IL-1Ra gene transfer potentiates BMP2-mediated bone healing by redirecting osteogenesis toward endochondral ossification.

An estimated 100,000 patients each year in the United States suffer severe disability from bone defects that fail to heal, a condition where bone-regenerative therapies could provide substantial clinical benefits. Although recombinant human bone morphogenetic protein-2 (rhBMP2) is an osteogenic growth factor that is clinically approved for this purpose, it is only effective when used at exceedingly high doses that incur substantial costs, induce severe inflammation, produce adverse side effects, and form morphologically abnormal bone. Using a validated rat femoral segmental defect model, we show that bone formed in response to clinically relevant doses of rhBMP2 is accompanied by elevated expression of interleukin-1 (IL-1). Local delivery of cDNA encoding the IL-1 receptor antagonist (IL-1Ra) achieved bridging of segmental, critical size defects in bone with a 90% lower dose of rhBMP2. Unlike use of high-dose rhBMP2, bone formation in the presence of IL-1Ra occurred via the native process of endochondral ossification, resulting in improved quality without sacrificing the mechanical properties of the regenerated bone. Our results demonstrate that local immunomodulation may permit effective use of growth factors at lower doses to recapitulate more precisely the native biology of healing, leading to higher-quality tissue regeneration.

Gene Delivery to Chondrocytes.

Delivering genes to chondrocytes offers new possibilities both clinically, for treating conditions that affect cartilage, and in the laboratory, for studying the biology of chondrocytes. Advances in gene therapy have created a number of different viral and non-viral vectors for this purpose. These vectors may be deployed in an ex vivo fashion, where chondrocytes are genetically modified outside the body, or by in vivo delivery where the vector is introduced directly into the body; in the case of articular and meniscal cartilage in vivo delivery is typically by intra-articular injection. Ex vivo delivery is favored in strategies for enhancing cartilage repair as these can be piggy-backed on existing cell-based technologies, such as autologous chondrocyte implantation, or used in conjunction with marrow-stimulating techniques such as microfracture. In vivo delivery to articular chondrocytes has proved more difficult, because the dense, anionic, extra-cellular matrix of cartilage limits access to the chondrocytes embedded within it. As Grodzinsky and colleagues have shown, the matrix imposes strict limits on the size and charge of particles able to diffuse through the entire depth of articular cartilage. Empirical observations suggest that the larger viral vectors, such as adenovirus (~100 nm), are unable to transduce chondrocytes in situ following intra-articular injection. However, adeno-associated virus (AAV; ~25 nm) is able to do so in horse joints. AAV is presently in clinical trials for arthritis gene therapy, and it will be interesting to see whether human chondrocytes are also transduced throughout the depth of cartilage by AAV following a single intra-articular injection. Viral vectors have been used to deliver genes to the intervertebral disk but there has been little research on gene transfer to chondrocytes in other cartilaginous tissues such as nasal, auricular or tracheal cartilage.

Neuromuscular Training Improves Biomechanical Deficits at the Knee in Anterior Cruciate Ligament-Reconstructed Athletes.

OBJECTIVE: Athletes who return to sport after anterior cruciate ligament reconstruction (ACLR) demonstrate persistent biomechanical and neuromuscular deficits of the knee. There is limited evidence on what effect a neuromuscular training (NMT) program has on knee biomechanics in a cohort of athletes with ACLR. Therefore, the primary aim of this study was to quantify the effect of an NMT program on knee biomechanics in a cohort of ACLR athletes. Second, the post-training knee biomechanics were compared between the cohort of ACLR and control athletes. DESIGN: Cohort study. SETTING: Controlled laboratory setting. PARTICIPANTS: Eighteen athletes with ACLR and 10 control athletes. INTERVENTIONS: Neuromuscular training. MAIN OUTCOME MEASURES: Knee kinematics and kinetics during a double-limb jump-landing task. RESULTS: There were no significant interactions (P > 0.05) observed for the athletes with ACLR. However, there was a significant main effect of biomechanics testing session (P < 0.05) for knee flexion angle and moments; athletes with ACLR demonstrated greater knee flexion angle and lower knee flexion moment during the post-training biomechanics testing session. Post-training comparison between the ACLR and control athletes demonstrated no significant interactions (P > 0.05) between the groups. There was a significant main effect of group (P < 0.05) for knee frontal angle, as athletes with ACLR landed with greater knee adduction than the control athletes. CONCLUSIONS: Significant improvements in knee sagittal plane biomechanical measures were observed after the NMT program by the athletes with ACLR. In addition, post-training comparison of the ACLR and control groups demonstrates comparable knee biomechanics.

