Nagelli, Christopher V.

Abstract Background: Osteochondral allograft and autograft transplantation for femoral head defects have emerged as promising treatments for concomitant cartilage and subchondral bone injuries in young patients. The purpose of this study was to evaluate the clinical and radiological outcomes of patients who underwent osteochondral allograft or autograft transplantation for femoral head defects and access any risk factors that may lead to conversion to THA. Methods: All patients who underwent osteochondral allograft or autograft transplantation for femoral head defects were analyzed. All patients had symptomatic femoral head osteochondral defects identifiable on advanced imaging such as computed tomography or magnetic resonance imaging. Clinical outcomes were assessed at final follow-up with the modified Harris Hip Score (mHHS), Hip Outcome Score – Activities of Daily Living (HOS-ADL), Hip Outcome Score – Sport-Specific Subscale (HOS-SSS), and International Hip Outcome Tool (iHOT-12). Additionally, patients were assessed radiographically preoperatively and at a final postoperative visit using anterior-posterior and lateral radiographs for osteoarthritis using Tönnis grading. Results: A total of 27 patients were included in this study (19 osteochondral allograft transplantation, 8 osteochondral autograft transplantation). The overall mean follow-up was 4.7 years. The average mHHS, HOS-ADL, HOS-SSS, and iHOT-12 for the allograft cohort were 86.7, 92.8, 81.4, and 79.0, respectively, while for the autograft cohort it was 87.6, 92.7, 83.1, and 82.0, respectively. For the allograft cohort, there were a total of 5 reoperations (26.3%) consisting of 4 THA at a mean of 1.9 years and 1 trochanteric osteotomy nonunion at 0.7 year. For the remaining allograft patients who did not undergo treatment failure, only one (6.7%) had radiographic osteoarthritis progression. None of the patients in the autograft cohort underwent THA. Overall, conversion to THA was 14.8%. Conclusion: Osteochondral allograft and autograft transplantation for femoral head defects demonstrated overall favorable clinical outcomes and conversion to THA at mean 5-year follow-up and should be considered for patients with focal femoral head defects.

Aging is a major risk factor for osteoarthritis (OA), but the specific mechanisms connecting aging and OA remain unclear. Although chondrocytes rarely divide in adult articular cartilage, they undergo replicative senescence in vitro, offering a model to study aging-related changes under controlled conditions. OA cartilage was obtained from an 80-year-old male and a 72-year-old female, while normal cartilage was sourced from a 26-year-old male. Chondrocyte cultures were established and sub-cultured to their Hayflick limit. Bulk RNA sequencing on early- and late-passage human articular chondrocytes identified transcriptomic changes associated with cellular aging. Early-passage OA chondrocytes already showed senescent phenotypes, unlike normal chondrocytes. All three cultures underwent 30 population doublings before replicative exhaustion, at which point all cells displayed senescence. During this process, cells lost their ability to form cartilaginous pellets. Differential gene expression analysis revealed distinct transcriptomic profiles between early- and late-passage chondrocytes and between normal and OA-derived cells. Genes related to matrix synthesis, degradation, inflammation, and the senescence-associated secretory phenotype (SASP) showed significant expression changes. Despite being a small pilot study, these findings suggest that further research into the molecular and metabolic changes during chondrocyte senescence could provide valuable insights into OA pathobiology.

Abstract Objective 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. Methods Cartilage was recovered from two knees with OA and one normal knee. Chondrocyte cultures were established and sub-cultured until their Hayflick limit. Bulk RNA sequencing on early- and late-passage human articular chondrocytes allowed identification of transcriptomic changes associated with cellular aging. Results One male (80 years old) and one female (72 years old) patient provided OA cartilage. The donor of normal chondrocytes was a 26-year old male. Early passage chondrocytes from the two OA samples already had the phenotype of senescing cells, unlike normal chondrocytes. Nevertheless, all three chondrocyte cultures underwent 30 population doublings before replicative exhaustion, by which point all cells displayed a senescent phenotype. During this process, the cells lost their ability to form cartilaginous pellets. Differentially expressed genes (DEGs) analysis confirmed distinct transcriptomic profiles between early- and late-passage chondrocytes, as well as between cells isolated from normal and OA cartilage. Various changes in expression of genes related to cartilage matrix synthesis, degradation, inflammation and the senescence-associated secretory phenotype (SASP) were noted. Conclusions Although only a small pilot study, its data suggest that a larger and deeper study of the molecular and metabolic events accompanying the senescence of chondrocytes could provide important insights into the pathobiology of OA.

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.

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.

AbstractThis 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.

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.

Background: Neuromuscular training (NMT) has been shown to attenuate high-risk biomechanics in uninjured athletes. At the time that athletes return to sport after anterior cruciate ligament (ACL) reconstruction (ACLR), they demonstrate hip biomechanical deficits associated with injury to the reconstructed knee versus the uninjured contralateral knee. Purpose: The primary purpose of the study was to examine whether an NMT program can improve single-leg drop (SLD) landing hip biomechanics for athletes after ACLR. Secondarily, we compared the posttraining SLD hip biomechanics of athletes after ACLR with a control group of athletes who also completed the NMT program. Study Design: Controlled laboratory study. Methods: A total of 18 ACLR and 10 uninjured athletes were recruited and completed a 12-session NMT program. A knee-specific questionnaire and biomechanics of an SLD task was evaluated for each athlete before and after NMT. Paired t tests were used to compare pre- and posttraining International Knee Documentation Committee (IKDC) scores. Repeated-measures analysis of variance (ANOVA) was performed to assess the main effects and interactions of testing session × limb for the ACLR athletes. A 2-way ANOVA was conducted to quantify the interactions and main effects of group × limb. Results: There was a significant increase ( P = .03) in IKDC scores from pre- to posttraining. For the ACLR athletes, there was a significant session × limb interaction for hip external rotation moment ( P = .02) and hip abduction angle ( P = .013). Despite increases in hip external rotation moment, no significant changes from pre- to posttraining were observed for the involved limbs. No significant changes were observed for hip abduction angle of the involved limbs between training sessions. Significant main effects of session ( P < .05) revealed that athletes landed with greater hip excursion, lower hip flexion moment, and lower ground-reaction force after training. The posttraining comparison between the ACLR and control groups found no significant group × limb interactions for any of the hip kinematic or kinetic variables. A significant main effect of group ( P < .05) revealed that the ACLR athletes landed with greater hip flexion angle and hip external rotation moment. Conclusion: ACLR athletes demonstrated an improvement in SLD hip biomechanics and neuromuscular control after participating in an NMT program. Clinical Relevance: This evidence indicates a potential role for NMT to improve hip biomechanics during an SLD task so as to reduce ACL injury risk.

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.

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.