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Irani M, Farzizadeh R, Abdolmaleki A, Asadi A. The Effect of Aerobic Exercise With an Omega-3 Supplement on the Tendon Healing Process. Am J Sports Med 2025:3635465251339025. [PMID: 40376939 DOI: 10.1177/03635465251339025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/18/2025]
Abstract
BACKGROUND An Achilles tendon rupture is a common orthopaedic injury in athletes and other people. Therefore, it is essential to investigate methods that may yield beneficial results for tendon healing by addressing the inflammatory and gene expression aspects of the healing process. PURPOSE The objective of this study was to examine the effect of combining aerobic exercise and omega-3 supplementation on the process of Achilles tendon healing in male Wistar rats. STUDY DESIGN Controlled laboratory study. METHODS For the purpose of this experiment, 50 male Wistar rats were randomly assigned to 5 groups, with each group containing 10 rats. These groups were identified as a sham group (surgery without tendon damage), a negative control group (tendon damage), and 3 experimental groups: exercise group (tendon damage + aerobic exercise), omega-3 group (tendon damage + omega-3 supplement), and exercise + omega-3 group (tendon damage + aerobic exercise + omega-3 supplement). The Achilles tendon was cut and subsequently repaired through a surgical intervention. Beginning the day after the injury, the groups receiving omega-3 received a dose of 4.6 g/kg EPA [eicosapentaenoic acid] and 3.8 g/kg DHA [docosahexaenoic acid] orally each day, and those in the exercise groups ran on a treadmill 6 days a week. At 48 hours after completing the protocol, both tissue and blood samples were taken and immediately sent for biochemical (TNF-α, IL-1β, MDA, and SOD), gene expression (MMP-3, MMP-9, and SCX), histological (hematoxylin and eosin and Masson trichrome staining), and tensile analyses. Rats were also administered the Achilles functional index at various time points. RESULTS The histological results revealed a marked improvement in the arrangement of cells and collagen in the extracellular matrix of the exercise + omega-3 group, displaying a notably uniform and condensed alignment of collagen fibers compared with the other groups, which exhibited a lack of organization. Biochemical results showed that TNF-α, IL-1β, and MDA levels were significantly reduced in the exercise + omega-3 group (P < .05). On the other hand, a significant increase in the Achilles functional index score was shown in the exercise + omega-3 group at all time points (P < .05). In the same group, real-time polymerase chain reaction results demonstrated that the expression of MMP-3 and SCX genes increased and that the expression of the MMP-9 gene decreased (P < .05). CONCLUSION Aerobic exercise with omega-3 supplementation was more beneficial for healing a surgically cut Achilles tendon in a rat model than aerobic exercise or omega-3 supplementation alone. CLINICAL RELEVANCE Our findings suggest that omega-3 supplementation combined with aerobic exercise after an Achilles tendon injury may be able to accelerate the process of Achilles tendon regeneration and healing.
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Affiliation(s)
- Meysam Irani
- Department of Exercise Physiology, Faculty of Educational Sciences and Psychology, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Reza Farzizadeh
- Department of Exercise Physiology, Faculty of Educational Sciences and Psychology, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Arash Abdolmaleki
- Department of Biophysics, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Asadollah Asadi
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
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Vinitpairot C, Yik JHN, Haudenschild DR, Szabo RM, Bayne CO. Current trends in the prevention of adhesions after zone 2 flexor tendon repair. J Orthop Res 2024; 42:2149-2158. [PMID: 38761143 DOI: 10.1002/jor.25874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 04/20/2024] [Accepted: 04/29/2024] [Indexed: 05/20/2024]
Abstract
Treating flexor tendon injuries within the digital flexor sheath (commonly referred to as palmar hand zone 2) presents both technical and logistical challenges. Success hinges on striking a delicate balance between safeguarding the surgical repair for tendon healing and initiating early rehabilitation to mitigate the formation of tendon adhesions. Adhesions between tendon slips and between tendons and the flexor sheath impede tendon movement, leading to postoperative stiffness and functional impairment. While current approaches to flexor tendon repair prioritize maximizing tendon strength for early mobilization and adhesion prevention, factors such as pain, swelling, and patient compliance may impede postoperative rehabilitation efforts. Moreover, premature mobilization could risk repair failure, necessitating additional surgical interventions. Pharmacological agents offer a potential avenue for minimizing inflammation and reducing adhesion formation while still promoting normal tendon healing. Although some systemic and local agents have shown promising results in animal studies, their clinical efficacy remains uncertain. Limitations in these studies include the relevance of chosen animal models to human populations and the adequacy of tools and measurement techniques in accurately assessing the impact of adhesions. This article provides an overview of the clinical challenges associated with flexor tendon injuries, discusses current on- and off-label agents aimed at minimizing adhesion formation, and examines investigational models designed to study adhesion reduction after intra-synovial flexor tendon repair. Understanding the clinical problem and experimental models may serve as a catalyst for future research aimed at addressing intra-synovial tendon adhesions following zone 2 flexor tendon repair.
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Affiliation(s)
- Chaiyos Vinitpairot
- Department of Orthopaedic Surgery, University of California Davis School of Medicine, Sacramento, California, USA
- Department of Orthopedics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Jasper H N Yik
- Department of Translational Orthopedic Research, Houston Methodist Research Institute, Houston, Texas, USA
| | - Dominik R Haudenschild
- Department of Translational Orthopedic Research, Houston Methodist Research Institute, Houston, Texas, USA
| | - Robert M Szabo
- Department of Orthopaedic Surgery, University of California Davis School of Medicine, Sacramento, California, USA
| | - Christopher O Bayne
- Department of Orthopaedic Surgery, University of California Davis School of Medicine, Sacramento, California, USA
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Li H, Li Y, Xiang L, Luo S, Zhang Y, Li S. Therapeutic potential of GDF-5 for enhancing tendon regenerative healing. Regen Ther 2024; 26:290-298. [PMID: 39022600 PMCID: PMC11252783 DOI: 10.1016/j.reth.2024.03.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 03/24/2024] [Accepted: 03/28/2024] [Indexed: 07/20/2024] Open
Abstract
Tendon injury is a common disorder of the musculoskeletal system, with a higher possibility of occurrence in elderly individuals and athletes. After a tendon injury, the tendon suffers from inadequate and slow healing, resulting in the formation of fibrotic scar tissue, ending up with inferior functional properties. Therapeutic strategies involving the application of growth factors have been advocated to promote tendon healing. Growth and differentiation-5 (GDF-5) represents one such factor that has shown promising effect on tendon healing in animal models and in vitro cultures. Although promising, these studies are limited as the molecular mechanisms by which GDF-5 exerts its effect remain incompletely understood. Starting from broadly introducing essential elements of current understanding about GDF-5, the present review aims to define the effect of GDF-5 and its possible mechanisms of action in tendon healing. Nevertheless, we still need more in vivo studies to explore dosage, application time and delivery strategy of GDF-5, so as to pave the way for future clinical translation.
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Affiliation(s)
- Hanyue Li
- School of Physical Education, Southwest Medical University, PR China
| | - Yini Li
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Sichuan, PR China
| | - Linmei Xiang
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, PR China
| | - Shengyu Luo
- School of Physical Education, Southwest Medical University, PR China
| | - Yan Zhang
- Luzhou Vocational and Technical College, PR China
| | - Sen Li
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, PR China
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Vidal L, Lopez-Garzon M, Venegas V, Vila I, Domínguez D, Rodas G, Marotta M. A Novel Tendon Injury Model, Induced by Collagenase Administration Combined with a Thermo-Responsive Hydrogel in Rats, Reproduces the Pathogenesis of Human Degenerative Tendinopathy. Int J Mol Sci 2024; 25:1868. [PMID: 38339145 PMCID: PMC10855568 DOI: 10.3390/ijms25031868] [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: 12/22/2023] [Revised: 01/25/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
Patellar tendinopathy is a common clinical problem, but its underlying pathophysiology remains poorly understood, primarily due to the absence of a representative experimental model. The most widely used method to generate such a model is collagenase injection, although this method possesses limitations. We developed an optimized rat model of patellar tendinopathy via the ultrasound-guided injection of collagenase mixed with a thermo-responsive Pluronic hydrogel into the patellar tendon of sixty male Wistar rats. All analyses were carried out at 3, 7, 14, 30, and 60 days post-injury. We confirmed that our rat model reproduced the pathophysiology observed in human patients through analyses of ultrasonography, histology, immunofluorescence, and biomechanical parameters. Tendons that were injured by the injection of the collagenase-Pluronic mixture exhibited a significant increase in the cross-sectional area (p < 0.01), a high degree of tissue disorganization and hypercellularity, significantly strong neovascularization (p < 0.01), important changes in the levels of types I and III collagen expression, and the organization and presence of intra-tendinous calcifications. Decreases in the maximum rupture force and stiffness were also observed. These results demonstrate that our model replicates the key features observed in human patellar tendinopathy. Collagenase is evenly distributed, as the Pluronic hydrogel prevents its leakage and thus, damage to surrounding tissues. Therefore, this model is valuable for testing new treatments for patellar tendinopathy.
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Affiliation(s)
- Laura Vidal
- Leitat Technological Center, Carrer de la Innovació 2, 08225 Terrassa, Spain
- Bioengineering, Cell Therapy and Surgery in Congenital Malformations Laboratory, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Maria Lopez-Garzon
- Leitat Technological Center, Carrer de la Innovació 2, 08225 Terrassa, Spain
- Bioengineering, Cell Therapy and Surgery in Congenital Malformations Laboratory, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Vanesa Venegas
- Leitat Technological Center, Carrer de la Innovació 2, 08225 Terrassa, Spain
- Bioengineering, Cell Therapy and Surgery in Congenital Malformations Laboratory, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Ingrid Vila
- Leitat Technological Center, Carrer de la Innovació 2, 08225 Terrassa, Spain
- Bioengineering, Cell Therapy and Surgery in Congenital Malformations Laboratory, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - David Domínguez
- Medical Department of Futbol Club Barcelona (FIFA Medical Center of Excellence) and Barça Innovation, 08970 Sant Joan Despí, Spain
| | - Gil Rodas
- Leitat Technological Center, Carrer de la Innovació 2, 08225 Terrassa, Spain
- Medical Department of Futbol Club Barcelona (FIFA Medical Center of Excellence) and Barça Innovation, 08970 Sant Joan Despí, Spain
- Sports Medicine Unit, Hospital Clínic and Sant Joan de Déu, 08950 Barcelona, Spain
- Faculty of Medicine and Health Sciences, University of Barcelona, 08007 Barcelona, Spain
| | - Mario Marotta
- Leitat Technological Center, Carrer de la Innovació 2, 08225 Terrassa, Spain
- Bioengineering, Cell Therapy and Surgery in Congenital Malformations Laboratory, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
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Xu B, Wang Y, He G, Tang KL, Guo L, Chen W. A novel and efficient murine model for investigating tendon-to-bone healing. J Orthop Surg Res 2024; 19:90. [PMID: 38273383 PMCID: PMC10809630 DOI: 10.1186/s13018-023-04496-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 12/19/2023] [Indexed: 01/27/2024] Open
Abstract
BACKGROUND Tendon-to-bone healing is a critical challenge in sports medicine, with its cellular and molecular mechanisms yet to be explored. An efficient murine model could significantly advance our understanding of this process. However, most existing murine animal models face limitations, including a propensity for bleeding, restricted operational space, and a steep learning curve. Thus, the need for a novel and efficient murine animal model to investigate the cellular and molecular mechanisms of tendon-to-bone healing is becoming increasingly evident. METHODS In our study, forty-four 9-week-old male C57/BL6 mice underwent transection and reattachment of the Achilles tendon insertion to investigate tendon-to-bone healing. At 2 and 4 weeks postoperatively, mice were killed for histological, Micro-CT, biomechanical, and real-time polymerase chain reaction tests. RESULTS Histological staining revealed that the original tissue structure was disrupted and replaced by a fibrovascular scar. Although glycosaminoglycan deposition was present in the cartilage area, the native structure had been destroyed. Biomechanical tests showed that the failure force constituted approximately 44.2% and 77.5% of that in intact tissues, and the ultimate tensile strength increased from 2 to 4 weeks postoperatively. Micro-CT imaging demonstrated a gradual healing process in the bone tunnel from 2 to 4 weeks postoperatively. The expression levels of ACAN, SOX9, Collagen I, and MMPs were detected, with all genes being overexpressed compared to the control group and maintaining high levels at 2 and 4 weeks postoperatively. CONCLUSIONS Our results demonstrate that the healing process in our model is aligned with the natural healing process, suggesting the potential for creating a new, efficient, and reproducible mouse animal model to investigate the cellular and molecular mechanisms of tendon-to-bone healing.
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Affiliation(s)
- Baoyun Xu
- Department of Orthopaedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Yunjiao Wang
- Department of Orthopaedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Gang He
- Department of Orthopaedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Kang-Lai Tang
- Department of Orthopaedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Shapingba District, Chongqing, 400038, People's Republic of China.
| | - Lin Guo
- Department of Orthopaedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Shapingba District, Chongqing, 400038, People's Republic of China.
| | - Wan Chen
- Department of Orthopaedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Shapingba District, Chongqing, 400038, People's Republic of China.
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Kwan KYC, Ng KWK, Rao Y, Zhu C, Qi S, Tuan RS, Ker DFE, Wang DM. Effect of Aging on Tendon Biology, Biomechanics and Implications for Treatment Approaches. Int J Mol Sci 2023; 24:15183. [PMID: 37894875 PMCID: PMC10607611 DOI: 10.3390/ijms242015183] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/07/2023] [Accepted: 09/20/2023] [Indexed: 10/29/2023] Open
Abstract
Tendon aging is associated with an increasing prevalence of tendon injuries and/or chronic tendon diseases, such as tendinopathy, which affects approximately 25% of the adult population. Aged tendons are often characterized by a reduction in the number and functionality of tendon stem/progenitor cells (TSPCs), fragmented or disorganized collagen bundles, and an increased deposition of glycosaminoglycans (GAGs), leading to pain, inflammation, and impaired mobility. Although the exact pathology is unknown, overuse and microtrauma from aging are thought to be major causative factors. Due to the hypovascular and hypocellular nature of the tendon microenvironment, healing of aged tendons and related injuries is difficult using current pain/inflammation and surgical management techniques. Therefore, there is a need for novel therapies, specifically cellular therapy such as cell rejuvenation, due to the decreased regenerative capacity during aging. To augment the therapeutic strategies for treating tendon-aging-associated diseases and injuries, a comprehensive understanding of tendon aging pathology is needed. This review summarizes age-related tendon changes, including cell behaviors, extracellular matrix (ECM) composition, biomechanical properties and healing capacity. Additionally, the impact of conventional treatments (diet, exercise, and surgery) is discussed, and recent advanced strategies (cell rejuvenation) are highlighted to address aged tendon healing. This review underscores the molecular and cellular linkages between aged tendon biomechanical properties and the healing response, and provides an overview of current and novel strategies for treating aged tendons. Understanding the underlying rationale for future basic and translational studies of tendon aging is crucial to the development of advanced therapeutics for tendon regeneration.
