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.

Heparanase stimulates chondrogenesis and is up-regulated in human ectopic cartilage: a mechanism possibly involved in hereditary multiple exostoses.

Hereditary multiple exostoses is a pediatric skeletal disorder characterized by benign cartilaginous tumors called exostoses that form next to growing skeletal elements. Hereditary multiple exostoses patients carry heterozygous mutations in the heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2, but studies suggest that EXT haploinsufficiency and ensuing partial HS deficiency are insufficient for exostosis formation. Searching for additional pathways, we analyzed presence and distribution of heparanase in human exostoses. Heparanase was readily detectable in most chondrocytes, particularly in cell clusters. In control growth plates from unaffected persons, however, heparanase was detectable only in hypertrophic zone. Treatment of mouse embryo limb mesenchymal micromass cultures with exogenous heparanase greatly stimulated chondrogenesis and bone morphogenetic protein signaling as revealed by Smad1/5/8 phosphorylation. It also stimulated cell migration and proliferation. Interfering with HS function both with the chemical antagonist Surfen or treatment with bacterial heparitinase up-regulated endogenous heparanase gene expression, suggesting a counterintuitive feedback mechanism that would result in further HS reduction and increased signaling. Thus, we tested a potent heparanase inhibitor (SST0001), which strongly inhibited chondrogenesis. Our data clearly indicate that heparanase is able to stimulate chondrogenesis, bone morphogenetic protein signaling, cell migration, and cell proliferation in chondrogenic cells. These properties may allow heparanase to play a role in exostosis genesis and pathogenesis, thus making it a conceivable therapeutic target in hereditary multiple exostoses.

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.

Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: a mechanism likely deranged in Hereditary Multiple Exostoses.

During limb skeletogenesis the cartilaginous long bone anlagen and their growth plates become delimited by perichondrium with which they interact functionally. Yet, little is known about how, despite being so intimately associated with cartilage, perichondrium acquires and maintains its distinct phenotype and exerts its border function. Because perichondrium becomes deranged and interrupted by cartilaginous outgrowths in Hereditary Multiple Exostoses (HME), a pediatric disorder caused by EXT mutations and consequent heparan sulfate (HS) deficiency, we asked whether EXT genes and HS normally have roles in establishing its phenotype and function. Indeed, conditional Ext1 ablation in perichondrium and lateral chondrocytes flanking the epiphyseal region of mouse embryo long bone anlagen - a region encompassing the groove of Ranvier - caused ectopic cartilage formation. A similar response was observed when HS function was disrupted in long bone anlagen explants by genetic, pharmacological or enzymatic means, a response preceded by ectopic BMP signaling within perichondrium. These treatments also triggered excess chondrogenesis and cartilage nodule formation and overexpression of chondrogenic and matrix genes in limb bud mesenchymal cells in micromass culture. Interestingly, the treatments disrupted the peripheral definition and border of the cartilage nodules in such a way that many nodules overgrew and fused with each other into large amorphous cartilaginous masses. Interference with HS function reduced the physical association and interactions of BMP2 with HS and increased the cell responsiveness to endogenous and exogenous BMP proteins. In sum, Ext genes and HS are needed to establish and maintain perichondrium's phenotype and border function, restrain pro-chondrogenic signaling proteins including BMPs, and restrict chondrogenesis. Alterations in these mechanisms may contribute to exostosis formation in HME, particularly at the expense of regions rich in progenitor cells including the groove of Ranvier.

Heparan sulfate in skeletal development, growth, and pathology: the case of hereditary multiple exostoses.

