved knee function and healing/maturation of the graft at 12 months. However, this improvement was not statistically significant compared to a control group undergoing ACL reconstruction alone.
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Affiliation(s)
- Eduard Alentorn-Geli
- 1 Instituto Cugat, Barcelona, Spain.,2 Mutualidad Catalana de Futbolistas, Real Federación Española de Fútbol, Delegación Cataluña, Barcelona, Spain.,3 Fundación García Cugat, Barcelona, Spain
| | - Roberto Seijas
- 1 Instituto Cugat, Barcelona, Spain.,3 Fundación García Cugat, Barcelona, Spain.,4 Universitat Internacional de Catalunya, Barcelona, Spain
| | - Adrián Martínez-De la Torre
- 5 Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland
| | - Xavier Cuscó
- 1 Instituto Cugat, Barcelona, Spain.,3 Fundación García Cugat, Barcelona, Spain
| | - Gilbert Steinbacher
- 2 Mutualidad Catalana de Futbolistas, Real Federación Española de Fútbol, Delegación Cataluña, Barcelona, Spain.,3 Fundación García Cugat, Barcelona, Spain
| | - Pedro Álvarez-Díaz
- 2 Mutualidad Catalana de Futbolistas, Real Federación Española de Fútbol, Delegación Cataluña, Barcelona, Spain.,3 Fundación García Cugat, Barcelona, Spain.,4 Universitat Internacional de Catalunya, Barcelona, Spain
| | - David Barastegui
- 1 Instituto Cugat, Barcelona, Spain.,2 Mutualidad Catalana de Futbolistas, Real Federación Española de Fútbol, Delegación Cataluña, Barcelona, Spain.,3 Fundación García Cugat, Barcelona, Spain
| | - Jordi Navarro
- 1 Instituto Cugat, Barcelona, Spain.,2 Mutualidad Catalana de Futbolistas, Real Federación Española de Fútbol, Delegación Cataluña, Barcelona, Spain.,3 Fundación García Cugat, Barcelona, Spain
| | - José Maria Serra-Renom
- 6 Institute of Aesthetic and Plastic Surgery Dr. Serra-Renom, Hospital Quironsalud, Barcelona, Spain
| | | | | | - Patricia Laiz
- 1 Instituto Cugat, Barcelona, Spain.,3 Fundación García Cugat, Barcelona, Spain
| | | | - Ramón Cugat
- 1 Instituto Cugat, Barcelona, Spain.,2 Mutualidad Catalana de Futbolistas, Real Federación Española de Fútbol, Delegación Cataluña, Barcelona, Spain.,3 Fundación García Cugat, Barcelona, Spain
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24
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Leong NL, Kator JL, Clemens TL, James A, Enamoto-Iwamoto M, Jiang J. Tendon and Ligament Healing and Current Approaches to Tendon and Ligament Regeneration. J Orthop Res 2020; 38:7-12. [PMID: 31529731 PMCID: PMC7307866 DOI: 10.1002/jor.24475] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Accepted: 09/10/2019] [Indexed: 02/04/2023]
Abstract
Ligament and tendon injuries are common problems in orthopedics. There is a need for treatments that can expedite nonoperative healing or improve the efficacy of surgical repair or reconstruction of ligaments and tendons. Successful biologically-based attempts at repair and reconstruction would require a thorough understanding of normal tendon and ligament healing. The inflammatory, proliferative, and remodeling phases, and the cells involved in tendon and ligament healing will be reviewed. Then, current research efforts focusing on biologically-based treatments of ligament and tendon injuries will be summarized, with a focus on stem cells endogenous to tendons and ligaments. Statement of clinical significance: This paper details mechanisms of ligament and tendon healing, as well as attempts to apply stem cells to ligament and tendon healing. Understanding of these topics could lead to more efficacious therapies to treat ligament and tendon injuries. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:7-12, 2020.
