Biologic Impact of Anterior Cruciate Ligament Injury and Reconstruction.

Surgical intervention after anterior cruciate ligament (ACL) tears is typically required because of the limited healing capacity of the ACL. However, mechanical factors and the inflammatory response triggered by the injury and surgery can impact patient outcomes. This review explores key aspects of ACL injury and reconstruction biology, including the inflammatory response, limited spontaneous healing, secondary inflammation after reconstruction, and graft healing processes. Understanding these biologic mechanisms is crucial for developing new treatment strategies and enhancing patient well-being. By shedding light on these aspects, clinicians and researchers can work toward improving quality of life for individuals affected by ACL tears.

Identifying Anterior Cruciate Ligament Injuries Through Automated Video Analysis of In-Game Motion Patterns.

Background: Failure to diagnose anterior cruciate ligament (ACL) injury during a game can delay adequate treatment and increase the risk of further injuries. Artificial intelligence (AI) has the potential to be an accurate, cost-efficient, and readily available diagnostic tool for ACL injury in in-game situations. Purpose: To develop an automated video analysis system that uses AI to identify biomechanical patterns associated with ACL injury and to evaluate whether the system can enhance the ability of orthopaedic and sports medicine specialists to identify ACL injuries on video. Study Design: Descriptive laboratory study. Methods: A total of 91 ACL injury and 38 control movement scenes from online available match recordings were analyzed. The videos were processed to identify and track athletes and to estimate their 3-dimensional (3D) poses. Geometric features, including knee flexion, knee and hip abduction, and foot and hip rotation, were extracted from the athletes' 3D poses. A recurrent neural network algorithm was trained to classify ACL injury, using these engineered features as its input. Analysis by 2 orthopaedic surgeons examined whether providing clinical experts with the reconstructed 3D poses and their derived signals could increase their diagnostic accuracy. Results: All AI models performed significantly better than chance. The best model, which used the long short-term memory network with engineered features, demonstrated decision interpretability and good performance (F1 score = 0.63 ± 0.01, area under the receiver operating characteristic curve = 0.88 ± 0.01). The analysis by the 2 orthopaedic surgeons demonstrated improved diagnostic accuracy for ACL injury recognition when provided with system data, resulting in a 0.08 increase in combined F1 scores. Conclusion: Our approach successfully reconstructed the 3D motion of athletes from a single-camera view and derived geometry-based biomechanical features from pose sequences. Our trained AI model was able to automatically detect ACL injuries with relatively good performance and prelabel and highlight regions of interest in video footage. Clinical Relevance: This study demonstrated the feasibility of using AI to automatically evaluate in-game video footage and identify dangerous motion patterns. Further research can explore the full potential of the biomechanical markers and use of the system by nonspecialists, potentially diminishing the rate of missed diagnosis and the detrimental outcomes that follow.

Hyperbaric oxygen therapy enhances graft healing and mechanical properties after anterior cruciate ligament reconstruction: An experimental study in rabbits.

Hyperbaric oxygen therapy (HBOT) has proven successful in wound healing. However, its potential effects on anterior cruciate ligament (ACL) injuries remain uncertain. This study aimed to investigate the impact of HBOT on graft healing following ACL reconstruction in rabbits. Male New Zealand rabbits underwent ACL reconstruction and were randomly divided into two groups: the HBOT group and the ambient air group. The HBOT group received 100% oxygen at 2.5 atmospheres absolute for 2 h daily for 5 consecutive days, starting from the first day after surgery. The ambient air group was maintained in normal room air throughout the entire period. After 12 weeks following the surgery, animals were euthanized, and their knees were harvested for analysis. The HBOT group demonstrated superior graft maturation and integration in comparison to the ambient air group, as evidenced by lower graft signal intensity on magnetic resonance imaging, decreased femoral and tibial tunnel size, and higher bone mineral density values on high-resolution peripheral quantitative computed tomography scans. Additionally, biomechanical testing indicated that the HBOT group had greater load to failure and stiffness values than the ambient air group. In conclusion, the adjuvant use of HBOT improved ACL graft maturation and integration, reduced tunnel widening, and enhanced the biomechanical properties of the graft. These results may provide important insights into the potential clinical application of HBOT as a therapeutic intervention to enhance graft healing after ACL reconstruction, paving the way for further research in this area.

Increased risk of reoperation and failure to attain clinically relevant improvement following autologous chondrocyte implantation of the knee in female patients and individuals with previous surgeries: a time-to-event analysis based on the German cartilage registry (KnorpelRegister DGOU).

