Faculty Bibliography

Hexavalent chromium [Cr(VI)] is extensively used in many industrial processes. Previous studies reported that Cr(VI) exposures during early embryonic development reduced body weight with musculoskeletal malformations in rodents while exposures in adult mice increased serum creatine kinase activity, a marker of muscle damage. However, the impacts of Cr(VI) on muscle differentiation remain largely unknown. Here, we report that acute exposures to Cr(VI) in mouse C2C12 myoblasts inhibit myogenic differentiation in a dose-dependent manner. Exposure to 2 μM of Cr(VI) resulted in delayed myotube formation, as evidenced by a significant decrease in myotube formation and expression of muscle-specific markers, such as muscle creatine kinase (Mck), Myocyte enhancer factor 2 (Mef2), Myomaker (Mymk) and Myomixer (Mymx). Interestingly, exposure to 5 μM of Cr(VI) completely abolished myotube formation in differentiating C2C12 cells. Moreover, the expression of key myogenic regulatory factors (MRFs) including myoblast determination protein 1 (MyoD), myogenin (MyoG), myogenic factor 5 (Myf5), and myogenic factor 6 (Myf6) were significantly altered in Cr(VI)-treated cells. The inhibitory effect of Cr(VI) on myogenic differentiation was further confirmed in freshly isolated mouse satellite cells, a stem cell population essential for adult skeletal muscle regeneration. Furthermore, Cr(VI) exposure to fully differentiated C2C12 myotubes resulted in a decrease in myotube diameter, which was exacerbated upon co-treatment with dexamethasone. Together, our results demonstrate that Cr(VI) inhibits myogenic differentiation and induces myotube atrophy in vitro.

Non-resorbable dental barrier membranes entail the risk of dehiscence due to their smooth and functionally inert surfaces. Non-thermal plasma (NTP) treatment has been shown to increase the hydrophilicity of a biomaterials and could thereby enhance cellular adhesion. This study aimed to elucidate the role of allyl alcohol NTP treatment of poly(tetrafluoroethylene) in its cellular adhesion. The materials (non-treated PTFE membranes (NTMem) and NTP-treated PTFE membranes (PTMem)) were subjected to characterization using scanning electron microscopy (SEM), contact angle measurements, X-ray photoelectron spectroscopy (XPS), and electron spectroscopy for chemical analysis (ESCA). Cells were seeded upon the different membranes, and cellular adhesion was analyzed qualitatively and quantitatively using fluorescence labeling and a hemocytometer, respectively. PTMem exhibited higher surface energies and the incorporation of reactive functional groups. NTP altered the surface topography and chemistry of PTFE membranes, as seen through SEM, XPS and ESCA, with partial defluorination and polymer chain breakage. Fluorescence labeling indicated significantly higher cell populations on PTMem relative to its untreated counterparts (NTMem). The results of this study support the potential applicability of allyl alcohol NTP treatment for polymeric biomaterials such as PTFE-to increase cellular adhesion for use as dental barrier membranes.

OBJECTIVE:To report on demographics, injury patterns, management strategies and outcomes of patients who sustained fractures of the tibial plateau seen at a single center over a 16-year period. DESIGN/METHODS:Prospective collection of data.Patients/ Participants: 716 patients with 725 tibia plateau fractures, were treated by one of 5 surgeons. INTERVENTION/METHODS:Treatment of tibial plateau fractures. MAIN OUTCOME MEASUREMENTS/METHODS:Outcomes were obtained at standard timepoints. Complications were recorded. Patients were stratified into 3 groups: those treated in the first 5 years, those treated in the second 5 years and those treated in the most recent 6 years. RESULTS:608 fractures were followed for a mean 13.4 months (6-120) and 82% had a minimum 1-year follow up. Patients returned to self-reported baseline function at a consistent proportion during the 3 time periods. The average knee arc was 125 degrees (75 - 135 degrees) at latest follow up and did not differ over time. The overall complication rate following surgery was 12% and did not differ between time periods. Radiographs demonstrated excellent rates of healing and low rates of PTOA and improved articular reductions at healing (0.58 mm in group 3 compared to 0.94 mm in Group 1 and 1.12 mm in Group 2) (P<0.05). CONCLUSION/CONCLUSIONS:The majority of patients regained their baseline functional status following surgical intervention and healing. Over time the ability of surgeons to achieve a more anatomic joint reduction was seen, however this did not correlate with improved functional outcomes. LEVEL OF EVIDENCE/METHODS:Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence.

