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Cao M, Ou Z, Sheng R, Wang Q, Chen X, Zhang C, Dai G, Wang H, Li J, Zhang X, Gao Y, Shi L, Rui Y. Efficacy and safety of mesenchymal stem cells in knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Stem Cell Res Ther 2025; 16:122. [PMID: 40055739 PMCID: PMC11887158 DOI: 10.1186/s13287-025-04252-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 02/20/2025] [Indexed: 05/13/2025] Open
Abstract
BACKGROUND The aim of this meta-analysis was to investigate the efficacy and safety of intra-articular injection of mesenchymal stem cells (MSCs) alone for the treatment of unoperated knee osteoarthritis (OA). METHODS Four databases were systematically searched (before August 1, 2024) to include randomized controlled trials (RCTs) of MSCs for OA. The population of this study was OA patients who had not received any surgical treatment. The intervention was intra-articular injection of MSCs without other adjuvant therapy. Outcomes included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), 100-mm Visual Analog Score (VAS), Knee Injury and Osteoarthritis Prognostic Score (KOOS), and adverse events. After screening the literature according to the eligibility criteria, extracting the data, and evaluating the quality, Meta-analysis was performed using Revman 5.3 software. The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS 8 RCTs and 502 patients with OA were included in the study. Compared with the control group, MSCs significantly improved 6-month WOMAC [MD = 7.44, 95% CI = (1.45, 13.42), P = 0.01] and 12-month WOMAC [MD = 10.31, 95% CI = (0.96, 19.67), P = 0.03]. MSCs also improved VAS and KOOS at 6 and 12 months in patients with OA. Subgroup analysis showed more significant efficacy of adipose source and high doses of MSCs. There was no significant difference between the adverse events in the MSCs group and the control group (P > 0.05). CONCLUSION Intra-articular injection of MSCs alone could significantly improve knee pain and dysfunction in patients with unoperated OA. MSCs are expected to be an effective treatment for OA with enhanced delivery efficiency.
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Affiliation(s)
- Mumin Cao
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, PR China
- School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, PR China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
| | - Zhengkuan Ou
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, PR China
- School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
| | - Renwang Sheng
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, PR China
- School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, PR China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
| | - Qianqian Wang
- Jiangsu Key Laboratory for Design and Manufacture of Micro-Nano Biomedical Instruments, School of Mechanical Engineering, Southeast University, Nanjing, PR China
| | - Xiangxu Chen
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, PR China
- School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, PR China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
| | - Cheng Zhang
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, PR China
- School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, PR China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
| | - Guangchun Dai
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, PR China
- School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, PR China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
| | - Hao Wang
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, PR China
- School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, PR China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
| | - Jiamin Li
- Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University, Nanjing, China
| | - Xihan Zhang
- School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
| | - Yucheng Gao
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, PR China
- School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, PR China
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China
| | - Liu Shi
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, PR China.
- School of Medicine, Southeast University, Nanjing, Jiangsu, PR China.
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, PR China.
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China.
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China.
| | - Yunfeng Rui
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, PR China.
- School of Medicine, Southeast University, Nanjing, Jiangsu, PR China.
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, PR China.
- Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China.
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China.
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Stocco E, Emmi A, De Caro R, Porzionato A, Macchi V. Knee adipose tissue: from its implication in osteoarthritis to its supposed role in tissue engineering. NPJ AGING 2025; 11:5. [PMID: 39900591 PMCID: PMC11790864 DOI: 10.1038/s41514-025-00195-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 01/16/2025] [Indexed: 02/05/2025]
Affiliation(s)
- Elena Stocco
- Section of Human Anatomy, Department of Neuroscience, University of Padova, Padua, Italy
- Department of Women's and Children's Health, University of Padova, Padua, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy
| | - Aron Emmi
- Section of Human Anatomy, Department of Neuroscience, University of Padova, Padua, Italy
| | - Raffaele De Caro
- Section of Human Anatomy, Department of Neuroscience, University of Padova, Padua, Italy.
| | - Andrea Porzionato
- Section of Human Anatomy, Department of Neuroscience, University of Padova, Padua, Italy
| | - Veronica Macchi
- Section of Human Anatomy, Department of Neuroscience, University of Padova, Padua, Italy.
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Triangga AFR, Asmara W, Magetsari R, Bachtiar I, Fazatamma DA, Saraswati PA, Huwaidi AF, Wirohadidjojo YW. Infrapatellar Fat Pad-Derived Non-Cellular Products in Therapy for Musculoskeletal Diseases: A Scoping Review. Orthop Rev (Pavia) 2024; 16:125841. [PMID: 39686964 PMCID: PMC11646799 DOI: 10.52965/001c.125841] [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] [Received: 09/24/2024] [Accepted: 10/30/2024] [Indexed: 12/18/2024] Open
Abstract
Background The complex nature of musculoskeletal diseases and the limitations of existing treatments have driven researchers to explore innovative solutions, particularly those involving stem cells and their derivatives. The utilization of the IPFP as a source of MSC-derived non-cellular products for the treatment of musculoskeletal diseases has gained recognition in recent years. This study aimed to identify the progress of IPFP-derived acellular biologics use in the treatment of orthopedic conditions such as osteoarthritis and ligament and/or tendon injuries. Methods A literature search was conducted through PubMed, Scopus and Google Scholar databases including studies over the past 10 years. This scoping review includes studies discussing the development of intercellular messenger signaling molecules (non-cellular products) in the form of exosomes, secretomes, and conditioned medium derived from the IPFP in the management of musculoskeletal diseases. The PRISMA-ScR guidelines were utilized in this review. Results Six studies met the inclusion criteria. Most studies reported the beneficial anti-inflammatory effects of IPFP-derived noncellular products in musculoskeletal conditions. The effects of IPFP-derived exosomes, secretomes, and conditioned medium administration are mostly reported in microscopic changes through cellular and matrix changes. Additionally, quantitative analyses involved assessing levels of anti-inflammatory and pro-inflammatory markers, proteins, fatty acids, and gene expression. Conclusions The use of IPFP-derived non-cellular products has shown significant promise in the regenerative therapy for musculoskeletal diseases. These agents have demonstrated beneficial effects, particularly in reducing inflammation, promoting cellular changes, and enhancing tissue regeneration. However, further research is needed to fully understand the characteristics and explore the potential applications of IPFP-derived non-cellular products in musculoskeletal cases.
