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Agyeman-Prempeh NO, Maas H, Burchell GL, Millar NL, Moen MH, Smit TH. Treatment options for Achilles tendinopathy: a scoping review of preclinical studies. PeerJ 2025; 13:e18143. [PMID: 39807157 PMCID: PMC11727660 DOI: 10.7717/peerj.18143] [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: 05/23/2024] [Accepted: 08/30/2024] [Indexed: 01/16/2025] Open
Abstract
Background Achilles tendinopathy (AT) management can be difficult, given the paucity of effective treatment options and the degenerative nature of the condition. Innovative therapies for Achilles tendinopathy are therefore direly needed. New therapeutic developments predominantly begin with preclinical animal and in vitro studies to understand the effects at the molecular level and to evaluate toxicity. Despite the publication of many preclinical studies, a comprehensive, quality-assessed review of the basic molecular mechanisms in Achilles tendinopathy is lacking. Objectives This scoping review aims to summarize the literature regarding in vitro and in vivo animal studies examining AT treatments and evaluate their effect on tendon properties. Also, a quality assessment of the included animal studies is done. We provide a comprehensive insight into the current state of preclinical AT treatment research which may guide preclinical researchers in future research. Eligibility criteria Treatment options of Achilles tendinopathy in chemically or mechanically induced in vivo or in vitro Achilles tendinopathy models, reporting biomechanical, histological, and/or biochemical outcomes were included. Sources of evidence A systematically conducted scoping review was performed in PubMed, Embase.com, Clarivate Analytics/Web of Science, and the Wiley/Cochrane Library. Studies up to May 4, 2023 were included. Charting Methods Data from the included articles were extracted and categorized inductively in tables by one reviewer. The risk-of-bias quality assessment of the included animal studies is done with Systematic Review Centre for Laboratory Animal Experimentation risk-of-bias tool. Results A total of 98 studies is included, which investigated 65 different treatment options. 80% of studies reported significant improvement in the Achilles tendon characteristics after treatment. The main results were; maximum load and stiffness improvement; fibre structure recovered and less inflammation was observed; collagen I fibrils increased, collagen III fibrils decreased, and fewer inflammatory cells were observed after treatment. However, 65.4% to 92.5% of the studies had an uncertain to high risk of bias according to the risk-of-bias tool of the Systematic Review Centre for Laboratory Animal Experimentation. Conclusions Despite promising preclinical treatment outcomes, translation to clinical practice lags behind. This may be due to the poor face validity of animal models, heterogeneity in Achilles tendinopathy induction, and low quality of the included studies. Preclinical treatments that improved the biomechanical, histological, and biochemical tendon properties may be interesting for clinical trial investigation. Future efforts should focus on developing standardized preclinical Achilles tendinopathy models, improving reporting standards to minimize risk of bias, and facilitating translation to clinical practice.
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Affiliation(s)
- Nathanael Opoku Agyeman-Prempeh
- University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Movement Sciences, Amsterdam, Netherlands
- Department Orthopedic Surgery and Sports Medicine, Amsterdam University Medical Centre, Amsterdam, Netherlands
| | - Huub Maas
- Amsterdam Movement Sciences, Amsterdam, Netherlands
- VU University Amsterdam, Amsterdam, Noord-Holland, Netherlands
| | | | - Neal L. Millar
- University of Glasgow, Glasgow, United Kingdom
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Maarten H. Moen
- Department of Sports Medicine, Bergman Clinics, Naarden, the Netherlands, Unaffliated, Naarden, Netherlands
- High-Performance Team, Dutch National Olympic Committee & National Sports Federation, Arnhem, Netherlands
| | - Theodoor Henri Smit
- University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Movement Sciences, Amsterdam, Netherlands
- Department Orthopedic Surgery and Sports Medicine, Amsterdam University Medical Centre, Amsterdam, Netherlands
- VU University Amsterdam, Amsterdam, Noord-Holland, Netherlands
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He W, Jiang C, Zhou P, Hu X, Gu X, Zhang S. Role of tendon-derived stem cells in tendon and ligament repair: focus on tissue engineer. Front Bioeng Biotechnol 2024; 12:1357696. [PMID: 39175617 PMCID: PMC11338810 DOI: 10.3389/fbioe.2024.1357696] [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: 12/18/2023] [Accepted: 07/29/2024] [Indexed: 08/24/2024] Open
Abstract
This review offered a comprehensive analysis of tendon and ligament injuries, emphasizing the crucial role of tendon-derived stem cells (TDSCs) in tissue engineering as a potential solution for these challenging medical conditions. Tendon and ligament injuries, prevalent among athletes, the elderly, and laborers, often result in long-term disability and reduced quality of life due to the poor intrinsic healing capacity of these avascular structures. The formation of biomechanically inferior scar tissue and a high rate of reinjury underscore the need for innovative approaches to enhance and guide the regenerative process. This review delved into the complexities of tendon and ligament structure and function, types of injuries and their impacts, and the limitations of the natural repair process. It particularly focused on the role of TDSCs within the context of tissue engineering. TDSCs, with their ability to differentiate into tenocytes, are explored in various applications, including biocompatible scaffolds for cell tracking, co-culture systems to optimize tendon-bone healing, and graft healing techniques. The review also addressed the challenges of immunoreactivity post-transplantation, the importance of pre-treating TDSCs, and the potential of hydrogels and decellularized matrices in supporting tendon regeneration. It concluded by highlighting the essential roles of mechanical and molecular stimuli in TDSC differentiation and the current challenges in the field, paving the way for future research directions.
