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Festinese VG, Faydaver M, Nardinocchi D, Di Giacinto O, El Khatib M, Mauro A, Turriani M, Canciello A, Berardinelli P, Russo V, Barboni B. Neural Markers Predict Tendon Healing Outcomes in an Ovine Achilles Tendon Injury Model: Spontaneous Repair Versus Amniotic Epithelial Cell-Induced Regeneration. Int J Mol Sci 2025; 26:2445. [PMID: 40141090 PMCID: PMC11942428 DOI: 10.3390/ijms26062445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 02/28/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Tendon injuries pose a clinical challenge due to tendons' limited recovery. Emerging evidence points to the nervous system's critical role in tendon healing, with neural markers NGF, NF-200, NPY, CGRP, and GAL modulating inflammation, cell proliferation, and extracellular matrix (ECM) remodeling. This study investigates the predictive role of selected neural markers in a validated ovine Achilles tendon injury model, comparing spatio-temporal expression patterns in regenerating tendons transplanted with amniotic epithelial stem cells (AECs) versus spontaneous healing (CTR) 14 and 28 days post-injury (p.i.). AEC-treated tissues showed a spatio-temporal modulation of NF-200, NGF, NPY, CGRP, GAL, and enhanced ECM remodeling, with greater cell alignment, lower angle deviation, and accelerated collagen maturation, with a favorable Collagen type 1 (COL1) to Collagen type 3 (COL3) ratio. Pearson's matrix analysis revealed significant positive correlations between NGF, CGRP, and GAL expression, along a positive correlation between the three neural markers and cell alignment and angle deviation. As opposed to CTR, in AEC-treated tendons, lower levels of NGF, CGRP, and GAL correlated positively with improved tissue organization, suggesting these markers may predict successful tendon regeneration. The findings highlight the neuro-mediated activity of AECs in tendon regeneration, with NGF, CGRP, and GAL emerging as key predictive biomarkers for tendon healing.
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Affiliation(s)
- Valeria Giovanna Festinese
- Unit of Basic and Applied Biosciences, Department of Biosciences, Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.G.F.); (M.F.); (O.D.G.); (M.E.K.); (A.M.); (M.T.); (A.C.)
- School of Advanced Studies, Center for Neuroscience, University of Camerino, 62032 Camerino, Italy
| | - Melisa Faydaver
- Unit of Basic and Applied Biosciences, Department of Biosciences, Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.G.F.); (M.F.); (O.D.G.); (M.E.K.); (A.M.); (M.T.); (A.C.)
| | - Delia Nardinocchi
- Unit of Basic and Applied Biosciences, Department of Biosciences, Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.G.F.); (M.F.); (O.D.G.); (M.E.K.); (A.M.); (M.T.); (A.C.)
| | - Oriana Di Giacinto
- Unit of Basic and Applied Biosciences, Department of Biosciences, Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.G.F.); (M.F.); (O.D.G.); (M.E.K.); (A.M.); (M.T.); (A.C.)
| | - Mohammad El Khatib
- Unit of Basic and Applied Biosciences, Department of Biosciences, Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.G.F.); (M.F.); (O.D.G.); (M.E.K.); (A.M.); (M.T.); (A.C.)
| | - Annunziata Mauro
- Unit of Basic and Applied Biosciences, Department of Biosciences, Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.G.F.); (M.F.); (O.D.G.); (M.E.K.); (A.M.); (M.T.); (A.C.)
| | - Maura Turriani
- Unit of Basic and Applied Biosciences, Department of Biosciences, Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.G.F.); (M.F.); (O.D.G.); (M.E.K.); (A.M.); (M.T.); (A.C.)
| | - Angelo Canciello
- Unit of Basic and Applied Biosciences, Department of Biosciences, Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.G.F.); (M.F.); (O.D.G.); (M.E.K.); (A.M.); (M.T.); (A.C.)
| | - Paolo Berardinelli
- Unit of Basic and Applied Biosciences, Department of Biosciences, Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.G.F.); (M.F.); (O.D.G.); (M.E.K.); (A.M.); (M.T.); (A.C.)
| | - Valentina Russo
- Unit of Basic and Applied Biosciences, Department of Biosciences, Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.G.F.); (M.F.); (O.D.G.); (M.E.K.); (A.M.); (M.T.); (A.C.)
| | - Barbara Barboni
- Unit of Basic and Applied Biosciences, Department of Biosciences, Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.G.F.); (M.F.); (O.D.G.); (M.E.K.); (A.M.); (M.T.); (A.C.)
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Darrieutort-Laffite C, Blanchard F, Soslowsky LJ, Le Goff B. Biology and physiology of tendon healing. Joint Bone Spine 2024; 91:105696. [PMID: 38307405 DOI: 10.1016/j.jbspin.2024.105696] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/11/2024] [Accepted: 01/23/2024] [Indexed: 02/04/2024]
Abstract
Tendon disorders affect people of all ages, from elite and recreational athletes and workers to elderly patients. After an acute injury, 3 successive phases are described to achieve healing: an inflammatory phase followed by a proliferative phase, and finally by a remodeling phase. Despite this process, healed tendon fails to recover its original mechanical properties. In this review, we proposed to describe the key factors involved in the process such as cells, transcription factors, extracellular matrix components, cytokines and growth factors and vascularization among others. A better understanding of this healing process could help provide new therapeutic approaches to improve patients' recovery while tendon disorders management remains a medical challenge.
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Affiliation(s)
- Christelle Darrieutort-Laffite
- Service de rhumatologie, CHU de Nantes, Nantes, France; Oniris, Regenerative Medicine and Skeleton, RMeS, UMR 1229, Inserm, CHU de Nantes, Nantes université, 44000 Nantes, France.
| | - Frédéric Blanchard
- Oniris, Regenerative Medicine and Skeleton, RMeS, UMR 1229, Inserm, CHU de Nantes, Nantes université, 44000 Nantes, France
| | - Louis J Soslowsky
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA
| | - Benoit Le Goff
- Service de rhumatologie, CHU de Nantes, Nantes, France; Oniris, Regenerative Medicine and Skeleton, RMeS, UMR 1229, Inserm, CHU de Nantes, Nantes université, 44000 Nantes, France
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Wang B, Chen Q, Zou X, Zheng P, Zhu J. Advances in non-coding RNA in tendon injuries. Front Genet 2024; 15:1396195. [PMID: 38836038 PMCID: PMC11148651 DOI: 10.3389/fgene.2024.1396195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 04/23/2024] [Indexed: 06/06/2024] Open
Abstract
Tendons serve as important weight-bearing structures that smoothly transfer forces from muscles to skeletal parts, allowing contracted muscle movements to be translated into corresponding joint movements. For body mechanics, tendon tissue plays an important role. If the tendons are damaged to varying degrees, it can lead to disability or pain in patients. That is to say, tendon injuries havea significant impact on quality of life and deserve our high attention. Compared to other musculoskeletal tissues, tendons are hypovascular and hypo-cellular, and therefore have a greater ability to heal, this will lead to a longer recovery period after injury or even disability, which will significantly affect the quality of life. There are many causes of tendon injury, including trauma, genetic factors, inflammation, aging, and long-term overuse, and the study of related mechanisms is of great significance. Currently, tendon there are different treatment modalities, like injection therapy and surgical interventions. However, they have a high failure rate due to different reasons, among which the formation of adhesions severely weakens the tissue strength, affecting the functional recovery and the patient's quality of life. A large amount of data has shown that non coding RNAs can play a huge role in this field, thus attracting widespread attention from researchers from various countries. This review summarizes the relevant research progress on non-coding RNAs in tendon injuries, providing new ideas for a deeper understanding of tendon injuries and exploring new diagnostic and therapeutic approaches.
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Affiliation(s)
- Bin Wang
- Department of Plastics, Tiantai People's Hospital of Zhejiang Province (Tiantai Branch of Zhejiang Provincial People's Hospital), Hangzhou Medical College, Taizhou, China
| | - Qiang Chen
- Center for Plastic and Reconstructive Surgery, Department of Hand and Reconstructive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Xiaodi Zou
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Ping Zheng
- Department of Plastics, Tiantai People's Hospital of Zhejiang Province (Tiantai Branch of Zhejiang Provincial People's Hospital), Hangzhou Medical College, Taizhou, China
| | - Jie Zhu
- Center for General Practice Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
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Tobaly D, Tétreault P, Cloutier G, Choinière M, Grondin P, Freire V, Julien AS, Bureau NJ. Assessing the treatment response of lateral elbow tendinopathy using time-dependent ultrasonography, Doppler imaging, and elastography. Insights Imaging 2024; 15:113. [PMID: 38734857 PMCID: PMC11088583 DOI: 10.1186/s13244-024-01695-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 04/13/2024] [Indexed: 05/13/2024] Open
Abstract
OBJECTIVE To investigate the structural alterations, neovascularity, and elasticity of tendons and the relationship between elasticity and the Patient Rated Tennis Elbow Evaluation score after undergoing US-guided fenestration or surgery in patients with chronic lateral elbow tendinopathy. METHODS Participants from the per-protocol population of a randomized trial conducted between October 2016 and June 2020 were included. The surgery and fenestration groups included 24 (mean age, 50 ± 7 years [standard deviation], 10 men) and 29 (47 ± 8 years, 18 men) participants, respectively. Ultrasound exams were performed at baseline, 6 months, and 12 months. Statistical analyses included linear mixed effects and generalized equation estimation models. RESULTS Fenestration had no significant impact on tendon thickness (p = 0.46). Conversely, surgery significantly increased tendon thickness at 6 months (p < 0.0001) and remained elevated at 12 months (p = 0.04). Tendon echostructure exhibited a group effect (p = 0.03), indicating a higher proportion of pathological scores in the surgery group post-intervention compared to the fenestration group. Both groups showed a similar reduction in neovascularity from 6 to 12 months postintervention (p = 0.006). Shear-wave velocity increased in the fenestration group at 6 months (p = 0.04), while the surgery group experienced a nonsignificant decrease at 6 months, with some improvement at 12 months (p = 0.08). Changes in shear-wave velocity did not correlate with clinical outcome. CONCLUSIONS Fenestration and surgery reduced tendon neovascularity over time. Unlike surgery, fenestration did not impact tendon size while improving tendon echostructure and elasticity. CRITICAL RELEVANCE STATEMENT Fenestration and surgery equally alleviated symptoms and decreased tendon neovascularity in lateral elbow tendinopathy; however, fenestration did not alter tendon thickness and improved echostructure and shear-wave velocity, suggesting shear-wave velocity's potential for quantitatively monitoring tendon elasticity during healing. KEY POINTS Reliable markers for monitoring healing response and informing treatment protocols in elbow tendinopathy are lacking. Fenestration and surgery reduced tendon neovascularity, while fenestration improved tendon echostructure and shear-wave velocity. Shear-wave velocity may provide quantitative measures to monitor tendon elasticity in response to treatment.
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Affiliation(s)
- David Tobaly
- Department of Radiology, St Mary's Hospital Center, 3830 Lacombe Avenue, Montreal, QC, H3T 1M5, Canada
| | - Patrice Tétreault
- Department of Orthopedics, Centre hospitalier de l'Université de Montréal (CHUM), 1000 rue Saint-Denis, Montreal, QC, H2X 0C1, Canada
| | - Guy Cloutier
- Research Center, Centre hospitalier de l'Université de Montréal (CHUM), 900 rue Saint-Denis, Montreal, QC, H2X 0A9, Canada
| | - Manon Choinière
- Research Center, Centre hospitalier de l'Université de Montréal (CHUM), 900 rue Saint-Denis, Montreal, QC, H2X 0A9, Canada
- Department of Anesthesiology and Pain Medicine, Université de Montréal, C.P. 6128, succursale Centre-ville, Montreal, QC, H3C 3J7, Canada
| | - Philippe Grondin
- Department of Orthopedics, Centre hospitalier de l'Université de Montréal (CHUM), 1000 rue Saint-Denis, Montreal, QC, H2X 0C1, Canada
| | - Véronique Freire
- Department of Radiology, Centre hospitalier de l'Université de Montréal (CHUM), 1000 rue Saint-Denis, Montreal, QC, H2X 0C1, Canada
| | - Anne-Sophie Julien
- Department of Mathematics and Statistic, Université Laval, 1045 avenue de la Médecine, Quebec City, QC, G1V 0A6, Canada
| | - Nathalie J Bureau
- Research Center, Centre hospitalier de l'Université de Montréal (CHUM), 900 rue Saint-Denis, Montreal, QC, H2X 0A9, Canada.
- Department of Radiology, Centre hospitalier de l'Université de Montréal (CHUM), 1000 rue Saint-Denis, Montreal, QC, H2X 0C1, Canada.
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Abstract
The Achilles tendon has a high incidence of ruptures often occurring in weekend warriors and the aging population. Based on anatomic studies of the Achilles tendon, ruptures are commonly found in the watershed area proximal to the insertion site. Traditionally, treatment options included conservative therapy with immobilization and a prolonged non-weight-bearing phase versus surgical treatment. Surgical treatment can vary between open, minimally invasive, or percutaneous approaches. In more recent years, early functional rehabilitation with or without surgery has shown to have successful results.