Knee Biomechanical Deficits During a Single-Leg Landing Task Are Addressed With Neuromuscular Training in Anterior Cruciate Ligament-Reconstructed Athletes.

OBJECTIVE: Faulty neuromuscular and biomechanical deficits of the knee are nearly ubiquitous in athletes after anterior cruciate ligament (ACL) reconstruction (ACLR). Knee biomechanical deficits are directly associated with an increased risk of second ACL injury, which typically occurs during a sports-related movement on a single limb. To date, the biomechanical effects of a neuromuscular training (NMT) program on knee biomechanics during a single-leg landing task have not been investigated. DESIGN: Prospective Cohort Study. SETTING: Controlled laboratory setting. PARTICIPANTS: Eighteen ACLR and 10 control athletes. INTERVENTIONS: Neuromuscular training. MAIN OUTCOME MEASURES: Knee kinematics and kinetics. RESULTS: There were no significant interactions of session and limb (P > 0.05) for the athletes with ACLR after training. However, there were several significant main effects of session (P < 0.05) for knee kinematics and kinetics during the single-leg landing task. After training, the athletes with ACLR landed with greater knee flexion angles, decreased knee abduction angles, increased knee flexion range of motion, and decreased knee excursion. Also, the ACLR athletes landed with lower knee flexion moments, greater knee adduction moments, and lower peak vertical ground reaction force. Post-training comparison of the ACLR and control cohorts found no significant interactions of group and limb (P > 0.05) and only a significant main effect of group (P < 0.05) for frontal plane knee angle at initial contact. The athletes with ACLR landed with greater knee adduction angles than the control group. CONCLUSIONS: Deficits in knee biomechanics that are associated with an increased risk of ACL injury are attenuated after completion of this NMT program.

Minimum 10-Year Outcomes of Matrix-Induced Autologous Chondrocyte Implantation in the Knee: A Systematic Review.

BACKGROUND: Matrix-induced autologous chondrocyte implantation (MACI) is an established cell-based therapy for the treatment of chondral defects of the knee. As long-term outcomes are now being reported in the literature, it is important to systematically review available evidence to better inform clinical practice. PURPOSE: To report (1) subjective patient-reported outcomes (PROs) and (2) the rate of graft failure, reoperation, and progression to total knee arthroplasty (TKA) after undergoing MACI of the knee at a minimum 10-year follow-up. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A comprehensive search of Ovid MEDLINE and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily; Ovid Embase; Ovid Cochrane Central Register of Controlled Trials; Ovid Cochrane Database of Systematic Reviews; and Scopus from 2008 to September 15, 2022, was conducted in the English language. Study eligibility criteria included (1) full-text articles in the English language, (2) patients undergoing a MACI within the knee, (3) clinical outcomes reported, and (4) a minimum 10-year follow-up. RESULTS: In total, 168 patients (99 male, 69 female; mean age, 37 years [range, 15-63 years]; mean body mass index, 26.2 [range, 18.6-39.4]) representing 188 treated chondral defects at a minimum 10-year follow-up after MACI were included in this review. Significant and durable long-term improvements were observed across multiple PRO measures. Follow-up magnetic resonance imaging (MRI), when performed, also demonstrated satisfactory defect fill and an intact graft in the majority of patients. The all-cause reoperation rate was 9.0%, with an overall 7.4% rate of progression to TKA at 10 to 17 years of follow-up. CONCLUSION: At a minimum 10-year follow-up, patients undergoing MACI for knee chondral defects demonstrated significant and durable improvements in PROs, satisfactory defect fill on MRI-based assessment, and low rates of reoperation and TKA. These data support the use of MACI as a long-term treatment of focal cartilage defects of the knee.

Primary Hip Arthroscopy in Patients With Acetabular Dysplasia: A Systematic Review of Published Clinical Outcomes at Minimum 5-Year Follow-up.