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Affiliation(s)
- Ka Yu Carissa Kwan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; (K.Y.C.K.); (K.W.K.N.); (Y.R.); (C.Z.); (R.S.T.); (D.F.E.K.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ka Wai Kerry Ng
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; (K.Y.C.K.); (K.W.K.N.); (Y.R.); (C.Z.); (R.S.T.); (D.F.E.K.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ying Rao
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; (K.Y.C.K.); (K.W.K.N.); (Y.R.); (C.Z.); (R.S.T.); (D.F.E.K.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Chenxian Zhu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; (K.Y.C.K.); (K.W.K.N.); (Y.R.); (C.Z.); (R.S.T.); (D.F.E.K.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Shengcai Qi
- Department of Prosthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200040, China;
| | - Rocky S. Tuan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; (K.Y.C.K.); (K.W.K.N.); (Y.R.); (C.Z.); (R.S.T.); (D.F.E.K.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, China
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Dai Fei Elmer Ker
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; (K.Y.C.K.); (K.W.K.N.); (Y.R.); (C.Z.); (R.S.T.); (D.F.E.K.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, China
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Ministry of Education Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Dan Michelle Wang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; (K.Y.C.K.); (K.W.K.N.); (Y.R.); (C.Z.); (R.S.T.); (D.F.E.K.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, China
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Ministry of Education Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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Data K, Kulus M, Ziemak H, Chwarzyński M, Piotrowska-Kempisty H, Bukowska D, Antosik P, Mozdziak P, Kempisty B. Decellularization of Dense Regular Connective Tissue-Cellular and Molecular Modification with Applications in Regenerative Medicine. Cells 2023; 12:2293. [PMID: 37759515 PMCID: PMC10528602 DOI: 10.3390/cells12182293] [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: 07/13/2023] [Revised: 08/31/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Healing of dense regular connective tissue, due to a high fiber-to-cell ratio and low metabolic activity and regeneration potential, frequently requires surgical implantation or reconstruction with high risk of reinjury. An alternative to synthetic implants is using bioscaffolds obtained through decellularization, a process where the aim is to extract cells from the tissue while preserving the tissue-specific native molecular structure of the ECM. Proteins, lipids, nucleic acids and other various extracellular molecules are largely involved in differentiation, proliferation, vascularization and collagen fibers deposit, making them the crucial processes in tissue regeneration. Because of the multiple possible forms of cell extraction, there is no standardized protocol in dense regular connective tissue (DRCT). Many modifications of the structure, shape and composition of the bioscaffold have also been described to improve the therapeutic result following the implantation of decellularized connective tissue. The available data provide a valuable source of crucial information. However, the wide spectrum of decellularization makes it important to understand the key aspects of bioscaffolds relative to their potential use in tissue regeneration.
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Affiliation(s)
- Krzysztof Data
- Division of Anatomy, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
| | - Magdalena Kulus
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Hanna Ziemak
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Mikołaj Chwarzyński
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Hanna Piotrowska-Kempisty
- Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Dorota Bukowska
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Paweł Antosik
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Paul Mozdziak
- Physiolgy Graduate Faculty, North Carolina State University, Raleigh, NC 27695, USA
- Prestage Department of Poultry Sciences, North Carolina State University, Raleigh, NC 27695, USA
| | - Bartosz Kempisty
- Division of Anatomy, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
- Physiolgy Graduate Faculty, North Carolina State University, Raleigh, NC 27695, USA
- Department of Obstetrics and Gynecology, University Hospital and Masaryk University, 601 77 Brno, Czech Republic
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Nguyen PK, Hart C, Hall K, Holt I, Kuo CK. Establishing in vivo and ex vivo chick embryo models to investigate fetal tendon healing. Sci Rep 2023; 13:9600. [PMID: 37311784 PMCID: PMC10264358 DOI: 10.1038/s41598-023-35408-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 05/17/2023] [Indexed: 06/15/2023] Open
Abstract
Injured adult tendons heal fibrotically and possess high re-injury rates, whereas fetal tendons appear to heal scarlessly. However, knowledge of fetal tendon wound healing is limited due in part to the need for an accessible animal model. Here, we developed and characterized an in vivo and ex vivo chick embryo tendon model to study fetal tendon healing. In both models, injury sites filled rapidly with cells and extracellular matrix during healing, with wound closure occurring faster in vivo. Tendons injured at an earlier embryonic stage improved mechanical properties to levels similar to non-injured controls, whereas tendons injured at a later embryonic stage did not. Expression levels of tendon phenotype markers, collagens, collagen crosslinking regulators, matrix metalloproteinases, and pro-inflammatory mediators exhibited embryonic stage-dependent trends during healing. Apoptosis occurred during healing, but ex vivo tendons exhibited higher levels of apoptosis than tendons in vivo. Future studies will use these in vivo and ex vivo chick embryo tendon injury models to elucidate mechanisms of stage-specific fetal tendon healing to inform the development of therapeutic approaches to regeneratively heal adult tendons.
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Affiliation(s)
- Phong K Nguyen
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Fischell Department of Bioengineering, University of Maryland, 4108 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
| | - Christoph Hart
- Fischell Department of Bioengineering, University of Maryland, 4108 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
| | - Kaitlyn Hall
- Fischell Department of Bioengineering, University of Maryland, 4108 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
| | - Iverson Holt
- Fischell Department of Bioengineering, University of Maryland, 4108 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
| | - Catherine K Kuo
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA.
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
- Fischell Department of Bioengineering, University of Maryland, 4108 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA.
- Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, USA.
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA.
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Ma Y, Lin Z, Chen X, Zhao X, Sun Y, Wang J, Mou X, Zou H, Chen J. Human hair follicle-derived mesenchymal stem cells promote tendon repair in a rabbit Achilles tendinopathy model. Chin Med J (Engl) 2023; 136:1089-1097. [PMID: 37052142 PMCID: PMC10228488 DOI: 10.1097/cm9.0000000000002542] [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: 10/19/2022] [Indexed: 04/14/2023] Open
Abstract
BACKGROUND Hair follicles are easily accessible and contain stem cells with different developmental origins, including mesenchymal stem cells (MSCs), that consequently reveal the potential of human hair follicle (hHF)-derived MSCs in repair and regeneration. However, the role of hHF-MSCs in Achilles tendinopathy (AT) remains unclear. The present study investigated the effects of hHF-MSCs on Achilles tendon repair in rabbits. METHODS First, we extracted and characterized hHF-MSCs. Then, a rabbit tendinopathy model was constructed to analyze the ability of hHF-MSCs to promote repair in vivo . Anatomical observation and pathological and biomechanical analyses were performed to determine the effect of hHF-MSCs on AT, and quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical staining were performed to explore the molecular mechanisms through which hHF-MSCs affects AT. Furthermore, statistical analyses were performed using independent sample t test, one-way analysis of variance (ANOVA), and one-way repeated measures multivariate ANOVA as appropriate. RESULTS Flow cytometry, a trilineage-induced differentiation test, confirmed that hHF-derived stem cells were derived from MSCs. The effect of hHF-MSCs on AT revealed that the Achilles tendon was anatomically healthy, as well as the maximum load carried by the Achilles tendon and hydroxyproline proteomic levels were increased. Moreover, collagen I and III were upregulated in rabbit AT treated with hHF-MSCs (compared with AT group; P < 0.05). Analysis of the molecular mechanisms revealed that hHF-MSCs promoted collagen fiber regeneration, possibly through Tenascin-C (TNC) upregulation and matrix metalloproteinase (MMP)-9 downregulation. CONCLUSIONS hHF-MSCs can be a treatment modality to promote AT repair in rabbits by upregulating collagen I and III. Further analysis revealed that treatment of AT using hHF-MSCs promoted the regeneration of collagen fiber, possibly because of upregulation of TNC and downregulation of MMP-9, thus suggesting that hHF-MSCs are more promising for AT.
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Affiliation(s)
- Yingyu Ma
- Plastic and Reconstructive Surgery Center, Department of Plastic and Reconstructive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
- Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Zhiwei Lin
- Zhejiang Healthfuture Biomedicine Co., Ltd, Hangzhou, Zhejiang 310052, China
| | - Xiaoyi Chen
- Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Xin Zhao
- Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Yi Sun
- Plastic and Reconstructive Surgery Center, Department of Plastic and Reconstructive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Ji Wang
- Plastic and Reconstructive Surgery Center, Department of Plastic and Reconstructive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Xiaozhou Mou
- Plastic and Reconstructive Surgery Center, Department of Plastic and Reconstructive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
- Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Hai Zou
- Department of Critical Care, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Jinyang Chen
- Zhejiang Healthfuture Biomedicine Co., Ltd, Hangzhou, Zhejiang 310052, China
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10
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Mavrogenis AF, Karampikas V, Zikopoulos A, Sioutis S, Mastrokalos D, Koulalis D, Scarlat MM, Hernigou P. Orthobiologics: a review. INTERNATIONAL ORTHOPAEDICS 2023:10.1007/s00264-023-05803-z. [PMID: 37071148 DOI: 10.1007/s00264-023-05803-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 03/30/2023] [Indexed: 04/19/2023]
Abstract
PURPOSE The use of biologic materials in orthopaedics (orthobiologics) has gained significant attention over the past years. To enhance the body of the related literature, this review article is aimed at summarizing these novel biologic therapies in orthopaedics and at discussing their multiple clinical implementations and outcomes. METHODS This review of the literature presents the methods, clinical applications, impact, cost-effectiveness, and outcomes, as well as the current indications and future perspectives of orthobiologics, namely, platelet-rich plasma, mesenchymal stem cells, bone marrow aspirate concentrate, growth factors, and tissue engineering. RESULTS Currently available studies have used variable methods of research including biologic materials as well as patient populations and outcome measurements, therefore making comparison of studies difficult. Key features for the study and use of orthobiologics include minimal invasiveness, great healing potential, and reasonable cost as a nonoperative treatment option. Their clinical applications have been described for common orthopaedic pathologies such as osteoarthritis, articular cartilage defects, bone defects and fracture nonunions, ligament injuries, and tendinopathies. CONCLUSIONS Orthobiologics-based therapies have shown noticeable clinical results at the short- and mid-term. It is crucial that these therapies remain effective and stable in the long term. The optimal design for a successful scaffold remains to be further determined.
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Affiliation(s)
- Andreas F Mavrogenis
- First Department of OrthopaedicsNational and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
| | - Vasileios Karampikas
- First Department of OrthopaedicsNational and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Alexandros Zikopoulos
- First Department of OrthopaedicsNational and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Spyridon Sioutis
- First Department of OrthopaedicsNational and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Dimitrios Mastrokalos
- First Department of OrthopaedicsNational and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Dimitrios Koulalis
- First Department of OrthopaedicsNational and Kapodistrian University of Athens, School of Medicine, Athens, Greece
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11
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Gains CC, Giannapoulos A, Zamboulis DE, Lopez-Tremoleda J, Screen HRC. Development and application of a novel in vivo overload model of the Achilles tendon in rat. J Biomech 2023; 151:111546. [PMID: 36958089 DOI: 10.1016/j.jbiomech.2023.111546] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 03/03/2023] [Accepted: 03/09/2023] [Indexed: 03/17/2023]
Abstract
Repetitive overload is a primary factor in tendon injury, causing progressive accumulation of matrix damage concurrent with a cellular response. However, it remains unclear how these events occur at the initial stages of the disease, making it difficult to identify appropriate treatment approaches. Here, we describe the development of a new model to cyclically load the Achilles tendon (AT) of rats in vivo and investigate the initial structural and cellular responses. The model utilizes controlled dorsiflexion of the ankle joint applied near maximal dorsiflexion, for 10,000 cycles at 3 Hz. Animals were subjected to a single bout of in vivo loading under anaesthesia, and either culled immediately (without recovery from anaesthesia), or 48 h or 4-weeks post-loading. Macro strains were assessed in cadavers, whilst tendon specific microdamage was assessed through collagen-hybridizing peptide (CHP) immunohistochemistry which highlighted a significant rise in CHP staining in loaded ATs compared to contralateral controls, indicating an accumulation of overload-induced damage. Staining for pro-inflammatory mediators (IL-6 and COX-2) and matrix degradation markers (MMP-3 and -13) also suggests an initial cellular response to overload. Model validation confirmed our approach was able to explore early overload-induced damage within the AT, with microdamage present and no evidence of broader musculoskeletal damage. The new model may be implemented to map the progression of tendinopathy in the AT, and thus study potential therapeutic interventions.
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Affiliation(s)
- Connor Charles Gains
- School of Engineering and Materials Science (SEMS), Queen Mary University of London, Mile End Road, London E1 4NS, United Kingdom.
| | - Antonios Giannapoulos
- School of Engineering and Materials Science (SEMS), Queen Mary University of London, Mile End Road, London E1 4NS, United Kingdom
| | - Danae Emilie Zamboulis
- School of Engineering and Materials Science (SEMS), Queen Mary University of London, Mile End Road, London E1 4NS, United Kingdom
| | - Jordi Lopez-Tremoleda
- Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, Mile End Road, London E1 4NS, United Kingdom
| | - Hazel R C Screen
- School of Engineering and Materials Science (SEMS), Queen Mary University of London, Mile End Road, London E1 4NS, United Kingdom
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12
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Biological and Mechanical Factors and Epigenetic Regulation Involved in Tendon Healing. Stem Cells Int 2023; 2023:4387630. [PMID: 36655033 PMCID: PMC9842431 DOI: 10.1155/2023/4387630] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/18/2022] [Accepted: 12/28/2022] [Indexed: 01/11/2023] Open
Abstract
Tendons are an important part of the musculoskeletal system. Connecting muscles to bones, tendons convert force into movement. Tendon injury can be acute or chronic. Noticeably, tendon healing requires a long time span and includes inflammation, proliferation, and remodeling processes. The mismatch between endogenous and exogenous healing may lead to adhesion causing further negative effects. Management of tendon injuries and complications such as subsequent adhesion formation are still challenges for clinicians. Due to numerous factors, tendon healing is a complex process. This review introduces the role of various biological and mechanical factors and epigenetic regulation processes involved in tendon healing.