Heparan sulfate (HS) is an essential component of cell surface and matrix-associated proteoglycans. Due to their sulfation patterns, the HS chains interact with numerous signaling proteins and regulate their distribution and activity on target cells. Many of these proteins, including bone morphogenetic protein family members, are expressed in the growth plate of developing skeletal elements, and several skeletal phenotypes are caused by mutations in those proteins as well as in HS-synthesizing and modifying enzymes. The disease we discuss here is hereditary multiple exostoses (HME), a disorder caused by mutations in HS synthesizing enzymes EXT1 and EXT2, leading to HS deficiency. The exostoses are benign cartilaginous-bony outgrowths, form next to growth plates, can cause growth retardation and deformities, chronic pain and impaired motion, and progress to malignancy in 2-5% of patients. We describe recent advancements on HME pathogenesis and exostosis formation deriving from studies that have determined distribution, activities and roles of signaling proteins in wild-type and HS-deficient cells and tissues. Aberrant distribution of signaling factors combined with aberrant responsiveness of target cells to those same factors appear to be a major culprit in exostosis formation. Insights from these studies suggest plausible and cogent ideas about how HME could be treated in the future.

Simultaneous inhibition of PI3K and PAK in preclinical models of neurofibromatosis type 2-related schwannomatosis.

Neurofibromatosis Type 2 (NF2)-related schwannomatosis is a genetic disorder that causes development of multiple types of nervous system tumors. The primary and diagnostic tumor type is bilateral vestibular schwannoma. There is no cure or drug therapy for NF2. Recommended treatments include surgical resection and radiation, both of which can leave patients with severe neurological deficits or increase the risk of future malignant tumors. Results of our previous pilot high-throughput drug screen identified phosphoinositide 3-kinase (PI3K) inhibitors as strong candidates based on loss of viability of mouse merlin-deficient Schwann cells (MD-SCs). Here we used novel human schwannoma model cells to conduct combination drug screens. We identified a class I PI3K inhibitor, pictilisib and p21 activated kinase (PAK) inhibitor, PF-3758309 as the top combination due to high synergy in cell viability assays. Both single and combination therapies significantly reduced growth of mouse MD-SCs in an orthotopic allograft mouse model. The inhibitor combination promoted cell cycle arrest and apoptosis in mouse merlin-deficient Schwann (MD-SCs) cells and cell cycle arrest in human MD-SCs. This study identifies the PI3K and PAK pathways as potential targets for combination drug treatment of NF2-related schwannomatosis.

Simultaneous Inhibition of PI3K and PAK in Preclinical Models of Neurofibromatosis Type 2-related Schwannomatosis.

Neurofibromatosis Type 2 (NF2)-related schwannomatosis is a genetic disorder that causes development of multiple types of nervous system tumors. The primary and diagnostic tumor type is bilateral vestibular schwannoma. There is no cure or drug therapy for NF2. Recommended treatments include surgical resection and radiation, both of which can leave patients with severe neurological deficits or increase the risk of future malignant tumors. Results of our previous pilot high-throughput drug screen identified phosphoinositide 3-kinase (PI3K) inhibitors as strong candidates based on loss of viability of mouse merlin-deficient Schwann cells (MD-SCs). Here we used novel human schwannoma model cells to conduct combination drug screens. We identified a class I PI3K inhibitor, pictilisib and p21 activated kinase (PAK) inhibitor, PF-3758309 as the top combination due to high synergy in cell viability assays. Both single and combination therapies significantly reduced growth of mouse MD-SCs in an orthotopic allograft mouse model. The inhibitor combination promoted cell cycle arrest and apoptosis in mouse merlin-deficient Schwann (MD-SCs) cells and cell cycle arrest in human MD-SCs. This study identifies the PI3K and PAK pathways as potential targets for combination drug treatment of NF2-related schwannomatosis.

Neptune versus canister-based surgical waste management in Europe: results of the GREEN study.

