Panos, Joseph A.

Purpose To identify risk factors for medial meniscus posterior root tears (MMPRT) and arthroplasty‐free survival in postmenopausal women, while secondary objectives included analyzing menopause‐specific factors associated with MMPRT and defining risk factors for conversion to arthroplasty in patients with a confirmed MMPRT. Methods All patients at our institution with a diagnosed meniscal tear through December 2024 were identified. From this cohort, women with a menopausal diagnosis preceding their meniscal tear were matched one‐to‐one with men by age and body mass index. Imaging studies were reviewed to identify MMPRTs. Subsequent arthroplasty, Charlson Comorbidity Index, menopausal type (surgical or physiologic), hormone replacement therapy, bisphosphonate usage, and bone mineral density were recorded. Logistic and Cox regression were used to define risk factors for MMPRT and arthroplasty; survivorship was determined using Kaplan‐Meier analyses. Results The final cohort consisted of 1564 patients (n = 782 women) with a median age of 63 years, of which 244 patients (15.6%) had MMPRT. Age and female sex were associated with MMPRT. The presence of an MMPRT, female sex, body mass index, and Charlson Comorbidity Index were associated with arthroplasty. Among postmenopausal women, age at menopause, surgical menopause, hormone replacement therapy, and bone mineral density were associated with MMPRT. For patients with MMPRT, female sex was associated with arthroplasty. Ten‐year survivorship‐free from arthroplasty in patients with MMPRT was 53.5% for women and 78.4% for men ( P = .02). Conclusions Postmenopausal status, age, and hormone replacement therapy usage are risk factors for MMPRT. Compared with men, postmenopausal women with MMPRT exhibit reduced arthroplasty‐free survival, underscoring the need for targeted interventions. Level of Evidence Level III, retrospective comparative study.

Abstract Introduction Periacetabular osteotomy (PAO) is performed in the setting of hip dysplasia to increase acetabular coverage of the femoral head and improve joint biomechanics and longevity. PAO fixation is generally achieved with two or three 4.5 mm screws, as compared to the generally more substantial plate and screw constructs used in the setting of acetabular fractures or pelvic ring injuries. The purpose of this study was to evaluate postoperative changes in hip joint center medialization and lateral acetabular coverage following PAO, understanding that these radiographic measures are generally used to guide intra-operative assessment of correction. Methods A retrospective chart review of 100 consecutive PAOs during 2021-2023 at a single academic institution by four surgeons was performed. Perioperative radiographs and fluoroscopy images were evaluated to measure lateral center edge angle (LCEA), Tönnis angle, and medialization of the hip joint center. The hip joint center was measured at one-third of the diameter of the femoral head from inferior to superior, to the ilioischial line, as previously validated by Fowler and colleagues. Results One hundred PAOs in 87 patients (87% female, mean age: 23.0 years) were included. Average preoperative radiographic parameters were 19.9° for LCEA, 12.5° for Tönnis angle, and 12.6 mm for distance from the femoral head to ilioischial line. Ninety-four cases (94%) used three screws, and 6 cases (6%) used two screws for unstable fragment fixation. On immediate postoperative films, average correction was to 28.3° for LCEA, 4.9° for Tönnis angle, and 1.9 mm of pre- to postoperative femoral head medialization (p≤0.001). Patients were radiographically followed for an average of 13.3 months, with an average time to radiographic union of 7.1 months. During the course of follow-up, LCEA increased to 29.3°, Tönnis angle remained to 5.0° (p=0.47), and medialization increased to 2.7 mm (p≤0.02), suggesting further significant but clinically modest increases in lateral coverage and femoral head medialization. Conclusion While the majority of lateral acetabular coverage and femoral head medialization occurs intra-operatively at the time of PAO, patients undergo modest but statistically significant postoperative increases in lateral coverage and medialization prior to radiographic union.

