Publications by authors named "Louis J Soslowsky"

195 Publications

Increasing Vascular Response to Injury Improves Tendon Early Healing Outcome in Aged Rats.

Ann Biomed Eng 2022 May 18;50(5):587-600. Epub 2022 Mar 18.

McKay Orthopaedic Research Laboratory, University of Pennsylvania, 307A Stemmler Hall, 36th Street & Hamilton Walk, Philadelphia, PA, 19104, USA.

Tendon injuries positively correlate with patient age, as aging has significant effects on tendon homeostatic maintenance and healing potential after injury. Vascularity is also influenced by age, with both clinical and animal studies demonstrating reduced blood flow in aged tissues. However, it is unknown how aging effects vascularity following tendon injury, and if this vascular response can be modulated through the delivery of angiogenic factors. Therefore, the objective of this study is to evaluate the vascular response following Achilles tendon injury in adult and aged rats, and to define the alterations to tendon healing in an aged model following injection of angiogenic factors. It was determined that aged rat Achilles tendons have a reduced angiogenesis following injury. Further, the delivery of vascular endothelial growth factor, VEGF, caused an increase in vascular response to tendon injury and improved mechanical outcome in this aged population. This work suggests that reduced angiogenic potential with aging may be contributing to impaired tendon healing response and that the delivery of angiogenic factors can rescue this impaired response. This study was also the first to relate changes in vascular response in an aged model using in vivo measures of blood perfusion to alterations in healing properties.
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http://dx.doi.org/10.1007/s10439-022-02948-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9107615PMC
May 2022

The Non-pregnant and Pregnant Human Cervix: a Systematic Proteomic Analysis.

Reprod Sci 2022 05 9;29(5):1542-1559. Epub 2022 Mar 9.

Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY, USA.

Appropriate timing of cervical remodeling (CR) is key to normal term parturition. To date, mechanisms behind normal and abnormal (premature or delayed) CR remain unclear. Recent studies show regional differences exist in human cervical tissue structure. While the entire cervix contains extracellular matrix (ECM), the internal os is highly cellular containing 50-60% cervical smooth muscle (CSM). The external os contains 10-20% CSM. Previously, we reported ECM rigidity and different ECM proteins influence CSM cell function, highlighting the importance of understanding not only how cervical cells orchestrate cervical ECM remodeling in pregnancy, but also how changes in specific ECM proteins can influence resident cellular function. To understand this dynamic process, we utilized a systematic proteomic approach to understand which soluble ECM and cellular proteins exist in the different regions of the human cervix and how the proteomic profiles change from the non-pregnant (NP) to the pregnant (PG) state. We found the human cervix proteome contains at least 4548 proteins and establish the types and relative abundance of cellular and soluble matrisome proteins found in the NP and PG human cervix. Further, we report the relative abundance of proteins involved with elastic fiber formation and ECM organization/degradation were significantly increased while proteins involved in RNA polymerase I/promoter opening, DNA methylation, senescence, immune system, and compliment activation were decreased in the PG compared to NP cervix. These findings establish an initial platform from which we can further comprehend how changes in the human cervix proteome results in normal and abnormal CR.
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http://dx.doi.org/10.1007/s43032-022-00892-4DOI Listing
May 2022

Biglycan has a major role in maintenance of mature tendon mechanics.

J Orthop Res 2022 Feb 16. Epub 2022 Feb 16.

Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Decorin and biglycan are two small leucine-rich proteoglycans (SLRPs) that regulate collagen fibrillogenesis and extracellular matrix assembly in tendon. The objective of this study was to determine the individual roles of these molecules in maintaining the structural and mechanical properties of tendon during homeostasis in mature mice. We hypothesized that knockdown of decorin in mature tendons would result in detrimental changes to tendon structure and mechanics while knockdown of biglycan would have a minor effect on these parameters. To achieve this objective, we created tamoxifen-inducible mouse knockdown models targeting decorin or biglycan inactivation. This enables the evaluation of the roles of these SLRPs in mature tendon without the abnormal tendon development caused by conventional knockout models. Contrary to our hypothesis, knockdown of decorin resulted in minor alterations to tendon structure and no changes to mechanics while knockdown of biglycan resulted in broad changes to tendon structure and mechanics. Specifically, knockdown of biglycan resulted in reduced insertion modulus, maximum stress, dynamic modulus, stress relaxation, and increased collagen fiber realignment during loading. Knockdown of decorin and biglycan produced similar changes to tendon microstructure by increasing the collagen fibril diameter relative to wild-type controls. Biglycan knockdown also decreased the cell nuclear aspect ratio, indicating a more spindle-like nuclear shape. Overall, the extensive changes to tendon structure and mechanics after knockdown of biglycan, but not decorin, provides evidence that biglycan plays a major role in the maintenance of tendon structure and mechanics in mature mice during homeostasis.
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http://dx.doi.org/10.1002/jor.25299DOI Listing
February 2022

Coordinate roles for collagen VI and biglycan in regulating tendon collagen fibril structure and function.

Matrix Biol Plus 2022 Feb 28;13:100099. Epub 2021 Dec 28.

National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.

Tendon is a vital musculoskeletal tissue that is prone to degeneration. Proper tendon maintenance requires complex interactions between extracellular matrix components that remain poorly understood. Collagen VI and biglycan are two matrix molecules that localize pericellularly within tendon and are critical regulators of tissue properties. While evidence suggests that collagen VI and biglycan interact within the tendon matrix, the relationship between the two molecules and its impact on tendon function remains unknown. We sought to elucidate potential coordinate roles of collagen VI and biglycan within tendon by defining tendon properties in knockout models of collagen VI, biglycan, or both molecules. We first demonstrated co-expression and co-localization of collagen VI and biglycan within the healing tendon, providing further evidence of cooperation between the two molecules during nascent tendon matrix formation. Deficiency in collagen VI and/or biglycan led to significant reductions in collagen fibril size and tendon mechanical properties. However, collagen VI-null tendons displayed larger reductions in fibril size and mechanics than seen in biglycan-null tendons. Interestingly, knockout of both molecules resulted in similar properties to collagen VI knockout alone. These results indicate distinct and non-additive roles for collagen VI and biglycan within tendon. This work provides better understanding of regulatory interactions between two critical tendon matrix molecules.
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http://dx.doi.org/10.1016/j.mbplus.2021.100099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749075PMC
February 2022

Nonsurgical treatment reduces tendon inflammation and elevates tendon markers in early healing.

