Gail M. Thornton

Changes in mechanical loading lead to tendonspecific alterations in MMP and TIMP expression: influence of stress deprivation and intermittent cyclic hydrostatic compression on rat supraspinatus and Achilles tendons.

Background Tendinopathy commonly occurs in tendons with large in vivo loading demands like the Achilles tendon (AT) and supraspinatus tendon (SST). In addition to differences in their local anatomic environment, these tendons are designed for different loading requirements because of the muscles to which they attach, with the AT experiencing higher loads than the SST. One possible factor in the progression of tendinopathy is the interplay between mechanical loading and the regulation of enzymes that degrade the extracellular matrix (matrix metalloproteinases (MMPs)) and their inhibitors (tissue inhibitor of metalloprotienases (TIMPs)). Thus, overuse injuries may have different biological consequences in tendons designed for different in vivo loading demands. Aim In this study, the tendon-specific regulation of MMP-13, MMP-3 and TIMP-2 expression in rat AT and SST exposed to two different mechanical environments was investigated. Methods Rat AT and SST were exposed to stress deprivation (ie, detached from attachments) and intermittent cyclic hydrostatic compression (with attachments intact). Levels of MMP-13, MMP-3 and TIMP-2 mRNA were evaluated in time-zero control, attached, stressdeprived and “compressed” tendons. Results Stress deprivation led to elevated expression of MMP-13, MMP-3 and TIMP-2 in both tendons, although the magnitude of the increase was greater for the SST than the AT. Intermittent cyclic hydrostatic compression of attached tendons increased expression of MMP-13 in the SST, but not the AT. Conclusions The results of this study suggest that stress deprivation may be one contributor to the progression of tendinopathy in AT and SST, where the tendon designed for the lower in vivo loading demand (SST) was the most affected by a change in mechanical loading. The unique upregulation of MMP-13 with hydrostatic compression supports the impingement injury theory for rotator cuff tears.

Complications following arthroscopic fixation of acromioclavicular separations: a systematic review of the literature.

Purpose Over the past decade, a number of arthroscopic or arthroscopically assisted reconstruction techniques have emerged for the management of acromioclavicular (AC) separations. These techniques provide the advantage of superior visualization of the base of the coracoid, less soft tissue dissection, and smaller incisions. While these techniques have been reported to provide excellent functional results with minimal complications, discrepancies exist within the literature. This systematic review aims to assess the rate of complications following these procedures. Methods Two independent reviewers completed a search of Medline, Embase, PubMed, and the Cochrane Library entries up to December 2013. The terms “Acromioclavicular Joint (MeSH)” OR “acromioclavicular* (text)” OR “coracoclavicular* (text)” AND “Arthroscopy (MeSH)” OR “Arthroscop* (text)” were used. Pooled estimates and 95% confidence intervals were calculated assuming a random-effects model. Statistical heterogeneity was quantified using the I2 statistic. Level of evidence IV Results A total of 972 abstracts met the search criteria. After removal of duplicates and assessment of inclusion/exclusion criteria, 12 articles were selected for data extraction. The rate of superficial infection was 3.8% and residual shoulder/AC pain or hardware irritation occurred at a rate of 26.7%. The rate of coracoid/clavicle fracture was 5.3% and occurred most commonly with techniques utilizing bony tunnels. Loss of AC joint reduction occurred in 26.8% of patients. Conclusion Arthroscopic AC reconstruction techniques carry a distinct complication profile. The TightRope/Endobutton techniques, when performed acutely, provide good radiographic outcomes at the expense of hardware irritation. In contrast, graft reconstructions in patients with chronic AC separations demonstrated a high risk for loss of reduction. Fractures of the coracoid/clavicle remain a significant complication occurring predominately with techniques utilizing bony tunnels.

