Knitted Poly-lactide-co-glycolide Scaffold Loaded with Bone Marrow Stromal Cells in Repair and Regeneration of Rabbit Achilles Tendon
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The objectives of this study were to evaluate the morphology and biomechanical function of Achilles tendons regenerated using knitted poly-lactide-co-glycolide (PLGA) loaded with bone marrow stromal cells (bMSCs). The animal model used was that of an adult female New Zealand White rabbit with a 10-mm gap defect of the Achilles tendon. In group I, 19 hind legs with the created defects were treated with allogeneic bMSCs seeded on knitted PLGA scaffold. In group II, the Achilles tendon defects in 19 hind legs were repaired using the knitted PLGA scaffold alone, and in group III, 6 hind legs were used as normal control. The tendon-implant constructs of groups I and II were evaluated postoperatively at 2, 4, 8, and 12 weeks using macroscopic, histological, and immunohistochemical techniques. In addition, specimens from group I (n = 7), group II (n = 7), and group III (n = 6) were harvested for biomechanical test 12 weeks after surgery. Postoperatively, at 2 and 4 weeks, the histology of group I specimens exhibited a higher rate of tissue formation and remodeling as compared with group II, whereas at 8 and 12 weeks postoperation, the histology of both group I and group II was similar to that of native tendon tissue. The wound sites of group I healed well and there was no apparent lymphocyte infiltration. Immunohistochemical analysis showed that the regenerated tendons were composed of collagen types I and type III fibers. The tensile stiffness and modulus of group I were 87 and 62.6% of normal tendon, respectively, whereas those of group II were about 56.4 and 52.9% of normal tendon, respectively. These results suggest that the knitted PLGA biodegradable scaffold loaded with allogeneic bone marrow stromal cells has the potential to regenerate and repair gap defect of Achilles tendon and to effectively restore structure and function.Keywords:
Histology
PLGA
Hindlimb
Enthesis
The whole-organ, three-dimensional microstructure of murine Achilles tendon entheses was visualized with micro-computed tomography (microCT). Contrast-enhancement was achieved either by staining with phosphotungstic acid (PTA) or by a combination of cell-maceration, demineralization and critical-point drying with low tube voltages and propagation-based phase-contrast (fibrous structure scan). By PTA-staining, X-ray absorption of the enthesial soft tissues became sufficiently high to segment the tendon and measure cross-sectional areas along its course. With the fibrous structure scans, three-dimensional visualizations of the collagen fiber networks of complete entheses were obtained. The characteristic tissues of entheses were identified in the volume data. The tendon proper was marked as a segment manually. The fibers within the tendon were marked by thresholding. Tendon and fiber cross-sectional areas were measured. The measurements were compared between individuals and protocols for contrast-enhancement, using a spatial reference system within the three-dimensional enthesis. The usefulness of the method for investigations of the fibrous structure of collagenous tissues is demonstrated.
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Entheses are regions of high‐stress concentration that are commonly affected by overuse injuries in sport. This review summarizes current knowledge of their structure–function relationships – at the macroscopic, microscopic and molecular levels. Consideration is given to how stress concentration is reduced at fibrocartilaginous entheses by various adaptations which ensure that stress is dissipated away from the hard–soft tissue interface. The fundamental question of how a tendon or ligament is anchored to bone is addressed – particularly in relation to the paucity of compact bone at fibrocartilaginous entheses. The concept of an “enthesis organ” is reviewed – i.e. the idea of a collection of tissues adjacent to the enthesis itself, which jointly serve a common function – stress dissipation. The archetypal enthesis organ is that of the Achilles tendon and the functional importance of its subtendinous bursa, with its fibrocartilaginous walls and protruding fat pad, is emphasized. The distribution of adipose tissue elsewhere at entheses is also explained and possible functions of insertion‐site fat are evaluated. Finally, a brief consideration is given to enthesopathies, with attention drawn to the possibility of degenerative changes affecting other regions of an enthesis organ, besides the enthesis itself.
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Abstract Background Composite scaffolds of poly(lactic-co-glycolic acid) (PLGA) and PLGA/COL I were developed by a low-temperature deposition manufacturing (LDM) technique using three-dimensional printing technology. Their physical properties were tested, and the scaffolds were then used as cell culture platforms to prepare an ideal scaffold for cartilage tissue engineering. Methods The LDM technique was used to fabricate PLGA and PLGA/COL I composite scaffolds. The macrostructure, micromorphology, porosity, hydrophobicity, mechanical properties, and chemical structure of these scaffolds were examined. Primary chondrocytes were isolated and identified, second-passage cells were seeded onto the two scaffolds, and the adhesion and proliferation of the cells were determined. Results Both the PLGA and PLGA/COL I scaffolds prepared by LDM displayed a regular three-dimensional structure with high porosity. The PLGA scaffold had better mechanical properties than the PLGA/COL I scaffold, while the latter had significantly higher hydrophilicity than the former. The PLGA/COL I scaffold cultured with chondrocytes exhibited a higher adhesion rate and proliferation rate than the PLGA/COL I scaffold. Conclusion The novel PLGA/COL I composite scaffold printed by the LDM technique exhibited favourable biocompatibility and biomechanical characteristics and could be a good candidate for cartilage tissue engineering.
