United States

Abstract Title: In vitro Murine Bioassay of IL-12-loaded PLGA Nanoparticles

Background: The cytokine Interleukin (IL)-12 has been shown to have significant anti-tumor effects through its impact on the differentiation of T helper cells and M1 activation of macrophages. While intravenous (i.v.) IL-12 has shown anti-tumor effects in murine models, in human clinical trials, research has been halted due to limited efficacy and serious side effects. These side effects are believed to be due to peripheral immune exhaustion associated i.v. IL-12 delivery. Nanoparticle encapsulation of IL-12 (nIL- 12) with Poly(D,L-lactide-co-glycolide) acid (PLGA) shows the potential to retain anti-tumor effects while mitigating dose-limiting toxicity. After injection, these PLGA nanospheres distribute systemically, deposit into tissues (limiting immune stimulation in the peripheral blood), and then slowly release encapsulated IL-12. Development of an in vitro bioassay is particularly important to ensure that the bioactivity of IL-12 is not altered following nanoparticle synthesis and encapsulation.

Methods: Following an in vitro study of nIL-12 elution, nIL-12 was used to stimulate male C57BL/6 murine splenocytes. Cultured splenocytes were exposed to five 10-fold serial dilutions of nIL-12, concentration-matched stock (unencapsulated) IL-12 (sIL-12), or unloaded nanoparticles. Production of IFN-γ was evaluated via ELISA; an ED-50 curve (IL-12 concentration vs IFN-γ production) was generated.

Results: nIL-12 and sIL-12 were diluted to an average of 18257.93, 1825.79, 182.57, 18.25, and 1.82 pg of IL-12. nIL-12 produced an average of 32652.26, 98022.06, 52440.92, 17883.45, and 991.26 pg of IFN- γ, respectively, yielding an ED50 of 40.4 ± 16.45 pg/mL. sIL-12 produced an average of 59404.67, 101668.97, 67137.01, 23587.61, and 7255.68 pg of IFN-γ, respectively, yielding an ED50 of 119.0±35.04 pg/mL. There was no statistically significant difference in ED50 between nIL-12 and sIL-12 (p = 0.1477). Thus, PLGA encapsulation was not found to alter cytokine bioactivity.

Conclusion: Successful validation of IL-12 bioactivity post-encapsulation is a critical quality control measure that shows IL-12 can be loaded into PLGA nanoparticles. These results support an in vitro dose- dependent IFN-γ response to nIL-12. Further experiments will evaluate in vivo immunological response in a murine model of metastatic osteosarcoma.

AMA Research Challenge 2022

In vitro Murine Bioassay of IL-12-loaded PLGA Nanoparticles

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poster

Intraoperative Full-Length Radiographs after Long Bone Nailing Increase Anesthesia Time and Costs, But Do Not Lead to Revision
Patrick Ryan, M21, Michael Beltran, MD2, Nihar Shah, MD2
1: University of Cincinnati College of Medicine, Cincinnati, Ohio
2: Department of Orthopaedic Surgery, University of Cincinnati College of Medicine

Background:
The treatment of long bone fractures places a large socioeconomic burden on the workforce of the USA. Plate fixation, external fixation, and intramedullary nailing are the most common treatment options for these fractures. Surgeons performing intramedullary nailing of lone bone fractures often employ intraoperative full-length radiographs prior to reversal of general anesthesia—even after utilizing intraoperative fluoroscopy, but it is unknown if this alters patient care. The purpose of this study is to determine if intraoperative full-length ‘check radiographs’ alter patient care. We theorized that these radiographs rarely alter care and are associated with increased costs and anesthesia time.
Methods:
Medical records of patients undergoing fluoroscopy-guided tibial and femoral nailing operations at the University of Cincinnati Medical Center between June 2018 and June 2021 were reviewed. Data about the patient demographics, fracture characteristics, operative details, and reintervention status were collected from 734 procedures. Standard statistical techniques were utilized to compare reintervention rates.
Results:
Of the 734 procedures reviewed, five were excluded because the status of intraoperative check radiograph imaging was not included in the chart. The remaining 729 procedures included 673 cases where check radiographs were taken (with a median of four images captured per procedure) and 56 cases where surgeons used only intraoperative fluoroscopic images to assess for proper nail placement. Only two of the 673 check radiographs (0.29% [0%, 0.7%]) led to intraoperative revision nailing during the same anesthetic event, and 36 check radiographs (5.3% [3.6%, 7.0%]) resulted in reintervention surgeries at later dates. In the cohort not receiving check radiographs, five patients (8.9% [1.5%, 16.4%]) required reintervention surgery at a later date. No significant difference in overall reintervention rate was found between procedures which did not use check radiographs and those procedures which did (odds ratio = 1.64 [0.62, 4.34]; p=0.317).
Conclusion:
Intraoperative full-length radiographs after tibial and femoral nailing rarely lead to revision surgery during the same anesthetic event. We found no difference in reintervention for tibial and femoral nailing procedures with and without check radiographs. The increased anesthesia time, costs, and surgical delays associated with obtaining these radiographs do not appear to be justified.