PURPOSE: This study aimed to analyze the risk of reoperation following autologous chondrocyte implantation (ACI) of the knee utilizing third-generation ACI products in a time-to-event analysis and report on the associated patient-reported outcome measures (PROM) in case of reoperation. METHODS: Patients undergoing ACI were included from a longitudinal database. Patient age, sex, body mass index (BMI), number of previous surgeries, lesion localization, lesion size, symptom duration, as well as time and type of reoperation was extracted. A cox proportional-hazards model was applied to investigate the influence of baseline variables on risk of reoperation. Reoperation was defined as any type of subsequent ipsilateral knee surgery, excluding hardware removal. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was utilized to compare PROM between patients with and without reoperation. RESULTS: A total of 2039 patients were included with 1359 (66.7%) having a minimum follow-up of 24 months. There were overall 243 reoperations (prevalence 17.9%). Minor arthroscopic procedures (n = 96, 39.5%) and revision cartilage repair procedures (n = 78, 32.1%) were the most common reoperations. Nineteen patients (0.9%) reported conversion arthroplasty at 17.7 (10.4) months after ACI. Female sex (HR 1.5, 95% CI [1.2, 2.0], p = 0.002) and the presence of 1-2 previous surgeries (HR 1.5, 95% CI [1.1, 2.0], p = 0.010), or more than 2 previous surgeries (HR 1.9, 95% CI [1.2, 2.9], p = 0.004) were significantly associated with increased risk of reoperation following ACI. Significantly less patients surpassed the minimal clinically important difference (MCID) in the reoperation group at 24 months regarding the KOOS subscores pain (OR 1.6, 95% CI [1.1, 2.2]), quality of life (OR 2.2, 95% CI [1.6, 3.2]), symptoms (OR 2.0 [1.4, 2.9]), and sports (OR 2.0 [1.4, 2.8]). CONCLUSION: Female patients and individuals with a history of previous surgeries face an elevated risk of requiring reoperation after undergoing ACI, which is associated with failure to attain clinically relevant improvements. A thorough evaluation of the indications for ACI is paramount, particularly when patients have a history of previous surgeries. LEVEL OF EVIDENCE: Level III.

Safety, Tolerability, and Pharmacokinetics of Same-Knee Intra-Articular Injection of Corticosteroid and Lorecivivint Within 7 Days: An Open-Label, Randomized, Parallel-Arm Study.

INTRODUCTION: Knee osteoarthritis (OA) is a common painful disorder. Intra-articular (IA) corticosteroid injections are frequently prescribed to treat knee pain. Lorecivivint (LOR), a novel IA cdc2-Like Kinase (CLK)/Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase (DYRK) inhibitor thought to modulate Wnt and inflammatory pathways, has appeared safe and demonstrated improved patient-reported outcomes compared with placebo. While LOR is proposed for stand-alone use, in clinical practice, providers might administer LOR in close time proximity to IA corticosteroid. This open-label, parallel-arm, healthy volunteer study assessed potential short-term safety, tolerability and pharmacokinetic (PK) interactions between IA LOR and triamcinolone acetonide (TCA) administered 7 days apart. METHODS: Healthy volunteers were randomized to Treatment Sequence 1 (IA 40 mg TCA followed by IA 0.07 mg LOR) or Treatment Sequence 2 (IA 0.07 mg LOR followed by IA 40 mg TCA). Treatment-emergent adverse events (TEAEs) were categorized by "epoch", with epoch 1 spanning from first until second injection, and epoch 2 spanning from second injection until end of study. Plasma PK was assessed pre injection and out to 22 days after to assess PK treatment interaction. RESULTS: A total of 18 TEAEs were reported by 11 (27.5%) of 40 enrolled participants, and there were no serious adverse events. Thirteen TEAEs were reported in Treatment Sequence 1 and five in Treatment Sequence 2, similarly distributed between epochs 1 and 2. In all participants and at all time points, plasma LOR concentrations were below the limit of quantification (0.100 ng/mL). Geometric mean concentrations and PK parameters for TCA were similar between treatment sequences. CONCLUSION: No safety signals were observed. There were no quantifiable plasma concentrations of LOR in either Treatment Sequence. The PK of TCA was unaffected by previous LOR injection. These results suggest that IA administration of LOR and TCA in close time proximity is unlikely to pose a safety concern. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04598542.

