Comparison of bone surface and trough fixation on bone–tendon healing in a rabbit patella–patellar tendon injury model

Abstract Background Tendon is a major component of musculoskeletal system connecting the muscles to the bone. Tendon injuries are very common orthopedics problems leading to impeded motion. Up to now, there still lacks effective treatments for tendon diseases. Methods Tendon stem/progenitor cells (TSPCs) were isolated from the patellar tendons of SD rats. The expression levels of genes were evaluated by quantitative RT-PCR. Immunohistochemistry staining was performed to confirm the presence of tendon markers in tendon tissues. Bioinformatics analysis of data acquired by RNA-seq was used to find out the differentially expressed genes. Rat patellar tendon injury model was used to evaluate the effect of U0126 on tendon injury healing. Biomechanical testing was applied to evaluate the mechanical properties of newly formed tendon tissues. Results In this study, we have shown that ERK inhibitor U0126 rather PD98059 could effectively increase the expression of tendon-related genes and promote the tenogenesis of TSPCs in vitro. To explore the underlying mechanisms, RNA sequencing was performed to identify the molecular difference between U0126-treated and control TSPCs. The result showed that GDF6 was significantly increased by U0126, which is an important factor of the TGFβ superfamily regulating tendon development and tenogenesis. In addition, NBM (nonwoven-based gelatin/polycaprolactone membrane) which mimics the native microenvironment of the tendon tissue was used as an acellular scaffold to carry U0126. The results demonstrated that when NBM was used in combination with U0126, tendon healing was significantly promoted with better histological staining outcomes and mechanical properties. Conclusion Taken together, we have found U0126 promoted tenogenesis in TSPCs through activating GDF6, and NBM loaded with U0126 significantly promoted tendon defect healing, which provides a new treatment for tendon injury.

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CD44 deficiency improves healing tendon mechanics and increases matrix and cytokine expression in a mouse patellar tendon injury model

Journal of Orthopaedic Research® ◽

10.1002/jor.20891 ◽

2009 ◽

Vol 27 (10) ◽

pp. 1386-1391 ◽

Cited By ~ 28

Author(s):

Heather L. Ansorge ◽

Pedro K. Beredjiklian ◽

Louis J. Soslowsky

Keyword(s):

Patellar Tendon ◽

Tendon Injury ◽

Cytokine Expression ◽

Tendon Mechanics ◽

Injury Model ◽

Healing Tendon

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Therapeutic Mechanisms of Human Adipose-Derived Mesenchymal Stem Cells in a Rat Tendon Injury Model

The American Journal of Sports Medicine ◽

10.1177/0363546517689874 ◽

2017 ◽

Vol 45 (6) ◽

pp. 1429-1439 ◽

Cited By ~ 29

Author(s):

Sang Yoon Lee ◽

Bomi Kwon ◽

Kyoungbun Lee ◽

Young Hoon Son ◽

Sun G. Chung

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tendon Healing ◽

Collagen Type I ◽

Tendon Injury ◽

Cell Group ◽

Type I ◽

Injury Model ◽

Human Specific

Background: Although survival of transplanted stem cells in vivo and differentiation of stem cells into tenocytes in vitro have been reported, there have been no in vivo studies demonstrating that mesenchymal stem cells (MSCs) could secrete their own proteins as differentiated tenogenic cells. Purpose/Hypothesis: Using a xenogeneic MSC transplantation model, we aimed to investigate whether MSCs could differentiate into the tenogenic lineage and secrete their own proteins. The hypothesis was that human MSCs would differentiate into the human tenogenic lineage and the cells would be able to secrete human-specific proteins in a rat tendon injury model. Study Design: Controlled laboratory study. Methods: The Achilles tendons of 57 Sprague Dawley rats received full-thickness rectangular defects. After the modeling, the defective tendons were randomly assigned to 3 groups: (1) cell group, implantation with human adipose-derived mesenchymal stem cells (hASCs) and fibrin glue (106 cells in 60 μL); (2) fibrin group, implantation with fibrin glue and same volume of cell media; and (3) sham group, identical surgical procedure without any treatment. Gross observation and biomechanical, histopathological, immunohistochemistry, and Western blot analyses were performed at 2 and 4 weeks after modeling. Results: hASCs implanted into the defective rat tendons were viable for 4 weeks as detected by immunofluorescence staining. Tendons treated with hASCs showed better gross morphological and biomechanical recovery than those in the fibrin and sham groups. Furthermore, the expression of both human-specific collagen type I and tenascin-C was significantly higher in the cell group than in the other 2 groups. Conclusion: Transplantation of hASCs enhanced rat tendon healing biomechanically. hASCs implanted into the rat tendon defect model survived for at least 4 weeks and secreted human-specific collagen type I and tenascin-C. These findings suggest that transplanted MSCs may be able to differentiate into the tenogenic lineage and contribute their own proteins to tendon healing. Clinical Relevance: In tendon injury, MSCs can enhance tendon healing by secreting their own protein and have potential as a therapeutic option in human tendinopathy.