Intraoperative Full-Length Radiographs after Long Bone Nailing Increase Anesthesia Time and Costs, But Do Not Lead to Revision

Abstract Title: Minimally Invasive Approach to Bicondylar Tibial Plateau Fractures: The Hopscotch Incision
Background
Bicondylar tibial plateau fractures represent a complex subset of fractures that are often difficult to treat and associated with high rates of infection. Open reduction and internal fixation (ORIF) was historically performed through a single midline incision; however, due to unacceptable rates of complications, technique has shifted to the use of a single anterolateral or dual anterolateral and medial incisions. With the goal of further improving rates of complication we present a minimally invasive alternative: the “hopscotch” approach.
Methods
Two adult males who sustained bicondylar tibial plateau fractures were treated with ORIF using the hopscotch approach. This approach segments either or both the anterolateral and medial incisions into proximal and distal components. The anterolateral incision is made 2 to 3 cm proximal to the joint line and continued distally over the Gerdy’s tubercle while remaining 1 cm lateral to the tibial crest. The medial incision is made 1 to 2 cm proximal to the joint in line and extended over the pes anserinus insertion and posteromedial border of the tibia. However, instead of completing the full length of the incisions, the proximal portions are extended only as far as needed for visualization and reduction of the fracture. Chosen implants are then inserted proximally and slid distally under the skin. Secondary incisions are then made distally for exposure and fixation of the chosen implant, leaving intervening bridges of skin and subcutaneous tissue intact.
Results
No complications were noted at two week and three month follow-up visits for either patient. Incisions were well healed with no evidence of infection or radiographic abnormality.
Conclusion
This study showcases two examples of bicondylar tibial plateau fractures treated operatively via the hopscotch approach. In theory, minimizing total incisional length, soft tissue manipulation, and disruption of vascular supply should decrease rates of infection and skin necrosis; however, prospective studies are required to fully evaluate the benefits of this approach.

Minimally Invasive Approach to Bicondylar Tibial Plateau Fractures: The Hopscotch Incision

Abstract Title: Mortality and Complications in Patients with Chronic Kidney Disease (CKD) Following Lower Extremity Trauma
Authors: Margaret Fisher MS, Jason McCartney BS, Kristin A Toy MD, MS, Beau White MD, Di Hu MS, Feng-Chang Lin PhD, Judith Siegel MD, Robert Ostrum MD, Andrew Chen MD, MPH

Background: Moderate-to-severe chronic kidney disease (CKD) and end-stage renal disease (ESRD) are independent risk factors for sustaining a fragility fracture due to abnormalities within bone structure and metabolism. This study aims to assess complications in these patients following surgical management of all lower extremity fractures, as previous studies have largely focused on only hip fractures. 

Methods: This was a single-center, retrospective study of patients with CKD/ESRD who underwent operative management of lower extremity fractures between 2008-2019. Patients were stratified into three cohorts by CKD stages using estimated glomerulus filtration rate (GFR) at the time of surgery (mild (stages 1-2); GFR ≥ 60, moderate-severe (stages 3-4); GFR 15-59, ESRD (stage 5); GFR <15 or dialysis). Charlson Comorbidity Index (CCI) and fracture characteristics were collected. Outcomes of interest including minor complications (DVT, cellulitis, delayed wound healing), major complications (hardware failure, nonunion/malunion, deep infection, peri-implant fracture), and 2-year mortality were compared between cohorts using Chi-squared, ANOVA, and Fisher’s exact tests. A multivariable logistic regression assessed independent associations of moderate-severe CKD/ESRD on mortality and complications. 