Partial Thickness Rotator Cuff Tears: Current Concepts

Partial thickness rotator cuff tears are a common cause of pain in the adult shoulder. Despite their high prevalence, the diagnosis and treatment of partial thickness rotator cuff tears remains controversial. While recent studies have helped to elucidate the anatomy and natural history of disease progression, the optimal treatment, both nonoperative and operative, is unclear. Although the advent of arthroscopy has improved the accuracy of the diagnosis of partial thickness rotator cuff tears, the number of surgical techniques used to repair these tears has also increased. While multiple repair techniques have been described, there is currently no significant clinical evidence supporting more complex surgical techniques over standard rotator cuff repair. Further research is required to determine the clinical indications for surgical and nonsurgical management, when formal rotator cuff repair is specifically indicated and when biologic adjunctive therapy may be utilized.

Fatigue is more damaging than creep in ligament revealed by modulus reduction and residual strength.

Following injury of a complementary joint restraint, ligaments can be subjected to higher than normal stresses. Normal ligaments are exposed to static (creep) and cyclic (fatigue) loading from which damage can accumulate at these higher than normal stresses. This study tracked damage accumulation during creep and fatigue loading of normal rabbit medial collateral ligaments (MCLs) over a range of stresses, using modulus reduction as a marker of damage. Creep tests were interrupted occasionally with unloading/reloading cycles to measure modulus. Test stresses were normalized to ultimate tensile strength (UTS): 60%, 30%, and 15% UTS. Not all creep and fatigues tests progressed until rupture but were stopped and followed by an assessment of the residual strength of that partially damaged ligament using a monotonic failure test. Fatigue loading caused earlier modulus reduction than creep. Modulus reduction occurred at lower increases in strain (strain relative to initial strain) for fatigue than creep. In other words, at the same time or increase in strain, fatigue is more damaging than creep because the modulus ratio reduction is greater. These findings suggest that creep and fatigue have different strain and damage mechanisms. Ligaments exposed to creep or fatigue loading which produced a modulus reduction had decreased residual strength and increased toe-region strain in a subsequent monotonic failure test. This finding confirmed that modulus reduction during creep and fatigue is a suitable marker of partial damage in ligament. Cyclic loading caused damage earlier than static loading, likely an important consideration when ligaments are loaded to higher than normal magnitudes following injury of a complementary joint restraint.

Aging affects mechanical properties and lubricin/PRG4 gene expression in normal ligaments

Age-related changes in ligament properties may have clinical implications for injuries in the mature athlete. Previous preclinical models documented mechanical and biochemical changes in ligaments with aging. The purpose of this study was to investigate the effect of aging on ligament properties (mechanical, molecular, biochemical) by comparing medial collateral ligaments (MCLs) from 1-year-old and 3-year-old rabbits. The MCLs underwent mechanical (n=7, 1-year-old; n=7, 3-year-old), molecular (n=8, 1-year-old; n=6, 3-year-old), collagen and glycosaminoglycan (GAG) content (n=8, 1-year-old; n=6, 3-year-old) and water content (n=8, 1-year-old; n=5, 3-year-old) assessments. Mechanical assessments evaluated total creep strain, failure strain, ultimate tensile strength and modulus. Molecular assessments using RT-qPCR evaluated gene expression for collagens, proteoglycans, hormone receptors, and matrix metalloproteinases and their inhibitors. While total creep strain and ultimate tensile strength were not affected by aging, failure strain was increased and modulus was decreased comparing MCLs from 3-year-old rabbits to those from 1-year-old rabbits. The mRNA expression levels for lubricin/proteoglycan 4 (PRG4) and tissue inhibitor of metalloproteinase-3 increased with aging; whereas, the mRNA expression levels for estrogen receptor and matrix metalloproteinase-1 decreased with aging. Collagen and GAG content assays and water content assessments did not demonstrate any age-related changes. The increased failure strain and decreased modulus with aging may have implications for increased susceptibility to ligament damage/injury with aging. Lubricin/PRG4 gene expression was affected by aging and its speculated role in ligament function may be related to interfascicular lubrication, which in turn may lead to altered mechanical function with aging and increases in potential for injury.