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The effect of tendon stem/progenitor cell (TSC) sheet on the early tendon healing in a rat Achilles tendon injury model

Acta Biomaterialia ◽

10.1016/j.actbio.2016.06.026 ◽

2016 ◽

Vol 42 ◽

pp. 136-146 ◽

Cited By ~ 24

Author(s):

Issei Komatsu ◽

James H-C. Wang ◽

Kiyotaka Iwasaki ◽

Tatsuya Shimizu ◽

Teruo Okano

Keyword(s):

Achilles Tendon ◽

Progenitor Cell ◽

Tendon Healing ◽

Tendon Injury ◽

Injury Model

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CD146 Delineates an Interfascicular Cell Sub-Population in Tendon That Is Recruited during Injury through Its Ligand Laminin-α4

International Journal of Molecular Sciences ◽

10.3390/ijms22189729 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9729

Author(s):

Neil Marr ◽

Richard Meeson ◽

Elizabeth F. Kelly ◽

Yongxiang Fang ◽

Mandy J. Peffers ◽

...

Keyword(s):

Expression Patterns ◽

Tendon Repair ◽

Tendon Healing ◽

Tendon Injury ◽

Focal Lesion ◽

Post Injury ◽

Surface Receptors ◽

Basement Membrane Protein ◽

Injury Model ◽

Cell Niche

The interfascicular matrix (IFM) binds tendon fascicles and contains a population of morphologically distinct cells. However, the role of IFM-localised cell populations in tendon repair remains to be determined. The basement membrane protein laminin-α4 also localises to the IFM. Laminin-α4 is a ligand for several cell surface receptors, including CD146, a marker of pericyte and progenitor cells. We used a needle injury model in the rat Achilles tendon to test the hypothesis that the IFM is a niche for CD146+ cells that are mobilised in response to tendon damage. We also aimed to establish how expression patterns of circulating non-coding RNAs alter with tendon injury and identify potential RNA-based markers of tendon disease. The results demonstrate the formation of a focal lesion at the injury site, which increased in size and cellularity for up to 21 days post injury. In healthy tendon, CD146+ cells localised to the IFM, compared with injury, where CD146+ cells migrated towards the lesion at days 4 and 7, and populated the lesion 21 days post injury. This was accompanied by increased laminin-α4, suggesting that laminin-α4 facilitates CD146+ cell recruitment at injury sites. We also identified a panel of circulating microRNAs that are dysregulated with tendon injury. We propose that the IFM cell niche mediates the intrinsic response to injury, whereby an injury stimulus induces CD146+ cell migration. Further work is required to fully characterise CD146+ subpopulations within the IFM and establish their precise roles during tendon healing.

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Platelet HMGB1 in Platelet-Rich Plasma Promotes Tendon Wound Healing

10.1101/2021.04.22.440884 ◽

2021 ◽

Author(s):

Jianying Zhang ◽

Feng Li ◽

Tyler Augi ◽

Kelly M. Williamson ◽

Kentaro Onishi ◽

...

Keyword(s):

