Inflammatory and degenerative phases resulting from anterior cruciate rupture in a non‐invasive murine model of post‐traumatic osteoarthritis

Joint injury is the predominant risk factor for post‐traumatic osteoarthritis development (PTOA). Several non‐invasive mouse models mimicking human PTOA investigate molecular mechanisms of disease development; none have characterized the inflammatory response to this acute traumatic injury. Our aim was to characterize the early inflammatory phase and later degenerative component in our in vivo non‐invasive murine model of PTOA induced by anterior cruciate ligament (ACL) rupture. Right knees of 12‐week‐old C57Bl6 mice were placed in flexion at a 30° offset position and subjected to a single compressive load (12N, 1.4 mm/s) to induce ACL rupture with no obvious damage to surrounding tissues. Tissue was harvested 4 h post‐injury and on days 3, 14, and 21; contralateral left knees served as controls. Histological, immunohistochemical, and gene analyzes were performed to evaluate inflammatory and degenerative changes. Immunohistochemistry revealed time‐dependent expression of mature (F4/80 positive) and inflammatory (CD11b positive) macrophage populations within the sub‐synovial infiltrate, developing osteophytes, and inflammation surrounding the ACL in response to injury. Up‐regulation of genes encoding acute pro‐inflammatory markers, inducible nitric oxide synthase, interleukin‐6 and interleukin‐17, and the matrix degrading enzymes, ADAMTS‐4 and MMP3 was detected in femoral cartilage, concomitant with extensive cartilage damage and bone remodelling over 21‐days post‐injury. Our non‐invasive model describes pathologically distinct phases of the disease, increasing our understanding of inflammatory episodes, the tissues/cells producing inflammatory mediators and the early molecular changes in the joint, thereby defining the early phenotype of PTOA. This knowledge will guide appropriate interventions to delay or arrest disease progression following joint injury. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 36:2118–2127, 2018.     

Relationship between altered knee kinematics and subchondral bone remodeling in a clinically translational model of ACL injury

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.     

Single intra‐articular dexamethasone injection immediately post‐surgery in a rabbit model mitigates early inflammatory responses and post‐traumatic osteoarthritis‐like alterations

Despite surgical reconstruction of the anterior cruciate ligament, a significant number of patients will still develop post‐traumatic osteoarthritis (PTOA). Our objective was to determine if mitigating aspects of the acute phase of inflammation following a defined knee surgery with a single administration of a glucocorticoid could prevent the development of PTOA‐like changes within an established rabbit model of surgically induced PTOA. An early and late post‐surgical time‐point was investigated in this study (48 h and 9 weeks post‐surgery) in which the following groups were repeated (each n = 6, for a total of 24 rabbits per time‐point, and 48 rabbits used in the study): control (age/sex matched), sham (arthrotomy), drill injury (arthrotomy + two drill holes to a non‐cartilaginous area of the femoral notch), and drill injury + single intra‐articular (IA) injection of dexamethasone (DEX). At 48 h post‐surgery, DEX treatment significantly lowered the mRNA levels for a subset of pro‐inflammatory mediators, and significantly lowered the histological grade. Nine weeks post surgery, DEX treatment significantly lowered the histological scores (presented as effect size) for synovium (3.8), lateral femoral condyle (3.9), and lateral tibial cartilage (5.1) samples. Thus, DEX likely acts to prevent injury induced inflammation that could contribute to subsequent joint damage. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1826–1834, 2015.     

