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Treating flexor tendon injuries within the digital flexor sheath (commonly referred to as palmar hand zone 2) presents both technical and logistical challenges. Success hinges on striking a delicate balance between safeguarding the surgical repair for tendon healing and initiating early rehabilitation to mitigate the formation of tendon adhesions. Adhesions between tendon slips and between tendons and the flexor sheath impede tendon movement, leading to postoperative stiffness and functional impairment. While current approaches to flexor tendon repair prioritize maximizing tendon strength for early mobilization and adhesion prevention, factors such as pain, swelling, and patient compliance may impede postoperative rehabilitation efforts. Moreover, premature mobilization could risk repair failure, necessitating additional surgical interventions. Pharmacological agents offer a potential avenue for minimizing inflammation and reducing adhesion formation while still promoting normal tendon healing. Although some systemic and local agents have shown promising results in animal studies, their clinical efficacy remains uncertain. Limitations in these studies include the relevance of chosen animal models to human populations and the adequacy of tools and measurement techniques in accurately assessing the impact of adhesions. This article provides an overview of the clinical challenges associated with flexor tendon injuries, discusses current on‐ and off‐label agents aimed at minimizing adhesion formation, and examines investigational models designed to study adhesion reduction after intra‐synovial flexor tendon repair. Understanding the clinical problem and experimental models may serve as a catalyst for future research aimed at addressing intra‐synovial tendon adhesions following zone 2 flexor tendon repair. [ABSTRACT FROM AUTHOR]

Although platelet‐rich plasma (PRP) has been widely used regardless of the severity of muscle strain, there have been very few basic studies in which its effects on muscle injury were examined by using models that accurately mimic the clinical muscle strain injury process. Therefore, the aim of this study was to confirm by physiological and structural analyses whether PRP purified by a general preparation method has a muscle healing effect on muscle damage caused by eccentric contraction (ECC). Male Wistar rats were subjected to muscle injury induced by ECC in bilateral plantar flexor muscles using electrical stimulation and an automatically dorsiflexing footplate. The rats were randomly assigned to three groups by type of injection: phosphate‐buffered saline (PBS), leukocyte‐poor PRP (LP‐PRP), or leukocyte‐rich PRP (LR‐PRP) injection into gastrocnemius muscles three times at weekly intervals. The platelet concentrations of the LP‐PRP and LR‐PRP were three to five times higher than that of whole blood. The recovery process of torque strength in the plantar flexor muscle, signal changes in MRI images, and histological evaluation 3 weeks after injury showed no obvious differences among the three groups, and every muscle recovered well from the injury without marked fibrosis. The results that neither LP‐PRP nor LR‐PRP was found to accelerate healing of muscle injuries suggested that conventional preparation and use of PRP for simple muscle injuries caused by muscle strain should be carefully considered, and further basic research using models that accurately mimic clinical practice should be carried out to determine the optimal use of PRP. [ABSTRACT FROM AUTHOR]

The standard grafts used for anterior cruciate ligament (ACL) reconstruction are tendon, either patellar tendon, hamstring, or quadriceps. However, the microstructure and composition of tendon differs from ligament. Ideally, the ACL would be replaced with the same tissue. To evaluate the incorporation of a bone‐ACL‐bone (B‐ACL‐B) graft for ACL reconstruction, we performed a controlled laboratory study in a rabbit model with microcomputed tomography (μCT). Forty‐six New Zealand white rabbits were used, with 17 donor rabbits to harvest bilateral B‐ACL‐B allografts and 29 rabbits undergoing unilateral ACL reconstruction with B‐ACL‐B allograft. Knee specimens were collected for biomechanical testing (n = 14) at 4 and 8 weeks and for μCT analysis (n = 15) at 2, 4, and 8 weeks after surgery. Gross inspection and μCT examination confirmed bone blocks in the appropriate anatomic position. Biomechanical tests revealed no difference in mean load‐to‐failure force for B‐ACL‐B allografts between 4 and 8 weeks. Progressive healing occurred between the bone block and the tunnel as demonstrated by a gradual increase on average bone‐volume fraction and total mineral density (TMD) in both femoral and tibial tunnels. Remodeling of the bone block was evidenced by a significant decrease in TMD of both tibial and femoral bone blocks. This is a report of a novel rabbit B‐ACL‐B allograft reconstruction model demonstrating early signs of graft remodeling and incorporation. Clinical Relevance: This study demonstrates ACL reconstruction using an anatomically matched ACL allograft, rather than a tendon graft, may be possible based on early findings in this lapine model. [ABSTRACT FROM AUTHOR]

This study aims to develop a comprehensive and easily executable histopathologic grading scheme for murine knee osteoarthritis (OA) using specific scoring criteria for both cartilage and periarticular changes, which may overcome important limitations of the existing grading systems. The new grading scheme was developed based on mouse knee OA models with observation periods up to 24 months of age (spontaneous OA) or 24‐week post‐injury (posttraumatic OA). Semi‐quantitative assessments of the histopathologic OA changes were applied to all four quadrants per femorotibial joint for 50 joints (200 quadrants) using specific scoring criteria rather than mild to severe grades. Scoring elements per quadrant were as follows: cartilage lesion (0–7), osteophyte (0–3), subchondral bone change (0–3), synovitis (0–3), and ectopic periarticular soft‐tissue chondrogenesis and ossification (0–3). The new histopathologic grading scheme had high intra‐ and interobserver reproducibility (correlation coefficients r > 0.95) across experienced and novice observers. Sensitivity and reliability analyses confirmed the ability of the new scheme to detect minimal but significant OA progression (p < 0.01) within a 2‐week interval and to accurately identify tissue‐ and quadrant‐specific OA severity within the joints. In conclusion, this study presents the first whole‐joint histopathologic grading scheme for murine knee OA that covers all‐stage osteoarthritic changes in all major joint tissues, including periarticular soft‐tissue ossification that is not included in any of the existing OA grading systems. This reproducible scheme is easy to execute and sensitive to minimal OA progression without using computer software, suitable for quick OA severity assessments of the entire femorotibial joint. [ABSTRACT FROM AUTHOR]

Anterior cruciate ligament (ACL) injuries are common knee ligament injuries. While generally successful, ACL reconstruction that uses a tendon graft to stabilize the knee is still associated with a notable percentage of failures and long‐term morbidities. Preclinical research that uses small laboratory species (i.e., mice, rats, and rabbits) to model ACL reconstruction are important to evaluate factors that can impact graft incorporation or posttraumatic osteoarthritis after ACL reconstruction. Small animal ACL reconstruction models are also used for proof‐of‐concept studies for the development of emerging biological strategies aimed at improving ACL reconstruction healing. The objective of this review is to provide an overview on the use of common small animal laboratory species to model ACL reconstruction. The review includes a discussion on comparative knee anatomy, technical considerations including types of tendon grafts employed amongst the small laboratory species (i.e., mice, rats, and rabbits), and common laboratory evaluative methods used to study healing and outcomes after ACL reconstruction in small laboratory animals. The review will also highlight common research questions addressed with small animal models of ACL reconstruction. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the efficacy of highly concentrated tricalcium phosphate (TCP) biocomposite screws on local bone formation in a rabbit model of osteoporosis induced by bilateral ovariohysterectomy (OHE). Fourteen 24‐week‐old female New Zealand rabbits (weight, 3–3.5 kg) were divided into two groups: (1) OHE and biodegradable poly(lactic‐co‐glycolic acid) (PLGA) without ß–TCP plate or screw insertion (OHE/Bio ScRew [BSR]) group and (2) OHE and biocomposite PLGA with highly concentrated ß–TCP plate and screw insertion (OHE/highly concentrated ß–triCalcium phosphate [HCCP]). Both groups underwent bilateral OHE and had two different types of screws and plates inserted at the proximal tibia. Bilateral tibiae were extracted at 25 weeks post‐OHE. The extracted tibiae were scanned with ex vivo microcomputed tomography (micro‐CT). Parameters including bone mineral density (BMD), trabecular bone volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb. Th), and trabecular separation (Tb. Sp) were evaluated after staining the tibial samples with hematoxylin and eosin (H&E) and Masson's trichrome. We then performed pathological assessments. Micro‐CT images revealed improved new bone formation near the implant in the OHE/HCCP group with higher values of BMD, BV/TV, and Tb.N but lower values of Tb. Th and Tb. Sp than the OHE/BSR group. Analyses of H&E and Masson's trichrome staining showed better new bone formation around the implant in the OHE/HCCP group than in the OHE/BSR group. The use of highly concentrated TCP biocomposite screw and plate might improve local bone formation and facilitate osteoconductivity in an osteoporotic rabbit model. [ABSTRACT FROM AUTHOR]