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Affiliation(s)
- Varsha Salunkhe Ivanova
- Kaiser Permanente Foot and Ankle Surgery, 700 Lawrence Expressway, Santa Clara, CA 95051, USA.
| | - Khanh Phuong Sieu Tong
- Kaiser Permanente Foot and Ankle Surgery, 700 Lawrence Expressway, Santa Clara, CA 95051, USA
| | - Cristian Neagu
- Kaiser Permanente Santa Clara Foot and Ankle Surgery, 700 Lawrence Expressway, Santa Clara, CA 95051, USA
| | - Christy M King
- Kaiser Permanente, Department of Foot & Ankle Surgery, 3600 Broadway, Clinic 17, Oakland, CA 94611, USA; Kaiser San Francisco Bay Area Foot & Ankle Residency Program, Oakland, CA, USA
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Wu CX, Xiong CY, Bai L, Chen SM, Yan YX, Wang L, Zhang XT. Achilles tendon thickening does not affect elasticity and functional outcome after surgical repair of Achilles rupture: A retrospective study. Chin J Traumatol 2023; 26:323-328. [PMID: 37940448 PMCID: PMC10755773 DOI: 10.1016/j.cjtee.2023.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/21/2023] [Accepted: 10/01/2023] [Indexed: 11/10/2023] Open
Abstract
PURPOSE Previous studies have confirmed that Achilles tendon occurs Achilles thickening after repair surgery of the rupture. Although this mechanism has been elucidated in the laboratory, there are few reports on its impact on clinical function. We designed a retrospective study to investigate the Achilles thickening after Achilles tendon rupture repair and its correlation between the elasticity and postoperative function. METHODS In this retrospective analysis, patients who underwent surgical treatment for acute Achilles tendon rupture from April 2016 to April 2020 were included. All the patients were regularly followed up at 3 months, 1 year, and 2 years after surgery. American Orthopaedic Foot Ankle Surgeon (AOFAS) scale and Leppilahti score were used to evaluate functional outcomes. Achilles elasticity was measured by ultrasound shear wave of elasticity. Achilles thickening was calculated as maximal transverse and longitudinal diameter in cross-sectional plane of magnetic resonance scan. Sample t-tests was used for different follow-up periods. Correlation between Achilles thickening and other factors were analyzed using Pearson's method. p < 0.05 indicates a statistically significant difference. RESULTS AOFAS scale and Leppilahti score at 1 year were significantly higher than at 3 months postoperatively (both p < 0.001). These functional scales were also improved at 2-year follow-up significantly (both p < 0.001). The dorsiflexion difference showed gradually recovery in each follow-up period (t = -17.907, p < 0.001). The elasticity of the Achilles appeared to continuously decreases during the postoperative follow-up period in all position sets (p < 0.001). In thickening evaluation, the cross-sectional area of the thickest plane of Achilles was significantly higher at 1 year postoperatively (310.5 ± 25.2) mm2 than that at 3 months postoperatively ((278.0 ± 26.2) mm2, t = -8.219, p < 0.001) and became thinner in 2-year magnetic resonance scan ((256.1 ± 15.1) mm2, t = 16.769, p < 0.001). The correlations between Achilles thickening, elasticity, and functional outcome did not show statistical significance (p > 0.05) in every follow-up period. CONCLUSION Achilles tendon thickens after surgery in the 1st year, but begins to gradually return to thinning about 2 years after surgery. There was no significant correlation between the increase and decrease of thickening and the patients' clinical function scores, Achilles elasticity, and bilateral ankle dorsiflexion difference.
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Affiliation(s)
- Chen-Xi Wu
- Department of Sports Medicine Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong province, China
| | - Chang-Yue Xiong
- Department of Sports Medicine Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong province, China
| | - Lu Bai
- Department of Sports Medicine Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong province, China.
| | - Su-Meng Chen
- Department of Sports Medicine Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong province, China
| | - Yu-Xin Yan
- Department of Sports Medicine Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong province, China
| | - Lu Wang
- Department of Statistics and Mathematical Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong province, China
| | - Xin-Tao Zhang
- Department of Sports Medicine Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong province, China
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Kaneda G, Chan JL, Castaneda CM, Papalamprou A, Sheyn J, Shelest O, Huang D, Kluser N, Yu V, Ignacio GC, Gertych A, Yoshida R, Metzger M, Tawackoli W, Vernengo A, Sheyn D. iPSC-derived tenocytes seeded on microgrooved 3D printed scaffolds for Achilles tendon regeneration. J Orthop Res 2023; 41:2205-2220. [PMID: 36961351 PMCID: PMC10518032 DOI: 10.1002/jor.25554] [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: 11/03/2022] [Revised: 03/06/2023] [Accepted: 03/11/2023] [Indexed: 03/25/2023]
Abstract
Tendons and ligaments have a poor innate healing capacity, yet account for 50% of musculoskeletal injuries in the United States. Full structure and function restoration postinjury remains an unmet clinical need. This study aimed to assess the application of novel three dimensional (3D) printed scaffolds and induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) overexpressing the transcription factor Scleraxis (SCX, iMSCSCX+ ) as a new strategy for tendon defect repair. The polycaprolactone (PCL) scaffolds were fabricated by extrusion through a patterned nozzle or conventional round nozzle. Scaffolds were seeded with iMSCSCX+ and outcomes were assessed in vitro via gene expression analysis and immunofluorescence. In vivo, rat Achilles tendon defects were repaired with iMSCSCX+ -seeded microgrooved scaffolds, microgrooved scaffolds only, or suture only and assessed via gait, gene expression, biomechanical testing, histology, and immunofluorescence. iMSCSCX+ -seeded on microgrooved scaffolds showed upregulation of tendon markers and increased organization and linearity of cells compared to non-patterned scaffolds in vitro. In vivo gait analysis showed improvement in the Scaffold + iMSCSCX+ -treated group compared to the controls. Tensile testing of the tendons demonstrated improved biomechanical properties of the Scaffold + iMSCSCX+ group compared with the controls. Histology and immunofluorescence demonstrated more regular tissue formation in the Scaffold + iMSCSCX+ group. This study demonstrates the potential of 3D-printed scaffolds with cell-instructive surface topography seeded with iMSCSCX+ as an approach to tendon defect repair. Further studies of cell-scaffold constructs can potentially revolutionize tendon reconstruction by advancing the application of 3D printing-based technologies toward patient-specific therapies that improve healing and functional outcomes at both the cellular and tissue level.
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Affiliation(s)
- Giselle Kaneda
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Julie L Chan
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Chloe M Castaneda
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Angela Papalamprou
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Julia Sheyn
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Oksana Shelest
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Dave Huang
- Orthopedics Biomechanics Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA
| | | | - Victoria Yu
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Gian C Ignacio
- Orthopedics Biomechanics Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Arkadiusz Gertych
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Ryu Yoshida
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Melodie Metzger
- Orthopedics Biomechanics Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Wafa Tawackoli
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA
| | | | - Dmitriy Sheyn
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA
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Liang W, Zhou C, Meng Y, Fu L, Zeng B, Liu Z, Ming W, Long H. An overview of the material science and knowledge of nanomedicine, bioscaffolds, and tissue engineering for tendon restoration. Front Bioeng Biotechnol 2023; 11:1199220. [PMID: 37388772 PMCID: PMC10306281 DOI: 10.3389/fbioe.2023.1199220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 05/29/2023] [Indexed: 07/01/2023] Open
Abstract
Tendon wounds are a worldwide health issue affecting millions of people annually. Due to the characteristics of tendons, their natural restoration is a complicated and lengthy process. With the advancement of bioengineering, biomaterials, and cell biology, a new science, tissue engineering, has developed. In this field, numerous ways have been offered. As increasingly intricate and natural structures resembling tendons are produced, the results are encouraging. This study highlights the nature of the tendon and the standard cures that have thus far been utilized. Then, a comparison is made between the many tendon tissue engineering methodologies proposed to date, concentrating on the ingredients required to gain the structures that enable appropriate tendon renewal: cells, growth factors, scaffolds, and scaffold formation methods. The analysis of all these factors enables a global understanding of the impact of each component employed in tendon restoration, thereby shedding light on potential future approaches involving the creation of novel combinations of materials, cells, designs, and bioactive molecules for the restoration of a functional tendon.
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Affiliation(s)
- Wenqing Liang
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, Zhejiang, China
| | - Chao Zhou
- Department of Orthopedics, Zhoushan Guanghua Hospital, Zhoushan, Zhejiang, China
| | - Yanfeng Meng
- Department of Orthopedics, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China
| | - Lifeng Fu
- Department of Orthopedics, Shaoxing City Keqiao District Hospital of Traditional Chinese Medicine, Shaoxing, Zhejiang, China
| | - Bin Zeng
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, Zhejiang, China
| | - Zunyong Liu
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, Zhejiang, China
| | - Wenyi Ming
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, Zhejiang, China
| | - Hengguo Long
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, Zhejiang, China
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9
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Zhang G, Zhou X, Hu S, Jin Y, Qiu Z. Large animal models for the study of tendinopathy. Front Cell Dev Biol 2022; 10:1031638. [PMID: 36393858 PMCID: PMC9640604 DOI: 10.3389/fcell.2022.1031638] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/12/2022] [Indexed: 11/23/2022] Open
Abstract
Tendinopathy has a high incidence in athletes and the aging population. It can cause pain and movement disorders, and is one of the most difficult problems in orthopedics. Animal models of tendinopathy provide potentially efficient and effective means to develop understanding of human tendinopathy and its underlying pathological mechanisms and treatments. The selection of preclinical models is essential to ensure the successful translation of effective and innovative treatments into clinical practice. Large animals can be used in both micro- and macro-level research owing to their similarity to humans in size, structure, and function. This article reviews the application of large animal models in tendinopathy regarding injuries to four tendons: rotator cuff, patellar ligament, Achilles tendon, and flexor tendon. The advantages and disadvantages of studying tendinopathy with large animal models are summarized. It is hoped that, with further development of animal models of tendinopathy, new strategies for the prevention and treatment of tendinopathy in humans will be developed.
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Affiliation(s)
- Guorong Zhang
- School of Clinical Medicine, Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Xuyan Zhou
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Shuang Hu
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Ye Jin
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Ye Jin, ; Zhidong Qiu,
| | - Zhidong Qiu
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Ye Jin, ; Zhidong Qiu,
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10
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Russo V, Mauro A, Peserico A, Di Giacinto O, Khatib ME, Citeroni MR, Rossi E, Canciello A, Mazzotti E, Barboni B. Tendon Healing Response Is Dependent on Epithelial-Mesenchymal-Tendon Transition State of Amniotic Epithelial Stem Cells. Biomedicines 2022; 10:biomedicines10051177. [PMID: 35625913 PMCID: PMC9138831 DOI: 10.3390/biomedicines10051177] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/05/2022] [Accepted: 05/17/2022] [Indexed: 11/24/2022] Open
Abstract
Tendinopathies are at the frontier of advanced responses to health challenges and sectoral policy targets. Cell-based therapy holds great promise for tendon disorder resolution. To verify the role of stepwise trans-differentiation of amniotic epithelial stem cells (AECs) in tendon regeneration, in the present research three different AEC subsets displaying an epithelial (eAECs), mesenchymal (mAECs), and tendon-like (tdAECs) phenotype were allotransplanted in a validated experimental sheep Achilles tendon injury model. Tissue healing was analyzed adopting a comparative approach at two early healing endpoints (14 and 28 days). All three subsets of transplanted cells were able to accelerate regeneration: mAECs with a lesser extent than eAECs and tdAECs as indicated in the summary of the total histological scores (TSH), where at day 28 eAECs and tdAECs had better significant scores with respect to mAEC-treated tendons (p < 0.0001). In addition, the immunomodulatory response at day 14 showed in eAEC-transplanted tendons an upregulation of pro-regenerative M2 macrophages with respect to mAECs and tdAECs (p < 0.0001). In addition, in all allotransplanted tendons there was a favorable IL10/IL12 compared to CTR (p < 0.001). The eAECs and tdAECs displayed two different underlying regenerative mechanisms in the tendon. The eAECs positively influenced regeneration mainly through their greater ability to convey in the host tissue the shift from pro-inflammatory to pro-regenerative responses, leading to an ordered extracellular matrix (ECM) deposition and blood vessel remodeling. On the other hand, the transplantation of tdAECs acted mainly on the proliferative phase by impacting the density of ECM and by supporting a prompt recovery, inducing a low cellularity and angle alignment of the host cell compartment. These results support the idea that AECs lay the groundwork for production of different cell phenotypes that can orient tendon regeneration through a crosstalk with the host tissue. In particular, the obtained evidence suggests that eAECs are a practicable and efficient strategy for the treatment of acute tendinopathies, thus reinforcing the grounds to move their use towards clinical practice.
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Affiliation(s)
- Valentina Russo
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
- Correspondence:
| | - Annunziata Mauro
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
| | - Alessia Peserico
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
| | - Oriana Di Giacinto
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
| | - Mohammad El Khatib
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
| | - Maria Rita Citeroni
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
| | - Emanuela Rossi
- Istituto Zooprofilattico Sperimentale dell’Abruzzo e del Molise “Giuseppe Caporale”, 64100 Teramo, Italy;
| | - Angelo Canciello
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
| | - Eleonora Mazzotti
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
| | - Barbara Barboni
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
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11
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Kosiol J, Keiler A, Loizides A, Gruber H, Henninger B, Bölderl A, Gruber L. Operative versus conservative treatment of acute Achilles tendon ruptures: preliminary results of clinical outcome, kinematic MRI and contrast-enhanced ultrasound. Arch Orthop Trauma Surg 2022; 143:2455-2465. [PMID: 35567608 PMCID: PMC10110640 DOI: 10.1007/s00402-022-04457-7] [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] [Received: 02/04/2022] [Accepted: 04/15/2022] [Indexed: 12/28/2022]
Abstract
INTRODUCTION There is no uniform consensus on the gold standard therapy for acute Achilles tendon rupture. The aim of this pilot study was to compare operative and conservative treatment regarding imaging findings and clinical outcome. MATERIALS AND METHODS Surgically or conservatively treated patients with acute Achilles tendon rupture were retrospectively evaluated. Differences in tendon length and diameter with and without load were analysed using kinematic MRI, tendon perfusion, structural alterations, movement and scar tissue by means of grey-scale and contrast-enhanced ultrasound (CEUS). Intra- and interobserver agreement were recorded. RESULTS No significant difference was detected regarding clinical outcome, B mode ultrasonography, contrast-enhanced sonography or MRI findings, although alterations in MRI-based measurements of tendon elasticity were found for both groups. Considerable elongation and thickening of the injured tendon were detected in both groups. CONCLUSION Both, conservative and surgical treatment showed comparable outcomes in our preliminary results and may suggest non-inferiority of a conservative approach.