Joint loads resulting in ACL rupture: Effects of age,sex, and body mass on injury load and mode of failure in a mouse model

Anterior cruciate ligament (ACL) tears are a common knee injury with a known but poorly understood association with secondary joint injuries and post‐traumatic osteoarthritis (OA). Female sex and age are known risk factors for ACL injury but these variables are rarely explored in mouse models of injury. This study aimed to further characterize a non‐surgical ACL injury model to determine its clinical relevance across a wider range of mouse specifications. Cadaveric and anesthetized C57BL/6 mice (9–52 weeks of age) underwent joint loading to investigate the effects of age, sex, and body mass on ACL injury mechanisms. The ACL injury load (whole joint load required to rupture the ACL) was measured from force‐displacement data, and mode of failure was assessed using micro‐dissection and histology. ACL injury load was found to increase with body mass and age (p < 0.001) but age was not significant when controlling for mass. Sex had no effect. In contrast, the mode of ACL failure varied with both age and sex groups. Avulsion fractures (complete or mixed with mid‐substance tears) were common in all age groups but the proportion of mixed and mid‐substance failures increased with age. Females were more likely than males to have a major avulsion relative to a mid‐substance tear (p < 0.01). This data compliments studies in human cadaveric knees, and provides a basis for determining the severity of joint injury relative to a major ACL tear in mice, and for selecting joint loading conditions in future experiments using this model. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1754–1763, 2017.

     

Longitudinal Effects of Acute Anterior Cruciate Ligament Tears on Peri‐Articular Bone in Human Knees Within the First Year of Injury

Anterior cruciate ligament (ACL) tears are common sports‐related knee injuries that increase the risk of developing post‐traumatic osteoarthritis. ACL tears are rarely an isolated injury but are often associated with traumatic bone marrow lesions (BMLs). While early loss of bone mass following the ACL injury has been previously described, to date, microarchitectural information has not been reported due to the limited resolution of clinical imaging systems. In this study, we provide the first evidence of detailed bone mass and microarchitectural changes in the first 10 months following an acute ACL tear, and localized to traumatic BMLs. Fifteen participants with an acute unilateral ACL tear were assessed at four‐time points using dual‐energy X‐ray absorptiometry and high‐resolution peripheral quantitative computed tomography, and traumatic BMLs were identified with magnetic resonance imaging. Loss of bone mass was localized to the injured knee (?4.6% to ?15.8%, depending on bone and depth) and was accelerated immediately following the injury before suggesting a recovery phase. This loss of bone was accelerated even greater in traumatic BMLs (?18.2% to ?20.6%, depending on bone). Bone loss was accompanied by microstructural degeneration of trabecular bone. For example, in the lateral femur of the injured knee, the subchondral bone plate decreased in thickness (?9.0%). This study confirmed loss of bone mass in the months following ACL tears and described the underlying bone microstructural changes. The presented bone changes were accelerated in regions of traumatic BMLs. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2325–2336, 2019     

Acute Changes in NADPH Oxidase 4 in Early Post‐Traumatic Osteoarthritis

Knee injuries cause structural damage and acute inflammation that initiates the development of post‐traumatic osteoarthritis (PTOA). NADPH oxidase 4 (Nox4), a member of a family of enzymes that generates reactive oxygen species (ROS), plays a pivotal role in normal development of the musculoskeletal system, but may increase ROS production to harmful levels after joint injury. The role of ROS in both normal joint homeostasis and injury is poorly understood, but inhibition of excessive ROS production by Nox4 after joint injury could be protective to the joint, decreasing oxidative stress, and initiation of PTOA. Knee injuries were simulated using inflammatory cytokines in cultured primary human chondrocytes and a non‐invasive mouse model of PTOA in C57BL/6N and Nox4 knockout mice. There is an acute decrease in Nox4 activity within 24 h after injury in both systems, followed by a subsequent sustained low‐level increase, a novel finding not seen in any other system. Inhibition of Nox4 activity by GKT137831 was protective against early structural changes after non‐invasive knee injury in a mouse model. Nox4 knockout mice had significant differences in structural and mechanical properties of bone, providing further evidence for the role of Nox4 in development of joint tissues and biochemical response after joint injury. Nox4 plays a significant role in the acute phase after joint injury, and targeted inhibition of inflammation caused by Nox4 may be protective against early joint changes in the pathogenesis of PTOA. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2429–2436, 2019     

The effects of graft width and graft laxity on the outcome of caprine anterior cruciate ligament reconstruction.

