Long-Term Effects of Reproduction and Lactation on the Rat Supraspinatus Tendon and Proximal Humerus.

During pregnancy and breastfeeding, women undergo hormonal fluctuations required for fetal development, parturition, and infant growth. These changes have secondary consequences on the maternal musculoskeletal system, increasing the risk for joint pain and osteoporosis. Though hormone levels return to prepregnancy levels postpartum, women may experience lasting musculoskeletal pain. Sex disparities exist in the prevalence of musculoskeletal disorders, but it remains unclear how reproductive history may impact sex differences. Specifically, the effects of both reproductive history and sex on the rotator cuff have not been studied. Pregnancy and lactation affect bone microstructure, suggesting possible impairments at the enthesis of rotator cuff tendons, where tears commonly occur. Therefore, our objective was to evaluate how reproductive history affects sex differences of the supraspinatus tendon and proximal humerus using male, virgin female, and female rats with a history of reproduction (referred to as reproductive females). We hypothesized tendon mechanical properties and humeral bone microstructure would be inferior in reproductive females compared to virgin females. Results showed sex differences independent of reproductive history, including greater tendon midsubstance modulus but lower subchondral bone mineral density (BMD) in females. When considering reproductive history, reproductive rats exhibited reduced tendon insertion site modulus and trabecular bone micro-architecture compared to virgin females with no differences from males. Overall, our study identified long-term changes in supraspinatus tendon mechanical and humeral trabecular bone properties that result following pregnancy and lactation, highlighting the importance of considering reproductive history in investigations of sex differences in the physiology and pathology of rotator cuff injuries.

Post-injury tendon mechanics are not affected by tamoxifen treatment.

PURPOSE: A growing interest in the mechanisms that govern tendon healing has resulted in the develop-ment of tools, such as the tamoxifen-inducible mouse knockdown model, to address these questions. However, tamoxifen is a selective estrogen receptor modulator and may interfere with the tendon healing process. The objective of this study was to evaluate the effects of tamoxifen on post-injury tendon mechanics in wild-type mice. METHODS: The mice underwent treatment at the time of injury using an established mouse injury model and the injured tendons were evaluated 3 weeks post-injury. The treatment contained tamoxifen suspended in corn oil and was compared to a treatment with only corn oil, as well as mice with no treatment. Tendons were evaluated by measuring the quasi-static and viscoelastic mechanics, collagen fiber realignment, cellularity, and nuclear morphology. RESULTS: Mechanical testing of the tendons post-injury revealed no changes to viscoelastic mechanics, quasi-static mechanics, or collagen realignment during loading after tamoxifen treatment with the dosage regimen utilized (three daily injections of 4.5 mg/40 g body weight). Additionally, histological analysis revealed no changes to cellularity or cell nuclear shape. CONCLUSION: Overall, this study revealed that tamoxifen treatment at the time of tendon injury did not result in changes to tendon mechanics or the histological parameters at 3 weeks post-injury.

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

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.

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

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.

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

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.

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

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.

Effects of pulsed electromagnetic field therapy at different frequencies and durations on rotator cuff tendon-to-bone healing in a rat model.

BACKGROUND: Rotator cuff tears affect millions of individuals each year, often requiring surgical intervention. However, repair failure remains common. We have previously shown that pulsed electromagnetic field (PEMF) therapy improved tendon-to-bone healing in a rat rotator cuff model. The purpose of this study was to determine the influence of both PEMF frequency and exposure time on rotator cuff healing. METHODS: Two hundred ten Sprague-Dawley rats underwent acute bilateral supraspinatus injury and repair followed by either Physio-Stim PEMF or high-frequency PEMF therapy for 1, 3, or 6 hours daily. Control animals did not receive PEMF therapy. Mechanical and histologic properties were assessed at 4, 8, and 16 weeks. RESULTS: Improvements in different mechanical properties at various endpoints were identified for all treatment modalities when compared with untreated animals, regardless of PEMF frequency or duration. Of note, 1 hour of Physio-Stim treatment showed significant improvements in tendon mechanical properties across all time points, including increases in both modulus and stiffness as early as 4 weeks. Collagen organization improved for several of the treatment groups compared with controls. In addition, improvements in type I collagen and fibronectin expression were identified with PEMF treatment. An important finding was that no adverse effects were identified in any mechanical or histologic property. CONCLUSIONS: Overall, our results suggest that PEMF therapy has a positive effect on rat rotator cuff healing for each electromagnetic fundamental pulse frequency and treatment duration tested in this study.