J Orthop Res 2021 Dec 21. Epub 2021 Dec 21.

McKay Orthopedic Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Operative treatment is assumed to provide superior outcomes to nonoperative (conservative) treatment following Achilles tendon rupture, however, this remains controversial. This study explores the effect of surgical repair on Achilles tendon healing. Rat Achilles tendons (n = 101) were bluntly transected and were randomized into groups receiving repair or non-repair treatments. By 1 week after injury, repaired tendons had inferior mechanical properties, which continued to 3- and 6-week post-injury, evidenced by decreased dynamic modulus and failure stress. Transcriptomics analysis revealed >7000 differentially expressed genes between repaired and non-repaired tendons after 1-week post-injury. While repaired tendons showed enriched inflammatory gene signatures, non-repaired tendons showed increased tenogenic, myogenic, and mechanosensitive gene signatures, with >200-fold enrichment in Tnmd expression. Analysis of gastrocnemius muscle revealed elevated MMP activity in tendons receiving repair treatment, despite no differences in muscle fiber morphology. Transcriptional regulation analysis highlighted that the highest expressed transcription factors in repaired tendons were associated with inflammation (Nfκb, SpI1, RelA, and Stat1), whereas non-repaired tendons expressed markers associated with tissue development and mechano-activation (Smarca1, Bnc2, Znf521, Fbn1, and Gli3). Taken together, these data highlight distinct differences in healing mechanism occurring immediately following injury and provide insights for new therapies to further augment tendons receiving repaired and non-repaired treatments.
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http://dx.doi.org/10.1002/jor.25251DOI Listing
December 2021

Achilles Tendon Ruptures in Middle-Aged Rats Heal Poorly Compared With Those in Young and Old Rats [Formula: see text].

Am J Sports Med 2022 01 1;50(1):170-181. Epub 2021 Dec 1.

McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Achilles tendon ruptures are painful and debilitating injuries and are most common in middle-aged patients. There is a lack of understanding of the underlying causes for increased rupture rates in middle-aged patients and how healing outcomes after a rupture might be affected by patient age. Therefore, the objective of this study was to define age-specific Achilles tendon healing by assessing ankle functional outcomes and Achilles tendon mechanical and histological properties after a rupture using a rat model.

Hypothesis: Rats representing the middle-aged patient population would demonstrate reduced healing capability after an Achilles tendon rupture, as demonstrated by a slower return to baseline ankle functional properties and inferior biomechanical and histological tendon properties.

Study Design: Controlled laboratory study.

Methods: Fischer 344 rats were categorized by age to represent young, middle-aged, and old patients, and Achilles tendon ruptures were induced in the right hindlimb. Animals were allowed to heal and were euthanized at 3 or 6 weeks after the injury. In vivo functional assays and ultrasound imaging were performed throughout the healing period, and ex vivo tendon mechanical and histological properties were assessed after euthanasia.

Results: Rats representing middle-aged patients displayed reduced healing potential compared with the other age groups, as they demonstrated decreased recovery of in vivo functional and ultrasound assessment parameters and inferior mechanical and histological properties after an Achilles tendon rupture.

Conclusion: These findings may help explain the increased rupture rate observed clinically in middle-aged patients by suggesting that there may be altered tendon responses to daily trauma.

Clinical Relevance: The results provide novel data on age-specific healing outcomes after an Achilles tendon rupture, which underscores the importance of considering a patient's age during treatment and expectations for outcomes.
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http://dx.doi.org/10.1177/03635465211055476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8819270PMC
January 2022

Pulsed electromagnetic field therapy alters early healing in a rat model of rotator cuff injury and repair: Potential mechanisms.

J Orthop Res 2022 Jul 17;40(7):1593-1603. Epub 2021 Oct 17.

McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Rotator cuff repair failure remains common due to poor tendon healing, particularly at the enthesis. We previously showed that pulsed electromagnetic field (PEMF) therapy improved the mechanical properties of the rat supraspinatus tendon postoperatively. However, little is known about the mechanisms behind PEMF-dependent contributions to improved healing in this injury model. The objective of this study was to determine the influence of PEMF treatment on tendon gene expression and cell composition, as well as bone microarchitecture and dynamic bone metabolism during early stages of healing. We hypothesized that PEMF treatment would amplify tendon-healing related signaling pathways while mitigating inflammation and improve bone metabolism at the repair site. Rats underwent rotator cuff injury and repair followed by assignment to either control (non-PEMF) or PEMF treatment groups. Gene and protein expression as well as tendon and bone histological assessments were performed 3, 7, 14, 21, and 28 days after injury. Gene expression data demonstrated an upregulation in the bone morphogenetic protein 2 signaling pathway and increases in pro-osteogenic genes at the insertion, supporting important processes to re-establish the tendon-bone interface. PEMF also downregulated genes related to a fibrotic healing response. Anti-inflammatory effects were demonstrated by both gene expression and macrophage phenotype. PEMF significantly increased the rate of kinetic bone formation directly adjacent to the tendon enthesis as well as the number of cuboidal surface osteoblasts (active osteoblasts) in the humeral head. This study has provided insight into how PEMF affects cellular and molecular processes in the supraspinatus tendon and adjacent bone after injury and repair.
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http://dx.doi.org/10.1002/jor.25185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9013393PMC
July 2022

Inhibition of glucose use improves structural recovery of injured Achilles tendon in mice.

J Orthop Res 2022 Jun 8;40(6):1409-1419. Epub 2021 Sep 8.

Department of Orthopaedics, University of Maryland, Baltimore, Maryland, USA.

Injured tendons do not regain their native structure except at fetal or very young ages. Healing tendons often show mucoid degeneration involving accumulation of sulfated glycosaminoglycans (GAGs), but its etiology and molecular base have not been studied substantially. We hypothesized that quality and quantity of gene expression involving the synthesis of proteoglycans having sulfated GAGs are altered in injured tendons and that a reduction in synthesis of sulfated GAGs improves structural and functional recovery of injured tendons. C57BL6/j mice were subjected to Achilles tendon tenotomy surgery. The injured tendons accumulated sulfate proteoglycans as early as 1-week postsurgery and continued so by 4-week postsurgery. Transcriptome analysis revealed upregulation of a wide range of proteoglycan genes that have sulfated GAGs in the injured tendons 1 and 3 weeks postsurgery. Genes critical for enzymatic reaction of initiation and elongation of chondroitin sulfate GAG chains were also upregulated. After the surgery, mice were treated with the 2-deoxy-d-glucose (2DG) that inhibits conversion of glucose to glucose-6-phosphate, an initial step of glucose metabolism as an energy source and precursors of monosaccharides of GAGs. The 2DG treatment reduced accumulation of sulfated proteoglycans, improved collagen fiber alignment, and reduced the cross-sectional area of the injured tendons. The modulus of the 2DG-treated groups was higher than that in the vehicle group, but not of statistical significance. Our findings suggest that mucoid degeneration in injured tendons may result from the upregulated expression of genes involved the synthesis of sulfate proteoglycans and can be inhibited by reduction of glucose utilization.
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http://dx.doi.org/10.1002/jor.25176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8882710PMC
June 2022

Limited Scar Resection for Chronic Achilles Tendon Repair: Use of a Rat Model.