Bone tissue regeneration is a complex process that proceeds along the well-established wound healing pathway of hemostasis, inflammation, proliferation, and remodeling. Recently, tissue engineering efforts have focused on the application of biological and technological principles for the development of soft and hard tissue substitutes. Aim is directed towards boosting pathways of the healing process to restore form and function of tissue deficits. Continued development of synthetic scaffolds, cell therapies, and signaling biomolecules seeks to minimize the need for autografting. Despite being the current gold standard treatment, it is limited by donor sites' size and shape, as well as donor site morbidity. Since the advent of computer-aided design/computer-aided manufacturing (CAD/CAM) and additive manufacturing (AM) techniques (3D printing), bioengineering has expanded markedly while continuing to present innovative approaches to oral and craniofacial skeletal reconstruction. Prime examples include customizable, high-strength, load bearing, bioactive ceramic scaffolds. Porous macro- and micro-architecture along with the surface topography of 3D printed scaffolds favors osteoconduction and vascular in-growth, as well as the incorporation of stem and/or other osteoprogenitor cells and growth factors. This includes platelet concentrates (PCs), bone morphogenetic proteins (BMPs), and some pharmacological agents, such as dipyridamole (DIPY), an adenosine A 2A receptor indirect agonist that enhances osteogenic and osteoinductive capacity, thus improving bone formation. This two-part review commences by presenting current biological and engineering principles of bone regeneration utilized to produce 3D-printed ceramic scaffolds with the goal to create a viable alternative to autografts for craniofacial skeleton reconstruction. Part II comprehensively examines recent preclinical data to elucidate the potential clinical translation of such 3D-printed ceramic scaffolds.

To determine if radiographic evidence of posttraumatic osteoarthritis (PTOA) following tibial plateau fracture correlates with poorer clinical and functional outcomes, patients with tibial plateau fractures were followed at 3, 6, and 12 months. All patients had baseline radiographs and computed tomography scan. Radiographs obtained at each follow-up were reviewed for healing, articular incongruence, hardware positional changes, and the development of postinjury arthritic change. Cohorts were determined based on the presence (PTOA) or absence (NPTOA) of radiographic evidence of PTOA. Demographics, fracture classification, complications, additional procedures, and functional status were compared between cohorts. Sixty patients had radiographic evidence of PTOA on follow-up radiographs at a mean final follow-up of 24.2 months. The NPTOA cohort was composed of 210 patients who were matched to the PTOA cohort based on age and Charlson comorbidity index. Mean time to fracture union for the overall cohort was 4.86 months. Cohorts did not differ in Schatzker classification, time to healing, injury mechanism, or baseline Short Musculoskeletal Function Assessment (SMFA). Patients with PTOA had a greater degree of initial depression and postoperative step-off, higher incidence of initial external fixator usage, higher rates of reoperation for any reason, and higher rates of wound complications. Associated soft tissue injury and meniscal repair did not coincide with the development of PTOA. Range of motion and SMFA scores were significantly worse at all time points in patients with PTOA. Although fracture patterns are similar, patients who required an initial external fixator, had a greater degree of initial depression or residual articular incongruity, underwent more procedures, and developed an infection were found to have increased incidence of PTOA. Radiographic evidence of osteoarthritis correlated with worse functional status in patients. The goal of surgery should be restoration of articular congruity and stability to mitigate the risk of PTOA, although this alone may not prevent degenerative changes. Patients with early loss of range of motion should be aggressively treated as this may precede the development of PTOA.

BACKGROUND:Despite the expanded application of thoracic endovascular aortic repair (TEVAR) in patients with significant cardiac comorbidities, the effect of decreased left ventricular ejection fraction (EF) on outcomes remains unknown. The aim of this study was to compare outcomes in patients with normal and abnormal EFs undergoing TEVAR for type-B aortic dissection (TBAD). METHODS:The Vascular Quality Initiative database was reviewed from 2012 to 2020. Patients were categorized into severely reduced (EF ≤ 30%), reduced (EF 30-50%) and normal EF (EF>50%). Baseline characteristics, procedural details and 18-month outcomes were compared. Multivariable logistic regression identified factors associated with mortality, major adverse cardiac events (MACEs), and aortic-related reintervention. RESULTS:Of 1,993 patients, 38 (2%) and 208 (10%) patients had severely reduced ejection fraction (SREF) and reduced ejection fraction (REF). Patients with abnormal EF were more likely to have cardiac comorbidities and be prescribed angiotensin-converting enzyme inhibitors and anticoagulants. Perioperatively, patients with SREF were more likely to experience mortality (13.2% vs. 6.7% vs. 4.4%, P = 0.018), MACE (26.3% vs. 11.5% vs. 8%, P < 0.001), hemodialysis (13.5% vs. 5% vs. 2.9%, P = 0.001) and aortic related reintervention (21.1% vs. 13% vs. 10%, P = 0.041), compared to REF and normal ejection fraction (NEF) patients. However, these associations were not present on multivariable analysis. At 18 months, mortality was significantly higher in patients with SREF, which was confirmed on multivariable analysis, but depressed EF was not associated with increased aortic reintervention compared to NEF. CONCLUSIONS:SREF was not independently associated with perioperative mortality or MACE compared to NEF. REF had similar risk of morbidity and mortality compared to NEF in both the perioperative and early postoperative periods. TEVAR-related complications were similar among the cohorts. As such, TEVAR may be offered to appropriately selected patients regardless of EF.

Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.