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Affiliation(s)
- Juana Kosiol
- Department of Orthopaedics and Traumatology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Alexander Keiler
- Department of Orthopaedics and Traumatology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
| | - Alexander Loizides
- Department of Radiology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Hannes Gruber
- Department of Radiology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Benjamin Henninger
- Department of Radiology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Andreas Bölderl
- Department of Orthopaedics and Traumatology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Leonhard Gruber
- Department of Radiology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
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12
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Wellings EP, Huang TCT, Li J, Peterson TE, Hooke AW, Rosenbaum A, Zhao CD, Behfar A, Moran SL, Houdek MT. Intrinsic Tendon Regeneration After Application of Purified Exosome Product: An In Vivo Study. Orthop J Sports Med 2022; 9:23259671211062929. [PMID: 34988236 PMCID: PMC8721391 DOI: 10.1177/23259671211062929] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/03/2021] [Indexed: 01/27/2023] Open
Abstract
Background: Tendons are primarily acellular, limiting their intrinsic regenerative capabilities. This limited regenerative potential contributes to delayed healing, rupture, and adhesion formation after tendon injury. Purpose: To determine if a tendon’s intrinsic regenerative potential could be improved after the application of a purified exosome product (PEP) when loaded onto a collagen scaffold. Study Design: Controlled laboratory study. Methods: An in vivo rabbit Achilles tendon model was used and consisted of 3 groups: (1) Achilles tenotomy with suture repair, (2) Achilles tenotomy with suture repair and collagen scaffold, and (3) Achilles tenotomy with suture repair and collagen scaffold loaded with PEP at 1 × 1012 exosomes/mL. Each group consisted of 15 rabbits for a total of 45 specimens. Mechanical and histologic analyses were performed at both 3 and 6 weeks. Results: The load to failure and ultimate tensile stress were found to be similar across all groups (P ≥ .15). The tendon cross-sectional area was significantly smaller for tendons treated with PEP compared with the control groups at 6 weeks, which was primarily related to an absence of external adhesions (P = .04). Histologic analysis confirmed these findings, demonstrating significantly lower adhesion grade both macroscopically (P = .0006) and microscopically (P = .0062) when tendons were treated with PEP. Immunohistochemical staining showed a greater intensity for type 1 collagen for PEP-treated tendons compared with collagen-only or control tendons. Conclusion: Mechanical and histologic results suggested that healing in the PEP-treated group favored intrinsic healing (absence of adhesions) while control animals and animals treated with collagen only healed primarily via extrinsic scar formation. Despite a smaller cross-sectional area, treated tendons had the same ultimate tensile stress. This pilot investigation shows promise for PEP as a means of effectively treating tendon injuries and enhancing intrinsic healing. Clinical Relevance: The production of a cell-free, off-the-shelf product that can promote tendon regeneration would provide a viable solution for physicians and patients to enhance tendon healing and decrease adhesions as well as shorten the time required to return to work or sports.
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Affiliation(s)
| | | | - Jialun Li
- Division of Plastic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Timothy E Peterson
- Department of Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Van Cleve Cardiac Regeneration Medicine Program, Mayo Clinic, Rochester, Minnesota, USA
| | - Alexander W Hooke
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Andrew Rosenbaum
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - Chunfeng D Zhao
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Atta Behfar
- Department of Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Van Cleve Cardiac Regeneration Medicine Program, Mayo Clinic, Rochester, Minnesota, USA
| | - Steven L Moran
- Division of Plastic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Matthew T Houdek
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
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13
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Tendon Tissue Repair in Prospective of Drug Delivery, Regenerative Medicines, and Innovative Bioscaffolds. Stem Cells Int 2021; 2021:1488829. [PMID: 34824586 PMCID: PMC8610661 DOI: 10.1155/2021/1488829] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 09/09/2021] [Indexed: 02/06/2023] Open
Abstract
The natural healing capacity of the tendon tissue is limited due to the hypovascular and cellular nature of this tissue. So far, several conventional approaches have been tested for tendon repair to accelerate the healing process, but all these approaches have their own advantages and limitations. Regenerative medicine and tissue engineering are interdisciplinary fields that aspire to develop novel medical devices, innovative bioscaffold, and nanomedicine, by combining different cell sources, biodegradable materials, immune modulators, and nanoparticles for tendon tissue repair. Different studies supported the idea that bioscaffolds can provide an alternative for tendon augmentation with an enormous therapeutic potentiality. However, available data are lacking to allow definitive conclusion on the use of bioscaffolds for tendon regeneration and repairing. In this review, we provide an overview of the current basic understanding and material science in the field of bioscaffolds, nanomedicine, and tissue engineering for tendon repair.
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14
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Kim WJ, Jung KJ, Ahn H, Yeo ED, Lee HS, Won SH, Lee DW, Ji JY, Yoon SJ, Hong YC. Reconstruction of a Neglected, Extensor Hallucis Longus Tendon Rupture Using Interposed Scar Tissue: A Case Report and Literature Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph182212157. [PMID: 34831920 PMCID: PMC8619473 DOI: 10.3390/ijerph182212157] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 11/25/2022]
Abstract
Injury of the extensor hallucis longus (EHL) tendon is relatively rare, but surgical repair is necessary to prevent deformity and gait disturbance. Primary suturing is possible if the condition is acute, but not when it is chronic. The scar tissue between the ruptured ends is a proliferative tissue composed of fibroblasts and collagen fibers. Given the histological similarity to normal tendons, several studies have reported tendon reconstruction using scar tissue. Here, we report a reconstruction of a neglected EHL rupture using interposed scar tissue. A 54-year-old female visited our clinic with a weak extension of a big toe. She had dropped a knife on her foot a month prior, but did not go to hospital. The wound had healed, but she noted dysfunctional extension of the toe and increasing pain. Magnetic resonance imaging (MRI) revealed that EHL continuity was lost and that the proximal tendon stump was displaced toward the midfoot. Scar tissue running in the direction of the original ligament was observed between the ruptured ends. In the surgical field, the scar tissue formed a shape similar to the extensor tendon. Therefore, we performed tendon reconstruction using the interposed scar tissue. For the first 2 postoperative weeks, the ankle and foot were immobilized to protect the repair. Six weeks after surgery, the patient commenced full weight-bearing. At the 3-month follow-up, active extension of the hallux was possible, with a full range of motion. The patient did not feel any discomfort during daily life. Postoperative MRI performed at 1 year revealed that the reconstructed EHL exhibited homogeneously low signal intensity, and was continuous. The AOFAS Hallux Metatarsophalangeal-Interphalangeal scale improved from 57 to 90 points and the FAAM scores improved from 74% to 95% (the Activities of Daily Living subscale) and from 64% to 94% (the Sports subscale). Scar tissue reconstruction is as effective as tendon autografting or allografting, eliminates the risk of donor site morbidity and infection, and requires only a small incision and a short operative time.
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Affiliation(s)
- Woo-Jong Kim
- Department of Orthopaedic Surgery, Soonchunhyang University Hospital Cheonan, 31, Suncheonhyang 6-gil, Dongam-gu, Cheonan 31151, Korea; (W.-J.K.); (K.-J.J.); (S.-J.Y.)
| | - Ki-Jin Jung
- Department of Orthopaedic Surgery, Soonchunhyang University Hospital Cheonan, 31, Suncheonhyang 6-gil, Dongam-gu, Cheonan 31151, Korea; (W.-J.K.); (K.-J.J.); (S.-J.Y.)
| | - Hyein Ahn
- Department of Pathology, Soonchunhyang University Hospital Cheonan, 31, Suncheonhyang 6-gil, Dongam-gu, Cheonan 31151, Korea;
| | - Eui-Dong Yeo
- Department of Orthopaedic Surgery, Veterans Health Service Medical Center, Seoul 05368, Korea;
| | - Hong-Seop Lee
- Department of Foot and Ankle Surgery, Nowon Eulji Medical Center, Eulji University, 68, Hangeulbiseok-ro, Nowon-gu, Seoul 01830, Korea;
| | - Sung-Hun Won
- Department of Orthopaedic Surgery, Soonchunhyang University Hospital Seoul, 59, Daesagwan-ro, Yongsan-gu, Seoul 04401, Korea;
| | - Dhong-Won Lee
- Department of Orthopaedic Surgery, Konkuk University Medical Center, 120-1, Neungdong-ro, Gwangjin-gu, Seoul 05030, Korea;
| | - Jae-Young Ji
- Department of Anesthesiology and Pain Medicine, Soonchunhyang University Hospital Cheonan, 31, Suncheonhyang 6-gil, Dongam-gu, Cheonan 31151, Korea;
| | - Sung-Joon Yoon
- Department of Orthopaedic Surgery, Soonchunhyang University Hospital Cheonan, 31, Suncheonhyang 6-gil, Dongam-gu, Cheonan 31151, Korea; (W.-J.K.); (K.-J.J.); (S.-J.Y.)
| | - Yong-Cheol Hong
- Department of Orthopaedic Surgery, Soonchunhyang University Hospital Cheonan, 31, Suncheonhyang 6-gil, Dongam-gu, Cheonan 31151, Korea; (W.-J.K.); (K.-J.J.); (S.-J.Y.)
- Correspondence: ; Tel.: +82-41-570-2170
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15
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Tuncer K, Demir M, Şenocak E, Mendil AS, Gezer A, Pür B, Öztürk R. The effects of Tendoflex® (polytendon complex) and Hypericum perforatum (St. John's wort oil) on repaired Achilles tendon healing in rats. Jt Dis Relat Surg 2021; 32:676-687. [PMID: 34842100 PMCID: PMC8650663 DOI: 10.52312/jdrs.2021.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 07/16/2021] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES This experimental study aims to examine the effects of Tendoflex® and Hypericum perforatum on tendon healing in rat models undergoing iatrogenic Achilles tendon rupture and similar surgical treatments. MATERIALS AND METHODS Eighty Wistar albino rats weighing 250 to 350 g were randomly divided into four groups. Group A: Tendoflex® was administered orally as 1 capsule/2.5 kg daily by gavage. Group B: Hypericum perforatum was administered orally as 300 mg/kg daily by gavage. Group C: Tendoflex® and Hypericum perforatum were co-administered orally by gavage at the prespecified doses. Group D: No medication was given to the control group. Five rats from each group were sacrificed weekly, and the tissue samples were examined histologically, followed by the biomechanical tests of the Achilles tendon. RESULTS In the mechanical testing, pulling forces were superior in all intervention groups and in all weeks over the control group. In particular, in the early periods (Weeks 1, 2, and 3), the mixed group showed the most favorable results, followed by the Hypericum perforatum group (p=0.010, p=0.591, and p=0.130, respectively). The most favorable collagen type I and type III expression values were found in the mixed and Hypericum perforatum groups at Weeks 2 and 3, respectively (p=0.025 and p=0.018). In the immunohistochemical and Western Blot examinations, extreme collagen type I and type III expression were detected in the mixed and Hypericum perforatum groups at Weeks 2, 3, and 4. CONCLUSION Tensile strength of the Achilles tendon increased by using Hypericum perforatum and Tendoflex® following rupture and repair of the Achilles tendon in rats. The combined use of these two agents yielded the most favorable mechanical and histological results, particularly in the early period. This result may be related to the higher level of collagen type I and type III immunity in all groups, compared to the control group.
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Affiliation(s)
| | | | | | | | | | | | - Recep Öztürk
- Dr. Abdurrahman Yurtaslan Ankara Onkoloji Eğitim ve Araştırma Hastanesi, Ortopedi ve Travmatoloji Kliniği, 06200 Yenimahalle, Ankara, Türkiye.
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16
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Zhao J, Wang X, Han J, Yu Y, Chen F, Yao J. Boost Tendon/Ligament Repair With Biomimetic and Smart Cellular Constructs. Front Bioeng Biotechnol 2021; 9:726041. [PMID: 34532315 PMCID: PMC8438196 DOI: 10.3389/fbioe.2021.726041] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 07/22/2021] [Indexed: 12/11/2022] Open
Abstract
Tendon and ligament are soft connective tissues that play essential roles in transmitting forces from muscle to bone or bone to bone. Despite significant progress made in the field of ligament and tendon regeneration over the past decades, many strategies struggle to recapitulate basic structure-function criteria of native ligament/tendon. The goal here is to provide a fundamental understanding of the structure and composition of ligament/tendon and highlight few key challenges in functional regeneration of these connective tissues. The remainder of the review will examine several biomaterials strategies including biomimetic scaffold with non-linear mechanical behavior, hydrogel patch with anisotropic adhesion and gene-activated scaffold for interactive healing of tendon/ligament. Finally, emerging technologies and research avenues are suggested that have the potential to enhance treatment outcomes of tendon/ligament injuries.