Am J Sports Med 2021 08 1;49(10):2707-2715. Epub 2021 Jul 1.

McKay Orthopaedic Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Achilles tendon rupture diagnosis is frequently missed, leading to the development of a chronic rupture that requires surgical intervention to remove scar tissue and return the elongated Achilles tendon to appropriate functional length. The limited scar resection (LSR) intervention strategy may provide an advantage over other techniques, as it is less invasive and nondestructive to other tissues, although there is little evidence comparing outcomes between intervention strategies.

Hypothesis: The LSR technique would be a viable treatment option for chronic Achilles tendon ruptures and would perform comparably with a more clinically accepted procedure, the gastrocnemius fascial turndown (GFT), in postintervention functional outcome measures and tendon mechanical and histological properties.

Study Design: Controlled laboratory study.

Methods: Chronic Achilles tendon ruptures were induced in the right hindlimb of Sprague-Dawley rats by Achilles tendon transection without repair, immobilization in dorsiflexion, and 5 weeks of cage activity. Animals were randomly divided between the intervention strategy groups (LSR and GFT), received 1 week of immobilization in plantarflexion, and were sacrificed at 3 or 6 weeks postintervention. In vivo functional outcome measures (gait kinetics, passive joint function, tendon vascular perfusion) were quantified during healing, and tendon mechanical and histological properties were assessed postsacrifice.

Results: When compared with the GFT, the LSR technique elicited a faster return to baseline in gait kinetics, although there were few differences between groups or with healing time in other functional outcome measures (passive joint function and vascular perfusion). Quasi-static mechanical properties were improved with healing in both surgical intervention groups, although only the LSR group showed an improvement in fatigue properties between 3 and 6 weeks postintervention. Histological properties were similar between intervention strategies, except for decreased cellularity in the LSR group at 6 weeks postintervention.

Conclusion: The LSR technique is a viable surgical intervention strategy for a chronic Achilles tendon rupture in a rodent model, and it performs similarly, if not better, when directly compared with a more clinically accepted surgery, the GFT.

Clinical Relevance: This study supports the increased clinical use of the LSR technique for treating chronic Achilles tendon rupture cases.
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http://dx.doi.org/10.1177/03635465211023096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8653705PMC
August 2021

Reticulocalbin 3 is involved in postnatal tendon development by regulating collagen fibrillogenesis and cellular maturation.

Sci Rep 2021 05 25;11(1):10868. Epub 2021 May 25.

McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104-6081, USA.

Tendon plays a critical role in the joint movement by transmitting force from muscle to bone. This transmission of force is facilitated by its specialized structure, which consists of highly aligned extracellular matrix consisting predominantly of type I collagen. Tenocytes, fibroblast-like tendon cells residing between the parallel collagen fibers, regulate this specialized tendon matrix. Despite the importance of collagen structure and tenocyte function, the biological mechanisms regulating fibrillogenesis and tenocyte maturation are not well understood. Here we examine the function of Reticulocalbin 3 (Rcn3) in collagen fibrillogenesis and tenocyte maturation during postnatal tendon development using a genetic mouse model. Loss of Rcn3 in tendon caused decreased tendon thickness, abnormal tendon cell maturation, and decreased mechanical properties. Interestingly, Rcn3 deficient mice exhibited a smaller collagen fibril distribution and over-hydroxylation in C-telopeptide cross-linking lysine from α1(1) chain. Additionally, the proline 3-hydroxylation sites in type I collagen were also over-hydroxylated in Rcn3 deficient mice. Our data collectively suggest that Rcn3 is a pivotal regulator of collagen fibrillogenesis and tenocyte maturation during postnatal tendon development.
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http://dx.doi.org/10.1038/s41598-021-90258-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149630PMC
May 2021

Mechanical properties of the different rotator cuff tendons in the rat are similarly and adversely affected by age.

J Biomech 2021 03 13;117:110249. Epub 2021 Jan 13.

McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Rotator cuff tendon tears and tendinopathies are common injuries affecting a large portion of the population and can result in pain and joint dysfunction. Incidence of rotator cuff tears significantly increases with advancing age, and up to 90% of these tears involve the supraspinatus. Previous literature has shown that aging can lead to inferior mechanics, altered composition, and changes in structural properties of the supraspinatus. However, there is little known about changes in supraspinatus mechanical properties in context of other rotator cuff tendons. Alterations in tendon mechanical properties may indicate damage and an increased risk of rupture, and thus, the purpose of this study was to use a rat model to define age-related alterations in rotator cuff tendon mechanics to determine why the supraspinatus is more susceptible to tears due to aging than the infraspinatus, subscapularis, and teres minor. Fatigue, viscoelastic, and quasi-static properties were evaluated in juvenile, adult, aged, and geriatric rats. Aging ubiquitously and adversely affected all rotator cuff tendons tested, particularly leading to increased stiffness, decreased stress relaxation, and decreased fatigue secant and tangent moduli in geriatric animals, suggesting a common intrinsic mechanism due to aging in all rotator cuff tendons. This study demonstrates that aging has a significant effect on rotator cuff tendon mechanical properties, though the supraspinatus was not preferentially affected. Thus, we are unable to attribute the aging-associated increase in supraspinatus tears to its mechanical response alone.
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http://dx.doi.org/10.1016/j.jbiomech.2021.110249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920936PMC
March 2021

Liquid Poly-N-acetyl Glucosamine (sNAG) Improves Achilles Tendon Healing in a Rat Model.

Ann Biomed Eng 2021 Feb 6;49(2):515-522. Epub 2021 Jan 6.

McKay Orthopaedic Research Laboratory, University of Pennsylvania, 3450 Hamilton Walk, 371 Stemmler Hall, Philadelphia, PA, 19104-6081, USA.