We studied how initial graft size and initial graft laxity affected the biomechanics of anterior cruciate ligament (ACL) reconstruction at six months. Sixteen goats had bilateral reconstructions staged eight weeks apart. Autografts 4 and 7 mm wide were taken from the central patellar tendon (PT). Lax grafts were created by adding 4 mm slack to the graft before fixing. We reconstructed each joint using a combination of width and laxity treatments. Both factors were changed for the contralateral joint and all combinations appeared with equal frequency. At six months we measured the joint extension limit, anterior-posterior (AP) translation, and osteoarthritic changes. The grafts were then tested to failure to determine their mechanical properties. After six months the difference in initial treatments had disappeared: there was no difference in graft cross-section due to the different initial widths and there was no difference in joint AP translation due to the initial graft laxity. We did observe that wide grafts were associated with a block to extension, decreased joint AP translation, and increased articular cartilage damage and osteophyte formation. While AP translation was reduced, it was correlated with decreased extension, possibly indicating an increase in scar tissue formation rather than a more functional graft. Neither graft width nor graft laxity produced differences in any graft mechanical properties. This suggests that the use of larger grafts to prevent increased AP translation has undesirable complications. Ultimately, we conclude that neither of these surgical treatments strongly affects the biomechanical result of caprine ACL reconstruction.     

Early inhibition of subchondral bone remodeling slows load-induced posttraumatic osteoarthritis development in mice

Posttraumatic osteoarthritis (PTOA) is associated with abnormal and increased subchondral bone remodeling. Inhibiting altered remodeling immediately following joint damage can slow PTOA progression. Clinically, however, inhibiting remodeling when significant joint damage is already present has minimal effects in slowing further disease progression. We sought to determine the treatment window following PTOA initiation in which inhibiting remodeling can attenuate progression of joint damage. We hypothesized that the most effective treatment would be to inhibit remodeling immediately after PTOA initiation. We used an animal model in which a single bout of mechanical loading was applied to the left tibia of 26-week-old male C57Bl/6 mice at a peak load of 9 N to initiate load-induced PTOA development. Following loading, we inhibited bone remodeling using daily alendronate (ALN) treatment administered either immediately or with 1 or 2 weeks' delay up to 3 or 6 weeks post-loading. A vehicle (VEH) treatment group controlled for daily injections. Cartilage and subchondral bone morphology and osteophyte development were analyzed and compared among treatment groups. Inhibiting remodeling using ALN immediately after load-induced PTOA initiation reduced cartilage degeneration, slowed osteophyte formation, and preserved subchondral bone volume compared to VEH treatment. Delaying the inhibition of bone remodeling at 1 or 2 weeks similarly attenuated cartilage degeneration at 6 weeks, but did not slow the development of osteoarthritis (OA)-related changes in the subchondral bone, including osteophyte formation and subchondral bone erosions. Immediate inhibition of subchondral bone remodeling was most effective in slowing PTOA progression across the entire joint, indicating that abnormal bone remodeling within the first week following PTOA initiation played a critical role in subsequent cartilage damage, subchondral bone changes, and overall joint degeneration. These results highlight the potential of anti-resorptive drugs as preemptive therapies for limiting PTOA development after joint injury, rather than as disease-modifying therapies after joint damage is established. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Platelet‐rich plasma alone is not sufficient to enhance suture repair of the ACL in skeletally immature animals: An in vivo study