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Affiliation(s)
- Wei He
- Shaoxing People’s Hospital, Shaoxing, Zhejiang, China
| | - Chao Jiang
- Shaoxing People’s Hospital, Shaoxing, Zhejiang, China
| | - Ping Zhou
- Shaoxing People’s Hospital, Shaoxing, Zhejiang, China
| | - Xujun Hu
- Shaoxing People’s Hospital, Shaoxing, Zhejiang, China
| | - XiaoPeng Gu
- Department of Clinical Medicine, Health Science Center, Ningbo University, Ningbo, Zhejiang, China
- Department of Orthopedics, Zhoushan Guhechuan Hospital, Zhoushan, Zhejiang, China
| | - SongOu Zhang
- Shaoxing People’s Hospital, Shaoxing, Zhejiang, China
- Department of Clinical Medicine, Health Science Center, Ningbo University, Ningbo, Zhejiang, China
- Department of Orthopedics, Zhoushan Guhechuan Hospital, Zhoushan, Zhejiang, China
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Lu J, Li H, Zhang Z, Xu R, Wang J, Jin H. Platelet-rich plasma in the pathologic processes of tendinopathy: a review of basic science studies. Front Bioeng Biotechnol 2023; 11:1187974. [PMID: 37545895 PMCID: PMC10401606 DOI: 10.3389/fbioe.2023.1187974] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 07/10/2023] [Indexed: 08/08/2023] Open
Abstract
Tendinopathy is a medical condition that includes a spectrum of inflammatory and degenerative tendon changes caused by traumatic or overuse injuries. The pathological mechanism of tendinopathy has not been well defined, and no ideal treatment is currently available. Platelet-rich plasma (PRP) is an autologous whole blood derivative containing a variety of cytokines and other protein components. Various basic studies have found that PRP has the therapeutic potential to promote cell proliferation and differentiation, regulate angiogenesis, increase extracellular matrix synthesis, and modulate inflammation in degenerative tendons. Therefore, PRP has been widely used as a promising therapeutic agent for tendinopathy. However, controversies exist over the optimal treatment regimen and efficacy of PRP for tendinopathy. This review focuses on the specific molecular and cellular mechanisms by which PRP manipulates tendon healing to better understand how PRP affects tendinopathy and explore the reason for the differences in clinical trial outcomes. This article has also pointed out the future direction of basic research and clinical application of PRP in the treatment of tendinopathy, which will play a guiding role in the design of PRP treatment protocols for tendinopathy.
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Affiliation(s)
- Jialin Lu
- Department of Pain, The Second Hospital of Jilin University, Changchun, China
- Norman Bethune Health Science Center of Jilin University, Changchun, China
| | - Han Li
- Norman Bethune Health Science Center of Jilin University, Changchun, China
| | - Ziyu Zhang
- Norman Bethune Health Science Center of Jilin University, Changchun, China
| | - Rui Xu
- Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jincheng Wang
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
| | - Hui Jin
- Department of Pain, The Second Hospital of Jilin University, Changchun, China
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
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Darrieutort-Laffite C, Soslowsky LJ, Le Goff B. Molecular and Structural Effects of Percutaneous Interventions in Chronic Achilles Tendinopathy. Int J Mol Sci 2020; 21:ijms21197000. [PMID: 32977533 PMCID: PMC7582801 DOI: 10.3390/ijms21197000] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/08/2020] [Accepted: 09/15/2020] [Indexed: 12/11/2022] Open
Abstract
Achilles tendinopathy (AT) is a common problem, especially in people of working age, as well as in the elderly. Although the pathogenesis of tendinopathy is better known, therapeutic management of AT remains challenging. Various percutaneous treatments have been applied to tendon lesions: e.g., injectable treatments, platelet-rich plasma (PRP), corticosteroids, stem cells, MMP inhibitors, and anti-angiogenic agents), as well as percutaneous procedures without any injection (percutaneous soft tissue release and dry needling). In this review, we will describe and comment on data about the molecular and structural effects of these treatments obtained in vitro and in vivo and report their efficacy in clinical trials. Local treatments have some impact on neovascularization, inflammation or tissue remodeling in animal models, but evidence from clinical trials remains too weak to establish an accurate management plan, and further studies will be necessary to evaluate their value.
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Affiliation(s)
- Christelle Darrieutort-Laffite
- Rheumatology Department, Nantes University Hospital, 44000 Nantes, France;
- INSERM UMR1238, Bone Sarcoma and Remodeling of Calcified Tissue, Nantes University, 44000 Nantes, France
- Correspondence: ; Tel.: +33-2-40-08-48-01
| | - Louis J. Soslowsky
- McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA 19401-6081, USA;
| | - Benoit Le Goff
- Rheumatology Department, Nantes University Hospital, 44000 Nantes, France;
- INSERM UMR1238, Bone Sarcoma and Remodeling of Calcified Tissue, Nantes University, 44000 Nantes, France
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Kia C, Baldino J, Bell R, Ramji A, Uyeki C, Mazzocca A. Platelet-Rich Plasma: Review of Current Literature on its Use for Tendon and Ligament Pathology. Curr Rev Musculoskelet Med 2018; 11:566-572. [PMID: 30203334 PMCID: PMC6220011 DOI: 10.1007/s12178-018-9515-y] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW Platelet-rich plasma (PRP) contains numerous growth factors and cytokines that potentially offer an alternative treatment modality to assist in the healing of multiple musculoskeletal issues. The purpose of this review was to examine the latest literature on the use of PRP for various ligament and tendon pathologies. RECENT FINDINGS Recent literature has shown moderate- to high-quality evidence that PRP can have positive clinical effects in certain conditions such as lateral epicondylitis and rotator cuff tendinopathy. Prospective studies have shown that it can also be useful in the treatment of patella tendinopathy. In summary, we found PRP to have variable success in ligament and tendon pathology; however, it should be considered a viable option in chronic musculoskeletal disease that has failed other treatments. Patient selection, duration of symptoms, and combining with other modalities such as physical therapy should all be taken into consideration in treatment with PRP.