Knee osteoarthritis (OA) is a common disorder characterized by pain and loss of function. This clinical trial tested if two different treatments for OA injected into the same knee 1 week apart would impact the safety or exposure of either treatment. The treatments evaluated were an injection of a corticosteroid, triamcinolone acetonide, and a potential OA treatment in development, lorecivivint, a novel small molecule thought to inhibit inflammation and a biological pathway called the Wnt pathway. The amount of either treatment found in circulation was not different when injected before or after the other treatment. The order of injection did not change the safety profile for either agent, suggesting injection of the two agents 1 week apart is unlikely to pose a safety concern.

The Combination of Depression and Obesity was Associated with Increased Incidence of Subsequent Total Knee Arthroplasty.

OBJECTIVE: Compare the incidence of total knee arthroplasty (TKA) within the first 5 years after knee OA diagnoses between matched groups of individuals with or without comorbid diagnoses of obesity and/or depression. We hypothesized that the greatest incidence of TKA within 5 years of OA diagnosis would be in the cohort of individuals with combined obesity and depression. METHODS: The PearlDiver Mariner Ortho157 database was used to identify four cohorts of individuals with knee OA based on diagnosis codes that were matched by age, sex, and Charlson Comorbidity Index: a group without diagnoses associated with depression or obesity (Control), those with obesity but not depression (Obesity), those with depression but not obesity (Depression), and those with diagnoses of both obesity and depression (Depression+Obesity). The incidence of subsequent TKA within the first 5 years after the index OA diagnosis were compared between the four matched cohorts. RESULTS: Each cohort was comprised of 274,403 unique individuals (180,563 females, 93,840 males; age=55±7 y). The incidence of TKA was greatest for the Depression+Obesity group (11.9%) when compared to the Control group (8.3%, p<0.0001, RR=1.43 [95%CI:1.41,1.45]), the Obesity group (10.2%, p<0.0001, RR=1.13 [95%CI:1.11,1.14], p<0.0001) or Depression (7.8%, p<0.0001, RR=1.53 [95%CI:1.50,1.55], p<0.0001). CONCLUSION: The incidence of subsequent TKA was greatest for those with the combination of obesity and depression when compared to the Control group and those with individual diagnosis of obesity or depression.

From Inflammation to Resolution: Specialized Pro-resolving Mediators in Posttraumatic Osteoarthritis.

PURPOSE OF REVIEW: To provide a comprehensive overview of the inflammatory response following anterior cruciate ligament (ACL) injury and to highlight the relationship between specialized pro-resolving mediators (SPMs) and inflammatory joint conditions, emphasizing the therapeutic potential of modulating the post-injury resolution of inflammation to prevent posttraumatic osteoarthritis (PTOA). RECENT FINDINGS: The inflammatory response triggered after joint injuries such as ACL tear plays a critical role in posttraumatic osteoarthritis development. Inflammation is a necessary process for tissue healing, but unresolved or overactivated inflammation can lead to chronic diseases. SPMs, a family of lipid molecules derived from essential fatty acids, have emerged as active players in the resolution of inflammation and tissue repair. While their role in other inflammatory conditions has been studied, their relationship with PTOA remains underexplored. Proinflammatory mediators contribute to cartilage degradation and PTOA pathogenesis, while anti-inflammatory and pro-resolving mediators may have chondroprotective effects. Therapies aimed at suppressing inflammation in PTOA have limitations, as inflammation is crucial for tissue healing. SPMs offer a pro-resolving response without causing immunosuppression, making them a promising therapeutic option. The known onset date of PTOA makes it amenable to early interventions, and activating pro-resolving pathways may provide new possibilities for preventing PTOA progression. Harnessing the pro-resolving potential of SPMs may hold promise for preventing PTOA and restoring tissue homeostasis and function after joint injuries.