The Achilles tendon, while the strongest and largest tendon in the body, is frequently injured. Even after surgical repair, patients risk re-rupture and long-term deficits in function. Poly-N-acetyl glucosamine (sNAG) polymer has been shown to increase the rate of healing of venous leg ulcers, and use of this material improved tendon-to-bone healing in a rat model of rotator cuff injury. Therefore, the purpose of this study was to investigate the healing properties of liquid sNAG polymer suspension in a rat partial Achilles tear model. We hypothesized that repeated sNAG injections throughout healing would improve Achilles tendon healing as measured by improved mechanical properties and cellular morphology compared to controls. Results demonstrate that sNAG has a positive effect on rat Achilles tendon healing at three weeks after a full thickness, partial width injury. sNAG treatment led to increased quasistatic tendon stiffness, and increased tangent and secant stiffness throughout fatigue cycling protocols. Increased dynamic modulus also suggests improved viscoelastic properties with sNAG treatment. No differences were identified in histological properties. Importantly, use of this material did not have any negative effects on any measured parameter. These results support further study of this material as a minimally invasive treatment modality for tendon healing.
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http://dx.doi.org/10.1007/s10439-020-02711-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178587PMC
February 2021

Chronic Nicotine Exposure Minimally Affects Rat Supraspinatus Tendon Properties and Bone Microstructure.

Ann Biomed Eng 2021 May 3;49(5):1333-1341. Epub 2020 Nov 3.

McKay Orthopaedic Research Laboratory, University of Pennsylvania, 3450 Hamilton Walk, 371 Stemmler Hall, Philadelphia, PA, 19104-6081, USA.

Cigarette smoking is the largest cause of preventable deaths, and a known risk factor for musculoskeletal issues including rotator cuff tendon tears. Tendon degeneration is believed to be due in part to changes in tendon cell health and collagen structure. Several studies have demonstrated that exposure to nicotine negatively impacts tendon healing, but surprisingly, nicotine exposure was shown to increase rat supraspinatus tendon stiffness. In order to address this seeming contradiction, the objective of this study was to comprehensively investigate the effects of long-term (18 weeks) exposure of nicotine on tendon-to-bone microstructural properties in a rat model. We hypothesized that long term subcutaneous nicotine delivery would lead to diminished tendon mechanical properties, decreased bone microstructure in the humeral head, and altered tendon cell morphology compared to age-matched control rats receiving saline. Results demonstrated a small decrease in tendon size and stiffness, with decreased cell density in the tendon midsubstance. However, no differences were found in the enthesis fibrocartilage or in the underlying subchondral or trabecular bone. In conclusion, our study revealed limited effects of nicotine on the homeostatic condition of the supraspinatus tendon, enthesis, and underlying bone. Future studies are needed to ascertain effects of other components of tobacco products.
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http://dx.doi.org/10.1007/s10439-020-02667-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062272PMC
May 2021

Collagen XII mediated cellular and extracellular mechanisms regulate establishment of tendon structure and function.

Matrix Biol 2021 01 20;95:52-67. Epub 2020 Oct 20.

College of Medicine, University of South Florida, Morsani, Tampa, FL, United States.

Tendons have a uniaxially aligned structure with a hierarchical organization of collagen fibrils crucial for tendon function. Collagen XII is expressed in tendons and has been implicated in the regulation of fibrillogenesis. It is a non-fibrillar collagen belonging to the Fibril-Associated Collagens with Interrupted Triple Helices (FACIT) family. Mutations in COL12A1 cause myopathic Ehlers Danlos Syndrome with a clinical phenotype involving both joints and tendons supporting critical role(s) for collagen XII in tendon development and function. Here we demonstrate the molecular function of collagen XII during tendon development using a Col12a1 null mouse model. Col12a1 deficiency altered tenocyte shape, formation of interacting cell processes, and organization resulting in impaired cell-cell communication and disruption of hierarchal structure as well as decreased tissue stiffness. Immuno-localization revealed that collagen XII accumulated on the tenocyte surface and connected adjacent tenocytes by building matrix bridges between the cells, suggesting that collagen XII regulates intercellular communication. In addition, there was a decrease in fibrillar collagen I in collagen XII deficient tenocyte cultures compared with controls suggesting collagen XII signaling specifically alters tenocyte biosynthesis. This suggests that collagen XII provides feedback to tenocytes regulating extracellular collagen I. Together, the data indicate dual roles for collagen XII in determination of tendon structure and function. Through association with fibrils it functions in fibril packing, fiber assembly and stability. In addition, collagen XII influences tenocyte organization required for assembly of higher order structure; intercellular communication necessary to coordinate long range order and feedback on tenocytes influencing collagen synthesis. Integration of both regulatory roles is required for the acquisition of hierarchal structure and mechanical properties.
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http://dx.doi.org/10.1016/j.matbio.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870578PMC
January 2021

Molecular and Structural Effects of Percutaneous Interventions in Chronic Achilles Tendinopathy.

Int J Mol Sci 2020 Sep 23;21(19). Epub 2020 Sep 23.

Rheumatology Department, Nantes University Hospital, 44000 Nantes, France.

Achilles tendinopathy (AT) is a common problem, especially in people of working age, as well as in the elderly. Although the pathogenesis of tendinopathy is better known, therapeutic management of AT remains challenging. Various percutaneous treatments have been applied to tendon lesions: e.g., injectable treatments, platelet-rich plasma (PRP), corticosteroids, stem cells, MMP inhibitors, and anti-angiogenic agents), as well as percutaneous procedures without any injection (percutaneous soft tissue release and dry needling). In this review, we will describe and comment on data about the molecular and structural effects of these treatments obtained in vitro and in vivo and report their efficacy in clinical trials. Local treatments have some impact on neovascularization, inflammation or tissue remodeling in animal models, but evidence from clinical trials remains too weak to establish an accurate management plan, and further studies will be necessary to evaluate their value.
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http://dx.doi.org/10.3390/ijms21197000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582801PMC
September 2020

Collagen XI regulates the acquisition of collagen fibril structure, organization and functional properties in tendon.

Matrix Biol 2020 12 17;94:77-94. Epub 2020 Sep 17.