BACKGROUND: Hip arthroscopy in patients with borderline hip dysplasia has satisfactory outcomes at short-term follow-up; however, the data on midterm outcomes are inconsistent, and failure rates are high in some studies, limiting understanding of the role and utility of hip arthroscopy in this patient cohort. PURPOSE: To provide an up-to-date, evidence-based review of the clinical outcomes of primary hip arthroscopy in patients with frank or borderline hip dysplasia at ≥5-year follow-up and report the failure rate and progression to total hip arthroplasty in this cohort. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A comprehensive literature search was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Studies were included if they evaluated outcomes of primary hip arthroscopy in patients with lateral center-edge angle (LCEA) <25° at ≥5-year follow-up. Risk of bias assessment was performed using the methodological index for non-randomized studies scoring system. Level of evidence was determined using criteria from the Oxford Centre for Evidence-Based Medicine. RESULTS: Nine studies were included in this review. Patients with LCEA <25° demonstrated satisfactory clinical outcomes, high patient satisfaction, and significant postoperative improvements in patient-reported outcomes (PROs) at follow-up ranging from a ≥5 to 10 years. Studies comparing patients with dysplasia to those without did not demonstrate significant differences in preoperative, postoperative, or delta PROs or in failure, reoperation, or revision rates. There was no overall significant correlation between outcomes and LCEA stratification. CONCLUSION: Hip arthroscopy in carefully selected patients with LCEA <25° can be successful at mid- to long-term follow-up and may provide clinical outcomes and failure rates comparable with patients with normal LCEA, understanding that this is a singular, 2-dimensional radiographic measure that does not differentiate instability from impingement or combinations thereof, warranting future studies delineating these differences. These findings suggest that hip dysplasia may not be an absolute contraindication for isolated hip arthroscopy and may serve as a viable intervention with consideration of staged future periacetabular osteotomy (PAO). Importantly, this review does not suggest that hip arthroscopy alters the natural history of dysplasia; therefore, patients with dysplasia should be counseled on the potential utility of PAO by appropriate hip preservation specialists.

Viral Gene Delivery in Chondrocytes.

Viral gene transfer, known as transduction, is a powerful research tool for studying the biology of chondrocytes in novel ways and also a technology enabling the use of gene therapy for regenerating cartilage and treating diseases that affect cartilage, such as osteoarthritis. Adenovirus, retrovirus, lentivirus, and adeno-associated virus (AAV) are most commonly used to transduce chondrocytes. Although AAV is able to transduce chondrocytes in situ by intra-articular injection, chondrocytes are most commonly transduced in monolayer culture using the four vectors mentioned above. Protocols for achieving this are described, along with a discussion of the variables that can influence transduction efficiency.

Transcriptomic changes during the replicative senescence of human articular chondrocytes.

Osteoarthritis (OA) is a degenerative joint disease and a leading cause of disability worldwide. Aging is a major risk factor for OA, but the specific mechanisms underlying this connection remain unclear. Although chondrocytes rarely divide in adult articular cartilage, they undergo replicative senescence in vitro which provides an opportunity to study changes related to aging under controlled laboratory conditions. In this pilot study, we performed bulk RNA sequencing on early- and late-passage human articular chondrocytes to identify transcriptomic changes associated with cellular aging. Chondrocytes were isolated from the articular cartilage of three donors, two with OA (age 70-80 years) and one with healthy cartilage (age 26 years). Chondrocytes were serially passaged until replicative senescence and RNA extracted from early- and late-passage cells. Principal component analysis of all genes showed clear separation between early- and late-passage chondrocytes, indicating substantial age-related differences in gene expression. Differentially expressed genes (DEGs) analysis confirmed distinct transcriptomic profiles between early- and late-passage chondrocytes. Hierarchical clustering revealed contrasting expression patterns between the two isolates from osteoarthritic samples and the healthy sample. Focused analysis of DEGs on transcripts associated with turnover of the extra-cellular matrix and the senescence-associated secretory phenotype (SASP) showed consistent downregulation of Col2A1 and ACAN, and upregulation of MMP19, ADAMTS4, and ADAMTS8 in late passage chondrocytes across all samples. SASP components including IL-1α, IL-1ß, IL-6, IL-7, p16INK4A (CDKN2A) and CCL2 demonstrated significant upregulation in late passage chondrocytes originally isolated from OA samples. Pathway analysis between sexes with OA revealed shared pathways such as extracellular matrix (ECM) organization, collagen formation, skeletal and muscle development, and nervous system development. Sex-specific differences were observed, with males showing distinctions in ECM organization, regulation of the cell cycle process as well as neuron differentiation. In contrast, females exhibited unique variations in the regulation of the cell cycle process, DNA metabolic process, and the PID-PLK1 pathway.

Segmental defect healing in the presence or absence of recombinant human BMP2: Novel insights from a rat model.