Effect of Tibiofemoral Rotation Angle on Graft Failure After Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Coronal and sagittal malalignment of the knee are well-recognized risk factors for failure after anterior cruciate ligament (ACL) reconstruction (ACLR). However, the effect of axial malalignment on graft survival after ACLR is yet to be determined. PURPOSE: To evaluate whether increased tibiofemoral rotational malalignment, namely, tibiofemoral rotation angle (TFA) and tibial tubercle-trochlear groove (TT-TG) distance, is associated with graft failure after ACLR. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: In this retrospective matched control study of a single center's database, 151 patients who underwent revision ACLR because of graft failure (ACLR failure group, defined as symptomatic patients with anterior knee instability and an ACL graft tear appreciated on magnetic resonance imaging [MRI] and confirmed during arthroscopic surgery) were compared with a matched control group of 151 patients who underwent primary ACLR with no evidence of failure after ≥2-year follow-up (intact ACLR group). Patients were matched by sex, age, and meniscal injury during primary ACLR. Axial malalignment was assessed on preoperative MRI through the TFA and the TT-TG distance. Sagittal alignment was measured through the posterior tibial slope on MRI. The optimal TFA cutoff associated with graft failure was identified by a receiver operating characteristic curve. The Kaplan-Meier curve with log-rank analysis was performed to evaluate the influence of the TFA on ACLR longevity. RESULTS: The mean age was 25.7 ± 10.4 years for the ACLR failure group and 25.9 ± 10.0 years for the intact ACLR group. Among all the included patients, 174 (57.6%) were male. In the ACLR failure group, the mean TFA was 5.8°± 4.5° (range, -5° to 16°), while it was 3.0°± 3.3° (range, -3° to 15°) in the intact ACLR group (P < .001). Neither the TT-TG distance nor the posterior tibial slope presented statistical differences between the groups. The receiver operating characteristic curve suggested an optimal TFA cutoff of 4.5° for graft failure (area under the curve = 0.71; P < .001; sensitivity, 68.2%; specificity, 75.5%). Considering this a threshold, patients who had a TFA ≥4.5° had 6.6 times higher odds of graft failure compared with patients with a TFA <4.5° (P < .001). Survival analysis demonstrated a 5-year survival rate of 81% in patients with a TFA <4.5°, while it was 44% in those with a TFA ≥4.5° (P < .001). CONCLUSION: An increased TFA was associated with increased odds of ACLR failure when the TFA was ≥4.5°. Measuring the TFA in patients with ACL tears undergoing reconstruction may inform the surgeon about additional factors that may require consideration before ACLR for a successful outcome.

Increased Effusion Synovitis for Those With a Dysregulated Inflammatory Response After an Anterior Cruciate Ligament Injury.

Introduction The progression to posttraumatic osteoarthritis (PTOA) after an anterior cruciate ligament (ACL) injury is likely multifactorial, involving biological, mechanical, and psychosocial factors. Following acute joint trauma, there appears to be a subset of patients that demonstrate a dysregulated inflammatory response. This pro-inflammatory phenotype, or "Inflamma-type," is characterized by an amplified pro-inflammatory response combined with a lack of attendant anti-inflammatory response and has been observed following both an ACL injury and an intra-articular fracture. The aims of this study were to: 1) compare magnetic resonance imaging (MRI)-measured effusion synovitis between those with vs. without a dysregulated inflammatory response, and 2) assess the correlations between effusion synovitis and synovial fluid concentrations of proinflammatory cytokines, degradative enzymes, and synovial fluid biomarkers of cartilage degradation. Methods A cluster analysis was previously performed with synovial fluid concentrations of biomarkers of inflammation and cartilage degradation from 35 patients with acute ACL injuries. Patients were then categorized into two groups: a pro-inflammatory phenotype ("Inflamma-type") and those with a more normal inflammatory response to injury (NORM). Effusion synovitis measured from each patient's preoperative clinical MRI scan was compared between the Inflamma-type and NORM groups using an independent, two-tailed t-test. In addition, Spearman's rho non-parametric correlations were calculated to evaluate the relationship between effusion synovitis and each of the synovial fluid concentrations of pro-inflammatory cytokines, degradative enzymes, and biomarkers of cartilage degradation and bony remodeling. Results Effusion synovitis was significantly greater for the Inflamma-type (10.9±3.8 mm) than the NORM group (7.4±4.4 mm, p=0.04, Cohen's d=0.82). Effusion synovitis significantly correlated with matrix metalloproteinase-3 (rho=0.63, p<0.001), matrix metalloproteinase-1 (rho=0.50, p=0.003), and sulfated glycosaminoglycan (rho=0.42, p=0.01). No other significant correlations were present. Conclusion Effusion synovitis was significantly greater for those that demonstrated a dysregulated inflammatory response after acute ACL injury than those with a more normal response to injury. Effusion synovitis was also found to significantly correlate with synovial fluid concentrations of degradative enzymes and a biomarker of early cartilage degradation. Future work is needed to determine if non-invasive methods, such as MRI or ultrasound, may accurately identify patients within this pro-inflammatory phenotype and whether this subset is more prone to more rapid PTOA changes after injury.

Quadriceps Tendon Reconstruction With Achilles Tendon Bone Block Allograft.