Graft Augmentation Versus Bridging for Large to Massive Rotator Cuff Tears: A Systematic Review

PURPOSEnTo systematically review the literature on the healing rates and clinical outcomes of the 2 different graft indications (i.e., augmentation vs bridging) during rotator cuff repair.nnnMETHODSnA systematic literature review was performed for clinical studies of rotator cuff repair using grafts for large to massive tears. The primary outcome was tendon healing on either magnetic resonance imaging or ultrasound. The secondary outcomes included visual analog scale for pain, American Shoulder and Elbow Surgeons score, and University of California at Los Angeles score, and forward elevation. Studies were divided into augmentation and bridging groups, and outcomes were compared statistically.nnnRESULTSnTwelve studies with 13 study groups were included: 167 repairs in the augmentation group and 247 repairs in the bridging group. For augmentation and bridging groups, the mean age was 62.2 and 62.8xa0years and the mean follow-up was 28.5 and 37.7xa0months, respectively. The estimated healing rates were 64.0% for augmentation and 77.9% for bridging. Although both procedures had improved clinical outcomes, no statistical difference between groups was detected except lower visual analog scale in the bridging group at follow-up.nnnCONCLUSIONSnBridging grafts had no significant difference in healing or clinical outcomes when compared with a graft used for augmentation. Bridging grafts may be considered for this difficult patient population with large to massive rotator cuff tears.nnnLEVEL OF EVIDENCEnLevel IV, systematic review of Level II to IV studies.

Regional molecular and cellular differences in the female rabbit Achilles tendon complex : potential implications for understanding responses to loading

The aim of this study was: (i) to analyze the morphology and expression of extracellular matrix genes in six different regions of the Achilles tendon complex of intact normal rabbits; and (ii) to assess the effect of ovariohysterectomy (OVH) on the regional expression of these genes. Female New Zealand White rabbits were separated into two groups: (i) intact normal rabbits (nu2005=u20054); and (ii) OVH rabbits (nu2005=u20058). For each rabbit, the Achilles tendon complex was dissected into six regions: distal gastrocnemius (DG); distal flexor digitorum superficialis; proximal lateral gastrocnemius (PLG); proximal medial gastrocnemius; proximal flexor digitorum superficialis; and paratenon. For each of the regions, hematoxylin and eosin staining was performed for histological evaluation of intact normal rabbit tissues and mRNA levels for proteoglycans, collagens and genes associated with collagen regulation were assessed by real‐time reverse transcription‐quantitative polymerase chain reaction for both the intact normal and OVH rabbit tissues. The distal regions displayed a more fibrocartilaginous phenotype. For intact normal rabbits, aggrecan mRNA expression was higher in the distal regions of the Achilles tendon complex compared with the proximal regions. Collagen Type I and matrix metalloproteinase‐2 expression levels were increased in the PLG compared to the DG in the intact normal rabbit tissues. The tendons from OVH rabbits had lower gene expressions for the proteoglycans aggrecan, biglycan, decorin and versican compared with the intact normal rabbits, although the regional differences of increased aggrecan expression in distal regions compared with proximal regions persisted. The tensile and compressive forces experienced in the examined regions may be related to the regional differences found in gene expression. The lower mRNA expression of the genes examined in the OVH group confirms a potential effect of systemic estrogen on tendon.

A Novel Application of the Principles of Linear Elastic Fracture Mechanics (LEFM) to the Fatigue Behavior of Tendon Tissue

BACKGROUNDnExperiments on the fatigue of tendons have shown that cyclic loading induces failure at stresses lower than the ultimate tensile strength (UTS) of the tendons. The number of cycles to failure (Nf) has been shown to be dependent upon the magnitude of the applied cyclic stress.nnnMETHOD OF APPROACHnUtilizing data collected by Schechtman (1995), we demonstrate that the principles of Linear Elastic Fracture Mechanics (LEFM) can be used to predict the fatigue behavior of tendons under cyclic loading for maximum stress levels that are higher than 10% of the ultimate tensile strength (UTS) of the tendon (the experimental results at 10% UTS did not fit with our equations).nnnCONCLUSIONSnLEFM and other FM approaches may prove to be very valuable in advancing our understanding of damage accumulation in soft connective tissues.