Department of Molecular Pharmacology & Physiology, University of South Florida, Morsani College of Medicine, 12901 Bruce B. Downs Blvd, Tampa, FL, 33612 USA; McKay Orthopedic Research Laboratory, University of Pennsylvania, Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA, 19104 USA. Electronic address:

Collagen XI is a fibril-forming collagen that regulates collagen fibrillogenesis. Collagen XI is normally associated with collagen II-containing tissues such as cartilage, but it also is expressed broadly during development in collagen I-containing tissues, including tendons. The goals of this study are to define the roles of collagen XI in regulation of tendon fibrillar structure and the relationship to function. A conditional Col11a1-null mouse model was created to permit the spatial and temporal manipulation of Col11a1 expression. We hypothesize that collagen XI functions to regulate fibril assembly, organization and, therefore, tendon function. Previous work using cho mice with ablated Col11a1 alleles supported roles for collagen XI in tendon fibril assembly. Homozygous cho/cho mice have a perinatal lethal phenotype that limited the studies. To circumvent this, a conditional Col11a1 mouse model was created where exon 3 was flanked with loxP sites. Breeding with Scleraxis-Cre (Scx-Cre) mice yielded a tendon-specific Col11a1-null mouse line, Col11a1. Col11a1 mice had no phenotype compared to wild type C57BL/6 mice and other control mice, e.g., Col11a1 and Scx-Cre. Col11a1 mice expressed Col11a1 mRNA at levels comparable to wild type and Scx-Cre mice. In contrast, in Col11a1 mice, Col11a1 mRNA expression decreased to baseline in flexor digitorum longus tendons (FDL). Collagen XI protein expression was absent in Col11a1 FDLs, and at ~50% in Col11a1 compared to controls. Phenotypically, Col11a1 mice had significantly decreased body weights (p < 0.001), grip strengths (p < 0.001), and with age developed gait impairment becoming hypomobile. In the absence of Col11a1, the tendon collagen fibrillar matrix was abnormal when analyzed using transmission electron microscopy. Reducing Col11a1 and, therefore collagen XI content, resulted in abnormal fibril structure, loss of normal fibril diameter control with a significant shift to small diameters and disrupted parallel alignment of fibrils. These alterations in matrix structure were observed in developing (day 4), maturing (day 30) and mature (day 60) mice. Altering the time of knockdown using inducible I-Col11a1 mice indicated that the primary regulatory foci for collagen XI was in development. In mature Col11a1 FDLs a significant decrease in the biomechanical properties was observed. The decrease in maximum stress and modulus suggest that fundamental differences in the material properties in the absence of Col11a1 expression underlie the mechanical deficiencies. These data demonstrate an essential role for collagen XI in regulation of tendon fibril assembly and organization occurring primarily during development.
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http://dx.doi.org/10.1016/j.matbio.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722227PMC
December 2020

Modulation of vascular response after injury in the rat Achilles tendon alters healing capacity.

J Orthop Res 2021 09 1;39(9):2000-2016. Epub 2020 Oct 1.

McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Tendons are relatively hypovascular but become hypervascular during both injury and degeneration. This is due to the angiogenic response, or the formation of new blood vessels, to tissue injury. The objective of this study was to evaluate the effect of vascular modulation in the rat Achilles tendons during healing. Fischer rats received a bilateral Achilles incisional injury followed by local injections of vascular endothelial growth factor (VEGF), anti-VEGF antibody (B20.4-1-1), or saline either early or late during the healing process. Vascular modulation and healing were evaluated using multiple in vivo ultrasound imaging modalities, in vivo functional assessment, and ex vivo measures of tendon compositional and mechanical properties. The late delivery of anti-VEGF antibody, B20, caused a temporary reduction in healing capacity during a time point where vascularity was also decreased, and then an improvement during a later time point where vascularity was increased relative to control. However, VEGF delivery had a minimal impact on healing and vascular changes in both early and late delivery times. This study was the first to evaluate vascular changes using both in vivo imaging methods and ex vivo histological methods, as well as functional and mechanical outcomes associated with these vascular changes. Clinical significance: this study demonstrates that the alteration of vascular response through the delivery of angiogenic growth factors has the ability to alter tendon healing properties.
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http://dx.doi.org/10.1002/jor.24861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960560PMC
September 2021

Induced Knockdown of Decorin, Alone and in Tandem With Biglycan Knockdown, Directly Increases Aged Murine Patellar Tendon Viscoelastic Properties.

J Biomech Eng 2020 11;142(11)

McKay Orthopaedic Research Laboratory, University of Pennsylvania, 307A Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104.

Tendon injuries increase with age, yet the age-associated changes in tendon properties remain unexplained. Decorin and biglycan are two matrix proteoglycans that play complex roles in regulating tendon formation, maturation, and aging, most notably in extracellular matrix assembly and maintenance. However, the roles of decorin and biglycan have not been temporally isolated in a homeostatic aged context. The goal of this work was to temporally isolate and define the roles of decorin and biglycan in regulating aged murine patellar tendon mechanical properties. We hypothesized that decorin would have a larger influence than biglycan on aged tendon mechanical properties and that biglycan would have an additive role in this regulation. When decorin and biglycan were knocked down in aged tendons, minimal changes in gene expression were observed, implying that these models directly define the roles of decorin and biglycan in regulating tendon mechanical properties. Knockdown of decorin or biglycan led to minimal changes in quasi-static mechanical properties. However, decorin deficiency led to increases in stress relaxation and phase shift that were exacerbated when coupled with biglycan deficiency. This study highlights an important role for decorin, alone and in tandem with biglycan, in regulating aged tendon viscoelastic properties.
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http://dx.doi.org/10.1115/1.4048030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580841PMC
November 2020

Pregnancy and Lactation Impair Subchondral Bone Leading to Reduced Rat Supraspinatus Tendon-to-Bone Insertion Site Failure Properties.

J Biomech Eng 2020 11;142(11)

McKay Orthopaedic Research Laboratory, University of Pennsylvania, Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104-6081.