There is growing interest in conservative treatment of Achilles tendon rupture. However, the majority of experimental studies of Achilles tendon have been performed by open tenotomy. More appropriate model of conservative treatment of Achilles tendon rupture is required. We performed an experimental study to evaluate whether outcomes differ between open tenotomy and percutaneous tenotomy of the Achilles tendon in rats. The Achilles tendons of 48 rats were transected. The animals were divided into two groups according to surgical technique: open tenotomy or microscopy‐assisted percutaneous tenotomy. After 1, 2, and 4 weeks, functional, biomechanical, and histological analyses were performed. Western blot was performed for quantitative molecular analysis at 1 week. The Achilles functional index was superior in the percutaneous tenotomy group, compared with the open tenotomy group, at 1 week. The cross‐sectional area was significantly larger in the percutaneous tenotomy group than in the open tenotomy group at 4 weeks. Relative to the native tendons, load to failure and stiffness yielded comparable results at 2 weeks in the percutaneous tenotomy group and at 4 weeks in the open tenotomy group. The histological score was significantly better in the percutaneous tenotomy group than in the open tenotomy group at 1 week. At 1 week, interleukin‐1β expression in the open tenotomy group was higher than in the percutaneous tenotomy group. In summary, Achilles tendon healing was substantially affected by the tenotomy method. We presume that our percutaneous tenotomy method might constitute a useful experimental animal model for conservative treatment of Achilles tendon rupture. [ABSTRACT FROM AUTHOR]

Although bone marrow‐derived mesenchymal stem cells (BMCs) have been widely used in spinal fusion procedures, adipose‐derived stem cells (ASCs) offer a number of advantages as an alternative clinical cell source. This study directly compares the efficacy of ASCs and BMCs from the same donor animals to achieve successful fusion when combined with a clinical‐grade bone graft substitute in a rat lumbar fusion model. ASCs and BMCs were isolated from the same Lewis donor rats and grown to passage 2 (P2). Single‐level bilateral posterolateral intertransverse process lumbar fusion surgery was performed on syngeneic rats divided into three experimental groups: clinical‐grade bone graft substitute alone (CBGS); CBGS+ rat ASCs (rASC); and, CBGS+ rat BMCs (rBMC). Eight weeks postoperatively, fusion was evaluated via micro‐CT, manual palpation and histology. In vitro analysis of the osteogenic capacity of rBMCs and rASCs was also performed. Results indicated that the average fusion volume in the rASC group was the largest and was significantly larger than the CBGS group. Although the rASC group displayed the highest fusion rates via micro‐CT and manual palpation, this difference was not statistically significant. Cell‐seeded grafts showed more histological bone formation than cell‐free grafts. P2 rASCs and rBMCs displayed similar in vitro osteogenic differentiation capacities. Overall, this study showed that, when combined with a clinical‐grade bone graft substitute in a rat model, rASCs cells yielded the largest fusion masses and comparable fusion results to rBMCs. These results add to growing evidence that ASCs provide an attractive alternative to BMCs for spinal fusion procedures. [ABSTRACT FROM AUTHOR]

Currently, steel implants are used for osteosynthesis of (comminuted) fractures and intra‐articular bone defects. These osteosyntheses can sometimes be complicated procedures and can have several drawbacks including stress shielding of the bone. A bone glue might be a safe and effective alternative to current materials. Despite numerous animal studies on bone adhesives, no such material is clinically applied yet. We have conducted a systematic review to summarize the evidence in experimental animal models used in research on bone adhesive materials for trauma and orthopedic surgery. Additionally, we analysed the efficacy of the different bone adhesives for different experimental designs. A heterogeneity in experimental parameters including animal species, defect types, and control measurements resulted in a wide variety in experimental models. In addition, no standard outcome measurements could be identified. Meta‐analysis on bone regeneration between adhesive treatment and nonadhesive treatment showed a high heterogeneity and no statistically significant overall effect (M: −0.71, 95% confidence interval [CI]: −1.63–0.21, p = 0.13). Besides, currently there is not enough evidence to draw conclusions based on the effectiveness of the individual types of adhesives or experimental models. A positive statistically significant effect was found for the adhesive treatment in comparison with conventional osteosynthesis materials (M: 2.49, 95% CI: 1.20–3.79, p = 0.0002). To enhance progression in bone adhesive research and provide valuable evidence for clinical application, more standard experimental parameters and a higher reporting quality in animal studies are needed. Statement of Clinical Significance: Current materials restoring anatomical alignments of bones have several drawbacks. A (biodegradable) adhesive for fixating bone defects can be a treatment breakthrough. Although numerous bone adhesives have been researched, most seemed to fail at the preclinical stage. An overview in this field is missing. This systematic review highlights the relevant parameters for design of experimental bone adhesive studies. It demonstrates evidence regarding benefit of bone adhesives but also that the quality of reporting and the risk of bias in studies need to be improved. The results will aid in designing better quality animal studies for bone adhesive research with higher translational value. [ABSTRACT FROM AUTHOR]

Abnormal joint kinematics are commonly reported in the acute and chronic stages of recovery after anterior cruciate ligament (ACL) injury and have long been mechanistically implicated as a primary driver in the development of posttraumatic osteoarthritis (PTOA). Though strongly theorized, it is unclear to what extent biomechanical adaptations after ACL injury culminate in the development of PTOA, as data that directly connects these factors does not exist. Using a preclinical, noninvasive ACL injury rodent model, our objective was to explore the direct effect of an isolated ACL injury on joint kinematics and the pathogenetic mechanisms involved in the development of PTOA. A total of 32, 16‐week‐old Long‐Evans rats were exposed to a noninvasive ACL injury. Marker‐less deep learning software (DeepLabCut) was used to track animal movement for sagittal‐plane kinematic analyses and micro computed tomography was used to evaluate subchondral bone architecture at days 7, 14, 28, and 56 following injury. There was a significant decrease in peak knee flexion during walking (p <.05), which had a moderate‐to‐strong negative correlation (r = −.59 to −.71; p <.001) with subchondral bone plate porosity in all load bearing regions of the femur and tibia. Additional comprehensive analyses of knee flexion profiles revealed dramatic alterations throughout the step cycle. This occurred alongside considerable loss of epiphyseal trabecular bone and substantial changes in anatomical orientation. Knee flexion angle and subchondral bone microarchitecture are severely impacted after ACL injury. Reductions in peak knee flexion angle after ACL injury are directly associated with subchondral bone plate remodeling. [ABSTRACT FROM AUTHOR]

Macrophages play an important role in the development and progression of osteoarthritis (OA). The aim of this study was to identify macrophage phenotypes in synovium and monocyte subsets in peripheral blood in C57BL/6 mice by destabilizing the medial meniscus (DMM), and the association of macrophage subsets with OA features. DMM, sham, and non‐operated knees were histologically assessed between 1 and 56 days for macrophage polarization states by immunohistochemistry (IHC), cartilage damage, synovial thickening, and osteophytes (n = 9 per timepoint). Naive knees (n = 6) were used as controls. Monocyte and polarized synovial macrophage subsets were evaluated by flow cytometry. CD64 and CD206 levels on IHC were higher at early timepoints in DMM and sham knees compared to naive knees. iNOS labeling intensity was higher in DMM and sham knees than in naive knees from d3 onwards. CD163 expression was unaltered at all timepoints. Even though macrophage polarization profiles were similar in DMM and sham knees, only in DMM knees the presence of iNOS and CD206 associated with synovial thickness, and CD163 staining inversely correlated with osteophyte presence. At day 14, monocyte subset distribution was different in peripheral blood of DMM mice compared with sham mice. In conclusion, monocyte subsets in blood and synovial macrophage phenotypes vary after joint surgery. High levels of iNOS+, CD163+, and CD206+ cells are found in both destabilized and sham‐operated knees, and coexistence with joint instability may be a requirement to initiate and exacerbate OA progression. [ABSTRACT FROM AUTHOR]