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Affiliation(s)
- Natalie L Leong
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
- Department of Surgery, Baltimore VA Medical Center, Baltimore, Maryland
| | - Jamie L Kator
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
| | - Thomas L Clemens
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
- Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, Maryland
| | - Aaron James
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland
| | - Motomi Enamoto-Iwamoto
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
| | - Jie Jiang
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
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25
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Ghayemi N, Sarrafzadeh-Rezaei F, Malekinejad H, Behfar M, Farshid AA. Effects of rabbit pinna-derived blastema cells on tendon healing. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2020; 23:13-19. [PMID: 32395204 PMCID: PMC7206831 DOI: 10.22038/ijbms.2019.29102.7045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 07/21/2019] [Indexed: 11/23/2022]
Abstract
OBJECTIVES Tendon healing is substantially slow and often associated with suboptimal repair. Cell therapy is one of the promising methods to improve tendon repair. Blastema, a population of undifferentiated cells, represents characteristics of pluripotent mesenchymal stem cells and has the potentials to be used in regenerative medicine. The aim of this study was to investigate the use of blastema allotransplantation in rabbit tendon healing. MATERIALS AND METHODS In this study, one rabbit was used as a blastema donor, and twenty-four rabbits were divided into control and treatment groups. Blastema cells were obtained from ear pinna upon punch hole injury in the donor rabbit. Under general anesthesia, a complete transverse tenotomy was performed on the midsubstance of deep digital flexor tendon followed by suture-repair. In the treatment group, 1 × 106 blastema cells suspended in buffer saline were injected intratendinously at the repair site, while the control group received only the buffer saline. Cast coaptation was maintained for two weeks. Eight weeks after the operation, tendons were harvested, and histopathological, biomechanical, and biochemical assays were performed on samples. RESULTS Mechanical testing showed a significant increase in ultimate load, energy absorption, stiffness, yield load, stress, and strain in blastema-treated tendons compared to controls. Also, higher hydroxyproline content and improved collagen alignment along with lower inflammatory cell infiltration and decreased angiogenesis were observed in blastema-treated tendons. CONCLUSION Increased levels of hydroxyproline and improved histopathological and biomechanical parameters in the treatment group suggest that blastema cells could be considered an adjunct to tendon repair in rabbits.
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Affiliation(s)
- Nooshin Ghayemi
- Department of Surgery and Diagnostic Imaging, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Farshid Sarrafzadeh-Rezaei
- Department of Surgery and Diagnostic Imaging, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Hassan Malekinejad
- Department of Pharmacy and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
| | - Mehdi Behfar
- Department of Surgery and Diagnostic Imaging, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Amir-Abbas Farshid
- Department of Pathology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
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26
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Effectiveness of Adhering Adipose-Derived Stem Cells to Defective Cartilage in Promoting Cartilage Regeneration in a Rabbit Model. Arthroscopy 2019; 35:2619-2626. [PMID: 31307837 DOI: 10.1016/j.arthro.2019.03.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 02/28/2019] [Accepted: 03/04/2019] [Indexed: 02/07/2023]
Abstract