Background: Ineffective surgical fluid waste management in operating rooms (OR) creates a significant environmental burden, reduces OR efficiency, and adds physical challenges for surgical staff. There is a need for waste management systems that improve OR efficiency, safety, and sustainability. The GREEN study (Greening operating Rooms in EuropE comparing Neptune vs. canisters) was conducted to compare the impact of two fluid waste management systems. Materials and methods: This 2-arm, nonrandomized, prospective service evaluation of fluid waste extraction was conducted using observational time series and surveys. Fluid waste-related data were collected from routine urologic and orthopedic surgeries across three European hospital sites. The primary endpoint of waste disposal impact was the volume of treated waste after surgery (kilograms) using Stryker's Neptune device (n=43) or canisters (n=41). The authors hypothesized that the surgical waste volume related to Neptune is less than the waste volume related to canisters. Secondary endpoints included time efficiency, user satisfaction, and staff ergonomics. Results: The total weight of device-related treated waste products was reduced by 98.5% when using Neptune (0.2±0.7 kg) compared with traditional canisters (13.2±16.6 kg; P<0.001). Decreased waste weight also translated to enhanced ergonomic safety for surgical staff, as Neptune reduced surgical fluid weight handled by staff by an average of 34 kg per procedure, a 96% reduction compared to canisters. Furthermore, the use of the Neptune system improved OR efficiency by reducing the number of staff required to manage the fluid suction device (P<0.001) and the time spent disposing of fluid waste (P<0.001). Conclusion: Stryker's Neptune waste management system significantly reduces the volume of treated waste per surgery and improves OR efficiency, staff safety, and user satisfaction over the traditional canister system. This is a more eco-responsible approach to OR fluid waste management and could be considered in any healthcare establishment that generates fluid waste.

Cotargeting Phosphoinositide 3-Kinase and Focal Adhesion Kinase Pathways Inhibits Proliferation of NF2 Schwannoma Cells.

Neurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor. Patients develop multiple benign tumor types in the nervous system including bilateral vestibular schwannomas (VS). Standard treatments include surgery and radiation therapy, which may lead to loss of hearing, impaired facial nerve function, and other complications. Kinase inhibitor monotherapies have been evaluated clinically for NF2 patients with limited success, and more effective nonsurgical therapies are urgently needed. Schwannoma model cells treated with PI3K inhibitors upregulate activity of the focal adhesion kinase (FAK) family as a compensatory survival pathway. We screened combinations of 13 clinically relevant PI3K and FAK inhibitors using human isogenic normal and merlin-deficient Schwann cell lines. The most efficacious combination was PI3K/mTOR inhibitor omipalisib with SRC/FAK inhibitor dasatinib. Sub-GI50 doses of the single drugs blocked phosphorylation of their major target proteins. The combination was superior to either single agent in promoting a G1 cell-cycle arrest and produced a 44% decrease in tumor growth over a 2-week period in a pilot orthotopic allograft model. Evaluation of single and combination drugs in six human primary VS cell models revealed the combination was superior to the monotherapies in 3 of 6 VS samples, highlighting inter-tumor variability between patients consistent with observations from clinical trials with other molecular targeted agents. Dasatinib alone performed as well as the combination in the remaining three samples. Preclinically validated combination therapies hold promise for NF2 patients and warrants further study in clinical trials.

CUDC907, a dual phosphoinositide-3 kinase/histone deacetylase inhibitor, promotes apoptosis of NF2 Schwannoma cells.

Neurofibromatosis Type 2 (NF2) is a rare tumor disorder caused by pathogenic variants of the merlin tumor suppressor encoded by NF2. Patients develop vestibular schwannomas (VS), peripheral schwannomas, meningiomas, and ependymomas. There are no approved drug therapies for NF2. Previous work identified phosphoinositide-3 kinase (PI3K) as a druggable target. Here we screened PI3K pathway inhibitors for efficacy in reducing viability of human schwannoma cells. The lead compound, CUDC907, a dual histone deacetylase (HDAC)/PI3K inhibitor, was further evaluated for its effects on isolated and nerve-grafted schwannoma model cells, and primary VS cells. CUDC907 (3 nM IG50) reduced human merlin deficient Schwann cell (MD-SC) viability and was 5-100 fold selective for MD over WT-SCs. CUDC907 (10 nM) promoted cell cycle arrest and caspase-3/7 activation within 24 h in human MD-SCs. Western blots confirmed a dose-dependent increase in acetylated lysine and decreases in pAKT and YAP. CUDC907 decreased tumor growth rate by 44% in a 14-day treatment regimen, modulated phospho-target levels, and decreased YAP levels. In five primary VS, CUDC907 decreased viability, induced caspase-3/7 cleavage, and reduced YAP levels. Its efficacy correlated with basal phospho-HDAC2 levels. CUDC907 has cytotoxic activity in NF2 schwannoma models and primary VS cells and is a candidate for clinical trials.