When long bones fracture, healing occurs spontaneously in about 90% of cases, while the remaining 10% result in non-union, presenting significant clinical challenges. The standard treatment for non-unions is autologous bone grafting, but this approach has limitations, including high complication rates, donor site morbidity, and limited graft availability. An alternative strategy involves using growth factors to promote bone regeneration, with recombinant bone morphogenetic protein-2 (rBMP-2) being the most common. Although effective, rBMP-2 requires supra-physiological doses that cause inflammation, poor bone quality, and severe side effects. Our previous work suggests that genetic delivery of BMP-2 may offer more controlled healing. We aim to develop a more effective therapy for non-unions using adeno-associated viral vectors. By lyophilizing the vector onto a scaffold, we also aim to increase treatment potency, reduce leakage, and improve transduction using cryoprotectant buffers.AAV6-GFP-Luciferase was used to compare the activity of AAV6 stored at −80°C versus lyophilized in cryoprotectant buffer. A rat critical-sized defect model was employed, as described in [1]. For standard storage, AAV was added to the collagen sponge before implantation into a 5mm defect. For lyophilization, AAV was mixed with cryoprotectant, loaded onto the sponge, and lyophilized. Rats were imaged at 7- and 10-days using IVIS. To assess therapeutic relevance, the experiment was repeated with AAV6-BMP2-IL1Ra, implanted into 5mm femoral defects on collagen sponges, with healing monitored by X-ray every 4 weeks (continuing through 12-weeks post-operation).The reporter and therapeutic vectors showed improved transduction efficiency with lyophilization. The reporter vector exhibited higher transgene expression at days 7 and 10. This boost in expression either remained significant through 4 weeks or continued to show better signal at that time, correlating with improved healing seen in the X-rays (Fig. 2).Preliminary data suggest that lyophilization could reduce the therapeutic dose of AAV needed for treating osseous nonunion with a bicistronic vector. Lyophilization offers various benefits: enhanced transduction efficiency, improved stability of the gene product at logistically feasible conditions, and reduced off-target effects due to less AAV leakage from the implantation site. While in vivo experiments with AAV6-BMP2-IL1Ra are ongoing, these findings warrant further investigation into lyophilized AAV therapies for this application.For any figures or tables, please contact the authors directly.

MicroRNAs (miRNAs) are short non-coding RNA sequences with the ability to inhibit the expression of a target mRNA at the post-transcriptional level, acting as modulators of both the degenerative and regenerative processes. Therefore, these molecules constitute a potential source of novel therapeutic tools. In this study, we investigated the miRNA expression profile that presented in enthesis tissue upon injury. For this, a rodent enthesis injury model was developed by creating a defect at a rat’s patellar enthesis. Following injury, explants were collected on days 1 (n = 10) and 10 (n = 10). Contra lateral samples (n = 10) were harvested to be used for normalization. The expression of miRNAs was investigated using a “Fibrosis” pathway-focused miScript qPCR array. Later, target prediction for the aberrantly expressed miRNAs was performed by means of the Ingenuity Pathway Analysis, and the expression of mRNA targets relevant for enthesis healing was confirmed using qPCRs. Additionally, the protein expression levels of collagens I, II, III, and X were investigated using Western blotting. The mRNA expression pattern of EGR1, COL2A1, RUNX2, SMAD1, and SMAD3 in the injured samples indicated their possible regulation by their respective targeting miRNA, which included miR-16, -17, -100, -124, -133a, -155 and -182. Furthermore, the protein levels of collagens I and II were reduced directly after the injury (i.e., day 1) and increased 10 days post-injury, while collagens III and X showed the opposite pattern of expression.

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.

Most gene-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are nonreplicating vectors. They deliver the gene or messenger RNA to the cell to express the spike protein but do not replicate to amplify antigen production. This study tested the utility of replication in a vaccine by comparing replication-defective adenovirus (RD-Ad) and replicating single-cycle adenovirus (SC-Ad) vaccines that express the SARS-CoV-2 spike protein. SC-Ad produced 100 times more spike protein than RD-Ad and generated significantly higher antibodies against the spike protein than RD-Ad after single immunization of Ad-permissive hamsters. SC-Ad–generated antibodies climbed over 14 weeks after single immunization and persisted for more than 10 months. When the hamsters were challenged 10.5 months after single immunization, a single intranasal or intramuscular immunization with SC-Ad-Spike reduced SARS-CoV-2 viral loads and damage in the lungs and preserved body weight better than vaccination with RD-Ad-Spike. This demonstrates the utility of harnessing replication in vaccines to amplify protection against infectious diseases.

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.