In this study, we hypothesize that supplementation of suture repair of the anterior cruciate ligament (ACL) with platelet‐rich plasma (PRP) will improve the biomechanics of the repair. Six 30‐kg pigs underwent bilateral suture repair of the ACL. One side was treated with suture repair alone, while the contralateral side was treated with suture repair augmented with PRP. After 14 weeks in vivo, anterior–posterior (AP) knee laxity and the tensile properties of the repaired ligament were measured. The addition of PRP to the suture repairs did not improve AP knee laxity at 30° (p = 0.73) or 60° (p = 0.65). It also did not improve the maximum tensile load (p = 0.64) or linear stiffness (p = 0.42) of the ACL repairs after 14 weeks in vivo. The model had 80% power to detect a 30% improvement of biomechanical properties with PRP; thus, we are confident that a clinically meaningful effect as a result of adding PRP is unlikely. Use of PRP alone to supplement suture repair of the ACL is ineffective in this animal model. Published by Wiley Periodicals, Inc. J Orthop Res 27: 639–645, 2009     

Anterior cruciate ligament injury versus tibial spine fracture in the skeletally immature knee: a comparison of skeletal maturation and notch width index

Both midsubstance anterior cruciate ligament (ACL) injury and tibial spine avulsion fracture occur in the skeletally immature knee. The purpose of this study was to determine whether there are differences in skeletal maturation or notch parameters between these two groups. A retrospective case-control study of 25 skeletally immature patients with tibial spine fractures compared with 25 age- and sex-matched skeletally immature patients with midsubstance ACL injuries was performed. Bone age and notch width index were determined from preoperative radiographs. There were no significant differences between the tibial spine fracture group and the ACL injury group with respect to skeletal maturation, comparing bone age to chronological age (-0.5 vs. -0.3 years; P = 0.617). The ACL injury group had narrower notch indices than the tibial spine fracture group (0.230 vs. 0.253; P = 0.020). Thus, in a comparison of age- and sex-matched skeletally immature patients, those with midsubstance ACL injuries had a significantly narrower notch index than those with tibial spine fractures. This association may account for some of the variation in injury patterns in the skeletally immature knee.     

SOST/Sclerostin Improves Posttraumatic Osteoarthritis and Inhibits MMP2/3 Expression After Injury

Patients with anterior cruciate ligament (ACL) rupture are two times as likely to develop posttraumatic osteoarthritis (PTOA). Annually, there are ～900,000 knee injuries in the United States, which account for ～12% of all osteoarthritis (OA) cases. PTOA leads to reduced physical activity, deconditioning of the musculoskeletal system, and in severe cases requires joint replacement to restore function. Therefore, treatments that would prevent cartilage degradation post‐injury would provide attractive alternatives to surgery. Sclerostin (Sost), a Wnt antagonist and a potent negative regulator of bone formation, has recently been implicated in regulating chondrocyte function in OA. To determine whether elevated levels of Sost play a protective role in PTOA, we examined the progression of OA using a noninvasive tibial compression overload model in SOST transgenic (SOST^TG) and knockout (Sost^‐/‐) mice. Here we report that SOST^TG mice develop moderate OA and display significantly less advanced PTOA phenotype at 16 weeks post‐injury compared with wild‐type (WT) controls and Sost^‐/‐. In addition, SOST^TG built ～50% and ～65% less osteophyte volume than WT and Sost^‐/‐, respectively. Quantification of metalloproteinase (MMP) activity showed that SOST^TG had ～2‐fold less MMP activation than WT or Sost^‐/‐, and this was supported by a significant reduction in MMP2/3 protein levels, suggesting that elevated levels of SOST inhibit the activity of proteolytic enzymes known to degrade articular cartilage matrix. Furthermore, intra‐articular administration of recombinant Sost protein, immediately post‐injury, also significantly decreased MMP activity levels relative to PBS‐treated controls, and Sost activation in response to injury was TNFα and NF‐κB dependent. These results provide in vivo evidence that sclerostin functions as a protective molecule immediately after joint injury to prevent cartilage degradation. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

Can suture repair of ACL transection restore normal anteroposterior laxity of the knee? An ex vivo study

