Benjamin V. Kelley

Bacterial biofilms on orthopedic implants are resistant to the host immune response and to traditional systemic antibiotics. Novel therapies are needed to improve patient outcomes. TRL1068 is a human monoclonal antibody (mAb) against a biofilm anchoring protein. For assessment of this agent in an orthopedic implant infection model, efficacy was measured by reduction in bacterial burden of Staphylococcus aureus, the most common pathogen for prosthetic joint infections (PJI). Systemic treatment with the biofilm disrupting mAb TRL1068 in conjunction with vancomycin eradicated S. aureus from steel pins implanted in the spine for 26 of 27 mice, significantly more than for vancomycin alone. The mechanism of action was elucidated by two microscopy studies. First, TRL1068 was localized to biofilm using a fluorescent antibody tag. Second, a qualitative effect on biofilm structure was observed using scanning electron microscopy (SEM) to examine steel pins that had been treated in vivo. SEM images of implants retrieved from control mice showed abundant three-dimensional biofilms, whereas those from mice treated with TRL1068 did not. Clinical Significance: TRL1068 binds at high affinity to S. aureus biofilms, thereby disrupting the three-dimensional structure and significantly reducing implant CFUs in a well-characterized orthopedic model for which prior tested agents have shown only partial efficacy. TRL1068 represents a promising systemic treatment for orthopedic implant infection.

Objectives: Implant prominence after ulnar fracture fixation may be mitigated by the use of lower profile plates. The biomechanical strength and stability of 2.7-mm and 3.5-mm locking compression plates for fixation were compared. Methods: Two fracture conditions, transverse (N = 10) and oblique (N = 10), were evaluated in an in vitro study. Half of the specimens for each condition were fixed with 2.7-mm plates and the other half with 3.5-mm plates, all fixed with conventional dynamic compression mechanisms. Specimens were loaded under ±2 Nm of cyclic axial torsion, then under 10 Nm of cyclic cantilever bending, and bending to failure. Interfragmentary motion and strain were analyzed to determine construct stability as a function of fracture pattern and plate size. Results: Interfragmentary motion was significantly larger in all constructs fixed with 2.7-mm plates, compared with 3.5-mm plates (P < 0.01). The 2.7-mm constructs with transverse fractures had the greatest motion, ranging between 5° and 10° under axial rotation and 5.0–6.0 mm under bending. Motions were the lowest for 3.5-mm constructs with oblique fractures, ranging between 3.2 and 4.2 mm under bending and 2°–3.5° for axial rotation. For oblique fractures, the bending moment at ultimate failure was 31.4 ± 3.6 Nm for the 2.7-mm constructs and 10.0 ± 1.9 Nm for 3.5-mm constructs (P < 0.01). Similarly, for transverse fractures, the bending moment was 17.9 ± 4.0 Nm for the 2.7-mm constructs and 9.7 ± 1.3 Nm for the 3.5-mm constructs (P < 0.01). Conclusions: Although 3.5-mm plates were more effective at reducing fracture motion, they were consistently associated with refracture at the distal-most screw hole under load to failure. By contrast, 2.7-mm plates plastically deformed despite excessive loads, potentially avoiding a subsequent fracture. Level of Evidence: Level V.

Background: Well known for their hemostatic function, platelets are increasingly becoming recognized as important immunomodulators. The purpose of the present study was to assess the impact of platelet depletion on antimicrobial host defense in a mouse model of periprosthetic joint infection (PJI). Methods: Thrombocytopenia (TCP) was induced in C57BL/6 mice with use of a selective antibody against platelet CD41 (anti-CD41). Whole blood from pre-treated mice was incubated with Staphylococcus aureus to assess antimicrobial efficacy with use of bioluminescent imaging, quantitative histological staining, and colony forming unit (CFU) quantification. In parallel, untreated heterologous platelets were added to TCP blood to assess potential rescue of antimicrobial efficacy. In vivo, TCP and control mice underwent placement of a titanium implant in the femur inoculated with bioluminescent Xen36 S. aureus. Longitudinal bioluminescent imaging was performed postoperatively to quantify the evolution of bacterial burden, which was confirmed via assessment of S. aureus CFUs on the implant and in peri-implant tissue on postoperative day (POD) 28. Results: Anti-CD41 treatment resulted in significant dose-dependent reductions in platelet count. Ex vivo, platelet-depleted whole blood demonstrated significantly less bacterial reduction than control blood. These outcomes were reversed with the addition of untreated rescue platelets. In vivo, infection burden was significantly higher in TCP mice and was inversely correlated with preoperative platelet count (r² = 0.63, p = 0.037). Likewise, CFU quantification on POD28 was associated with increased bacterial proliferation and severity of periprosthetic infection in TCP mice compared with controls. Conclusions: Thrombocytopenia resulted in an increased bacterial burden both ex vivo and in vivo in a mouse model of PJI. Clinical Relevance: In orthopaedic patients, deficiencies in platelet quantity or function represent an easily modifiable risk factor for PJI.