PURPOSE To evaluate the therapeutic effect of using a local adherent technique to transplant adipose-derived stem cells (ADSCs) for cartilage regeneration in a rabbit model for patients with traumatic damage or osteochondritis dissecans. METHODS Cartilage defects were created in the trochlear groove of 60 adult white rabbit knees. The rabbits were either left untreated (control group), treated with intra-articularly injected ADSCs (injected group), or treated by adhering ADSCs (adherent group). The 3 groups were compared at 4, 12, and 24 weeks postoperatively using the International Cartilage Repair Society macroscopic scoring system and a modified Wakitani histologic grading system to quantitatively evaluate the regenerated cartilage. The degree of defect repair, integration to the border zone, macroscopic appearance, cell morphology, matrix staining, surface regularity, cartilage thickness, and integration of the donor with the host were evaluated. RESULTS The mean International Cartilage Repair Society scores in the control, injected, and adherent groups were 6.4 ± 2.9, 7.6 ± 0.8, and 7.6 ± 1.4, respectively, at 4 weeks; 6.2 ± 2.4, 8.2 ± 1.5, and 9.6 ± 1.0, respectively, at 8 weeks; and 7.6 ± 1.0, 8.4 ± 1.4, and 10.2 ± 1.7, respectively, at 24 weeks. Although the scores were higher in the adherent group, no significant difference was noted. The mean modified Wakitani scores in the control, injected, and adherent groups were 3.8 ± 2.0, 5.1 ± 1.8, and 7.8 ± 1.3, respectively, at 4 weeks (P = .041); 5.1 ± 1.0, 5.4 ± 2.7, and 9.6 ± 1.4, respectively, at 12 weeks (P = .016); and 5.4 ± 1.0, 5.9 ± 1.5, and 9.8 ± 1.8, respectively, at 24 weeks (P = .007). CONCLUSIONS The histologic modified Wakitani scores showed that adhering ADSCs to osteochondral cartilage defects was more effective than intra-articular injection for promoting cartilage regeneration. CLINICAL RELEVANCE Local adhesion of ADSCs can promote cartilage regeneration and may be a treatment option for cartilage repair.
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27
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Sun Y, Chen W, Hao Y, Gu X, Liu X, Cai J, Liu S, Chen J, Chen S. Stem Cell-Conditioned Medium Promotes Graft Remodeling of Midsubstance and Intratunnel Incorporation After Anterior Cruciate Ligament Reconstruction in a Rat Model. Am J Sports Med 2019; 47:2327-2337. [PMID: 31306585 DOI: 10.1177/0363546519859324] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Stem cell-conditioned medium (CM) has been increasingly used in regenerative medicine. However, its effect on graft-host integration after anterior cruciate ligament (ACL) reconstruction (ACLR) remains unclear. PURPOSE To examine the effect of human bone marrow stem cell (hBMSC)-CM on graft-bone integration and graft midsubstance ligamentization in a rat model of ACLR. STUDY DESIGN Controlled laboratory study. METHODS CM was obtained from the supernatant of commercially available hBMSCs in serum-free Dulbecco's modified Eagle medium (DMEM). In a rat model of an ACL injury, isometric ACLR was performed. Three groups were established: CM injection group (CM; n = 40), control injection group (CI; n = 40) with serum-free DMEM injections, and no injection group (NI; n = 40). An intra-articular injection was performed weekly. Micro-computed tomography was conducted at 2, 4, and 8 weeks postoperatively. Histological and biomechanical analyses were conducted at 4 and 8 weeks postoperatively. The NIH3T3 fibroblast was utilized as a model in vitro to examine the effect of CM using the cell counting kit-8 (CCK-8) assay and immunofluorescence staining of Ki-67, α-smooth muscle actin (α-SMA), and collagen 1 (Col 1). RESULTS At 4 and 8 weeks, the femoral and tibial bone tunnel areas as well as the interface between the graft and host bone were smaller, while the bone volume/total volume ratio was higher, in the CM group. Sharpey-like fibers formed at 8 weeks in the CM group. At 4 and 8 weeks, more Col 1 was noticed in the CM group than in the NI group (both P < .001) or CI group (both P < .001). Immunohistochemically, the α-SMA-positive area was up-regulated at the graft-bone interface at 4 weeks (P < .001) and declined at 8 weeks (P < .001) in the CM group compared with the other 2 groups. At the midsubstance, α-SMA expression decreased from 4 to 8 weeks in all groups and was significantly lower in the CM group than in the NI group (P < .01) or CI group (P < .05) at 8 weeks. The CCK-8 assay showed that CM increased NIH3T3 viability (P < .001) and the level of Ki-67 (P < .05), α-SMA (P < .001), and Col 1 (P < .001) in CM-educated NIH3T3 cells. CONCLUSION hBMSC-CM accelerates graft-bone incorporation and midsubstance ligamentization and enhances the proliferation, differentiation, and collagen synthesis of fibroblasts. CLINICAL RELEVANCE Graft-host integration is essential after ACLR. The current study identified a novel agent, that is, hBMSC-CM, as a candidate for promoting integration.