OBJECTIVE:To determine if a peri-operative pain cocktail injection improves post-operative pain, ambulation distance and long-term outcomes in hip fracture patients. DESIGN/METHODS:Prospective, single-blinded, randomized controlled trial. SETTING/METHODS:Academic Medical Center. PATIENTS/PARTICIPANTS/METHODS:Patients with OTA/AO 31A1-3 and 31B1-3 fractures undergoing operative fixation, excluding arthroplasty. INTERVENTION/METHODS:Multimodal local injection of bupivacaine (Marcaine), morphine sulfate (Duramorph), ketorolac (Toradol) given at the fracture site at the time of hip fracture surgery (Hip Fracture Injection, HiFI). MAIN OUTCOME MEASUREMENTS/METHODS:Patient-reported pain, American Pain Society Patient Outcome Questionnaire (APS-POQ), narcotic usage, length of stay, post-operative ambulation, Short Musculoskeletal Function Assessment (SMFA). RESULTS:75 patients were in the treatment group and 109 in the control group. Patients in the HiFI group had a significant reduction in pain and narcotic usage compared to the control group on post-operative day (POD) 0 (p<0.01). Based on the APS-POQ, patients in the control group had a significantly harder time falling asleep, staying asleep, and experienced increased drowsiness on POD 1 (p<0.01). Patient ambulation distance was greater on POD 2 (p<0.01) and POD 3 (p<0.05) in the HiFI group. The control group experienced more major complications (p<0.05). At six-weeks post-op, patients in the treatment group reported significantly less pain, better ambulatory function, less insomnia, less depression, and better satisfaction than the control group as measured by the APS-POQ. The SMFA bothersome index was also significantly lower for patients in the HiFI group, p<0.05. CONCLUSIONS:Intraoperative HiFI not only improved early pain management and increased ambulation in patients undergoing hip fracture surgery while in the hospital, it was also associated with early improved health related quality of life following discharge. LEVEL OF EVIDENCE/METHODS:Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

The aim of this study was to evaluate the bone healing of tight-fit implants placed in the maxilla and mandible of subjects compromised with metabolic syndrome (MS) and type-2 Diabetes Mellitus (T2DM). Eighteen Göttingen minipigs were randomly distributed into three groups: (i) control (normal diet), (ii) MS (cafeteria diet for obesity induction), (iii) T2DM (cafeteria diet for obesity induction + Streptozotocin for T2DM induction). Maxillary and mandibular premolars and molar were extracted. After 8 weeks of healing, implants with progressive small buttress threads were placed, and allowed to integrate for 6 weeks after which the implant/bone blocks were retrieved for histological processing. Qualitative and quantitative histomorphometric analyses (percentage of bone-to-implant contact, %BIC, and bone area fraction occupancy within implant threads, %BAFO) were performed. The bone healing process around the implant occurred predominantly through interfacial remodeling with subsequent bone apposition. Data as a function of systemic condition yielded significantly higher %BIC and %BAFO values for healthy and MS relative to T2DM. Data as a function of maxilla and mandible did not yield significant differences for either %BIC and %BAFO. When considering both factors, healthy and MS subjects had %BIC and %BAFO trend towards higher values in the mandible relative to maxilla, whereas T2DM yielded higher %BIC and %BAFO in the maxilla relative to mandible. All systemic conditions presented comparable levels of %BIC and %BAFO in the maxilla; healthy and MS presented significantly higher %BIC and %BAFO relative to T2DM in the mandible. T2DM presented lower amounts of bone formation around implants relative to MS and healthy. Implants placed in the maxilla and in the mandible showed comparable amounts of bone in proximity to implants.

Collagen, an abundant extracellular matrix protein, has shown hemostatic, chemotactic, and cell adhesive characteristics, making it an attractive choice for the fabrication of tissue engineering scaffolds. The aim of this study was to synthesize a fibrillar colloidal gel from Type 1 bovine collagen, as well as three dimensionally (3D) print scaffolds with engineered pore architectures. 3D-printed scaffolds were also subjected to post-processing through chemical crosslinking (in N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide) and lyophilization. The scaffolds were physicochemically characterized through Fourier Transform Infrared Spectroscopy (FTIR), Thermogravimetric Analysis, Differential Scanning Calorimetry, and mechanical (tensile) testing. In vitro experiments using Presto Blue and Alkaline Phosphatase assays were conducted to assess cellular viability and the scaffolds' ability to promote cellular proliferation and differentiation. Rheological analysis indicated shear thinning capabilities in the collagen gels. Crosslinked and lyophilized 3D-printed scaffolds were thermally stable at 37 °C and did not show signs of denaturation, although crosslinking resulted in poor mechanical strength. PB and ALP assays showed no signs of cytotoxicity as a result of crosslinking. Fibrillar collagen was successfully formulated into a colloidal gel for extrusion through a direct inkjet writing printer. 3D-printed scaffolds promoted cellular attachment and proliferation, making them a promising material for customized, patient-specific tissue regenerative applications.