Accumulation of oxidized LDL in the tendon tissues of C57BL/6 or apolipoprotein E knock-out mice that consume a high fat diet: potential impact on tendon health.

Objective Clinical studies have suggested an association between dyslipidemia and tendon injuries or chronic tendon pain; the mechanisms underlying this association are not yet known. The objectives of this study were (1) to evaluate the impact of a high fat diet on the function of load-bearing tendons and on the distribution in tendons of oxidized low density lipoprotein (oxLDL), and (2) to examine the effect of oxLDL on tendon fibroblast proliferation and gene expression. Methods Gene expression (Mmp2, Tgfb1, Col1a1, Col3a1), fat content (Oil Red O staining), oxLDL levels (immunohistochemistry) and tendon biomechanical properties were examined in mice (C57Bl/6 or ApoE -/-) receiving a standard or a high fat diet. Human tendon fibroblast proliferation and gene expression (COL1A1, COL3A1, MMP2) were examined following oxLDL exposure. Results In both types of mice (C57Bl/6 or ApoE -/-), consumption of a high fat diet led to a marked increase in oxLDL deposition in the load-bearing extracellular matrix of the tendon. The consumption of a high fat diet also reduced the failure stress and load of the patellar tendon in both mouse types, and increased Mmp2 expression. ApoE -/- mice exhibited more pronounced reductions in tendon function than wild-type mice, and decreased expression of Col1a1 compared to wild type mice. Human tendon fibroblasts responded to oxLDL by increasing their proliferation and their mRNA levels of MMP2, while decreasing their mRNA levels for COL1A1 and COL3A1. Conclusion The consumption of a high fat diet resulted in deleterious changes in tendon function, and these changes may be explained in part by the effects of oxLDL, which induced a proliferative, matrix-degrading phenotype in human tenocytes.

Can Grafts Provide Superior Tendon Healing and Clinical Outcomes After Rotator Cuff Repairs?: A Meta-analysis

Background: Arthroscopic repair of large to massive rotator cuff tears commonly retear. To improve healing rates, a number of different approaches have been utilized, including the use of grafts, which may enhance the biomechanical and biologic aspects of the repair construct. However, the outcomes after the use of grafts are diverse. Purpose: To systematically review the literature for large to massive rotator cuff tears to determine whether the use of grafts generally provides superior tendon healing and clinical outcomes to the repairs without grafts. Study Design: Systematic review; Level of evidence, 3. Methods: A systematic review of the literature was performed. Clinical studies comparing the repairs with (graft group) and without grafts (control group) were included and analyzed. The primary outcome was tendon healing on either magnetic resonance imaging or ultrasound. The secondary outcome measures included visual analog scale for pain, University of California at Los Angles (UCLA) score, and forward elevation range. Differences between groups in all outcome measures were statistically analyzed. Results: Six comparative studies (level of evidence 2 or 3) with 13 study groups were included. A total of 242 repairs in the graft group (mean age, 62.5 ± 4.6 years) and 185 repairs in the control group (mean age, 62.5 ± 5.0 years) were analyzed. The graft types utilized included autograft (fascia lata) in 1 study, allograft (human dermis) in 2 studies, xenograft (bovine pericardium, porcine small intestine submucosa) in 2 studies, synthetic graft (polypropylene) in 1 study, and a combination of autograft (the long head of biceps) and synthetic graft (polypropylene) in 1 study. The overall mean follow-up time was 28.4 ± 9.0 months. When 1 or 2 studies/study groups were excluded due to practical or statistical reasons, the graft group demonstrated significantly improved healing (odds ratio, 2.48; 95% CI, 1.58-3.90; P < .0001) and all clinical outcome measures at final follow-up (P ≤ .02). Conclusion: The use of grafts generally provides superior tendon healing and clinical outcomes compared to repairs without grafts, except for some specific graft types (eg, porcine small intestine submucosa, bovine pericardium). Further investigations are required to determine the benefits of the use of grafts.