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

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.

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

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.

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

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.

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

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.

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

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-ß1. 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.

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

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.

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

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.

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

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.

Biceps Detachment Preserves Joint Function in a Chronic Massive Rotator Cuff Tear Rat Model.

BACKGROUND: Lesions of the long head of the biceps tendon are often associated with massive rotator cuff tears (MRCTs), and biceps tenotomy is frequently performed for pain relief and functional reservation. However, the efficacy and safety of biceps tenotomy regarding the effects on the surrounding tissues in chronic MRCT are unclear. HYPOTHESIS: Biceps tenotomy would result in improved mechanical and histological properties of the intact subscapularis tendon and improved in vivo shoulder function while not compromising glenoid cartilage properties. STUDY DESIGN: Controlled laboratory study. METHODS: Right supraspinatus and infraspinatus tendons were detached in 25 male Sprague-Dawley rats, followed by 4 weeks of cage activity to create a chronic MRCT condition. Animals were randomly divided into 2 groups and received either biceps tenotomy (n = 11) or sham surgery (n = 14) and were sacrificed 4 weeks thereafter. Forelimb gait and ground-reaction forces were recorded 1 day before the tendon detachment (baseline), 1 day before the surgical intervention (biceps tenotomy or sham), and 3, 7, 10, 14, 21, and 28 days after the intervention to assess in vivo shoulder joint function. The subscapularis tendon and glenoid cartilage were randomly allocated for mechanical testing or histologic assessment after the sacrifice. RESULTS: Compared with sham surgery, biceps tenotomy partially restored the in vivo shoulder joint function, with several gait and ground-reaction force parameters returning closer to preinjury baseline values at 4 weeks. With biceps tenotomy, mechanical properties of the subscapularis tendons were improved, while mechanical properties and histological Mankin scores of the glenoid cartilage were not diminished when compared with the sham group. CONCLUSION: Biceps tenotomy in the presence of chronic MRCT partially preserves overall shoulder function and potentially restores subscapularis tendon health without causing detrimental effects to joint cartilage. This laboratory study adds to the growing literature regarding the protective effects of biceps tenotomy on the shoulder joint in a chronic MRCT model. CLINICAL RELEVANCE: This study provides important basic science evidence supporting the use of biceps tenotomy in patients with massive rotator cuff tears.

Pulsed electromagnetic field therapy improves tendon-to-bone healing in a rat rotator cuff repair model.

Rotator cuff tears are common musculoskeletal injuries often requiring surgical intervention with high failure rates. Currently, pulsed electromagnetic fields (PEMFs) are used for treatment of long-bone fracture and lumbar and cervical spine fusion surgery. Clinical studies examining the effects of PEMF on soft tissue healing show promising results. Therefore, we investigated the role of PEMF on rotator cuff healing using a rat rotator cuff repair model. We hypothesized that PEMF exposure following rotator cuff repair would improve tendon mechanical properties, tissue morphology, and alter in vivo joint function. Seventy adult male Sprague-Dawley rats were assigned to three groups: bilateral repair with PEMF (n = 30), bilateral repair followed by cage activity (n = 30), and uninjured control with cage activity (n = 10). Rats in the surgical groups were sacrificed at 4, 8, and 16 weeks. Control group was sacrificed at 8 weeks. Passive joint mechanics and gait analysis were assessed over time. Biomechanical analysis and µCT was performed on left shoulders; histological analysis on right shoulders. Results indicate no differences in passive joint mechanics and ambulation. At 4 weeks the PEMF group had decreased cross-sectional area and increased modulus and maximum stress. At 8 weeks the PEMF group had increased modulus and more rounded cells in the midsubstance. At 16 weeks the PEMF group had improved bone quality. Therefore, results indicate that PEMF improves early tendon healing and does not alter joint function in a rat rotator cuff repair model. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:902-909, 2017.