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Affiliation(s)
- Cameron Kia
- University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, USA.
| | - Joshua Baldino
- University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, USA
| | - Ryan Bell
- University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, USA
| | - Alim Ramji
- University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, USA
| | - Colin Uyeki
- University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, USA
| | - Augustus Mazzocca
- University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, USA
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Pauly S, Klatte-Schulz F, Stahnke K, Scheibel M, Wildemann B. The effect of autologous platelet rich plasma on tenocytes of the human rotator cuff. BMC Musculoskelet Disord 2018; 19:422. [PMID: 30497435 PMCID: PMC6267832 DOI: 10.1186/s12891-018-2339-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 11/14/2018] [Indexed: 12/29/2022] Open
Abstract
Background Platelet rich plasma (PRP) is widely used in rotator cuff repairs but its effect on the healing process is unclear. Several cell culture studies on the effect of allogenic PRP have reported promising results but are not transferable to clinical practice. The aim of the present study is to assess the possible effect of autologous PRP on rotator cuff tendon cells. The amount of growth factors involved with tendon-bone healing (PDGF-AB, IGF-1, TGF-β1, BMP-7 and -12) is quantified. Methods Rotator cuff tissue samples were obtained from (n = 24) patients grouped by age (>/< 65 years) and sex into four groups and cells were isolated and characterized. Later, autologous PRP preparations were obtained and the effect was analyzed by means of cell proliferation, collagen I synthesis and expression of collagen I and III. Furthermore, the PRPs were quantified for growth factor content by means of platelet-derived growth factor (PDGF-AB), insulin-like growth factor (IGF-1), transforming growth factor (TGF-β1), as well as bone morphogenetic protein (BMP) -7 and − 12. Results Cell proliferation and absolute synthesis of collagen I were positively affected by PRP exposure compared to controls (p < 0.05), but expression and relative synthesis of collagen I (normalized to cell proliferation) were significantly reduced. PRP contained high amounts of IGF-1 and lower levels of TGF-β1 and PDGF-AB. The amounts of BMP-7 and -12 were below the detection limits. Conclusions PRP is a source of growth factors such involved with tendon-bone healing. PRP had an anabolic effect on the human rotator cuff tenocytes of the same individual in vitro by means of cell proliferation and absolute, but not relative collagen I synthesis. These results encourage further studies on clinical outcomes with more comparable standards in terms of preparation and application methods. Level of evidence Controlled laboratory study.
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Affiliation(s)
- Stephan Pauly
- Julius Wolff Institut, Center for Musculoskeletal Surgery, Charité-Universitaetsmedizin, Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Franka Klatte-Schulz
- Julius Wolff Institut, Center for Musculoskeletal Surgery, Charité-Universitaetsmedizin, Augustenburger Platz 1, 13353, Berlin, Germany.,Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitaetsmedizin, Berlin, Germany
| | - Katharina Stahnke
- Julius Wolff Institut, Center for Musculoskeletal Surgery, Charité-Universitaetsmedizin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Markus Scheibel
- Julius Wolff Institut, Center for Musculoskeletal Surgery, Charité-Universitaetsmedizin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Britt Wildemann
- Julius Wolff Institut, Center for Musculoskeletal Surgery, Charité-Universitaetsmedizin, Augustenburger Platz 1, 13353, Berlin, Germany.,Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitaetsmedizin, Berlin, Germany.,Department of Experimental Traumatology, Universitaetsklinikum Jena, Jena, Germany
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Sansone V, Maiorano E, Galluzzo A, Pascale V. Calcific tendinopathy of the shoulder: clinical perspectives into the mechanisms, pathogenesis, and treatment. Orthop Res Rev 2018; 10:63-72. [PMID: 30774461 PMCID: PMC6209365 DOI: 10.2147/orr.s138225] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Calcific tendinopathy (CT) of the shoulder is a common, painful condition characterized by the presence of calcium deposits in the rotator cuff tendons. Current theories indicate that CT may be the result of a cell-mediated process in which, after a stage of calcium deposition, calcifications are spontaneously resorbed. However, in a minority of cases, this self-healing process is somehow disrupted, resulting in symptoms. Recent literature shows an emerging role of biological and genetic factors underlying CT. This new evidence could supplement the classic mechanical theory of rotator cuff tendinopathy complicated by calcium precipitation, and it may also explain why the majority of the therapies currently in use are only able to provide partially satisfactory outcomes. This review aims to summarize the current knowledge about the pathological processes underlying CT of the shoulder and thereby justify the quest for advanced biological treatments of this condition when it becomes symptomatic.