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Affiliation(s)
- Jianping Zhao
- Department of Orthopedics Trauma and Hand Surgery & Guangxi Key Laboratory of Regenerative Medicine, International Joint Laboratory on Regeneration of Bone and Soft Tissue, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.,Center for Materials Synthetic Biology, Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Xiang Wang
- Center for Materials Synthetic Biology, Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Jinyu Han
- Center for Materials Synthetic Biology, Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Yin Yu
- Center for Materials Synthetic Biology, Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Fei Chen
- Center for Materials Synthetic Biology, Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Jun Yao
- Department of Orthopedics Trauma and Hand Surgery & Guangxi Key Laboratory of Regenerative Medicine, International Joint Laboratory on Regeneration of Bone and Soft Tissue, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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17
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Ding L, Wang M, Qin S, Xu L. The Roles of MicroRNAs in Tendon Healing and Regeneration. Front Cell Dev Biol 2021; 9:687117. [PMID: 34277629 PMCID: PMC8283311 DOI: 10.3389/fcell.2021.687117] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/11/2021] [Indexed: 01/20/2023] Open
Abstract
Tendons connect the muscle abdomen of skeletal muscles to the bone, which transmits the force generated by the muscle abdomen contraction and pulls the bone into motion. Tendon injury is a common clinical condition occurring in certain populations, such as repeated tendon strains in athletes. And it can lead to substantial pain and loss of motor function, in severe cases, significant disability. Tendon healing and regeneration have attracted growing interests. Some treatments including growth factors, stem cell therapies and rehabilitation programs have been tried to improve tendon healing. However, the basic cellular biology and pathology of tendons are still not fully understood, and the management of tendon injury remains a considerable challenge. Regulating gene expression at post-transcriptional level, microRNA (miRNA) has been increasingly recognized as essential regulators in the biological processes of tendon healing and regeneration. A wide range of miRNAs in tendon injury have been shown to play vital roles in maintaining and regulating its physiological function, as well as regulating the tenogenic differentiation potential of stem cells. In this review, we show the summary of the latest information on the role of miRNAs in tendon healing and regeneration, and also discuss potentials for miRNA-directed diagnosis and therapy in tendon injuries and tendinopathy, which may provide new theoretical foundation for tenogenesis and tendon healing.
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Affiliation(s)
- Lingli Ding
- Lingnan Medical Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Min Wang
- Lingnan Medical Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shengnan Qin
- Department of Orthopaedics, Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, China
| | - Liangliang Xu
- Lingnan Medical Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
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18
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Stäudle B, Seynnes O, Laps G, Göll F, Brüggemann GP, Albracht K. Recovery from Achilles Tendon Repair: A Combination of Postsurgery Outcomes and Insufficient Remodeling of Muscle and Tendon. Med Sci Sports Exerc 2021; 53:1356-1366. [PMID: 33433154 DOI: 10.1249/mss.0000000000002592] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
INTRODUCTION Achilles tendon rupture (ATR) patients have persistent functional deficits in the triceps surae muscle-tendon unit (MTU). The complex remodeling of the MTU accompanying these deficits remains poorly understood. The purpose of the present study was to associate in vivo and in silico data to investigate the relations between changes in MTU properties and strength deficits in ATR patients. METHODS Eleven male subjects who had undergone surgical repair of complete unilateral ATR were examined 4.6 ± 2.0 (mean ± SD) yr after rupture. Gastrocnemius medialis (GM) tendon stiffness, morphology, and muscle architecture were determined using ultrasonography. The force-length relation of the plantar flexor muscles was assessed at five ankle joint angles. In addition, simulations (OpenSim) of the GM MTU force-length properties were performed with various iterations of MTU properties found between the unaffected and the affected side. RESULTS The affected side of the patients displayed a longer, larger, and stiffer GM tendon (13% ± 10%, 105% ± 28%, and 54% ± 24%, respectively) compared with the unaffected side. The GM muscle fascicles of the affected side were shorter (32% ± 12%) and with greater pennation angles (31% ± 26%). A mean deficit in plantarflexion moment of 31% ± 10% was measured. Simulations indicate that pairing an intact muscle with a longer tendon shifts the optimal angular range of peak force outside physiological angular ranges, whereas the shorter muscle fascicles and tendon stiffening seen in the affected side decrease this shift, albeit incompletely. CONCLUSIONS These results suggest that the substantial changes in MTU properties found in ATR patients may partly result from compensatory remodeling, although this process appears insufficient to fully restore muscle function.
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Affiliation(s)
| | - Olivier Seynnes
- Department of Physical Performance, Norwegian School of Sport Sciences, Oslo, NORWAY
| | - Guido Laps
- Orthopaedie am Guerzenich, Cologne, GERMANY
| | - Fabian Göll
- Institute of Movement and Neurosciences, German Sport University Cologne, Cologne, GERMANY
| | - Gert-Peter Brüggemann
- Institute of Biomechanics and Orthopaedics, German Sport University Cologne, Cologne, GERMANY
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19
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Species variations in tenocytes' response to inflammation require careful selection of animal models for tendon research. Sci Rep 2021; 11:12451. [PMID: 34127759 PMCID: PMC8203623 DOI: 10.1038/s41598-021-91914-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 05/24/2021] [Indexed: 01/23/2023] Open
Abstract
For research on tendon injury, many different animal models are utilized; however, the extent to which these species simulate the clinical condition and disease pathophysiology has not yet been critically evaluated. Considering the importance of inflammation in tendon disease, this study compared the cellular and molecular features of inflammation in tenocytes of humans and four common model species (mouse, rat, sheep, and horse). While mouse and rat tenocytes most closely equalled human tenocytes’ low proliferation capacity and the negligible effect of inflammation on proliferation, the wound closure speed of humans was best approximated by rats and horses. The overall gene expression of human tenocytes was most similar to mice under healthy, to horses under transient and to sheep under constant inflammatory conditions. Humans were best matched by mice and horses in their tendon marker and collagen expression, by horses in extracellular matrix remodelling genes, and by rats in inflammatory mediators. As no single animal model perfectly replicates the clinical condition and sufficiently emulates human tenocytes, fit-for-purpose selection of the model species for each specific research question and combination of data from multiple species will be essential to optimize translational predictive validity.
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Molecular Mechanisms of Fetal Tendon Regeneration Versus Adult Fibrous Repair. Int J Mol Sci 2021; 22:ijms22115619. [PMID: 34070692 PMCID: PMC8198517 DOI: 10.3390/ijms22115619] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 05/22/2021] [Accepted: 05/23/2021] [Indexed: 12/31/2022] Open
Abstract
Tendinopathies are painful, disabling conditions that afflict 25% of the adult human population. Filling an unmet need for realistic large-animal models, we here present an ovine model of tendon injury for the comparative study of adult scarring repair and fetal regeneration. Complete regeneration of the fetal tendon within 28 days is demonstrated, while adult tendon defects remained macroscopically and histologically evident five months post-injury. In addition to a comprehensive histological assessment, proteome analyses of secretomes were performed. Confirming histological data, a specific and pronounced inflammation accompanied by activation of neutrophils in adult tendon defects was observed, corroborated by the significant up-regulation of pro-inflammatory factors, neutrophil attracting chemokines, the release of potentially tissue-damaging antimicrobial and extracellular matrix-degrading enzymes, and a response to oxidative stress. In contrast, secreted proteins of injured fetal tendons included proteins initiating the resolution of inflammation or promoting functional extracellular matrix production. These results demonstrate the power and relevance of our novel ovine fetal tendon regeneration model, which thus promises to accelerate research in the field. First insights from the model already support our molecular understanding of successful fetal tendon healing processes and may guide improved therapeutic strategies.
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21
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Gleich J, Milz S, Ockert B. [Principles of tendon healing at the shoulder and consequences for their treatment : Importance of platelet-rich plasma and regenerative medicine]. Unfallchirurg 2020; 124:89-95. [PMID: 33346862 DOI: 10.1007/s00113-020-00941-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/03/2020] [Indexed: 11/30/2022]
Abstract
Tendon pathologies are a frequent cause of shoulder pain and can lead to significant decline in the quality of life. Conservative treatment is suitable for most tendon pathologies. In addition to classical conservative treatment options, such as physiotherapy, oral analgesia and infiltrations, there are a number of additive treatment options to promote structural tendon healing and clinical outcome. Furthermore, there are approaches to improve the results of the surgical treatment of tendon injuries by biological augmentation. The objective of this article is to give an overview of biological and regenerative therapeutic options in the treatment of tendon injuries of the shoulder. Therefore, the anatomical and molecular biological principles of the tendon structure and their importance for tendon healing are explained in order to highlight the various therapeutic options for daily practice. Biological augmentation procedures and regenerative medicine represent a promising therapeutic option for tendon injuries of the shoulder, however, the benefits are so far supported by little or no evidence at all.
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Affiliation(s)
- J Gleich
- Sektion Schulter- und Ellenbogenchirurgie, Klinik für Allgemeine, Unfall- und Wiederherstellungschirurgie, LMU Klinikum, Ludwig-Maximilians-Universität München, Nussbaumstr. 20, 80336, München, Deutschland.
| | - S Milz
- Anatomische Anstalt, Ludwig-Maximilians-Universität, München, Deutschland
| | - B Ockert
- Sektion Schulter- und Ellenbogenchirurgie, Klinik für Allgemeine, Unfall- und Wiederherstellungschirurgie, LMU Klinikum, Ludwig-Maximilians-Universität München, Nussbaumstr. 20, 80336, München, Deutschland
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22
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Bian X, Liu T, Yang M, Gu C, He G, Zhou M, Tang H, Lu K, Lai F, Wang F, Yang Q, Gustafsson JÅ, Fan X, Tang K. The absence of oestrogen receptor beta disturbs collagen I type deposition during Achilles tendon healing by regulating the IRF5-CCL3 axis. J Cell Mol Med 2020; 24:9925-9935. [PMID: 32776630 PMCID: PMC7520326 DOI: 10.1111/jcmm.15592] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 06/11/2020] [Accepted: 06/17/2020] [Indexed: 12/15/2022] Open
Abstract
Achilles tendon healing (ATH) remains an unanswered question in the field of sports medicine because it does not produce tissue with homology to the previously uninjured tissue. Oestrogen receptor β (ERβ) is involved in the injury and repair processes of tendons. Our previous study confirmed that ERβ plays a role in the early stage of ATH by affecting adipogenesis, but its role in extracellular matrix (ECM) remodelling is unknown. We established a 4‐week Achilles tendon repair model to investigate the mechanism through which ERβ affects ATH at the very beginning of ECM remodelling phase. In vitro studies were performed using tendon‐derived stem cells (TDSCs) due to their promising role in tendon healing. Behavioural and biomechanical tests revealed that ERβ‐deficient mice exhibit weaker mobility and inferior biomechanical properties, and immunofluorescence staining and qRT‐PCR showed that these mice exhibited an erroneous ECM composition, as mainly characterized by decreased collagen type I (Col I) deposition. The changes in gene expression profiles between ERβ‐knockout and WT mice at 1 week were analysed by RNA sequencing to identify factors affecting Col I deposition. The results highlighted the IRF5‐CCL3 axis, and this finding was verified with CCL3‐treated TDSCs. These findings revealed that ERβ regulates Col I deposition during ATH via the IRF5‐CCL3 axis.
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Affiliation(s)
- Xuting Bian
- Department of Orthopedic Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Tianyao Liu
- Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University, Army Medical University, Chongqing, China
| | - Mingyu Yang
- Department of Orthopedic Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Chengyi Gu
- Department of Orthopedic Surgery, Affiliated Renhe Hospital of China Three Gorges University, China Three Gorges University, Yichang, China
| | - Gang He
- Department of Orthopedic Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Mei Zhou
- Department of Orthopedic Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Hong Tang
- Department of Orthopedic Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Kang Lu
- Department of Orthopedic Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Fan Lai
- Department of Orthopedic Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Feng Wang
- Department of Orthopedic Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Qiandong Yang
- Department of Orthopedic Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Jan-Åke Gustafsson
- Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA.,Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institute, Novum, Sweden
| | - Xiaotang Fan
- Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University, Army Medical University, Chongqing, China
| | - Kanglai Tang
- Department of Orthopedic Surgery, Southwest Hospital, Army Medical University, Chongqing, China
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23
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No YJ, Castilho M, Ramaswamy Y, Zreiqat H. Role of Biomaterials and Controlled Architecture on Tendon/Ligament Repair and Regeneration. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2020; 32:e1904511. [PMID: 31814177 DOI: 10.1002/adma.201904511] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 11/10/2019] [Indexed: 06/10/2023]
Abstract
Engineering synthetic scaffolds to repair and regenerate ruptured native tendon and ligament (T/L) tissues is a significant engineering challenge due to the need to satisfy both the unique biological and biomechanical properties of these tissues. Long-term clinical outcomes of synthetic scaffolds relying solely on high uniaxial tensile strength are poor with high rates of implant rupture and synovitis. Ideal biomaterials for T/L repair and regeneration need to possess the appropriate biological and biomechanical properties necessary for the successful repair and regeneration of ruptured tendon and ligament tissues.