Recent work has suggested the transected anterior cruciate ligament (ACL) can heal and support reasonable loads if repaired with sutures and a bioactive scaffold; however, use of a traditional suture configuration results in knees with increased anterior–posterior (AP) laxity. The objective was to determine whether one of five different suture repair constructs when performed at two different joint positions would restore normal AP knee laxity. AP laxity of the porcine knee at 60° of flexion was evaluated for five suture repair techniques. Femoral fixation for all repair techniques utilized a suture anchor. Primary repair was to either the tibial stump, one of three bony locations in the ACL footprint, or a hybrid bony fixation. All five repairs were tied with the knee in first 30° and then 60° of flexion for a total of 10 repair constructs. Suture repair to bony fixation points within the anterior half of the normal ACL footprint resulted in knee laxity values within 0.5 mm of the ACL‐intact joint when the sutures were tied with the knee at 60° flexion. Suture repair to the tibial stump, or with the knee at 30° of flexion, did not restore normal AP laxity of the knee. Three specific suture repair techniques for the transected porcine ACL restored the normal AP laxity of the knee at the time of surgery. Additional studies defining the changes in laxity with cyclic loading and in vivo healing are indicated. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:1500–1505, 2008     

Organ‐level histological and biomechanical responses from localized osteoarticular injury in the rabbit knee

The processes of whole‐joint osteoarthritis development following localized joint injuries are not well understood. To demonstrate this local‐to‐global linkage, we hypothesized that a localized osteoarticular injury in the rabbit knee would not only cause biomechanical and histological abnormalities in the involved compartment but also concurrent histological changes in the noninvolved compartment. Twenty rabbits had an acute osteoarticular injury that involved localized joint incongruity (a 2‐mm osteochondral defect created in the weight‐bearing area of the medial femoral condyle), while another 20 received control sham surgery. At the time of euthanasia at 8 or 16 weeks post‐surgery, the experimental knees were subjected to sagittal‐plane laxity measurement, followed by cartilage histo‐morphological evaluation using the Mankin score. The immediate effects of defect creation on joint stability and contact mechanics were explored in concomitant rabbit cadaver experimentation. The injured animals had cartilage histological scores significantly higher than in the sham surgery group (p < 0.01) on the medial femoral, medial tibial, and lateral femoral surfaces (predominantly on the medial surfaces), accompanied by slight (mean 20%) increase of sagittal‐plane laxity. Immediate injury‐associated alterations in the medial compartment contact mechanics were also demonstrated. Localized osteoarticular injury in this survival animal model resulted in global joint histological changes. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:340–346, 2011     

Local administration of alendronate reduced peri‐tunnel bone loss and promoted graft‐bone tunnel healing with minimal systemic effect on bone in contralateral knee

Continued systemic administration of alendronate was reported to reduce peri‐tunnel bone resorption and promoted graft‐bone tunnel healing at the early stage post‐anterior cruciate ligament (ACL) reconstruction. However, systemic increase in bone mineral density (BMD) in the contralateral intact knee was observed. We tested if single local administration of alendronate into the bone tunnel during ACL reconstruction could achieve similar benefits yet without the systemic effect on bone. Seventy‐two rats with unilateral ACL reconstruction were divided into three groups: saline, low‐dose (6 μg/kg) and mid‐dose (60 μg/kg) alendronate. For local administration, alendronate was applied to the bone tunnels for 2 min before graft insertion and repair. At weeks 2 and 6, the reconstructed complex was harvested for high‐resolution computed tomography (vivaCT) imaging followed by biomechanical test or histology. Our results showed that local administration of low‐dose alendronate showed comparable benefits on the reduction of peri‐tunnel bone loss, enhancement of bone tunnel mineralization, tunnel graft integrity, graft osteointegration and mechanical strength of the reconstructed complex at early stage post‐reconstruction, yet with minimal systemic effect on mineralized tissue at the contralateral intact knee. A single local administration of alendronate at the low‐dose therefore might be used to promote early tunnel graft healing post‐reconstruction. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1897–1906, 2013     

Biochemical markers of cartilage metabolism are associated with walking biomechanics 6‐months following anterior cruciate ligament reconstruction