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Affiliation(s)
- Aditya Fuad Robby Triangga
- Department of Orthopaedics and Traumatology, RSUP Dr. Sardjito, Yogyakarta, Indonesia
- Division of Adult Reconstructive Surgery and Sports Injury, RSUP Dr. Sardjito, Yogyakarta, Indonesia
- Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Widya Asmara
- Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Rahadyan Magetsari
- Department of Orthopaedics and Traumatology, RSUP Dr. Sardjito, Yogyakarta, Indonesia
- Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | | | - Dandy Ardhan Fazatamma
- Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Paramita Ayu Saraswati
- Department of Orthopaedics and Traumatology, RSUP Dr. Sardjito, Yogyakarta, Indonesia
- Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - A Faiz Huwaidi
- Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Yohanes Widodo Wirohadidjojo
- Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
- Department of Dermatology and Venereology, RSUP Dr. Sardjito, Yogyakarta, Indonesia
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Liu B, Liu T, Li Y, Tan C. Innovative Biotherapies and Nanotechnology in Osteoarthritis: Advancements in Inflammation Control and Cartilage Regeneration. Int J Mol Sci 2024; 25:13384. [PMID: 39769149 PMCID: PMC11677281 DOI: 10.3390/ijms252413384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/04/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
Osteoarthritis (OA) is among the most prevalent degenerative joint disorders worldwide, particularly affecting the aging population and imposing significant disability and economic burdens. The disease is characterized by progressive degradation of articular cartilage and chronic inflammation, with no effective long-term treatments currently available to address the underlying causes of its progression. Conventional therapies primarily manage symptoms such as pain and inflammation but fail to repair damaged tissues. Emerging biotherapies and regenerative medicine approaches offer promising alternatives by addressing cartilage repair and inflammation control at the molecular level. This review explores the recent advancements in biotherapeutic strategies, including mesenchymal stem cell (MSC) therapy, growth factors, and tissue engineering, which hold the potential for promoting cartilage regeneration and modulating the inflammatory microenvironment. Additionally, the integration of nanotechnology has opened new avenues for targeted drug delivery systems and the development of innovative nanomaterials that can further enhance the efficacy of biotherapies by precisely targeting inflammation and cartilage damage. This article concludes by discussing the current clinical applications, the ongoing clinical trials, and the future research directions necessary to confirm the safety and efficacy of these advanced therapies for OA management. With these advancements, biotherapies combined with nanotechnology may revolutionize the future of OA treatment by offering precise and effective solutions for long-term disease management and improved patient outcomes.
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Affiliation(s)
| | | | - Yanhong Li
- Department of Rheumatology and Immunology, West China Hospital of Sichuan University, Chengdu 610041, China; (B.L.); (T.L.)
| | - Chunyu Tan
- Department of Rheumatology and Immunology, West China Hospital of Sichuan University, Chengdu 610041, China; (B.L.); (T.L.)
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Maslennikov S, Avramenko Y, Tumanskiy V, Golovakha M. Comparative characteristics of the stem cells' number in the stromal vascular fraction of infrapatellar fat pad and subcutaneous fat tissue. J ISAKOS 2024; 9:615-619. [PMID: 38763383 DOI: 10.1016/j.jisako.2024.05.011] [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] [Received: 01/18/2024] [Revised: 04/30/2024] [Accepted: 05/15/2024] [Indexed: 05/21/2024]
Abstract
OBJECTIVES The use of infrapatellar fat pad adipose stem cells (IPFP-ASCs) shows an age-independent proliferation and differentiation potential. In addition, the pronounced chondrogenic potential of IPFP-ASCs makes them promising candidates for research for use in other methods of regenerative therapy. The purpose of this study was to ascertain the presence and compare the relative abundance of cells exhibiting an immunohistochemical profile characteristic of adipose-derived mesenchymal stem cells in selected samples of the stromal vascular fraction (SVF) obtained from the IPFP and subcutaneous fat tissue. METHODS A direct immunohistochemical study was carried out in serial paraffin sections of the SVF of the infrapatellar fat pad (IPFP) and subcutaneous tissue, using monoclonal antibodies. The minimum criteria were established by the International Society for Cell Therapy to ensure the identity of mesenchymal stem cells use CD73, CD90, and CD105 as positive markers and CD34, CD31, and CD45 as a negative. RESULTS According to the results of histological, immunohistochemical, morphometric, and statistical studies, it was found that in the SVF of IPFP and subcutaneous adipose tissue, the relative number of cells with the profile CD105+, CD73+, CD34+, CD31-, CD45- in the standard field of view (×200), the SVF of IPFP was 1.58%, whereas the SVF of subcutaneous adipose tissue was 6.92 %, which was statistically significantly greater by 4.38 times (p < 0.05). CONCLUSION The presence of a sufficient number of mesenchymal stromal cells in IPFP in combination with their topographic relationship with the structures of the joint determines the use of the SVF of the IPFP for the treatment of diseases of the knee joint. LEVEL OF EVIDENCE III.
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Affiliation(s)
- Serhii Maslennikov
- Department of Traumatology and Orthopedics of Zaporizhzhia State Medical and Pharmaceutical University, Ukraine.
| | - Yuliia Avramenko
- Department of Pathological Anatomy and Forensic Medicine of Zaporizhzhia State Medical and Pharmaceutical University, Ukraine
| | - Valeriy Tumanskiy
- Department of Pathological Anatomy and Forensic Medicine, Vice-Rector for Research, Zaporizhzhia State Medical and Pharmaceutical University, Ukraine
| | - Maksym Golovakha
- Department of Traumatology and Orthopedics of Zaporizhzhia State Medical and Pharmaceutical University, Ukraine
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Sriram M, Priya S, Mahajan A, Katti DS. Directing ligament-mimetic bi-directional cell organization in scaffolds through zone-specific microarchitecture for ligament tissue engineering. Biofabrication 2024; 16:025015. [PMID: 38277689 DOI: 10.1088/1758-5090/ad22f2] [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] [Received: 10/13/2023] [Accepted: 01/26/2024] [Indexed: 01/28/2024]
Abstract
Ligament tissues exhibit zone-specific anisotropic cell organization. The cells in ligament-proper are longitudinally oriented, whereas, the cells in epiligament are circumferentially oriented. Therefore, scaffolds developed to regenerate ligament tissues should possess adequate architectural features to govern ligament-mimetic bi-directional cell organization. The scaffold architectural features along with ligament-mimetic cell organization may ultimately yield neo-tissues with ligament-like extracellular matrix (ECM) structure and biomechanical properties. Towards this goal, we fabricated a silk/gelatin-based core-shell scaffold (csSG) with zone-specific anisotropic architectural features, wherein, the core of the scaffold possessed longitudinally aligned pores while the shell of the scaffold possessed parallel microgrooves that are aligned circumferentially around the surface of the scaffold. The ligament-mimetic architectural features significantly improved the mechanical properties of the scaffold. Moreover, architectural features of the csSG scaffold governed zone-specific anisotropic organization of cells. The cells in the core were longitudinally oriented as observed in the ligament-proper and the cells on the shell were circumferentially oriented as observed in epiligament. This bi-directional cell orientation partially mimicked the complex cellular network in native ligament tissue. Additionally, both the core and the shell individually supported fibrogenic differentiation of stem cells which further improved their potential for ligament tissue engineering. Further, the aligned pores of the core could govern unidirectional organization of ECM deposited by cells which is crucial for regenerating anisotropic tissues like ligaments. Finally, when implanted subcutaneously in mice, the scaffolds retained their anisotropic architecture for at least 2 weeks, were biocompatible, supported cell infiltration and governed anisotropic organization of cells and ECM. Taken together, the fabricated biomimetic csSG scaffold, through its zone-specific architectural features, could govern ligament-mimetic cellular and ECM organization which is ultimately expected to achieve regeneration of ligament tissues with native-like hierarchical structure and biomechanical properties. Consequently, this study introduces bi-directional structural parameters as design criteria for developing scaffolds for ligament tissue engineering.