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Objective. To investigate the relationship between physical examination (PE) and sonographic features of enthesitis, based on anatomical sites. Methods. The analysis was done using merged raw data of 3 studies on 2298 entheses. Results. Patients with clinical Achilles enthesitis had more abnormalities on ultrasound (US): hypoechogenicity, p < 0.001; thickening, p = 0.001; Doppler signals, p = 0.002; and erosions, p = 0.02. The patellar tendon origin also correlated with PE but distal patellar tendon insertion and plantar aponeurosis were uncoupled from the US. Conclusion. The relationship between clinical and sonographic findings for large entheses is dependent on the anatomical site. For the patellar tendon origin and Achilles entheses, PE is significantly linked to US findings.
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Abstract Background/Aims Enthesitis, which is the inflammation of the entheses area where the tendon or ligaments are attached into the bone, is considered a hallmark and pathological feature for spondyloarthropathies (SpA). The lower limb entheses are more prone to being affected than the upper extremity enthesis, the most common one is Achilles tendon where heel enthesitis is considered the most frequent finding in SpA patients. Ultrasound is widely used by rheumatologists because it has higher sensitivity and specificity in detecting enthesitis compared with clinical assessment. The abnormal characteristics of enthesitis in greyscale ultrasound includes the hypoechoic area at the insertion or body of the tendon due to the loss of the normal fibrillar pattern, increase in the tendon thickness, bone erosion, calcification and increase in Dopplar signals. Although ultrasound has many advantages compared with other imaging modalities, it is operator-dependent and the diagnosis is exposed to the subjectivity of the observer, which leads to the variability in defining the abnormal features of enthesitis. Using static ultrasound images of Achilles tendon entheses of patients with SpA, we first determined the intra- and inter-observer reliability of grading ‘hypoechogenicity’ using a panel of readers and second, compared a computerised pixel counting method against an expert consensus score to determine the level of agreement between approaches. Methods Six participants (rheumatologists and sonographer) with experience in ultrasound scored the presence of hypoechogenicity in 100 static images of Achilles tendon entheses of patients with SpA. Two scoring systems were used- an OMERACT derived SQ system (0-3) of the whole enthesis and binary score system of the distal 2mm (0-1). The intra-class correlation coefficient (ICC) and Cohen's kappa was used to assess inter-observer reliability. The ImageJ software was used to measure the mean grey values (MGV) of the pixels within the enthesis. Results The inter-observer reliability was good for using the SQ score (ICC 0.780 (95% CI 0.691-0.849) and moderate for the binary score (ICC 0.632 (95% CI 0.490-0.745)). There was no match between the results from the quantitative score of the pixels MGV and the expert semi-quantitative score. Conclusion This study is novel as in that it has specifically evaluated the scoring of hypoechogenicity within the entheses of patients with SpA. It has demonstrated variation in scoring between observers and highlighted the challenges of image interpretation. A lack of correlation of expert scoring with the manual pixel MGV was limited by the image artefacts and different machine settings which may have implications as we work towards future AI systems. Disclosure A.S. Aldahes: None. R. Wakefield: None. K. Smith: None.
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The interphase between tendon and bone consists of a highly specialised tissue called enthesis. Typically, the enthesis is described as a succession of four different zones: tendon, non-mineralised fibrocartilage, mineralised fibrocartilage and bone. However, the microstructure of the entheses, cellular composition and mechanical properties vary depending on their anatomical location. The present study aimed to characterise three of the most relevant sites of enthesis injury in a rat model: the patellar tendon, the Achilles tendon and the supraspinatus enthesis, in terms of biomechanics, histology and genetic expression. The patellar enthesis presented the highest ultimate load and lowest stiffness of the three, while the supraspinatus was the weakest and stiffest. The histological characterisation revealed key differences at the insertion site for each enthesis. The patellar enthesis showed a large cartilaginous area at the tendon-to-bone interphase whilst this interphase was smaller in the supraspinatus entheses samples. Furthermore, the Achilles tendon enthesis displayed a more abrupt transition from tendon to bone. Additionally, each enthesis exhibited a particular and distinct pattern of expression of tenogenic, chondrogenic and osteogenic markers. This study provided valuable insights for a better understanding of the three entheses at relevant anatomical sites. Moreover, the larger cross-sectional area of the patellar enthesis, the strong mechanical properties and the easier surgical access to this location led to the conclusion that the patellar tendon enthesis site could be most suitable for the development of a preclinical model for general enthesis regeneration studies in rats.
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Poly(lactic-co-glycolic) acid (PLGA) has attracted a considerable amount of interest for biomedical application due to its biocompatibility, tailored biodegradation rate (depending on the molecular weight and copolymer ratio), approval for clinical use in humans by the U.S. Food and Drug Administration (FDA), the potential to change surface properties to create better interaction with biological materials and being suitable for export to countries and cultures where planting products with animals is unusable. For commercial use and research, PLGA has been widely studied to control small molecule drugs, proteins, and other macromolecules. This study aims to review the studies that used PLGA scaffolding and its composites as a scaffold and drug delivery in cartilage tissue engineering. It is concluded from the results that the PLGA scaffold as a synthetic scaffold, when combined with natural scaffolds or hybrids, strengthens its biological properties and performs its function better.