Chronic quadriceps tendon ruptures are relatively uncommon albeit debilitating injuries to the knee extensor mechanism. Previous literature demonstrates worse reported outcomes with delayed surgical intervention, and no gold-standard technique currently exists for managing chronic quadriceps tendon ruptures. The goal of this technique is to provide orthopaedic surgeons an additional option that may provide a greater mechanical load to failure and greater allograft acceptance for cases with large tendon gapping or poor tissue quality that may not be viable to other lengthening techniques. We describe the repair of a chronic quadriceps tendon rupture using an Achilles tendon bone block allograft.

Synovial Fluid Inflammatory Profiles did not Differ between Isolated Anterior Cruciate Ligament and Multi-ligament Knee Injuries.

Objective and design: The purpose of this study was to compare synovial concentrations of pro- and anti-inflammatory cytokines between multiple-ligament knee injured (MLKI) and anterior cruciate ligament (ACL)-injured patients. Subjects: 14 patients with MLKI and 10 patients with isolated ACL injury. Methods: Synovial fluid was aspirated from the operative knee at the time of surgery and the concentrations of pro- and anti-inflammatory markers in the synovial fluid were determined. Structures injured, the time between injury and surgery, and demographic factors were collected. Linear regressions were used to determine the association between injury pattern and synovial inflammatory markers when controlling for age, BMI, and time between injury and surgery. Results: When adjusting for group differences in age, BMI and the time between injury and surgery, no group differences were detected (interferon gamma (p = 0.11), interleukin-1beta (IL-1b, p = 0.35), IL-2 (p = 0.28), IL-4 (p = 0.64), IL-6 (p = 0.37), IL-8 (p = 0.54), IL-10 (p = 0.25), IL-12p70 (p = 0.81), IL-13 (p = 0.31), and tumor necrosis factor-alpha (p = 0.90)). Conclusion: Synovial fluid inflammatory markers did not differ between MLKI and isolated ACL injuries. MLKIs have a greater prevalence of postoperative arthrofibrosis when compared to isolated ACL injuries; however, this may be due in part to factors other than the inflammatory status of the joint.

Human synovial fluid interleukin-6, but not type II collagen breakdown, positively correlated with pain after anterior cruciate ligament injury and reconstruction.

Anterior cruciate ligament (ACL) injury initiates a biochemical cascade thought to contribute to the onset and progression of posttraumatic osteoarthritis (PTOA). Interleukin-1ß (IL-1ß), IL-6, and C-telopeptide fragments of type II collagen (CTX-II) are implicated in joint inflammation and cartilage degradation following ACL injury; however, their association with pain is still being explored. The purpose of this study was to evaluate the associations between synovial fluid concentrations of IL-1ß, IL-6, and CTX-II with pain following ACL injury and reconstruction. We hypothesized that greater IL-1ß, IL-6, and CTX-II would correlate with greater Pain Visual Analogue Scale (VAS) scores. This was a secondary analysis of 23 patients (mean age = 18.4 years, BMI = 27.4, 13 females/10 males) with acute ACL tears who participated in a pilot randomized trial. Synovial fluid and VAS scores were collected on the day of initial presentation, at ACL reconstruction, and 1 and 4 weeks after surgery. Synovial fluid concentrations of IL-1ß, IL-6, and CTX-II were assessed using enzyme-linked immunoabsorbent assays, and repeated measures correlations were used to assess the relationships between pain and synovial IL-1ß, IL-6, or CTX-II after ACL injury and reconstruction. Pain was positively correlated with synovial fluid IL-6 concentrations (r = 0.52, p < 0.001); however, pain was inversely correlated with CTX-II (r = -0.39, p = 0.002). IL-1ß had no significant correlation with pain. Statement of clinical relevance: PTOA has been described as a "silent killer" and these results suggest that early PTOA may have pro-inflammatory pathways that are not primarily associated with pain but still lead to progressive cartilage loss.

Systematic Review of Clinical Results After Medial Meniscus Allograft Transplantation Reveals Improved Patient Reported Outcomes at Greater Than 5 Years Follow-Up.