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Affiliation(s)
- Young Jung No
- Biomaterials and Tissue Engineering Research Unit, School of Biomedical Engineering, University of Sydney, Sydney, NSW, 2006, Australia
- Australian Research Council Training Centre for Innovative BioEngineering, Sydney, NSW, 2006, Australia
| | - Miguel Castilho
- Department of Orthopedics, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
- Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB, Eindhoven, The Netherlands
| | - Yogambha Ramaswamy
- Biomaterials and Tissue Engineering Research Unit, School of Biomedical Engineering, University of Sydney, Sydney, NSW, 2006, Australia
- Australian Research Council Training Centre for Innovative BioEngineering, Sydney, NSW, 2006, Australia
| | - Hala Zreiqat
- Biomaterials and Tissue Engineering Research Unit, School of Biomedical Engineering, University of Sydney, Sydney, NSW, 2006, Australia
- Australian Research Council Training Centre for Innovative BioEngineering, Sydney, NSW, 2006, Australia
- Radcliffe Institute for Advanced Study, Harvard University, Cambridge, MA, 02138, USA
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24
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Ribitsch I, Gueltekin S, Keith MF, Minichmair K, Peham C, Jenner F, Egerbacher M. Age-related changes of tendon fibril micro-morphology and gene expression. J Anat 2019; 236:688-700. [PMID: 31792963 PMCID: PMC7083562 DOI: 10.1111/joa.13125] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2019] [Indexed: 12/15/2022] Open
Abstract
Aging is hypothesized to be associated with changes in tendon matrix composition which may lead to alteration of tendon material properties and hence propensity to injury. Altered gene expression may offer insights into disease pathophysiology and thus open new perspectives toward designing pathophysiology‐driven therapeutics. Therefore, the current study aimed at identifying naturally occurring differences in tendon micro‐morphology and gene expression of newborn, young and old horses. Age‐related differences in the distribution pattern of tendon fibril thickness and in the expression of the tendon relevant genes collagen type 1 (Col1), Col3, Col5, tenascin‐C, decorin, tenomodulin, versican, scleraxis and cartilage oligomeric matrix protein were investigated. A qualitative and quantitative gene expression and collagen fibril diameter analysis was performed for the most frequently injured equine tendon, the superficial digital flexor tendon, in comparison with the deep digital flexor tendon. Most analyzed genes (Col1, Col3, Col5, tenascin‐C, tenomodulin, scleraxis) were expressed at a higher level in foals (age ≤ 6 months) than in horses of 2.75 years (age at which flexor tendons become mature in structure) and older, decorin expression increased with age. Decorin was previously reported to inhibit the lateral fusion of collagen fibrils, causing a thinner fibril diameter with increased decorin concentration. The results of this study suggested that reduction of tendon fibril diameters commonly seen in equine tendons with increasing age might be a natural age‐related phenomenon leading to greater fibril surface areas with increased fibrillar interaction and reduced sliding at the fascicular/fibrillar interface and hence a stiffer interfascicular/interfibrillar matrix. This may be a potential reason for the higher propensity to tendinopathies with increasing age.
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Affiliation(s)
- Iris Ribitsch
- Department for Companion Animals and Horses, Veterm, University Equine Hospital, Vetmeduni Vienna, Vienna, Austria
| | - Sinan Gueltekin
- Department for Companion Animals and Horses, Veterm, University Equine Hospital, Vetmeduni Vienna, Vienna, Austria
| | - Marlies Franziska Keith
- Department of Pathobiology, Unit of Histology and Embryology, Vetmeduni Vienna, Vienna, Austria
| | - Kristina Minichmair
- Department of Pathobiology, Unit of Histology and Embryology, Vetmeduni Vienna, Vienna, Austria
| | - Christian Peham
- Department for Companion Animals and Horses, Veterm, University Equine Hospital, Vetmeduni Vienna, Vienna, Austria
| | - Florien Jenner
- Department for Companion Animals and Horses, Veterm, University Equine Hospital, Vetmeduni Vienna, Vienna, Austria
| | - Monika Egerbacher
- Department of Pathobiology, Unit of Histology and Embryology, Vetmeduni Vienna, Vienna, Austria
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25
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Lim WL, Liau LL, Ng MH, Chowdhury SR, Law JX. Current Progress in Tendon and Ligament Tissue Engineering. Tissue Eng Regen Med 2019; 16:549-571. [PMID: 31824819 PMCID: PMC6879704 DOI: 10.1007/s13770-019-00196-w] [Citation(s) in RCA: 126] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 05/07/2019] [Accepted: 05/22/2019] [Indexed: 02/08/2023] Open
Abstract
Background Tendon and ligament injuries accounted for 30% of all musculoskeletal consultations with 4 million new incidences worldwide each year and thus imposed a significant burden to the society and the economy. Damaged tendon and ligament can severely affect the normal body movement and might lead to many complications if not treated promptly and adequately. Current conventional treatment through surgical repair and tissue graft are ineffective with a high rate of recurrence. Methods In this review, we first discussed the anatomy, physiology and pathophysiology of tendon and ligament injuries and its current treatment. Secondly, we explored the current role of tendon and ligament tissue engineering, describing its recent advances. After that, we also described stem cell and cell secreted product approaches in tendon and ligament injuries. Lastly, we examined the role of the bioreactor and mechanical loading in in vitro maturation of engineered tendon and ligament. Results Tissue engineering offers various alternative ways of treatment from biological tissue constructs to stem cell therapy and cell secreted products. Bioreactor with mechanical stimulation is instrumental in preparing mature engineered tendon and ligament substitutes in vitro. Conclusions Tissue engineering showed great promise in replacing the damaged tendon and ligament. However, more study is needed to develop ideal engineered tendon and ligament.
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Affiliation(s)
- Wei Lee Lim
- Tissue Engineering Centre, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Kuala Lumpur, Malaysia
| | - Ling Ling Liau
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, JalanYaacob Latif, 56000 Kuala Lumpur, Malaysia
| | - Min Hwei Ng
- Tissue Engineering Centre, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Kuala Lumpur, Malaysia
| | - Shiplu Roy Chowdhury
- Tissue Engineering Centre, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Kuala Lumpur, Malaysia
| | - Jia Xian Law
- Tissue Engineering Centre, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Kuala Lumpur, Malaysia
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26
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Baldwin M, Snelling S, Dakin S, Carr A. Augmenting endogenous repair of soft tissues with nanofibre scaffolds. J R Soc Interface 2019; 15:rsif.2018.0019. [PMID: 29695606 DOI: 10.1098/rsif.2018.0019] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 04/04/2018] [Indexed: 12/21/2022] Open
Abstract
As our ability to engineer nanoscale materials has developed we can now influence endogenous cellular processes with increasing precision. Consequently, the use of biomaterials to induce and guide the repair and regeneration of tissues is a rapidly developing area. This review focuses on soft tissue engineering, it will discuss the types of biomaterial scaffolds available before exploring physical, chemical and biological modifications to synthetic scaffolds. We will consider how these properties, in combination, can provide a precise design process, with the potential to meet the requirements of the injured and diseased soft tissue niche. Finally, we frame our discussions within clinical trial design and the regulatory framework, the consideration of which is fundamental to the successful translation of new biomaterials.
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Affiliation(s)
- Mathew Baldwin
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Sarah Snelling
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Stephanie Dakin
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Andrew Carr
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
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27
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Barboni B, Russo V, Berardinelli P, Mauro A, Valbonetti L, Sanyal H, Canciello A, Greco L, Muttini A, Gatta V, Stuppia L, Mattioli M. Placental Stem Cells from Domestic Animals: Translational Potential and Clinical Relevance. Cell Transplant 2019; 27:93-116. [PMID: 29562773 PMCID: PMC6434480 DOI: 10.1177/0963689717724797] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The field of regenerative medicine is moving toward clinical practice in veterinary science. In this context, placenta-derived stem cells isolated from domestic animals have covered a dual role, acting both as therapies for patients and as a valuable cell source for translational models. The biological properties of placenta-derived cells, comparable among mammals, make them attractive candidates for therapeutic approaches. In particular, stemness features, low immunogenicity, immunomodulatory activity, multilineage plasticity, and their successful capacity for long-term engraftment in different host tissues after autotransplantation, allo-transplantation, or xenotransplantation have been demonstrated. Their beneficial regenerative effects in domestic animals have been proven using preclinical studies as well as clinical trials starting to define the mechanisms involved. This is, in particular, for amniotic-derived cells that have been thoroughly studied to date. The regenerative role arises from a mutual tissue-specific cell differentiation and from the paracrine secretion of bioactive molecules that ultimately drive crucial repair processes in host tissues (e.g., anti-inflammatory, antifibrotic, angiogenic, and neurogenic factors). The knowledge acquired so far on the mechanisms of placenta-derived stem cells in animal models represent the proof of concept of their successful use in some therapeutic treatments such as for musculoskeletal disorders. In the next future, legislation in veterinary regenerative medicine will be a key element in order to certify those placenta-derived cell-based protocols that have already demonstrated their safety and efficacy using rigorous approaches and to improve the degree of standardization of cell-based treatments among veterinary clinicians.
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Affiliation(s)
- B Barboni
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - V Russo
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - P Berardinelli
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - A Mauro
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - L Valbonetti
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - H Sanyal
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - A Canciello
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - L Greco
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - A Muttini
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - V Gatta
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - L Stuppia
- 2 Medical Genetics, University "G. d'Annunzio" of Chieti Pescara, Chieti, Italy
| | - M Mattioli
- 3 Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise "G. Caporale," Teramo, Italy
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28
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Abstract
Objectives The incidence of acute Achilles tendon rupture appears to be increasing. The aim of this study was to summarize various therapies for acute Achilles tendon rupture and discuss their relative merits. Methods A PubMed search about the management of acute Achilles tendon rupture was performed. The search was open for original manuscripts and review papers limited to publication from January 2006 to July 2017. A total of 489 papers were identified initially and finally 323 articles were suitable for this review. Results The treatments of acute Achilles tendon rupture include operative and nonoperative treatments. Operative treatments mainly consist of open repair, percutaneous repair, mini-open repair, and augmentative repair. Traditional open repair has lower re-rupture rates with higher risks of complications. Percutaneous repair and mini-open repair show similar re-rupture rates but lower overall complication rates when compared with open repair. Percutaneous repair requires vigilance against nerve damage. Functional rehabilitation combining protected weight-bearing and early controlled motion can effectively reduce re-rupture rates with satisfactory outcomes. Biological adjuncts help accelerating tendon healing by adhering rupture ends or releasing highly complex pools of signalling factors. Conclusion The optimum treatment for complete rupture remains controversial. Both mini-open repair and functional protocols are attractive alternatives, while biotherapy is a potential future development. Cite this article: X. Yang, H. Meng, Q. Quan, J. Peng, S. Lu, A. Wang. Management of acute Achilles tendon ruptures: A review. Bone Joint Res 2018;7:561–569. DOI: 10.1302/2046-3758.710.BJR-2018-0004.R2.
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Affiliation(s)
- X Yang
- Department of Orthopedic Surgery, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing Key Lab of Regenerative Medicine in Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - H Meng
- Department of Orthopedic Surgery, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing Key Lab of Regenerative Medicine in Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - Q Quan
- Department of Orthopedic Surgery, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing Key Lab of Regenerative Medicine in Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - J Peng
- Department of Orthopedic Surgery, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing Key Lab of Regenerative Medicine in Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - S Lu
- Department of Orthopedic Surgery, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing Key Lab of Regenerative Medicine in Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - A Wang
- Department of Orthopedic Surgery, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing Key Lab of Regenerative Medicine in Orthopedics, Chinese PLA General Hospital, Beijing, China
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Abstract
This is a study of amniotic epithelial cells, which form the innermost layer of the amniotic membrane. These cells can be easily isolated and display peculiar and unique properties, such as plasticity and differentiation potential toward the 3 germinal layers, that may aid regeneration and/or repair of damaged or diseased tissues and organs. A robust literature based on in vitro, experimental, and clinical studies in large animals demonstrates that these cells can enhance the regeneration of tendons, bone, and articular cartilage. On the basis of these considerations, allotransplantation of human amniotic epithelial cells could be proposed for clinical trials in human orthopedic conditions.
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30
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Lipar M, Zdilar B, Kreszinger M, Ćorić M, Radišić B, Samardžija M, Žic R, Pećin M. Extracellular matrix supports healing of transected rabbit Achilles tendon. Heliyon 2018; 4:e00781. [PMID: 30225380 PMCID: PMC6138787 DOI: 10.1016/j.heliyon.2018.e00781] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Revised: 07/20/2018] [Accepted: 09/06/2018] [Indexed: 01/17/2023] Open
Abstract
Extracellular matrix (ECM) has been intensively used in cardio surgery. The main goal of this research was to determine if Achilles tendon healing could be promoted by applying extracellular matrix scaffold (CorMatrix®, USA). Sixteen (n = 16) New Zealand white mature rabbits (Oryctolagus cuniculus) were randomly allocated into two groups. Following complete surgical transection, rabbits in group A (ECM applied) (n = 8) had their Achilles tendons reconstructed using both, nylon suture and extracellular matrix scaffold, whereas in group B (without ECM) the tendons were reconstructed using nylon suture only. After four weeks, the rabbits were euthanized and tendon samples harvested and stained with hematoxylin eosin, Mallory, and Gomory and subsequently histologically analyzed according to modified Bonnar scale. Group B had significantly stronger inflammatory response, including abundant cell infiltration and neovascularization. In group A collagen fibers were predominantly found, whereas in group B reticular fibers were more abundant. Extracellular matrix scaffold has been found to have the real potential for promoting tendon healing through accelerating collagen formation, which is crucial for restoring biomechanical properties of a tendon, decreasing peritendineous adhesion formation, and reducing inflammatory edema and subsequently pain.
