Matthew S. Harkey

Osteoarthritis-related biomarkers following anterior cruciate ligament injury and reconstruction: a systematic review

OBJECTIVE There is an increased risk of developing knee osteoarthritis (OA) following anterior cruciate ligament (ACL) injury. Biomarkers may provide diagnostic, prognostic, or burden of disease indicators of OA before radiographic changes become apparent. Unfortunately, there has been no systematic review to clarify which biomarkers may be most informative following injury. Therefore, this review critically investigated existing studies of OA-related biomarkers in ACL-deficient (ACL-D) and reconstructed (ACL-R) patients to summarize the current evidence and identify knowledge gaps. DESIGN A systematic review of the literature in Web of Science and PubMed databases (1960-June 2014) was performed. All English-language case-control and longitudinal studies assessing OA-related biomarkers in ACL-D and ACL-R patients were considered. Data regarding biomarker changes over time within ACL-D and ACL-R patients as well as differences in ACL-D/ACL-R patients compared with a control group were extracted from pertinent studies. RESULTS A descriptive summary of 20 included studies was produced. In ACL-D patients compared with controls, synovial fluid biomarkers indicated elevated collagen turnover, while the inflammatory cytokine response was inconclusive. In ACL-R patients, serum concentrations indicated decreased collagen breakdown, but urine concentrations were indicative of greater collagen breakdown when compared to controls. Compared to preoperative values, the overall inflammatory cytokine response measured with synovial fluid biomarkers increased while plasma biomarkers did not change following reconstruction. CONCLUSION Patients with ACL-D or ACL-R have altered biomarkers indicative of OA. More research with standardized reporting is needed to effectively determine which biomarkers are the most indicative for OA development and progression following ACL injury.

Disinhibitory interventions and voluntary quadriceps activation: a systematic review.

OBJECTIVE To determine the effects of various therapeutic interventions on increasing voluntary quadriceps muscle activation. BACKGROUND Decreased voluntary quadriceps activation is commonly associated with knee injury. Recently, research has focused on developing specific disinhibitory interventions to improve voluntary quadriceps activation; yet, it remains unknown which interventions are most effective in promoting this improvement. DATA SOURCES We searched Web of Science from January 1, 1965 through September 27, 2012, using the key words quadriceps activation and transcutaneous electrical nerve stimulation, transcranial magnetic stimulation, cryotherapy, focal joint cooling, joint mobilization, joint mobilisation, joint manipulation, manual therapy, and neuromuscular electrical stimulation. STUDY SELECTION Studies evaluating the effect of disinhibitory interventions on volitional quadriceps activation were used in our review. Standardized effect sizes (Cohen d) and 95% confidence intervals (CIs) were calculated from voluntary quadriceps activation means and standard deviations measured at baseline and at all available postintervention time points from each study. DATA SYNTHESIS Ten studies were grouped into 5 categories based on intervention type: manual therapy (4 studies), transcutaneous electrical nerve stimulation (2 studies), cryotherapy (2 studies), neuromuscular electrical stimulation (2 studies), and transcranial magnetic stimulation (1 study). Transcutaneous electrical nerve stimulation demonstrated the strongest immediate effects (d = 1.03; 95% CI = 0.06, 1.92) and long-term effects (d = 1.93; 95% CI = 0.91, 2.83). Cryotherapy (d = 0.76; 95% CI = -0.13, 1.59) and transcranial magnetic stimulation (d = 0.54; 95% CI = -0.33, 1.37) had moderate immediate effects in improving voluntary quadriceps activation, whereas manual therapy (d = 0.38; 95% CI = -0.35, 1.09) elicited only weak immediate effects. Neuromuscular electrical stimulation produced weak negative to strong positive effects (range of d values = -0.50 to 1.87) over a period of 3 weeks to 6 months. CONCLUSIONS Transcutaneous electrical nerve stimulation demonstrated the strongest and most consistent effects in increasing voluntary quadriceps activation and may be the best disinhibitory intervention for improving the same.

Quadriceps Strength Predicts Self-reported Function Post-ACL Reconstruction.