Background: The current U.S. orthopaedic residency application process is becoming increasingly impersonal in the wake of an increasing number of applications. Through an analysis of orthopaedic surgery residency application statistics, we have highlighted the effect that the number of orthopaedic applications has on match rate, and we have suggested methods for a more personalized application process. Methods: Data from the Association of American Medical Colleges (AAMC) and the National Resident Matching Program (NRMP) for United States orthopaedic residency applicants from 2008 to 2018 were collected. These data included the average number of applications submitted per applicant, the average number of applications received per program, the total number of residency positions offered in the U.S., the total number of U.S. applicants, and the total number of U.S. applicants who matched to a U.S. orthopaedic surgery residency program. U.S. applicant match rates and the average number of applications received per residency position offered were calculated. Linear regression models were used to determine the rate at which these variables changed over time. Results: The average number of applications submitted by an applicant increased from 46.5 in 2008 to 74.9 in 2018. The average number of applications received per residency position offered increased from 54.1 in 2008 to 85.7 in 2018. The number of U.S. applicants was 740 in 2008 and 849 in 2018. The number of U.S. orthopaedic residency programs only slightly increased from 160 in 2008 to 171 in 2018. The match rate for U.S. medical school applicants has remained stable from 2008 to 2018 at a mean of 76.9% and a standard deviation of 2.3%. Conclusions: The match rate has remained stable from 2008 to 2018 despite an increase in the number of applications per position. This discrepancy suggests that increasing the number of submitted applications may not correlate with applicant success. We address this discrepancy and suggest methods that can potentially allow for a more targeted orthopaedic application experience.

Recent studies demonstrated a 5% increase in cartilage repair procedures annually in the United States. There is currently no consensus regarding a superior technique, nor has there been a comprehensive evaluation of postoperative clinical outcomes with respect to a minimal clinically important difference (MCID). To determine the proportion of available cartilage repair studies that meet or exceed MCID values for clinical outcomes improvement over short-, mid-, and long-term follow-up. Systematic review and meta-analysis. A systematic review was performed via the Medline, Scopus, and Cochrane Library databases. Available studies were included that investigated clinical outcomes for microfracture (MFX), osteoarticular transfer system (OATS), osteochondral allograft transplantation, and autologous chondrocyte implantation/matrix-induced autologous chondrocyte implantation (ACI/MACI) for the treatment of symptomatic knee chondral defects. Cohorts were combined on the basis of surgical intervention by performing a meta-analysis that utilized inverse-variance weighting in a DerSimonian-Laird random effects model. Weighted mean improvements in International Knee Documentation Committee (IKDC), Lysholm, and visual analog scale for pain (VAS pain) scores were calculated from preoperative to short- (1-4 years), mid- (5-9 years), and long-term (≥10 years) postoperative follow-up. Mean values were compared with established MCID values per 2-tailed 1-sample Student t tests. A total of 89 studies with 3894 unique patients were analyzed after full-text review. MFX met MCID values for all outcome scores at short- and midterm follow-up with the exception of VAS pain in the midterm. OATS met MCID values for all outcome scores at all available time points; however, long-term data were not available for VAS pain. Osteochondral allograft transplantation met MCID values for IKDC at short- and midterm follow-up and for Lysholm at short-term follow-up, although data were not available for other time points or for VAS pain. ACI/MACI met MCID values for all outcome scores (IKDC, Lysholm, and VAS pain) at all time points. In the age of informed consent, it is important to critically evaluate the clinical outcomes and durability of cartilage surgery with respect to well-established standards of clinical improvement. MFX failed to maintain VAS pain improvements above MCID thresholds with follow-up from 5 to 9 years. All cartilage repair procedures met MCID values at short- and midterm follow-up for IKDC and Lysholm scores; ACI/MACI and OATS additionally met MCID values in the long term, demonstrating extended maintenance of clinical benefits for patients undergoing these surgical interventions as compared with MFX.