Results: 356 patients with fractures of the pelvis/acetabulum (4.6%), hip (28.0%), femoral/tibial shafts (18.0%), peri-articular (22.4%), ankle (25.1%) and patella (1.9%) were included. Demographics were similar between cohorts except for age, race, and CCI. Mortality rates were significantly different between ESRD and mild CKD groups at 90 days (15.7% vs. 5.5%; p=.033), 1 year (27.1% vs. 10.5%; p=.005), and 2 years (47.1% vs. 17.0%; p<.0001). Overall complications and major complications were higher with increasing CKD severity (14.8%, 31.0%, 40.7%, p<0.0001 and 13.3%, 22.5%, 33.9%, p<0.001). After adjusting for CCI, multivariate analysis demonstrated a positive association between ESRD and mortality at 90 days (OR 4.5, 95%CI 1.3, 15.1), 1 year (OR 2.7, 95%CI 1.1, 6.5) and 2 years (OR 5.2, 95%CI 2.3, 11.6). Complications were associated with moderate/severe CKD (OR 2.2, 95% CI 1.1, 4.3, p=.0004) and ESRD (OR 4.1, 95%CI 1.8, 9.4, p<.0001). 

Conclusion: This study demonstrates high mortality and complication rates for patients with moderate-to-severe CKD who undergo operative fixation of a lower extremity fracture. These findings can be used to counsel patients regarding realistic expectations of complications.

Mortality and Complications in Patients with Chronic Kidney Disease Following Lower Extremity Trauma

Background
Distal femur fractures (DFFs) represent approximately 1% of all fractures and 3-6% of femur fractures. Management of DFFs can be challenging, particularly in the aged female population due to predisposition to osteoporosis and osteopenia and higher risk of other comorbidities. This retrospective study aims to analyze the surgical outcomes of aged female patients with non-periprosthetic DFFs treated with a locking plate (LP).

Methods
Fifty-five female patients (mean age of 71 years) with non-periprosthetic DFF underwent open reduction internal fixation using a LP from 2005 to 2019. The mean follow-up time was 67 weeks from the date of injury. Criteria used for diagnosis of nonunion included one or more of the following: (1) three consecutive months without progression of healing on postoperative radiographs, (2) a total of nine months without complete healing, or (3) physician-diagnosed nonunion using clinical judgement. Outcome data was analyzed and compared amongst patients with and without obesity or diabetes. Statistical analysis was performed with a standard statistically significant p-value of < 0.05.

Results
Thirty-two patients (58%) with DFF achieved union after initial treatment while 23 patients (42%) resulted with nonunion. 14 patients (61%) underwent revision with nine of these patients (64%) achieving union while five patients (36%) had persistent nonunion. Average healing time from initial treatment was 29 weeks, while average time from definitive treatment to union was 22 weeks. Obese (BMI >30) and non-obese patients had a nonunion rate of 65% and 28%, respectively (p = 0.008). Patients with diabetes had a nonunion rate of 65%, while patients without diabetes had a nonunion rate of 28% (p = 0.008).

Conclusion
Union can be successfully achieved in aged female patients with distal femur fractures treated with locking plate. However, the risks for nonunion and revision remain high and patients with obesity and diabetes appear to be at an increased risk. Further research should be conducted with a prospective study or multivariate analysis and increased number of patients to reaffirm this data.

Obesity and Diabetes in Distal Femur Fracture Treatment with Locking Plate

Background: Patellar Tendinopathy (Jumper’s Knee) affects up to 17% of the general population and may become recalcitrant in up to 20% of cases. While these cases often require surgery, it is unclear whether an open or arthroscopic procedure should be performed.

Methods: A systematic search of articles published 2000-present studying outcomes after surgical intervention for patellar tendinopathy was performed across PubMed, Embase, CINAHL, Scopus, and Cochrane databases and screened using PRISMA guidelines. Outcomes assessed included Patient Reported Outcome Measures (PROM), ie Victorian Institute of Sports Assessment (VISA-P), Visual Analog Scale (VAS), modified Blazina, Lysholm, Tegner, IKDC, and SANE scores, and subjective Success and Return to Sport (RTS) data at follow-up. Descriptive statistics with weighted averages were used to assess differences between groups but no meta-analysis was performed due to heterogeneity of intervention groups. 