This study defined and compared the course of native, impaired and growth factor-stimulated bone regeneration in a rat femoral defect model. A mid-diaphyseal defect with rigid internal fixation was surgically created in the right femur of male Fischer rats and serially analyzed over 36 weeks. Native bone regeneration was modeled using a sub-critical, 1 mm size defect, which healed uneventfully. Critical size defects of 5 mm were used to analyze impaired bone regeneration. In a third group, the 5 mm defects were filled with 11 µg of recombinant human bone morphogenetic protein 2 (rhBMP2) impregnated onto an absorbable collagen sponge, modeling its clinical use. Native bone regeneration was characterized by endochondral ossification with progressive remodeling to ultimately resemble intact femora. An endochondral response was also observed under conditions of impaired bone regeneration, but by week 8 medullary capping occurred with fibrofatty consolidation of the tissue within the defect, resembling an atrophic non-union. rhBMP2 treatment was associated with prolonged inflammatory cytokine expression and rapid intramembranous bone formation occurring with reduced expression of cartilage-associated collagens. Between weeks 4 and 36, rhBMP2-treated bones demonstrated decreased trabecular number and increased trabecular separation, which resulted in inferior mechanical properties compared with bones that healed naturally. Clinical Significance: Recombinant human bone morphogenetic protein 2 (rhBMP2) is used clinically to promote healing of long bones. Our data suggest that it drives intramembraneous ossification producing an inferior regenerate that deteriorates with time. Clinical outcomes would be improved by technologies favoring endochondral regenerative ossification.

Efficient healing of large osseous segmental defects using optimized chemically modified messenger RNA encoding BMP-2.

Large segmental osseous defects heal poorly. Recombinant, human bone morphogenetic protein-2 (rhBMP-2) is used clinically to promote bone healing, but it is applied at very high doses that cause adverse side effects and raise costs while providing only incremental benefit. We describe a previously unexplored, alternative approach to bone regeneration using chemically modified messenger RNA (cmRNA). An optimized cmRNA encoding BMP-2 was delivered to critical-sized femoral osteotomies in rats. The cmRNA remained orthotopically localized and generated BMP locally for several days. Defects healed at doses ≥25 µg of BMP-2 cmRNA. By 4 weeks, all animals treated with 50 µg of BMP-2 cmRNA had bridged bone defects without forming the massive callus seen with rhBMP-2. Moreover, such defects recovered normal mechanical strength quicker and initiated bone remodeling faster. cmRNA regenerated bone via endochondral ossification, whereas rhBMP-2 drove intramembranous osteogenesis; cmRNA provides an innovative, safe, and highly translatable technology for bone healing.

Expedited gene delivery for osteochondral defect repair in a rabbit knee model: A one-year investigation.

Objective: To evaluate a single-step, gene-based procedure for repairing osteochondral lesions. Design: Osteochondral lesions were created in the patellar groove of skeletally mature rabbits. Autologous bone marrow aspirates were mixed with adenovirus vectors carrying cDNA encoding green fluorescent protein (Ad.GFP) or transforming growth factor-ß1 (Ad.TGF-ß1) and allowed to clot. The clotted marrow was press-fit into the defects. Animals receiving Ad.GFP were euthanized at 2 weeks and intra-articular expression of GFP examined by fluorescence microscopy. Animals receiving Ad.TGF-ß1 were euthanized at 3 months and 12 months; repair was compared to empty defects using histology and immunohistochemistry. Complementary in vitro experiments assessed transgene expression and chondrogenesis in marrow clots and fibrin gels. In a subsequent pilot study, repair at 3 months using a fibrin gel to encapsulate Ad.TGF-ß1 was evaluated. Results: At 2 weeks, GFP expression was seen at variable levels within the cartilaginous lesion. At 3 months, there was no statistically significant improvement (p > 0.05) in healing of lesions receiving Ad.TGF-ß1 and variability was high. At 12 months, there were still no significant difference (p > 0.05) between the empty defects and those receiving Ad.TGF-ß1 in the overall, cartilage, and bone scores. Variability was still high. In vitro experiments suggested that variability reflected variable transduction efficiency and chondrogenic activity of the marrow clots; using fibrin gels instead of marrow may address this issue but more research is needed. Conclusions: This approach to improving the repair of osteochondral lesions needs further refinement to reduce variability and provide a more robust outcome.

The association of psychological readiness to return to sport after anterior cruciate ligament reconstruction and hip and knee landing kinematics.