Background: Achilles tendon rupture is a common injury and the best treatment option remains uncertain between surgical and nonoperative methods. Biologic approaches using multipotent stem cells such as perivascular stem cells pose a possible treatment option, although there is currently a paucity of evidence regarding their clinical therapeutic use. Questions/purposes: The purpose of this study was to determine whether injected perivascular stem cells (PSCs) would (1) improve histologic signs of tendon healing (such as percent area of collagen); and (2) improve biomechanical properties (peak load or stiffness) in a rat model of Achilles tendon transection. Methods: Two subtypes of PSCs were derived from human adipose tissue: pericytes (CD146⁺CD34^-CD45^-CD31^-) and adventitial cells (CD146^-CD34⁺CD45^-CD31^-). Thirty-two athymic rats underwent right Achilles transection and were randomized to receive injection with saline (eight tendons), hydrogel (four tendons), pericytes in hydrogel (four tendons), or adventitial cells in hydrogel (eight tendons) 3 days postoperatively with the left serving as an uninjured control. Additionally, a subset of pericytes was labeled with CM-diI to track cell viability and localization. At 3 weeks, the rats were euthanized, and investigators blinded to treatment group allocation evaluated tendon healing by peak load and stiffness using biomechanical testing and percent area of collagen using histologic analysis with picrosirius red staining. Results: Histologic analysis showed a higher mean percent area collagen for pericytes (30%) and adventitial cells (28%) than hydrogel (21%) or saline (26%). However, a nonparametric statistical analysis yielded no statistical difference. Mechanical testing demonstrated that the pericyte group had a higher peak load than the saline group (41 ± 7 N versus 26 ± 9 N; mean difference 15 N; 95% confidence interval [CI], 4-27 N; p = 0.003) and a higher peak load than the hydrogel group (41 ± 7 N versus 25 ± 3 N; mean difference 16; 95% CI, 8-24 N; p = 0.001). The pericyte group demonstrated higher stiffness than the hydrogel group (36 ± 12 N/mm versus 17 ± 6 N/mm; mean difference 19 N/mm; 95% CI, 5-34 N/mm; p = 0.005). Conclusions: Our results suggest that injection of PSCs improves mechanical but not the histologic properties of early Achilles tendon healing. Clinical Relevance: This is a preliminary study that provides more insight into the use of adipose-derived PSCs as a percutaneous therapy in the setting of Achilles tendon rupture. Further experiments to characterize the function of these cells may serve as a pathway to development of minimally invasive intervention aimed at improving nonoperative management while avoiding the complications associated with surgical treatment down the line.

To perform a systematic review of clinical outcomes following microfracture (MFX), autologous chondrocyte implantation (ACI), osteochondral allograft transplantation (OCA), and osteochondral autograft transplantation system (OATS) to treat articular cartilage lesions in pediatric and adolescent patients. We sought to compare postoperative improvements for each cartilage repair method to minimal clinically important difference (MCID) thresholds. MEDLINE, Web of Science, Scopus, and Cochrane Library databases were searched for studies reporting MCID-validated outcome scores in a minimum of 5 patients ≤19 years treated for symptomatic knee chondral lesions with minimum 1-year follow-up. One-sample t tests were used to compare mean outcome score improvements to established MCID thresholds. Twelve studies reporting clinical outcomes on a total of 330 patients following cartilage repair were identified. The mean age of patients ranged from 13.7 to 16.7 years and the mean follow-up was 2.2 to 9.6 years. Six studies reported on ACI, 4 studies reported on MFX, 2 studies reported on OATS, and 1 study reported on OCA. ACI (P < 0.001, P = 0.008) and OCA (P < 0.001) showed significant improvement for International Knee Documentation Committee (IKDC) scores with regard to MCID while MFX (P = 0.66) and OATS (P = 0.11) did not. ACI (P < 0.001) and OATS (P = 0.010) both showed significant improvement above MCID thresholds for Lysholm scores. MFX (P = 0.002) showed visual analog scale (VAS) pain score improvement above MCID threshold while ACI (P = 0.037, P = 0.070) was equivocal. Outcomes data on cartilage repair in the pediatric and adolescent knee are limited. This review demonstrates that all available procedures provide postoperative improvement above published MCID thresholds for at least one reported clinical pain or functional outcome score.