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13
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Xu X, Zhang Y, Ha P, Chen Y, Li C, Yen E, Bai Y, Chen R, Wu BM, Da Lio A, Ting K, Soo C, Zheng Z. A novel injectable fibromodulin-releasing granular hydrogel for tendon healing and functional recovery. Bioeng Transl Med 2023; 8:e10355. [PMID: 36684085 PMCID: PMC9842059 DOI: 10.1002/btm2.10355] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 05/06/2022] [Accepted: 05/07/2022] [Indexed: 01/25/2023] Open
Abstract
A crucial component of the musculoskeletal system, the tendon is one of the most commonly injured tissues in the body. In severe cases, the ruptured tendon leads to permanent dysfunction. Although many efforts have been devoted to seeking a safe and efficient treatment for enhancing tendon healing, currently existing treatments have not yet achieved a major clinical improvement. Here, an injectable granular hyaluronic acid (gHA)-hydrogel is engineered to deliver fibromodulin (FMOD)-a bioactive extracellular matrix (ECM) that enhances tenocyte mobility and optimizes the surrounding ECM assembly for tendon healing. The FMOD-releasing granular HA (FMOD/gHA)-hydrogel exhibits unique characteristics that are desired for both patients and health providers, such as permitting a microinvasive application and displaying a burst-to-sustained two-phase release of FMOD, which leads to a prompt FMOD delivery followed by a constant dose-maintaining period. Importantly, the generated FMOD-releasing granular HA hydrogel significantly augmented tendon-healing in a fully-ruptured rat's Achilles tendon model histologically, mechanically, and functionally. Particularly, the breaking strength of the wounded tendon and the gait performance of treated rats returns to the same normal level as the healthy controls. In summary, a novel effective FMOD/gHA-hydrogel is developed in response to the urgent demand for promoting tendon healing.
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Affiliation(s)
- Xue Xu
- Department of Oral and Maxillofacial Plastic and Traumatic SurgeryBeijing Stomatological Hospital of Capital Medical UniversityBeijingChina
- Division of Plastic and Reconstructive SurgeryDavid Geffen School of Medicine, University of CaliforniaLos AngelesCaliforniaUSA
- Division of Growth and DevelopmentSchool of Dentistry, University of CaliforniaLos AngelesCaliforniaUSA
| | - Yulong Zhang
- School of DentistryUniversity of CaliforniaLos AngelesCaliforniaUSA
| | - Pin Ha
- Division of Plastic and Reconstructive SurgeryDavid Geffen School of Medicine, University of CaliforniaLos AngelesCaliforniaUSA
- Division of Growth and DevelopmentSchool of Dentistry, University of CaliforniaLos AngelesCaliforniaUSA
| | - Yao Chen
- School of DentistryUniversity of CaliforniaLos AngelesCaliforniaUSA
| | - Chenshuang Li
- Department of OrthodonticsSchool of Dental Medicine, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Emily Yen
- Arcadia High SchoolArcadiaCaliforniaUSA
| | - Yuxing Bai
- Department of OrthodonticsBeijing Stomatological Hospital of Capital Medical UniversityBeijingChina
| | - Renji Chen
- Department of Oral and Maxillofacial Plastic and Traumatic SurgeryBeijing Stomatological Hospital of Capital Medical UniversityBeijingChina
| | - Benjamin M. Wu
- School of DentistryUniversity of CaliforniaLos AngelesCaliforniaUSA
| | - Andrew Da Lio
- Division of Plastic and Reconstructive SurgeryDavid Geffen School of Medicine, University of CaliforniaLos AngelesCaliforniaUSA
| | - Kang Ting
- Forsyth Research InstituteHarvard UniversityCambridgeMassachusettsUSA
- Samueli School of EngineeringUniversity of CaliforniaLos AngelesCaliforniaUSA
| | - Chia Soo
- Division of Plastic and Reconstructive Surgery, Department of Orthopaedic SurgeryThe Orthopaedic Hospital Research Center, University of CaliforniaLos AngelesCaliforniaUSA
| | - Zhong Zheng
- Division of Plastic and Reconstructive SurgeryDavid Geffen School of Medicine, University of CaliforniaLos AngelesCaliforniaUSA
- Division of Growth and DevelopmentSchool of Dentistry, University of CaliforniaLos AngelesCaliforniaUSA
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Koch DW, Schnabel LV, Ellis IM, Bates RE, Berglund AK. TGF-β2 enhances expression of equine bone marrow-derived mesenchymal stem cell paracrine factors with known associations to tendon healing. Stem Cell Res Ther 2022; 13:477. [PMID: 36114555 PMCID: PMC9482193 DOI: 10.1186/s13287-022-03172-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 09/07/2022] [Indexed: 12/01/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) secrete paracrine factors and extracellular matrix proteins that contribute to their ability to support tissue healing and regeneration. Both the transcriptome and the secretome of MSCs can be altered by treating the cells with cytokines, but neither have been thoroughly investigated following treatment with the specific cytokine transforming growth factor (TGF)-β2. Methods RNA-sequencing and western blotting were used to compare gene and protein expression between untreated and TGF-β2-treated equine bone marrow-derived MSCs (BM-MSCs). A co-culture system was utilized to compare equine tenocyte migration during co-culture with untreated and TGF-β2-treated BM-MSCs. Results TGF-β2 treatment significantly upregulated gene expression of collagens, extracellular matrix molecules, and growth factors. Protein expression of collagen type I and tenascin-C was also confirmed to be upregulated in TGF-β2-treated BM-MSCs compared to untreated BM-MSCs. Both untreated and TGF-β2-treated BM-MSCs increased tenocyte migration in vitro. Conclusions Treating equine BM-MSCs with TGF-β2 significantly increases production of paracrine factors and extracellular matrix molecules important for tendon healing and promotes the migration of tenocytes in vitro. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03172-9.
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15
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Zakirova E, Aimaletdinov A, Mansurova M, Titova A, Kurilov I, Rutland CS, Malanyeva A, Rizvanov A. Artificial Microvesicles: New Perspective on Healing Tendon Wounds. Cells Tissues Organs 2022; 213:24-39. [PMID: 36049461 DOI: 10.1159/000526845] [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: 06/01/2022] [Accepted: 08/15/2022] [Indexed: 11/19/2022] Open
Abstract
Tendons have a limited capacity to repair both naturally and following clinical interventions. Damaged tissue often presents with structural and functional differences, adversely affecting animal performance, mobility, health, and welfare. Advances in cell therapies have started to overcome some of these issues, however complications such as the formation of ectopic bone remain a complication of this technique. Regenerative medicine is therefore looking toward future therapies such as the introduction of microvesicles (MVs) derived from stem cells (SCs). The aim of the present study was to assess the characteristics of artificially derived MVs, from equine mesenchymal stem cells (MSCs), when delivered to rat tendon cells in vitro and damaged tendons in vivo. The initial stages of extracting MVs from equine MSCs and identifying and characterizing the cultured tendon stem/progenitor cells (TSCs) from rat Achilles tendons were undertaken successfully. The horse MSCs and the rat tendon cells were both capable of differentiating in 3 directions: adipogenic, osteogenic, and chondrogenic pathways. The artificially derived equine MVs successfully fused with the TSC membranes, and no cytotoxic or cytostimulating effects were observed. In addition, co-cultivation of TSCs with MVs led to stimulation of cell proliferation and migration, and cytokine VEGF and fractalkine expression levels were significantly increased. These experiments are the first to show that artificially derived MVs exhibited regeneration-stimulating effects in vitro, and that fusion of cytoplasmic membranes from diploid cell lines originating from different species was possible. The experiment in vivo demonstrated the influence of MVs on synthesis of collagen I and III types in damaged tendons of rats. Explorations in vivo showed accelerated regeneration of injured tendons after introduction of the MVs into damaged areas. The results from the studies performed indicated obvious positive modifying effects following the administration of MVs. This represents the initial successful step required prior to translating this regenerative medicine technique into clinical trials, such as for tendon repair in injured horses.
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Affiliation(s)
- Elena Zakirova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation
| | - Alexander Aimaletdinov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation
| | - Milana Mansurova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation
| | - Angelina Titova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation
| | - Igor Kurilov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation
| | - Catrin Sian Rutland
- Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, University of Nottingham, Nottingham, UK
| | - Albina Malanyeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation,
| | - Albert Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation
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16
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Gundogdu K, Yilmaz Tasci S, Gundogdu G, Terim Kapakin KA, Totik Y, Demirkaya Miloglu F. Evaluation of cytokines in protective effect of docosahexaenoic acid in experimental achilles tendinopathy rat model induced with type-1 collagenase. Connect Tissue Res 2022; 63:393-405. [PMID: 34612118 DOI: 10.1080/03008207.2021.1982915] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND We aimed to investigate the effectiveness of docosahexaenoic acid (DHA) as a treatment for Achilles tendinopathy (AT) induced with type-I collagenase in rats and compare it with collagen. METHODS The AT model was induced with type I collagenase, and animals were randomly assigned to groups. Group 1:AT, Group 2: Collagen (7.2 mg/kg/day), Group 3:DHA (300 mg/kg/day), and Group 4:DHA (100 mg/kg/day). Right tendons of Group1 were used as a healthy control (HC). Oral treatments were applied for eight weeks. Serum tumor necrosis factor-alpha(TNF-α), matrix metalloproteinase-13 (MMP-13), and interleukin-1 beta(IL-1β) concentrations were determined by ELISA. Tendon samples were taken for histopathological evaluation and examined immunohistochemically with antibodies specific for Col1A1, TNF-α, MMP-13, IL-1β, and nitric oxide synthase-2(NOS-2). The ultimate tensile force (UTF) yield force(YF) and stiffness were measured by biomechanical assessments. RESULTS UTF,YF and stiffness values were increased in all treatment groups compared to the AT control, a significant increase was found in Group 2 (p < 0.05). There was severe degeneration of tendon cells in the AT control. The tendon cells in samples from Groups 2-3 were less degraded, and this was statistically significant (p < 0.05). TNF-α, MMP-13, IL-1β, and NOS-2 expressions were significantly higher in the AT control compared to the HC. In all treatment groups, their concentrations were lower than in the AT control. Serum TNF-α, MMP-13, and IL-1β levels were lower in all treatment groups (Especially in Group3 (p < 0.001)) compared to Group1. CONCLUSION The efficacy of high-dose DHA as a treatment for AT was investigated from biochemical, histopathological, and biomechanical perspectives. The results showed that DHA could be an alternative treatment compound to collagen.
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Affiliation(s)
- Koksal Gundogdu
- Department of Orthopedics and Traumatology, Denizli State Hospital, Denizli, Turkey
| | | | - Gulsah Gundogdu
- Department of Physiology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Kubra Asena Terim Kapakin
- Department of Veterinary Pathology, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey
| | - Yasar Totik
- Department of Machine Engineering, Faculty of Engineering, Ataturk University, Erzurum, Turkey
| | - Fatma Demirkaya Miloglu
- Department of Analytical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey
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Enthesis Healing Is Dependent on Scaffold Interphase Morphology—Results from a Rodent Patellar Model. Cells 2022; 11:cells11111752. [PMID: 35681447 PMCID: PMC9179925 DOI: 10.3390/cells11111752] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/19/2022] [Accepted: 05/23/2022] [Indexed: 01/27/2023] Open
Abstract
The use of multiphasic scaffolds to treat injured tendon-to-bone entheses has shown promising results in vitro. Here, we used two versions of a biphasic silk fibroin scaffold to treat an enthesis defect created in a rat patellar model in vivo. One version presented a mixed transition between the bony and the tendon end of the construct (S-MT) while this transition was abrupt in the second version (S-AT). At 12 weeks after surgery, the S-MT scaffold promoted better healing of the injured enthesis, with minimal undesired ossification of the insertion area. The expression of tenogenic and chondrogenic markers was sustained for longer in the S-MT-treated group and the tangent modulus of the S-MT-treated samples was similar to the native tissue at 12 weeks while that of the S-AT-treated enthesis was lower. Our study highlights the important role of the transition zone of multiphasic scaffolds in the treatment of complex interphase tissues such as the tendon-to-bone enthesis.
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18
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Cetik RM, Yabanoglu Ciftci S, Arica B, Baysal I, Akarca Dizakar SO, Erbay Elibol FK, Gencer A, Demir T, Ayvaz M. Evaluation of the Effects of Transforming Growth Factor-Beta 3 (TGF-β3) Loaded Nanoparticles on Healing in a Rat Achilles Tendon Injury Model. Am J Sports Med 2022; 50:1066-1077. [PMID: 35188807 DOI: 10.1177/03635465211073148] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Achilles tendon (AT) midsubstance injuries may heal suboptimally, especially in athletes. Transforming growth factor-beta 3 (TGF-β3) shows promise because of its recently discovered tendinogenic effects. Using poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles (NPs) may enhance the results by a sustained-release effect. HYPOTHESIS The application of TGF-β3 will enhance AT midsubstance healing, and the NP form will achieve better outcomes. STUDY DESIGN Controlled laboratory study. METHODS A total of 80 rats underwent unilateral AT transection and were divided into 4 groups: (1) control (C); (2) empty chitosan film (Ch); (3) chitosan film containing free TGF-β3 (ChT); and (4) chitosan film containing TGF-β3-loaded NPs (ChN). The animals were sacrificed at 3 and 6 weeks. Tendons were evaluated for morphology (length and cross-sectional area [CSA]), biomechanics (maximum load, stress, stiffness, and elastic modulus), histology, immunohistochemical quantification (types I and III collagen [COL1 and COL3]), and gene expression (COL1A1, COL3A1, scleraxis, and tenomodulin). RESULTS Morphologically, at 3 weeks, ChT (15 ± 2.7 mm) and ChN (15.6 ± 1.6 mm) were shorter than C (17.6 ± 1.8 mm) (P = .019 and = .004, respectively). At 6 weeks, the mean CSA of ChN (10.4 ± 1.9 mm2) was similar to that of intact tendons (6.4 ± 1.1 mm2) (P = .230), while the other groups were larger. Biomechanically, at 3 weeks, ChT (42.8 ± 4.9 N) had a higher maximum load than C (27 ± 9.1 N; P = .004) and Ch (29.2 ± 5.7 N; P = .005). At 6 weeks, ChN (26.9 ± 3.9 MPa) had similar maximum stress when compared with intact tendons (34.1 ± 7.8 MPa) (P = .121); the other groups were significantly lower. Histologically, at 6 weeks, the mean Movin score of ChN (4.5 ± 1.5) was lower than that of ChT (6.3 ± 1.8). Immunohistochemically, ChN had higher COL3 (1.469 ± 0.514) at 3 weeks and lower COL1 (1.129 ± 0.368) at 6 weeks. COL1A1 gene expression was higher in ChT and ChN at 3 weeks, but COL3A1 gene expression was higher in ChN. CONCLUSION The application of TGF-β3 had a positive effect on AT midsubstance healing, and the sustained-release NP form improved the outcomes, more specifically accelerating the remodeling process. CLINICAL RELEVANCE This study demonstrated the effectiveness of TGF-β3 on tendon healing on a rat model, which is an important step toward clinical use. The novel method of using PLGA-b-PEG NPs as a drug-delivery system with sustained-release properties had promising results.