BACKGROUND: Anterior cruciate ligament tears have a negative psychological impact on athletes. Currently, it is not clear if psychological readiness to return to sport has an impact on an athlete's landing biomechanics. Thus the purpose of the study is to investigate whether there is an association of psychological readiness to return to sport and single-leg landing biomechanics. METHODS: Athletes with an anterior cruciate ligament reconstruction (n = 18) completed the Anterior Cruciate Ligament-Return to Sport after Injury scale to measure psychological readiness to return to sport, knee strength testing, and a single-leg landing task. A multivariate linear regression model was built for the involved and uninvolved limb based on sagittal and frontal plane knee and hip range of motion. Significance was set at p < 0.05. FINDINGS: Knee extensor/flexor strength testing showed significant differences (p < 0.05) between involved and uninvolved limbs. Nearly 40% of the variance in psychological readiness scores (p = 0.025) can be accounted for by the involved limb's frontal plane hip and knee range of motion. Knee frontal plane range of motion was the only significant factor, and the standardized coefficients indicate that greater knee frontal plane range of motion and lower hip frontal plane range of motion were associated with higher psychological readiness. No other associations were found between psychological readiness and sagittal or frontal plane sing-leg biomechanics of the involved or uninvolved limbs. INTERPRETATION: Greater psychological readiness to return to sport is associated with the involved limb's frontal plane knee and hip range of motion during a single-leg landing biomechanics.

Multiplanar Loading of the Knee and Its Influence on Anterior Cruciate Ligament and Medial Collateral Ligament Strain During Simulated Landings and Noncontact Tears.

BACKGROUND: Anterior cruciate ligament (ACL) tears and concomitant medial collateral ligament (MCL) injuries are known to occur during dynamic athletic tasks that place combinatorial frontal and transverse plane loads on the knee. A mechanical impact simulator that produces clinical presentation of ACL injury allows for the quantification of individual loading contributors leading to ACL failure. PURPOSE/HYPOTHESIS: The objective was to delineate the relationship between knee abduction moment, anterior tibial shear, and internal tibial rotation applied at the knee and ACL strain during physiologically defined simulations of impact at a knee flexion angle representative of initial contact landing from a jump. The hypothesis tested was that before ACL failure, abduction moment would induce greater change in ACL strain during landing than either anterior shear or internal rotation. STUDY DESIGN: Controlled laboratory study. METHODS: Nineteen cadaveric specimens were subjected to simulated landings in the mechanical impact simulator. During simulations, external knee abduction moment, internal tibial rotation moment, and anterior tibial shear loads were derived from a previously analyzed in vivo cohort and applied to the knee in varying magnitudes with respect to injury risk classification. Implanted strain gauges were used to track knee ligament displacement throughout simulation. Kruskal-Wallis tests were used to assess strain differences among loading factors, with Wilcoxon each pair post hoc tests used to assess differences of magnitude within each loading. RESULTS: Each loading factor significantly increased ACL strain (P < .005). Within factors, the high-risk magnitude of each factor significantly increased ACL strain relative to the baseline condition (P≤ .002). However, relative to knee abduction moment specifically, ACL strain increased with each increased risk magnitude (P≤ .015). CONCLUSION: Increased risk levels of each load factor contributed to increased levels of ACL strain during a simulated jump landing. The behavior of increased strain between levels of increased risk loading was most prevalent for changes in knee abduction moment. This behavior was observed in the ACL and MCL. CLINICAL RELEVANCE: Knee abduction moment may be the predominant precursor to ACL injury and concomitant MCL injury. As knee abduction occurs within the frontal plane, primary preventative focus should incorporate reduction of frontal plane knee loading in landing and cutting tasks, but secondary reduction of transverse plane loading could further increase intervention efficacy. Constraint of motion in these planes should restrict peak ACL strain magnitudes during athletic performance.

External loads associated with anterior cruciate ligament injuries increase the correlation between tibial slope and ligament strain during in vitro simulations of in vivo landings.