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Affiliation(s)
- Yaying Sun
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Wenbo Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuefeng Hao
- Department of Orthopaedic Surgery, Northern Branch of Suzhou Municipal Hospital, Suzhou, China
| | - Xueping Gu
- Department of Orthopaedic Surgery, Northern Branch of Suzhou Municipal Hospital, Suzhou, China
| | - Xingwang Liu
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiangyu Cai
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Shaohua Liu
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiwu Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Shiyi Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
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Calejo I, Costa-Almeida R, Reis RL, Gomes ME. Enthesis Tissue Engineering: Biological Requirements Meet at the Interface. TISSUE ENGINEERING PART B-REVIEWS 2019; 25:330-356. [DOI: 10.1089/ten.teb.2018.0383] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Isabel Calejo
- 3B's Research Group, I3Bs—Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Raquel Costa-Almeida
- 3B's Research Group, I3Bs—Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Rui L. Reis
- 3B's Research Group, I3Bs—Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães, Portugal
- The Discoveries Center for Regenerative and Precision Medicine, Headquarters at University of Minho, Guimarães, Portugal
| | - Manuela E. Gomes
- 3B's Research Group, I3Bs—Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães, Portugal
- The Discoveries Center for Regenerative and Precision Medicine, Headquarters at University of Minho, Guimarães, Portugal
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29
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Kuroda Y, Matsumoto T, Hayashi S, Hashimoto S, Takayama K, Kirizuki S, Tsubosaka M, Kamenaga T, Takashima Y, Matsushita T, Niikura T, Kuroda R. Intra-articular autologous uncultured adipose-derived stromal cell transplantation inhibited the progression of cartilage degeneration. J Orthop Res 2019; 37:1376-1386. [PMID: 30378173 DOI: 10.1002/jor.24174] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 10/22/2018] [Indexed: 02/04/2023]
Abstract
The role of uncultured adipose-derived stromal cells for osteoarthritis treatment remains unclear despite sporadic reports supporting their use in clinical settings. This study aimed to evaluate the therapeutic effects of autologous uncultured adipose-derived stromal cell transplantation in a rabbit osteoarthritis model. Uncultured adipose-derived stromal cells isolated from rabbits were administered via intra-articular injection into the knees after osteoarthritis onset. Animals were sacrificed at 8 and 12 weeks after osteoarthritis onset to compare the macroscopic, histological, and immunohistochemical characteristics between the uncultured adipose-derived stromal cell and control groups. Co-culture assay was also performed. The chondrocytes isolated from the model were co-cultured with adipose-derived stromal cells. The cell viability of chondrocytes and expression of chondrocyte-specific genes in the co-culture (uncultured adipose-derived stromal cell) group were compared with the mono-culture (control; chondrocytes only) group. In macroscopic and histological analyses, the uncultured adipose-derived stromal cell group showed less damage to the cartilage surface than the control group at 8 and 12 weeks after osteoarthritis onset. In immunohistochemical and co-culture assay, the uncultured adipose-derived stromal cell group showed higher expression of collagen type II and SRY box-9 and lower expression of matrix metalloproteinase-13 than the control group. The cell viability of chondrocytes in the uncultured adipose-derived stromal cell group was higher than that in the control group. Intra-articular autologous uncultured adipose-derived stromal cell transplantation inhibited the progression of cartilage degeneration in a rabbit osteoarthritis model by regulating chondrocyte viability and secreting chondrocyte-protecting cytokines or growth factors, which promote anabolic factors and inhibit catabolic factors. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1376-1386, 2019.