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To define the best cut-off value for identifying Achilles tendon thickening using ultrasound (US) in patients with spondyloarthropathies (SpA) and to assess its diagnostic utility in comparison with different cut-off values used in the literature.One-hundred and one subjects (55 SpA patients and 46 age and body mass index ((BMI)-matched healthy controls (HC)) were investigated. US was performed using a MyLab70 US system (Esaote Biomedica, Genoa, Italy) with a linear probe (6-18 MHz). Three images per Achilles enthesis were stored and the antero-posterior thickness of the enthesis was measured at the level of the Achilles tendon deeper margin insertion into the calcaneal bone on the longitudinal median scan. The best cut-off value for each gender was determined by ROC curve analysis and compared to the other cut-off values in the literature: 1) 5.29 mm for both genders, and 2) 5.5 mm for females and 6.2 mm for males. The number of measurements exceeding the cut-off values as well as sensitivity (SE), specificity (SP), positive (PPV) and negative (NPV) predictive values were calculated.A significant difference was observed for Achilles enthesis thickness between genders (mean±SD: 4.6±0.7 mm in males vs. 4.0±0.8 mm in females, p<0.00) and between SpA patients and HC (mean±SD: 4.4±0.8 mm in SpA patients vs. 4.0±0.8 mm in HC, p<0.001). The ROC curve analysis revealed the best cut-off value to be 3.7 mm for females and 4.8 mm for males (SE: 43-70%, SP: 59-85%, PPV: 66-79%, NPV: 54-63%). Previously reported cut-off values were found to have high SP (91-98%) but very low SE (2-11%).Achilles tendon thickness differs between genders; thus, it is crucial to refer to normal values that are specific for gender. High cut-off values, as previously suggested, showed very low SE in the current study. When Achilles enthesis thickening is used for the purpose of screening enthesitis in SpA patients, a lower cut-off value has a higher SE with slightly worse SP, PPV and NPVs.
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The development of the rotator cuff enthesis is still poorly understood. The processes in the early and late developmental steps are gradually elucidated, but it is still unclear how cell activities are coordinated during development and maturation of the structured enthesis. This review summarizes current knowledge about development and age-related degradation of the supraspinatus enthesis. Healing and repair of an injured and degenerated supraspinatus enthesis also remain a challenge, as the original graded transitional tissue of the fibrocartilaginous insertion is not re-created after the tendon is surgically reattached to bone. Instead, mechanically inferior and disorganized tissue forms at the healing site because of scar tissue formation. Consequently, the enthesis never reaches mechanical properties comparable to those of the native enthesis. So far, no novel biologic healing approach has been successful in enhancing healing of the injured enthesis. The results revealed in this review imply the need for further research to pave the way for better treatment of patients with rotator cuff disorder. The development of the rotator cuff enthesis is still poorly understood. The processes in the early and late developmental steps are gradually elucidated, but it is still unclear how cell activities are coordinated during development and maturation of the structured enthesis. This review summarizes current knowledge about development and age-related degradation of the supraspinatus enthesis. Healing and repair of an injured and degenerated supraspinatus enthesis also remain a challenge, as the original graded transitional tissue of the fibrocartilaginous insertion is not re-created after the tendon is surgically reattached to bone. Instead, mechanically inferior and disorganized tissue forms at the healing site because of scar tissue formation. Consequently, the enthesis never reaches mechanical properties comparable to those of the native enthesis. So far, no novel biologic healing approach has been successful in enhancing healing of the injured enthesis. The results revealed in this review imply the need for further research to pave the way for better treatment of patients with rotator cuff disorder. Rotator cuff (RC) lesions are one of the most common conditions affecting the shoulder. The prevalence of RC tears is age dependent, and the prevalence of both partial- and full-thickness RC tears increases markedly after 50 years of age.51Milgrom C. Schaffler M. Gilbert S. van Holsbeeck M. Rotator-cuff changes in asymptomatic adults. The effect of age, hand dominance and gender.J Bone Joint Surg Br. 1995; 77: 296-298Crossref PubMed Google Scholar, 83Yamaguchi K. Ditsios K. Middleton W.D. Hildebolt C.F. Galatz L.M. Teefey S.A. The demographic and morphological features of rotator cuff disease. A comparison of asymptomatic and symptomatic shoulders.J Bone Joint Surg Am. 2006; 88: 1699-1704http://dx.doi.org/10.2106/jbjs.e.00835Crossref PubMed Scopus (654) Google Scholar The etiology of RC diseases is multifactorial, but the supraspinatus (SS) tendon