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Affiliation(s)
- Marija Lipar
- Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55, 10000 Zagreb, Croatia
| | - Boris Zdilar
- Hospital Sveti Duh, Ulica Sveti Duh 1, 10000 Zagreb, Croatia
| | - Mario Kreszinger
- Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55, 10000 Zagreb, Croatia
| | - Marijana Ćorić
- School of Medicine, University of Zagreb, Ulica Šalata 2, 10000 Zagreb, Croatia
| | - Berislav Radišić
- Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55, 10000 Zagreb, Croatia
| | - Marko Samardžija
- Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55, 10000 Zagreb, Croatia
| | - Rado Žic
- School of Medicine, University of Zagreb, Ulica Šalata 2, 10000 Zagreb, Croatia
| | - Marko Pećin
- Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55, 10000 Zagreb, Croatia
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31
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Hiramatsu K, Tsujii A, Nakamura N, Mitsuoka T. Ultrasonographic Evaluation of the Early Healing Process After Achilles Tendon Repair. Orthop J Sports Med 2018; 6:2325967118789883. [PMID: 30135861 PMCID: PMC6090484 DOI: 10.1177/2325967118789883] [Citation(s) in RCA: 7] [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] [Indexed: 01/14/2023] Open
Abstract
Background: Little is known about early healing of repaired Achilles tendons on imaging, particularly up to 6 months postoperatively, when patients generally return to participation in sports. Purpose: To examine changes in repaired Achilles tendon healing with ultrasonography for up to 12 months after surgery. Study Design: Case series; Level of evidence, 4. Methods: Ultrasonographic images of 26 ruptured Achilles tendons were analyzed at 1, 2, 3, 4, 6, and 12 months after primary repair. The cross-sectional areas (CSAs) and intratendinous morphology of the repaired tendons were evaluated using the authors’ own grading system (tendon repair scores), which assessed the anechoic tendon defect area, intratendinous hyperechoic area, continuity of intratendinous fibrillar appearance, and paratendinous edema. Results: The mean ratios (%) of the CSA for the affected versus unaffected side of repaired Achilles tendons gradually increased postoperatively, reached a maximum (632%) at 6 months, and then decreased at 12 months. The mean tendon repair scores increased over time and reached a plateau at 6 months. Conclusion: Ultrasonography is useful to observe the intratendinous morphology of repaired Achilles tendons and to provide useful information for patients who wish to return to sports. Clinical parameters such as strength, functional performance, and quality of healed repaired tendons should also be assessed before allowing patients to return to sports.
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Affiliation(s)
- Kunihiko Hiramatsu
- Department of Orthopaedic Surgery, Yao Municipal Hospital, Yao, Japan.,Department of Orthopaedic Surgery, Tamai Orthopaedic Hospital, Hannan, Japan
| | - Akira Tsujii
- Department of Orthopaedic Surgery, Yao Municipal Hospital, Yao, Japan.,Department of Orthopaedic Surgery, Hoshigaoka Medical Center, Hirakata, Japan
| | - Norimasa Nakamura
- Institute for Medical Science in Sports, Osaka Health Science University, Osaka, Japan
| | - Tomoki Mitsuoka
- Department of Orthopaedic Surgery, Yao Municipal Hospital, Yao, Japan
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Ribitsch I, Mayer RL, Egerbacher M, Gabner S, Kańduła MM, Rosser J, Haltmayer E, Auer U, Gültekin S, Huber J, Bileck A, Kreil DP, Gerner C, Jenner F. Fetal articular cartilage regeneration versus adult fibrocartilaginous repair: secretome proteomics unravels molecular mechanisms in an ovine model. Dis Model Mech 2018; 11:11/7/dmm033092. [PMID: 29991479 PMCID: PMC6078409 DOI: 10.1242/dmm.033092] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 05/18/2018] [Indexed: 12/27/2022] Open
Abstract
Osteoarthritis (OA), a degenerative joint disease characterized by progressive cartilage degeneration, is one of the leading causes of disability worldwide owing to the limited regenerative capacity of adult articular cartilage. Currently, there are no disease-modifying pharmacological or surgical therapies for OA. Fetal mammals, in contrast to adults, are capable of regenerating injured cartilage in the first two trimesters of gestation. A deeper understanding of the properties intrinsic to the response of fetal tissue to injury would allow us to modulate the way in which adult tissue responds to injury. In this study, we employed secretome proteomics to compare fetal and adult protein regulation in response to cartilage injury using an ovine cartilage defect model. The most relevant events comprised proteins associated with the immune response and inflammation, proteins specific for cartilage tissue and cartilage development, and proteins involved in cell growth and proliferation. Alarmins S100A8, S100A9 and S100A12 and coiled-coil domain containing 88A (CCDC88A), which are associated with inflammatory processes, were found to be significantly upregulated following injury in adult, but not in fetal animals. By contrast, cartilage-specific proteins like proteoglycan 4 were upregulated in response to injury only in fetal sheep postinjury. Our results demonstrate the power and relevance of the ovine fetal cartilage regeneration model presented here for the first time. The identification of previously unrecognized modulatory proteins that plausibly affect the healing process holds great promise for potential therapeutic interventions. Summary: Secretome proteomics identifies differential regulation of inflammation modulators during fetal and adult articular cartilage defect healing, offering novel strategies for therapy.
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Affiliation(s)
- Iris Ribitsch
- VETERM, University Equine Hospital, University of Veterinary Medicine Vienna, Vienna 1210, Austria
| | - Rupert L Mayer
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
| | - Monika Egerbacher
- Histology & Embryology, Department of Pathobiology, University of Veterinary Medicine Vienna, Vienna 1210, Austria
| | - Simone Gabner
- Histology & Embryology, Department of Pathobiology, University of Veterinary Medicine Vienna, Vienna 1210, Austria
| | - Maciej M Kańduła
- Department of Biotechnology, Boku University Vienna, Vienna 1180, Austria.,Institute of Bioinformatics, Johannes Kepler University, Linz 4040, Austria
| | - Julie Rosser
- VETERM, University Equine Hospital, University of Veterinary Medicine Vienna, Vienna 1210, Austria
| | - Eva Haltmayer
- VETERM, University Equine Hospital, University of Veterinary Medicine Vienna, Vienna 1210, Austria
| | - Ulrike Auer
- Department of Companion Animals and Horses, University of Veterinary Medicine Vienna, Vienna 1210, Austria
| | - Sinan Gültekin
- VETERM, University Equine Hospital, University of Veterinary Medicine Vienna, Vienna 1210, Austria
| | - Johann Huber
- Teaching and Research Farm Kremesberg, Clinical Unit for Herd Health Management in Ruminants, Department for Farm Animals and Veterinary Public Health, University of Veterinary Medicine Vienna, Vienna 1210, Austria
| | - Andrea Bileck
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
| | - David P Kreil
- Department of Biotechnology, Boku University Vienna, Vienna 1180, Austria
| | - Christopher Gerner
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
| | - Florien Jenner
- VETERM, University Equine Hospital, University of Veterinary Medicine Vienna, Vienna 1210, Austria
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Sun J, Mou C, Shi Q, Chen B, Hou X, Zhang W, Li X, Zhuang Y, Shi J, Chen Y, Dai J. Controlled release of collagen-binding SDF-1α from the collagen scaffold promoted tendon regeneration in a rat Achilles tendon defect model. Biomaterials 2018; 162:22-33. [DOI: 10.1016/j.biomaterials.2018.02.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 01/21/2018] [Accepted: 02/02/2018] [Indexed: 10/18/2022]
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Barboni B, Russo V, Gatta V, Bernabò N, Berardinelli P, Mauro A, Martelli A, Valbonetti L, Muttini A, Di Giacinto O, Turriani M, Silini A, Calabrese G, Abate M, Parolini O, Stuppia L, Mattioli M. Therapeutic potential of hAECs for early Achilles tendon defect repair through regeneration. J Tissue Eng Regen Med 2017; 12:e1594-e1608. [PMID: 29024514 DOI: 10.1002/term.2584] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 09/26/2017] [Accepted: 09/29/2017] [Indexed: 12/26/2022]
Abstract
Cell-based therapy holds great promise for tendon disorders, a widespread debilitating musculoskeletal condition. Even if the cell line remains to be defined, preliminary evidences have proven that amniotic-derived cells possess in vitro and in vivo a great tenogenic potential. This study investigated the efficacy of transplanted human amniotic epithelial cells (hAECs) by testing their early regenerative properties and mechanisms involved on a validated ovine Achilles tendon partial defect performed on 29 animals. The injured tendons treated with hAECs recovered rapidly, in 28 days, structural and biomechanical properties undertaking a programmed tissue regeneration, differently from the spontaneous healing tissues. hAECs remained viable within the host tendons establishing with the endogenous progenitor cells an active dialogue. Through the secretion of modulatory factors, hAECs inhibited the inflammatory cells infiltration, activated the M2 macrophage subpopulation early recruitment, and accelerated blood vessel as well as extracellular matrix remodelling. In parallel, some in situ differentiated hAECs displayed a tenocytelike phenotype. Both paracrine and direct hAECs stimulatory effects were confirmed analysing their genome profile before and after transplantation. The 49 human up-regulated transcripts recorded in transplanted hAECs belonged to tendon lineage differentiation (epithelial-mesenchymal transition, connective specific matrix components, and skeleton or muscle system development-related transcripts), as well as the in situ activation of paracrine signalling involved in inflammatory and immunomodulatory response. Altogether, these evidences support the hypothesis that hAECs are a practicable and efficient strategy for the acute treatment of tendinopathy, reinforcing the idea of a concrete use of amniotic epithelial cells towards the clinical practice.
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Affiliation(s)
- Barbara Barboni
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Valentina Russo
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Valentina Gatta
- Medical Genetics, University "G. d'Annunzio" of Chieti Pescara, Chieti, Italy
| | - Nicola Bernabò
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Paolo Berardinelli
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Annunziata Mauro
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Alessandra Martelli
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Luca Valbonetti
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Aurelio Muttini
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Oriana Di Giacinto
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Maura Turriani
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Antonietta Silini
- Centro di Ricerca "E. Menni", Fondazione Poliambulanza-Istituto Ospedaliero, Brescia, Italy
| | - Giuseppe Calabrese
- Medical Genetics, University "G. d'Annunzio" of Chieti Pescara, Chieti, Italy
| | - Michele Abate
- Department of Medicine and Science of Aging, University "G. d'Annunzio" Chieti Pescara, Chieti, Italy
| | - Ornella Parolini
- Centro di Ricerca "E. Menni", Fondazione Poliambulanza-Istituto Ospedaliero, Brescia, Italy
| | - Liborio Stuppia
- Medical Genetics, University "G. d'Annunzio" of Chieti Pescara, Chieti, Italy
| | - Mauro Mattioli
- Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise "G. Caporale", Teramo, Italy
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Open Repair of Quadriceps Tendon With Suture Anchors and Semitendinosus Tendon Allograft Augmentation. Arthrosc Tech 2017; 6:e2071-e2077. [PMID: 29348999 PMCID: PMC5766257 DOI: 10.1016/j.eats.2017.08.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 08/04/2017] [Indexed: 02/03/2023] Open
Abstract
Quadriceps tendinopathy in an increasingly recognized diagnosis can lead to quadriceps tendon rupture, especially in the older population. It can be caused by repeated micro trauma or also predisposed by systemic diseases such as diabetes mellitus and connective tissue disorders that can in turn lead to extensor mechanism deficits. Although a trial of conservative treatment is advocated, operative treatment should be performed in cases of persistent pain, extension deficit, or complete rupture of the tendon. The purpose of this Technical Note is to describe in detail a procedure for open repair of a quadriceps tendon, with significant degeneration due to quadriceps tendinopathy, using suture anchors and semitendinosus tendon allograft augmentation.
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Haen TX, Roux A, Soubeyrand M, Laporte S. Shear waves elastography for assessment of human Achilles tendon's biomechanical properties: an experimental study. J Mech Behav Biomed Mater 2017; 69:178-184. [PMID: 28086149 DOI: 10.1016/j.jmbbm.2017.01.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 12/30/2016] [Accepted: 01/04/2017] [Indexed: 11/20/2022]
Abstract
INTRODUCTION Achilles tendon is the most frequently ruptured tendon, but its optimal treatment is increasingly controversial. The mechanical properties of the healing tendon should be studied further. Shear waves elastography (SWE) measures the shear modulus, which is proven to be correlated to elastic modulus in animal tendons. The aim of our study was to study whether the shear moduli of human cadaveric Achilles tendon, given by SWE, were correlated with the apparent elastic moduli of those tendons given by tensile tests. MATERIALS AND METHODS Fourteen cadaveric lower-limbs were studied. An elastographic study of the Achilles tendon (AT) was first done in clinical-like conditions. SWE was performed at three successive levels (0, 3 and 6cm from tendon insertion) with elastographic probe oriented parallel to tendon fibers, blindly, for three standardized ankle positions (25° plantar flexion, neutral position, and maximal dorsal flexion). The mean shear moduli were collected through blind offline data-analysis. Then, AT with triceps were harvested. They were subjected to tensile tests. A continuous SWE of the Achilles tendon was performed simultaneously. The apparent elastic modulus was obtained from the experimental stress-strain curve, and correlation with shear modulus (given by SWE) was studied. RESULTS Average shear moduli of harvested AT, given by SWE made an instant before the tensile tests, were significantly correlated with shear moduli of the same AT made at the same level, previously in clinical-like condition (p<0.05), only in neutral position. There was a statistical correlation (p<0.005) and a correlation coefficient R² equal to 0.95±0.05, between shear moduli (SWE) and apparent elastic moduli (tensile tests), for 11 tendons (3 tendons were inoperable due to technical error), before a constant disruption in the correlation curves. DISCUSSION We demonstrated a significant correlation between SWE of Achilles tendon performed in clinical-like conditions (in neutral position) and SWE performed in harvested tendon. We also found a correlation between SWE performed on harvested tendon and apparent elastic moduli obtained with tensile tests (for 11 specimens). As a consequence, we can suppose that SWE of AT in clinical-like conditions is related to tensile tests. To our knowledge, the ability of SWE to reliably assess biomechanical properties of a tendon or muscle was, so far, only demonstrated in animal models. CONCLUSION SWE can provide biomechanical information of the human AT non-invasively.