Tensile Mechanical Properties and Dynamic Collagen Fiber Re-Alignment of the Murine Cervix are Dramatically Altered Throughout Pregnancy.

The cervix is a unique organ able to dramatically change its shape and function by serving as a physical barrier for the growing fetus and then undergoing dramatic dilation allowing for delivery of a term infant. As a result, the cervix endures changing mechanical forces from the growing fetus. There is an emerging concept that the cervix may change or remodel "early" in many cases of spontaneous preterm birth (sPTB). However, the mechanical role of the cervix in both normal and preterm birth remains unclear. Therefore, the primary objective of this study was to determine the mechanical and structural responses of murine cervical tissue throughout a normal gestational time course. In this study, both tissue structural and material properties were determined via a quasi-static tensile load-to-failure test, while simultaneously obtaining dynamic collagen fiber re-alignment via cross-polarization imaging. This study demonstrated that the majority of the mechanical properties evaluated decreased at midgestation and not just at term, while collagen fiber re-alignment occurred earlier in the loading curve for cervices at term. This suggests that although structural changes in the cervix occur throughout gestation, the differences in material properties function in combination with collagen fiber re-alignment as mechanical precursors to regulate term gestation. This work lays a foundation for investigating cervical biomechanics and the role of the cervix in preterm birth.

P2 porous titanium implants improve tendon healing in an acute rat supraspinatus repair model.

BACKGROUND: Current techniques in rotator cuff repair often lack structural integrity. P2 porous titanium-coated constructs (DJO Surgical, Austin, TX, USA) promote osseointegration and soft tissue ingrowth. This study examined the ability of this material to improve the structural integrity of supraspinatus tendon repair in a rat model. We hypothesized that P2 implants placed at the tendon-to-bone interface would improve mechanical and histologic measures of supraspinatus healing. METHODS: Forty rats underwent supraspinatus repairs with P2 implants in 1 shoulder and standard repair in the other. Rats were humanely killed at time 0 (n = 3), 2 weeks (n = 8), 4 weeks (n = 15), and 12 weeks (n = 14). Tendon-to-bone composite specimens were harvested and evaluated mechanically and histologically. RESULTS: Tendon cross-sectional area was decreased in the P2 implant group at 4 weeks, percentage of relaxation was increased at 2 weeks, elastic modulus was increased at 4 weeks, and maximum load and maximum stress were both increased at 2 and 4 weeks. Histologic analysis revealed no foreign body reactions within or around the P2 implant, and healthy viable bone was visible within the P2 implant. CONCLUSION: The results support our hypothesis, specifically in early healing, in this randomized controlled animal study. These data support the use of P2 porous titanium implants to improve tendon-to-bone healing.

Targeted deletion of collagen V in tendons and ligaments results in a classic Ehlers-Danlos syndrome joint phenotype.

Collagen V mutations underlie classic Ehlers-Danlos syndrome, and joint hypermobility is an important clinical manifestation. We define the function of collagen V in tendons and ligaments, as well as the role of alterations in collagen V expression in the pathobiology in classic Ehlers-Danlos syndrome. A conditional Col5a1(flox/flox) mouse model was bred with Scleraxis-Cre mice to create a targeted tendon and ligament Col5a1-null mouse model, Col5a1(Δten/Δten). Targeting was specific, resulting in collagen V-null tendons and ligaments. Col5a1(Δten/Δten) mice demonstrated decreased body size, grip weakness, abnormal gait, joint laxity, and early-onset osteoarthritis. These gross changes were associated with abnormal fiber organization, as well as altered collagen fibril structure with increased fibril diameters and decreased fibril number that was more severe in a major joint stabilizing ligament, the anterior cruciate ligament (ACL), than in the flexor digitorum longus tendon. The ACL also had a higher collagen V content than did the flexor digitorum longus tendon. The collagen V-null ACL and flexor digitorum longus tendon both had significant alterations in mechanical properties, with ACL exhibiting more severe changes. The data demonstrate critical differential regulatory roles for collagen V in tendon and ligament structure and function and suggest that collagen V regulatory dysfunction is associated with an abnormal joint phenotype, similar to the hypermobility phenotype in classic Ehlers-Danlos syndrome.

Mechanisms of mesenchymal stem cell correction of the impaired biomechanical properties of diabetic skin: The role of miR-29a.