BACKGROUND: The aim of the present study was to evaluate the relationship between tibial slope angle and ligament strain during in vitro landing simulations that induce ACL failure through the application of variable external loading at the knee. The hypothesis tested was that steeper posterior tibial slope angle would be associated with higher ACL strain during a simulated landing task across all external loading conditions. METHODS: Kinetics previously derived from an in vivo cohort performing drop landings were reproduced on 45 cadaveric knees via the mechanical impact simulator. MRIs were taken of each specimen and used to calculate medial compartment posterior tibial slope, lateral compartment posterior tibial slope, and coronal plane tibial slope. Linear regression analyses were performed between these angles and ACL strain to determine whether tibial slope was a predictive factor for ACL strain. FINDINGS: Medial and lateral posterior tibial slope were predictive factors for ACL strain during some landings with higher combined loads. Medial posterior slope was more predictive of ACL strain in most landings for male specimens, while lateral posterior and coronal slope were more predictive in female specimens, but primarily when high abduction moments were applied. INTERPRETATION: Tibial slope has the potential to influence ACL strain during landing, especially when large abduction moments are present at the knee. Deleterious external loads to the ACL increase the correlation between tibial slope and ACL strain, which indicates that tibial slope angles are an additive factor for athletes apt to generate large out-of-plane knee moments during landing tasks.

Factors Associated With Psychological Readiness to Return to Sport After Anterior Cruciate Ligament Reconstruction Surgery.

BACKGROUND: Anterior cruciate ligament (ACL) injury has a significant psychological effect, and a negative psychological state is a commonly cited reason for a reduction or cessation of sports participation after ACL reconstruction (ACLR) surgery. PURPOSE: To identify factors that contribute to an athlete's psychological readiness to return to sport (RTS) after ACLR. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A cohort of 635 athletes (389 male, 246 female) who underwent ACLR and had been cleared to RTS completed the Anterior Cruciate Ligament-Return to Sport After Injury (ACL-RSI) scale at an average 12 months (range, 11-24 months) after surgery. Demographics (age, sex), sporting outcomes (preinjury frequency), surgical timing (injury to surgery interval), clinical factors (laxity), functional measures (single-limb hop symmetry), and symptoms of pain and function (International Knee Documentation Committee subjective) were also taken, and univariate and multiple regression models were used to determine the association between these and the psychological readiness of the athlete to RTS (ACL-RSI scores). Data for the entire cohort were initially analyzed; then, patients were grouped according to whether they had returned to competitive sport, and the analysis repeated for each group (return/nonreturn). RESULTS: Univariate analysis for the entire group showed that all of the following had a positive effect on psychological readiness: male sex (ß = 5.8; 95% CI, 2-10), younger age (ß = -0.2; 95% CI, -0.4 to 0.01), a shorter interval between injury and surgery (ß = -0.1; 95% CI, -0.1 to -0.02), a higher frequency of preinjury sport participation (ß = 5.4; 95% CI, 2-9), greater limb symmetry (ß = 0.5; 95% CI, 0.3-0.6), and higher subjective knee scores (ß = 1.3; 95% CI, 1.1-1.4). In the multivariate model, subjective knee scores and age significantly accounted for 37% of the variance in psychological readiness ( r2 = 0.37, P < .0001). The only difference between the groups who had and had not returned to sport was that female sex was a significant contributor for the nonreturn group. CONCLUSION: Self-reported symptoms and function were most associated with psychological readiness to RTS after ACLR surgery. Male patients who participated frequently in sport before ACL injury had higher psychological readiness. Conversely, female patients had a more negative outlook and may therefore benefit more from interventions designed to facilitate a smooth transition back to sport.

Validation of Noncontact Anterior Cruciate Ligament Tears Produced by a Mechanical Impact Simulator Against the Clinical Presentation of Injury.

BACKGROUND: Anterior cruciate ligament (ACL) injuries are catastrophic events that affect athletic careers and lead to long-term degenerative knee changes. As injuries are believed to occur within the first 50 milliseconds after initial contact during a rapid deceleration task, impact simulators that rapidly deliver impulse loads to cadaveric specimens have been developed. However, no impactor has reproducibly and reliably created ACL injures in a distribution that mimics clinical observation. PURPOSE: To better understand ACL injury patterns through a cadaveric investigation that applied in vivo-measured external loads to the knee during simulated landings. STUDY DESIGN: Controlled laboratory study. METHODS: A novel mechanical impact simulator reproduced kinetics from in vivo-recorded drop landing tasks on 45 cadaveric knees. Specimens were exposed to a randomized order of variable knee abduction moment, anterior tibial shear, and internal tibial rotation loads before the introduction of an impulse load at the foot. This process was repeated until a hard or soft tissue injury was induced on the joint. Injuries were assessed by an orthopaedic surgeon, and ligament strain was recorded by implanted strain gauges. RESULTS: The mechanical impact simulator induced ACL injuries in 87% of specimens, with medial collateral ligament (MCL) injuries in 31%. ACL tear locations were 71% femoral side, 21% midsubstance, and 9% tibial side. Peak strain before failure for ACL-injured specimens was 15.3% ± 8.7% for the ACL and 5.1% ± 5.6% for the MCL ( P < .001). CONCLUSION: The ACL injuries induced by the mechanical impact simulator in the present study have provided clinically relevant in vitro representations of in vivo ACL injury patterns as cited in the literature. Additionally, current ligament strains corroborate the literature to support disproportionate loading of the ACL relative to the MCL during athletic tasks. CLINICAL RELEVANCE: These findings indicate that the mechanical impact simulator is an appropriate model for examining independent mechanical variables, treatment techniques, and preventive interventions during athletic tasks leading up to and including an ACL injury. Accordingly, this system can be utilized to further parse out contributing factors to an ACL injury as well as assess the shortcomings of ACL reconstruction techniques in a dynamic, simulated environment that is better representative of in vivo injury scenarios.