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Affiliation(s)
- Valerio Sansone
- Department of Orthopaedics, University of Milan, .,Department of Orthopaedics, I.R.C.C.S. Istituto Ortopedico Galeazzi, Milan, Italy,
| | | | | | - Valerio Pascale
- Department of Orthopaedics, University of Milan, .,Department of Orthopaedics, I.R.C.C.S. Istituto Ortopedico Galeazzi, Milan, Italy,
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Wang D, Tan H, Lebaschi AH, Nakagawa Y, Wada S, Donnelly PE, Ying L, Deng XH, Rodeo SA. Kartogenin Enhances Collagen Organization and Mechanical Strength of the Repaired Enthesis in a Murine Model of Rotator Cuff Repair. Arthroscopy 2018; 34:2579-2587. [PMID: 30037570 PMCID: PMC6371391 DOI: 10.1016/j.arthro.2018.04.022] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 04/18/2018] [Accepted: 04/24/2018] [Indexed: 02/02/2023]
Abstract
PURPOSE To investigate the use of kartogenin (KGN) in augmenting healing of the repaired enthesis after rotator cuff repair in a murine model. METHODS Seventy-two C57BL/6 wild-type mice underwent unilateral detachment and transosseous repair of the supraspinatus tendon augmented with either fibrin sealant (control group; n = 36) or fibrin sealant containing 100 μmol/L of KGN (experimental group; n = 36) applied at the repair site. Postoperatively, mice were allowed free cage activity without immobilization. Mice were humanely killed at 2 and 4 weeks postoperatively. Repair site integrity was evaluated histologically through fibrocartilage formation and collagen fiber organization and biomechanically through load-to-failure testing of the supraspinatus tendon-bone construct. RESULTS At 2 weeks, no differences were noted in percent area of fibrocartilage, collagen organization, or ultimate strength between groups. At 4 weeks, superior collagen fiber organization (based on collagen birefringence [17.3 ± 2.0 vs 7.0 ± 6.5 integrated density/μm2; P < .01]) and higher ultimate failure loads (3.5 ± 0.6 N vs 2.3 ± 1.1 N; P = .04) were seen in the KGN group. The percent area of fibrocartilage (13.2 ± 8.4% vs 4.4 ± 5.4%; P = .04) was higher in the control group compared with the KGN group. CONCLUSIONS Rotator cuff repair augmentation with KGN improved the collagen fiber organization and biomechanical strength of the tendon-bone interface at 4 weeks in a murine model. CLINICAL RELEVANCE These findings have implications for improving the structural integrity of the repaired enthesis and potentially reducing the retear rate after rotator cuff repair, which can ultimately lead to improvements in clinical outcomes.
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Affiliation(s)
- Dean Wang
- Sports Medicine and Shoulder Service, Hospital for Special Surgery, New York, New York, U.S.A., Laboratory for Joint Tissue Repair and Regeneration Hospital for Special Surgery, New York, New York, U.S.A
| | - Hongbo Tan
- Laboratory for Joint Tissue Repair and Regeneration Hospital for Special Surgery, New York, New York, U.S.A
| | - Amir H. Lebaschi
- Laboratory for Joint Tissue Repair and Regeneration Hospital for Special Surgery, New York, New York, U.S.A
| | - Yusuke Nakagawa
- Laboratory for Joint Tissue Repair and Regeneration Hospital for Special Surgery, New York, New York, U.S.A
| | - Susumu Wada
- Laboratory for Joint Tissue Repair and Regeneration Hospital for Special Surgery, New York, New York, U.S.A
| | - Patrick E. Donnelly
- Laboratory for Joint Tissue Repair and Regeneration Hospital for Special Surgery, New York, New York, U.S.A
| | - Liang Ying
- Laboratory for Joint Tissue Repair and Regeneration Hospital for Special Surgery, New York, New York, U.S.A
| | - Xiang-Hua Deng
- Laboratory for Joint Tissue Repair and Regeneration Hospital for Special Surgery, New York, New York, U.S.A
| | - Scott A. Rodeo
- Sports Medicine and Shoulder Service, Hospital for Special Surgery, New York, New York, U.S.A
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Cai G, Liu W, He Y, Huang J, Duan L, Xiong J, Liu L, Wang D. Recent advances in kartogenin for cartilage regeneration. J Drug Target 2018; 27:28-32. [PMID: 29772932 DOI: 10.1080/1061186x.2018.1464011] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Either osteoarthritis or sports-related injuries can lead to cartilage defects, whereas both chondrocyte self-renewal and conventional treatments face limitations. In cartilage regenerative medicine, growth factors are commonly used to induce chondrogenic differentiation of stem cells. However, application of growth factors is confined by some drawbacks. Emerging small molecules are regarded as an alternative for cartilage regeneration. A recently discovered small-molecule compound, kartogenin (KGN), has been proven to be a chondrogenic and chondroprotective agent and is more effective in inducing cartilage regeneration when compared with growth factors. KGN has been processed and applied in many forms, such as in intra-articular injection, in collaboration with growth factors, in incorporation in drug delivery systems, and in combination with scaffolds. Fortunately, progress has been achieved in KGN applications. The current review discusses the recent advances in KGN for cartilage regeneration and thus presents new concepts in cartilage repair in clinical settings.