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Affiliation(s)
- M Sriram
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh, India
- Mehta Family Centre for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh, India
| | - Smriti Priya
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh, India
| | - Aman Mahajan
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh, India
- Mehta Family Centre for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh, India
| | - Dhirendra S Katti
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh, India
- Mehta Family Centre for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh, India
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Jia D, Chen H, Dai J, He S, Liu Y, Liu Z, Zhang Y, Li X, Sun Y, Wang Q. Human Infrapatellar Fat Pad Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibit Fibroblast Proliferation by Regulating MT2A to Reduce Knee Arthrofibrosis. Stem Cells Int 2023; 2023:9067621. [PMID: 37091533 PMCID: PMC10115539 DOI: 10.1155/2023/9067621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 09/20/2022] [Accepted: 09/27/2022] [Indexed: 04/25/2023] Open
Abstract
Knee arthrofibrosis is one of the most serious complications of knee surgery; however, its pathogenesis is unclear, and current treatment methods have not achieved satisfactory results. Mesenchymal stem cells (MSCs) have good anti-inflammatory and antifibrotic properties, and studies have reported that human infrapatellar fat pad-derived MSCs (IPFSCs) have the advantages of strong proliferative and differentiating ability, ease of acquisition, and minimal harm to the donor. Increasing evidence has shown that MSCs function through their paracrine extracellular vesicles (EVs). Our study is aimed at exploring the effects of human IPFSC-derived EVs (IPFSC-EVs) on knee arthrofibrosis and the underlying mechanisms in vivo and in vitro. In the in vivo study, injecting IPFSC-EVs into the knee joint cavity effectively reduced surgery-induced knee arthrofibrosis in rats. In the in vitro study, IPFSC-EVs were found to inhibit the proliferation of fibroblasts in the inflammatory environment. Additionally, we screened a potential IPFSC-EV molecular target, metallothionein 2A (MT2A), using RNA sequencing. We found that silencing MT2A partially reversed the inhibitory effect of IPFSC-EVs on fibroblast proliferation in the inflammatory environment. In conclusion, IPFSC-EVs inhibit the progression of knee arthrofibrosis by regulating MT2A, which inhibits fibroblast proliferation in the inflammatory environment.
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Affiliation(s)
- Dazhou Jia
- Department of Orthopedics, Affiliated Hospital of Yangzhou University, Yangzhou, 225001 Jiangsu, China
| | - Hui Chen
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Jihang Dai
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Shiping He
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Yangyang Liu
- Department of Orthopedics, Affiliated Hospital of Yangzhou University, Yangzhou, 225001 Jiangsu, China
| | - Zhendong Liu
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Yaxin Zhang
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Xiaolei Li
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Yu Sun
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Qiang Wang
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
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Guo Z, Zhang Y, Yan F. Potential of Mesenchymal Stem Cell-Based Therapies for Pulmonary Fibrosis. DNA Cell Biol 2022; 41:951-965. [DOI: 10.1089/dna.2022.0327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Zhihou Guo
- Stem Cell Lab, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yaping Zhang
- Center for Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Furong Yan
- Center for Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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Exploring Anatomo-Morphometric Characteristics of Infrapatellar, Suprapatellar Fat Pad, and Knee Ligaments in Osteoarthritis Compared to Post-Traumatic Lesions. Biomedicines 2022; 10:biomedicines10061369. [PMID: 35740391 PMCID: PMC9220326 DOI: 10.3390/biomedicines10061369] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/06/2022] [Accepted: 06/07/2022] [Indexed: 11/17/2022] Open
Abstract
Several studies have investigated cartilage degeneration and inflammatory subchondral bone and synovial membrane changes using magnetic resonance (MR) in osteoarthritis (OA) patients. Conversely, there is a paucity of data exploring the role of knee ligaments, infrapatellar fat pad (IFP), and suprapatellar fat pad (SFP) in knee OA compared to post-traumatic cohorts of patients. Therefore, the aim of this study was to analyze the volumetric and morphometric characteristics of the following joint tissues: IFP (volume, surface, depth, femoral and tibial arch lengths), SFP (volume, surface, oblique, antero−posterior, and cranio−caudal lengths), anterior (ACL) and posterior cruciate ligament (PCL) (volume, surface, and length), and patellar ligament (PL) (volume, surface, arc, depth, and length). Eighty-nine MR images were collected in the following three groups: (a) 32 patients with meniscal tears, (b) 29 patients with ACL rupture (ACLR), and (c) 28 patients affected by end-stage OA. Volume, surface, and length of both ACL and PCL were determined in groups a and c. A statistical decrease of IFP volume, surface, depth, femoral and tibial arch lengths was found in end-stage OA compared to patients with meniscal tear (p = 0.002, p = 0.008, p < 0.0001, p = 0.028 and p < 0.001, respectively) and patients with ACLR (p < 0.0001, p < 0.0001, p = 0.008 and p = 0.011, respectively). An increment of volume and surface SFP was observed in group b compared to both groups a and c, while no differences were found in oblique, antero−posterior, and cranio−caudal lengths of SFP among the groups. No statistical differences were highlighted comparing volume, surface, arc, and length of PL between the groups, while PL depth was observed to be decreased in end-OA patients compared with meniscal tear patients (p = 0.023). No statistical differences were observed comparing ACL and PCL lengths between patients undergoing meniscectomy and TKR. Our study confirms that IFP MR morphometric characteristics are different between controls and OA, supporting an important role of IFP in OA pathology and progression in accordance with previously published studies. In addition, PL depth changes seem to be associated with OA pathology. Multivariate analysis confirmed that OA patients had a smaller IFP compared to patients with meniscal tears, confirming its involvement in OA.