Epigenetic factors, such as DNA methylation, play an influential role in the development of the degenerative joint disease osteoarthritis (OA). These molecular mechanisms have been heavily studied in humans, and although OA affects several other animals in addition to humans, few efforts have taken an evolutionary perspective. This study explores the evolution of OA epigenetics by assessing the relationship between DNA methylation variation and knee OA development in baboons (Papio spp.) and by comparing these findings to human OA epigenetic associations. Genome‐wide DNA methylation patterns were identified in bone and cartilage of the right distal femora from 56 pedigreed, adult baboons (28 with and 28 without knee OA) using the Illumina Infinium MethylationEPIC BeadChip. Several significantly differentially methylated positions (DMPs) and regions were found between tissue types. Substantial OA‐related differential methylation was also identified in cartilage, but not in bone, suggesting that cartilage epigenetics may be more influential in OA than bone epigenetics. Additionally, some genes containing OA‐related DMPs overlap with and display methylation patterns similar to those previously identified in human OA, revealing a mixture of evolutionarily conserved and divergent OA‐related methylation patterns in primates. Overall, these findings reinforce the current etiological perspectives of OA and enhance our evolutionary understanding of epigenetic mechanisms associated with OA. This study further establishes baboons as a valuable nonhuman primate model of OA, and continued investigations in baboons will help to disentangle the molecular mechanisms contributing to OA and their evolutionary histories. [ABSTRACT FROM AUTHOR]

Fracture healing is a complex process requiring mechanical stability, an osteoconductive matrix, and osteoinductive and osteogenic biology. This intricate process is easily disrupted by various patient factors such as chronic disease and lifestyle. As the medical complexity and age of patients with fractures continue to increase, the importance of developing relevant experimental models is becoming paramount in preclinical research. The objective of this review is to describe the most common small animal models of systemically impaired fracture healing used in the orthopedic literature including osteoporosis, diabetes mellitus, smoking, alcohol use, obesity, and ageing. This review will provide orthopedic researchers with a summary of current models of systemically impaired fracture healing used in small animals and present an overview of the methods of induction for each condition. [ABSTRACT FROM AUTHOR]

Frozen shoulder is a common shoulder disorder characterized by a gradual increase of pain and a limited range of motion. However, its pathophysiologic mechanisms remain unclear and there is no consensus as to the most effective treatment. The purpose of the study was to investigate the effect of transforming growth factor‐β (TGF‐β) on fibrosis and inflammatory response of the shoulder joint of rat models and to explore the therapeutic effect of the peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) agonist. In the study, the effect of PPAR‐γ agonist CDDO‐IM treatment on cell proliferation, migration, and extracellular matrix proteins synthesis (vimentin, α‐smooth muscle actin, collagen I, and collagen III) were tested by cell proliferation test, scratches test, real‐time quantitative polymerase chain reaction, and Western blot analysis. The frozen shoulder was also established on the rat model by injecting adenovirus‐TGF‐β1 into rats' shoulder capsule. Pathological changes of the frozen shoulder tissue of the experimental group and PPAR‐γ agonist treatment group were evaluated. The stiffness of joints of the three groups was tested. Inflammatory mediators' expression including cyclooxygenase‐1, interleukin‐1β, and tumor necrosis factor‐α of the shoulder was tested by enzyme‐linked immunosorbent assay, and the expression of extracellular matrix proteins was evaluated by hematoxylin and eosin staining and immunohistochemistry. The results showed that pathological changes of the frozen shoulder in the rat model include an abnormal proliferation of fibroblasts, infiltration of inflammatory cells, and disorder of fibrous structure, while rosiglitazone reduced the severity of the frozen shoulder in the treatment group. Clinically, PPAR‐γ agonists may be a promising target for the treatment of the frozen shoulder. [ABSTRACT FROM AUTHOR]

Osteomyelitis is a devastating complication of orthopaedic surgery and commonly caused by Staphylococcus aureus (S. aureus) and Group B Streptococcus (GBS, S. agalactiae). Clinically, S. aureus osteomyelitis is associated with local inflammation, abscesses, aggressive osteolysis, and septic implant loosening. In contrast, S. agalactiae orthopaedic infections generally involve soft tissue, with acute life‐threatening vascular spread. While preclinical models that recapitulate the clinical features of S. aureus bone infection have proven useful for research, no animal models of S. agalactiae osteomyelitis exist. Here, we compared the pathology caused by these bacteria in an established murine model of implant‐associated osteomyelitis. In vitro scanning electron microscopy and CFU quantification confirmed similar implant inocula for both pathogens (~105 CFU/pin). Assessment of mice at 14 days post‐infection demonstrated increased S. aureus virulence, as S. agalactiae infected mice had significantly greater body weight, and fewer CFU on the implant and in bone and adjacent soft tissue (p < 0.05). X‐ray, µCT, and histologic analyses showed that S. agalactiae induced significantly less osteolysis and implant loosening, and fewer large TRAP+ osteoclasts than S. aureus without inducing intraosseous abscess formation. Most notably, transmission electron microscopy revealed that although both bacteria are capable of digesting cortical bone, S. agalactiae have a predilection for colonizing blood vessels embedded within cortical bone while S. aureus primarily colonizes the osteocyte lacuno‐canalicular network. This study establishes the first quantitative animal model of S. agalactiae osteomyelitis, and demonstrates a vasculotropic mode of S. agalactiae infection, in contrast to the osteotropic behavior of S. aureus osteomyelitis. [ABSTRACT FROM AUTHOR]

To investigate the effect of inhibiting transforming growth factor‐β (TGF‐β1)/Smad2/3 signaling on rotator cuff (RC) healing. A bilateral supraspinatus tendon detachment‐repair model of Sprague‐Dawley (SD) rats was utilized. A total of 120 SD rats were randomly assigned to six groups and each group received the subacromial injection of normal saline, empty vectors, or lentiviral vectors containing small interfering RNA against TGF‐β1, Smad2, Smad3 at the bone‐tendon junction. Biomechanical and histological analyses were performed to evaluate bone‐tendon junction healing quality at 8 weeks after repair. Histologically, scar healing was found in all surgical groups. Animals with inhibited Smad3 exhibited better bone‐tendon junction structures with higher density, parallel orientation, and collagen fiber continuity than other surgical group animals. Immunohistochemistry revealed that the protein expression level of collagen I in animals with inhibited Smad3 was more prominent compared with all other surgical groups. Biomechanically, Animals with inhibited Smad3 showed better results in the maximum load at 4, 6, and 8 weeks after surgery compared with other surgical groups. Besides, C3H10T1/2 (Smad3−) cells increased TT‐D6 cell migration and tendon‐associated genes expression (scleraxis, tenascin C, collagen I) in coculture system. We conclude that inhibition of Smad3 promotes RC tendon healing in the rat supraspinatus model. [ABSTRACT FROM AUTHOR]