Sex-Based Differences of Medial Collateral Ligament and Anterior Cruciate Ligament Strains With Cadaveric Impact Simulations.

BACKGROUND: Female patients sustain noncontact knee ligament injuries at a greater rate compared with their male counterparts. The cause of these differences in the injury rate and the movements that load the ligaments until failure are still under dispute in the literature. PURPOSE/HYPOTHESES: This study was designed to determine differences in anterior cruciate ligament (ACL) and medial collateral ligament (MCL) strains between male and female cadaveric specimens during a simulated athletic task. The primary hypothesis tested was that female limbs would demonstrate significantly greater ACL strain compared with male limbs under similar loading conditions. A secondary hypothesis was that MCL strain would not differ between sexes. STUDY DESIGN: Controlled laboratory study. METHODS: Motion analysis of 67 athletes performing a drop vertical jump was conducted. Kinetic data were used to categorize injury risk according to tertiles, and these values were input into a cadaveric impact simulator to assess ligamentous strain during a simulated landing task. Uniaxial and multiaxial load cells and differential variable reluctance transducer strain sensors were utilized to collect mechanical data for analysis. Conditions of external loads applied to the cadaveric limbs (knee abduction moment, anterior tibial shear, and internal tibial rotation) were varied and randomized. Data were analyzed using 1-way analysis of variance (ANOVA), 2-way repeated-measures ANOVA, and the Fisher exact test. RESULTS: There were no significant differences (P = .184) in maximum ACL strain between male (13.2% ± 8.1%) and female (16.7% ± 8.3%) specimens. Two-way ANOVA demonstrated that across all controlled external load conditions, female specimens consistently attained at least 3.5% increased maximum ACL strain compared with male specimens (F1,100 = 4.188, P = .043); however, when normalized to initial contact, no significant difference was found. There were no significant differences in MCL strain between sexes for similar parameters. CONCLUSION: When compared with baseline, female specimens exhibited greater values of ACL strain at maximum, initial contact, and after impact (33, 66, and 100 milliseconds, respectively) than male specimens during similar loading conditions, with a maximum strain difference of at least 3.5%. During these same loading conditions, there were no differences in MCL loading between sexes, and only a minimal increase of MCL loading occurred during the impact forces. Our results indicate that female patients are at an increased risk for ACL strain across all similar conditions compared with male patients. CLINICAL RELEVANCE: These data demonstrate that female specimens, when loaded similarly to male specimens, experience additional strain on the ACL. As the mechanical environment was similar for both sexes with these simulations, the greater ACL strain of female specimens must be attributed to ligament biology, anatomic differences, or muscular stiffness.

Ligament Strain Response Between Lower Extremity Contralateral Pairs During In Vitro Landing Simulation.