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Affiliation(s)
- T X Haen
- Arts et Metiers ParisTech, Institut de Biomécanique Humaine Georges Charpak, 151 bd de l'Hôpital, 75013 Paris, France; Service de Chirurgie Orthopédique, Hôpital Raymond Poincaré (A.P.-H.P), 104 bd Raymond Poincaré, 92380 Garches (Paris area), France.
| | - A Roux
- Arts et Metiers ParisTech, Institut de Biomécanique Humaine Georges Charpak, 151 bd de l'Hôpital, 75013 Paris, France
| | - M Soubeyrand
- Service de Chirurgie Orthopédique, Hôpital de Bicêtre (A.P.-H.P.), 78 rue du Général Leclerc, 94270 Le Kremlin-Bicêtre (Paris area), France
| | - S Laporte
- Arts et Metiers ParisTech, Institut de Biomécanique Humaine Georges Charpak, 151 bd de l'Hôpital, 75013 Paris, France
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Aujla R, Kumar A, Bhatia M. Non-surgical treatment of Achilles rupture: Does duration in functional weight bearing orthosis matter? Foot Ankle Surg 2016; 22:254-258. [PMID: 27810024 DOI: 10.1016/j.fas.2015.11.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 11/01/2015] [Accepted: 11/07/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND The treatment of acute Achilles tendon ruptures is continually being debated. The success of non-surgical regimes is now evident yet there remains a high rate of surgery in the United States of America and Scandinavia. Recent studies have investigated functional outcome rather than complication rates as primary outcome but the current data are still sparse. We aimed to investigate whether there is any difference in functional outcomes between two dynamic regimes of differing durations for acute Achilles tendon ruptures. METHODS The patients in the two groups were matched for age, gender, follow-up duration and mechanism of injury. Forty-four patients were managed in a regime of 11 weeks and another 44 patients for 8 weeks. Demographics, injury details, complications and functional outcome were recorded. The validated Achilles Tendon Rupture Score (ATRS) was used to assess functional outcomes. Minimum follow-up was 1 year. RESULTS The 11-week group had a mean age of 50.8 years (range: 27-80) with 36 (82%) males. The 8-week group had a mean age of 52.0 years (range: 32-77) with 36 (82%) males. The mean ATRS for the 11-week group was 76.0 (range: 8-100). The mean ATRS for the 8-week group was 76.1 (range: 30-100). There were no re-ruptures in the 11-week group and one in the 8-week group. There were three episodes of venous thromboembolism in the 11-week group and four in the 8-week group. CONCLUSION A reduction in duration of dynamic rehabilitation for non-operative treatment of Achilles tendon rupture from 11 weeks to 8 weeks does not lead to a significant detriment in functional outcomes or complication rates.
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Affiliation(s)
- Randeep Aujla
- Trauma & Orthopaedic Surgery, University Hospitals of Leicester, Leicester, United Kingdom.
| | - Amit Kumar
- Trauma & Orthopaedic Surgery, University Hospitals of Leicester, Leicester, United Kingdom
| | - Maneesh Bhatia
- Trauma & Orthopaedic Surgery, University Hospitals of Leicester, Leicester, United Kingdom
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Arble JR, Lalley AL, Dyment NA, Joshi P, Shin DG, Gooch C, Grawe B, Rowe D, Shearn JT. The LG/J murine strain exhibits near-normal tendon biomechanical properties following a full-length central patellar tendon defect. Connect Tissue Res 2016; 57:496-506. [PMID: 27552106 PMCID: PMC10552235 DOI: 10.1080/03008207.2016.1213247] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 07/08/2016] [Indexed: 02/03/2023]
Abstract
PURPOSE OF THE STUDY Identifying biological success criteria is needed to improve therapies, and one strategy for identifying them is to analyze the RNA transcriptome for successful and unsuccessful models of tendon healing. We have characterized the MRL/MpJ murine strain and found improved mechanical outcomes following a central patellar tendon (PT) injury. In this study, we evaluate the healing of the LG/J murine strain, which comprises 75% of the MRL/MpJ background, to determine if the LG/J also exhibits improved biomechanical properties following injury and to determine differentially expressed transcription factors across the C57BL/6, MRL/MpJ and the LG/J strains during the early stages of healing. MATERIALS AND METHODS A full-length, central PT defect was created in 16-20 week old MRL/MpJ, LG/J, and C57BL/6 murine strains. Mechanical properties were assessed at 2, 5, and 8 weeks post surgery. Transcriptomic expression was assessed at 3, 7, and 14 days following injury using a novel clustering software program to evaluate differential expression of transcription factors. RESULTS Average LG/J structural properties improved to 96.7% and 97.2% of native LG/J PT stiffness and ultimate load by 8 weeks post surgery, respectively. We found the LG/J responded by increasing expression of transcription factors implicated in the inflammatory response and collagen fibril organization. CONCLUSIONS The LG/J strain returns to normal structural properties by 8 weeks, with steadily increasing properties at each time point. Future work will characterize the cell populations responding to injury and investigate the role of the differentially expressed transcription factors during healing.
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Affiliation(s)
- Jessica R. Arble
- Biomedical Engineering Program, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH, USA
| | - Andrea L. Lalley
- Engineered Skin Laboratories, Shriners Hospital for Children, Cincinnati, OH, USA
| | - Nathaniel A. Dyment
- Department of Reconstructive Sciences, College of Dental Medicine, University of Connecticut Health Center, Farmington, CT, USA
| | - Pujan Joshi
- Computer Science and Engineering, University of Connecticut, Storrs, CT, USA
| | - Dong-Guk Shin
- Computer Science and Engineering, University of Connecticut, Storrs, CT, USA
| | - Cynthia Gooch
- Biomedical Engineering Program, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH, USA
| | - Brian Grawe
- Department of Orthopaedic Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - David Rowe
- Department of Reconstructive Sciences, College of Dental Medicine, University of Connecticut Health Center, Farmington, CT, USA
| | - Jason T. Shearn
- Biomedical Engineering Program, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH, USA
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Mauro A, Russo V, Di Marcantonio L, Berardinelli P, Martelli A, Muttini A, Mattioli M, Barboni B. M1 and M2 macrophage recruitment during tendon regeneration induced by amniotic epithelial cell allotransplantation in ovine. Res Vet Sci 2016; 105:92-102. [PMID: 27033915 DOI: 10.1016/j.rvsc.2016.01.014] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 11/25/2015] [Accepted: 01/19/2016] [Indexed: 12/31/2022]
Abstract
Recently, we have demonstrated that ovine amniotic epithelial cells (oAECs) allotransplanted into experimentally induced tendon lesions are able to stimulate tissue regeneration also by reducing leukocyte infiltration. Amongst leukocytes, macrophages (Mφ) M1 and M2 phenotype cells are known to mediate inflammatory and repairing processes, respectively. In this research it was investigated if, during tendon regeneration induced by AECs allotransplantation, M1Mφ and M2Mφ phenotype cells are recruited and differently distributed within the lesion site. Ovine AECs treated and untreated (Ctr) tendons were explanted at 7, 14, and 28 days and tissue microarchitecture was analyzed together with the distribution and quantification of leukocytes (CD45 positive), Mφ (CD68 pan positive), and M1Mφ (CD86, and IL12b) and M2Mφ (CD206, YM1 and IL10) phenotype related markers. In oAEC transplanted tendons CD45 and CD68 positive cells were always reduced in the lesion site. At day 14, oAEC treated tendons began to recover their microarchitecture, contextually a reduction of M1Mφ markers, mainly distributed close to oAECs, and an increase of M2Mφ markers was evidenced. CD206 positive cells were distributed near the regenerating areas. At day 28 oAECs treated tendons acquired a healthy-like structure with a reduction of M2Mφ. Differently, Ctr tendons maintained a disorganized morphology throughout the experimental time and constantly showed high values of M1Mφ markers. These findings indicate that M2Mφ recruitment could be correlated to tendon regeneration induced by oAECs allotransplantation. Moreover, these results demonstrate oAECs immunomodulatory role also in vivo and support novel insights into their allogeneic use underlying the resolution of tendon fibrosis.
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Affiliation(s)
- Annunziata Mauro
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy; StemTeCh Group, Italy
| | - Valentina Russo
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy; StemTeCh Group, Italy.
| | - Lisa Di Marcantonio
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy
| | - Paolo Berardinelli
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy
| | - Alessandra Martelli
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy
| | - Aurelio Muttini
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy; StemTeCh Group, Italy
| | - Mauro Mattioli
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy
| | - Barbara Barboni
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy; StemTeCh Group, Italy
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Martin JA, Biedrzycki AH, Lee KS, DeWall RJ, Brounts SH, Murphy WL, Markel MD, Thelen DG. In Vivo Measures of Shear Wave Speed as a Predictor of Tendon Elasticity and Strength. ULTRASOUND IN MEDICINE & BIOLOGY 2015; 41. [PMID: 26215492 PMCID: PMC4556570 DOI: 10.1016/j.ultrasmedbio.2015.06.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
The purpose of this study was to assess the potential for ultrasound shear wave elastography (SWE) to measure tissue elasticity and ultimate stress in both intact and healing tendons. The lateral gastrocnemius (Achilles) tendons of 41 New Zealand white rabbits were surgically severed and repaired with growth factor coated sutures. SWE imaging was used to measure shear wave speed (SWS) in both the medial and lateral tendons pre-surgery, and at 2 and 4 wk post-surgery. Rabbits were euthanized at 4 wk, and both medial and lateral tendons underwent mechanical testing to failure. SWS significantly (p < 0.001) decreased an average of 17% between the intact and post-surgical state across all tendons. SWS was significantly (p < 0.001) correlated with both the tendon elastic modulus (r = 0.52) and ultimate stress (r = 0.58). Thus, ultrasound SWE is a potentially promising non-invasive technology for quantitatively assessing the mechanical integrity of pre-operative and post-operative tendons.
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Affiliation(s)
- Jack A Martin
- Materials Science Program, University of Wisconsin-Madison, Madison, Wisconsin, USA.
| | - Adam H Biedrzycki
- School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Kenneth S Lee
- Department of Radiology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Ryan J DeWall
- Department of Radiology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Sabrina H Brounts
- School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - William L Murphy
- Materials Science Program, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Mechanical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Mark D Markel
- School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Darryl G Thelen
- Materials Science Program, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Mechanical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA
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Runesson E, Ackermann P, Karlsson J, Eriksson BI. Nucleostemin- and Oct 3/4-positive stem/progenitor cells exhibit disparate anatomical and temporal expression during rat Achilles tendon healing. BMC Musculoskelet Disord 2015; 16:212. [PMID: 26290425 PMCID: PMC4545962 DOI: 10.1186/s12891-015-0658-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 07/31/2015] [Indexed: 01/24/2023] Open
Abstract
Background The recent discovery of residing tendon stem/progenitor cells has triggered a growing interest in stem cells as a useful tool in tendon repair. Our knowledge of their involvement in naturally healing tendons is, however, sparse. The aim of this study was to identify and determine stem/progenitor cells in relation to different healing phases and regions in a rat model of Achilles tendon rupture. Methods Surgery was performed to create a mid-tendon rupture on the right Achilles tendon of 24 rats, whereas the left tendon was used as a control. Tendons were harvested at one, two, eight and 17 weeks post-rupture and stained with antibodies specific to stem/progenitor cells (Octamer-binding transcription factor 3/4 (Oct 3/4) and nucleostemin), migrating cells (Dynamin 2 (Dyn 2)) and leukocytes (CD45). A histological examination was performed on sections stained with Alcian blue. Results At one and two weeks post-rupture, a large number of stem/progenitor cells were discovered throughout the tendon. Most of these cells were nucleostemin positive, whereas only a few Oct 3/4-positive cells were found, mainly situated inside the injury region (I region). At eight and 17 weeks, the increment in stem/progenitor cells had diminished to equal that in the control tendons. At all time points, Oct 3/4-positive cells were also found in the connective tissue surrounding the tendon and at the muscle-tendon junction in both ruptured and control tendons and were often seen at the same location as the migration marker, Dyn 2. Conclusions The whole length of the Achilles tendon is infiltrated by stem/progenitor cells at early time points after a mid-tendon rupture. However, different stem/progenitor cell populations exhibit varying anatomical and temporal expressions during Achilles tendon healing, suggesting distinct reparative implications. Oct 3/4 may thus act as a more local, migrating stem/progenitor cell involved in injury-site-specific regenerative effects, as compared to the more general proliferative role of nucleostemin-positive stem/progenitor cells.
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Affiliation(s)
- Eva Runesson
- Department of Orthopaedics, Lundberg Laboratory for Orthopaedic Research, Institute of Clinical Sciences, University of Gothenburg, Gröna Stråket 12, Sahlgrenska University Hospital, SE-413 45, Gothenburg, Sweden.
| | - Paul Ackermann
- Integrative Orthopaedic Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
| | - Jón Karlsson
- Department of Orthopaedics, Lundberg Laboratory for Orthopaedic Research, Institute of Clinical Sciences, University of Gothenburg, Gröna Stråket 12, Sahlgrenska University Hospital, SE-413 45, Gothenburg, Sweden.
| | - Bengt I Eriksson
- Department of Orthopaedics, Lundberg Laboratory for Orthopaedic Research, Institute of Clinical Sciences, University of Gothenburg, Gröna Stråket 12, Sahlgrenska University Hospital, SE-413 45, Gothenburg, Sweden.
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Scharf A, Holmes S, Thoresen M, Mumaw J, Stumpf A, Peroni J. Superparamagnetic iron oxide nanoparticles as a means to track mesenchymal stem cells in a large animal model of tendon injury. CONTRAST MEDIA & MOLECULAR IMAGING 2015; 10:388-97. [PMID: 26033748 DOI: 10.1002/cmmi.1642] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Revised: 02/12/2015] [Accepted: 03/15/2015] [Indexed: 12/11/2022]
Abstract
The goal of this study was to establish an SPIO-based cell-tracking method in an ovine model of tendonitis and to determine if this method may be useful for further study of cellular therapies in tendonitis in vivo. Functional assays were performed on labeled and unlabeled cells to ensure that no significant changes were induced by intracellular SPIOs. Following biosafety validation, tendon lesions were mechanically (n = 4) or chemically (n = 4) induced in four sheep and scanned ex vivo at 7 and 14 days to determine the presence and distribution of intralesional cells. Ovine MSCs labeled with 50 µg SPIOs/mL remained viable, proliferate, and undergo tri-lineage differentiation (p < 0.05). Labeled ovine MSCs remained detectable in vitro in concentrated cell numbers as low as 10 000 and in volumetric distributions as low as 100 000 cells/mL. Cells remained detectable by MRI at 7 days, as confirmed by correlative histology for dually labeled SPIO+/GFP+ cells. Histological evidence at 14 days suggested that SPIO particles remained embedded in tissue, providing MRI signal, although cells were no longer present. SPIO labeling has proven to be an effective method for cell tracking for a large animal model of tendon injury for up to 7 days post-injection. The data obtained in this study justify further investigation into the effects of MSC survival and migration on overall tendon healing and tissue regeneration.