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Affiliation(s)
- Gaorui Cai
- a Department of Traumatic Orthopedics , the First Affiliated Hospital of Shenzhen University , Shenzhen , Guangdong Province , China.,b Shenzhen Key Laboratory of Tissue Engineering , Shenzhen , Guangdong Province , China
| | - Wei Liu
- a Department of Traumatic Orthopedics , the First Affiliated Hospital of Shenzhen University , Shenzhen , Guangdong Province , China.,c Department of Sports Medicine , the First Affiliated Hospital of Shenzhen University , Shenzhen , Guangdong Province , China
| | - Yong He
- b Shenzhen Key Laboratory of Tissue Engineering , Shenzhen , Guangdong Province , China
| | - Jianghong Huang
- a Department of Traumatic Orthopedics , the First Affiliated Hospital of Shenzhen University , Shenzhen , Guangdong Province , China.,c Department of Sports Medicine , the First Affiliated Hospital of Shenzhen University , Shenzhen , Guangdong Province , China
| | - Li Duan
- b Shenzhen Key Laboratory of Tissue Engineering , Shenzhen , Guangdong Province , China
| | - Jianyi Xiong
- a Department of Traumatic Orthopedics , the First Affiliated Hospital of Shenzhen University , Shenzhen , Guangdong Province , China.,b Shenzhen Key Laboratory of Tissue Engineering , Shenzhen , Guangdong Province , China.,c Department of Sports Medicine , the First Affiliated Hospital of Shenzhen University , Shenzhen , Guangdong Province , China
| | - Lijun Liu
- a Department of Traumatic Orthopedics , the First Affiliated Hospital of Shenzhen University , Shenzhen , Guangdong Province , China
| | - Daping Wang
- a Department of Traumatic Orthopedics , the First Affiliated Hospital of Shenzhen University , Shenzhen , Guangdong Province , China.,b Shenzhen Key Laboratory of Tissue Engineering , Shenzhen , Guangdong Province , China.,c Department of Sports Medicine , the First Affiliated Hospital of Shenzhen University , Shenzhen , Guangdong Province , China
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10
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Zhang J, Yuan T, Zheng N, Zhou Y, Hogan MV, Wang JHC. The combined use of kartogenin and platelet-rich plasma promotes fibrocartilage formation in the wounded rat Achilles tendon entheses. Bone Joint Res 2017; 6:231-244. [PMID: 28450316 PMCID: PMC5415905 DOI: 10.1302/2046-3758.64.bjr-2017-0268.r1] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 02/10/2017] [Indexed: 01/01/2023] Open
Abstract
Objectives After an injury, the biological reattachment of tendon to bone is a challenge because healing takes place between a soft (tendon) and a hard (bone) tissue. Even after healing, the transition zone in the enthesis is not completely regenerated, making it susceptible to re-injury. In this study, we aimed to regenerate Achilles tendon entheses (ATEs) in wounded rats using a combination of kartogenin (KGN) and platelet-rich plasma (PRP). Methods Wounds created in rat ATEs were given three different treatments: kartogenin platelet-rich plasma (KGN-PRP); PRP; or saline (control), followed by histological and immunochemical analyses, and mechanical testing of the rat ATEs after three months of healing. Results Histological analysis showed well organised arrangement of collagen fibres and proteoglycan formation in the wounded ATEs in the KGN-PRP group. Furthermore, immunohistochemical analysis revealed fibrocartilage formation in the KGN-PRP-treated ATEs, evidenced by the presence of both collagen I and II in the healed ATE. Larger positively stained collagen III areas were found in both PRP and saline groups than those in the KGN-PRP group. Chondrocyte-related genes, SOX9 and collagen II, and tenocyte-related genes, collagen I and scleraxis (SCX), were also upregulated by KGN-PRP. Moreover, mechanical testing results showed higher ultimate tensile strength in the KGN-PRP group than in the saline control group. In contrast, PRP treatment appeared to have healed the injured ATE but induced no apparent formation of fibrocartilage. The saline-treated group showed poor healing without fibrocartilage tissue formation in the ATEs. Conclusions Our results show that injection of KGN-PRP induces fibrocartilage formation in the wounded rat ATEs. Hence, KGN-PRP may be a clinically relevant, biological approach to regenerate injured enthesis effectively. Cite this article: J. Zhang, T. Yuan, N. Zheng, Y. Zhou, M. V. Hogan, J. H-C. Wang. The combined use of kartogenin and platelet-rich plasma promotes fibrocartilage formation in the wounded rat Achilles tendon entheses. Bone Joint Res 2017;6:231–244. DOI: 10.1302/2046-3758.64.BJR-2017-0268.R1.