is particularly vulnerable to become injured.8Benson R.T. McDonnell S.M. Knowles H.J. Rees J.L. Carr A.J. Hulley P.A. Tendinopathy and tears of the rotator cuff are associated with hypoxia and apoptosis.J Bone Joint Surg Br. 2010; 92: 448-453http://dx.doi.org/10.1302/0301-620X.92B3.23074Crossref PubMed Scopus (100) Google Scholar Longitudinal data suggest that tears progress over time.84Yamaguchi K. Tetro A.M. Blam O. Evanoff B.A. Teefey S.A. Middleton W.D. Natural history of asymptomatic rotator cuff tears: a longitudinal analysis of asymptomatic tears detected sonographically.J Shoulder Elbow Surg. 2001; 10: 199-203Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar Approximately 30% of surgical repairs will fail, and the failure rate is as high as 90% in patients with large chronic tears.21Galatz L.M. Ball C.M. Teefey S.A. Middleton W.D. Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears.J Bone Joint Surg Am. 2004; 86-A: 219-224Crossref PubMed Scopus (1518) Google Scholar, 74Sugaya H. Maeda K. Matsuki K. Moriishi J. Repair integrity and functional outcomes after arthroscopic double-row rotator cuff repair.J Bone Joint Surg Am. 2007; 89-A: 953-960http://dx.doi.org/10.2106/JBJS.F.00512Crossref Scopus (643) Google Scholar The attachment site of the SS tendon at the footprint of the greater tuberosity of the humerus defines a classic enthesis made of 4 zones (Fig. 1). Degenerative changes may be seen in all 4 zones, and the severity of a lesion depends on the degenerative status of the enthesis and the adjacent tissues involved. The SS tendon makes up the roof of the shoulder joint, with the joint side of the tendon being covered by synovial tissue and the acromial side by bursal tissue.8Benson R.T. McDonnell S.M. Knowles H.J. Rees J.L. Carr A.J. Hulley P.A. Tendinopathy and tears of the rotator cuff are associated with hypoxia and apoptosis.J Bone Joint Surg Br. 2010; 92: 448-453http://dx.doi.org/10.1302/0301-620X.92B3.23074Crossref PubMed Scopus (100) Google Scholar, 46Liu X. Joshi S.K. Ravishankar B. Laron D. Kim H.T. Feeley B.T. Upregulation of transforming growth factor-β signaling in a rat model of rotator cuff tears.J Shoulder Elbow Surg. 2014; 23: 1709-1716http://dx.doi.org/10.1016/j.jse.2014.02.029Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar It is believed that damage to the enthesis can induce an inflammatory reaction in the synovium or bursal tissue characterized by expression of matrix-degrading molecules and increased proliferation and differentiation of osteoclasts. This may cause excessive degradation of the enthesis matrix,20Dyment N.A. Hagiwara Y. Matthews B.G. Li Y. Kalajzic I. Rowe D.W. Lineage tracing of resident tendon progenitor cells during growth and natural healing.PLoS ONE. 2014; 9: e96113http://dx.doi.org/10.1371/journal.pone.0096113Crossref PubMed Scopus (97) Google Scholar, 44Kovacevic D. Fox A.J. Bedi A. Ying L. Deng X. Warren R.F. et al.Calcium-phosphate matrix with or without TGF-β3 improves tendon-bone healing after rotator cuff repair.Am J Sports Med. 2011; 39: 811-819http://dx.doi.org/10.1177/0363546511399378Crossref PubMed Scopus (128) Google Scholar, 46Liu X. Joshi S.K. Ravishankar B. Laron D. Kim H.T. Feeley B.T. Upregulation of transforming growth factor-β signaling in a rat model of rotator cuff tears.J Shoulder Elbow Surg. 2014; 23: 1709-1716http://dx.doi.org/10.1016/j.jse.2014.02.029Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 68Shah M. Foreman D.M. Ferguson M.W. Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring.J Cell Sci. 1995; 108: 985-1002Crossref PubMed Google Scholar, 76Tatara A.M. Lipner J.H. Das R. Kim H.M. Patel N. Ntouvali E. et al.The role of muscle loading on bone (re)modeling at the developing enthesis.PLoS One. 2014; 9: e97375http://dx.doi.org/10.1371/journal.pone.0097375Crossref PubMed Scopus (33) Google Scholar leading to inadequate enthesis function. The induced imbalance in the enthesis remodeling process is a crucial event in the onset of RC tears and pathologic RC disease. Both the development and maturation of the native enthesis are poorly understood. Muscle loading (ie, exertion of force on tendon and bone by muscles) is critical for maturation of the developing enthesis, as tissue deformity and diminished mineralization are apparent in mouse models where 1 shoulder has been paralyzed.76Tatara A.M. Lipner J.H. Das R. Kim H.M. Patel N. Ntouvali E. et al.The role of muscle loading on bone (re)modeling at the developing enthesis.PLoS One. 2014; 9: e97375http://dx.doi.org/10.1371/journal.pone.0097375Crossref PubMed Scopus (33) Google Scholar, 77Thomopoulos S. Kim H-M. Rothermich S.Y. Biederstadt C. Das R. Galatz L.M. Decreased muscle loading delays maturation of the tendon enthesis during postnatal development.J Orthop Res. 2007; 25: 1154-1163http://dx.doi.org/10.1002/jor.20418Crossref PubMed Scopus (122) Google Scholar Besides muscle loading, molecular factors are critical for the development of a functional enthesis.61Pryce B.A. Watson S.S. Murchison N.D. Staverosky J.A. Dünker N. Schweitzer R. Recruitment and maintenance of tendon progenitors by TGFbeta signaling are essential for tendon formation.Development. 