BACKGROUND: Limb asymmetries, as determined through in vivo biomechanical measures, are known risk factors for anterior cruciate ligament (ACL) injury. Previous cadaveric studies have shown a lack of significant differences in ligament strain between contralateral lower extremities when identical kinematics were simulated on specimens. Recent methodological developments have applied in vivo knee kinetics to exert landing forces on cadaveric lower extremities to mimic ACL injury events, but it is unknown whether contralateral limbs fail in a consistent manner during impact simulator testing. HYPOTHESIS: It was hypothesized that contralateral lower extremities would not exhibit side-to-side differences in ligament strains. Furthermore, it was hypothesized that failure loads and failure locations would be independent of limb dominance. STUDY DESIGN: Controlled laboratory study. METHODS: Fourteen pairs of cadaveric lower extremities were obtained from an anatomic donations program (8 female, 6 male; mean ± SD: age, 41.7 ± 8.1 years; mass, 86.8 ± 27.0 kg; body mass index, 29.4 ± 9.0 kg/m2). A mechanical impact simulator was used to re-create the impulse ground-reaction force generated during an in vivo landing task. Ligament strains were recorded by differential variable force transducers implanted on the ACL and medial collateral ligament (MCL). RESULTS: No significant differences were observed in peak ACL or peak MCL strain for 5 loading conditions. Fisher exact tests of independence revealed that limb dominance was independent of both load at failure and failure location. CONCLUSION: There were no significant differences in ACL and MCL strain values between limb sides during in vitro impact simulation testing. This finding indicates that limb dominance does not influence the failure threshold of the ACL, since there was no significant difference in failure strains. The functional mechanics of the ACL are comparable between contralateral pairs from the same healthy specimen. CLINICAL RELEVANCE: Injury mechanisms and intra-articular mechanics cannot be ethically studied in an in vivo setting. The current study provides additional insight into limb asymmetry that is observed among athletes in clinical sports medicine settings.

Should Return to Sport be Delayed Until 2 Years After Anterior Cruciate Ligament Reconstruction? Biological and Functional Considerations.

Anterior cruciate ligament (ACL) tears are common knee injuries sustained by athletes during sports participation. A devastating complication of returning to sport following ACL reconstruction (ACLR) is a second ACL injury. Strong evidence now indicates that younger, more active athletes are at particularly high risk for a second ACL injury, and this risk is greatest within the first 2 years following ACLR. Nearly one-third of the younger cohort that resumes sports participation will sustain a second ACL injury within the first 2 years after ACLR. The evidence indicates that the risk of second injury may abate over this time period. The incidence rate of second injuries in the first year after ACLR is significantly greater than the rate in the second year. The lower relative risk in the second year may be related to athletes achieving baseline joint health and function well after the current expected timeline (6-12 months) to be released to unrestricted activity. This highlights a considerable debate in the return to sport decision process as to whether an athlete should wait until 2 years after ACLR to return to unrestricted sports activity. In this review, we present evidence in the literature that athletes achieve baseline joint health and function approximately 2 years after ACLR. We postulate that delay in returning to sports for nearly 2 years will significantly reduce the incidence of second ACL injuries.

Does Anterior Cruciate Ligament Innervation Matter for Joint Function and Development of Osteoarthritis?

Complications following anterior cruciate ligament (ACL) injury and reconstruction that include chronic dysfunction, second ACL injury, and posttraumatic osteoarthritis (OA) may be interrelated and stem from the inability to fully restore native ACL integrity and function. The loss of ACL sensory input following injury may significantly contribute to joint dysfunction. We developed a novel preclinical animal model to assess the contributions of ACL sensory afferents to knee joint function and health. We hypothesized that ACL sensory denervation would manifest in knee joint dysfunction and development of early OA. Purpose-bred, adult research dogs (n = 9 dogs, 18 knees) underwent arthroscopic surgery to create three treatment groups: (1) partial ACL tear, (2) ACL denervated, and (3) whole-joint denervated. A neurotoxin injected directly into the ACL or into the joint space was used to induce sensory denervation, and sham procedures were done on contralateral knees. After intervention, dogs participated in a regimented exercise program. Gait analysis and clinically relevant functional assessments were performed. At week 12, the animals were humanely euthanatized for arthroscopic, gross, and histologic assessments. ACL partial tear group demonstrated the greatest overall knee dysfunction. Clinical measures of function revealed a significant difference between the ACL partial tear and ACL denervated group (p < 0.05), but these differences were not observed between the ACL and whole-joint denervated groups (p > 0.05). A significant reduction in limb loading was experienced by the ACL partial tear group compared with controls (p < 0.05) but not between other groups. Arthroscopic evaluation found no evidence for overt articular cartilage damage, meniscal pathology, or osteophyte formation was noted in any group. No significant differences (p > 0.05) were observed in ACL pathology and OA severity scores between the ACL partial tear and the ACL denervated groups. The results of our study indicate that ACL sensory loss may contribute to joint dysfunction and subsequent OA changes. Further investigation and development of this model are important to improve clinical therapies and optimize patient outcomes following ACL injury.