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Affiliation(s)
- J Zhang
- Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213, USA
| | - T Yuan
- Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213, USA
| | - N Zheng
- Department of Mechanical Engineering, University of North Carolina, 9201 University City Blvd, Mechanical Engineering, Duke 201, Charlotte, North Carolina, USA
| | - Y Zhou
- Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213, USA
| | - M V Hogan
- Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213, USA
| | - J H-C Wang
- Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213, USA
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PRP Treatment Efficacy for Tendinopathy: A Review of Basic Science Studies. BIOMED RESEARCH INTERNATIONAL 2016; 2016:9103792. [PMID: 27610386 PMCID: PMC5004020 DOI: 10.1155/2016/9103792] [Citation(s) in RCA: 138] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 07/08/2016] [Accepted: 07/20/2016] [Indexed: 11/18/2022]
Abstract
Platelet-Rich Plasma (PRP) has been widely used in orthopaedic surgery and sport medicine to treat tendon injuries. However, the efficacy of PRP treatment for tendinopathy is controversial. This paper focuses on reviewing the basic science studies on PRP performed under well-controlled conditions. Both in vitro and in vivo studies describe PRP's anabolic and anti-inflammatory effects on tendons. While some clinical trials support these findings, others refute them. In this review, we discuss the effectiveness of PRP to treat tendon injuries with evidence presented in basic science studies and the potential reasons for the controversial results in clinical trials. Finally, we comment on the approaches that may be required to improve the efficacy of PRP treatment for tendinopathy.
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Therapeutic Roles of Tendon Stem/Progenitor Cells in Tendinopathy. Stem Cells Int 2016; 2016:4076578. [PMID: 27195010 PMCID: PMC4853952 DOI: 10.1155/2016/4076578] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 03/10/2016] [Indexed: 02/07/2023] Open
Abstract
Tendinopathy is a tendon disorder characterized by activity-related pain, local edema, focal tenderness to palpation, and decreased strength in the affected area. Tendinopathy is prevalent in both athletes and the general population, highlighting the need to elucidate the pathogenesis of this disorder. Current treatments of tendinopathy are both conservative and symptomatic. The discovery of tendon stem/progenitor cells (TSPCs) and erroneous differentiation of TSPCs have provided new insights into the pathogenesis of tendinopathy. In this review, we firstly present the histopathological characteristics of tendinopathy and explore the cellular and molecular cues in the pathogenesis of tendinopathy. Current evidence of the depletion of the stem cell pool and altered TSPCs fate in the pathogenesis of tendinopathy has been presented. The potential regulatory factors for either tenogenic or nontenogenic differentiation of TSPCs are also summarized. The regulation of endogenous TSPCs or supplementation with exogenous TSPCs as therapeutic targets for the treatment of tendinopathy is proposed. Therefore, inhibiting the erroneous differentiation of TSPCs and regulating the differentiation of TSPCs into tendon cells might be important areas of future research and could provide new clinical treatments for tendinopathy. The current evidence suggests that TSPCs are promising therapeutic targets for the management of tendinopathy.
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Kaux JF, Drion P, Croisier JL, Crielaard JM. Tendinopathies and platelet-rich plasma (PRP): from pre-clinical experiments to therapeutic use. J Stem Cells Regen Med 2015. [PMID: 26195890 PMCID: PMC4498322 DOI: 10.46582/jsrm.1101003] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The restorative properties of platelets, through the local release of growth factors, are used in various medical areas. This article reviews fundamental and clinical research relating to platelet-rich plasma applied to tendinous lesions. MATERIALS AND METHOD Articles in French and English, published between 1 January 2012 and 31 December 2014. dealing with PRP and tendons were searched for using the Medline and Scopus data bases. RESULTS Forty-seven articles were identified which addressed pre-clinical and clinical studies: 27 relating to in vitro and in vivo animal studies and 20 relating to human studies. Of these, five addressed lateral epicondylitis, two addressed rotator cuff tendinopathies, ten dealt with patellar tendinopathies and three looked at Achilles tendinopathies. CONCLUSIONS The majority of pre-clinical studies show that PRP stimulates the tendon's healing process. However, clinical series remain more controversial and level 1, controlled, randomised studies are still needed.
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Affiliation(s)
- Jean-François Kaux
- Physical Medicine and Sports Traumatology Department, University and University Hospital of Liège, Liège, Belgium
| | - Pierre Drion
- ULg-GIGA-R, Experimental Surgery, University of Liège, Belgium
| | - Jean-Louis Croisier
- Physiotherapy Service, Department of Motility Sciences, University of Liège, Liège, Belgium
| | - Jean-Michel Crielaard
- Physical Medicine and Sports Traumatology Department, University and University Hospital of Liège, Liège, Belgium
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Zhou Y, Zhou B, Tang K. The effects of substance p on tendinopathy are dose-dependent: an in vitro and in vivo model study. J Nutr Health Aging 2015; 19:555-61. [PMID: 25923486 DOI: 10.1007/s12603-014-0576-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
OBJECTIVES Substance P (SP) is known to be involved in neuropathic pain, chronic inflammation, and tendinopathy. The present study evaluated the effects of different doses of SP on tendon-derived stem cells (TDSCs) in vitro and tendons in vivo. METHODS For the in vitro study, TDSCs cultured in growth medium with different concentrations of SP (negative control, 0.1 nM, and 1.0 nM). The effects of SP on TDSCs were examined with respect to their ability to proliferate and differentiate. For the in vivo study, we injected different doses of SP (saline control, 0.5 nmol, and 5.0 nmol) into rat patella tendons to investigate the effects of SP on tendons. RESULTS Low and high doses SP significantly enhanced the proliferation ability of TDSCs. Low-dose of SP induced the expression of tenocyte-related genes; however, high-dose of SP induced the expression of non-tenocyte genes, which was evident by the high expression of PPARγ and collagen type II. In the in vivo study, only high-doses of SP (5.0 nmol) induced the tendinosis-like changes in the patella tendon injection model. Low doses of SP (0.5 nmol) enhanced the tenogenesis compared with saline injection and the high-dose SP group. CONCLUSIONS SP enhances the proliferation of TDSCs in vitro and the effects of SP on tendinopathy are dose-dependent in vivo.
