Faculty Bibliography

OBJECTIVE:To assess the effectiveness of a multimodal analgesic regimen containing "safer" opioid and non-narcotic pain medications in decreasing opioid prescriptions following surgical fixation in orthopedic trauma. DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:One urban, academic medical center. SUBJECTS/METHODS:Traumatic fracture patients from 2018 (848) and 2019 (931). METHODS:In 2019 our orthopedic trauma division began a standardized protocol of post-operative pain medications that included: 50 mg of tramadol four times daily, 15 mg of meloxicam once daily, 200 mg gabapentin twice daily, and 1 g of acetaminophen every 6 hours as needed. This multimodal regimen was dubbed the "Lopioid" protocol. We compared this protocol to all patients from the prior year who followed a standard protocol that included Schedule II narcotics. RESULTS:Greater mean MME were prescribed at discharge from fracture surgery under the standard protocol compared to the Lopioid protocol (252.3 vs 150.0; p < 0.001) and there was a difference in the type of opioid medication prescribed (p < 0.001). There was a difference in the number of refills filled for patients discharged with opioids after surgical treatment between standard and Lopioid cohorts (0.31 vs 0.21; p = 0.002). There was no difference in the types of medication-related complications (p = 0.710) or the need for formal pain management consults (p = 0.199), but patients in the Lopioid cohort had lower pain scores at discharge (2.2 vs 2.7; p = 0.001). CONCLUSIONS:The Lopioid protocol was effective in decreasing the amount of Schedule II narcotics prescribed at discharge and the number of opioid refills following orthopedic surgery for fractures.

PURPOSE/OBJECTIVE:Chronic use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression has been linked to an imbalance in bone metabolism leading to osteoporosis. More recently, the use of SSRIs in murine models has been shown to delay bone healing both in vivo and in vitro by decreasing the osteoblastic differentiation and mineralization. The purpose of this study was to evaluate whether or not chronic use of SSRI's in nonunion patients increases their time to union after surgical intervention. METHODS:We retrospectively analyzed 343 patients in a nonunion database to determine which patients were on SSRI medication. Of these patients, 139 could be contacted and of those 102 were not taking SSRIs and 37 were taking SSRIs. Patient's time to union from nonunion surgical intervention between each cohort at our institution was recorded as the primary outcome. Patient's medical comorbidities that could affect union rates such as diabetes and smoking status were also noted. Baseline Short Musculoskeletal Function Assessment (SMFA) index for bother and function were recorded from the time of nonunion surgery as well as last follow-up. RESULTS:Compared to recent census data, we found significantly more patients in the nonunion cohort using SSRIs (26.6%) than patients in the general population using any type of antidepressant (11%). There was no significant difference in the patients' baseline characteristics other than patients on SSRI treatment had a higher body mass index (BMI) and age (p = 0.048 and p = 0.043, respectively). There was no significant difference noted in the fracture types (p = 0.2063). Patients on SSRIs had a higher SMFA bother index and function index on follow-up (p = 0.0103, p = 0.0147). Patients in the SSRI group had a mean time to union from nonunion surgery of 6.1 months compared to 6.0 in patients without SSRI usage (p = 0.74). These did not reach statistical significance when subcohort analysis for long bone fractures was performed for the femur, tibia, and humerus. CONCLUSION/CONCLUSIONS:To our knowledge, this is the first clinical study to investigate the effects of SSRIs on fracture healing. While in vivo and in vitro murine models have shown that SSRIs can have a deleterious effect on osteoblastic activity, our retrospective analysis did not show a significant difference in time to union between patients with chronic SSRI use and patients who have not been on SSRIs. However, this investigation did show a higher incidence of SSRI use in the nonunion cohort when compared to the general population. In the context of the recent animal model study, this may point to a negative effect of SSRI use on the acute fracture healing process.

SUMMARY/CONCLUSIONS:This case presentation described a technique for repairing an acute quadriceps tendon rupture with suture anchors. The patient was a 51-year-old man who sustained an acute quadriceps tendon rupture after a fall. We used a midline incision over the quadriceps tendon and muscle. The tendon was found to be completely avulsed from the superior border of the patella. Three suture anchors were used to re-approximate the quadriceps tendon to the patella and additional sutures were used to repair the medial and lateral patellar retinacula. The patient had excellent range of motion at his 6-week follow-up appointment after the procedure.

The current standard of care for an alveolar cleft defect is an autogenous bone graft, typically from the iliac crest. Given the limitations of alveolar bone graft surgery, such as limited supply, donor site morbidity, graft failure, and need for secondary surgery, there has been growing interest in regenerative medicine strategies to supplement and replace traditional alveolar bone grafts. Though there have been preliminary clinical studies investigating bone tissue engineering methods in human subjects, lack of consistent results as well as limitations in study design make it difficult to determine the efficacy of these interventions. As the field of bone tissue engineering is rapidly advancing, reconstructive surgeons should be aware of the preclinical studies informing these regenerative strategies. We review preclinical studies investigating bone tissue engineering strategies in large animal maxillary or mandibular defects and provide an overview of scaffolds, stem cells, and osteogenic agents applicable to tissue engineering of the alveolar cleft. An electronic search conducted in the PubMed database up to December 2021 resulted in 35 studies for inclusion in our review. Most studies showed increased bone growth with a tissue engineering construct compared to negative control. However, heterogeneity in the length of follow up, method of bone growth analysis, and inconsistent use of positive control groups make comparisons across studies difficult. Future studies should incorporate a pediatric study model specific to alveolar cleft with long-term follow up to fully characterize volumetric defect filling, cellular ingrowth, bone strength, tooth movement, and implant support.