Results: 21 studies were included for analysis that analyzed 13 arthroscopic, 8 open, and 2 combined treatment groups with follow-up ranging from 6-96 months. 2 retrospective studies directly compared open vs arthroscopic and reported earlier RTS time in arthroscopic patients (mean 5.5 vs 8.0mo) but no differences in VISA-P, overall success, or RTS rate. Open surgical patients required repeat surgery in 4 instances. Summary analysis of all data showed arthroscopic patients had earlier RTS (3.8 vs 8.7mo) and slightly higher RTS rate (88.5% vs 74.9%), but similarly high rates of overall success (89.1% vs 83.1%). Arthroscopic groups generally had higher average VISA-P and Blazina scores compared to Open groups. Combined open/arthroscopic procedures exhibited a mean success and RTS rate of 86.6% and 91.3%. Complications were reported in 3 open groups (surgical site complication, repeat surgery required, algodystrophy), 2 arthroscopic groups (failed tendon release, new-onset PFPS), and 1 combined group (repeat surgery required). 

Conclusions: In patients with refractory patellar tendinopathy and varying baseline activity levels, both open and arthroscopic surgical approaches, as well as combined procedures, lead to high rates of success and return to sport. Arthroscopic approaches may lead to quicker return to sport and greater improvements in patient-reported outcome measures than open procedures. 

Clinical Relevance: Arthroscopic intervention may yield similar or better clinical outcomes compared to open techniques with quicker return to sport for patellar tendinopathy refractory to conservative management.

Open versus Arthroscopic Management of Patellar Tendinopathy

Case: Three skeletally immature patients with scoliosis with a thoracolumbar/lumbar Cobb angle ≥40º, Risser grade 0, who had lumbar posterior spinal tethering (PST) performed by a single surgeon at an academic medical center from 2018-2022 are included in this report. 
Conclusion: This is the first paper to describe outpatient PST. At minimum 21 months postoperatively, the three outpatient PST patients had significantly reduced Cobb angles (p=0.002), decreased pain (p=0.04), no complications, no revisions, and reported being able to return to both daily life and sport. Outpatient PST may be a less morbid surgical approach to pediatric scoliosis in select patients.


Posterior Spinal Tethering as an Outpatient Surgical Option for the Treatment of Select Cases of Pediatric Scoliosis: A Report of 3 Cases

Predicting 10-Year Risk of Osteoporosis in Pre- and Perimenopausal Women

Background: Minimal clinically important differences (MCID) reflect significant changes in the health-
related quality of life after a clinical intervention. Although MCID is widely used in spine literature, few studies have been done to establish the radiographic and clinical predictors of achieving MCID in elderly
patients undergoing surgery for adult spinal deformity (ASD) correction. This study assesses preoperative and post-operative radiographic parameters, comorbidities and peri-operative complications as potential predictors of MCID in elderly patients ≥65yr with ASD. We hypothesized that patients who failed to meet MCID thresholds for ASD surgery are more likely to have significant
preoperative spinal imbalance and clinical co-morbidities.

Methods: Patients included were ≥65yr with ASD, had ≥5 levels fusion including the lumbosacral junction, and had complete preoperative, postoperative and 2yr Oswestry Disability Index (ODI), Visual Analog Scale (VAS), and radiographic measurements. Patients with 2yr postoperative improvement of ODI >10 or VAS >2.5 when compared with preoperative baseline were considered to meet MCID. A Student t test was used to assess the difference of variables across patients that achieved MCID and those that did not.

Results:104 patients ≥65yr surgically managed for ASD were separated into 2 cohorts: 67 patients that met MCID and 37 patients that did not. Patients that met MCID had significantly lower preoperative sagittal alignment (8.66 vs 11.88 cm, p=0.05) when compared with those without improvement. Other preoperative radiographic parameters such as coronal balance and T1-pelvic angle were not significantlydifferent. Post-operative radiographic parameters were all similar between the two groups. Patients meeting MCID had a lower rate of previous spinal surgery (22.3%) vs the non-improved group (51.4%) (p<0.01). The MCID group also had a lower rate of pre-existing stroke (3%) compared with the non- improved group (13.5%) (p=0.04). Achieving MCID is also more likely in patients with scoliosis as
compared to kyphosis (84% vs 45% p=0.03).

Conclusion: Preoperative sagittal mal-alignment, a predominantly kyphotic deformity, revision surgery,
and a history of stroke are predictive of failure to meet MCID in deformity surgery for patients ≥65yr. Knowledge of these characteristics can be beneficial in counseling patients about prognosis after surgery and post-operative expectations.