Animal osteoarthritis (OA) models have been developed to understand OA progression and evaluate new OA therapies. However, individual variations in joint lesions remain a critical problem in most current OA models. We established a novel rabbit model by creating a longitudinal tear in the medial meniscus body that was reproducible and similar to posttraumatic biomechanical disturbances in human OA. New Zealand rabbits underwent surgery and were assessed for 9 weeks. The rabbits were randomized into the sham control, medial meniscal tear (MMT), and anterior cruciate ligament transection (ACLT) groups. The animals were sacrificed at 4, 6, and 9 weeks posttreatment. The knee joints were harvested for histological and gene expression assessments. Both the MMT and ACLT procedures led to time‐dependent degenerative changes in the femoral condyle cartilage. At each time point, the MMT group cartilage showed more severe degenerative changes than did the ACLT group cartilage. Consistently, inflammatory cytokine and catabolic gene expression were significantly higher, and anabolic gene expression was significantly lower in the MMT group than in the ACLT group. MMT treatment caused more severe structural damage to the cartilage and higher catabolic gene expression levels than the ACLT model at each time point. The MMT model may be highly beneficial in investigating posttraumatic OA (PTOA) development, especially PTOA from a meniscal injury. The MMT model replicated key features of human PTOA, including meniscal lesions, inflammatory responses, and the progression to osteoarthritic cartilage degeneration, thereby providing an exciting new avenue for translating promising treatments to clinical practice. [ABSTRACT FROM AUTHOR]

Small animal models are essential for studying anterior cruciate ligament (ACL) injury, one of the leading risk factors for post‐traumatic osteoarthritis (PTOA). Non‐surgical models of ACL rupture have recently surged as a new tool to study PTOA, as they circumvent the confounding effects of surgical disruption of the joint. These models primarily have been explored in mice and rabbits, but are relatively understudied in rats. The purpose of this work was to establish a non‐invasive, mechanical overload model of ACL rupture in the rat and to study the disease pathogenesis following the injury. ACL rupture was induced via non‐invasive tibial compression in Lewis rats. Disease state was characterized for 4 months after ACL rupture via histology, computed tomography, and biomarker capture from the synovial fluid. The non‐invasive knee injury (NIKI) model created consistent ACL ruptures without direct damage to other tissues and resulted in conventional OA pathology. NIKI knees exhibited structural changes as early as 4 weeks post‐injury, including regional structural changes to cartilage, chondrocyte and cartilage disorganization, changes to the bone architecture, synovial hyperplasia, and the increased presence of biomarkers of cartilage fragmentation and pro‐inflammatory cytokines. These results suggest that this model can be a valuable tool to study PTOA. By establishing the fundamental pathogenesis of this injury, additional opportunities are created to evaluate unique contributing factors and potential therapeutic interventions for this disease. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:356‐367, 2020 [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Subacromial impingement is associated with a spectrum of disorders—including rotator cuff disease—but their relationship is complex. We have established a novel murine model of subacromial impingement to study supraspinatus tendinopathy. The purpose of this study was to evaluate changes in gene expression in this murine shoulder impingement model to further elucidate the mechanisms underlying the development of tendinopathy. Twenty‐eight C57BL/6 mice were used in this study. All mice underwent bilateral surgery with insertion of a small metal clip in the subacromial space or a sham procedure. The supraspinatus tendons underwent histological analyses, biomechanical testing, and RNA extraction for multiplex gene expression analysis (NanoString, Seattle, WA). Histology demonstrated increased cellularity and disorganized collagen fibers of the supraspinatus tendon in the clip impingement group. Mean load to failure (5.20 vs. 1.50 N, p < 0.001) and mean stiffness (4.95 vs. 1.47 N/mm, p < 0.001) were lower in the impingement group than the sham group. NanoString analyses revealed 111 differentially expressed genes (DEGs) between the impingement and sham groups. DEGs of interest included Mmp3 (expression ratio [ER]: 2.68, p = 0.002), Tgfb1 (ER: 1.76, p = 0.01), Col3a1 (ER: 1.66, p = 0.03), and Tgfbr2 (ER: 1.53, p = 0.01). Statement of clinical significance: We identified 111 DEGs that may contribute to the development of tendinopathy in this model. Further studies of these specific genes will allow identification of their roles in the initiation and regulation of tendon damage, and their potential to serve as novel therapeutic targets in the treatment of rotator cuff disease. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2575–2582, 2019 [ABSTRACT FROM AUTHOR]