Diabetic skin has impaired wound healing properties following injury. We have further shown that diabetic skin has weakened biomechanical properties at baseline. We hypothesize that the biomechanical properties of diabetic skin decline during the progression of the diabetic phenotype, and that this decline is due to the dysregulation of miR-29a, resulting in decreased collagen content. We further hypothesize that treatment with mesenchymal stem cells (MSCs) may improve diabetic wound healing by correction of the dysregulated miR-29a expression. We analyzed the biomechanical properties, collagen gene expression, collagen protein production, and miR-29a levels in skin harvested from 6 to 18 week old mice during the development of the diabetic phenotype. We also examined the correction of these impairments by both MSC treatment and the inhibition of miR-29a. Diabetic skin demonstrated a progressive impairment of biomechanical properties, decreased collagen content, and increased miR-29a levels during the development of the diabetic phenotype. MSC treatment decreased miR-29a levels, increased collagen content, and corrected the impaired biomechanical properties of diabetic skin. Additionally, direct inhibition of miR-29a also increased collagen content in diabetic skin. This decline in the biomechanical properties of diabetic skin during the progression of diabetes may increase the susceptibility of diabetic skin to injury and miR-29a appears to play a key role in this process.

Tendon Homeostasis in Hypercholesterolemia.

Hypercholesterolemia is a serious health problem that is associated not only with heart disease, but also tendon pathology. In high cholesterol environments (e.g. familial hyperlipidemia), lipids accumulate within the tendon extracellular matrix and form deposits called xanthomas. Lipid-related changes are known to affect several tendon mechanical properties, including stiffness and modulus, in uninjured and injured tendons, alike. Mechanisms to explain these cholesterol-related changes are multiple, including alterations in tenocyte gene and protein expression, matrix turnover, tissue vascularity, and cytokine production. Clinically, rotator cuff tear and Achilles tendon rupture are clearly associated with metabolic derangements, and elevated total cholesterol is often among the specific metabolic parameters implicated. Treatment of hypercholesterolemia using statin medications has also been shown to affect tendon properties, resulting in normalization of tendon thickness and improved tendon healing. Despite current work, the pathophysiology of lipid-related tendon pathology remains incompletely understood, and additional hypothesis-generating studies, including those incorporating whole-genome and whole-transcriptome technologies, will help to point the field in new directions.

Tendon progenitor cells in injured tendons have strong chondrogenic potential: the CD105-negative subpopulation induces chondrogenic degeneration.

To study the cellular mechanism of the tendon repair process, we used a mouse Achilles tendon injury model to focus on the cells recruited to the injured site. The cells isolated from injured tendon 1 week after the surgery and uninjured tendons contained the connective tissue progenitor populations as determined by colony-forming capacity, cell surface markers, and multipotency. When the injured tendon-derived progenitor cells (inTPCs) were transplanted into injured Achilles tendons, they were not only integrated in the regenerating area expressing tenogenic phenotype but also trans-differentiated into chondrogenic cells in the degenerative lesion that underwent ectopic endochondral ossification. Surprisingly, the micromass culture of the inTPCs rapidly underwent chondrogenic differentiation even in the absence of exogenous bone morphogenetic proteins or TGFßs. The cells isolated from human ruptured tendon tissues also showed connective tissue progenitor properties and exhibited stronger chondrogenic ability than bone marrow stromal cells. The mouse inTPCs contained two subpopulations one positive and one negative for CD105, a coreceptor of the TGFß superfamily. The CD105-negative cells showed superior chondrogenic potential in vitro and induced larger chondroid degenerative lesions in mice as compared to the CD105-positive cells. These findings indicate that tendon progenitor cells are recruited to the injured site of tendons and have a strong chondrogenic potential and that the CD105-negative population of these cells would be the cause for chondroid degeneration in injured tendons. The newly identified cells recruited to the injured tendon may provide novel targets to develop therapeutic strategies to facilitate tendon repair.

Rotator cuff biology and biomechanics: a review of normal and pathological conditions.

The glenohumeral joint is a complex anatomic structure commonly affected by injury such as tendinopathy and rotator cuff tears. This review presents an up-to-date overview of research on tendon biology and structure, shoulder joint motion and stability, tendon healing, and current and potential future repair strategies. Recent studies have provided information demonstrating the serious impact on uninjured tissues after a rotator cuff tear or other cause of altered shoulder joint mechanics. Another major focus of recent research is biological augmentation of rotator cuff repair with the goal of successfully reinstating normal tendon-to-bone structure. To effectively treat shoulder pathologies, clinicians need to understand normal tendon biology, the healing process and environment, and whole shoulder stability and function.

Effect of scapular dyskinesis on supraspinatus repair healing in a rat model.