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Affiliation(s)
- Yuichi Kuroda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tomoyuki Matsumoto
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shinya Hayashi
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shingo Hashimoto
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Koji Takayama
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shinsuke Kirizuki
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Masanori Tsubosaka
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tomoyuki Kamenaga
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoshinori Takashima
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takehiko Matsushita
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takahiro Niikura
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Ryosuke Kuroda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
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Progress in biological reconstruction and enhanced bone revitalization for bone defects. J Orthop Sci 2019; 24:387-392. [PMID: 30797666 DOI: 10.1016/j.jos.2019.01.015] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 11/27/2018] [Accepted: 01/09/2019] [Indexed: 11/22/2022]
Abstract
Bone defect reconstruction with artificial materials may produce good functional recovery in the short term. Over time, the durability of artificial materials becomes an issue, and therefore, artificial materials cannot be considered a permanent solution to reconstruction. For long-term outcomes, the goal is to regain function, permanence, and form that are as close to normal as possible. Thus, physiological materials are desirable for use in reconstruction. Biological reconstruction involves the use of materials that are modified in vivo following reconstruction of bone defects. The goal is to achieve bone union, bone revival and remodeling, with biointegration of soft tissue and bone. Allograft use has been the mainstay of bone defect reconstruction in most parts of the world, although in some countries like Japan, allogeneic bone is difficult to obtain due to socio-religious concerns. Therefore, we developed new biological reconstruction techniques to overcome this problem. Bone derived from distraction osteogenesis is autologous bone, which must be an ideal reconstruction material for its biological affinity, strength, resilience, and immunity to infection. When applying this method to patients with malignant disease however, it is important to preserve as much of the local soft tissue as possible, and the clinician must be especially careful of infection and callus formation. Liquid nitrogen treatment of tumor-bearing bone produces equal, if not better, bone revitalization compared to other forms of treatment to date. Reconstruction with liquid nitrogen-treated bone involves resecting the diseased bone and returning it to the body following liquid nitrogen treatment (free-freezing method). Another method involves dislocating the joint proximal to the tumor, or cutting the bone while the distal side remains attached to the body and the limb inverted and treated with liquid nitrogen (pedicle freezing method). When both methods are possible, the pedicle freezing method is preferable since it is performed with minimal osteotomy. Our recent research has looked into the possible role of adipose-derived stem cells in promoting bone fusion and revitalization. This method has produced promising results for the future of biological reconstruction.
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Chen C, Zhang T, Liu F, Qu J, Chen Y, Fan S, Chen H, Sun L, Zhao C, Hu J, Lu H. Effect of Low-Intensity Pulsed Ultrasound After Autologous Adipose-Derived Stromal Cell Transplantation for Bone-Tendon Healing in a Rabbit Model. Am J Sports Med 2019; 47:942-953. [PMID: 30870031 DOI: 10.1177/0363546518820324] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Low-intensity pulsed ultrasound (LIPUS), as a safe biophysiotherapy, can enhance bone-tendon (B-T) healing in vivo and induce osteogenic or chondrogenic differentiation of mesenchymal stromal cells in vitro. This study aimed to determine whether LIPUS can improve the efficacy of transplanted mesenchymal stromal cells on B-T healing. HYPOTHESIS LIPUS can induce lineage-specific differentiation of transplanted adipose-derived stromal cells (ASCs) at the B-T healing site, thus resulting in superior healing quality when compared with LIPUS or ASCs alone. STUDY DESIGN Controlled laboratory study. METHODS A total of 112 mature rabbits with partial patellectomy in the hindlimb were randomly assigned into mock sonication without ASCs (control), ultrasonication without ASCs (LIPUS), mock sonication with ASCs (ASCs), and ultrasonication with ASCs (LIPUS + ASCs). The treatment time of the mock sonication or ultrasonication was 20 minutes per day. Autologous ASCs were transplanted to the healing site by fibrin glue during the operation, and LIPUS was delivered daily starting at postoperative day 3 until euthanasia. The patella-patellar tendon junctions were postoperatively