The purpose of our study was to determine the association between biomechanical outcomes of walking gait (peak vertical ground reaction force [vGRF], vGRF loading rate [vGRF‐LR], and knee adduction moment [KAM]) 6 months following anterior cruciate ligament reconstruction (ACLR) and biochemical markers of serum type‐II collagen turnover (collagen type‐II cleavage product to collagen type‐II C‐propeptide [C2C:CPII]), plasma degenerative enzymes (matrix metalloproteinase‐3 [MMP‐3]), and a pro‐inflammatory cytokine (interleukin‐6 [IL‐6]). Biochemical markers were evaluated within the first 2 weeks (6.5 ± 3.8 days) following ACL injury and again 6 months following ACLR in eighteen participants. All peak biomechanical outcomes were extracted from the first 50% of the stance phase of walking gait during a 6‐month follow‐up exam. Limb symmetry indices (LSI) were used to normalize the biomechanical outcomes in the ACLR limb to that of the contralateral limb (ACLR/contralateral). Bivariate correlations were used to assess associations between biomechanical and biochemical outcomes. Greater plasma MMP‐3 concentrations after ACL injury and at the 6‐month follow‐up exam were associated with lesser KAM LSI. Lesser KAM was associated with greater plasma IL‐6 at the 6‐month follow‐up exam. Similarly, lesser vGRF‐LR LSI was associated with greater plasma MMP‐3 concentrations at the 6‐month follow‐up exam. Lesser peak vGRF LSI was associated with higher C2C:CPII after ACL injury, yet this association was not significant after accounting for walking speed. Therefore, lesser biomechanical loading in the ACLR limb, compared to the contralateral limb, 6 months following ACLR may be related to deleterious joint tissue metabolism that could influence future cartilage breakdown. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2288–2297, 2017.

     

A comparison of joint stability between anterior cruciate intact and deficient knees: a new canine model of anterior cruciate ligament disruption.

Transection of the canine anterior cruciate ligament (ACL) is a well-established osteoarthritis (OA) model. This study evaluated a new method of canine ACL disruption as well as canine knee joint laxity and joint capsule (JC) contribution to joint stability at two time points (16 and 26 weeks) after ACL disruption (n=5/time interval). Ten crossbreed hounds were evaluated with force plate gait analysis and radiographs at intervals up to 34 weeks after monopolar radiofrequency energy (MRFE) treatment of one randomly selected ACL. Each contralateral ACL was sham treated. The MRFE treated ACLs ruptured approximately eight weeks (mean 52.5 days, SEM+/-1.0, range 48-56 days) after treatment. Gait analysis and radiographic changes were consistent with established canine ACL transection models of OA. Anterior-posterior (AP) translation and medial-lateral (ML) rotation were measured in each knee at 30 degrees, 60 degrees, and 90 degrees of flexion with and then without JC with loads of 40 N in AP translation and 4 Nm in ML rotation. A statistically significant interaction in AP translation included JC by cruciate (P=0.02), and there was a trend for a cruciate by time (P=0.07) interaction. Significant interactions in ML rotational testing included the presence of joint capsule (P=0.0001) and angle by cruciate (P=0.0012). This study describes a model in which canine ACLs predictably rupture approximately eight weeks after arthroscopic surgery and details the contribution of JC to canine knee stability in both ACL intact and deficient knees. The model presented here avoids the introduction of potential surgical variables at the time of ACL rupture and may contribute to studies of OA pathogenesis and inhibition. This model may also be useful for insight into the pathologic changes that occur in the knee as the ACL undergoes degeneration prior to rupture.     