PURPOSE: To systematically summarize the medial meniscus allograft transplantation (MAT) reported outcomes and evaluate whether the surgical technique is associated with allograft extrusion and knee function. METHODS: Systematic review was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Inclusion criteria were English-language clinical studies involving arthroscopically assisted medial MAT that reported the surgical technique and the presence of graft extrusion or functional outcomes after surgery. Studies in which outcomes for medial MAT could not be separated from lateral MAT were excluded. Surgical technique, allograft-related characteristics, and clinical outcomes were extracted. RESULTS: Twenty-four studies with 328 medial MAT were included, 58.3% studies qualified as level 4 of evidence, 29.2% as level 3, and 12.5% as level 2. Allograft fixation techniques were bone plug (235/328 [71.6%]), bone bridge/trough (55/328 [16.8%]), and soft-tissue suture fixation only (38/328 [11.6%]). Relative percentage of extrusion after surgery ranged from 24.8% to 53.7%. Major extrusion (>3 mm) ranged from zero to 78%. Overall, functional scores improved after medial MAT. None of surgical techniques were associated with poor functional outcomes or extruded meniscus; however, nonanatomical placement of the anterior and posterior horns appeared to increase meniscus extrusion. CONCLUSION: Medial MAT provides favorable outcomes, with acceptable rates of complication and failure regardless of surgical technique. Although allograft extrusion appears equivalent for both bone plug and soft-tissue fixation techniques, positioning allograft horns at the native meniscal footprint may be critical for preventing extrusion. However, the heterogeneity and low level of evidence of the studies included in this review prevent decisive conclusions regarding optimal MAT fixation techniques, clinical significance of allograft extrusion, or comparative clinical outcomes after medial MAT. LEVEL OF EVIDENCE: Level IV - systematic review of Level II to IV studies.

Pain Early After Anterior Cruciate Ligament Reconstruction is Associated With 6-Month Loading Mechanics During Running.

BACKGROUND: Anterior cruciate ligament reconstruction (ACLR) results in persistent altered knee biomechanics, but contributing factors such as pain or patient function, leading to the altered loading, are unknown. HYPOTHESIS: Individuals with worse self-reported pain after ACLR would have poorer biomechanics during running, and poor loading mechanics would be present in the ACLR limb compared with contralateral and control limbs. STUDY DESIGN: Cohort pilot study. LEVEL OF EVIDENCE: Level 3. METHODS: A total of 20 patients after ACLR (age, 18.4 ± 2.7 years; height, 1.7 ± 0.1 m; mass, 84.2 ± 19.4 kg) completed visual analog scale and Knee Injury and Osteoarthritis Outcomes Score (KOOS) at 1 and 6 months postsurgery. At 6 months postsurgery, patients underwent biomechanical testing during running. A total of 20 control individuals also completed running biomechanical analyses. Associations between patient outcomes and biomechanics were conducted, and differences in running biomechanics between groups were analyzed. RESULTS: KOOS pain score 1 month after surgery was associated with peak ACLR knee abduction moment (R2 = 0.35;P = 0.01). At 6-months, KOOS sport score was related to peak abduction moment in the ACLR limb (R2 = 0.23; P = 0.05). For change scores, the improvement in pain scores related to ACLR limb peak knee abduction moment (R2 = 0.55; P = 0.001). The ACLR limb had lower knee excursion, extension moments, and ground-reaction forces compared with the uninvolved and control limb. The uninvolved limb also had higher ground-reaction forces compared with the ACLR limb and control limb. CONCLUSION: These results suggest that patient-reported outcomes 1 and 6 months after surgery are associated with running mechanics 6 months after ACLR. Further, the underloading present in the ACLR limb and overloading in the uninvolved limb indicates greater need for running rehabilitation after ACLR. CLINICAL RELEVANCE: Understanding pain and how it may be linked to movement dysfunction is important for improving long-term outcomes.

Harvest Technique Does Affect the Quality of Osteochondral Grafts: Histologic Evaluation Comparing Commercial Standards versus Scalpel Blade Technique.

OBJECTIVE: While the percentage of viable cells is a major determinant of graft performance during osteochondral allograft (OCA) transplantation, the baseline chondrocyte viability at the periphery of osteochondral plugs is defined at the time of harvest. In this laboratory study, we aimed to determine the optimal technique for OCA plug harvest by evaluating commercial standard techniques compared to sharp blade harvest technique. DESIGN: Osteochondral explants were harvested from bovine and human samples using 3 different techniques: (1) standard OATS manual punch device (Osteochondral Autograft Transplant System OATS; Arthrex, Naples, FL), (2) powered trephine device, and (3) fresh scalpel blade. Chondrocyte viability and the dead area at the periphery of the tissue were evaluated by LIVE/DEAD staining. Safranin-O and fast-green were performed for structural evaluation. RESULTS: For both bovine and human samples, the dead area at the periphery of the explant was significantly smaller after scalpel blade preparation compared to harvest with OATS (P < 0.001) and powered trephine devices (P < 0.001). In addition, while powered device had a smaller remaining dead area compared to the OATS device (P < 0.001), there was significantly greater tissue loss and peripheral contour change for plugs harvested with the powered trephine device. CONCLUSION: Our study demonstrated that OCA plugs harvested with OATS and powered device lead to a significant mechanical injury at the periphery of the explants compared to a scalpel. We propose that the optimal technique for OCA harvest utilizes a combined approach incorporating a scalpel blade/circular scalpel to prepare the chondral surface and a powered trephine to prepare the osseous surface.