Juvenile osteochondritis dissecans (JOCD) is a developmental disease characterized by formation of intra‐articular (osteo)chondral flaps or fragments. Evidence‐based treatment guidelines for JOCD are currently lacking. An animal model would facilitate study of JOCD and evaluation of diagnostic and treatment approaches. The purpose of this study was to assess the suitability of miniature pigs as a model of JOCD at the distal femur. First, stifle (knee) joints harvested from three juvenile miniature pigs underwent magnetic resonance imaging (MRI) to establish the vascular architecture of the distal femoral epiphyseal cartilage. Second, vessels supplying the axial or abaxial aspects of the medial femoral condyle were surgically interrupted in four additional juvenile miniature pigs, and the developing epiphyseal cartilage lesions were monitored using three consecutive MRI examinations over nine weeks. The miniature pigs were then euthanized, and their distal femora were harvested for histological evaluation. Vascular architecture of the distal femoral epiphyseal cartilage in the miniature pigs was found to be nearly identical to that of juvenile human subjects, characterized by separate vascular beds supplying the axial and abaxial aspects of the condyles. Surgical interruption of the vascular supply to the abaxial aspect of the medial femoral condyle resulted in ischemic cartilage necrosis (a precursor lesion of JOCD) in 75% (3/4) of the miniature pigs. Cartilage lesions were identified during the first MRI performed 3 weeks post‐operatively. No clinically apparent JOCD‐like lesions developed. In conclusion, miniature pigs are suitable for modeling JOCD precursor lesions. Further investigation of the model is warranted to assess induction of clinically apparent JOCD lesions. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2130–2137, 2019 [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Tendinopathy includes cases with chronic tendon pain and spontaneous tendon ruptures, which is putatively resulted from failed tendon healing. Overuse is a major risk factor of tendinopathy, which can impose mechanical and oxidative stress to tendons. Previous studies investigated the influences of mechanical stress, but the direct impact of oxidative stress on tendon healing remains unclear. We hypothesized that imposed oxidative stress can impair tendon healing and lead to tendinopathic changes. Thirty‐nine rats were operated for patellar tendon window injury. From weeks 3–5 post‐operation, the rats received three weekly subcutaneous injections of saline, 50 or 500 μM H2O2 (n = 13) over patellar tendon. Gait analysis for pain assessment and 3D ultrasound imaging for detection of tendinopathic changes were performed at pre‐injury and 6‐week post‐operation. At week 6, knee specimens were harvested for histology or tensile mechanical test. Elastic modulus of the healing patellar tendons was significantly lower in 50 μM but not 500 μM H2O2 group, while ultimate mechanical stress was not significantly different across groups. Similarly, only the 50 μM H2O2 group exhibited pain‐associated gait asymmetry. Significant tendon swelling with increased tendon volume was observed in the 50 μM H2O2 group. There were hypoechogenic changes in the tendon wound, but there was no significant difference in percentage vascularity. H2O2 impaired tendon healing and elicited tendinopathic changes, with respect to pain and structural abnormalities. Oxidative stress plays a role in the failed tendon healing of tendinopathies, and H2O2‐induced failed tendon healing may serve as a good animal model to study tendinopathy. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:3268–3274, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACT: Flexor tendon injuries are common and pose a clinical challenge for functional restoration. The purpose of our study was to assess the adequacy of the turkey as a large animal model for flexor tendon injuries in vivo. Twenty‐four male turkeys underwent surgical flexor tendon cut and repair. Turkeys were allocated to five groups postoperatively: (1) foot casted in extension and sacrificed after 3 weeks; (2) foot casted in extension and sacrificed after 6 weeks; (3) foot casted in flexion and sacrificed after 3 weeks; (4) foot casted in flexion and sacrificed after 6 weeks; and (5) foot casted in flexion for 6 weeks and then free roaming allowed for an additional 3 weeks before sacrifice. After sacrifice, digits were collected and analyzed for adhesion formation, healing at the macrolevel and histologically, and biomechanical properties—including friction, work of flexion, stiffness, and strength of repair. All turkeys survived anesthesia and surgery. Tendon rupture occurred in all extension casts and in 11% of those casted in flexion. Friction and work of flexion were significantly higher in the repaired digit than the control digit. There was a correlation between duration of immobilization and repair strength. Histologically, the tendon healed with tenocytes migrating into the gap and producing collagen fibers. We have, for the first time, studied flexor tendon injury and repair using turkeys in terms of anesthesia, surgical procedures, postoperative care, and animal husbandry. The findings regarding functional and histological results from this novel avian model were comparable to the most commonly used mammal model. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2497–2505, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACT: Sheep hips have a natural non‐spherical head similar to a cam‐type deformity in human beings. By performing an intertrochanteric varus osteotomy, cam‐type femoroacetabular impingement can be induced experimentally. In sheep, the aspherical portion is located superiorly—exactly matching the region where the superior retinacular vessels enter the femoral head–neck junction in human beings. In order to fully exploit the potential of this experimental FAI model, a safe osteochondroplasty of the superior asphericity would need to be done without the risk of avascular necrosis. The aim of this study was to describe the vascular anatomy of the femoral head in sheep from the aorta to the retinacular vessels in order to perform safe femoral osteochondroplasty of the superior femoral asphericity in sheep. Sixty‐two ovine hips were analyzed using CT angiography (30 hips), post mortem intravascular latex injection (6 hips), vascular corrosion casting (6 hips), and analysis of the distribution of vascular foramina around the femoral head–neck junction in macerated ovine femora (20 hips). The ovine femoral head receives its blood supply from anterior retinacular arteries from the lateral femoral circumflex artery, and from posterior retinacular arteries from the medial femoral circumflex artery. The superior aspherical portion is free of vessels. Detailed knowledge about vascular anatomy of sheep hips is of clinical significance since it allows to perform osteochondroplasty of the superior aspherical portion in the experimental ovine FAI model safely without the risk of osteonecrosis. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2340–2348, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACT: To determine the transcriptional profile of synovium during the molecular phase of post‐traumatic osteoarthritis, anterior cruciate ligament transections (ACL) were performed in 36 Yucatan minipigs. Equal numbers were randomly assigned to no further treatment, ACL reconstruction or repair. Perimeniscal synovium for histopathology and RNA‐sequencing was harvested at 1 and 4 weeks post‐operatively and from six healthy control animals. Microscopic synovitis scores significantly worsened at 1 (p < 0.001) and 4 weeks (p = 0.003) post‐surgery relative to controls, and were driven by intimal hyperplasia and increased stromal cellularity without inflammatory infiltrates. Synovitis scores were similar between no treatment, reconstruction, and repair groups (p ≥ 0.668). Relative to no treatment at 1 week, 88 and 367 genes were differentially expressed in the reconstruction and repair groups, respectively (227 and 277 at 4 weeks). Relative to controls and with the treatment groups pooled, 1,683 transcripts were concordantly differentially expressed throughout the post‐surgery time‐course. Affected pathways included, proteolysis_connective tissue degradation (including upregulations of protease‐encoding MMP1, MMP13, and ADAMTS4), and development_cartilage development (including upregulations of ACAN, SOX9, and RUNX2), among others. Using linear regression, significant associations of post‐surgery synovial expression levels of 20 genes with the articular cartilage glycosaminoglycan loss were identified. These genes were predominantly related to embryonic skeletal system development and included RUNX2. In conclusion, this study confirmed an increased synovial expression of genes that may serve as targets to prevent cartilage degradation, including MMP1, MMP13, and ADAMTS4, in knees with microscopic synovitis and cartilage proteoglycan loss. Attractive novel targets include regulators of embryonic developmental processes in synovium. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2128–2139, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACT: Neonatal brachial plexus injury (NBPI) results in substantial postural and functional impairments associated with underlying muscular and osseous deformities. We examined the relationship between glenoid deformity severity and gait in a rat model of NBPI, an established model for studying the in vivo pathomechanics of NBPI. At 8 weeks post‐operatively, we monitored the gait of 24 rat pups who exhibited varying degrees of glenoid deformity following unilateral brachial plexus neurectomy and chemodenervation interventions administered 5 days postnatal. Five basic stride and stance metrics were calculated for the impaired forelimbs over four consecutive gait cycles. Bilateral differences in glenoid version (ΔGAv) and inclination (ΔGAi) angles were computed from data for the same rats as reported in a previous study. A linear regression model was generated for each deformity‐gait pair to identify significant relationships between the two. ΔGAv was not significantly correlated with any gait measurements, while ΔGAi significantly correlated with all five gait measurements. Specifically, ΔGAi was significantly positively correlated with stride length (R2 = 0.38, p = 0.001) and stance factor (R2 = 0.45, p < 0.001), and significantly negatively correlated with stance width (R2 = 0.24, p = 0.016), swing/stance ratio (R2 = 0.17, p = 0.046), and stride frequency (R2 = 0.33, p = 0.003). Rats with declined glenoids exhibited the most altered gait. Clinical significance: Our findings link musculoskeletal changes and functional outcomes in an NBPI rat model. Thus, gait analysis is a potentially useful, non‐invasive, quantitative way to investigate the effects of injury and deformity on limb function in the NBPI rat model. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1991–1997, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACT: Chronic low back pain is a major cause of disability and health care costs. Effective treatments are inadequate for many patients. Animal models are essential to further understanding of the pain mechanism and testing potential therapies. Currently, a number of preclinical models have been developed attempting to mimic aspects of clinical conditions that contribute to low back pain (LBP). This review focused on describing these animal models and the main behavioral tests for assessing pain in each model. Animal models of LBP can be divided into the following five categories: Discogenic LBP, radicular back pain, facet joint osteoarthritis back pain, muscle‐induced LBP, and spontaneous occurring LBP models. These models are important not only for enhancing our knowledge of how LBP is generated, but also for the development of novel therapeutic regimens to treat LBP in patients. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1305–1312, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACT: New treatment options are urgently required in the field of chondrosarcoma, particularly of chondrosarcomas with a well‐differentiated hyaline cartilage‐like extracellular matrix (e.g., collagen II and proteoglycan‐rich) phenotype, notoriously resistant to drug penetration, and having potential of progression towards higher grade. We investigated the feasibility of using 5′‐methylschweinfurthin G (MeSG) as a tumor suppressor agent in the Swarm rat chondrosarcoma, an intermediate‐ to high‐grade chondrosarcoma model, having a hyaline cartilage‐like phenotype. Tumor cell culture studies were performed to identify their proliferative and cytotoxicity sensitivity to MeSG. Tumor burden mice were treated with MeSG and analyzed for tumor growth, morphology and regression. The chondrosarcoma tumor cells had a half maximum cytotoxicity concentration (IC50) of 35 nM MeSG; approximately 300‐fold less than freshly isolated rat chondrocytes (IC50 of 11 µM). Multiple injections of MeSG (20 mg/kg, body weight) resulted in reduced/eliminated tumor growth over a 17‐day period in mice, and an 83% reduction (p = 0.023) in tumor mass. Three out of ten MeSG treated mice had complete elimination of tumor. Tumors of treated mice had a decrease in chondrosarcoma cell proliferation (p = 0.012) and an increase in cell death (p = 0.030) compared with tumors of control mice. These findings in an animal model demonstrate the effectiveness of MeSG for treatment of rat chondrosarcomas, and may have the potential use as a therapeutic option for the difficult‐to‐treat intermediate‐to high‐grade hyaline cartilage‐like chondrosarcoma. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1283–1293, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACT: In this review, we broadly define and discuss the preclinical rodent models that are used for orthopedics and bone tissue engineering. These range from implantation models typically used for biocompatibility testing and high‐throughput drug screening, through to fracture and critical defect models used to model bone healing and severe orthopedic injuries. As well as highlighting the key methods papers describing these techniques, we provide additional commentary based on our substantive practical experience with animal surgery and in vivo experimental design. This review also briefly touches upon the descriptive and functional outcome measures and power calculations that are necessary for an informative study. Obtaining informative and relevant research outcomes can be very dependent on the model used, and we hope this evaluation of common models will serve as a primer for new researchers looking to undertake preclinical bone studies. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:832–840, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACT: Evidence is growing for the existence of an obesity‐related phenotype of osteoarthritis in which low‐grade inflammation and a disturbed metabolic profile play a role. The contribution of an obesity‐induced metabolic dysbalance to the progression of the features of osteoarthritis upon mechanically induced cartilage damage was studied in a rat in vivo model. Forty Wistar rats were randomly allocated 1:1 to a standard diet or a high‐fat diet. After 12 weeks, in 14 out of 20 rats in each group, cartilage was mechanically damaged in the right knee joint. The remaining six animals in each group served as controls. After a subsequent 12 weeks, serum was collected for metabolic state, subchondral bone changes assessed by μCT imaging, osteoarthritis severity determined by histology, and macrophage presence assessed by CD68 staining. The high‐fat diet increased statistically all relevant metabolic parameters, resulting in a dysmetabolic state and subsequent synovial inflammation, whereas cartilage degeneration was hardly influenced. The high‐fat condition in combination with mechanical cartilage damage resulted in a clear statistically significant progression of the osteoarthritic features, with increased synovitis and multiple large osteophytes. Both the synovium and osteophytes contained numerous CD68 positive cells. It is concluded that a metabolic dysbalance due to a high‐fat diet increases joint inflammation without cartilage degeneration. The dysmetabolic state clearly accelerates progression of osteoarthritis upon surgically induced cartilage damage supported by inflammatory responses as demonstrated by histology and increased CD68 expressing cells localized on the synovial membrane and osteophytes. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:881–890, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACT: Elevated chemokine receptor Ccr7 is observed in knee osteoarthritis (OA) and associated with severity of symptoms. In this study, we confirmed that CCR7 protein expression is elevated in synovial tissue from OA patients by immunohistochemical staining. We then investigated whether Ccr7 deficiency impacted structural and functional joint degeneration utilizing a murine model of OA. OA‐like disease was induced in male C57BL/6 and Ccr7‐deficient (Ccr7−/−) mice by destabilization of the medial meniscus (DMM). Functional deficits were measured by computer integrated monitoring of spontaneous activity every 4 weeks after DMM surgery up 16 weeks. Joint degeneration was evaluated at 6 and 19 weeks post‐surgery by histopathology, and subchondral bone changes analyzed by microCT. Results showed reduction in locomotor activities in DMM‐operated C57BL/6 mice by 8 weeks, while activity decreases in Ccr7−/− mice were delayed until 16 weeks. Histopathologic evaluation showed minimal protection from early cartilage degeneration (p = 0.06) and osteophytosis (p = 0.04) in Ccr7−/− mice 6 weeks post‐DMM compared to C57BL/6 controls, but not at 19 weeks. However, subchondral bone mineral density (p = 0.03) and histologic sclerosis (p = 0.02) increased in response to surgery in C57BL/6 mice at 6 weeks, while Ccr7−/− mice were protected from these changes. Our results are the first to demonstrate a role for Ccr7 in early development of functional deficits and subchondral bone changes in the DMM model. Understanding the mechanism of Ccr7 receptor signaling in the initiation of joint pathology and disability will inform the development of innovative therapies to slow symptomatic OA development after injury. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. J Orthop Res 36:864–875, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACT: The pathogenesis of intervertebral disc degeneration is unclear, but it is a major cause of several spinal diseases. Animal models have historically provided an appropriate benchmark for understanding the human spine. However, there is little information about when intervertebral disc degeneration begins in the mouse or regarding the relationship between magnetic resonance imaging and histological findings. The aim for this study was to obtain information about age‐related spontaneous intervertebral disc degeneration in the mouse lumbar spine using magnetic resonance imaging and a histological score regarding when the intervertebral disc degeneration started and how rapidly it progressed, as well as how our histological score detected the degeneration. The magnetic resonance imaging index yielded a moderate correlation with our Age‐related model score. The Pfirrmann grade and magnetic resonance imaging index had moderate correlations with age. However, our Age‐related model score had a high correlation with age. Intervertebral disc level was not a significant variable for the severity of disc degeneration. Both Pfirrmann grade and the Age‐related model score were higher in the ≥14‐month‐old group than in the 6‐month‐old group. The present results indicated that mild but significant intervertebral disc degeneration occurred in 14‐month‐old mice, and the degree of degeneration progressed slowly, reaching a moderate to severe condition for 22‐month‐old mice. At least a 14‐month follow‐up is mandatory for evaluating spontaneous age‐related mouse intervertebral disc degeneration. The histological classification score can precisely detect the gradual progression of age‐related spontaneous intervertebral disc degeneration in the mouse lumbar spine, and is appropriate for evaluating it. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:224–232, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACT: To identify the molecular pathophysiology present in early post‐traumatic osteoarthritis (PTOA), the transcriptional profile of articular cartilage and its response to surgical PTOA induction were determined. Thirty six Yucatan minipigs underwent anterior cruciate ligament (ACL) transection and were randomly assigned in equal numbers to no further treatment, reconstruction or ligament repair. Cartilage was harvested at 1 and 4 weeks post‐operatively and histology and RNA‐sequencing were performed and compared to controls. Microscopic cartilage scores significantly worsened at 1 (p = 0.028) and 4 weeks (p = 0.001) post‐surgery relative to controls, but did not differ between untreated, reconstruction or repair groups. Gene expression after ACL reconstruction and ACL transection were similar, with only 0.03% (including SERPINB7 and CR2) and 0.2% of transcripts (including INHBA) differentially expressed at 1 and 4 weeks respectively. COL2A1, COMP, SPARC, CHAD, and EF1ALPHA were the most highly expressed non ribosomal, non mitochondrial genes in the controls and remained abundant after surgery. A total of 1,275 genes were differentially expressed between 1 and 4 weeks post‐surgery. With the treatment groups pooled, 682 genes were differentially expressed at both time‐points, with the most significant changes observed in MMP1, COCH, POSTN, CYTL1, and PTGFR. This study confirmed the development of a microscopic PTOA stage after ACL surgery in the porcine model. Upregulation of multiple proteases (including MMP1 and ADAMTS4) were found; however, the level of expression remained orders of magnitude below that of extracellular matrix protein‐coding genes (including COL2A1 and ACAN). In summary, genes with established roles in PTOA as well as novel targets for specific intervention were identified. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:318–329, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACT: The caudal discs of rats have been proposed as a puncture model in which intervertebral disc (IVD) degeneration can be induced and novel therapies can be tested. For biological repair, treatments for ongoing IVD degeneration are ideally administered during the earlier stages. The purpose of this study was to elucidate the optimal puncture needle size for creating a model that mimicked the earlier stages of IVD degeneration. According to the disc height index, histologic score, and MRI grading, a puncture needle sized 21G or larger induced rapid degenerative processes in rat caudal discs during the initial 2–4 weeks. The degenerative changes were severe and continued deteriorating after 4 weeks. Conversely, puncture injury induced by needles sized 25G or smaller also produced degenerative changes in rat caudal discs during initial 2–4 weeks; however, the changes were less severe. Furthermore, the degenerative process became stabilized and showed no further deterioration or spontaneous recovery after 4 weeks. In the discs punctured by 25G needles, the expression of collagen I was increased at 2–4 weeks with a gradually fibrotic transformation thereafter. The expressions of collagen II and SOX9 were enhanced initially but returned to pre‐injury levels at 4–8 weeks. The above‐mentioned findings were more compatible with earlier degeneration in discs punctured by needles sized 25G or smaller than by needles sized 21G or larger, and the appropriate timing for intradiscal administration of proposed therapeutic agents would be 4 weeks or longer after puncture. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:202–211, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACT: Using flexible tethering techniques, porcine models of experimental scoliosis have shown scoliotic curves with vertebral wedging but very limited axial rotation. The aim of this experimental work was to induce a severe progressive scoliosis in a growing porcine model for research purposes. A unilateral spinal bent rigid tether was anchored to two ipsilateral pedicle screws in eight pigs. The spinal tether was removed after 8 weeks. Ten weeks later, the animals were sacrificed. Conventional radiographs and 3D CT‐scans were taken to evaluate changes in the alignment of the thoracic spine. After the first 8 weeks of rigid tethering, all animals developed scoliotic curves (mean Cobb angle: 24.3°). Once the interpedicular tether was removed, the scoliotic curves progressed in all animals during 10 weeks reaching a mean Cobb angle of 49.9°. The sagittal alignment of the thoracic spine showed loss of physiologic kyphosis (Mean: −18.3°). Axial rotation ranged from 10° to 49° (Mean 25.7°). Release of the spinal tether results in progression of the deformity with the development of proximal and distal compensatory curves. In conclusion, temporary interpedicular tethering at the thoracic spine induces severe scoliotic curves in pigs, with significant wedging and rotation of the vertebral bodies, and true compensatory curves. Clinical Relevance: The tether release model will be used to evaluate corrective non‐fusion technologies in future investigations. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:174–182, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACT Pigs are favorable experimental animals for infectious diseases in humans. However, implant-associated osteomyelitis (IAO) models in pigs have only been evaluated using high-inoculum infection (>108 CFU) models in 1975 and 1993. Therefore, the aim of this paper was to present a new low inoculum porcine model of human IAO based on 42 experimental pigs. The model was created by drilling an implant cavity in the tibial bone followed by insertion of a small steel implant and simultaneous inoculation of Staphylococcus aureus bacteria ( n = 32) or saline ( n = 10). The infected pigs were either inoculated with 104 CFU ( n = 26) or 102 and 103 CFU ( n = 6). All animals were euthanized 5 days after insertion of implants. Pigs receiving the high-inoculum infections showed a significantly higher volume of bone lesion, number of neutrophils around the implant, concentrations of acute phase proteins in serum, and enlargement of regional lymph nodes. A positive correlation was present between a high number of surrounding neutrophils and high values of all other parameters. Furthermore, a threshold of 40 neutrophils per 10 high power fields for the histopathological diagnosis of high grade IAO was defined. In conclusion: This paper describes a novel low-inoculum S. aureus porcine model of IAO which was demonstrated to be reliable, reproducible and discriminative to human IAO, and represents a requested and valuable tool in orthopedic research. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2211-2221, 2017. [ABSTRACT FROM AUTHOR]