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Affiliation(s)
- Y Zhou
- Kanglai Tang, Department of Orthopedic Surgery, Third Military Medical University Affiliated Southwest Hospital, Gaotanyan Str. 30, Chongqing 400038, People's Republic of China, Telephone number: 86-23-68765289; Fax number: 86-23-65656500. E-mail:
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15
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Gaspar D, Spanoudes K, Holladay C, Pandit A, Zeugolis D. Progress in cell-based therapies for tendon repair. Adv Drug Deliv Rev 2015; 84:240-56. [PMID: 25543005 DOI: 10.1016/j.addr.2014.11.023] [Citation(s) in RCA: 127] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 11/08/2014] [Accepted: 11/12/2014] [Indexed: 02/07/2023]
Abstract
The last decade has seen significant developments in cell therapies, based on permanently differentiated, reprogrammed or engineered stem cells, for tendon injuries and degenerative conditions. In vitro studies assess the influence of biophysical, biochemical and biological signals on tenogenic phenotype maintenance and/or differentiation towards tenogenic lineage. However, the ideal culture environment has yet to be identified due to the lack of standardised experimental setup and readout system. Bone marrow mesenchymal stem cells and tenocytes/dermal fibroblasts appear to be the cell populations of choice for clinical translation in equine and human patients respectively based on circumstantial, rather than on hard evidence. Collaborative, inter- and multi-disciplinary efforts are expected to provide clinically relevant and commercially viable cell-based therapies for tendon repair and regeneration in the years to come.
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Affiliation(s)
- Diana Gaspar
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway (NUI Galway), Galway, Ireland
| | - Kyriakos Spanoudes
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway (NUI Galway), Galway, Ireland
| | - Carolyn Holladay
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway (NUI Galway), Galway, Ireland
| | - Abhay Pandit
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway (NUI Galway), Galway, Ireland
| | - Dimitrios Zeugolis
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway (NUI Galway), Galway, Ireland.
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Abstract
Injuries of the Achilles tendon are relatively common with potentially devastating outcomes. Healing Achilles tendons form a fibrovascular scar resulting in a tendon which may be mechanically weaker than the native tendon. The resulting strength deficit causes a high risk for reinjury and other complications. Treatments using biologics aim to restore the normal properties of the native tendon and reduce the risk of rerupture and maximize tendon function. The purpose of this review was to summarize the current findings of various therapies using biologics in an attempt to improve the prognosis of Achilles tendon ruptures and tendinopathies. A PubMed search was performed using specific search terms. The search was open for original manuscripts and review papers limited to publication within the last 10 years. From these searches, papers were included in the review if they investigated the effects of biological augmentation on Achilles tendon repair or healing. Platelet-rich plasma may assist in the healing process of Achilles tendon ruptures, while the evidence to support its use in the treatment of chronic Achilles tendinopathies remains insufficient. The use of growth factors such as hepatocyte growth factor, recombinant human platelet-derived growth factor-BB, interleukin-6, and transforming growth factor beta as well as several bone morphogenetic proteins have shown promising results for Achilles tendon repair. In vitro and preclinical studies have indicated the potential effectiveness of bone marrow aspirate as well. Stem cells also have positive effects on Achilles tendon healing, particularly during the early phases. Polyhydroxyalkanoates (PHA), decellularized tendon tissue, and porcine small intestinal submucosa (SIS) are biomaterials which have shown promising results as scaffolds used in Achilles tendon repair. The application of biological augmentation techniques in Achilles tendon repair appears promising; however, several techniques require further investigation to evaluate their clinical application.
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Affiliation(s)
- Evan Shapiro
- Orthopedics Department, Feinstein Institute for Medical Research, 350 Community Dr, Manhasset, NY, 11030, USA
| | - Daniel Grande
- Orthopedics Department, Feinstein Institute for Medical Research, 350 Community Dr, Manhasset, NY, 11030, USA.
| | - Mark Drakos
- Orthopedics Department, Feinstein Institute for Medical Research, 350 Community Dr, Manhasset, NY, 11030, USA
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Nau T, Teuschl A. Regeneration of the anterior cruciate ligament: Current strategies in tissue engineering. World J Orthop 2015; 6:127-136. [PMID: 25621217 PMCID: PMC4303781 DOI: 10.5312/wjo.v6.i1.127] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 06/19/2014] [Accepted: 07/29/2014] [Indexed: 02/06/2023] Open
Abstract
Recent advancements in the field of musculoskeletal tissue engineering have raised an increasing interest in the regeneration of the anterior cruciate ligament (ACL). It is the aim of this article to review the current research efforts and highlight promising tissue engineering strategies. The four main components of tissue engineering also apply in several ACL regeneration research efforts. Scaffolds from biological materials, biodegradable polymers and composite materials are used. The main cell sources are mesenchymal stem cells and ACL fibroblasts. In addition, growth factors and mechanical stimuli are applied. So far, the regenerated ACL constructs have been tested in a few animal studies and the results are encouraging. The different strategies, from in vitro ACL regeneration in bioreactor systems to bio-enhanced repair and regeneration, are under constant development. We expect considerable progress in the near future that will result in a realistic option for ACL surgery soon.