Periostin regulation and cartilage degradation early after anterior cruciate ligament reconstruction.

OBJECTIVE AND DESIGN: The purpose of this study was to explore pathological processes during the first 4 weeks after anterior cruciate ligament reconstruction (ACLR). SUBJECTS: Sixteen ACL-injured patients (8 females/8 males, mean age = 19.1, mean BMI = 28.6). METHODS: Arthrocentesis was performed 1 and 4 weeks after ACLR. Proteins in the synovial fluid were identified using nanoLC-ESI-MS/MS. Differentially up- or down-regulated proteins were identified and quantified, and a pathway analysis was performed. All identified proteins were mapped into a protein-protein interaction (PPI) network, and networks of PPIs with a combined score > 0.9 were then visualized. RESULTS: Seven pathways were upregulated after ACLR: PI3K-AKT signaling pathway, extracellular matrix (ECM)-receptor interaction, focal adhesion, protein digestion and absorption, ameobiasis, and platelet activation. Network analyses identified 8 proteins that were differentially upregulated with strong PPI interactions (periostin and 7 collagen-related proteins). Increases in periostin moderately correlated with increases in a synovial fluid biomarker of type II cartilage degradation (ρ = 0.51, p = 0.06). CONCLUSION: Pro-inflammatory pathways and periostin were upregulated after ACLR. Periostin demonstrated strong network connections with markers of collagen breakdown, and future work is needed to determine whether periostin may offer a biomarker of early cartilage degradation after ACLR and/or play an active role in early post-traumatic osteoarthritis (PTOA) progression.

Complement system dysregulation in synovial fluid from patients with persistent inflammation following anterior cruciate ligament reconstruction surgery.

Introduction: Patients with anterior cruciate ligament injury are at high risk of posttraumatic osteoarthritis and their response to reconstructive surgery and rehabilitation vary. Proteins identified in the orchestration of the acute inflammatory response may be predictive of patient outcomes. Objective: An unbiased, bottom-up proteomics approach was used to discover novel targets for therapeutics in relation to dysregulation in the orchestration of inflammatory pathways implicated in persistent joint inflammation subsequent to joint trauma. Methods: Synovial fluid was aspirated from patients at 1 week and 4 weeks after anterior cruciate ligament reconstruction (ACLR) and interleukin 6 (IL-6) concentrations were quantified by enzyme-linked immunosorbent assay. Patients were segregated into IL-6low and IL-6high groups based on IL-6 concentrations in synovial fluid at 4-weeks postoperation and proteins in synovial fluid were analyzed using qualitative, bottom-up proteomics. Abundance ratios were calculated for IL-6high and IL-6low groups as 4 weeks postoperation:1 week postoperation. Results: A total of 291 proteins were detected in synovial fluid, 34 of which were significantly (P < .05) differentially regulated between groups. Proteins associated with the classical and alternative complement cascade pathways were increased in the IL-6high compared to IL-6low group. Insulin-like growth factor-binding protein 6 (IGFBP-6) was increased by nearly 60-fold in the IL-6low group. Conclusions: Patients segregated by IL-6 concentration in synovial fluid at 4 weeks post-ACLR demonstrated differential regulation of multiple pathways, providing opportunities to investigate novel targets, such as IGFBP-6, and to take advantage of therapeutics already approved for clinical use in other diseases that target inflammatory pathways, including the complement system.

Regulatory and Ethical Aspects of Orthobiologic Therapies.

Orthobiologic therapies show significant promise to improve outcomes for patients with musculoskeletal pathology. There are considerable research efforts to develop strategies that seek to modulate the biological environment to promote tissue regeneration and healing and/or provide symptomatic relief. However, the regulatory pathways overseeing the clinical translation of these therapies are complex, with considerable worldwide variation. The introduction of novel biologic treatments into clinical practice raises several ethical dilemmas. In this review, we describe the process for seeking approval for biologic therapies in the United States, Europe, and Japan. We highlight a number of ethical issues raised by the clinical translation of these treatments, including the design of clinical trials, monitoring outcomes, biobanking, "off-label" use, engagement with the public, marketing of unproven therapies, and scientific integrity.