ABSTRACT Obesity is a well-known risk factor for osteoarthritis, but it is unknown what it does on cartilage repair. Here we investigated whether a high fat diet (HFD) influences cartilage repair in a mouse model of cartilage repair. We fed DBA/1 mice control or HFD (60% energy from fat). After 2 weeks, a full thickness cartilage defect was made in the trochlear groove. Mice were sacrificed, 1, 8, and 24 weeks after operation. Cartilage repair was evaluated on histology. Serum glucose, insulin and amyloid A were measured 24 h before operation and at endpoints. Immunohistochemical staining was performed on synovium and adipose tissue to evaluate macrophage infiltration and phenotype. One week after operation, mice on HFD had defect filling with fibroblast-like cells and more cartilage repair as indicated by a lower Pineda score. After 8 weeks, mice on a HFD still had a lower Pineda score. After 24 weeks, no mice had complete cartilage repair and we did not detect a significant difference in cartilage repair between diets. Bodyweight was increased by HFD, whereas serum glucose, amyloid A and insulin were not influenced. Macrophage infiltration and phenotype in adipose tissue and synovium were not influenced by HFD. In contrast to common wisdom, HFD accelerated intrinsic cartilage repair in DBA/1 mice on the short term. Resistance to HFD induced inflammatory and metabolic changes could be associated with accelerated cartilage repair. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1258-1264, 2017. [ABSTRACT FROM AUTHOR]