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Affiliation(s)
- Alexandra Scharf
- Department of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, H-322, Athens, GA, 30602, USA.,Department of Biological and Agricultural Engineering, College of Engineering, University of Georgia, Athens, GA, 30602, USA
| | - Shannon Holmes
- Veterinary Biosciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA
| | - Merrilee Thoresen
- Department of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, H-322, Athens, GA, 30602, USA
| | - Jennifer Mumaw
- Department of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, H-322, Athens, GA, 30602, USA
| | - Alaina Stumpf
- Department of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, H-322, Athens, GA, 30602, USA
| | - John Peroni
- Department of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, H-322, Athens, GA, 30602, USA
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Agres AN, Duda GN, Gehlen TJ, Arampatzis A, Taylor WR, Manegold S. Increased unilateral tendon stiffness and its effect on gait 2-6 years after Achilles tendon rupture. Scand J Med Sci Sports 2015; 25:860-7. [DOI: 10.1111/sms.12456] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/22/2015] [Indexed: 12/15/2022]
Affiliation(s)
- A. N. Agres
- Julius Wolff Institute; Charité - Universitätsmedizin Berlin; Berlin Germany
| | - G. N. Duda
- Julius Wolff Institute; Charité - Universitätsmedizin Berlin; Berlin Germany
| | - T. J. Gehlen
- Center for Musculoskeletal Surgery; Charité - Universitätsmedizin Berlin; Berlin Germany
| | - A. Arampatzis
- Department of Training and Movement Science; Humboldt University of Berlin; Berlin Germany
| | - W. R. Taylor
- Institute for Biomechanics; ETH Zurich; Zürich Switzerland
| | - S. Manegold
- Center for Musculoskeletal Surgery; Charité - Universitätsmedizin Berlin; Berlin Germany
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Russo V, Mauro A, Martelli A, Di Giacinto O, Di Marcantonio L, Nardinocchi D, Berardinelli P, Barboni B. Cellular and molecular maturation in fetal and adult ovine calcaneal tendons. J Anat 2014; 226:126-42. [PMID: 25546075 PMCID: PMC4304568 DOI: 10.1111/joa.12269] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/07/2014] [Indexed: 02/06/2023] Open
Abstract
Processes of development during fetal life profoundly transform tendons from a plastic tissue into a highly differentiated structure, characterised by a very low ability to regenerate after injury in adulthood. Sheep tendon is frequently used as a translational model to investigate cell-based regenerative approaches. However, in contrast to other species, analytical and comparative baseline studies on the normal developmental maturation of sheep tendons from fetal through to adult life are not currently available. Thus, a detailed morphological and biochemical study was designed to characterise tissue maturation during mid- (2 months of pregnancy: 14 cm of length) and late fetal (4 months: 40 cm of length) life, through to adulthood. The results confirm that ovine tendon morphology undergoes profound transformations during this period. Endotenon was more developed in fetal tendons than in adult tissues, and its cell phenotype changed through tendon maturation. Indeed, groups of large rounded cells laying on smaller and more compacted ones expressing osteocalcin, vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) were identified exclusively in fetal mid-stage tissues, and not in late fetal or adult tendons. VEGF, NGF as well as blood vessels and nerve fibers showed decreased expression during tendon development. Moreover, the endotenon of mid- and late fetuses contained identifiable cells that expressed several pluripotent stem cell markers [Telomerase Reverse Transcriptase (TERT), SRY Determining Region Y Box-2 (SOX2), Nanog Homeobox (NANOG) and Octamer Binding Transcription Factor-4A (OCT-4A)]. These cells were not identifiable in adult specimens. Ovine tendon development was also accompanied by morphological modifications to cell nuclei, and a progressive decrease in cellularity, proliferation index and expression of connexins 43 and 32. Tendon maturation was similarly characterised by modulation of several other gene expression profiles, including Collagen type I, Collagen type III, Scleraxis B, Tenomodulin, Trombospondin 4 and Osteocalcin. These gene profiles underwent a dramatic reduction in adult tissues. Transforming growth factor-1 expression (involved in collagen synthesis) underwent a similar decrease. In conclusion, these morphological studies carried out on sheep tendons at different stages of development and aging offer normal structural and molecular baseline data to allow accurate evaluation of data from subsequent interventional studies investigating tendon healing and regeneration in ovine experimental models.
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Sutured tendon repair; a multi-scale finite element model. Biomech Model Mechanobiol 2014; 14:123-33. [PMID: 24840732 PMCID: PMC4282689 DOI: 10.1007/s10237-014-0593-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Accepted: 05/05/2014] [Indexed: 12/12/2022]
Abstract
Following rupture, tendons are sutured to reapproximate the severed ends and permit healing. Several repair techniques are employed clinically, with recent focus towards high-strength sutures, permitting early active mobilisation thus improving resultant joint mobility. However, the arrangement of suture repairs locally alters the loading environment experienced by the tendon. The extent of the augmented stress distribution and its effect on the tissue is unknown. Stress distribution cannot be established using traditional tensile testing, in vivo, or ex vivo study of suture repairs. We have developed a 3D finite element model of a Kessler suture repair employing multiscale modelling to represent tendon microstructure and incorporate its highly orthotropic behaviour into the tissue description. This was informed by ex vivo tensile testing of porcine flexor digitorum profundus tendon. The transverse modulus of the tendon was 0.2551 \documentclass[12pt]{minimal}
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\begin{document}$$\pm $$\end{document}± 0.0454 MPa in proximal and distal tendon samples, respectively, and the interfibrillar tissue modulus ranged from 0.1021 to 0.0416 MPa. We observed an elliptically shaped region of high stress around the suture anchor, consistent with a known region of acellularity which develop 72 h post-operatively and remain for at least a year. We also observed a stress shielded region close to the severed tendon ends, which may impair collagen fibre realignment during the remodelling stage of repair due to the lack of tensile stress.
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Veres SP, Brennan-Pierce EP, Lee JM. Macrophage-like U937 cells recognize collagen fibrils with strain-induced discrete plasticity damage. J Biomed Mater Res A 2014; 103:397-408. [PMID: 24616426 DOI: 10.1002/jbm.a.35156] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Revised: 02/14/2014] [Accepted: 02/21/2014] [Indexed: 11/12/2022]
Abstract
At its essence, biomechanical injury to soft tissues or tissue products means damage to collagen fibrils. To restore function, damaged collagen must be identified, then repaired or replaced. It is unclear at present what the kernel features of fibrillar damage are, how phagocytic or synthetic cells identify that damage, and how they respond. We recently identified a nanostructural motif characteristic of overloaded collagen fibrils that we have termed discrete plasticity. In this study, we have demonstrated that U937 macrophage-like cells respond specifically to overload-damaged collagen fibrils. Tendons from steer tails were bisected, one half undergoing 15 cycles of subrupture mechanical overload and the other serving as an unloaded control. Both halves were decellularized, producing sterile collagen scaffolds that contained either undamaged collagen fibrils, or fibrils with discrete plasticity damage. Matched-pairs were cultured with U937 cells differentiated to a macrophage-like form directly on the substrate. Morphological responses of the U937 cells to the two substrates-and evidence of collagenolysis by the cells-were assessed using scanning electron microscopy. Enzyme release into medium was quantified for prototypic matrix metalloproteinase-1 (MMP-1) collagenase, and MMP-9 gelatinase. When adherent to damaged collagen fibrils, the cells clustered less, showed ruffled membranes, and frequently spread: increasing their contact area with the damaged substrate. There was clear structural evidence of pericellular enzymolysis of damaged collagen-but not of control collagen. Cells on damaged collagen also released significantly less MMP-9. These results show that U937 macrophage-like cells recognize strain-induced discrete plasticity damage in collagen fibrils: an ability that may be important to their removal or repair.
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Affiliation(s)
- Samuel P Veres
- Division of Engineering, Saint Mary's University, Halifax, Canada; School of Biomedical Engineering, Dalhousie University, Halifax, Canada
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Lee SH, Lee KB. Reconstruction of Chronic Extensor Hallucis Longus Tendon Rupture Using Interposed Scar Tissue: A Case Report. ACTA ACUST UNITED AC 2014. [DOI: 10.14193/jkfas.2014.18.4.208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Seung-Hun Lee
- Department of Orthopaedic Surgery, Chonnam National University Medical School, Gwangju, Korea
| | - Keun-Bae Lee
- Department of Orthopaedic Surgery, Chonnam National University Medical School, Gwangju, Korea
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Huri G, Biçer ÖS, Ozgözen L, Uçar Y, Garbis NG, Hyun YS. A novel repair method for the treatment of acute Achilles tendon rupture with minimally invasive approach using button implant: a biomechanical study. Foot Ankle Surg 2013; 19:261-6. [PMID: 24095235 DOI: 10.1016/j.fas.2013.06.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Revised: 05/15/2013] [Accepted: 06/25/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND Minimally invasive Q3 repair has been proposed for acute Achilles tendon rupture with low rate of complications. However there are still controversies about optimal technique. In this study we aimed to describe Endobutton-assisted modified Bunnell configuration as a new Achilles tendon repair technique and evaluate its biomechanical properties comparing with native tendon and Krackow technique. METHODS 27 ovine Achilles tendons were obtained and randomly placed into 3 groups with 9 specimens ineach. The Achilles tendons were repaired with Endobutton-assisted modified Bunnell technique in group 1, Krackow suture technique in group 2 and group 3 was defined as the control group including native tendons. Unidirectional tensile loading to failure was performed at 25mm/min. Biomechanicalproperties such as peak force to failure (N), stress at peak (MPa), elongation at failure, and Young'smodulus (GPa) was measured for each group. All groups were compared with each other using one-wayANOVA followed by the Tukey HSD multiple comparison test (a=0.05). RESULTS The average peak force (N) to failure of group 1 and group 2 and control group was 415.6±57.6, 268.1±65.2 and 704.5±85.8, respectively. There was no statistically significant difference between native tendon and group 1 for the amount elongation at failure (p>0.05). CONCLUSIONS Regarding the results, we concluded that Endobutton-assisted modified Bunnell technique provides stronger fixation than conventional techniques. It may allow early range of motion and can be easily applied in minimally invasive and percutaneous methods particularly for cases with poor quality tendon at the distal part of rupture. LEVEL OF EVIDENCE Level II, Biomechanical research study.
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Affiliation(s)
- Gazi Huri
- Department of Orthopaedic and Traumatology Surgery, Cukurova University, Adana, Turkey; Department of Orthopaedics and Traumatology Surgery, Division of Sport Medicine, Johns Hopkins University, Baltimore, MD, USA
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Massoud EIE. Healing of subcutaneous tendons: Influence of the mechanical environment at the suture line on the healing process. World J Orthop 2013; 4:229-240. [PMID: 24147258 PMCID: PMC3801242 DOI: 10.5312/wjo.v4.i4.229] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Accepted: 08/29/2013] [Indexed: 02/06/2023] Open
Abstract
Tendon ruptures remain a significant musculoskeletal injury. Despite advances in surgical techniques and procedures, traditional repair techniques maintain a high incidence of rerupture or tendon elongation. Mechanical loading and biochemical signaling both control tissue healing. This has led some researchers to consider using a technique based on tension regulation at the suture line for obtaining good healing. However, it is unknown how they interact and to what extent mechanics control biochemistry. This review will open the way for understanding the interplay between mechanical loading and the process of tendon healing.
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50
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Galloway MT, Lalley AL, Shearn JT. The role of mechanical loading in tendon development, maintenance, injury, and repair. J Bone Joint Surg Am 2013; 95:1620-8. [PMID: 24005204 PMCID: PMC3748997 DOI: 10.2106/jbjs.l.01004] [Citation(s) in RCA: 165] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Tendon injuries often result from excessive or insufficient mechanical loading, impairing the ability of the local tendon cell population to maintain normal tendon function. The resident cell population composing tendon tissue is mechanosensitive, given that the cells are able to alter the extracellular matrix in response to modifications of the local loading environment. Natural tendon healing is insufficient, characterized by improper collagen fibril diameter formation, collagen fibril distribution, and overall fibril misalignment. Current tendon repair rehabilitation protocols focus on implementing early, well-controlled eccentric loading exercises to improve repair outcome. Tissue engineers look toward incorporating mechanical loading regimens to precondition cell populations for the creation of improved biological augmentations for tendon repair.
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Affiliation(s)
- Marc T. Galloway
- Cincinnati Sports Medicine and Orthopaedic Center, 7423 Mason Montgomery Road, Cincinnati, OH 45249
| | - Andrea L. Lalley
- Engineering Research Center, University of Cincinnati, 2901 Woodside Drive, ERC Room 701, Cincinnati, OH 45221. E-mail address for A.L. Lalley:
| | - Jason T. Shearn
- Engineering Research Center, University of Cincinnati, 2901 Woodside Drive, ERC Room 701, Cincinnati, OH 45221. E-mail address for A.L. Lalley:
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