ABSTRACTIt is unclear whether treatment of intraarticular pathology should be performed during periacetabular osteotomy (PAO) to improve outcomes. Therefore, we asked: (i) What are the clinical results of PAO in patients with and without intraarticular intervention? (ii) Is there a difference in reoperations with and without intraarticular intervention? and (iii) Is there a difference in clinical results and reoperations depending on preoperative Tönnis Grade if intraarticular intervention is performed? Prospective evaluation of 161 PAO in 146 patients was performed. The cohort was 84.5% female, mean age was 26.7 ± 7.9 years and mean follow-up was 2.4 years; 112 hips had Grade 0 changes and 49 hips had Grade 1 changes. Patients were classified into three groups based on treatments during PAO: major (labral repair, femoral head–neck osteochondroplasty), minor (labral debridement, femoral/acetabular chondroplasty) or no intervention. A subset of eight patient-reported outcome measures (PROMs) was analyzed to determine whether the minimal clinically important difference (MCID) was achieved. Major, minor and no intervention groups exceeded the MCID in 5, 8 and 8, of 8 PROMs (P ≥ 0.20), respectively; intraarticular interventions did not influence reoperation-free survival (P ≥ 0.35). By Tönnis Grade, PROMs exceeding MCID decreased in Grade 1 versus 0 receiving no intervention (P < 0.001) but did not decrease for either intervention (P ≥ 0.14); intraarticular interventions did not influence reoperation-free survival (P ≥ 0.38). Overall, intraarticular intervention was associated with excellent PROMs and reoperation-free survival. Although Grade 1 patients had fewer PROM which achieved MCID, intraarticular interventions attenuated this decrease, suggesting a therapeutic advantage of intraarticular procedures for more advanced pathology.

Background: After anterior cruciate ligament (ACL) reconstruction (ACLR), changes in the appearance of the ACL graft can be monitored using magnetic resonance imaging (MRI). Purpose: The purpose of this study was to evaluate and compare the MRI signal intensity (SI) of hamstring and quadriceps tendon grafts during the first postoperative year after ACLR. As a secondary aim, the relationship of SI to clinical and anatomic measurements was analyzed. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 78 patients who underwent ACLR with an autologous graft were reviewed; 55 received hamstring grafts and 23 received quadriceps tendon grafts. At 3 and 9 months postoperatively, 3-T MRI was performed using a dedicated knee coil, and the median SI of the intra-articular ACL graft was measured on sagittal-plane images. Postoperative lateral radiographs were analyzed to determine medial and lateral posterior tibial slope (PTS). Side-to-side difference in anterior knee laxity between injured and uninjured limbs was measured at 6 and 12 months postoperatively. Results: The median SI of quadriceps grafts was significantly greater than hamstring grafts at 3 months after ACLR ( P = .02). Between 3 and 9 months, the median SI of quadriceps grafts decreased ( P < .001), while that of hamstring grafts did not significantly change ( P = .55). The lateral PTS was significantly correlated with median SI measurements at 3 and 9 months such that greater lateral PTS values were associated with greater median SI. The side-to-side difference in anterior knee laxity decreased for the quadriceps group ( P = .04) between 6 and 12 months but did not change for the hamstring group ( P = .88). Conclusion: The median SI of quadriceps grafts significantly decreased on MRI between 3 and 9 months after ACLR, while the median SI of hamstring grafts did not significantly change. The change in MRI appearance of the quadriceps grafts was paralleled by a reduction in anterior knee laxity between 6 and 12 months after surgery. In the absence of standardized imaging techniques and imaging analysis methods, the role of MRI in determining graft maturation, and the implications for progression through rehabilitation to return to sport, remain uncertain.

AbstractPeriacetabular osteotomy (PAO) is effective in the management of developmental dysplasia of the hip and femoroacetabular impingement secondary to acetabular retroversion. During anteverting PAO for acetabular retroversion, the need for both labral treatment and femoral head–neck junction osteochondroplasty remains equivocal. Accordingly, this study evaluated patient-reported outcome measures (PROM) and reoperation rates after anteverting PAO with or without intraarticular intervention. Cases of anteverting PAO performed at a single institution between November 2009 and January 2016 were retrospectively reviewed. Patients were divided into three groups: no intervention and intraarticular intervention with arthrotomy or arthroscopy. Subsequently, patients were reclassified by the intraarticular procedure performed at surgery into major (labral repair, femoral head–neck osteochondroplasty) and minor (labral debridement, femoral/acetabular chondroplasty) groups. The cohort was 75% female, median age was 19.5 years and mean body mass index was 25.0 kg/m2. Preoperative to postoperative improvement was compared to minimal clinically important differences (MCID) for eight PROM. Patients receiving major interventions exceeded MCID in a greater proportion of PROM compared to minor and no intervention groups (P &lt; 0.007); major or minor interventions did not increase the risk of reoperation over no intervention (P ≥ 0.39). Based on the current data, surgeons performing anteverting PAO for acetabular retroversion should perform arthroscopic or open labral repair and assess for impingement after the correction and perform a head–neck junction osteochondroplasty if indicated.