Pregnant women experience weight gain, gait changes, and biochemical fluctuations that impair joint function and alter the maternal skeleton. Hormonal changes increase pelvic ligament laxity in preparation for childbirth and affect peripheral joint laxity. Calcium demands also rise during pregnancy and lactation, resulting in reduced bone mineral density (BMD) and maternal bone loss. Altered tendon properties and bone loss during pregnancy and lactation may impact tendon insertion sites, such as rotator cuff tendons where insertion site ruptures are common. However, the effects of pregnancy and lactation at the tendon-to-bone interface have not been investigated. Therefore, the objective of this study was to evaluate supraspinatus tendon mechanical properties and insertion site microstructure during pregnancy, lactation, and postweaning recovery in female rats. We hypothesized that pregnancy and lactation would compromise supraspinatus tendon mechanical properties and subchondral bone microstructure. Female rats were divided into virgin, pregnancy, lactation, and recovery groups, and supraspinatus tendons were mechanically evaluated. Surprisingly, tendon mechanics was unaffected by pregnancy and lactation. However, tendon modulus decreased two-weeks postweaning. Additionally, tendons failed by bony avulsion at the insertion site, and the lactation group exhibited reduced failure properties corresponding to decreased subchondral bone mineralization. Lactation also resulted in dramatic bone loss at the epiphysis, but trabecular bone microarchitecture recovered postweaning. In conclusion, lactation following pregnancy impaired trabecular bone microstructure and subchondral bone mineralization, leading to reduced supraspinatus tendon-to-bone insertion site failure properties. These findings will contribute toward understanding the pathogenesis of tendon-to-bone disorders.
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http://dx.doi.org/10.1115/1.4047629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580662PMC
November 2020

Biocompatibility and bioactivity of an FGF-loaded microsphere-based bilayer delivery system.

Acta Biomater 2020 07 16;111:341-348. Epub 2020 May 16.

Department of Orthopaedic Surgery, University of Pennsylvania, McKay Orthopaedic Research Laboratory, 36th Street and Hamilton Walk, 374 Stemmler Hall, Philadelphia, PA 19104-6081, USA; Translational Musculoskeletal Research Center, Philadelphia VA Medical Center, 3900 Woodland Avenue, Building 21, Room A200, Philadelphia, PA 19104, USA. Electronic address:

Many drug delivery systems rely on degradation or dissolution of the carrier material to regulate release. In cases where mechanical support is required during regeneration, this necessitates composite systems in which the mechanics of the implant are decoupled from the drug release profile. To address this need, we developed a system in which microspheres (MS) were sequestered in a defined location between two nanofibrous layers. This bilayer delivery system (BiLDS) enables simultaneous structural support and decoupled release profiles. To test this new system, PLGA (poly-lactide-co-glycolic acid) microspheres were prepared using a water-in-oil-in-water (w/o/w) emulsion technique and incorporated Alexa Fluor-tagged bovine serum albumin (BSA) and basic fibroblast growth factor (bFGF). These MS were secured in a defined pocket between two polycaprolactone (PCL) nanofibrous scaffolds, where the layered scaffolds provide a template for new tissue formation while enabling independent and local release from the co-delivered MS. Scanning electron microscopy (SEM) images showed that the assembled BiLDS could localize and retain MS in the central pocket that was surrounded by a continuous seal formed along the margin. Cell viability and proliferation assays showed enhanced cell activity when exposed to BiLDS containing Alexa Fluor-BSA/bFGF-loaded MS, both in vitro and in vivo. MS delivered via the BiLDS system persisted in a localized area after subcutaneous implantation for at least 4 weeks, and bFGF release increased colonization of the implant. These data establish the BiLDS technology as a sustained in vivo drug delivery platform that can localize protein and other growth factor release to a surgical site while providing a structural template for new tissue formation. STATEMENT OF SIGNIFICANCE: Localized and controlled delivery systems for the sustained release of drugs are essential. Many strategies have been developed for this purpose, but most rely on degradation (and loss of material properties) for delivery. Here, we developed a bilayer delivery system (BiLDS) that decouples the physical properties of a scaffold from its delivery kinetics. For this, biodegradable PLGA microspheres were sequestered within a central pocket of a slowly degrading nanofibrous bilayer. Using this device, we show enhanced cell activity with FGF delivery from the BiLDS both in vitro and in vivo. These data support that BiLDS can localize sustained protein and biofactor delivery to a surgical site while also serving as a mechanical scaffold for tissue repair and regeneration.
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http://dx.doi.org/10.1016/j.actbio.2020.04.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868956PMC
July 2020

Short- and Long-Term Exercise Results in a Differential Achilles Tendon Mechanical Response.

J Biomech Eng 2020 08;142(8)

McKay Orthopaedic Research Laboratory, University of Pennsylvania, G13A Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104-6081.

The study was conducted to define the biomechanical response of rat Achilles tendon after a single bout of exercise and a short or long duration of daily exercise. We hypothesized that a single bout or a short duration of exercise would cause a transient decrease in Achilles tendon mechanical properties and a long duration of daily exercise would improve these properties. One hundred and thirty-six Sprague-Dawley rats were divided into cage activity (CA) or exercise (EX) groups for a single bout, short-term, or long-term exercise. Animals in single bout EX groups were euthanized, 3, 12, 24, or 48 h upon completion of a single bout of exercise (10 m/min, 1 h) on a flat treadmill. Animals in short-term EX groups ran on a flat treadmill for 3 days, 1, or 2 weeks while animals in long-term EX groups ran for 8 weeks. Tendon quasi-static and viscoelastic response was evaluated for all Achilles tendons. A single bout of exercise increased tendon stiffness after 48 h of recovery. Short-term exercise up to 1 week decreased cross-sectional area, stiffness, modulus, and dynamic modulus of the Achilles tendon. In contrast, 8 weeks of daily exercise increased stiffness, modulus, and dynamic modulus of the tendon. This study highlights the response of Achilles tendons to single and sustained bouts of exercise. Adequate time intervals are important to allow for tendon adaptations when initiating a new training regimen and overall beneficial effects to the Achilles tendon.
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http://dx.doi.org/10.1115/1.4046864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477707PMC
August 2020

Localized delivery of ibuprofen via a bilayer delivery system (BiLDS) for supraspinatus tendon healing in a rat model.

J Orthop Res 2020 11 7;38(11):2339-2349. Epub 2020 Apr 7.

Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania.