INTRODUCTION/PURPOSE Quadriceps strength is a useful clinical predictor of self-reported function after anterior cruciate ligament reconstruction (ACLR). However, it remains unknown if quadriceps strength normalized to body mass (QBM) or quadriceps strength limb symmetry index (QLSI) is the best predictor of self-reported function in individuals with ACLR. We sought to determine whether QBM and QLSI are able to predict individuals with ACLR who self-report high function (≥90% on the international knee documentation committee (IKDC) index). METHODS Ninety-six individuals with a history of a primary unilateral ACLR were recruited for a multisite cross-sectional descriptive laboratory experiment. Bilateral isometric quadriceps strength was collected at 90° of knee flexion to calculate QBM and QLSI (ratio of the ACLR limb to the contralateral limb). Area under the curve (AUC) values were calculated using receiver operating characteristic curve analyses to determine the capacity of QBM and QLSI to predict individuals with high self-reported function on the IKDC index. RESULTS QBM displayed high accuracy (AUC = 0.76; 95% confidence interval, 0.66-0.86) for identifying participants with an IKDC index ≥90%. A QBM cutoff score of 3.10 N·m·kg was found to maximize sensitivity (0.61) and specificity (0.84), and displayed 8.15 (3.09-21.55) times higher odds of reporting high function. QLSI displayed a moderate accuracy (AUC = 0.62, 0.50-0.73) for identifying participants with an IKDC index ≥90%. A QLSI cutoff score of 96.5% maximized sensitivity (0.55) and specificity (0.70), and represented 2.78 (1.16-6.64) times higher odds reporting high function. CONCLUSION QBM is a stronger predictor of high self-reported function compared with QLSI in individuals with ACLR. Rehabilitation guidelines may benefit from incorporating the use of QBM measurements for the purpose of predicting participants that may maintain high self-reported function.

Greater Mechanical Loading During Walking Is Associated With Less Collagen Turnover in Individuals With Anterior Cruciate Ligament Reconstruction

Background: Individuals who have sustained an anterior cruciate ligament (ACL) injury and undergo ACL reconstruction (ACLR) are at higher risk of developing knee osteoarthritis. It is hypothesized that altered knee loading may influence the underlying joint metabolism and hasten development of posttraumatic knee osteoarthritis. Purpose: To explore the associations between serum biomarkers of cartilage metabolism and peak vertical ground-reaction force (vGRF) and vGRF loading rate in the injured and uninjured limbs of individuals with ACLR. Study Design: Descriptive laboratory study. Methods: Patients with a history of a primary unilateral ACLR who had returned to unrestricted physical activity (N = 19) participated in the study. Resting blood was collected from each participant before completing 5 walking gait trials at a self-selected comfortable speed. Peak vGRF was extracted for both limbs during the first 50% of the stance phase of gait, and the linear vGRF loading rate was determined between heel strike and peak vGRF. Sera were assessed for collagen breakdown (collagen type II cleavage product [C2C]) and synthesis (collagen type II C-propeptide [CPII]), as well as aggrecan concentrations, via commercially available specific enzyme-linked immunosorbent assays. Pearson product-moment correlations (r) and Spearman rank-order correlations (ρ) were used to evaluate associations between loading characteristics and biomarkers of cartilage metabolism. Results: Lower C2C:CPII ratios were associated with higher peak vGRF in the injured limb (ρ = −0.59, uncorrected P = .007). There were no significant associations between peak vGRF or linear vGRF loading rate and CPII, C2C, or aggrecan serum concentrations. Conclusion: Lower C2C:CPII ratios were associated with higher peak vGRF in the ACLR limb during gait, suggesting that higher peak loading in the ACLR limb is related to lower type II collagen breakdown relative to type II collagen synthesis. Clinical Relevance: These data suggest that type II collagen synthesis may be higher relative to the amount of type II collagen breakdown in the ACLR limb with higher lower extremity loading. Future study should determine if metabolic compensations to increase collagen synthesis may affect the risk of developing osteoarthritis after ACLR.

The influence of ankle dorsiflexion and self-reported patient outcomes on dynamic postural control in participants with chronic ankle instability.

We investigated the influence of ankle dorsiflexion range of motion (DF-ROM) and self-reported patient outcomes on dynamic postural control assessed with the Star Excursion Balance Test (SEBT) in individuals with chronic ankle instability (CAI). Twenty-nine participants with self-reported CAI volunteered. The primary outcome measurements were categorized into clinician-and patient-generated. Clinician-generated outcome measurements included anterior (SEBT-A), posteriormedial (SEBT-PM) and posteriorlateral (SEBT-PL) reach distances (cm) normalized by leg length (cm) of the SEBT, maximum weight-bearing dorsiflexion (WB-DF) (cm), and open-chain DF-ROM (°). Self-reported patient-generated outcome measures included the foot and ankle ability measure and the level of perceived pain, stiffness, stability, and function of their involved ankle on a 10-cm visual analog scale (VAS). Pearson product moment correlations were used to examine the relationship of the SEBT performances with DF-ROM and self-reported patient outcome measures. A multiple linear regression was performed to determine the influence of patient- and clinician-generated measures on the SEBT. SEBT-A performance was significantly and fairly correlated with WB-DF (r=0.410, p=0.014), perceived ankle stiffness (r=0.477, p=0.014), and open-chain DF-ROM (r=0.404, p=0.015). The strongest predictor of the variance in SEBT-A was the combination of the variance in WB-DF and VAS-stiffness (R2=0.348, p=0.004). There were no significant correlations with the SEBT-PM and SEBT-PL. WB-DF and VAS-stiffness may represent targets for intervention that need to be addressed to produce the best outcome in participants with CAI when altered dynamic postural control is detected on the SEBT-A.

Quadriceps Function and Gait Kinetics after Anterior Cruciate Ligament Reconstruction.