2009; 136: 1351-1361http://dx.doi.org/10.1242/dev.027342Crossref PubMed Scopus (318) Google Scholar Recently, several transcription factors, including scleraxis (Scx), SRY-box 9 (Sox9), and GLI-Kruppel family member 1 (Gli1), have been detected in early progenitor cells of the developing enthesis and are crucial for development.10Blitz E. Sharir A. Akiyama H. Zelzer E. Tendon-bone attachment unit is formed modularly by a distinct pool of Scx- and Sox9-positive progenitors.Development. 2013; 140: 2680-2690http://dx.doi.org/10.1242/dev.093906Crossref PubMed Scopus (171) Google Scholar, 19Dyment N.A. Breidenbach A.P. Schwartz A.G. Russell R.P. Aschbacher-Smith L. Liu H. et al.GDF5 progenitors give rise to fibrocartilage cells that mineralize via hedgehog signaling to form the zonal enthesis.Dev Biol. 2015; 405: 96-107http://dx.doi.org/10.1016/j.ydbio.2015.06.020Crossref PubMed Scopus (71) Google Scholar, 20Dyment N.A. Hagiwara Y. Matthews B.G. Li Y. Kalajzic I. Rowe D.W. Lineage tracing of resident tendon progenitor cells during growth and natural healing.PLoS ONE. 2014; 9: e96113http://dx.doi.org/10.1371/journal.pone.0096113Crossref PubMed Scopus (97) Google Scholar, 75Sugimoto Y. Takimoto A. Akiyama H. Kist R. Scherer G. Nakamura T. et al.Scx+/Sox9+ progenitors contribute to the establishment of the junction between cartilage and tendon/ligament.Development. 2013; 140: 2280-2288http://dx.doi.org/10.1242/dev.096354Crossref PubMed Scopus (183) Google Scholar However, many questions remain unanswered as to what drives development and differentiation of the progenitor cells and how this is regulated. The reparative capacity of the damaged enthesis is inadequate because the repaired enthesis never regenerates its native structure after an SS tendon tear. Instead, excessive scar tissue formation with inadequate biomechanical properties appears at the repair site.70Shindle M.K. Chen C.C.T. Robertson C. DiTullio A.E. Paulus M.C. Clinton C.M. et al.Full-thickness supraspinatus tears are associated with more synovial inflammation and tissue degeneration than partial-thickness tears.J Shoulder Elbow Surg. 2011; 20: 917-927http://dx.doi.org/10.1016/j.jse.2011.02.015Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 71Silacci P. Dayer J.M. Desgeorges A. Peter R. Manueddu C. Guernet P.A. Interleukin (IL)-6 and its soluble receptor induce TIMP-1 expression in synoviocytes and chondrocytes, and block IL-1-induced collagenolytic activity.J Biol Chem. 1998; 273: 13625-13629Crossref PubMed Scopus (95) Google Scholar Attempts to enhance the healing process of damaged RC tendons have thus been directed toward biologic enhancement at the repair site, just as stimulation of the regenerative repair processes also has attracted attention.6Benjamin M. McGonagle D. The enthesis organ concept and its relevance to the spondyloarthropathies.Adv Exp Med Biol. 2009; 649: 57-70http://dx.doi.org/10.1007/978-1-4419-0298-6_4Crossref PubMed Scopus (164) Google Scholar, 21Galatz L.M. Ball C.M. Teefey S.A. Middleton W.D. Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears.J Bone Joint Surg Am. 2004; 86-A: 219-224Crossref PubMed Scopus (1518) Google Scholar Transforming growth factor β (TGF-β) isoforms have received special attention as important mediators in both scar-less and scar-mediated healing processes.6Benjamin M. McGonagle D. The enthesis organ concept and its relevance to the spondyloarthropathies.Adv Exp Med Biol. 2009; 649: 57-70http://dx.doi.org/10.1007/978-1-4419-0298-6_4Crossref PubMed Scopus (164) Google Scholar, 21Galatz L.M. Ball C.M. Teefey S.A. Middleton W.D. Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears.J Bone Joint Surg Am. 2004; 86-A: 219-224Crossref PubMed Scopus (1518) Google Scholar This review provides an overview of recent knowledge on the developmental steps of the fibrocartilaginous enthesis, the inflammatory response after SS tear, and the early characteristics of enthesis healing after damage, touching on therapeutic applications and considerations about biologic augmentation. A comprehensive search for peer-reviewed articles, excluding conference papers or reports, was conducted on the basis of the following MeSH terms: enthesis, rotator cuff, supraspinatus, growth and development, inflammation, scleraxis, SRY-box 9, Indian hedgehog, transforming growth factor β, arthritis, tendinopathy, osteoclastogenesis, tumor necrosis factor, synovial, synovium, RANK, and healing. The following databases were searched for literature: PubMed, Embase, and Web of Science. The reference section of each article was also inspected to find additional articles. The process yielded 85 articles published from 1986 to September 2017. The native SS tendon enthesis develops postnatally and is viewed as a 4-zone structure at maturity (Fig. 1). The tendinous first zone is composed primarily of type 1 collagen, with the proteoglycans decorin and biglycan present. This zone is equivalent to the tendon and is populated by tendon fibroblasts.23Galatz L.M. Rothermich S. Vanderploeg K. Petersen B. Sandell L. Thomopoulos S. Development of the supraspinatus tendon-to-bone insertion: localized expression of