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Affiliation(s)
- Riza Mert Cetik
- Hacettepe University Faculty of Medicine, Department of Orthopedics and Traumatology, Ankara, Turkey
| | | | - Betul Arica
- Hacettepe University Faculty of Pharmacy, Department of Pharmaceutical Technology, Ankara, Turkey
| | - Ipek Baysal
- Hacettepe University Vocational School of Health Services, Ankara, Turkey
| | | | - Fatma Kubra Erbay Elibol
- TOBB ETÜ University of Economics and Technology, Department of Biomedical Engineering, Ankara, Turkey
| | - Ayse Gencer
- Hacettepe University Faculty of Pharmacy, Department of Pharmaceutical Technology, Ankara, Turkey
| | - Teyfik Demir
- TOBB ETÜ University of Economics and Technology, Department of Mechanical Engineering, Ankara, Turkey
| | - Mehmet Ayvaz
- Hacettepe University Faculty of Medicine, Department of Orthopedics and Traumatology, Ankara, Turkey
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19
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Investigating the histological and structural properties of tendon gel as an artificial biomaterial using the film model method in rabbits. J Exp Orthop 2022; 9:1. [PMID: 34978637 PMCID: PMC8724385 DOI: 10.1186/s40634-021-00434-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 11/23/2021] [Indexed: 11/10/2022] Open
Abstract
Purpose This study aimed to evaluate the properties of tendon gel by investigating the histological and structural differences among tendon gels under different preservation periods using a rabbit model. Methods Forty mature female rabbits were divided into four groups, each containing ten rabbits, on the basis of in-vivo preservation periods of tendon gels (3, 5, 10, and 15 days). We created the Achilles tendon rupture models using the film model method to obtain tendon gels. Tensile stress was applied to the tendon gel to promote maturation. Histological and structural evaluations of the tendon gel were performed before and after applying the tensile force, and the results obtained from the four groups were compared. Results Although the day-3 and day-5 tendon gels before applying tensile stress were histologically more immature than the day-10 and day-15 gels, type I collagen fibers equivalent to those of normal tendons were observed in all groups after the tensile process. Based on the surface and molecular structural evaluations, the day-3 tendon gels after the tensile process were molecularly cross-linked, and thick collagen fibers similar to those present in normal tendons were observed. Structural maturation observed in the day-3 tendon gels caused by traction was hardly observed in the day-5, -10, and -15 tendon gels. Conclusions The day-3 tendon gel had the highest regenerative potential to become a normal tendon by applying a traction force. Supplementary Information The online version contains supplementary material available at 10.1186/s40634-021-00434-y.
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Jiang K, Li Y, Xiang C, Xiong Y, Jia J. TGF-β3 regulates adhesion formation through the JNK/c-Jun pathway during flexor tendon healing. BMC Musculoskelet Disord 2021; 22:843. [PMID: 34592976 PMCID: PMC8485513 DOI: 10.1186/s12891-021-04691-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 09/03/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The injured flexor tendon has poor healing ability, which is easy to cause tendon adhesion. It can affect the recovery of tendon function, which is still a long-term and difficult task for surgeons. Transforming growth factor β (TGF-β) has been widely considered to play an important role in flexor tendon repair in recent years. AIM This work was to investigate the anti-adhesion and anti-inflammatory effects of TGF-β3 on flexor digitorum longus (FDL) tendon repair rats. METHOD Anastomosis models of tendon laceration in the flexion toes of rats were delivered with no treatment, vehicle, or TGF-β3 -overexpressed adenovirus vector (ad-TGF-β3) locally to the injured tendon area from day 3 to 8. Subsequently, the expression of TGF-β3, TGF-β1/2, Smad3, Smad7, JNK, phosphorylation (p)-JNK, c-Jun, and phosphorylation (p)-c-Jun were detected by western blot, the expression of Mmp9 and Mmp2 by RT-qPCR, the Range of motion (ROM) and gliding resistance by adhesion formation testing, the mechanical strength of tendon healing by biomechanical testing, the pathologic changes of flexor tendon tissues by HE staining, the expression of collagen type III by immunohistochemical staining, and the levels of IL-6, TNF-α, COX2 and IL-1β in serum by ELISA, respectively. RESULTS Rat models treated with no treatment showed a lower elevation of TGF-β3 and Smad7 expression, and a higher elevation of TGF-β1/2 and Smad3 expression, during day 14 to day 28. Besides, under the treatment of ad-TGF-β3, a significantly increase was reflected in the expression of TGF-β3 and Smad7, ROM, as well as mechanical strength of flexor tendon, whereas significantly reduction was shown in gliding resistance, the content of inflammatory cytokines, the ratio of p-JNK/JNK, p-c-Jun/c-Jun, as well as the expression of TGF-β1/2, Smad3, Mmp9, and Mmp2 genes, as compared to those from vehicle treatment. Meanwhile, TGF-β3 demonstrated a better pathologic recovery process with no obvious necrosis or fracture of collagen fibers. Besides, TGF-β3 revealed a significant reduction of collagen type-III expression in the flexor tendon healing tissues. CONCLUSION These findings suggested that TGF-β3 effectively protected against flexor tendon injury via regulating adhesion formation.
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Affiliation(s)
- Ke Jiang
- Department of Orthopaedics, Affilliated Hospital of North Sichuan Medical College, 63 Wenhua Road, Nanchong, Sichuan, 637000, People's Republic of China
- Key Laboratory of Emergency and Trauma, Ministry of Education, College of Emergency and Trauma, Hainan Medical University, Haikou, 571199, People's Republic of China
| | - Yuling Li
- Department of Orthopaedics, Affilliated Hospital of North Sichuan Medical College, 63 Wenhua Road, Nanchong, Sichuan, 637000, People's Republic of China.
| | - Chao Xiang
- Department of Orthopaedics, Affilliated Hospital of North Sichuan Medical College, 63 Wenhua Road, Nanchong, Sichuan, 637000, People's Republic of China
| | - Yan Xiong
- Department of Orthopaedics, Daping Hospital, Army Medical University, Chongqing, 400042, People's Republic of China
| | - Jiameng Jia
- Department of Rehabilitation, Affilliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000, People's Republic of China
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Lu V, Tennyson M, Zhang J, Khan W. Mesenchymal Stem Cell-Derived Extracellular Vesicles in Tendon and Ligament Repair-A Systematic Review of In Vivo Studies. Cells 2021; 10:cells10102553. [PMID: 34685532 PMCID: PMC8533909 DOI: 10.3390/cells10102553] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/18/2021] [Accepted: 09/22/2021] [Indexed: 12/23/2022] Open
Abstract
Tendon and ligament injury poses an increasingly large burden to society. This systematic review explores whether mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) can facilitate tendon/ligament repair in vivo. On 26 May 2021, a systematic search was performed on PubMed, Web of Science, Cochrane Library, Embase, to identify all studies that utilised MSC-EVs for tendon/ligament healing. Studies administering EVs isolated from human or animal-derived MSCs into in vivo models of tendon/ligament injury were included. In vitro, ex vivo, and in silico studies were excluded, and studies without a control group were excluded. Out of 383 studies identified, 11 met the inclusion criteria. Data on isolation, the characterisation of MSCs and EVs, and the in vivo findings in in vivo models were extracted. All included studies reported better tendon/ligament repair following MSC-EV treatment, but not all found improvements in every parameter measured. Biomechanics, an important index for tendon/ligament repair, was reported by only eight studies, from which evidence linking biomechanical alterations to functional improvement was weak. Nevertheless, the studies in this review showcased the safety and efficacy of MSC-EV therapy for tendon/ligament healing, by attenuating the initial inflammatory response and accelerating tendon matrix regeneration, providing a basis for potential clinical use in tendon/ligament repair.
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Affiliation(s)
- Victor Lu
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK; (V.L.); (J.Z.)
| | - Maria Tennyson
- Department of Trauma and Orthopaedic Surgery, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, UK;
| | - James Zhang
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK; (V.L.); (J.Z.)
| | - Wasim Khan
- Department of Trauma and Orthopaedic Surgery, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, UK;
- Correspondence: ; Tel.: +44-(0)-7791-025554
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22
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Alt E, Rothoerl R, Hoppert M, Frank HG, Wuerfel T, Alt C, Schmitz C. First immunohistochemical evidence of human tendon repair following stem cell injection: A case report and review of literature. World J Stem Cells 2021; 13:944-970. [PMID: 34367486 PMCID: PMC8316863 DOI: 10.4252/wjsc.v13.i7.944] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/29/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Current clinical treatment options for symptomatic, partial-thickness rotator cuff tear (sPTRCT) offer only limited potential for true tissue healing and improvement of clinical results. In animal models, injections of adult stem cells isolated from adipose tissue into tendon injuries evidenced histological regeneration of tendon tissue. However, it is unclear whether such beneficial effects could also be observed in a human tendon treated with fresh, uncultured, autologous, adipose derived regenerative cells (UA-ADRCs). A specific challenge in this regard is that UA-ADRCs cannot be labeled and, thus, not unequivocally identified in the host tissue. Therefore, histological regeneration of injured human tendons after injection of UA-ADRCs must be assessed using comprehensive, immunohistochemical and microscopic analysis of biopsies taken from the treated tendon a few weeks after injection of UA-ADRCs.
CASE SUMMARY A 66-year-old patient suffered from sPTRCT affecting the right supraspinatus and infraspinatus tendon, caused by a bicycle accident. On day 18 post injury [day 16 post magnetic resonance imaging (MRI) examination] approximately 100 g of abdominal adipose tissue was harvested by liposuction, from which approximately 75 × 106 UA-ADRCs were isolated within 2 h. Then, UA-ADRCs were injected (controlled by biplanar X-ray imaging) adjacent to the injured supraspinatus tendon immediately after isolation. Despite fast clinical recovery, a follow-up MRI examination 2.5 mo post treatment indicated the need for open revision of the injured infraspinatus tendon, which had not been treated with UA-ADRCs. During this operation, a biopsy was taken from the supraspinatus tendon at the position of the injury. A comprehensive, immunohistochemical and microscopic analysis of the biopsy (comprising 13 antibodies) was indicative of newly formed tendon tissue.
CONCLUSION Injection of UA-ADRCs can result in regeneration of injured human tendons by formation of new tendon tissue.
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Affiliation(s)
- Eckhard Alt
- Chairman of the Board, Isarklinikum Munich, Munich 80331, Germany
| | - Ralf Rothoerl
- Department of Spine Surgery, Isarklinikum Munich, Munich 80331, Germany
| | - Matthias Hoppert
- Department for Orthopedics and Trauma Surgery, Isarklinikum Munich, Munich 80331, Germany
| | - Hans-Georg Frank
- Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich 80336, Germany
| | - Tobias Wuerfel
- Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich 80336, Germany
| | - Christopher Alt
- Director of Science and Research, InGeneron GmbH, Munich 80331, Germany
| | - Christoph Schmitz
- Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich 80336, Germany
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Yang Y, Wu Y, Zhou K, Wu D, Yao X, Heng BC, Zhou J, Liu H, Ouyang H. Interplay of Forces and the Immune Response for Functional Tendon Regeneration. Front Cell Dev Biol 2021; 9:657621. [PMID: 34150755 PMCID: PMC8213345 DOI: 10.3389/fcell.2021.657621] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 04/26/2021] [Indexed: 01/11/2023] Open
Abstract
Tendon injury commonly occurs during sports activity, which may cause interruption or rapid decline in athletic career. Tensile strength, as one aspect of tendon biomechanical properties, is the main parameter of tendon function. Tendon injury will induce an immune response and cause the loss of tensile strength. Regulation of mechanical forces during tendon healing also changes immune response to improve regeneration. Here, the effects of internal/external forces and immune response on tendon regeneration are reviewed. The interaction between immune response and internal/external forces during tendon regeneration is critically examined and compared, in relation to other tissues. In conclusion, it is essential to maintain a fine balance between internal/external forces and immune response, to optimize tendon functional regeneration.
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Affiliation(s)
- Yuwei Yang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Yicong Wu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Ke Zhou
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Dongmei Wu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Xudong Yao
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Boon Chin Heng
- Central Laboratories, School of Stomatology, Peking University, Beijing, China
| | - Jing Zhou
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Hua Liu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Hongwei Ouyang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China
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Iwanaga Y, Morizaki Y, Uehara K, Tanaka S, Sakai T, Saito T. Robust Suture Combination for Rat Flexor Tendon Repair Model. JOURNAL OF HAND SURGERY GLOBAL ONLINE 2020; 2:354-358. [PMID: 35415525 PMCID: PMC8991537 DOI: 10.1016/j.jhsg.2020.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 08/05/2020] [Indexed: 11/16/2022] Open
Abstract
Purpose We aimed to develop a rat flexor tendon repair model that could be applied to experiments in similar clinical settings. Methods We prepared 3 different combinations of sutures in rat flexor tendons: group A had 3 single peripheral sutures plus a 2-strand core suture; group B had 3 figure-of-eight peripheral sutures alone; and group C had 3 figure-of-eight peripheral sutures plus a 2-strand core suture. We examined the in vitro tensile strength of the repaired tendons by a biomechanical test, the rerupture rate within 3 weeks, and histological findings in vivo. Results Group C displayed the greatest ultimate strength by the mechanical test. The flexor tendons in group C did not rerupture within 3 weeks after surgery, whereas many of those in groups A and B reruptured. Fibrous scar tissue was observed in the gap of the tendon stumps in groups A and B, but not in group C. Conclusions The combination of figure-of-eight peripheral sutures and a 2-strand core suture provided the repaired rat flexor tendon with enough strength to prevent rerupture without cast fixation or immobilization after surgery. Clinical relevance This combination of sutures is useful to reproduce flexor tendon repair similar to that performed in clinical settings and will contribute to various translational experiments in vivo.
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25
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Sánchez-Sánchez JL, Calderón-Díez L, Herrero-Turrión J, Méndez-Sánchez R, Arias-Buría JL, Fernández-de-las-Peñas C. Changes in Gene Expression Associated with Collagen Regeneration and Remodeling of Extracellular Matrix after Percutaneous Electrolysis on Collagenase-Induced Achilles Tendinopathy in an Experimental Animal Model: A Pilot Study. J Clin Med 2020; 9:jcm9103316. [PMID: 33076550 PMCID: PMC7602800 DOI: 10.3390/jcm9103316] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/21/2020] [Accepted: 10/12/2020] [Indexed: 01/04/2023] Open
Abstract
Percutaneous electrolysis is an emerging intervention proposed for the management of tendinopathies. Tendon pathology is characterized by a significant cell response to injury and gene expression. No study investigating changes in expression of those genes associated with collagen regeneration and remodeling of extracellular matrix has been conducted. The aim of this pilot study was to investigate gene expression changes after the application of percutaneous electrolysis on experimentally induced Achilles tendinopathy with collagenase injection in an animal model. Fifteen Sprague Dawley male rats were randomly divided into three different groups (no treatment vs. percutaneous electrolysis vs. needling). Achilles tendinopathy was experimentally induced with a single bolus of collagenase injection. Interventions consisted of 3 sessions (one per week) of percutaneous electrolysis or just needling. The rats were euthanized, and molecular expression of genes involved in tendon repair and remodeling, e.g., Cox2, Mmp2, Mmp9, Col1a1, Col3a1, Vegf and Scx, was examined at 28 days after injury. Histological tissue changes were determined with hematoxylin–eosin and safranin O analyses. The images of hematoxylin–eosin and Safranin O tissue images revealed that collagenase injection induced histological changes compatible with a tendinopathy. No further histological changes were observed after the application of percutaneous electrolysis or needling. A significant increase in molecular expression of Cox2, Mmp9 and Vegf genes was observed in Achilles tendons treated with percutaneous electrolysis to a greater extent than after just needling. The expression of Mmp2, Col1a1, Col3a1, or Scx genes also increased, but did not reach statistical significance. This animal study demonstrated that percutaneous electrolysis applied on an experimentally induced Achilles tendinopathy model could increase the expression of some genes associated with collagen regeneration and remodeling of extracellular matrix. The observed gene overexpression was higher with percutaneous electrolysis than with just needling.