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Martin CA, Radhakrishnan S, Ribelles JLG, Trentz O, Eak N, Reddy MS, Rela M, Subbaraya NK. Adipose tissue derived stromal cells in a gelatin based 3D matrix with exclusive ascorbic acid signalling emerged as a novel neural tissue engineering construct – An innovative prototype for soft tissue. Regen Biomater 2022; 9:rbac031. [PMID: 35702348 PMCID: PMC9188297 DOI: 10.1093/rb/rbac031] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 03/30/2022] [Accepted: 05/05/2022] [Indexed: 11/17/2022] Open
Abstract
The current study investigated a triad, which comprises of adipose tissue derived stem cells isolated from infrapatellar fat pad and gelatin/polyvinyl alcohol (PVA)-based matrix with exclusive ascorbic acid signalling. Though, the bio-mechanical properties of the gelatin–PVA blended scaffolds in wet condition are equivalent to the ECM of soft tissues in general, in this study, the triad was tested as a model for neural tissue engineering. Apart from being cytocompatible and biocompatible, the porosity of the scaffold has been designed in such a manner that it facilitates the cell signalling and enables the exchange of nutrients and gases. The highly proliferative stem cells from Passage 2 were characterized using both, mesenchymal and embryonic stem cell markers. As an initial exploration the mesenchymal stem cells at Passage 4 were exposed to ascorbic acid and basic fibroblast growth factor signalling for neuronal differentiation in 2D environment independently. The MSCs successfully differentiated and acquired neuron specific markers related to cytoskeleton and synapses. Subsequently, three phases of experiments have been conducted on the 3D gelatin/PVA matrix to prove their efficacy, the growth of stem cells, growth of differentiated neurons and the in situ growth and differentiation of MSCs. The scaffold was conducive and directed MSCs to neuronal lineage under specific signalling. Overall, this organotypic model triad could open a new avenue in the field of soft tissue engineering as a simple and effective tissue construct.
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Affiliation(s)
- Catherine Ann Martin
- Crystal Growth Centre, Anna University, Chennai-600025, India
- Cell Laboratory, National Foundation for Liver Research, Chrompet, Chennai-600044, India
| | - Subathra Radhakrishnan
- Cell Laboratory, National Foundation for Liver Research, Chrompet, Chennai-600044, India
| | - Jose Luis Gómez Ribelles
- Center for Biomaterials and Tissue Engineering (CBIT), Universitat Politècnica de València, Camino de Vera s/n., 46022, Valencia, Spain
- Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain
| | - Omana Trentz
- MIOT Institute of Research, MIOT Hospitals, Chennai-600089, India
| | - Nivethaa Eak
- Crystal Growth Centre, Anna University, Chennai-600025, India
| | - Mettu Srinivas Reddy
- Cell Laboratory, National Foundation for Liver Research, Chrompet, Chennai-600044, India
| | - Mohamed Rela
- Cell Laboratory, National Foundation for Liver Research, Chrompet, Chennai-600044, India
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Methodological Flaws in Meta-Analyses of Clinical Studies on the Management of Knee Osteoarthritis with Stem Cells: A Systematic Review. Cells 2022; 11:cells11060965. [PMID: 35326416 PMCID: PMC8946093 DOI: 10.3390/cells11060965] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 12/13/2022] Open
Abstract
(1) Background: Conclusions of meta-analyses of clinical studies may substantially influence opinions of prospective patients and stakeholders in healthcare. Nineteen meta-analyses of clinical studies on the management of primary knee osteoarthritis (pkOA) with stem cells, published between January 2020 and July 2021, came to inconsistent conclusions regarding the efficacy of this treatment modality. It is possible that a separate meta-analysis based on an independent, systematic assessment of clinical studies on the management of pkOA with stem cells may reach a different conclusion. (2) Methods: PubMed, Web of Science, and the Cochrane Library were systematically searched for clinical studies and meta-analyses of clinical studies on the management of pkOA with stem cells. All clinical studies and meta-analyses identified were evaluated in detail, as were all sub-analyses included in the meta-analyses. (3) Results: The inconsistent conclusions regarding the efficacy of treating pkOA with stem cells in the 19 assessed meta-analyses were most probably based on substantial differences in literature search strategies among different authors, misconceptions about meta-analyses themselves, and misconceptions about the comparability of different types of stem cells with regard to their safety and regenerative potential. An independent, systematic review of the literature yielded a total of 183 studies, of which 33 were randomized clinical trials, including a total of 6860 patients with pkOA. However, it was not possible to perform a scientifically sound meta-analysis. (4) Conclusions: Clinicians should interpret the results of the 19 assessed meta-analyses of clinical studies on the management of pkOA with stem cells with caution and should be cautious of the conclusions drawn therein. Clinicians and researchers should strive to participate in FDA and/or EMA reviewed and approved clinical trials to provide clinically and statistically valid efficacy.
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12
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Phenotypic and functional properties of dedifferentiated fat cells derived from infrapatellar fat pad. Regen Ther 2022; 19:35-46. [PMID: 35059478 PMCID: PMC8739472 DOI: 10.1016/j.reth.2021.12.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 12/12/2021] [Accepted: 12/20/2021] [Indexed: 01/03/2023] Open
Abstract
Introduction Mature adipocyte-derived dedifferentiated fat cells (DFATs) are mesenchymal stem cell (MSC)-like cells with high proliferative ability and multilineage differentiation potential. In this study, we first examined whether DFATs can be prepared from infrapatellar fat pad (IFP) and then compared phenotypic and functional properties of IFP-derived DFATs (IFP-DFATs) with those of subcutaneous adipose tissue (SC)-derived DFATs (SC-DFATs). Methods Mature adipocytes isolated from IFP and SC in osteoarthritis patients (n = 7) were cultured by ceiling culture method to generate DFATs. Obtained IFP-DFATs and SC-DFATs were subjected to flow cytometric and microarray analysis to compare their immunophenotypes and gene expression profiles. Cell proliferation assay and adipogenic, osteogenic, and chondrogenic differentiation assays were performed to evaluate their functional properties. Results DFATs could be prepared from IFP and SC with similar efficiency. IFP-DFATs and SC-DFATs exhibited similar immunophenotypes (CD73+, CD90+, CD105+, CD31-, CD45-, HLA-DR-) and tri-lineage (adipogenic, osteogenic, and chondrogenic) differentiation potential, consistent with the minimal criteria for defining MSCs. Microarray analysis revealed that the gene expression profiles in IFP-DFATs were very similar to those in SC-DFATs, although there were certain number of genes that showed different levels of expression. The proliferative activity in IFP-DFATs was significantly (p < 0.05) higher than that in the SC-DFATs. IFP-DFATs showed higher chondrogenic differentiation potential than SC-DFATs in regard to production of soluble galactosaminogalactan and gene expression of type II collagen. Conclusions IFP-DFATs showed higher cellular proliferative potential and higher chondrogenic differentiation capacity than SC-DFATs. IFP-DFAT cells may be an attractive cell source for chondrogenic regeneration.