Mood Disorders Are Associated with Increased Perioperative Opioid Usage and Health Care Costs in Patients Undergoing Knee Cartilage Restoration Procedure.

OBJECTIVE: To identify the prevalence of mood disorder diagnoses in patients undergoing cartilage transplantation procedures and determine the relationship between mood disorders, opioid usage, and postoperative health care costs. DESIGN: Patients with current procedural terminology (CPT) codes for osteochondral autograft transplantation (OAT), osteochondral allograft transplantation (OCA), and autologous chondrocyte implantation (ACI) were identified in the Truven Health Marketscan database (January 2009-September 2014). Patients were grouped based on having a preoperative mood disorder diagnosis (preMDD). Preoperative opioids, postoperative opioids ≥90 days, and health care costs within the year postoperative were compared for those with and without mood disorders. Costs were analyzed, adjusting for preoperative cost, sex, age, and opioid usage, for those with and without mood disorders. RESULTS: A total of 3,682 patients were analyzed (ACI: 690, OAT: 1,294, OCA: 1,698). A quarter of patients had preMDD (ACI: 25.4%, OAT: 20.6%, OCA: 22.7%). Postoperative opioid use was more prevalent in preMDD patients (OAT: 37.1% vs. 24.1%, P < 0.001; OCA: 30.4% vs. 24.8%, P = 0.032; ACI: 33.7% vs. 26.2%, P = 0.070) (odds ratio [OR] ranged from 1.29 to 1.86). First-year postoperative log-transformed costs were significantly greater for preMDD patients (ACI: $7,733 vs. $5,689*, P = 0.012; OAT: $5,221 vs. $3,823*, P < 0.001; OCA: $6,973 vs. $3,992*, P < 0.001; *medians reported). The estimated adjusted first postoperative year cost increase for preMDD OCA patients was 41.7% (P < 0.001) and 28.0% for OAT patients (P = 0.034). There was no statistical difference for ACI patients (P = 0.654). CONCLUSION: Cartilage transplantation patients have a high prevalence of preoperative mood disorders. Opioid use and health care costs were significantly greater for patients with preoperative mood disorder diagnoses. LEVEL OF EVIDENCE: Level III, retrospective therapeutic study.

Association of Sex Mismatch Between Donor and Recipient With Graft Survivorship at 5 Years After Osteochondral Allograft Transplantation.

BACKGROUND: Sex mismatch between donor and recipient has been considered a potential contributor to adverse outcomes after solid organ transplantation. However, the influence of sex mismatching in osteochondral allograft (OCA) transplantation has yet to be determined. PURPOSE: To evaluate whether donor-recipient sex mismatching affects graft survival after OCA transplantation. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: In this review of prospectively collected data, patients who underwent OCA transplantation between November 2013 and November 2017 by a single surgeon were analyzed. Cumulative survival was assessed via the Kaplan-Meier method using log-rank tests to compare patients with similar donor groups. Multivariable Cox regression analysis adjusted for patient age, graft size, and body mass index was used to evaluate the influence of donor-recipient sex on graft survival. RESULTS: A total of 154 patients were included: 102 (66.2%) who received OCAs from a same-sex donor and 52 (33.8%) who received OCAs from a different-sex donor. At 5-year follow-up, a significantly lower graft survival rate was observed for different-sex donor transplantation in comparison with same-sex donorship (63% vs 92%; P = .01). When correcting for age, graft size, and body mass index, donor-recipient sex-mismatch transplantation demonstrated a 2.9-times greater likelihood to fail at 5 years compared with donor-recipient same-sex transplantation (95% CI, 1.11-7.44; P = .03). A subgroup analysis showed no significant difference in graft survival between the female-to-female and female-to-male groups (91% and 84%, respectively). Conversely, male-to-male transplantation demonstrated a significantly higher cumulative 5-year survival (94%; P = .04), whereas lower survival was found with male-to-female donorship (64%; P = .04). Multivariable Cox regression indicated a 2.6-times higher likelihood of failure for the male-to-female group in comparison with the other groups (95% CI, 1.03-6.69; P = .04). Male-to-male transplantation had a tendency toward decreased likelihood of OCA failure (hazard ratio, 0.33), although without statistical significance (95% CI, 0.11-1.01; P = .052). CONCLUSION: Mismatch between donor and recipient sex had a negative effect on OCA survival after transplantation, particularly in those cases when male donor tissue was transplanted into a female recipient.