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Affiliation(s)
- José Luis Sánchez-Sánchez
- Department of Physical Therapy, Universidad de Salamanca, 37007 Salamanca, Spain; (J.L.S.-S.); (L.C.-D.); (R.M.-S.)
| | - Laura Calderón-Díez
- Department of Physical Therapy, Universidad de Salamanca, 37007 Salamanca, Spain; (J.L.S.-S.); (L.C.-D.); (R.M.-S.)
- Physical Therapy Department, Mutua Accidentes Laborales, FREMAP, 37007 Salamanca, Spain
| | - Javier Herrero-Turrión
- Instituto de Neurociencias de Castilla y León, Universidad de Salamanca, 37007 Salamanca, Spain;
- Instituto Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, 37007 Salamanca, Spain
| | - Roberto Méndez-Sánchez
- Department of Physical Therapy, Universidad de Salamanca, 37007 Salamanca, Spain; (J.L.S.-S.); (L.C.-D.); (R.M.-S.)
| | - José L. Arias-Buría
- Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Universidad Rey Juan Carlos (URJC), Alcorcón, 28922 Madrid, Spain;
- Cátedra Institucional en Docencia, Clínica e Investigación en Fisioterapia: Terapia Manual, Punción Seca y Ejercicio Terapéutico, Universidad Rey Juan Carlos, Alcorcón, 28922 Madrid, Spain
| | - César Fernández-de-las-Peñas
- Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Universidad Rey Juan Carlos (URJC), Alcorcón, 28922 Madrid, Spain;
- Cátedra Institucional en Docencia, Clínica e Investigación en Fisioterapia: Terapia Manual, Punción Seca y Ejercicio Terapéutico, Universidad Rey Juan Carlos, Alcorcón, 28922 Madrid, Spain
- Correspondence: ; Tel.: +34-91-488-88-84
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26
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O Bortolazzo F, D Lucke L, de Oliveira Fujii L, Marqueti RDC, Vieira Ramos G, Theodoro V, Bombeiro AL, Felonato M, A Dalia R, D Carneiro G, Pontes Vicente C, A M Esquisatto M, A S Mendonça F, T Dos Santos GM, R Pimentel E, de Aro AA. Microcurrent and adipose-derived stem cells modulate genes expression involved in the structural recovery of transected tendon of rats. FASEB J 2020; 34:10011-10026. [PMID: 32558993 DOI: 10.1096/fj.201902942rr] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 05/02/2020] [Accepted: 05/05/2020] [Indexed: 01/30/2023]
Abstract
Tendon injuries are common and have a high incidence of re-rupture that can cause loss of functionality. Therapies with adipose-derived stem cells (ASC) and the microcurrent (low-intensity electrical stimulation) application present promising effects on the tissue repair. We analyzed the expression of genes and the participation of some molecules potentially involved in the structural recovery of the Achilles tendon of rats, in response to the application of both therapies, isolated and combined. The tendons were distributed in five groups: normal (N), transected (T), transected and ASC (C) or microcurrent (M) or with ASC, and microcurrent (MC). Microcurrent therapy was beneficial for tendon repair, as it was observed a statistically significant increase in the organization of the collagen fibers, with involvement of the TNC, CTGF, FN, FMDO, and COL3A1 genes as well as PCNA, IL-10, and TNF-α. ASC therapy significantly increased the TNC and FMDO genes expression with no changes in the molecular organization of collagen. With the association of therapies, a significant greater collagen fibers organization was observed with involvement of the FMOD gene. The therapies did not affect the expression of COL1A1, SMAD2, SMAD3, MKX, and EGR1 genes, nor did they influence the amount of collagen I and III, caspase-3, tenomodulin (Tnmd), and hydroxyproline. In conclusion, the application of the microcurrent isolated or associated with ASC increased the organization of the collagen fibers, which can result in a greater biomechanical resistance in relation to the tendons treated only with ASC. Future studies will be needed to demonstrate the biological effects of these therapies on the functional recovery of injured tendons.
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Affiliation(s)
- Fernanda O Bortolazzo
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas-UNICAMP, São Paulo, Brazil
| | - Letícia D Lucke
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas-UNICAMP, São Paulo, Brazil
| | - Lucas de Oliveira Fujii
- Biomedical Sciences Graduate Program, University Center of Herminio Ometto Foundation/FHO, São Paulo, Brazil
| | - Rita de Cassia Marqueti
- Graduate Program of rehabilitation science and Graduate Program of Sciences and Technology of Health and Rehabilitation Sciences, University of Brasilia (UnB), Brasília, Brazil
| | | | - Viviane Theodoro
- Biomedical Sciences Graduate Program, University Center of Herminio Ometto Foundation/FHO, São Paulo, Brazil
| | - André L Bombeiro
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas-UNICAMP, São Paulo, Brazil
| | - Maíra Felonato
- Biomedical Sciences Graduate Program, University Center of Herminio Ometto Foundation/FHO, São Paulo, Brazil
| | - Rodrigo A Dalia
- Biomedical Sciences Graduate Program, University Center of Herminio Ometto Foundation/FHO, São Paulo, Brazil
| | - Giane D Carneiro
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas-UNICAMP, São Paulo, Brazil
| | - Cristina Pontes Vicente
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas-UNICAMP, São Paulo, Brazil
| | - Marcelo A M Esquisatto
- Biomedical Sciences Graduate Program, University Center of Herminio Ometto Foundation/FHO, São Paulo, Brazil
| | - Fernanda A S Mendonça
- Biomedical Sciences Graduate Program, University Center of Herminio Ometto Foundation/FHO, São Paulo, Brazil
| | - Gláucia Maria T Dos Santos
- Biomedical Sciences Graduate Program, University Center of Herminio Ometto Foundation/FHO, São Paulo, Brazil
| | - Edson R Pimentel
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas-UNICAMP, São Paulo, Brazil
| | - Andrea A de Aro
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas-UNICAMP, São Paulo, Brazil.,Biomedical Sciences Graduate Program, University Center of Herminio Ometto Foundation/FHO, São Paulo, Brazil
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27
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Moreira JA, Vasconcelos IC, Fachi JL, Theodoro V, Dalia RA, Aro AA, Pimentel ER, Gaspi FO, Andrade TA, Amaral ME, Esquisatto MA, Mendonça FA, Santos GM. Application of Solidago chilensis and laser improved the repair of burns in diabetic rats. Biomed J 2020; 44:709-716. [PMID: 35166209 PMCID: PMC8847841 DOI: 10.1016/j.bj.2020.05.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 05/30/2019] [Accepted: 05/15/2020] [Indexed: 11/14/2022] Open
Abstract
Background The repair of burns in diabetic patients is a clinical problem. It is relevant to study alternative therapies that can improve the healing process. Our aim was to investigate the effects of Solidago chilensis associated or not with laser on burns in diabetic rats. Methods The animals were divided in four groups (n = 30): C- without treatment; S– S. chilensis extract; L-laser irradiated; LS- laser and S. chilensis. In 7, 14 and 21 days samples were collected after the injury to structural, morphometric and molecular analysis. Results Our results demonstrate the association of S. chilensis and laser reduced the inflammatory infiltrate and favored the angiogenesis. In the groups treated only with laser or with the plant extract showed higher levels of VEGF. The low-level laser therapy (LLLT) promoted higher collagen I and reduction of collagen III. It was also observed higher MMP-2 activation and a decreasing of the active isoform of MMP-9 in the S, L and LS groups. Conclusions The treatments improved the repair of burns in diabetic rats, since it reduced the inflammatory infiltrate and favored the collagen organization presenting similar effects in the burn repair of the diabetics.
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Flexor Tendon: Development, Healing, Adhesion Formation, and Contributing Growth Factors. Plast Reconstr Surg 2020; 144:639e-647e. [PMID: 31568303 DOI: 10.1097/prs.0000000000006048] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Management of flexor tendon injuries of the hand remains a major clinical problem. Even with intricate repair, adhesion formation remains a common complication. Significant progress has been made to better understand the mechanisms of healing and adhesion formation. However, there has been slow progress in the clinical prevention and reversal of flexor tendon adhesions. The goal of this article is to discuss recent literature relating to tendon development, tendon healing, and adhesion formation to identify areas in need of further research. Additional research is needed to understand and compare the molecular, cellular, and genetic mechanisms involved in flexor tendon morphogenesis, postoperative healing, and mechanical loading. Such knowledge is critical to determine how to improve repair outcomes and identify new therapeutic strategies to promote tissue regeneration and prevent adhesion formation.
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Leong NL, Kator JL, Clemens TL, James A, Enamoto-Iwamoto M, Jiang J. Tendon and Ligament Healing and Current Approaches to Tendon and Ligament Regeneration. J Orthop Res 2020; 38:7-12. [PMID: 31529731 PMCID: PMC7307866 DOI: 10.1002/jor.24475] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Accepted: 09/10/2019] [Indexed: 02/04/2023]
Abstract
Ligament and tendon injuries are common problems in orthopedics. There is a need for treatments that can expedite nonoperative healing or improve the efficacy of surgical repair or reconstruction of ligaments and tendons. Successful biologically-based attempts at repair and reconstruction would require a thorough understanding of normal tendon and ligament healing. The inflammatory, proliferative, and remodeling phases, and the cells involved in tendon and ligament healing will be reviewed. Then, current research efforts focusing on biologically-based treatments of ligament and tendon injuries will be summarized, with a focus on stem cells endogenous to tendons and ligaments. Statement of clinical significance: This paper details mechanisms of ligament and tendon healing, as well as attempts to apply stem cells to ligament and tendon healing. Understanding of these topics could lead to more efficacious therapies to treat ligament and tendon injuries. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:7-12, 2020.
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Affiliation(s)
- Natalie L Leong
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
- Department of Surgery, Baltimore VA Medical Center, Baltimore, Maryland
| | - Jamie L Kator
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
| | - Thomas L Clemens
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
- Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, Maryland
| | - Aaron James
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland
| | - Motomi Enamoto-Iwamoto
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
| | - Jie Jiang
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
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Lu CC, Zhang T, Amadio PC, An KN, Moran SL, Gingery A, Zhao C. Lateral slit delivery of bone marrow stromal cells enhances regeneration in the decellularized allograft flexor tendon. J Orthop Translat 2019; 19:58-67. [PMID: 31844614 PMCID: PMC6896678 DOI: 10.1016/j.jot.2019.05.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 05/09/2019] [Accepted: 05/14/2019] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND/OBJECTIVE Stem cell-based therapy has been applied to accelerate the revitalization of allograft tendon into a viable and functional tendon. Although many authors have proposed different methods to help the seeded stem cell distribution in the decellularized allograft, limited success has been achieved as tendon is a high dense connective tissue. We hypothesized that bone marrow stromal cells (BMSCs), seeded through the lateral slit, can regenerate the decellularized tendon (DCT) graft. The cell proliferation, cell viability, and tendon-specific gene expression are increased with the seeded cell density. METHODS Eighty-seven flexor digitorum profundus tendons were equally and randomly divided into 6 treatment groups that were seeded with low-density (2 × 107 cells/mL) and high-density (5 × 107 cells/mL) BMSCs through lateral slits cultured for 2 and 4 weeks, DCT without cells, and fresh live tendons. Tendons were evaluated for cell distribution, cell proliferation, cell viability, gene expression of Collagen I and Collagen III, tenogenic markers, and MMPs. RESULTS Histologic evaluation revealed BMSCs distributed from the lateral slit to the whole DCT. BMSCs were proliferated and kept viable in lateral slit decellularized tendon (LSDCT) in both seeded cell density groups after 2 and 4 weeks of culture. However, no significant differences in the cell proliferation between both cell density groups at 2 and 4 weeks of culture were observed. The lowest cell viability was found in the high-density group after 4 weeks of culture. BMSCs in LSDCT showed a significant tendency of higher gene expression of Collagen I, Collagen III, tenascin C, MMP2, MMP9, and MMP13 compared to normal tendons in both cell density groups at 2 and 4 weeks of culture. CONCLUSION BMSCs proliferated and remained viable after 2 and 4 weeks of culture with distribution throughout the lateral slits. Lateral slit preparation allows for the effective delivery and maintenance of mesenchymal cells with proliferation and generating a tenogenic behaviour of DCT in both the low and high cell densities in an in vitro model. THE TRANSLATION POTENTIAL OF THIS ARTICLE Revitalizing the implanted decellularized allograft is important for clinical application. In this study, we demonstrated that the DCT, with lateral slits, could harbour the seeded stem cell and stimulate proliferation with collagen synthesis. This evidence was presented for clinical application of the lateral slit technique, in DCT grafts, which would repopulate the seeded BMSCs during tendon and ligament reconstruction.
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Affiliation(s)
- Cheng-Chang Lu
- Biomechanics & Tendon and Soft Tissue Biology Laboratories, Division of Orthopedic Research, Mayo Clinic, Rochester, MN, USA
- Kaohsiung Medical University Hospital, Orthopaedic Department, Kaohsiung, Taiwan
- Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tao Zhang
- Biomechanics & Tendon and Soft Tissue Biology Laboratories, Division of Orthopedic Research, Mayo Clinic, Rochester, MN, USA
| | - Peter C. Amadio
- Biomechanics & Tendon and Soft Tissue Biology Laboratories, Division of Orthopedic Research, Mayo Clinic, Rochester, MN, USA
| | - Kai-Nan An
- Biomechanics & Tendon and Soft Tissue Biology Laboratories, Division of Orthopedic Research, Mayo Clinic, Rochester, MN, USA
| | - Steven L. Moran
- Biomechanics & Tendon and Soft Tissue Biology Laboratories, Division of Orthopedic Research, Mayo Clinic, Rochester, MN, USA
| | - Anne Gingery
- Biomechanics & Tendon and Soft Tissue Biology Laboratories, Division of Orthopedic Research, Mayo Clinic, Rochester, MN, USA
| | - Chunfeng Zhao
- Biomechanics & Tendon and Soft Tissue Biology Laboratories, Division of Orthopedic Research, Mayo Clinic, Rochester, MN, USA
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Jafari L, Hassanisaber H, Savard M, Gobeil F, Langelier E. Efficacy of Combining PRP and MMP Inhibitors in Treating Moderately Damaged Tendons Ex Vivo. J Orthop Res 2019; 37:1838-1847. [PMID: 31042324 DOI: 10.1002/jor.24319] [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: 09/13/2018] [Accepted: 03/25/2019] [Indexed: 02/04/2023]
Abstract
Platelet-rich plasma (PRP) and broad-spectrum matrix metalloproteinase inhibitors (MMPIs) have been used as therapeutic options for tendinopathy. However, mixed results have been reported regarding their efficacy. We posited that the combination of these two treatment strategies would be more beneficial for healing tendons than each treatment alone. Rat tail tendons were harvested and cultured without mechanical stress for 0, 4, or 10 days. Single and combination treatment with PRP and MMPIs with either broad- or narrow-spectrum (MMP-13 selective), was administered to 4-day stress-deprived (SD) tendons, an ex vivo model for moderate tendinopathy. This treatment was applied to the damaged tendons over 6 days. At the end of their culture time, the tendons were subjected to traction testing and pathohistology, immunohistochemistry, and viability assays. The results showed better histological features for the PRP + narrow-spectrum MMPI group compared with all individual treatment modalities. Moreover, higher fiber density, more elongated nucleus shape, smaller space between fibers, and a trend toward higher mechanical strength were noted for PRP + narrow-spectrum MMPI group compared with 10-day SD tendons. This study shows that the combination of PRP + narrow-spectrum MMPI is a potentially effective treatment approach for tendinopathy. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1838-1847, 2019.