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Chen JL, Zhang W, Liu ZY, Heng BC, Ouyang HW, Dai XS. Physical regulation of stem cells differentiation into teno-lineage: current strategies and future direction. Cell Tissue Res 2014; 360:195-207. [DOI: 10.1007/s00441-014-2077-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Accepted: 11/17/2014] [Indexed: 12/18/2022]
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Holladay C, Abbah SA, O'Dowd C, Pandit A, Zeugolis DI. Preferential tendon stem cell response to growth factor supplementation. J Tissue Eng Regen Med 2014; 10:783-98. [PMID: 24474722 DOI: 10.1002/term.1852] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Revised: 09/30/2013] [Accepted: 11/06/2013] [Indexed: 12/14/2022]
Abstract
Tendon injuries are increasingly prevalent around the world, accounting for more than 100 000 new clinical cases/year in the USA alone. Cell-based therapies have been proposed as a therapeutic strategy, with recent data advocating the use of tendon stem cells (TSCs) as a potential cell source with clinical relevance for tendon regeneration. However, their in vitro expansion is problematic, as they lose their multipotency and change their protein expression profile in culture. Herein, we ventured to assess the influence of insulin-like growth factor 1 (IGF-1), growth and differentiation factor-5 (GDF-5) and transforming growth factor-β1 (TGFβ1) supplementation in TSC culture. IGF-1 preserved multipotency for up to 28 days. Upregulation of decorin and scleraxis expression was observed as compared to freshly isolated cells. GDF-5 treated cells exhibited reduced differentiation along adipogenic and chondrogenic pathways after 28 days, and decorin, scleraxis and collagen type I expression was increased. After 28 days, TGFβ1 supplementation led to increased scleraxis, osteonectin and collagen type II expression. The varied responses to each growth factor may reflect their role in tendon repair, suggesting that: GDF-5 promotes the transition of tendon stem cells towards tenocytes; TGFβ1 induces differentiation along several pathways, including a phenotype indicative of fibrocartilage or calcified tendon, common problems in tendon healing; and IGF-1 promotes proliferation and maintenance of TSC phenotypes, thereby creating a population sufficient to have a beneficial effect. Copyright © 2014 John Wiley & Sons, Ltd.
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Affiliation(s)
- Carolyn Holladay
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland Galway (NUI Galway), Ireland.,Vornia Biomaterials, Galway, Ireland
| | - Sunny-Akogwu Abbah
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland Galway (NUI Galway), Ireland
| | | | - Abhay Pandit
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland Galway (NUI Galway), Ireland
| | - Dimitrios I Zeugolis
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland Galway (NUI Galway), Ireland.
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The effects of platelet-rich clot releasate on the expression of MMP-1 and type I collagen in human adult dermal fibroblasts: PRP is a stronger MMP-1 stimulator. Mol Biol Rep 2013; 41:3-8. [PMID: 24293148 DOI: 10.1007/s11033-013-2718-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 09/14/2013] [Indexed: 02/02/2023]
Abstract
Platelet-rich plasma is widely used in acute and chronic ulcers due to its capacity to enhance the wound healing process. Fibroblasts are believed to be the most important cells in the production and remodeling of the extracellular matrix (ECM). Matrix metalloproteinase (MMP)-1 is the proteolytic enzyme of collagen I, and has a key role in collagen remodeling during wound healing. Whether or not platelet-rich clot releasate (PRCR) is able to effectively modulate the ECM, and the effect of PRCR on the expression of type I collagen and MMP-1 in human dermal fibroblasts was evaluated. Specifically, human adult dermal fibroblasts were incubated in PRCR-containing solutions for 24 and 48 h, after which the levels of collagen and MMP-1 were quantified by reverse transcription PCR at the transcriptional level, and ELISA and immunoblot analyses at the post-transcriptional level. PRCR markedly up-regulated the expression of MMP-1 and type I collagen in fibroblasts incubated in 20 % PRCR solutions for 48 h. These findings suggest that increased MMP-1 expression after PRCR treatment enable remodeling the ECM.
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21
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Yuan T, Zhang CQ, Wang JHC. Augmenting tendon and ligament repair with platelet-rich plasma (PRP). Muscles Ligaments Tendons J 2013. [PMID: 24367773 DOI: 10.11138/mltj/2013.3.3.139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Tendon and ligament injuries (TLI) commonly occur in athletes and non-athletes alike, and remarkably debilitate patients' athletic and personal abilities. Current clinical treatments, such as reconstruction surgeries, do not adequately heal these injuries and often result in the formation of scar tissue that is prone to re-injury. Platelet-rich plasma (PRP) is a widely used alternative option that is also safe because of its autologous nature. PRP contains a number of growth factors that are responsible for its potential to heal TLIs effectively. In this review, we provide a comprehensive report on PRP. While basic science studies in general indicate the potential of PRP to treat TLIs effectively, a review of existing literature on the clinical use of PRP for the treatment of TLIs indicates a lack of consensus due to varied treatment outcomes. This suggests that current PRP treatment protocols for TLIs may not be optimal, and that not all TLIs may be effectively treated with PRP. Certainly, additional basic science studies are needed to develop optimal treatment protocols and determine those TLI conditions that can be treated effectively.
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Affiliation(s)
- Ting Yuan
- Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, USA ; Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai, China
| | - Chang-Qing Zhang
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai, China
| | - James H-C Wang
- Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, USA
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