extracellular matrix and growth factor genes.J Orthop Res. 2007; 25: 1621-1628http://dx.doi.org/10.1002/jor.20441Crossref PubMed Scopus (95) Google Scholar The uncalcified fibrocartilage of the second zone consists of collagen types 1 and 2 with aggrecan, produced by resident fibrochondrocytes.19Dyment N.A. Breidenbach A.P. Schwartz A.G. Russell R.P. Aschbacher-Smith L. Liu H. et al.GDF5 progenitors give rise to fibrocartilage cells that mineralize via hedgehog signaling to form the zonal enthesis.Dev Biol. 2015; 405: 96-107http://dx.doi.org/10.1016/j.ydbio.2015.06.020Crossref PubMed Scopus (71) Google Scholar, 34Hettrich C.M. Gasinu S. Beamer B.S. Stasiak M. Fox A. Birmingham P. et al.The effect of mechanical load on tendon-to-bone healing in a rat model.Am J Sports Med. 2014; 42: 1233-1241http://dx.doi.org/10.1177/0363546514526138Crossref PubMed Scopus (48) Google Scholar Calcification of the fibrocartilage occurs in the third zone of mineralized fibrocartilage. This represents the actual transition of noncalcified to calcified tissue, demarcated by a clear straight line called the tidemark (Fig. 1).6Benjamin M. McGonagle D. The enthesis organ concept and its relevance to the spondyloarthropathies.Adv Exp Med Biol. 2009; 649: 57-70http://dx.doi.org/10.1007/978-1-4419-0298-6_4Crossref PubMed Scopus (164) Google Scholar, 7Benjamin M. Ralphs J.R. Fibrocartilage in tendons and ligaments—an adaptation to compressive load.J Anat. 1998; 193: 481-494Crossref PubMed Google Scholar, 19Dyment N.A. Breidenbach A.P. Schwartz A.G. Russell R.P. Aschbacher-Smith L. Liu H. et al.GDF5 progenitors give rise to fibrocartilage cells that mineralize via hedgehog signaling to form the zonal enthesis.Dev Biol. 2015; 405: 96-107http://dx.doi.org/10.1016/j.ydbio.2015.06.020Crossref PubMed Scopus (71) Google Scholar It consists of hypertrophic fibrochondrocytes producing collagen type 2, collagen type X, aggrecan, and alkaline phosphatase (AP).19Dyment N.A. Breidenbach A.P. Schwartz A.G. Russell R.P. Aschbacher-Smith L. Liu H. et al.GDF5 progenitors give rise to fibrocartilage cells that mineralize via hedgehog signaling to form the zonal enthesis.Dev Biol. 2015; 405: 96-107http://dx.doi.org/10.1016/j.ydbio.2015.06.020Crossref PubMed Scopus (71) Google Scholar, 34Hettrich C.M. Gasinu S. Beamer B.S. Stasiak M. Fox A. Birmingham P. et al.The effect of mechanical load on tendon-to-bone healing in a rat model.Am J Sports Med. 2014; 42: 1233-1241http://dx.doi.org/10.1177/0363546514526138Crossref PubMed Scopus (48) Google Scholar, 69Shen G. The role of type X collagen in facilitating and regulating endochondral ossification of articular cartilage.Orthod Craniofac Res. 2005; 8: 11-17http://dx.doi.org/10.1111/j.1601-6343.2004.00308.xCrossref PubMed Scopus (170) Google Scholar Collagen type X is believed to stimulate tissue mineralization.69Shen G. The role of type X collagen in facilitating and regulating endochondral ossification of articular cartilage.Orthod Craniofac Res. 2005; 8: 11-17http://dx.doi.org/10.1111/j.1601-6343.2004.00308.xCrossref PubMed Scopus (170) Google Scholar During maturity of the interface, the loss of hypertrophic chondrocytes leads to increased mineralization density, and although unexpected, collagen type X is still present.23Galatz L.M. Rothermich S. Vanderploeg K. Petersen B. Sandell L. Thomopoulos S. Development of the supraspinatus tendon-to-bone insertion: localized expression of extracellular matrix and growth factor genes.J Orthop Res. 2007; 25: 1621-1628http://dx.doi.org/10.1002/jor.20441Crossref PubMed Scopus (95) Google Scholar The fourth zone consists of dense collagen type 1 bone23Galatz L.M. Rothermich S. Vanderploeg K. Petersen B. Sandell L. Thomopoulos S. Development of the supraspinatus tendon-to-bone insertion: localized expression of extracellular matrix and growth factor genes.J Orthop Res. 2007; 25: 1621-1628http://dx.doi.org/10.1002/jor.20441Crossref PubMed Scopus (95) Google Scholar (Fig. 1). By histologic analysis of mouse SS tendons obtained from different embryonic (E) and postnatal (P) periods, Galatz et al identified a transition zone between the SS tendon and the humeral head at P7, with a visible 4-zone transition at P21 and P28 (Table I). The fully mature interface was present at P56.23Galatz L.M. Rothermich S. Vanderploeg K. Petersen B. Sandell L. Thomopoulos S. Development of the supraspinatus tendon-to-bone insertion: localized expression of extracellular matrix and growth factor genes.J Orthop Res. 2007; 25: 1621-1628http://dx.doi.org/10.1002/jor.20441Crossref PubMed Scopus (95) Google Scholar In support of this, Schwartz et al found a graded mineralization in the calcified zone with the presence of hypertrophic chondrocytes in P7 mice.67Schwartz A.G. Pasteris J.D. Genin G.M. Daulton T.L. Thomopoulos S. Mineral distributions at the developing tendon enthesis.PLoS One. 2012; 7: e48630http://dx.doi.org/10.1371/journal.pone.0048630Crossref PubMed Scopus (136) Google Scholar Using micro–computed tomography scanning, they also observed a mineralization front adjacent to the SS tendon at P14 and an increase in bone mineral density over time.67Schwartz A.G. Pasteris J.D. Genin