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Affiliation(s)
- Leila Jafari
- Department of Mechanical Engineering, Université de Sherbrooke, Sherbrooke, Québec J1K 2R1, Canada
| | - Hamid Hassanisaber
- Department of Chemical and Biotechnological Engineering, Université de Sherbrooke, Sherbrooke, Québec J1K 2R1, Canada
| | - Martin Savard
- Department of Pharmacology-Physiology, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Fernand Gobeil
- Department of Pharmacology-Physiology, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Eve Langelier
- Department of Mechanical Engineering, Université de Sherbrooke, Sherbrooke, Québec J1K 2R1, Canada
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Lu CC, Zhang T, Reisdorf RL, Amadio PC, An KN, Moran SL, Gingery A, Zhao C. Biological analysis of flexor tendon repair-failure stump tissue: A potential recycling of tissue for tendon regeneration. Bone Joint Res 2019; 8:232-245. [PMID: 31346451 PMCID: PMC6609868 DOI: 10.1302/2046-3758.86.bjr-2018-0239.r1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Objectives Re-rupture is common after primary flexor tendon repair. Characterization of the biological changes in the ruptured tendon stumps would be helpful, not only to understand the biological responses to the failed tendon repair, but also to investigate if the tendon stumps could be used as a recycling biomaterial for tendon regeneration in the secondary grafting surgery. Methods A canine flexor tendon repair and failure model was used. Following six weeks of repair failure, the tendon stumps were analyzed and characterized as isolated tendon-derived stem cells (TDSCs). Results Failed-repair stump tissue showed cellular accumulation of crumpled and disoriented collagen fibres. Compared with normal tendon, stump tissue had significantly higher gene expression of collagens I and III, matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and insulin-like growth factor (IGF). The stump TDSCs presented both mesenchymal stem and haematopoietic cell markers with significantly increased expression of CD34, CD44, and CD90 markers. Stump TDSCs exhibited similar migration but a lower proliferation rate, as well as similar osteogenic differentiation but a lower chondrogenic/adipogenic differentiation capability, compared with normal TDSCs. Stump TDSCs also showed increasing levels of SRY-box 2 (Sox2), octamer-binding transcription factor 4 (Oct4), tenomodulin (TNMD), and scleraxis (Scx) protein and gene expression. Conclusion We found that a failed repair stump had increased cellularity that preserved both mesenchymal and haematopoietic stem cell characteristics, with higher collagen synthesis, MMP, and growth factor gene expression. This study provides evidence that tendon stump tissue has regenerative potential. Cite this article: C-C. Lu, T. Zhang, R. L. Reisdorf, P. C. Amadio, K-N. An, S. L. Moran, A. Gingery, C. Zhao. Biological analysis of flexor tendon repair-failure stump tissue: A potential recycling of tissue for tendon regeneration. Bone Joint Res 2019;8:232–245. DOI: 10.1302/2046-3758.86.BJR-2018-0239.R1.
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Affiliation(s)
- C-C Lu
- Biomechanics & Tendon and Soft Tissue Biology Laboratories, Division of Orthopedic Research, Mayo Clinic, Rochester, Minnesota, USA; Orthopaedic Department, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Kaohsiung Medical University, Kaohsiung, Taiwan
| | - T Zhang
- Biomechanics & Tendon and Soft Tissue Biology Laboratories, Division of Orthopedic Research, Mayo Clinic, Rochester, Minnesota, USA
| | - R L Reisdorf
- Biomechanics & Tendon and Soft Tissue Biology Laboratories, Division of Orthopedic Research, Mayo Clinic, Rochester, Minnesota, USA
| | - P C Amadio
- Biomechanics & Tendon and Soft Tissue Biology Laboratories, Division of Orthopedic Research, Mayo Clinic, Rochester, Minnesota, USA
| | - K-N An
- Biomechanics & Tendon and Soft Tissue Biology Laboratories, Division of Orthopedic Research, Mayo Clinic, Rochester, Minnesota, USA
| | - S L Moran
- Biomechanics & Tendon and Soft Tissue Biology Laboratories, Division of Orthopedic Research, Mayo Clinic, Rochester, Minnesota, USA
| | - A Gingery
- Biomechanics & Tendon and Soft Tissue Biology Laboratories, Division of Orthopedic Research, Mayo Clinic, Rochester, Minnesota, USA
| | - C Zhao
- Biomechanics & Tendon and Soft Tissue Biology Laboratories, Division of Orthopedic Research, Mayo Clinic, Rochester, Minnesota, USA
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Rodríguez MA, Sandgren Hochhard K, Vicente A, Liu JX, Pedrosa Domellöf F. Gene expression profile of extraocular muscles following resection strabismus surgery. Exp Eye Res 2019; 182:182-193. [PMID: 30953624 DOI: 10.1016/j.exer.2019.03.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 03/25/2019] [Accepted: 03/28/2019] [Indexed: 10/27/2022]
Abstract
This paper aims to identify key biological processes triggered by resection surgery in the extraocular muscles (EOMs) of a rabbit model of strabismus surgery by studying changes in gene expression. Resection surgery was performed in the superior rectus of 16 rabbits and a group of non-operated rabbits served as control. Muscle samples were collected from groups of four animals 1, 2, 4 and 6 weeks after surgery and processed for RNA-sequencing and immunohistochemistry. We identified a total of 164; 136; 64 and 12 differentially expressed genes 1, 2, 4 and 6 weeks after surgery. Gene Ontology enrichment analysis revealed that differentially expressed genes were involved in biological pathways related to metabolism, response to stimulus mainly related with regulation of immune response, cell cycle and extracellular matrix. A complementary pathway analysis and network analysis performed with Ingenuity Pathway Analysis tool corroborated and completed these findings. Collagen I, fibronectin and versican, evaluated by immunofluorescence, showed that changes at the gene expression level resulted in variation at the protein level. Tenascin-C staining in resected muscles demonstrated the formation of new tendon and myotendinous junctions. These data provide new insights about the biological response of the EOMs to resection surgery and may form the basis for future strategies to improve the outcome of strabismus surgery.
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Affiliation(s)
| | | | - André Vicente
- Department of Clinical Sciences, Ophthalmology, Umeå University, 907 87, Umea, Sweden
| | - Jing-Xia Liu
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, 901 87, Umea, Sweden
| | - Fatima Pedrosa Domellöf
- Department of Clinical Sciences, Ophthalmology, Umeå University, 907 87, Umea, Sweden; Department of Integrative Medical Biology, Section for Anatomy, Umeå University, 901 87, Umea, Sweden.
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Baldwin SJ, Kreplak L, Lee JM. MMP-9 selectively cleaves non-D-banded material on collagen fibrils with discrete plasticity damage in mechanically-overloaded tendon. J Mech Behav Biomed Mater 2019; 95:67-75. [PMID: 30954916 DOI: 10.1016/j.jmbbm.2019.03.020] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 02/15/2019] [Accepted: 03/19/2019] [Indexed: 01/06/2023]
Abstract
The mechanical properties of tendon are due to the properties and arrangement of its collagen fibril content. Collagen fibrils are highly-organized supermolecular structures with a periodic banding pattern (D-band) indicative of the geometry of molecular organization. Following mechanical overload of whole tendon, collagen fibrils may plastically deform at discrete sites along their length, forming kinks, and acquiring a fuzzy, non-D-banded, outer layer (shell). Termed discrete plasticity, such non-uniform damage to collagen fibrils suggests localized cellular response at the fibril level during subsequent repair/replacement. Matrix metallo-proteinases (MMPs) are enzymes which act upon the extracellular matrix, facilitating cell mobility and playing important roles in wound healing. A sub-group within this family are the gelatinases, MMP-2 and MMP-9, which selectively cleave denatured collagen molecules. Of these two, MMP-9 is specifically upregulated during the initial stages of tendon repair. This suggests a singular function in damage debridement. Using atomic force microscopy (AFM), a novel fibril-level enzymatic assay was employed to assess enzymatic removal of material by trypsin and MMP-9 from individual fibrils which were: (i) untreated, (ii) partially heat denatured, (iii) or displaying discrete plasticity damaged after repeated mechanical overload. Both enzymes removed material from heat denatured and discrete plasticity-damaged fibrils; however, only MMP-9 demonstrated the selective removal of non-D-banded material, with greater removal from more damaged fibrils. The selectivity of MMP-9, coupled with documented upregulation, suggests a likely mechanism for the in vivo debridement of individual collagen fibrils, following tendon overload injury, and prior to deposition of new collagen.
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Affiliation(s)
- Samuel J Baldwin
- Department of Physics and Atmospheric Science, Dalhousie University, Sir James Dunn Building, 6310 Coburg Road, Main Office Rm 218, Halifax, NS, Canada B3H 4R2.
| | - Laurent Kreplak
- Department of Physics and Atmospheric Science, Dalhousie University, Sir James Dunn Building, 6310 Coburg Road, Main Office Rm 218, Halifax, NS, Canada B3H 4R2; School of Biomedical Engineering, Dalhousie University, 5981 University Avenue, Halifax, NS, Canada B3H 4R2
| | - J Michael Lee
- School of Biomedical Engineering, Dalhousie University, 5981 University Avenue, Halifax, NS, Canada B3H 4R2; Department of Applied Oral Sciences, Dalhousie University, 5981 University Avenue, Halifax, NS, Canada B3H 4R2.
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Sugiyama Y, Naito K, Goto K, Kojima Y, Furuhata A, Igarashi M, Nagaoka I, Kaneko K. Effect of aging on the tendon structure and tendon-associated gene expression in mouse foot flexor tendon. Biomed Rep 2019; 10:238-244. [PMID: 30972219 DOI: 10.3892/br.2019.1200] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 03/07/2019] [Indexed: 01/23/2023] Open
Abstract
To evaluate the biological changes in tendons during the aging process, the present study examined the effect of aging on the tendon structure, distribution of collagen types I and III, and expression of tendon-associated genes, using flexor tendons in a mouse model. Histological assessment of the tendon structure and distribution of collagen types I and III were performed, and the expression of tendon-associated genes was evaluated in flexor digitorium longus tendons of young (8 weeks) and aged (78 weeks) female C57BL/6 mice. The results indicated that the Soslowsky score, based on the analysis of cellularity, fibroblastic changes, and collagen fiber orientation and disruption, was significantly increased, or worsened, in the tendons of the aged group compared with those in the young group. Furthermore, in the aged group, the distribution of type I collagen was decreased and the distribution of type III collagen was relatively increased compared with the young group. Finally, the mRNA expression levels of collagen (type I and type III) and tenogenic markers (Mohawk homeobox, tenomodulin and scleraxis BHLH transcription factor) were significantly decreased in the aged group compared with the young group. The present observations demonstrated that the structure of the tendons, distribution of types I and III collagen and the expression of tendon-associated genes were modulated by aging in the flexor tendon, and that these changes may contribute to the degeneration of tendons in tendinopathy.
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Affiliation(s)
- Yoichi Sugiyama
- Department of Medicine for Motor Organs, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Kiyohito Naito
- Department of Medicine for Motor Organs, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Kenji Goto
- Department of Medicine for Motor Organs, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Yuko Kojima
- Laboratory of Morphology and Image Analysis, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Atsushi Furuhata
- Laboratory of Morphology and Image Analysis, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Mamoru Igarashi
- Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Isao Nagaoka
- Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Kazuo Kaneko
- Department of Medicine for Motor Organs, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
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Cury DP, Schäfer BT, de Almeida SRY, Righetti MMDS, Watanabe IS. Application of a Purified Protein From Natural Latex and the Influence of Suture Type on Achilles Tendon Repair in Rats. Am J Sports Med 2019; 47:901-914. [PMID: 30759353 DOI: 10.1177/0363546518822836] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND The prolonged tendon-healing process, the high costs associated with treatment, the increase in the number of injuries over the past decades, and the lack of consensus on the optimal treatment of tendon injuries are a global problem. Restoring the normal tendon anatomy and decreasing the healing time are key factors for treatment advancement. HYPOTHESIS Application of a purified protein from natural latex (PPNL) accelerates the healing process, increasing collagen synthesis and decreasing metalloproteinases. PPNL associated with a simpler suture technique should decrease the healing time. STUDY DESIGN Controlled laboratory study. METHODS Injury, surgery, and treatment with PPNL were conducted with male Sprague-Dawley rats. Two suture techniques were used: U-suture, a simpler and lesser traumatic technique, and Kessler-Tajima, to avoid strangulation of the microcirculation. Achilles tendons were completely sectioned, and 100 µL of 0.1% PPNL was applied on the tendon during surgery. Tendon morphology, distribution, and quantity of collagen types I and III, as well as expression of TIMP-1, TIMP-2, MMP-2, and MMP-9 and ultrastructural aspects of cells and collagen fibrils, were assessed after 2 and 4 weeks. RESULTS PPNL treatment improved collagen type I synthesis and reduced MMP-2 expression. All groups showed a 6.8-times increase in tendon weight as compared with the control group after 2 weeks and a 5.2-times increase after 4 weeks. All groups showed an increase in diameter after 4 weeks, except for the ones treated with PPNL, which showed a slight reduction in diameter. The peak of concentration of collagen fibrils with a 80-nm diameter was 27.79% in the control group; all other experimental groups presented fibrils between 50 and 60 nm. However, the best results were observed with Kessler-Tajima suture associated with PPNL. CONCLUSION/CLINICAL RELEVANCE There are no known medicines or substances capable of aiding the tendon healing process besides surgery. The discovery of a substance able to improve this process and decrease its duration represents an important advancement in orthopaedic medicine.