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Xu J, Ye Z, Han K, Zheng T, Zhang T, Dong S, Jiang J, Yan X, Cai J, Zhao J. Infrapatellar Fat Pad Mesenchymal Stromal Cell-Derived Exosomes Accelerate Tendon-Bone Healing and Intra-articular Graft Remodeling After Anterior Cruciate Ligament Reconstruction. Am J Sports Med 2022; 50:662-673. [PMID: 35224997 DOI: 10.1177/03635465211072227] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Exosomes derived from mesenchymal stromal cells (MSCs) reportedly enhance the healing process. However, no studies have investigated the effect of exosomes from infrapatellar fat pad (IPFP) MSCs on tendon-bone healing and intra-articular graft remodeling after anterior cruciate ligament reconstruction (ACLR). PURPOSE To evaluate the in vivo effect of exosomes from IPFP MSCs on tendon-bone healing and intra-articular graft remodeling in a rat model of ACLR. STUDY DESIGN Controlled laboratory study. METHODS A total of 90 skeletally mature male Sprague Dawley rats underwent unilateral ACLR using an autograft. All rats were randomly divided into 3 groups: sham injection (SI) group (n = 30), control injection (CI) group (n = 30), and IPFP MSC-derived exosome injection (IMEI) group (n = 30). At 2, 4, and 8 weeks postoperatively, tendon-bone healing and intra-articular graft remodeling were evaluated via biomechanical testing, micro-computed tomography, and histological analysis; macrophage polarization was evaluated using immunohistochemical staining. RESULTS Biomechanical testing demonstrated a significantly higher failure load and stiffness in the IMEI group than in the SI and CI groups at 4 and 8 weeks postoperatively. Moreover, a thinner graft-to-bone healing interface with more fibrocartilage was observed in the IMEI group at both time points. Micro-computed tomography revealed greater new bone ingrowth in the IMEI group than in the other groups, as demonstrated by smaller mean bone tunnel areas and a larger bone volume/total volume ratio. Additionally, more cellular infiltration was observed in the intra-articular graft in the IMEI group than in the other groups at 4 weeks, followed by more regularly organized fibers with mature collagen at 8 weeks. Notably, similar trends of macrophage polarization were found at both the graft-to-bone interface and the intra-articular graft in the IMEI group, with significantly fewer proinflammatory M1 macrophages and larger numbers of reparative M2 macrophages than in the SI and CI groups. CONCLUSION IPFP MSC-derived exosomes accelerated tendon-bone healing and intra-articular graft remodeling after ACLR, which may have resulted from the immunomodulation of macrophage polarization. CLINICAL RELEVANCE The IPFP can be easily harvested by most orthopaedic surgeons. Exosomes from IPFP MSCs, constituting a newly emerging cell-free approach, may represent a treatment option for improving tendon-bone healing and intra-articular graft remodeling after ACLR.
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Affiliation(s)
- Junjie Xu
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Zipeng Ye
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Kang Han
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Ting Zheng
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Tianlun Zhang
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Shikui Dong
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jia Jiang
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xiaoyu Yan
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jiangyu Cai
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jinzhong Zhao
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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14
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Extracellular Vesicles in Musculoskeletal Regeneration: Modulating the Therapy of the Future. Cells 2021; 11:cells11010043. [PMID: 35011605 PMCID: PMC8750529 DOI: 10.3390/cells11010043] [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] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 12/12/2022] Open
Abstract
Tissue regeneration is a hot topic in health sciences, particularly because effective therapies promoting the healing of several cell types are lacking, specifically those of the musculoskeletal system. Mesenchymal Stem/Stromal Cells (MSCs) have been identified as crucial players in bone homeostasis, and are considered a promising therapy for diseases such as osteoarthritis (OA) and Rheumatoid Arthritis (RA). However, some known drawbacks limit their use, particularly ethical issues and immunological rejections. Thus, MSCs byproducts, namely Extracellular Vesicles (EVs), are emerging as potential solutions to overcome some of the issues of the original cells. EVs can be modulated by either cellular preconditioning or vesicle engineering, and thus represent a plastic tool to be implemented in regenerative medicine. Further, the use of biomaterials is important to improve EV delivery and indirectly to modulate their content and secretion. This review aims to connect the dots among MSCs, EVs, and biomaterials, in the context of musculoskeletal diseases.
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Adipose Tissue-Derived Mesenchymal Stem Cells as a Potential Restorative Treatment for Cartilage Defects: A PRISMA Review and Meta-Analysis. Pharmaceuticals (Basel) 2021; 14:ph14121280. [PMID: 34959680 PMCID: PMC8705514 DOI: 10.3390/ph14121280] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/03/2021] [Accepted: 12/04/2021] [Indexed: 12/13/2022] Open
Abstract
Cartilage defects are a predisposing factor for osteoarthritis. Conventional therapies are mostly palliative and there is an interest in developing newer therapies that target the disease’s progression. Mesenchymal stem cells (MSCs) have been suggested as a promising therapy to restore hyaline cartilage to cartilage defects, though the optimal cell source has remained under investigation. A PRISMA systematic review was conducted utilising five databases (MEDLINE, EMBASE, Cochrane Library, Scopus, Web of Science) which identified nineteen human studies that used adipose tissue-derived MSC (AMSC)-based therapies, including culture-expanded AMSCs and stromal vascular fraction, to treat cartilage defects. Clinical, imaging and histological outcomes, as well as other relevant details pertaining to cartilage regeneration, were extracted from each study. Pooled analysis revealed a significant improvement in WOMAC scores (mean difference: −25.52; 95%CI (−30.93, −20.10); p < 0.001), VAS scores (mean difference: −3.30; 95%CI (−3.72, −2.89); p < 0.001), KOOS scores and end point MOCART score (mean: 68.12; 95%CI (62.18, 74.05)), thus showing improvement. The studies in this review demonstrate the safety and efficacy of AMSC-based therapies for cartilage defects. Establishing standardised methods for MSC extraction and delivery, and performing studies with long follow-up should enable future high-quality research to provide the evidence needed to bring AMSC-based therapies into the market.
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16
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Sharma S, Muthu S, Jeyaraman M, Ranjan R, Jha SK. Translational products of adipose tissue-derived mesenchymal stem cells: Bench to bedside applications. World J Stem Cells 2021; 13:1360-1381. [PMID: 34786149 PMCID: PMC8567449 DOI: 10.4252/wjsc.v13.i10.1360] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/02/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
With developments in the field of tissue engineering and regenerative medicine, the use of biological products for the treatment of various disorders has come into the limelight among researchers and clinicians. Among all the available biological tissues, research and exploration of adipose tissue have become more robust. Adipose tissue engineering aims to develop by-products and their substitutes for their regenerative and immunomodulatory potential. The use of biodegradable scaffolds along with adipose tissue products has a major role in cellular growth, proliferation, and differentiation. Adipose tissue, apart from being the powerhouse of energy storage, also functions as the largest endocrine organ, with the release of various adipokines. The progenitor cells among the heterogeneous population in the adipose tissue are of paramount importance as they determine the capacity of regeneration of these tissues. The results of adipose-derived stem-cell assisted fat grafting to provide numerous growth factors and adipokines that improve vasculogenesis, fat graft integration, and survival within the recipient tissue and promote the regeneration of tissue are promising. Adipose tissue gives rise to various by-products upon processing. This article highlights the significance and the usage of various adipose tissue by-products, their individual characteristics, and their clinical applications.