harvested at 8 and 16 weeks for radiological, histological, and mechanical evaluations. Additionally, 9 animals were used for ASC tracking with mCherry protein. RESULTS Radiologically, there was more new bone formation and remodeling in the LIPUS + ASCs group as compared with the other groups. Synchrotron radiation micro-computed tomography showed that the LIPUS + ASCs group significantly increased bone volume fraction, trabecular thickness, and trabecular number at the healing site as compared with the other groups at postoperative 8 weeks ( P < .05 for all). Histologically, immunohistochemical staining confirmed that the transplanted mCherry-ASCs can differentiate into osteoblasts and fibrochondrocytic-like cells. Meanwhile, as compared with the other groups, the LIPUS + ASCs group showed more formation and maturity of the fibrocartilage layer and new bone at postoperative weeks 8 and 16 ( P < .05 for all). Biomechanically, the LIPUS + ASCs group showed significantly higher failure load and stiffness versus the other groups at postoperative weeks 8 and 16 ( P < .05 for all). CONCLUSION Autologous ASC transplantation stimulated with LIPUS can result in superior B-T healing quality when compared with LIPUS or ASCs alone. CLINICAL RELEVANCE This study demonstrates the effectiveness of using ASC transplantation stimulated with LIPUS for B-T healing and provides a foundation for future clinical studies.
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Affiliation(s)
- Can Chen
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Tao Zhang
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Fei Liu
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Jin Qu
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Yang Chen
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Silong Fan
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Huabin Chen
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Lunquan Sun
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Chunfeng Zhao
- Division of Orthopedic Research and Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Jianzhong Hu
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China.,Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Hongbin Lu
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
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Chen C, Liu F, Tang Y, Qu J, Cao Y, Zheng C, Chen Y, Li M, Zhao C, Sun L, Hu J, Lu H. Book-Shaped Acellular Fibrocartilage Scaffold with Cell-loading Capability and Chondrogenic Inducibility for Tissue-Engineered Fibrocartilage and Bone-Tendon Healing. ACS APPLIED MATERIALS & INTERFACES 2019; 11:2891-2907. [PMID: 30620556 DOI: 10.1021/acsami.8b20563] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Functional fibrocartilage regeneration is a bottleneck during bone-tendon healing, and the currently available tissue-engineering strategies for fibrocartilage regeneration are insufficient because of a lack of appropriate scaffold that can load large seeding-cells and induce chondrogenesis of stem cells. The acellular fibrocartilage scaffold (AFS) contains active growth factors as well as tissue-specific epitopes for cell-matrix interactions, which make it a potential scaffold for tissue-engineered fibrocartilage. A limitation to this scaffold is that its low porosity inhibits cells loading and infiltration. Here, inspired by book appearance, we sectioned native fibrocartilage tissue (NFT) into book-shape to improve cells loading and infiltration, and then decellularized with four protocols: (1) 2% SDS for 6-h, (2) 2% SDS for 24-h, (3) 4 SDS for 6-h, (4) 4% SDS for 24-h, followed by nuclease digestion. The optimal protocol was screened with respect to microstructures, DNA residence, native ingredients reservation, and chondrogenic inducibility of the AFS. In vitro studies demonstrated that this screened scaffold is noncytotoxicity and low-immunogenicity, allows adipose-derived stromal cells (ASCs) attachment and proliferation, shows superior chondrogenic inducibility, and stimulates collagen or glycosaminoglycans secretion. The underlying mechanism for this chondrogenic inducibility may be related to hedgehog pathway activating. Additionally, a novel pattern for fabricating tissue-engineered fibrocartilage was developed to enlarge seeding-cells loading, namely, cell-sheets sandwiched by book-shaped scaffold. In-vivo studies indicate that this screened scaffold alone could induce endogenous cells to satisfactorily regenerate fibrocartilage at 16-week, as characterized by fibrocartilaginous extracellular matrix (ECM) deposition and good interface integration. Interleaving this book-shaped AFS with autologous ASCs-sheets significantly enhanced its ability to regenerate fibrocartilage. Cell tracking demonstrated that fibrochondrocytes, osteoblasts, and osteocytes in the healing interface at postoperative 8-week partly originated from the sandwiched ASCs-sheets. On that basis, we propose the use of this book-shaped AFS and cell sheet technique for fabricating tissue-engineered fibrocartilage to improve bone-tendon healing.