PURPOSE Chronic quadriceps dysfunction has been implicated as a contributor to knee osteoarthritis (OA) development after anterior cruciate ligament reconstruction (ACLR). This dysfunction potentially leads to impulsive/high-rate loading during gait, thus accelerating cartilage degradation. The purpose of this study was to examine relationships between several indices of quadriceps function and gait biomechanics linked to knee OA development in individuals with ACLR. METHODS Gait biomechanics and quadriceps function were assessed in 39 individuals with ACLR. Indices of quadriceps function included isometric peak torque and rate of torque development (RTD), isokinetic peak torque and power, and the central activation ratio. Gait biomechanics included the peak vertical ground reaction force and loading rate, and the heel strike transient (HST) magnitude and loading rate. RESULTS Isometric peak torque was not associated with any of the gait biomechanical variables. However, greater RTD was associated with lesser peak vertical ground reaction force linear (r = -0.490, P = 0.003) and instantaneous (r = -0.352, P = 0.031) loading rates, as well as a lesser HST magnitude (r = -0.312, P = 0.049) and instantaneous loading rate (r = -0.355, P = 0.029). Greater central activation ratio was associated with greater HST instantaneous (r = 0.311, P = 0.050) and linear (r = 0.328, P = 0.033) loading rates. Isokinetic peak torque and power were not associated with any of the biomechanical variables. CONCLUSION Poor quadriceps function, especially RTD, is associated with gait kinetics linked to cartilage degradation in individuals with ACLR. These results highlight the likely role of chronic quadriceps dysfunction in OA development after ACLR and the need to emphasize improving quadriceps function as a primary rehabilitation goal.

Biochemical markers of cartilage metabolism are associated with walking biomechanics 6-months following anterior cruciate ligament reconstruction: Biomechanics and Biomarkers Post ACLR

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.

Sagittal plane kinematics predict kinetics during walking gait in individuals with anterior cruciate ligament reconstruction

BACKGROUND Alterations in mechanical loading following anterior cruciate ligament reconstruction may lead to the development of knee osteoarthritis. Feedback that cues a change in knee kinematics during walking gait may influence mechanical loading, yet it remains unknown if knee kinematics predict kinetics during walking gait. Our aim was to determine if sagittal plane knee kinematics predict kinetics during walking gait in anterior cruciate ligament reconstructed individuals. METHODS Forty-one individuals with a history of primary, unilateral anterior cruciate ligament reconstruction completed a motion capture walking gait analysis. Hierarchical linear regression analyses were used in order to determine the amount of variance in the kinetic variables of interest (peak vertical ground reaction force, instantaneous and linear vertical ground reaction force loading rate) that was individually predicted by the kinematic variables of interest (knee flexion angle at heelstrike, peak knee flexion angle, and knee flexion excursion). FINDINGS Knee flexion excursion of the injured limb significantly predicted 11% of the variance in peak vGRF of the injured limb after accounting for gait speed and peak knee flexion angle (ΔR2=0.11, P=0.004). After accounting for gait speed and knee flexion angle at heelstrike, knee flexion excursion significantly predicted 16% of the variance in the injured limb peak vertical ground reaction force (ΔR2=0.16, P=0.001). No kinematic variable predicted vertical ground reaction force loading rate. INTERPRETATION Altering knee flexion excursion may be useful as a future therapeutic target for modifying peak vertical ground reaction force during walking gait following anterior cruciate ligament reconstruction.

Walking Speed As a Potential Indicator of Cartilage Breakdown Following Anterior Cruciate Ligament Reconstruction.

To determine whether or not self‐selected walking speed associates with serum biomarkers of cartilage (collagen and proteoglycan) breakdown in anterior cruciate ligament reconstructed (ACLR) individuals.

Greater intracortical inhibition associates with lower quadriceps voluntary activation in individuals with ACL reconstruction

Decreased voluntary activation contributes to quadriceps weakness following anterior cruciate ligament reconstruction (ACLR). Alterations in neural excitability are likely responsible for reductions in quadriceps voluntary activation, and may be due to specific alterations in intracortical inhibition and facilitation. Therefore, we sought to determine if intracortical inhibition (SICI) and intracortical facilitation (ICF) associate with quadriceps voluntary activation in individuals with ACLR. Twenty-seven participants with a primary, unilateral ACLR were enrolled in this study. Bilateral central activation ratio (CAR) and paired-pulse transcranial magnetic stimulation were used to assess quadriceps voluntary activation, as well as SICI and ICF in the vastus medalis, respectively. Pearson Product Moment correlations were used to determine the association between CAR and (1) SICI, and (2) ICF in each limb. Lesser CAR associated with lesser SICI amplitude (r = 0.502, P = 0.008) in the ACLR limb. No associations in the contralateral limb were significant. Our results suggest greater intracortical inhibition associates with lesser voluntary activation in individuals with ACL. Implementing interventions that target intracortical inhibition may aid in restoring quadriceps voluntary activation following ACLR.