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Affiliation(s)
- Diego Pulzatto Cury
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Bárbara Tavares Schäfer
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | | | | | - Ii-Sei Watanabe
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
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Li J, Stoppato M, Schiele NR, Graybeal KL, Nguyen PK, Kuo CK. Embryonic and postnatal tendon cells respond differently to interleukin-1β. Ann N Y Acad Sci 2019; 1442:118-127. [PMID: 30815893 DOI: 10.1111/nyas.14013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 12/17/2018] [Accepted: 01/07/2019] [Indexed: 01/04/2023]
Abstract
Adult tendons heal as scar tissue, whereas embryonic tendons heal scarlessly via unknown mechanisms. Scarred tendon healing results from inflammation-driven imbalances in anabolic and catabolic functions. To test scarless versus scarring age tendon cell responses to inflammatory conditions, we treated embryonic and postnatal tendon cells with interleukin (IL)-1β and characterized expression of collagens, matrix metalloproteinases (MMPs), inflammatory mediators, and phosphorylation of signaling molecules. At baseline, postnatal cells expressed significantly higher levels of inflammatory mediators. When treated with IL-1β, both postnatal and embryonic cells upregulated inflammatory mediators and MMPs. Notably, postnatal cells secreted inflammatory factors up to 12.5 times the concentration in embryonic cultures. IL-1β activated NF-κB p65 and p38 mitogen-activated protein kinase (MAPK) pathways in both cell types, but phosphorylated p38 MAPK levels were two times higher in postnatal than embryonic cells. Our results suggest that scarred healing tendon cells respond to proinflammatory cytokines by promoting an imbalance in anabolic and catabolic functions, and that the heightened response involves p38 MAPK signaling activity. In contrast, embryonic cell responses are smaller in magnitude. These intriguing findings support a potential role for tendon cells in determining scarless versus scarred healing outcomes by regulating the balance between anabolic and catabolic functions during tendon healing.
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Affiliation(s)
- Jiewen Li
- Department of Biomedical Engineering, University of Rochester, Rochester, New York
| | | | | | | | - Phong K Nguyen
- Department of Biomedical Engineering, University of Rochester, Rochester, New York.,Center for Musculoskeletal Research, University of Rochester School of Medicine, Rochester, New York
| | - Catherine K Kuo
- Department of Biomedical Engineering, University of Rochester, Rochester, New York.,Center for Musculoskeletal Research, University of Rochester School of Medicine, Rochester, New York.,Department of Orthopaedics, University of Rochester School of Medicine, Rochester, New York.,Genetics, Development, and Stem Cells Program, University of Rochester School of Medicine, Rochester, New York.,Materials Science Graduate Program, University of Rochester, Rochester, New York
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38
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Lucke LD, Bortolazzo FO, Theodoro V, Fujii L, Bombeiro AL, Felonato M, Dalia RA, Carneiro GD, Cartarozzi LP, Vicente CP, Oliveira ALR, Mendonça FAS, Esquisatto MAM, Pimentel ER, de Aro AA. Low-level laser and adipose-derived stem cells altered remodelling genes expression and improved collagen reorganization during tendon repair. Cell Prolif 2019; 52:e12580. [PMID: 30734394 PMCID: PMC6536450 DOI: 10.1111/cpr.12580] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 12/20/2018] [Accepted: 12/28/2018] [Indexed: 12/21/2022] Open
Abstract
Objectives The cellular therapy using adipose‐derived mesenchymal stem cells (ASCs) aims to improve tendon healing, considering that repaired tendons often result in a less resistant tissue. Our objective was to evaluate the effects of the ASCs combination with a low‐level laser (LLL), an effective photobiostimulation for the healing processes. Materials and methods Rats calcaneal tendons were divided into five groups: normal (NT), transected (T), transected and ASCs (SC) or LLL (L), or with ASCs and LLL (SCL). Results All treated groups presented higher expression of Dcn and greater organization of collagen fibres. In comparison with T, LLL also up‐regulated Gdf5 gene expression, ASCs up‐regulated the expression of Tnmd, and the association of LLL and ASCs down‐regulated the expression of Scx. No differences were observed for the expression of Il1b, Timp2, Tgfb1, Lox, Mmp2, Mmp8 and Mmp9, neither in the quantification of hydroxyproline, TNF‐α, PCNA and in the protein level of Tnmd. A higher amount of IL‐10 was detected in SC, L and SCL compared to T, and higher amount of collagen I and III was observed in SC compared to SCL. Conclusions Transplanted ASCs migrated to the transected region, and all treatments altered the remodelling genes expression. The LLL was the most effective in the collagen reorganization, followed by its combination with ASCs. Further investigations are needed to elucidate the molecular mechanisms involved in the LLL and ASCs combination during initial phases of tendon repair.
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Affiliation(s)
- Letícia D Lucke
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil
| | - Fernanda O Bortolazzo
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil
| | - Viviane Theodoro
- Biomedical Sciences Graduate Program, Herminio Ometto University Center - UNIARARAS, Araras, São Paulo, Brazil
| | - Lucas Fujii
- Biomedical Sciences Graduate Program, Herminio Ometto University Center - UNIARARAS, Araras, São Paulo, Brazil
| | - André L Bombeiro
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil
| | - Maíra Felonato
- Biomedical Sciences Graduate Program, Herminio Ometto University Center - UNIARARAS, Araras, São Paulo, Brazil
| | - Rodrigo A Dalia
- Biomedical Sciences Graduate Program, Herminio Ometto University Center - UNIARARAS, Araras, São Paulo, Brazil
| | - Giane D Carneiro
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil
| | - Luciana P Cartarozzi
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil
| | - Cristina Pontes Vicente
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil
| | - Alexandre L R Oliveira
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil
| | - Fernanda A S Mendonça
- Biomedical Sciences Graduate Program, Herminio Ometto University Center - UNIARARAS, Araras, São Paulo, Brazil
| | - Marcelo A M Esquisatto
- Biomedical Sciences Graduate Program, Herminio Ometto University Center - UNIARARAS, Araras, São Paulo, Brazil
| | - Edson R Pimentel
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil
| | - Andrea A de Aro
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil.,Biomedical Sciences Graduate Program, Herminio Ometto University Center - UNIARARAS, Araras, São Paulo, Brazil
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Fêo HB, Biancalana A, Romero Nakagaki W, Aparecida de Aro A, Gomes L. Morphological Alterations and Increased Gelatinase Activity in the Superficial Digital Flexor Tendon of Chickens During Growth and Maturation. Anat Rec (Hoboken) 2018; 302:964-972. [DOI: 10.1002/ar.24027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 07/30/2018] [Accepted: 08/28/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Haline Ballestero Fêo
- Department of Structural and Functional BiologyInstitute of Biology, State University of Campinas – UNICAMP Campinas Brazil
| | - Adriano Biancalana
- Department of Structural and Functional BiologyInstitute of Biology, State University of Campinas – UNICAMP Campinas Brazil
- Laboratory of Cellular and Molecular BiologyFederal University of Pará – UFPA Soure Brazil
| | - Wilson Romero Nakagaki
- Department of Structural and Functional BiologyInstitute of Biology, State University of Campinas – UNICAMP Campinas Brazil
- Master's Program in Health SciencesUniversity of Western São Paulo – UNOESTE Presidente Prudente Brazil
| | - Andrea Aparecida de Aro
- Department of Structural and Functional BiologyInstitute of Biology, State University of Campinas – UNICAMP Campinas Brazil
- Biomedical Sciences Graduate ProgramHerminio Ometto University Center –UNIARARAS Araras Brazil
| | - Laurecir Gomes
- Department of Structural and Functional BiologyInstitute of Biology, State University of Campinas – UNICAMP Campinas Brazil
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Hsieh JL, Jou IM, Wu CL, Wu PT, Shiau AL, Chong HE, Lo YT, Shen PC, Chen SY. Estrogen and mechanical loading-related regulation of estrogen receptor-β and apoptosis in tendinopathy. PLoS One 2018; 13:e0204603. [PMID: 30296306 PMCID: PMC6175495 DOI: 10.1371/journal.pone.0204603] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 09/11/2018] [Indexed: 12/11/2022] Open
Abstract
Female-dominant tendinopathies are musculoskeletal disorders caused by repetitive hand posture and motion; they are considered overuse syndromes. Both external mechanical stress and changes in hormone levels might affect disease progression. We have previously reported that estrogen receptor-β (ER)-β expression was associated with the pathogenesis of de Quervain's disease. To study the underlying mechanisms, a cyclic stretching culture system was applied to tendon tissue from ovariectomized (OVX) rats. Furthermore, a collagenase I-induced rat tendinopathy model was established to examine the association of ER-β with disease progression. Our results showed that ER-β expression and the number of apoptotic cells were higher and associated with disease severity in rats with tendinopathy. Mechanical stress altered the morphology of primary tenocytes and collagen fiber alignment in tendons, and up-regulated the expression of matrix metalloproteinase-9, ER-β, and interleukin-1β, as well as induced apoptosis in tenocytes and tendon tissue from OVX rats. This is the first report on the effects of ER-β and mechanical stress in tendinopathy. We hope these findings contribute to new pharmacological therapies targeting ER-β signaling pathways to treat tendon-related diseases.
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Affiliation(s)
- Jeng-Long Hsieh
- Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan
| | - I-Ming Jou
- Department of Orthopedics, E-DA Hospital, Kaohsiung, Taiwan
| | - Chao-Liang Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Po-Ting Wu
- Department of Orthopedics, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ai-Li Shiau
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hao-Earn Chong
- Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan
| | - Yu-Ting Lo
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Po-Chuan Shen
- Department of Orthopedics, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan
- Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan
- * E-mail: (PCS); (SYC)
| | - Shih-Yao Chen
- Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- * E-mail: (PCS); (SYC)
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41
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de Aro AA, Carneiro GD, Teodoro LFR, da Veiga FC, Ferrucci DL, Simões GF, Simões PW, Alvares LE, de Oliveira ALR, Vicente CP, Gomes CP, Pesquero JB, Esquisatto MAM, de Campos Vidal B, Pimentel ER. Injured Achilles Tendons Treated with Adipose-Derived Stem Cells Transplantation and GDF-5. Cells 2018; 7:cells7090127. [PMID: 30200326 PMCID: PMC6162699 DOI: 10.3390/cells7090127] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 08/17/2018] [Accepted: 08/23/2018] [Indexed: 12/22/2022] Open
Abstract
Tendon injuries represent a clinical challenge in regenerative medicine because their natural repair process is complex and inefficient. The high incidence of tendon injuries is frequently associated with sports practice, aging, tendinopathies, hypertension, diabetes mellitus, and the use of corticosteroids. The growing interest of scientists in using adipose-derived mesenchymal stem cells (ADMSC) in repair processes seems to be mostly due to their paracrine and immunomodulatory effects in stimulating specific cellular events. ADMSC activity can be influenced by GDF-5, which has been successfully used to drive tenogenic differentiation of ADMSC in vitro. Thus, we hypothesized that the application of ADMSC in isolation or in association with GDF-5 could improve Achilles tendon repair through the regulation of important remodeling genes expression. Lewis rats had tendons distributed in four groups: Transected (T), transected and treated with ADMSC (ASC) or GDF-5 (GDF5), or with both (ASC+GDF5). In the characterization of cells before application, ADMSC expressed the positive surface markers, CD90 (90%) and CD105 (95%), and the negative marker, CD45 (7%). ADMSC were also differentiated in chondrocytes, osteoblast, and adipocytes. On the 14th day after the tendon injury, GFP-ADMSC were observed in the transected region of tendons in the ASC and ASC+GDF5 groups, and exhibited and/or stimulated a similar genes expression profile when compared to the in vitro assay. ADMSC up-regulated Lox, Dcn, and Tgfb1 genes expression in comparison to T and ASC+GDF5 groups, which contributed to a lower proteoglycans arrangement, and to a higher collagen fiber organization and tendon biomechanics in the ASC group. The application of ADMSC in association with GDF-5 down-regulated Dcn, Gdf5, Lox, Tgfb1, Mmp2, and Timp2 genes expression, which contributed to a lower hydroxyproline concentration, lower collagen fiber organization, and to an improvement of the rats’ gait 24 h after the injury. In conclusion, although the literature describes the benefic effect of GDF-5 for the tendon healing process, our results show that its application, isolated or associated with ADMSC, cannot improve the repair process of partial transected tendons, indicating the higher effectiveness of the application of ADMSC in injured Achilles tendons. Our results show that the application of ADMSC in injured Achilles tendons was more effective in relation to its association with GDF-5.
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Affiliation(s)
- Andrea Aparecida de Aro
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
- Biomedical Sciences Graduate Program, Herminio Ometto University Center⁻UNIARARAS, 13607-339 Araras, SP, Brazil.
| | - Giane Daniela Carneiro
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Luis Felipe R Teodoro
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Fernanda Cristina da Veiga
- Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Danilo Lopes Ferrucci
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Gustavo Ferreira Simões
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Priscyla Waleska Simões
- Engineering, Modeling and Applied Social Sciences Center (CECS), Biomedical Engineering Graduate Program (PPGEBM), Universidade Federal do ABC (UFABC), Alameda da Universidade s/n, 09606-045 São Bernardo do Campo, SP, Brazil.
| | - Lúcia Elvira Alvares
- Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Alexandre Leite R de Oliveira
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Cristina Pontes Vicente
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Caio Perez Gomes
- Department of Biophysics, Federal University of Sao Paulo⁻Unifesp, Pedro de Toledo, 699, 04039-032 Sao Paulo, SP, Brazil.
| | - João Bosco Pesquero
- Department of Biophysics, Federal University of Sao Paulo⁻Unifesp, Pedro de Toledo, 699, 04039-032 Sao Paulo, SP, Brazil.
| | - Marcelo Augusto M Esquisatto
- Biomedical Sciences Graduate Program, Herminio Ometto University Center⁻UNIARARAS, 13607-339 Araras, SP, Brazil.
| | - Benedicto de Campos Vidal
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Edson Rosa Pimentel
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
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Lebaschi AH, Deng XH, Camp CL, Zong J, Cong GT, Carballo CB, Album Z, Rodeo SA. Biomechanical, Histologic, and Molecular Evaluation of Tendon Healing in a New Murine Model of Rotator Cuff Repair. Arthroscopy 2018; 34:1173-1183. [PMID: 29459078 PMCID: PMC6340398 DOI: 10.1016/j.arthro.2017.10.045] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 10/22/2017] [Accepted: 10/24/2017] [Indexed: 02/02/2023]
Abstract
PURPOSE To develop a clinically relevant, robust murine model of rotator cuff tendon repair to examine cellular and molecular mechanisms of healing. METHODS Sixty C57BL/6 male mice underwent rotator cuff transection and repair using microsurgical techniques. A modified Kessler suturing technique was used prior to tendon detachment. Sutures were passed through 2 intersecting bone tunnels that were made at the tendon attachment site. Mice were sacrificed at 2 and 4 weeks with subsequent biomechanical, histologic, micro-CT, and gene expression evaluations. RESULTS Failure forces in the 2- and 4-week groups were 36% and 75% of the intact tendon, respectively. Histologic evaluation revealed complete reattachment of the tendon with no observable gap. Healing occurred by formation of fibrovascular tissue at the tendon-bone interface, similar to larger animal models. Molecular analysis revealed gene expression consistent with gradual healing of the reattached tendon over a period of 4 weeks. Comparisons were made using 1-way analysis of variance. CONCLUSIONS This model is distinguished by use of microsurgical suturing techniques, which provides a robust, reproducible, and economic animal model to study various aspects of rotator cuff pathology. CLINICAL RELEVANCE Improvement of clinical outcomes of rotator cuff pathology requires in-depth understanding of the underlying cellular and molecular mechanisms of healing. This study presents a robust murine model of supraspinatus repair to serve as a standard research tool for basic and translational investigations into signaling pathways, gene expression, and the effect of biologic augmentation approaches.