G.M. Daulton T.L. Thomopoulos S. Mineral distributions at the developing tendon enthesis.PLoS One. 2012; 7: e48630http://dx.doi.org/10.1371/journal.pone.0048630Crossref PubMed Scopus (136) Google Scholar A 4-zone transition with mineralized fibrocartilage was visible at P28.67Schwartz A.G. Pasteris J.D. Genin G.M. Daulton T.L. Thomopoulos S. Mineral distributions at the developing tendon enthesis.PLoS One. 2012; 7: e48630http://dx.doi.org/10.1371/journal.pone.0048630Crossref PubMed Scopus (136) Google Scholar Interestingly, they also noticed that the mineralization was located intercellularly but did not always surround the cells. Thus, mineralization in some instances occurred on only 1 side of the cells. This observation indicates either that the cells are able to control mineralization or that mineralization occurs by transportation and deposition of calcium by cells located away from the interface.67Schwartz A.G. Pasteris J.D. Genin G.M. Daulton T.L. Thomopoulos S. Mineral distributions at the developing tendon enthesis.PLoS One. 2012; 7: e48630http://dx.doi.org/10.1371/journal.pone.0048630Crossref PubMed Scopus (136) Google Scholar The mineralized fibrocartilage of the enthesis does not become reabsorbed, as observed for bone formation. Instead, the mineralized fibrocartilage is maintained throughout life, and so it does not become vascularized.19Dyment N.A. Breidenbach A.P. Schwartz A.G. Russell R.P. Aschbacher-Smith L. Liu H. et al.GDF5 progenitors give rise to fibrocartilage cells that mineralize via hedgehog signaling to form the zonal enthesis.Dev Biol. 2015; 405: 96-107http://dx.doi.org/10.1016/j.ydbio.2015.06.020Crossref PubMed Scopus (71) Google ScholarTable ITime frame of the developing enthesisProgressTimeSpecies and modelAppearance of scx+/sox9+ progenitor cell lineE11.5Mouse, Sox9Cre/+; Ail4 and R26R67Schwartz A.G. Pasteris J.D. Genin G.M. Daulton T.L. Thomopoulos S. Mineral distributions at the developing tendon enthesis.PLoS One. 2012; 7: e48630http://dx.doi.org/10.1371/journal.pone.0048630Crossref PubMed Scopus (136) Google ScholarMouse, Scx-Sox9 KO10Blitz E. Sharir A. Akiyama H. Zelzer E. Tendon-bone attachment unit is formed modularly by a distinct pool of Scx- and Sox9-positive progenitors.Development. 2013; 140: 2680-2690http://dx.doi.org/10.1242/dev.093906Crossref PubMed Scopus (171) Google ScholarDistinct SS tendon appearsE13.5Mouse, Scx−/−47Lorda-Diez C.I. Montero J.A. Martinez-Cue C. Garcia-Porrero J.A. Hurle J.M. Transforming growth factors β coordinate cartilage and tendon differentiation in the developing limb mesenchyme.J Biol Chem. 2009; 284: 29988-29996http://dx.doi.org/10.1074/jbc.M109.014811Crossref PubMed Scopus (139) Google ScholarMouse, CD-121Galatz L.M. Ball C.M. Teefey S.A. Middleton W.D. Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears.J Bone Joint Surg Am. 2004; 86-A: 219-224Crossref PubMed Scopus (1518) Google ScholarTGF-β3 expression in the developing enthesisE13.5-15.5Mouse, CD-121Galatz L.M. Ball C.M. Teefey S.A. Middleton W.D. Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears.J Bone Joint Surg Am. 2004; 86-A: 219-224Crossref PubMed Scopus (1518) Google ScholarShift from TGF-β3 to TGF-β1 expressionE15.5Mouse, CD-121Galatz L.M. Ball C.M. Teefey S.A. Middleton W.D. Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears.J Bone Joint Surg Am. 2004; 86-A: 219-224Crossref PubMed Scopus (1518) Google ScholarTGF-β1 expression in the developing enthesisE15.5-18.5Mouse, CD-121Galatz L.M. Ball C.M. Teefey S.A. Middleton W.D. Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears.J Bone Joint Surg Am. 2004; 86-A: 219-224Crossref PubMed Scopus (1518) Google ScholarCells in the SS tendon become increasingly more spindle shaped and oriented with the tendonE18.5Mouse, CD-121Galatz L.M. Ball C.M. Teefey S.A. Middleton W.D. Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears.J Bone Joint Surg Am. 2004; 86-A: 219-224Crossref PubMed Scopus (1518) Google ScholarTwo populations of Hh-responsive cells are evidentP8Mouse, ScxCre;Smofl/fl58O'Brien W. Fissel B.M. Maeda Y. Yan J. Ge X. Gravallese E.M. et al.RANK-independent osteoclast formation and bone erosion in inflammatory arthritis.Arthritis Rheumatol. 2016; 68: 2889-2900http://dx.doi.org/10.1002/art.39837Crossref PubMed Scopus (86) Google ScholarInitial mineralizationFibrocartilage appearsCollagen type 1– and type 2–expressing fibrochondrocytes at the base of the enthesisP7-14Mouse, Col1/2/10 triple TG18Deon D. Ahmed S. Tai K. Scaletta N. Herrero C. Lee I. et al.Cross-talk between IL-1 and IL-6 signaling pathways in rheumatoid arthritis synovial fibroblasts.J Immunol. 2001; 167: 5395-5403Crossref PubMed Scopus (86) Google ScholarCol3.6-cyan:ColX-cherry double TG18Deon D. Ahmed S. Tai K. Scaletta N. Herrero C. Lee I. et al.Cross-talk between IL-1 and IL-6 signaling pathways in rheumatoid arthritis synovial fibroblasts.J Immunol. 2001; 167: 5395-5403Crossref PubMed Scopus (86) Google ScholarMouse, ScxCre;Smof/−38Kay J. Calabrese L. The role of interleukin-1 in the pathogenesis of rheumatoid arthritis.Rheumatology. 2004; 43: iii2-iii9http://dx.doi.org/10.1093/rheumatology/keh201PubMed Google ScholarMouse, CD-121Galatz L.M. Ball C.M. Teefey S.A. Middleton W.D. Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears.J Bone Joint Surg Am. 2004; 86-A: 219-224Crossref PubMed Scopus (1518) Google ScholarMouse, CD-159Ousema P.H. Moutos F.T. Estes B.T. Caplan A.I. Lennon D.P. Guilak F. et al.The inhibition by interleukin 1 of MSC chondrogenesis and the development of biomechanical properties in biomimetic 3D woven PCL scaffolds.Biomaterials. 2012; 33: 8967-8974http://dx.doi.org/10.1016/j.biomaterials.2012.08.045Crossref PubMed Scopus (46) Google ScholarType X collagen expression occursP14Mouse, CD-121Galatz L.M. Ball C.M. Teefey S.A. Middleton W.D. Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears.J Bone Joint Surg Am. 2004; 86-A: 219-224Crossref PubMed Scopus (1518) Google ScholarHh-responsive cells span the whole developing enthesisP15Mouse, ScxCre;Smofl/fl58O'Brien W. Fissel B.M. Maeda Y. Yan J. Ge X. Gravallese E.M. et al.RANK-independent osteoclast formation and bone erosion in inflammatory arthritis.Arthritis Rheumatol. 2016; 68: 2889-2900http://dx.doi.org/10.1002/art.39837Crossref PubMed Scopus (86) Google ScholarEarly maturity of enthesis with appearance of a modest 4-zone structureMineralized humeral headFibrocartilage is fully mineralizedP21-28Mouse, CD-121Galatz L.M. Ball C.M. Teefey S.A. Middleton W.D. Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears.J Bone Joint Surg Am. 2004; 86-A: 219-224Crossref PubMed Scopus (1518) Google ScholarMouse, ScxCre;Smofl/fl58O'Brien W. Fissel B.M. Maeda Y. Yan J. Ge X. Gravallese E.M. et al.RANK-independent osteoclast formation and bone erosion in inflammatory arthritis.Arthritis Rheumatol. 2016; 68: 2889-2900http://dx.doi.org/10.1002/art.39837Crossref PubMed Scopus (86) Google ScholarMouse, CD-169Shen G. The role of type X collagen in facilitating and regulating endochondral ossification of articular cartilage.Orthod Craniofac Res. 2005; 8: 11-17http://dx.doi.org/10.1111/j.1601-6343.2004.00308.xCrossref PubMed Scopus (170) Google ScholarMouse, CD-159Ousema P.H. Moutos F.T. Estes B.T. Caplan A.I. Lennon D.P. Guilak F. et al.The inhibition by interleukin 1 of MSC chondrogenesis and the development of biomechanical properties in biomimetic 3D woven PCL scaffolds.Biomaterials. 2012; 33: 8967-8974http://dx.doi.org/10.1016/j.biomaterials.2012.08.045Crossref PubMed Scopus (46) Google ScholarHh-responsive cells are restricted to the unmineralized areaEnthesis is fully mature with classical 4-zone structureHypertrophic chondrocytes are absent from the mature enthesisP56Mouse, ScxCre;Smofl/fl58O'Brien W. Fissel B.M. Maeda Y. Yan J. Ge X. Gravallese E.M. et al.RANK-independent osteoclast formation and bone erosion in inflammatory arthritis.Arthritis Rheumatol. 2016; 68: 2889-2900http://dx.doi.org/10.1002/art.39837Crossref PubMed Scopus (86) Google ScholarMouse, CD-121Galatz L.M. Ball C.M. Teefey S.A. Middleton W.D. Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears.J Bone Joint Surg Am. 2004; 86-A: 219-224Crossref PubMed Scopus (1518) Google ScholarMouse, CD-169Shen G. The role of type X collagen in facilitating and regulating endochondral ossification of articular cartilage.Orthod Craniofac Res. 2005; 8: 11-17http://dx.doi.org/10.1111/j.1601-6343.2004.00308.xCrossref PubMed Scopus (170) Google ScholarSS, supraspinatus; TGF, transforming growth factor; Hh, Hedgehog; E, embryonic; P, postnatally; KO, knockout. Open table in a new tab SS, supraspinatus; TGF, transforming growth factor; Hh, Hedgehog; E, embryonic; P, postnatally; KO, knockout. Temporal expression of a number of genes has been linked to the successful and functional development of the native enthesis. The earliest progenitor cells found in the transitional zone express both Scx and Sox9 (Scx+/Sox9+ cells).10Blitz E. Sharir A. Akiyama H. Zelzer E. Tendon-bone attachment unit is formed modularly by a distinct pool of Scx- and Sox9-positive progenitors.Development. 2013; 140: 2680-2690http://dx.doi.org/10.1242/dev.093906Crossref PubMed Scopus (171) Google Scholar, 75Sugimoto Y. Takimoto A. Akiyama H. Kist R. Scherer G. Nakamura T. et al.Scx+/Sox9+ progenitors contribute to the establishment of the junction between cartilage and tendon/ligament.Development. 2013; 140: 2280-2288http://dx.doi.org/10.1242/dev.096354Crossref PubMed Scopus (183) Google Scholar These cells also express growth and differentiation factor 5 (GDF5), also known as bone morphogenetic protein 14 (BMP-14) or cartilage-derived morphogenetic protein 1 (CDMP-1), during the early stage of development.20Dyment N.A. Hagiwara Y. Matthews B.G. Li Y. Kalajzic I. Rowe D.W. Lineage tracing of resident tendon progenitor cells during growth and natural healing.PLoS ONE. 2014; 9: e96113http://dx.doi.org/10.1371/journal.pone.0096113Crossref PubMed Scopus (97) Google Scholar Both Scx and Sox9 are crucial for the formation of a proper functional enthesis.40Killian M.L. Thomopoulos S. Scleraxis is required for the development of a functional tendon enthesis.FASEB J. 2016; 30: 301-311http://dx.doi.org/10.1096/fj.14-258236Crossref PubMed Scopus (47) Google Scholar Scx is required for the d
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