The high prevalence of tendon retear following rotator cuff repair motivates the development of new therapeutics to promote improved tendon healing. Controlled delivery of non-steroidal anti-inflammatory drugs to the repair site via an implanted scaffold is a promising option for modulating inflammation in the healing environment. Furthermore, biodegradable nanofibrous delivery systems offer an optimized architecture and surface area for cellular attachment, proliferation, and infiltration while releasing soluble factors to promote tendon regeneration. To this end, we developed a bilayer delivery system (BiLDS) for localized and controlled release of ibuprofen (IBP) to temporally mitigate inflammation and enhance tendon remodeling following surgical repair by promoting organized tissue formation. In vitro evaluation confirmed the delayed and sustained release of IBP from Labrafil-modified poly(lactic-co-glycolic) acid microspheres within sintered poly(ε-caprolactone) electrospun scaffolds. Biocompatibility of the BiLDS was demonstrated with primary Achilles tendon cells in vitro. Implantation of the IBP-releasing BiLDS at the repair site in a rat rotator cuff injury and repair model led to decreased expression of proinflammatory cytokine, tumor necrotic factor-α, and increased anti-inflammatory cytokine, transforming growth factor-β1. The BiLDS remained intact for mechanical reinforcement and recovered the tendon structural properties by 8 weeks. These results suggest the therapeutic potential of a novel biocompatible nanofibrous BiLDS for localized and tailored delivery of IBP to mitigate tendon inflammation and improve repair outcomes. Future studies are required to define the mechanical implications of an optimized BiLDS in a rat model beyond 8 weeks or in a larger animal model.
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http://dx.doi.org/10.1002/jor.24670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529744PMC
November 2020

Effects of Pulsed Electromagnetic Field Therapy on Rat Achilles Tendon Healing.

J Orthop Res 2020 01 15;38(1):70-81. Epub 2019 Oct 15.

McKay Orthopaedic Research Laboratory, University of Pennsylvania, 3450 Hamilton Walk, 371 Stemmler Hall, Philadelphia, Pennsylvania, 19104.

The Achilles tendon is frequently injured. Data to support specific treatment strategies for complete and partial tears is inconclusive. Regardless of treatment, patients risk re-rupture and typically have long-term functional deficits. We previously showed that pulsed electromagnetic field (PEMF) therapy improved tendon-to-bone healing in a rat rotator cuff model. This study investigated the effects of PEMF on rat ankle function and Achilles tendon properties after (i) complete Achilles tendon tear and repair with immobilization, (ii) partial Achilles tendon tear without repair and with immobilization, and (iii) partial Achilles tendon tear without repair and without immobilization. We hypothesized that PEMF would improve tendon properties, increase collagen organization, and improve joint function, regardless of injury type. After surgical injury, animals were assigned to a treatment group: (i) no treatment control, (ii) 1 h of PEMF per day, or (iii) 3 h of PEMF per day. Animals were euthanized at 1, 3, and 6 weeks post-injury. Joint mechanics and gait analysis were assessed over time, and fatigue testing and histology were performed at each time point. Results indicate no clear differences in Achilles healing with PEMF treatment. Some decreases in tendon mechanical properties and ankle function suggest PEMF may be detrimental after complete tear. Some early improvements were seen with PEMF after partial tear with immobilization; however, immobilization was found to be a confounding factor. This body of work emphasizes the distinct effects of PEMF on tendon-to-bone healing and supports trialing potential treatment strategies pre-clinically across tendons before applying them clinically. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:70-81, 2020.
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http://dx.doi.org/10.1002/jor.24487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917903PMC
January 2020

Tendon Biomechanics and Crimp Properties Following Fatigue Loading Are Influenced by Tendon Type and Age in Mice.

J Orthop Res 2020 01 23;38(1):36-42. Epub 2019 Jul 23.

McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania.

In tendon, type-I collagen assembles together into fibrils, fibers, and fascicles that exhibit a wavy or crimped pattern that uncrimps with applied tensile loading. This structural property has been observed across multiple tendons throughout aging and may play an important role in tendon viscoelasticity, response to fatigue loading, healing, and development. Previous work has shown that crimp is permanently altered with the application of fatigue loading. This opens the possibility of evaluating tendon crimp as a clinical surrogate of tissue damage. The purpose of this study was to determine how fatigue loading in tendon affects crimp and mechanical properties throughout aging and between tendon types. Mouse patellar tendons (PT) and flexor digitorum longus (FDL) tendons were fatigue loaded while an integrated plane polariscope simultaneously assessed crimp properties at P150 and P570 days of age to model mature and aged tendon phenotypes (N = 10-11/group). Tendon type, fatigue loading, and aging were found to differentially affect tendon mechanical and crimp properties. FDL tendons had higher modulus and hysteresis, whereas the PT showed more laxity and toe region strain throughout aging. Crimp frequency was consistently higher in FDL compared with PT throughout fatigue loading, whereas the crimp amplitude was cycle dependent. This differential response based on tendon type and age further suggests that the FDL and the PT respond differently to fatigue loading and that this response is age-dependent. Together, our findings suggest that the mechanical and structural effects of fatigue loading are specific to tendon type and age in mice. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:36-42, 2020.
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http://dx.doi.org/10.1002/jor.24407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917867PMC
January 2020

Ultrasound Evaluation of Anti-Vascular Endothelial Growth Factor-Induced Changes in Vascular Response Following Tendon Injury.

Ultrasound Med Biol 2019 07 30;45(7):1841-1849. Epub 2019 Apr 30.

McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

While vascular ingrowth is necessary for tendon healing, hypervascularization following tendon injury is not always believed to be beneficial, and there is now evidence showing beneficial results of anti-angiogenic treatments in the context of tendon healing. However, the dose-dependency of anti-angiogenic-altered vascular response, as well as methods for evaluating these changes in vivo, has not been fully investigated. Therefore, the objective of this study was to evaluate if in vivo ultrasound imaging can detect dose-dependent, anti-angiogenic treatment-induced changes in vascularity in rat Achilles tendon after injury. Color Doppler ultrasound revealed an increase in vascularity in a low-dosage group, while photoacoustic imaging demonstrated a decrease in vascularity in mid- and high-dosage groups. Histologic staining supported the decrease in vascularity observed in the mid-dosage group. This study demonstrates dose-dependent vascular alterations from the delivery of an anti-angiogenic factor after tendon injury that can be detected through ultrasound imaging methods.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2019.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555687PMC
July 2019

Ultrasound-Guided Dry Needling of the Healthy Rat Supraspinatus Tendon Elicits Early Healing Without Causing Permanent Damage.

J Orthop Res 2019 09 20;37(9):2035-2042. Epub 2019 May 20.

Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.