ABSTRACT Rotator cuff tendon tears are one of the most common shoulder pathologies, especially in the aging population. Due to a poor healing response and degenerative changes associated with aging, rotator cuff repair failure remains common. Although cell-based therapies to augment rotator cuff repair appear promising, it is unknown whether the success of such a therapy is age-dependent. We hypothesized that autologous cell therapy would improve tendon-to-bone healing across age groups, with autologous juvenile cells realizing the greatest benefit. In this study, juvenile, adult, and aged rats underwent bilateral supraspinatus tendon repair with augmentation of one shoulder with autologous tendon-derived cell-seeded polycaprolactone scaffolds. At 8 weeks, shoulders treated with cells in both juvenile and aged animals exhibited increased cellularity, increased collagen organization, and improved mechanical properties. No changes between treated and control limbs were seen in adult rats. These findings suggest that cell delivery during supraspinatus repair initiates earlier matrix remodeling in juvenile and aged animals. This may be due to the relative 'equilibrium' of adult tendon tissue with regards to catabolic and anabolic processes, contrasted with actively growing juvenile tendons and degenerative aged tendons. This study demonstrates the potential for autologous cell-seeded scaffolds to improve repairs in both the juvenile and aged population. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1250-1257, 2017. [ABSTRACT FROM AUTHOR]

ABSTRACT 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. [ABSTRACT FROM AUTHOR]

ABSTRACT Due to the degradation of osteoarthritic (OA) cartilage in post-traumatic OA (PTOA), these tissues are challenging to study and manipulate in vitro. In this study, chondrocytes isolated from either PTOA (meniscal-release (MR) model) or normal (contralateral limb) cartilage of canine knee joints were used to form micropellets to assess the maintenance of the OA chondrocyte phenotype in vitro. Media samples from the micropellet cultures were used to measure matrix metalloproteinase (MMP), chemokine, and cytokine concentrations. Significant differences in matrix synthesis were observed as a function of disease with OA chondrocytes generally synthesizing more extracellular matrix with increasing time in culture. No donor dependent differences were detected. Luminex multiplex analysis of pellet culture media showed disease and time-dependent differences in interleukin (IL)-8, keratinocyte chemoattractant (KC)-like protein, MMP-1, MMP-2, and MMP-3, which are differentially expressed in OA. This memory of their diseased phenotype persists for the first 2 weeks of culture. These results demonstrate the potential to use chondrocytes from an animal model of OA to study phenotype alterations during the progression and treatment of OA. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:829-836, 2017. [ABSTRACT FROM AUTHOR]

ABSTRACT We have developed a laser-textured superhydrophilic Ti-6Al-4V surface with unique surface chemistry and topography that substantially promotes osteoblast adhesion in culture. Here we investigate the osteointegration of laser-textured implants in an ovine model. Our hypothesis was that laser-textured implants, without any surface coating (LT), would encourage comparable amounts of bone-implant contact and interfacial strength when compared with widely accepted hydroxyapatite (HA) coated implants. Additionally, we hypothesized that LT would significantly increase bony integration compared with machine-finished (MF) and grit-blasted (GB) implants. Forty-eight tapered transcortical pins were implanted into six sheep. Four experimental groups (LT, HA, MF, and GB) were investigated ( n = 12) and implants remained in vivo for 6 weeks. Bone apposition rates, interfacial shear strength, and bone-implant contact (BIC) were quantified. The interfacial strength of LT and HA implants were found to be significantly greater than GB ( p = 0.032 and p = 0.004) and MF ( p = 0.004 and p = 0.004, respectively), but no significant difference between LT and HA implants was observed. Significantly increased BIC was measured adjacent to HA implants when compared with both LT and GB implant surfaces ( p = 0.022 and p = 0.006, respectively). No significant difference was found when LT and GB implants were compared. However, all surface finishes encouraged significantly increased BIC when compared with the MF surface. Maximizing implant fixation to host bone is vital for its long-term success. The production of an LT surface is a simple and cheap manufacturing process and this study demonstrated that laser-textured implants are a very promising technical development that warrants further research. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:820-828, 2017. [ABSTRACT FROM AUTHOR]