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Affiliation(s)
- Shilpa Sharma
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi 110029, India
- Indian Stem Cell Study Group, Lucknow, Uttar Pradesh 226010, India
| | - Sathish Muthu
- Indian Stem Cell Study Group, Lucknow, Uttar Pradesh 226010, India
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul, Tamil Nadu 624304, India
- Research Scholar, Department of Biotechnology, School of Engineering and Technology, Greater Noida, Sharda University, Uttar Pradesh 201306, India
| | - Madhan Jeyaraman
- Indian Stem Cell Study Group, Lucknow, Uttar Pradesh 226010, India
- Research Scholar, Department of Biotechnology, School of Engineering and Technology, Greater Noida, Sharda University, Uttar Pradesh 201306, India
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh 201306, India.
| | - Rajni Ranjan
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh 201306, India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh 201306, India
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17
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Comparison between Intra-Articular Injection of Infrapatellar Fat Pad (IPFP) Cell Concentrates and IPFP-Mesenchymal Stem Cells (MSCs) for Cartilage Defect Repair of the Knee Joint in Rabbits. Stem Cells Int 2021; 2021:9966966. [PMID: 34367294 PMCID: PMC8337123 DOI: 10.1155/2021/9966966] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 06/30/2021] [Accepted: 07/13/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic method in regenerative medicine. Our previous research adopted a simple nonenzymatic strategy for the preparation of a new type of ready-to-use infrapatellar fat pad (IPFP) cell concentrates. The aim of this study was to compare the therapeutic efficacy of intra-articular (IA) injection of autologous IPFP cell concentrates and allogeneic IPFP-MSCs obtained from these concentrates in a rabbit articular cartilage defect model. IPFP-MSCs sprouting from the IPFP cell concentrates were characterized via flow cytometry as well as based on their potential for differentiation into adipocytes, osteoblasts, and chondrocytes. In the rabbit model, cartilage defects were created on the trochlear groove, followed by treatment with IPFP cell concentrates, IPFP-MSCs, or normal saline IA injection. Distal femur samples were evaluated at 6 and 12 weeks posttreatment via macroscopic observation and histological assessment based on the International Cartilage Repair Society (ICRS) macroscopic scoring system as well as the ICRS visual histological assessment scale. The macroscopic score and histological score were significantly higher in the IPFP-MSC group compared to the IPFP cell concentrate group at 12 weeks. Further, both treatment groups had higher scores compared to the normal saline group. In comparison to the latter, the groups treated with IPFP-MSCs and IPFP cell concentrates showed considerably better cartilage regeneration. Overall, IPFP-MSCs represent an effective therapeutic strategy for stimulating articular cartilage regeneration. Further, due to the simple, cost-effective, nonenzymatic, and safe preparation process, IPFP cell concentrates may represent an effective alternative to stem cell-based therapy in the clinic.
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18
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Comment on "Recent Advance in Source, Property, Differentiation, and Applications of Infrapatellar Fat Pad Adipose-Derived Stem Cells". Stem Cells Int 2021; 2021:9824616. [PMID: 33953755 PMCID: PMC8060084 DOI: 10.1155/2021/9824616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 02/24/2021] [Indexed: 11/17/2022] Open
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19
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Yang Z, Li H, Tian Y, Fu L, Gao C, Zhao T, Cao F, Liao Z, Yuan Z, Liu S, Guo Q. Biofunctionalized Structure and Ingredient Mimicking Scaffolds Achieving Recruitment and Chondrogenesis for Staged Cartilage Regeneration. Front Cell Dev Biol 2021; 9:655440. [PMID: 33842484 PMCID: PMC8027342 DOI: 10.3389/fcell.2021.655440] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 03/05/2021] [Indexed: 11/13/2022] Open
Abstract
It remains scientifically challenging to regenerate injured cartilage in orthopedics. Recently, an endogenous cell recruitment strategy based on a combination of acellular scaffolds and chemoattractants to specifically and effectively recruit host cells and promote chondrogenic differentiation has brought new hope for in situ articular cartilage regeneration. In this study, a transforming growth factor-β3 (TGF-β3)-loaded biomimetic natural scaffold based on demineralized cancellous bone (DCB) and acellular cartilage extracellular matrix (ECM) was developed and found to improve chondral repair by enhancing cell migration and chondrogenesis. The DCB/ECM scaffold has porous microstructures (pore size: 67.76 ± 8.95 μm; porosity: 71.04 ± 1.62%), allowing the prolonged release of TGF-β3 (up to 50% after 42 days in vitro) and infrapatellar fat pad adipose-derived stem cells (IPFSCs) that maintain high cell viability (>96%) and favorable cell distribution and phenotype after seeding onto the DCB/ECM scaffold. The DCB/ECM scaffold itself can also provide a sustained release system to effectively promote IPFSC migration (nearly twofold in vitro). Moreover, TGF-β3 loaded on scaffolds showed enhanced chondrogenic differentiation (such as collagen II, ACAN, and SOX9) of IPFSCs after 3 weeks of culture. After implanting the composite scaffold into the knee joints of rabbits, enhanced chondrogenic differentiation was discovered at 1, 2, and 4 weeks post-surgery, and improved repair of cartilage defects in terms of biochemical, biomechanical, radiological, and histological results was identified at 3 and 6 months post-implantation. To conclude, our study demonstrates that the growth factor (GF)-loaded scaffold can facilitate cell homing, migration, and chondrogenic differentiation and promote the reconstructive effects of in vivo cartilage formation, revealing that this staged regeneration strategy combined with endogenous cell recruitment and pro-chondrogenesis is promising for in situ articular cartilage regeneration.