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Affiliation(s)
- Can Chen
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Fei Liu
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Yifu Tang
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Jin Qu
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Yong Cao
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Cheng Zheng
- Department of Orthopedics , Hospital of Wuhan Sports University , Wuhan , Hubei , China , 430079
| | - Yang Chen
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Muzhi Li
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Chunfeng Zhao
- Division of Orthopedic Research and Department of Orthopedic Surgery , Mayo Clinic , Rochester , Minnesota 55905 , United States
| | | | - Jianzhong Hu
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Hongbin Lu
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
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Calejo I, Costa-Almeida R, Gomes ME. Cellular Complexity at the Interface: Challenges in Enthesis Tissue Engineering. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1144:71-90. [PMID: 30632116 DOI: 10.1007/5584_2018_307] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The complex heterogeneous cellular environment found in tendon-to-bone interface makes this structure a challenge for interface tissue engineering. Orthopedic surgeons still face some problems associated with the formation of fibrotic tissue or re-tear occurring after surgical re-attachment of tendons to the bony insertion or the application of grafts. Unfortunately, an understanding of the cellular component of enthesis lags far behind of other well-known musculoskeletal interfaces, which blocks the development of new treatment options for the healing and regeneration of this multifaceted junction. In this chapter, the main characteristics of tendon and bone cell populations are introduced, followed by a brief description of the interfacial cellular niche, highlighting molecular mechanisms governing tendon-to-bone attachment and mineralization. Finally, we describe and critically assess some challenges faced concerning the use of cell-based strategies in tendon-to-bone healing and regeneration.
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Affiliation(s)
- Isabel Calejo
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Raquel Costa-Almeida
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Manuela E Gomes
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal. .,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal. .,The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at University of Minho, Guimarães, Portugal.
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Hexter AT, Thangarajah T, Blunn G, Haddad FS. Biological augmentation of graft healing in anterior cruciate ligament reconstruction: a systematic review. Bone Joint J 2018; 100-B:271-284. [PMID: 29589505 DOI: 10.1302/0301-620x.100b3.bjj-2017-0733.r2] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Aims The success of anterior cruciate ligament reconstruction (ACLR) depends on osseointegration at the graft-tunnel interface and intra-articular ligamentization. Our aim was to conduct a systematic review of clinical and preclinical studies that evaluated biological augmentation of graft healing in ACLR. Materials and Methods In all, 1879 studies were identified across three databases. Following assessment against strict criteria, 112 studies were included (20 clinical studies; 92 animal studies). Results Seven categories of biological interventions were identified: growth factors, biomaterials, stem cells, gene therapy, autologous tissue, biophysical/environmental, and pharmaceuticals. The methodological quality of animal studies was moderate in 97%, but only 10% used clinically relevant outcome measures. The most interventions in clinical trials target the graft-tunnel interface and are applied intraoperatively. Platelet-rich plasma is the most studied intervention, but the clinical outcomes are mixed, and the methodological quality of studies was suboptimal. Other biological therapies investigated in clinical trials include: remnant-augmented ACLR; bone substitutes; calcium phosphate-hybridized grafts; extracorporeal shockwave therapy; and adult autologus non-cultivated stem cells. Conclusion There is extensive preclinical research supporting the use of biological therapies to augment ACLR. Further clinical studies that meet the minimum standards of reporting are required to determine whether emerging biological strategies will provide tangible benefits in patients undergoing ACLR. Cite this article: Bone Joint J 2018;100-B:271-84.