Predictors of Minimally Clinical Importance Difference in Elderly Patients (≥ 65 years of age) Undergoing Spinal Deformity Surgery

Background. The peroneus longus (PL) and peroneus brevis (PB) tendons comprise the lateral compartment of the leg and work to stabilize the foot during weight-bearing. Peroneal tendinopathy can precipitate persistent lateral ankle pain and induce substantial functional disability. The process by which peroneal pathology can progress to significant lateral ankle dysfunction is thought to stem from asymptomatic, subclinical peroneal tendinopathy. As such, there is substantial clinical benefit to identifying asymptomatic patients with this condition before it progresses to disability. Various ultrasound (US) characteristics have been observed in peroneal tendinopathy. The purpose of this study is to identify the frequency of subclinical tendinopathic characteristics in asymptomatic peroneal tendons. 
Methods. A total of 170 participants underwent bilateral US examination of the foot and ankle. These images were assessed for abnormalities of the PL and PB tendons by a group of physicians, and frequencies of abnormalities were recorded. This team consisted of an orthopedic surgeon specializing in foot and ankle surgery, a fifth-year orthopedic surgery resident, and a family medicine physician with musculoskeletal sonographer certification.
Results. 340 PL and 340 PB tendons were assessed. Of these, 68 (20%) PL and 41 (12.1%) PB tendons had abnormal traits. Specifically, 24 PLs (7.1%) and 22 PBs (6.5%) had circumferential fluid, 16 PLs (4.7%) and 9 PBs (2.6%) had noncircumferential fluid, 27 PLs (7.9%) and 6 PBs (1.8%) had thickening, 36 PLs (10.6%) and 12 PBs (3.5%) had heterogenicity, 10 PLs (2.9%) and 2 PBs (0.6%) had hyperemia, and 1 PL (0.3%) had calcification. 
Conclusion. Of the 170 participants, 34% had at least one abnormal PL characteristic identified on US. Twenty-two percent of participants were found to have at least one abnormal PB trait. In the study population, heterogenicity was the most prevalent abnormality found in PL tendons, while circumferential fluid was the most common abnormal trait in PB tendons. Understanding the frequency of abnormalities in asymptomatic peroneal tendons may aid clinicians in identifying subclinical tendinopathy before it progresses to dysfunction.

Prevalence of Abnormal Ultrasound Findings in Asymptomatic Peroneal Tendons

Background: Scoliosis is a common spinal malformation, which is typically diagnosed and assessed for severity by measuring the Cobb angle on a plain radiograph. Although manual methods are still considered the gold standard, recent studies have shown that PACS (picture archiving and communication systems methods) have comparable intraobserver and interobserver reliability levels for experienced clinicians. However, there is limited data for these reliability measures in less experienced medical personnel, especially with digital methods like PACS.

Methods: 10 radiographic images of scoliosis patients were obtained via a retrospective chart review. After a brief training exercise, Cobb angle measurements were performed twice on each radiograph, separated by one week, using the PACS method. Subject groups ranged in their level of prior training and experience with Cobb angle measurements from inexperienced medical students, to more experienced resident physicians, and highly experienced orthopedic surgeons and radiologists. Data was compared for interrater reliability levels within groups and between groups, and for individual intra-rater reliability levels. Intra-class correlation coefficient (ICC) between averaged measured were calculated and a Cronbach’s α obtained. An α of ≥ 0.9 is considered excellent agreement, 0.9 > α ≥ 0.8 is good, 0.8 > α ≥ 0.7 is acceptable, 0.7 > α ≥ 0.6 is questionable and α < 0.6 is poor or unacceptable reliability. 

Results: Resident physicians, orthopedic surgeons, and radiologist subject groups had significant levels of between-group and within-group inter-rater reliability as well as individual intra-rater reliability levels (α ≥ 0.9, p<0.001). Inexperienced medical student raters had poor within-group interrater reliability (α = -0.176). One medical student had a significant level of individual intra-rater reliability (α > 0.9, p<0.001) while the other had poor intra-rater reliability (α < 0.6, p=0.035). Between-group inter-rater reliability for medical students and more experienced professionals was poor (α < 0.6).

Conclusions: While PACS has been shown to be a reliable method for measuring Cobb angle and an acceptable substitute for conventional manual techniques, it is not a reliable method in less experienced trainees such as medical students.

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In vitro Murine Bioassay of IL-12-loaded PLGA Nanoparticles

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