BACKGROUND: Rotator cuff tears are common conditions that often require surgical repair to improve function and to relieve pain. Unfortunately, repair failure remains a common problem after rotator cuff repair surgery. Several factors may contribute to repair failure, including age, tear size, and time from injury. However, the mechanical mechanisms resulting in repair failure are not well understood, making clinical management difficult. Specifically, altered scapular motion (termed scapular dyskinesis) may be one important and modifiable factor contributing to the risk of repair failure. Therefore, the objective of this study was to determine the effect of scapular dyskinesis on supraspinatus tendon healing after repair. METHODS: A rat model of scapular dyskinesis was used. Seventy adult male Sprague-Dawley rats (400-450 g) were randomized into 2 groups: nerve transection of the accessory and long thoracic nerves (SD) or sham nerve transection (Sham control). After this procedure, all rats underwent unilateral detachment and repair of the supraspinatus tendon. All rats were sacrificed at 2, 4, and 8 weeks after surgery. Shoulder function, passive joint mechanics, and tendon properties (mechanical, histologic, organizational, and compositional) were evaluated. RESULTS: Scapular dyskinesis alters joint function and may lead to compromised supraspinatus tendon properties. Specifically, diminished mechanical properties, altered histology, and decreased tendon organization were observed for some parameters. CONCLUSION: This study identifies scapular dyskinesis as one underlying mechanism leading to compromise of supraspinatus healing after repair. Identifying modifiable factors that lead to compromised tendon healing will help improve clinical outcomes after repair.

Analysis of collagen organization in mouse achilles tendon using high-frequency ultrasound imaging.

Achilles tendon ruptures are traumatic injuries, and techniques for assessing repair outcomes rely on patient-based measures of pain and function, which do not directly assess tendon healing. Consequently, there is a need for a quantitative, in vivo measure of tendon properties. Therefore, the purpose of this study was to validate ultrasound imaging for evaluating collagen organization in tendons. In this study, we compared our novel, high-frequency ultrasound (HFUS) imaging and analysis method to a standard measure of collagen organization, crossed polarizer (CP) imaging. Eighteen mouse Achilles tendons were harvested and placed into a testing fixture where HFUS and CP imaging could be performed simultaneously in a controlled loading environment. Two experiments were conducted: (1) effect of loading on collagen alignment and (2) effect of an excisional injury on collagen alignment. As expected, it was found that both the HFUS and CP methods could reliably detect an increase in alignment with increasing load, as well as a decrease in alignment with injury. This HFUS method demonstrates that structural measures of collagen organization in tendon can be determined through ultrasound imaging. This experiment also provides a mechanistic evaluation of tissue structure that could potentially be used to develop a targeted approach to aid in rehabilitation or monitor return to activity after tendon injury.

The detrimental effects of systemic Ibuprofen delivery on tendon healing are time-dependent.

BACKGROUND: Current clinical treatment after tendon repairs often includes prescribing NSAIDs to limit pain and inflammation. The negative influence of NSAIDs on bone repair is well documented, but their effects on tendon healing are less clear. While NSAIDs may be detrimental to early tendon healing, some evidence suggests that they may improve healing if administered later in the repair process. QUESTIONS/PURPOSES: We asked whether the biomechanical and histologic effects of systemic ibuprofen administration on tendon healing are influenced by either immediate or delayed drug administration. METHODS: After bilateral supraspinatus detachment and repair surgeries, rats were divided into groups and given ibuprofen orally for either Days 0 to 7 (early) or Days 8 to 14 (delayed) after surgery; a control group did not receive ibuprofen. Healing was evaluated at 1, 2, and 4 weeks postsurgery through biomechanical testing and histologic assessment. RESULTS: Biomechanical evaluation resulted in decreased stiffness and modulus at 4 weeks postsurgery for early ibuprofen delivery (mean ± SD [95% CI]: 10.8 ± 6.4 N/mm [6.7-14.8] and 8.9 ± 5.9 MPa [5.4-12.3]) when compared to control repair (20.4 ± 8.6 N/mm [16.3-24.5] and 15.7 ± 7.5 MPa [12.3-19.2]) (p = 0.003 and 0.013); however, there were no differences between the delayed ibuprofen group (18.1 ± 7.4 N/mm [14.2-22.1] and 11.5 ± 5.6 MPa [8.2-14.9]) and the control group. Histology confirmed mechanical results with reduced fiber reorganization over time in the early ibuprofen group. CONCLUSIONS: Early administration of ibuprofen in the postoperative period was detrimental to tendon healing, while delayed administration did not affect tendon healing. CLINICAL RELEVANCE: Historically, clinicians have often prescribed ibuprofen after tendon repair, but this study suggests that the timing of ibuprofen administration is critical to adequate tendon healing. This research necessitates future clinical studies investigating the use of ibuprofen for pain control after rotator cuff repair and other tendon injuries.