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Affiliation(s)
- Zhen Yang
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Hao Li
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Yue Tian
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China
| | - Liwei Fu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Cangjian Gao
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Tianyuan Zhao
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Fuyang Cao
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhiyao Liao
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Zhiguo Yuan
- Department of Bone and Joint Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shuyun Liu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China
| | - Quanyi Guo
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
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20
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Radhakrishnan S, Martin CA, Dhayanithy G, Reddy MS, Rela M, Kalkura SN, Sellathamby S. Hypoxic Preconditioning Induces Neuronal Differentiation of Infrapatellar Fat Pad Stem Cells through Epigenetic Alteration. ACS Chem Neurosci 2021; 12:704-718. [PMID: 33508941 DOI: 10.1021/acschemneuro.0c00728] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hypoxia is considered a key factor in cellular differentiation and proliferation, particularly during embryonic development; the process of early neurogenesis also occurs under hypoxic conditions. Apart from these developmental processes, hypoxia preconditioning or mild hypoxic sensitization develops resistance against ischemic stroke in deteriorating tissues. We therefore hypothesized that neurons resulting from hypoxia-regulated neuronal differentiation could be the best choice for treating brain ischemia, which contributes to neurodegeneration. In this study, infrapatellar fat pad (IFP), an adipose tissue present beneath the knee joint, was used as the stem cell source. IFP-derived stem cells (IFPSCs) are totally adherent and are mesenchymal stem cells. The transdifferentiation protocol involved hypoxia preconditioning, the use of hypoxic-conditioned medium, and maintenance in maturation medium with α-lipoic acid. The differentiated cells were characterized using microscopy, reverse transcription PCR, real time PCR, and immunocytochemistry. To evaluate the epigenetic reprogramming of IFPSCs to become neuron-like cells, methylation microarrays were performed. Hypoxia preconditioning stabilized and allowed for the translocation of hypoxia inducible factor 1α into the nucleus and induced achaete-scute homologue 1 and doublecortin expression. Following induction, the resultant cells expressed neuronal markers neuron-specific enolase, neurofilament-light chain, growth associated protein 43, synaptosome associated protein 25, and β-III tubulin. The differentiated neural-lineage cells had functional gene expression pertaining to neurotransmitters, their release, and their receptors. The molecular signaling mechanisms regulated developmental neurogenesis. Furthermore, the in vitro physiological condition regulated neurotransmitter respecification or switching during IFPSC differentiation to neurons. Thus, differentiated neurons were fabricated against the ischemic region to treat neurodegenerative diseases.
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Affiliation(s)
- Subathra Radhakrishnan
- National Foundation for Liver Research, Cell Laboratory, Dr. Rela Institute and Medical Centre, Chennai 600 044, India
- Department of Biomedical Science, Bharathidasan University, Tiruchirappalli 620024, India
| | - Catherine Ann Martin
- National Foundation for Liver Research, Cell Laboratory, Dr. Rela Institute and Medical Centre, Chennai 600 044, India
- Crystal Growth Centre, Anna University, Chennai 600025, India
| | | | - Mettu Srinivas Reddy
- National Foundation for Liver Research, Cell Laboratory, Dr. Rela Institute and Medical Centre, Chennai 600 044, India
| | - Mohamed Rela
- National Foundation for Liver Research, Cell Laboratory, Dr. Rela Institute and Medical Centre, Chennai 600 044, India
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Testa G, Giardina SMC, Culmone A, Vescio A, Turchetta M, Cannavò S, Pavone V. Intra-Articular Injections in Knee Osteoarthritis: A Review of Literature. J Funct Morphol Kinesiol 2021; 6:15. [PMID: 33546408 PMCID: PMC7931012 DOI: 10.3390/jfmk6010015] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/30/2021] [Accepted: 02/01/2021] [Indexed: 02/07/2023] Open
Abstract
Knee osteoarthritis (OA) is a chronic, degenerative, and progressive disease of articular cartilage, producing discomfort and physical disability in older adults. Thirteen percent of elderly people complain of knee OA. Management options for knee OA could be divided into the following categories: conservative, pharmacological, procedural, and surgical. Joint replacement is the gold standard, reserved for severe grades of knee OA, due to its complications rate and increased risk of joint revision. A nonsurgical approach is the first choice in the adult population with cartilage damage and knee OA. Yearly, more than 10% of knee OA-affected patients undergo intra-articular injections of different drugs, especially within three months after OA diagnosis. Several molecules, such as corticosteroids injection, hyaluronic acid (HA), and platelet-rich plasma (PRP), are managed to reduce the symptoms of patients with knee OA. The aim of this review was to offer an overview of intra-articular injections used for the treatment of OA and report the conventional pharmacological products used.
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Affiliation(s)
| | | | | | | | | | | | - Vito Pavone
- Department of General Surgery and Medical Surgical Specialties, Section of Orthopaedics and Traumatology, P.O. “Policlinico Gaspare Rodolico”, University of Catania, 95123 Catania, Italy; (G.T.); (S.M.C.G.); (A.C.); (A.V.); (M.T.); (S.C.)
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22
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Sriwatananukulkit O, Tawonsawatruk T, Rattanapinyopituk K, Luangwattanawilai T, Srikaew N, Hemstapat R. Scaffold-Free Cartilage Construct from Infrapatellar Fat Pad Stem Cells for Cartilage Restoration. Tissue Eng Part A 2020; 28:199-211. [PMID: 32972295 DOI: 10.1089/ten.tea.2020.0167] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Once damaged, the articular cartilage has a very limited intrinsic capacity for self-renewal due to its avascular nature. If left untreated, damaged cartilage can lead to progressive degeneration of bone and eventually causes pain. Infrapatellar fat pad adipose-derived mesenchymal stromal cells (IPFP-ASCs) has a potential role for cartilage restoration. However, the therapeutic role for IPFP-ASCs remains to be evaluated in an appropriate osteochondral defect model. Thus, this study aimed to investigate the potential of using a three-dimensional (3D) cartilage construct of IPFP-ASCs as a promising source of cells to restore articular cartilage and to attenuate pain associated with the cartilage defect in an osteochondral defect model. The chondrogenic differentiation potential of the 3D cartilage construct derived from IPFP-ASCs was determined before implantation and postimplantation by gene expression and immunohistochemistry analysis. Pain-related behavior was also assessed by using a weight-bearing test. A significant pain-associated with the osteochondral defect was observed in this model in all groups postinduction; however, this pain can spontaneously resolve within 3 weeks postimplantation regardless of implantation of IPFP-ASCs constructs. The expression of SOX9 and COL2A1 genes in addition to protein expression were strongly expressed in 3D construct IPFP-ASCs. The existence of mature chondrocytes, along with significant (p < 0.05) positive immunostaining for type II collagen and aggrecan, were identified in the implanted site for up to 12 weeks compared with the untreated group, indicating hyaline cartilage regeneration. Taken together, this study demonstrated the successful outcome of osteochondral regeneration with scaffold-free IPFP-ASCs constructs in an osteochondral defect rat model. It provides novel and interesting insights into the current hypothesis that 3D construct IPFP-ASCs may offer potential benefits as an alternative approach to repair the cartilage defect. Impact statement This study provides evidence of using the human 3D scaffold-free infrapatellar fat pad adipose-derived mesenchymal stromal cells (IPFP-ASCs) construct to restore the full-thickness osteochondral defect in a rat model. This study showed that chondrogenic features of the construct could be retained for up to 12 weeks postimplantation. The results of this proof-of-concept study support that human 3D scaffold-free IPFP-ASCs construct has potential benefits in promoting the hyaline-like native cartilage restoration, which may be beneficial as a tissue-specific stem cell for cell-based cartilage therapy. There are several clinical advantages of IPFP-ASC including ease and minimal invasive harvesting, chondrogenic inducible property, and tissue-specific progenitors in the knee.