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Affiliation(s)
- A T Hexter
- Institute of Orthopaedics and Musculoskeletal Science, Division of Surgery and Interventional Science, University College London, and Royal National Orthopaedic Hospital Brockley Hill, Stanmore, Middlesex HA7 4LP, UK
| | - T Thangarajah
- Institute of Orthopaedics and Musculoskeletal Science, Division of Surgery and Interventional Science, University College London, and Royal National Orthopaedic Hospital Brockley Hill, Stanmore, Middlesex HA7 4LP, UK
| | - G Blunn
- Institute of Orthopaedics and Musculoskeletal Science, Division of Surgery and Interventional Science, University College London, and Royal National Orthopaedic Hospital Brockley Hill, Stanmore, Middlesex HA7 4LP, UK
| | - F S Haddad
- University College London Hospitals, 235 Euston Road, London, NW1 2BU, UK and NIHR University College London Hospitals Biomedical Research Centre, UK
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Siegel KR, Clevenger TN, Clegg DO, Proctor DA, Proctor CS. Adipose Stem Cells Incorporated in Fibrin Clot Modulate Expression of Growth Factors. Arthroscopy 2018; 34:581-591. [PMID: 29100775 DOI: 10.1016/j.arthro.2017.08.250] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 07/30/2017] [Accepted: 08/03/2017] [Indexed: 02/02/2023]
Abstract
PURPOSE To evaluate the platelet capture rate of whole blood fibrin clots and the expression, secretion, and retention of the growth factors vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) from fibrin clots and to determine how these levels may be modulated by allogeneic adipose-derived stem cells (ASCs). METHODS Whole blood from 10 human volunteers was transferred to a clotting device and the platelet capture rate determined. Two experimental conditions and 1 control were evaluated over 2 weeks in vitro. Clots made from human whole blood without ASCs, clot(-)ASC, were compared with clots with ASCs incorporated, clot(+)ASC, and a control group of synthetic polyethylene glycol gels with ASCs incorporated, control(+)ASCs. All conditions were examined for secretion and retention of VEGF, PDGF, and bFGF via enzyme-linked immunosorbent assay and immunohistochemistry. The analysis of platelet retention for clots made with this device was performed. RESULTS Enzyme-linked immunosorbent assay analysis showed significantly higher (P < .001) secretion of VEGF in clot(+)ASC compared with clot(-)ASC or control(+)ASC. In contrast, clot(-)ASC produced soluble PDGF, and the addition of ASCs results in decreased soluble PDGF with concomitant increases in PDGF immunoreactivity of ASCs. Soluble bFGF levels were low in clot(-)ASC, and were found to increase at early time points in clot(+)ASC. Furthermore, bFGF immunoreactivity could be detected in clot(+)ASC, whereas no bFGF immunoreactivity is present in clot(-)ASC or control(+)ASC. Control(+)ASC displayed a spike in bFGF secretion at day 0, which may be due to a stress response elicited by the encapsulation process. Approximately 98% of available platelets in whole blood were concentrated in the clot on formation. CONCLUSIONS Fibrin clots made by this method retain high concentrations of platelets, and when incorporated with ASCs show modulated secretion and immunoreactivity of VEGF, PDGF, and bFGF. CLINICAL RELEVANCE Whole blood fibrin clots capture platelets and release growth factors, and the addition of ASCs increases VEGF release for up to 2 weeks after clot formation. This suggests that whole blood fibrin clots may be a viable scaffold and delivery vehicle for future stem cell treatments.
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Affiliation(s)
- Kelsy R Siegel
- Center for Stem Cell Biology and Engineering, Neuroscience Research Institute, and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, California, U.S.A..
| | - Tracy N Clevenger
- Center for Stem Cell Biology and Engineering, Neuroscience Research Institute, and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, California, U.S.A
| | - Dennis O Clegg
- Center for Stem Cell Biology and Engineering, Neuroscience Research Institute, and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, California, U.S.A
| | - Duncan A Proctor
- Center for Stem Cell Biology and Engineering, Neuroscience Research Institute, and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, California, U.S.A
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