Characterization of Post-Traumatic Osteoarthritis in Rats Following Anterior Cruciate Ligament Rupture by Non-Invasive Knee Injury (NIKI)

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     

An unusual rotational injury: pantibial ligamentous injury

Pantibial ligamentous injury including knee dislocation and tibiotalar joint subluxation is an uncommon severe rotational injury. A 21-year-old male injured his right knee falling from a motorcycle. Physical examination revealed effusion on the right knee and ankle, and posterior translation of the tibia as well. The MRI of the right knee and ankle demonstrated the following findings: a complete disruption of cruciate ligaments, the medial collateral ligament, posteromedial corner injury together with a peripheric tear in the medial meniscus, the ruptured deltoid ligament, ankle syndesmosis space widening (>5 mm) and lateral subluxation of talus. Deltoid ligament of the right ankle was repaired and ankle syndesmosis was fixed with a cortical screw. The PCL and ACL were reconstructed arthroscopically with autogeneous bone-patellar tendon-bone graft. The midsubstance tear of MCL, posteromedial corner and medial meniscus tear were primarily repaired with nonabsorbable sutures. 3 years after the surgery, the patient was called for the final examination. MRI and X-ray findings of the knee and ankle joint demonstrated the continuity of ACL, PCL, MCL, and deltoid ligament. The patient, who is a farmer, can go back to his job and perform his daily activities. We presented a previously unreported case that involves both simultaneous occurrence of knee dislocation and tibiotalar joint subluxation. We used the term “Pantibial ligamentous injury” for this case.     

Effect of tension and placement of a prosthetic anterior cruciate ligament on the anteroposterior laxity of the knee.

We wished to determine the optimal tension required to restore normal joint laxity to anterior cruciate ligament (ACL)-deficient knees using a braided polyethylene ACL prosthesis (PACL). In 10 cadaveric specimens, we measured the anteroposterior (AP) laxity of the intact knee at 10 degrees, 30 degrees, 60 degrees, and 90 degrees of flexion. The ACL was then removed and replaced with the PACL using tunnel-tunnel (T-T) and "over-the-top" (OTT) placement techniques. In both positions, the PACL was initially tensioned to 0, 9, 18, and 27 N with the knee flexed to 30 degrees. AP joint laxity was then measured at each flexion angle. With an increase in initial tension, there was a corresponding decrease in AP laxity. At 30 degrees and 90 degrees of flexion, AP laxity was not significantly different from normal using T-T placement and an initial tension of 0 N. At 90 degrees of flexion, AP laxity was not significantly different from normal using OTT placement at 0 or 9 N of initial tension. For both positions, all other tension levels and flexion angles constrained AP laxity. No laxity differences were detected between the OTT and T-T positions at any flexion angle. The variability in AP laxity of the T-T position was significantly greater than OTT. With a 150-N anterior shear force applied to the proximal tibia, the maximum tensions developed in the PACL were not significantly different between the two positions except at 90 degrees. The results suggest that implantation of the PACL is best performed using OTT positioning with an initial tension of 0 N applied at 30 degrees of knee flexion.     

Joint instability and cartilage compression in a mouse model of posttraumatic osteoarthritis

Joint instability and cartilage trauma have been previously studied and identified as key mediators in the development of posttraumatic osteoarthritis (PTOA). The purpose of this study was to use an in vivo model to compare the effect of joint instability, caused by the rupture of the anterior cruciate ligament (ACL), versus cartilage compression. In this study, mice were subjected to cyclical axial loads of twelve Newtons (N) for 240 cycles or until the ACL ruptured. One and eight weeks after this procedure, knees were sectioned coronally and evaluated for osteoarthritis by histology. Using a scoring scale established by [Pritzker K, Gay S, Jimenez S, et al. (2006): Osteoarthritis Cartilage 14:13–29], the articular cartilage across each surface was scored and combined to produce a total degeneration score. The ACL‐ruptured group had a significantly greater total degeneration score than either control or compression treated joints at 1 and 8 weeks. Additionally, only sections from ACL‐ruptured knees consistently showed synovitis after 1 week and osteophyte formation after 8 weeks. Thus, it appears using that ACL rupture consistently creates a severe osteoarthritis phenotype, while axial cartilage compression alone does not appear to be an appropriate method of inducing PTOA in vivo. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:318–323, 2014.