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Affiliation(s)
| | | | - Kasem Rattanapinyopituk
- Department of Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | | | - Narongrit Srikaew
- Research Centre, Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand
| | - Ruedee Hemstapat
- Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand
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23
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Belluzzi E, Macchi V, Fontanella CG, Carniel EL, Olivotto E, Filardo G, Sarasin G, Porzionato A, Granzotto M, Pozzuoli A, Berizzi A, Scioni M, Caro RD, Ruggieri P, Vettor R, Ramonda R, Rossato M, Favero M. Infrapatellar Fat Pad Gene Expression and Protein Production in Patients with and without Osteoarthritis. Int J Mol Sci 2020; 21:ijms21176016. [PMID: 32825633 PMCID: PMC7503946 DOI: 10.3390/ijms21176016] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 08/14/2020] [Accepted: 08/19/2020] [Indexed: 11/16/2022] Open
Abstract
Osteoarthritis (OA) is one of the most common joint disorders. Evidence suggests that the infrapatellar fat pad (IFP) is directly involved in OA pathology. However, a comparison between OA versus non-OA IFP is still missing. Thus, the aim of this study was to compare IFP molecular, adipocytes and extracellular matrix characteristics of patients affected by OA, and patients undergoing anterior cruciate ligament (ACL) reconstruction. We hypothesized that not only inflammation but also changes in adipocytes and extracellular matrix (ECM) composition might be involved in OA pathogenesis. Fifty-three patients were enrolled. IFP biopsies were obtained, evaluating: (a) lymphocytic infiltration and vascularization; (b) adipocytes area and number; (c) adipo-cytokines and extracellular matrix gene expression levels; (d) IL-6 and VEGF protein production; (e) collagen fibers distribution. OA IFP was more inflamed and vascularized compared to ACL IFP. OA IFP adipocytes were larger and numerically lower (1.3-fold) than ACL IFP adipocytes. An increase of gene expression of typical white adipose tissue genes was observed in OA compared to ACL IFP. Collagen-types distribution was different in the OA IFP group compared to controls, possibly explaining the change of the biomechanical characteristics found in OA IFP. Statistical linear models revealed that the adipocyte area correlated with BMI in the OA group. In conclusion, inflammation and fibrotic changes of OA IFP could represent novel therapeutic targets to counteract OA.
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Affiliation(s)
- Elisa Belluzzi
- Musculoskeletal Pathology and Oncology Laboratory, Orthopedic and Traumatologic Clinic, Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padova, 35128 Padova, Italy; (E.B.); (A.P.)
| | - Veronica Macchi
- Institute of Human Anatomy, Department of Neurosciences, University of Padova, 35121 Padova, Italy; (V.M.); (G.S.); (A.P.); (R.D.C.)
- L.i.f.e. L.a.b. Program, Consorzio per la Ricerca Sanitaria (CORIS), Veneto Region, 35128 Padova, Italy
| | - Chiara Giulia Fontanella
- Department of Civil, Environmental and Architectural Engineering, University of Padova, 35131 Padova, Italy;
- Centre for Mechanics of Biological Materials, University of Padova, 35131 Padova, Italy;
| | - Emanuele Luigi Carniel
- Centre for Mechanics of Biological Materials, University of Padova, 35131 Padova, Italy;
- Department of Industrial Engineering, University of Padova, 35131 Padova, Italy
| | - Eleonora Olivotto
- RAMSES Laboratory, RIT Department, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy;
| | - Giuseppe Filardo
- Applied and Translational Research (ATR) Center, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy;
| | - Gloria Sarasin
- Institute of Human Anatomy, Department of Neurosciences, University of Padova, 35121 Padova, Italy; (V.M.); (G.S.); (A.P.); (R.D.C.)
| | - Andrea Porzionato
- Institute of Human Anatomy, Department of Neurosciences, University of Padova, 35121 Padova, Italy; (V.M.); (G.S.); (A.P.); (R.D.C.)
- L.i.f.e. L.a.b. Program, Consorzio per la Ricerca Sanitaria (CORIS), Veneto Region, 35128 Padova, Italy
| | - Marnie Granzotto
- Clinica Medica 3, Department of Medicine—DIMED, University of Padova, School of Medicine, 35128 Padova, Italy; (M.G.); (R.V.)
| | - Assunta Pozzuoli
- Musculoskeletal Pathology and Oncology Laboratory, Orthopedic and Traumatologic Clinic, Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padova, 35128 Padova, Italy; (E.B.); (A.P.)
| | - Antonio Berizzi
- Orthopaedic and Traumatologic Clinic, Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, 35128 Padova, Italy; (A.B.); (P.R.)
| | - Manuela Scioni
- Department of Statistical Sciences, University of Padova, 35121 Padova, Italy;
| | - Raffaele De Caro
- Institute of Human Anatomy, Department of Neurosciences, University of Padova, 35121 Padova, Italy; (V.M.); (G.S.); (A.P.); (R.D.C.)
- L.i.f.e. L.a.b. Program, Consorzio per la Ricerca Sanitaria (CORIS), Veneto Region, 35128 Padova, Italy
| | - Pietro Ruggieri
- Orthopaedic and Traumatologic Clinic, Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, 35128 Padova, Italy; (A.B.); (P.R.)
| | - Roberto Vettor
- Clinica Medica 3, Department of Medicine—DIMED, University of Padova, School of Medicine, 35128 Padova, Italy; (M.G.); (R.V.)
| | - Roberta Ramonda
- Rheumatology Unit, Department of Medicine-DIMED, University—Hospital of Padova, Via Giustiniani, 2, 35128 Padova, Italy; (R.R.); (M.F.)
| | - Marco Rossato
- Clinica Medica 3, Department of Medicine—DIMED, University of Padova, School of Medicine, 35128 Padova, Italy; (M.G.); (R.V.)
- Correspondence: ; Tel.: +39-049-8218747
| | - Marta Favero
- Rheumatology Unit, Department of Medicine-DIMED, University—Hospital of Padova, Via Giustiniani, 2, 35128 Padova, Italy; (R.R.); (M.F.)
- Internal Medicine I, Cà Foncello Hospital, 31100 Treviso, Italy
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