BACKGROUND:Tibial nonunion remains a considerable burden for patients and the surgeons who treat them. In recent years, alternatives to autogenous grafts for the treatment of tibial nonunions have been sought. The purpose of this study was to evaluate the efficacy of autogenous iliac crest bone graft (ICBG) in the treatment of tibial shaft nonunions. MATERIAL AND METHODS/METHODS:Sixty-nine patients were identified who underwent ICBG for repair of atrophic or oligotrophic tibial nonunion and had complete data with at least one year of follow-up (mean 27.9 months). Surgical treatments consisted of revision/supplemental fixation ± ICBG. Surgical approaches for graft placement were either posterolateral (PL), anterolateral (AL), or direct medial (DM). Healing status, time to union, postoperative pain, and functional outcomes were assessed. RESULTS:Bony union was achieved by 97.1% (67/69) of patients at a mean time of 7.8 ± 3.2 months postoperatively. There was no significant difference in mean time to union between the three surgical approach groups: (PL (44.9%) = 7.3 months, AL (20.3%) = 9.2 months, DM (34.8%) = 7.6 months; p = 0.22). Intraoperative cultures obtained at the time of nonunion surgery were positive in 27.5% of patients (19/69). Positive cultures were associated with need for secondary surgery as 8/19 patients (42.1%) with positive cultures required re-operation. Two out of four patients that developed iliac donor site hematomas/infections requiring washout had positive intraoperative cultures as well. There was no difference in final SMFA among the three surgical approach groups. CONCLUSIONS:Autogenous ICBG remains the gold standard in the management of persistent tibial nonunions regardless of surgical approach. There is a small risk for complication at the iliac crest donor site. Given the high union rate, autogenous iliac crest bone grafting for tibial nonunion remains the gold standard for this difficult condition. LEVEL OF EVIDENCE/METHODS:Level III.

Segmental bone defects (SBD) are difficult to treat, requiring a comprehensive understanding of the bone and soft tissue injury. Defect size, fracture characteristics, and local and systemic biology all help dictate treatment options. Bone grafting with autograft or allograft, Masquelet technique, and bone transport with external or internal fixation can all be used successfully in the correct patient. When deciding on the best treatment option and addressing any complications throughout the process, it is important to always keep in mind the three principles of bone healing: sterility, stability, and biology. The goal of this review is to present the history of treatment for critical SBD, including the indications and challenges that have been addressed and current and emerging treatment options.

Tissue injury leads to the well-orchestrated mobilization of systemic and local innate and adaptive immune cells. During aging, immune cell recruitment is dysregulated, resulting in an aberrant inflammatory response that is detrimental for successful healing. Here, we precisely define the systemic and local immune cell response after femur fracture in young and aging mice and identify increased toll-like receptor signaling as a potential culprit for the abnormal immune cell recruitment observed in aging animals. Myd88, an upstream regulator of TLR-signaling lies at the core of this aging phenotype, and local treatment of femur fractures with a Myd88 antagonist in middle-aged mice reverses the aging phenotype of impaired fracture healing, thus offering a promising therapeutic target that could overcome the negative impact of aging on bone regeneration.

OBJECTIVES/OBJECTIVE:Osteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signalling in chondrocytes and OA. METHODS:Biochemical copurification and proteomics screen were performed to isolate the intracellular cofactors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3ε) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3ε. Various cell-based assays and genetically modified mice with naturally occurring and surgically induced OA were performed to examine the importance of this pathway in chondrocytes and OA. RESULTS:Signalling molecule 14-3-3ε was identified as an intracellular component of TNFR2 complexes in chondrocytes in response to progranulin (PGRN), a growth factor known to protect against OA primarily through activating TNFR2. 14-3-3ε was downregulated in OA and its deficiency deteriorated OA. 14-3-3ε was required for PGRN regulation of chondrocyte metabolism. In addition, both global and chondrocyte-specific deletion of 14-3-3ε largely abolished PGRN's therapeutic effects against OA. Furthermore, PGRN/TNFR2/14-3-3ε signalled through activating extracellular signal-regulated kinase (ERK)-dependent Elk-1 while suppressing nuclear factor kappa B (NF-κB) in chondrocytes. CONCLUSIONS:This study identifies 14-3-3ε as an inducible component of TNFR2 receptor complex in response to PGRN in chondrocytes and presents a previously unrecognised TNFR2 pathway in the pathogenesis of OA.

Methotrexate (MTX) is widely used for the treatment of rheumatoid arthritis due to its well-known anti-inflammatory role in immune cells but its impact on brown and beige adipose tissue biology has not yet been investigated. Here, we present the novel evidence that MTX treatment increases the gene expression of thermogenic genes in brown and beige adipose tissues in a fat cell autonomous manner. Furthermore, we show that treatment of mice with MTX is associated with cold resistance, improved glucose homeostasis, decreased inflammation, and reduced hepatosteatosis in high-fat diet states. Overall, our data provide novel evidence of a role of MTX on thermogenic tissues not previously appreciated.