Overuse-induced tendinopathy is highly prevalent in the general population. Percutaneous fenestration, or dry needling, techniques have been increasing in popularity, but despite their current use, there are no controlled laboratory studies to provide fundamental support for this practice. The objective of this study was to establish a model for percutaneous needling of the rat supraspinatus tendon using ultrasound guidance and to evaluate the biological response of needling healthy tendon. A total of 44 male Sprague-Dawley rats (477 ± 39 g) were used to evaluate the effect of dry needling on healthy supraspinatus tendon properties. Ten rats were reserved as un-needled control animals, and the remaining animals underwent either mild or moderate bilateral needling protocols and were sacrificed at 1 or 6 weeks post-needling (n = 8-10/group). Color Doppler ultrasound imaging was performed to analyze blood flow within the tendon. Histological and immunohistochemical analyses were used to determine cellular, inflammatory, and extracellular matrix properties of the tissue. Finally, quasi-static tensile mechanical analysis was performed to obtain viscoelastic, structural, and material properties to evaluate the tendon healing outcome. Data were tested for normality, and then two-way analysis of variance tests were performed followed by post hoc tests for multiple comparisons. Both the mild and moderate needling groups caused a transient healing response at early time points as shown by a statistically significant (p < 0.05) reduction in mechanical properties, and increase in blood flow, inflammation, and production of collagen III and glycosaminoglycans as compared to the control. Furthermore, mild needling properties returned to or exceeded pre-needling values at the 6-week time point. Clinical significance: Needling the rat supraspinatus tendon is a feasible technique that causes a transient healing response followed by a return to, or improvement of, normal tendon properties, indicating potential applicability in understanding the effects of current practices utilizing dry needling of tendons in humans. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2035-2042, 2019.
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http://dx.doi.org/10.1002/jor.24329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688919PMC
September 2019

Quantitative comparison of three rat models of Achilles tendon injury: A multidisciplinary approach.

J Biomech 2019 May 27;88:194-200. Epub 2019 Mar 27.

McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

The Achilles tendon, while the strongest and largest tendon in the body, is frequently injured. Inconclusive evidence exists regarding treatment strategies for both complete tears and partial tears. Well-characterized animal models of tendon injury are important for understanding physiological processes of tendon repair and testing potential therapeutics. Utilizing three distinct models of rat Achilles tendon injury, the objective of this study was to define and compare the effects and relative impact on tendon properties and ankle function of both tear severity (complete tear versus partial tear, both with post-operative immobilization) and immobilization after partial tear (partial tear with versus without immobilization). We hypothesized that a complete tear would cause inferior post-injury properties compared to a partial tear, and that immediate loading after partial tear would improve post-injury properties compared to immobilization. All models were reproducible and had distinct effects on measured parameters. Injury severity drastically influenced tendon healing, with complete tear causing decreased ankle mobility and tendon mechanics compared to partial tears. One week of plantarflexion immobilization had a strong effect on animals receiving a partial tear. Tendons with partial tears and immobilization failed early during fatigue cycling three weeks post-injury. Partial tear without immobilization had no effect on ankle range of motion through dorsiflexion at any time point compared to the pre-surgery value, while partial tear with immobilization demonstrated diminished function at all post-injury time points. All three models of Achilles injury could be useful for tendon healing investigations, chosen based on the prospective applications of a potential therapeutic.
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http://dx.doi.org/10.1016/j.jbiomech.2019.03.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499652PMC
May 2019

Chronic Nicotine Exposure Alters Uninjured Tendon Vascularity and Viscoelasticity.

Foot Ankle Orthop 2019 Apr 24;4(2). Epub 2019 Apr 24.

McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA.

Background: Although nicotine and tobacco use are well established to have adverse health effects, the effects on tendons are less well understood. The purpose of this study was to investigate the effect of chronic nicotine exposure on Achilles tendon (AT) and supraspinatus tendon (SS) physiologic and mechanical properties in a rodent model.

Methods: Sprague-Dawley rats (n = 20) were exposed to either 0.9% saline or 36 mg/mL nicotine through an implantable osmotic pump for 12 weeks. At 12 weeks, the AT was imaged in vivo with contrast-enhanced ultrasound (CE-US) to assess vascularity. Bilateral AT and SS were then harvested for ex vivo biomechanical analysis. Statistical analysis was performed using Student test and Mann Whitney test.

Results: AT CE-US demonstrated a significantly increased wash-in rate in the nicotine group compared to the saline group, indicating an increase in tissue perfusion rate in the nicotine group. AT percent stress relaxation, a measure of tendon viscoelasticity, was significantly increased in the nicotine group compared to the saline group. Similarly, there was a trend toward increased SS percent stress relaxation in the nicotine group compared to the saline group. No differences in other mechanical properties were observed.

Conclusion: AT perfusion rate increased and both AT and SS viscoelasticity were altered with chronic nicotine exposure at a clinically relevant dose that models the average smoker in the United States (14 cigarettes per day). Further studies are necessary to link these properties with tendon degeneration and injury.

Clinical Relevance: Chronic nicotine exposure affects tendon health. Patients should be counseled as such.
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http://dx.doi.org/10.1177/2473011419842529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723357PMC
April 2019

Effects of immobilization angle on tendon healing after achilles rupture in a rat model.

J Orthop Res 2019 03 28;37(3):562-573. Epub 2019 Feb 28.

McKay Orthopaedic Laboratory, University of Pennsylvania, 110 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, Pennsylvania, 19104-6081.

Conservative (non-operative) treatment of Achilles tendon ruptures is a common alternative to operative treatment. Following rupture, ankle immobilization in plantarflexion is thought to aid healing by restoring tendon end-to-end apposition. However, early activity may improve limb function, challenging the role of immobilization position on tendon healing, as it may affect loading across the injury site. This study investigated the effects of ankle immobilization angle in a rat model of Achilles tendon rupture. We hypothesized that manipulating the ankle from full plantarflexion into a more dorsiflexed position during the immobilization period would result in superior hindlimb function and tendon properties, but that prolonged casting in dorsiflexion would result in inferior outcomes. After Achilles tendon transection, animals were randomized into eight immobilization groups ranging from full plantarflexion (160°) to mid-point (90°) to full dorsiflexion (20°), with or without angle manipulation. Tendon properties and ankle function were influenced by ankle immobilization position and time. Tendon lengthening occurred after 1 week at 20° compared to more plantarflexed angles, and was associated with loss of propulsion force. Dorsiflexing the ankle during immobilization from 160° to 90° produced a stiffer, more aligned tendon, but did not lead to functional changes compared to immobilization at 160°. Although more dorsiflexed immobilization can enhance tissue properties and function of healing Achilles tendon following rupture, full dorsiflexion creates significant tendon elongation regardless of application time. This study suggests that the use of moderate plantarflexion and earlier return to activity can provide improved clinical outcomes. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
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http://dx.doi.org/10.1002/jor.24241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534419PMC
March 2019
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