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Wagner JR, Taguchi T, Cho JY, Charavaryamath C, Griffon DJ. Evaluation of Stem Cell Therapies in a Bilateral Patellar Tendon Injury Model in Rats. J Vis Exp 2018. [PMID: 29658926 DOI: 10.3791/56810] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Regenerative medicine provides novel alternatives to conditions that challenge traditional treatments. The prevalence and morbidity of tendinopathy across species, combined with the limited healing properties of this tissue, have prompted the search for cellular therapies and propelled the development of experimental models to study their efficacy. Umbilical cord matrix-derived mesenchymal stem cells (UCM-MSC) are appealing candidates because they are abundant, easy to collect, circumvent the ethical concerns and risk of teratoma formation, yet resemble primitive embryonic stem cells more closely than adult tissue-derived MSCs. Significant interest has focused on chitosan as a strategy to enhance the properties of MSCs through spheroid formation. This paper details techniques to isolate UCM-MSCs, prepare spheroids on chitosan film, and analyze the effect of spheroid formation on surface marker expression. Consequently, creation of a bilateral patellar tendon injury model in rats is described for in vivo implantation of UCM-MSC spheroids formed on chitosan film. No complication was observed in the study with respect to morbidity, stress rising effects, or tissue infection. The total functional score of the operated rats at 7 days was lower than that of normal rats, but returned to normal within 28 days after surgery. Histological scores of tissue-healing confirmed the presence of a clot in treated defects evaluated at 7 days, absence of foreign body reaction, and progressing healing at 28 days. This bilateral patella tendon defect model controls inter-individual variation via creation of an internal control in each rat, was associated with acceptable morbidity, and allowed detection of differences between untreated tendons and treatments.
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Affiliation(s)
- John R Wagner
- College of Veterinary Medicine, Western University of Health Sciences
| | - Takashi Taguchi
- College of Veterinary Medicine, Western University of Health Sciences
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Lipman K, Wang C, Ting K, Soo C, Zheng Z. Tendinopathy: injury, repair, and current exploration. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:591-603. [PMID: 29593382 PMCID: PMC5865563 DOI: 10.2147/dddt.s154660] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Both acute and chronic tendinopathy result in high morbidity, requiring management that is often lengthy and expensive. However, limited and conflicting scientific evidence surrounding current management options has presented a challenge when trying to identify the best treatment for tendinopathy. As a result of shortcomings of current treatments, response to available therapies is often poor, resulting in frustration in both patients and physicians. Due to a lack of understanding of basic tendon-cell biology, further scientific investigation is needed in the field for the development of biological solutions. Optimization of new delivery systems and therapies that spatially and temporally mimic normal tendon physiology hold promise for clinical application. This review focuses on the clinical importance of tendinopathy, the structure of healthy tendons, tendon injury, and healing, and a discussion of current approaches for treatment that highlight the need for the development of new nonsurgical interventions.
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Affiliation(s)
| | - Chenchao Wang
- Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA, USA.,First Hospital of China Medical University, Shenyang, China.,Division of Plastic and Reconstructive Surgery, Department of Orthopaedic Surgery, Orthopaedic Hospital Research Center, University of California, Los Angeles, CA, USA
| | - Kang Ting
- Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA, USA
| | - Chia Soo
- Division of Plastic and Reconstructive Surgery, Department of Orthopaedic Surgery, Orthopaedic Hospital Research Center, University of California, Los Angeles, CA, USA
| | - Zhong Zheng
- Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA, USA
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Evaluation of microstructurally motivated constitutive models to describe age-dependent tendon healing. Biomech Model Mechanobiol 2017; 17:793-814. [PMID: 29234987 PMCID: PMC5948310 DOI: 10.1007/s10237-017-0993-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 11/30/2017] [Indexed: 12/27/2022]
Abstract
Tendon injuries are common to all ages. Injured tendons typically do not recover full functionality. The amount and organization of tendon constituents dictate their mechanical properties. The impact of changes in these constituents during (patho)physiologic processes (e.g., aging and healing) are not fully understood. Toward this end, microstructurally motivated strain energy functions (SEFs) offer insight into underlying mechanisms of age-dependent healing. Several SEFs have been adapted for tendon; however, most are phenomenological. Therefore, the aims of this study are: (1) evaluate the descriptive capability of SEFs in age-dependent murine patellar tendon healing and (2) identify a SEF for implementation in a growth and remodeling (G&R) model. To accomplish these aims, models were fitted to patellar tendon tensile data from multiple age groups and post-injury timepoints. Model sensitivity to parameters and the determinability of the parameters were assessed. A two-way analysis of variance was used to identify changes in parameters and the feasibility of implementing each model into a G&R model is discussed. The evaluated SEFs exhibited adequate descriptive capability. Parameter determinability and sensitivity analysis, however, highlighted the need for additional data to inform and validate the models to increase physiologic relevance and enable G&R model formulation to determine underlying mechanisms of age-dependent healing. This work, as a first, evaluated changes in tendon mechanical properties both as functions of age and injury in an age-dependent manner using microstructurally motivated models, highlights inherent dependencies between parameters of widely used hyperelastic models, and identified unique post-injury behavior by the aging group compared to the mature and aged groups.
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Minkwitz S, Schmock A, Kurtoglu A, Tsitsilonis S, Manegold S, Wildemann B, Klatte-Schulz F. Time-Dependent Alterations of MMPs, TIMPs and Tendon Structure in Human Achilles Tendons after Acute Rupture. Int J Mol Sci 2017; 18:ijms18102199. [PMID: 29053586 PMCID: PMC5666880 DOI: 10.3390/ijms18102199] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 10/10/2017] [Accepted: 10/17/2017] [Indexed: 12/27/2022] Open
Abstract
A balance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) is required to maintain tendon homeostasis. Variation in this balance over time might impact on the success of tendon healing. This study aimed to analyze structural changes and the expression profile of MMPs and TIMPs in human Achilles tendons at different time-points after rupture. Biopsies from 37 patients with acute Achilles tendon rupture were taken at surgery and grouped according to time after rupture: early (2–4 days), middle (5–6 days), and late (≥7 days), and intact Achilles tendons served as control. The histological score increased from the early to the late time-point after rupture, indicating the progression towards a more degenerative status. In comparison to intact tendons, qRT-PCR analysis revealed a significantly increased expression of MMP-1, -2, -13, TIMP-1, COL1A1, and COL3A1 in ruptured tendons, whereas TIMP-3 decreased. Comparing the changes over time post rupture, the expression of MMP-9, -13, and COL1A1 significantly increased, whereas MMP-3 and -10 expression decreased. TIMP expression was not significantly altered over time. MMP staining by immunohistochemistry was positive in the ruptured tendons exemplarily analyzed from early and late time-points. The study demonstrates a pivotal contribution of all investigated MMPs and TIMP-1, but a minor role of TIMP-2, -3, and -4, in the early human tendon healing process.
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Affiliation(s)
- Susann Minkwitz
- Julius Wolff Institute, Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany.
- Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany.
| | - Aysha Schmock
- Julius Wolff Institute, Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany.
| | - Alper Kurtoglu
- Julius Wolff Institute, Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany.
| | - Serafeim Tsitsilonis
- Julius Wolff Institute, Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany.
| | - Sebastian Manegold
- Julius Wolff Institute, Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany.
| | - Britt Wildemann
- Julius Wolff Institute, Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany.
- Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany.
| | - Franka Klatte-Schulz
- Julius Wolff Institute, Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany.
- Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany.
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Wang S, Wang Y, Song L, Chen J, Ma Y, Chen Y, Fan S, Su M, Lin X. Decellularized tendon as a prospective scaffold for tendon repair. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2017; 77:1290-1301. [DOI: 10.1016/j.msec.2017.03.279] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Revised: 12/12/2016] [Accepted: 03/28/2017] [Indexed: 01/12/2023]
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48
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Romero A, Barrachina L, Ranera B, Remacha A, Moreno B, de Blas I, Sanz A, Vázquez F, Vitoria A, Junquera C, Zaragoza P, Rodellar C. Comparison of autologous bone marrow and adipose tissue derived mesenchymal stem cells, and platelet rich plasma, for treating surgically induced lesions of the equine superficial digital flexor tendon. Vet J 2017; 224:76-84. [DOI: 10.1016/j.tvjl.2017.04.005] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 04/03/2017] [Accepted: 04/12/2017] [Indexed: 12/24/2022]
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Lee SY, Kwon B, Lee K, Son YH, Chung SG. Therapeutic Mechanisms of Human Adipose-Derived Mesenchymal Stem Cells in a Rat Tendon Injury Model. Am J Sports Med 2017; 45:1429-1439. [PMID: 28291954 DOI: 10.1177/0363546517689874] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Although survival of transplanted stem cells in vivo and differentiation of stem cells into tenocytes in vitro have been reported, there have been no in vivo studies demonstrating that mesenchymal stem cells (MSCs) could secrete their own proteins as differentiated tenogenic cells. Purpose/Hypothesis: Using a xenogeneic MSC transplantation model, we aimed to investigate whether MSCs could differentiate into the tenogenic lineage and secrete their own proteins. The hypothesis was that human MSCs would differentiate into the human tenogenic lineage and the cells would be able to secrete human-specific proteins in a rat tendon injury model. STUDY DESIGN Controlled laboratory study. METHODS The Achilles tendons of 57 Sprague Dawley rats received full-thickness rectangular defects. After the modeling, the defective tendons were randomly assigned to 3 groups: (1) cell group, implantation with human adipose-derived mesenchymal stem cells (hASCs) and fibrin glue (106 cells in 60 μL); (2) fibrin group, implantation with fibrin glue and same volume of cell media; and (3) sham group, identical surgical procedure without any treatment. Gross observation and biomechanical, histopathological, immunohistochemistry, and Western blot analyses were performed at 2 and 4 weeks after modeling. RESULTS hASCs implanted into the defective rat tendons were viable for 4 weeks as detected by immunofluorescence staining. Tendons treated with hASCs showed better gross morphological and biomechanical recovery than those in the fibrin and sham groups. Furthermore, the expression of both human-specific collagen type I and tenascin-C was significantly higher in the cell group than in the other 2 groups. CONCLUSION Transplantation of hASCs enhanced rat tendon healing biomechanically. hASCs implanted into the rat tendon defect model survived for at least 4 weeks and secreted human-specific collagen type I and tenascin-C. These findings suggest that transplanted MSCs may be able to differentiate into the tenogenic lineage and contribute their own proteins to tendon healing. CLINICAL RELEVANCE In tendon injury, MSCs can enhance tendon healing by secreting their own protein and have potential as a therapeutic option in human tendinopathy.
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Affiliation(s)
- Sang Yoon Lee
- Department of Physical Medicine & Rehabilitation, Chung-Ang University College of Medicine, Seoul, South Korea.,Department of Rehabilitation Medicine, Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Bomi Kwon
- Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Kyoungbun Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Young Hoon Son
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, South Korea
| | - Sun G Chung
- Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Institute of Aging, Seoul National University, Seoul, South Korea.,Rheumatism Research Institute, Medical Research Center, Seoul National University, Seoul, South Korea
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50
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Zarychta-Wiśniewska W, Burdzinska A, Kulesza A, Gala K, Kaleta B, Zielniok K, Siennicka K, Sabat M, Paczek L. Bmp-12 activates tenogenic pathway in human adipose stem cells and affects their immunomodulatory and secretory properties. BMC Cell Biol 2017; 18:13. [PMID: 28214472 PMCID: PMC5316159 DOI: 10.1186/s12860-017-0129-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Accepted: 02/08/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Cell-based therapy is a treatment method in tendon injuries. Bone morphogenic protein 12 (BMP-12) possesses tenogenic activity and was proposed as a differentiating factor for stem cells directed to transplantation. However, BMPs belong to pleiotropic TGF-β superfamily and have diverse effect on cells. Therefore, the aim of this study was to determine if BMP-12 induces tenogenic differentiation of human adipose stem cells (hASCs) and how it affects other features of this population. RESULTS Human ASCs from 6 healthy donors were treated or not with BMP-12 (50 or 100 ng/ml, 7 days) and tested for gene expression (COLL1, SCX, MKH, DCN, TNC, RUNX2), protein expression (COLL1, COLL3, MKH), proliferation, migration, secretory activity, immunomodulatory properties and susceptibility to oxidative stress. RT-PCR revealed up-regulation of SCX, MKH and RUNX2 genes in BMP-12 treated cells (2.05, 2.65 and 1.87 fold in comparison to control, respectively, p < 0.05) and Western Blot revealed significant increase of COLL1 and MHK expression after BMP-12 treatment. Addition of BMP-12 significantly enhanced secretion of VEGF, IL-6, MMP-1 and MPP-8 by hASCs while had no effect on TGF-β, IL-10, EGF and MMP-13. Moreover, BMP-12 presence in medium attenuated inhibitory effect of hASCs on allo-activated lymphocytes proliferation. At the same time BMP-12 displayed no influence on hASCs proliferation, migration and susceptibility to oxidative stress. CONCLUSION BMP-12 activates tenogenic pathway in hASCs but also affects secretory activity and impairs immunomodulatory potential of this population that can influence the clinical outcome after cell transplantation.
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Affiliation(s)
- Weronika Zarychta-Wiśniewska
- Department of Immunology, Transplantology and Internal Medicine, Transplantation Institute, Medical University of Warsaw, Nowogrodzka str. 59, 02-006, Warsaw, Poland
| | - Anna Burdzinska
- Department of Immunology, Transplantology and Internal Medicine, Transplantation Institute, Medical University of Warsaw, Nowogrodzka str. 59, 02-006, Warsaw, Poland.
| | - Agnieszka Kulesza
- Department of Immunology, Transplantology and Internal Medicine, Transplantation Institute, Medical University of Warsaw, Nowogrodzka str. 59, 02-006, Warsaw, Poland
| | - Kamila Gala
- Department of Immunology, Transplantology and Internal Medicine, Transplantation Institute, Medical University of Warsaw, Nowogrodzka str. 59, 02-006, Warsaw, Poland
| | - Beata Kaleta
- Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland
| | - Katarzyna Zielniok
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - Katarzyna Siennicka
- Department of Regenerative Medicine, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland
| | - Marek Sabat
- Department of Immunology, Transplantology and Internal Medicine, Transplantation Institute, Medical University of Warsaw, Nowogrodzka str. 59, 02-006, Warsaw, Poland
| | - Leszek Paczek
- Department of Immunology, Transplantology and Internal Medicine, Transplantation Institute, Medical University of Warsaw, Nowogrodzka str. 59, 02-006, Warsaw, Poland.,Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
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