Platelet Rich Plasma ◽

Tendon Healing ◽

High Mobility ◽

Tendon Injury ◽

Tendon Injuries ◽

Stem Cell Markers ◽

Wound Area ◽

Injury Model ◽

Collagen Iii ◽

Cell Densities

AbstractPlatelet-rich plasma (PRP) is a widely used autologous treatment for tendon injuries in clinics, but clinical trials often produce conflicting results. Platelets (PLTs) are a major source of high mobility group box1 (HMGB1) that is gaining attention as a chemoattractant that can recruit stem cells to the wound area to enhance healing; however, the contribution of PLT HMGB1 in wounded tendon healing remains unexplored. This study investigated the effect of PLT HMGB1 within PRP to enhance healing in an acute patellar tendon injury model in PLT HMGB1 knockout (KO) mice and GFP mice. A window defect was created in the patellar tendons of both groups of mice, and wounds were treated with either saline, PRP isolated from PLT HMGB1 KO mice, or PRP isolated from GFP mice. Seven days post-treatment, animals were sacrificed and analyzed by gross inspection, histology, and immunostaining for characteristic signs of tendon healing and repair. Our results showed that in comparison to mice treated with PRP from PLT HMGB1-KO mice, wounds treated with PRP from GFP mice healed faster and exhibited a better organization in tendon structure. Mice treated with PRP from PLT HMGB1-KO mice produced tendon tissue with large premature wound areas and low cell densities. However, wounds of PLT HMGB1 KO mice showed better healing with PRP from HMGB1 KO mice compared to saline treatment. Moreover, wounds treated with PRP from GFP mice had increased extracellular HMGB1, decreased CD68, increased stem cell markers CD146 and CD73, and increased collagen III protein expression levels compared to those treated with PRP from PLT HMGB1 KO mice. Thus, PLT HMGB1 within PRP plays an important role in the healing of wounded tendon. Our findings also suggest that the efficacy of PRP treatment for tendon injuries in clinics may be affected by PLT HMGB1 within PRP preparations.

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Effectiveness of Ozone Therapy on Tendon Healing: An Experimental Study in Generated Achilles Tendon Injury Model in Rats

Journal of Hard Tissue Biology ◽

10.2485/jhtb.27.309 ◽

2018 ◽

Vol 27 (4) ◽

pp. 309-314

Author(s):

Volkan Kizilkaya ◽

Vedat Uruc ◽

Ali Levent ◽

Ozgur Kanat ◽

Mustafa Turgut Yildizgoren ◽

...

Keyword(s):

Experimental Study ◽

Achilles Tendon ◽

Tendon Healing ◽

Tendon Injury ◽

Ozone Therapy ◽

Injury Model

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Visualization of microstructural change affected by mechanical stimulation in tendon healing with a novel tensionless model

Microscopy ◽

10.1093/jmicro/dfaa043 ◽

2020 ◽

Author(s):

Junya Oshima ◽

Kaoru Sasaki ◽

Naoto Yamamoto ◽

Tomoharu Kiyosawa ◽

Mitsuru Sekido

Keyword(s):

Mechanical Stimulation ◽

Three Dimensional ◽

Tendon Healing ◽

Dry Weight ◽

Tendon Sheath ◽

Tendon Injury ◽

Collagen Fibers ◽

Injury Model ◽

A Cell ◽

Tendon Tension

Abstract Since the majority of a tendon’s dry weight is collagen fibers, tendon healing consists mainly of collagen repair and observing three-dimensional networks of collagen fibers with scanning electron microscopy (SEM) is optimal for investigating this process. In this report, a cell-maceration/SEM method was used to investigate extrasynovial tendon (unwrapped tendon in synovial tissue such as the tendon sheath) healing of an injured Achilles tendon in a rat model. In addition, since mechanical stimulation is important for tendon healing, a novel, tensionless, rat lower leg tendon injury model was established and verified by visualizing the structural change of collagen fibers under tensionless conditions by SEM. This new model was created by transplanting the leg of a rat with a tendon laceration to the back, removing mechanical stimulation. We then compared the process of tendon healing with and without tension using SEM. Under tension, collagen at the tendon stump shows axial alignment and repair that subsequently demarcates the paratenon (connective tissue on the surface of an extrasynovial tendon) border. In contrast, under tensionless conditions, the collagen remains randomly arranged. Our findings demonstrate that mechanical stimulation contributes to axial arrangement and reinforces the importance of tendon tension in wound healing.

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Molecular Mechanisms of Fetal Tendon Regeneration Versus Adult Fibrous Repair

International Journal of Molecular Sciences ◽

10.3390/ijms22115619 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5619

Author(s):

Iris Ribitsch ◽

Andrea Bileck ◽

Alexander D. Aldoshin ◽

Maciej M. Kańduła ◽

Rupert L. Mayer ◽

...

Keyword(s):

Extracellular Matrix ◽

Molecular Mechanisms ◽

Unmet Need ◽

Tendon Healing ◽

Tendon Injury ◽

Inflammatory Factors ◽

Large Animal ◽

Post Injury ◽

Tendon Regeneration ◽

Large Animal Models

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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