ABSTRACT Cell-based therapies offer a promising approach to treat intervertebral disc (IVD) degeneration. The impact of the injury microenvironment on treatment efficacy has not been established. This study used a rat disc stab injury model with administration of mesenchymal stromal cells (MSCs) at 3, 14, or 30 days post injury (DPI) to evaluate the impact of interventional timing on IVD biochemistry and biomechanics. We also evaluated cellular localization within the disc with near infrared imaging to track the time and spatial profile of cellular migration after in vivo delivery. Results showed that upon injection into a healthy disc, MSCs began to gradually migrate outwards over the course of 14 days, as indicated by decreased signal intensity from the disc space and increased signal within the adjacent vertebrae. Cells administered 14 or 30 DPI also tended to migrate out 14 days after injection but cells injected 3 DPI were retained at a significantly higher amount versus the other groups ( p < 0.05). Correspondingly the 3 DPI group, but not 14 or 30 DPI groups, had a higher GAG content in the MSC injected discs ( p = 0.06). Enrichment of MSCs and increased GAG content in 3 DPI group did not lead to increased compressive biomechanical properties. Findings suggest that cell therapies administered at an early stage of injury/disease progression may have greater chances of mitigating matrix loss, possibly through promotion of MSC activity by the inflammatory microenvironment associated with injury. Future studies will evaluate the mode and driving factors that regulate cellular migration out of the disc. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:32-40, 2017. [ABSTRACT FROM AUTHOR]

ABSTRACT Hypercholesterolemia is a common condition and is a risk factor for tendon rupture, specifically in the supraspinatus tendon. In the clinic, statins are commonly prescribed to lower cholesterol, but little information is available examining the effect of statin treatment on the musculoskeletal system. Therefore, the objective of this study was to determine the biomechanical and histological effects of statin treatment in a diet-induced hypercholesterolemia model. We hypothesized that hypercholesterolemic rats treated with statins would have improved tendon biomechanical and histological properties compared to hypercholesterolemic rats not receiving daily statin treatment. Thirty adult male Sprague-Dawley rats ate either high-cholesterol (HC) diet ( n = 20) or normal chow (CTL, n = 10). After 6 months, a subset of HC rats began daily oral simvastatin dosing (HC+S) at 20 mg/kg. All rats were sacrificed after a total of 9 months (3 months of statin treatment) and evaluated for histology and mechanics. For mechanics, at the insertion region, HC+S group had increased tendon cross-sectional area decreased and modulus. No differences were noted in mechanical properties at the midsubstance. For histology, no differences were noted in the insertion region. In the midsubstance region, HC+S group had more spindle shaped cells. Our results suggest that 3 months of simvastatin treatment in a diet-induced hypercholesterolemia rat model alters some tendon mechanical and histological properties, although a strong conclusion in support of improved parameters cannot be drawn. Therefore, we conclude that simvastatin treatment does not negatively affect tendon properties. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2009-2015, 2016. [ABSTRACT FROM AUTHOR]

ABSTRACT The objective of this study was to assess the safety and efficacy of intra-articular injections of hyaluronic acid (HA) versus saline for symptomatic treatment of osteoarthritis (OA). Twenty-five adult purpose-bred dogs underwent meniscal release of one knee. Clinical, arthroscopic, and radiographic signs of OA were confirmed in all dogs prior to treatment. Dogs were randomized into five groups: HA-1 ( n = 5), HA-3 ( n = 5), HA-5 ( n = 5), Saline-1 ( n = 5), and Saline-3 ( n = 5). Each dog received intra-articular injections of the respective substance into the affected knee at the pre-determined time points. Dogs were assessed for heat, swelling, and erythema after each injection and for lameness, pain, effusion, range of motion, kinetics, radiographic OA scoring, and arthroscopic scoring prior to treatment and for 6 months after injection. Dogs were then humanely euthanatized and the knees assessed grossly and histologically. Only mild heat, swelling, and/or erythema were noted in some dogs following injection and resolved within 1 week. Dogs treated with HA-1, HA-3, and HA-5 were significantly ( p < 0.05) better than dogs treated with Saline-1 and Saline-3 at the 4, 8, and 12 week time points based on at least one outcome measure. OA severity was not significantly different among groups at any time point, but increased in severity over time in all groups. Gross and histologic OA scores were not significantly different among groups. These data suggest the three HA injection protocols were safe, superior to saline for short-term amelioration of symptoms associated with chronic OA, and can be translated to human OA treatment. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1772-1779, 2016. [ABSTRACT FROM AUTHOR]

ABSTRACT The purpose of this study was to investigate the role of elastase on tendinopathy, as well as to evaluate the potential for peritendinous injections of elastase into rats to cause tendinopathy. We first investigated the expression of elastase in the tendons of patients with tendinopathy, and then established the effects of elastase injection on the Achilles tendons of rats. Ultrasonographic and incapacitance testing was used to conduct tests for 8 weeks. Tendon tissues were collected for histological observation and protein levels of collagen type I and type III were detected using Western blotting. The percentage of elastase-positive cells increased in human specimens with grades II and III tendinopathy. The rat model demonstrated that the thickness of the tendon increased after elastase injection during Week 2-8. Hypercellularity and focal lesions were detected after Week 2. The expression of elastase was increased and elastin was decreased in Week 8. Collagen type I expression was decreased, but type III was increased in Week 4. These results suggested that elastase may be involved in the development of chronic tendinopathy, and that peritendinous injection of elastase may result in tendinopathy in rats. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:471-477, 2016. [ABSTRACT FROM AUTHOR]

ABSTRACT Post-traumatic joint stiffness (PTJS) of the elbow is a debilitating condition that poses unique treatment challenges. While previous research has implicated capsular tissue in PTJS, much regarding the development and progression of this condition remains unknown. The objective of this study was to develop an animal model of post-traumatic elbow contracture and evaluate its potential for studying the etiology of PTJS. The Long-Evans rat was identified as the most appropriate species /breed for development due to anatomical and functional similarities to the human elbow joint. Two surgical protocols of varying severity were utilized to replicate soft tissue damage seen in elbow subluxation/dislocation injuries, including anterior capsulotomy and lateral collateral ligament transection, followed by 6 weeks of unilateral joint immobilization. Following sacrifice, flexion-extension mechanical joint testing demonstrated decreased range-of-motion and increased stiffness for injured-immobilized limbs compared to control and sham animals, where functional impact correlated with severity of injury. Histological evaluation showed increased cellularity, adhesion, and thickness of capsule tissue in injured limbs, consistent with clinical evidence. To our knowledge, this is the first animal model capable of examining challenges unique to the anatomically and biomechanically complex elbow joint. Future studies will use this animal model to investigate mechanisms responsible for PTJS. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:354-364, 2016. [ABSTRACT FROM AUTHOR]

ABSTRACT Supraspinatus tears often result in the setting of chronic tendinopathy. However, the typical repair model utilizes an acute injury. In recognition of that distinction, our laboratory developed an overuse animal model; however it is unclear whether induced overuse is necessary in the repair model. We studied the repair properties of overuse-induced tendons compared to normal tendons. We hypothesized that histological and mechanical properties would not be altered between the overuse-induced and normal tendons 1 and 4 weeks after repair. Thirty-one adult male Sprague-Dawley rats were subjected to either overuse or cage activity for 4 weeks prior to bilateral supraspinatus tendon repair surgery. Rats were sacrificed at 1 and 4 weeks post-surgery and evaluated for histology and mechanics. Results at 1 week showed no clear histologic changes, but increased inflammatory protein expression in overuse tendons. At 4 weeks, percent relaxation was slightly increased in the overuse group. No other alterations in mechanics or histology were observed. Our results suggest that the effects of the surgical injury overshadow the changes evoked by overuse. Because clinically relevant mechanical parameters were not altered in the overuse group, we conclude that when examining tendons 4 weeks after repair in the classic rat supraspinatus model, inducing overuse prior to surgery is likely to be unnecessary. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:161-166, 2016. [ABSTRACT FROM AUTHOR]