Biceps detachment decreases joint damage in a rotator cuff tear rat model.

BACKGROUND: Pathology in the long head of the biceps tendon often occurs in patients with rotator cuff tears. Arthroscopic tenotomy is the most common treatment. However, the role of the long head of the biceps at the shoulder and the consequences of surgical detachment on the remaining shoulder structures remain unknown. QUESTIONS/PURPOSES: We hypothesized that detachment of the long head of the biceps, in the presence of supraspinatus and infraspinatus tears, would decrease shoulder function and decrease mechanical and histologic properties of both the subscapularis tendon and the glenoid articular cartilage. METHODS: We detached the supraspinatus and infraspinatus or the supraspinatus, infraspinatus, and long head of the biceps after 4 weeks of overuse in a rat model. Animals were gradually returned to overuse activity after detachment. At 8 weeks, the subscapularis and glenoid cartilage biomechanical and histologic properties were evaluated and compared. RESULTS: The supraspinatus, infraspinatus, and long head of the biceps group had a decreased change in braking and vertical force. [corrected]. This group also had an increased upper and lower subscapularis modulus but without any differences in glenoid cartilage modulus. Finally, this group had a significantly lower cell density in both the upper and lower subscapularis tendons, although cartilage histology was not different. CONCLUSIONS: Detachment of the long head of the biceps tendon in the presence of a posterior-superior cuff tear resulted in improved shoulder function and less joint damage in this animal model. CLINICAL RELEVANCE: This study provides evidence in an animal model that supports the use of tenotomy for the management of long head of the biceps pathology in the presence of a two-tendon cuff tear. However, long-term clinical trials are required.

Rat rotator cuff tendon-to-bone healing properties are adversely affected by hypercholesterolemia.

BACKGROUND: Rotator cuff tendon tears represent a major component of reported orthopaedic injuries. In addition, more than one quarter of U.S. adults either currently have high cholesterol levels or have reduced their previously high cholesterol levels through the use of pharmaceuticals. Our clinical data have already linked hypercholesterolemia to full-thickness rotator cuff tears, and experimental data from our laboratory have shown effects on native tendon properties in multiple species. The objective of this study was to evaluate healing of supraspinatus tendons in our rat rotator cuff injury model. We hypothesized that tendon healing would be inferior in rats receiving a high-cholesterol diet for 6 months compared with those receiving standard chow. METHODS: All animals were subjected to a unilateral supraspinatus detachment and repair surgery, with contralateral limbs serving as within-animal comparative data. Animals continued their respective diet courses, and their supraspinatus tendons were biomechanically or histologically evaluated at 2, 4, and 8 weeks postoperatively. RESULTS: Biomechanical testing revealed a significant reduction in normalized stiffness in hypercholesterolemic rats compared with controls at 4 weeks after injury, whereas histologic analyses showed no significant differences in collagen organization, cellularity, or cell shape between groups. CONCLUSION: On the basis of our findings, hypercholesterolemia may have a detrimental biomechanical effect on tendon healing in our rat rotator cuff injury and repair model. LEVEL OF EVIDENCE: Basic science study, animal model.

Neonatal Achilles Tendon Microstructure is Negatively Impacted by Decorin and Biglycan Knockdown After Injury and During Development.

Interest in studying neonatal development and the improved healing response observed in neonates is increasing, with the goal of using this work to create better therapeutics for tendon injury. Decorin and biglycan are two small leucine-rich proteoglycans that play important roles in collagen fibrillogenesis to develop, maintain, and repair tendon structure. However, little is known about the roles of decorin and biglycan in early neonatal development and healing. The goal of this study was to determine the effects of decorin and biglycan knockdown on Achilles tendon structure and mechanics during neonatal development and recovery of these properties after injury of the neonatal tendon. We hypothesized that knockdown of decorin and biglycan would disrupt the neonatal tendon developmental process and produce tendons with impaired mechanical and structural properties. We found that knockdown of decorin and biglycan in an inducible, compound decorin/biglycan knockdown model, both during development and after injury, in neonatal mice produced tendons with reduced mechanical properties. Additionally, the collagen fibril microstructure resembled an immature tendon with a large population of small diameter fibrils and an absence of larger diameter fibrils. Overall, this study demonstrates the importance of decorin and biglycan in facilitating tendon growth and maturation during neonatal development.