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Physiochemical and bactericidal activity evaluation: Silver-augmented 3D-printed scaffolds-An in vitro study

Nayak, Vasudev Vivekanand; Tovar, Nick; Hacquebord, Jacques Henri; Duarte, Simone; Panariello, Beatriz H D; Tonon, Caroline; Atria, Pablo J; Coelho, Paulo G; Witek, Lukasz
HYPOTHESIS/OBJECTIVE:Injuries requiring resection of tissue followed by autogenous bone transfer may be prone to infection by Staphylococcus aureus, impeding recovery and increasing medical costs. For critical sized defects, the common approach to reconstruction is a tissue transfer procedure but is subject to limitations (e.g., donor site morbidity, cost, operating time). Utilizing beta tricalcium phosphate (β-TCP) as bone grafting material augmented with silver (Ag), a custom graft may be 3D printed to overcome limitations and minimize potential infections. EXPERIMENTS/METHODS:) groups followed by electron microscopy, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) to gather information of chemical and physical properties. Preliminary biocompatibility and bactericidal capacity of the scaffolds were tested using human osteoprogenitor (hOP) cells and methicillin-sensitive S. aureus strain, respectively. RESULTS:groups, whereas electron microscopy showed a decrease in Ca and an increase in Ag ions, decreasing Ca/P ratio with increasing surfactant concentrations. PrestoBlue assays yielded an increase in fluorescence cell counts among experimental groups with lower concentrations of Ag characterized by their characteristic trapezoidal shape whereas cytotoxicity was observed at higher concentrations. Similar observations were made with alkaline phosphatase assays. Antimicrobial evaluation showed reduced colony-forming units (CFU) among all experimental groups when compared to 100% β-TCP. β-TCP scaffolds augmented with Ag ions facilitate antibacterial effects while promoting osteoblast adhesion and proliferation.
PMID: 34196107
ISSN: 1552-4981
CID: 4932082

14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis

Fu, Wenyu; Hettinghouse, Aubryanna; Chen, Yujianan; Hu, Wenhuo; Ding, Xiang; Chen, Meng; Ding, Yuanjing; Mundra, Jyoti; Song, Wenhao; Liu, Ronghan; Yi, Young-Su; Attur, Mukundan; Samuels, Jonathan; Strauss, Eric; Leucht, Philipp; Schwarzkopf, Ran; Liu, Chuan-Ju
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.
PMID: 34226187
ISSN: 1468-2060
CID: 4932152

Effects of relative centrifugation force on L-PRF: An in vivo submandibular boney defect regeneration study

Tovar, Nick; Benalcázar Jalkh, Ernesto B; Ramalho, Ilana S; Rodriguez Colon, Ricardo; Kim, Heoijin; Bonfante, Estevam A; Torroni, Andrea; Coelho, Paulo G; Witek, Lukasz
Properties and composition of leukocyte- and platelet-rich fibrin (L-PRF) clots may be largely affected by centrifugation protocols (function of relative centrifugal force [RCF]), which may impact biological potential repair in bone regeneration. The present in vivo study sought to assess the effect of the RCF on the composition of L-PRF clots, as well as to compare the repair potential of L-PRF clots obtained with different RCF protocols in submandibular boney defects using PLGA scaffolds for bone regeneration. Complete blood count and volumetric evaluations were performed on L-PRF clots obtained through centrifugation for 12 min at 200, 400, and 600 RCF-clot centrifugation speeds. These evaluations were completed from blood collected immediately prior to any surgical procedures. The in vivo portion comprised of three submandibular unilateral, full thickness, osteotomies (~0.40cm3 ) which were created in the submandibular region of six sheep, using rotary instrumentation under continuous irrigation. Subsequently, poly(lactic-co-glycolic acid) (PLGA) scaffolds were enveloped in a L-PRF membrane from one of the three spinning speeds (n = 6/RCF) and inserted into the defect (sites were interpolated to avoid site bias). Six-weeks after surgery, the mandibles were harvested en bloc and prepared for volumetric and histomorphometric evaluations. Membranes harvested from 600 RCF produced significantly larger L-PRF clots (6.97g ± 0.95) in comparison to the lower 200 RCF (5.7g ± 0.95), with no significant differences between 600 and 400, and from 400 and 200 RCF. The three tested RCFs did not alter the platelet count of the L-PRF clot. For the in vivo component, quantitative bone regeneration analyses demonstrated significantly higher values obtained with L-PRF membranes extracted post 600 RCF (27.01 ± 8%) versus 200 RCF (17.54 ± 8%), with no significant differences regarding 400 RCF (~23 ± 8%). At the qualitative histological analyses, L-PRF membranes obtained at 600 and 400 RCFs yielded improved healing throughout the defect, where the L-PRF sourced from the lowest speed, 200 RCF, presented healing primarily at the margins along with the presence of connective tissue at the central aspect of the surgical defect. Higher 600 RCF yielded larger L-PRF clots/membranes, resulting in enhanced bone repair potential in association with PLGA scaffolds for the treatment of critical size bone defects.
PMID: 34080775
ISSN: 1552-4981
CID: 4905812

Self-assembling human skeletal organoids for disease modeling and drug testing

Abraham, Diana M; Herman, Calvin; Witek, Lukasz; Cronstein, Bruce N; Flores, Roberto L; Coelho, Paulo G
Skeletal conditions represent a considerable challenge to health systems globally. Barriers to effective therapeutic development include a lack of accurate preclinical tissue and disease models. Most recently, work was attempted to present a novel whole organ approach to modeling human bone and cartilage tissues. These self-assembling skeletal organoids mimic the cellular milieu and extracellular organization present in native tissues. Bone organoids demonstrated osteogenesis and micro vessel formation, and cartilage organoids showed evidence of cartilage development and maturation. Skeletal organoids derived from both bone and cartilage tissues yielded spontaneous polarization of their cartilaginous and bone components. Using these hybrid skeletal organoids, we successfully generated "mini joint" cultures, which we used to model inflammatory disease and test Adenosine (A2A ) receptor agonists as a therapeutic agent. The work and respective results indicated that skeletal organoids can be an effective biological model for tissue development and disease as well as to test therapeutic agents.
PMID: 34837719
ISSN: 1552-4981
CID: 5063982

Small-molecule antagonism of the interaction of the RAGE cytoplasmic domain with DIAPH1 reduces diabetic complications in mice

Manigrasso, Michaele B; Rabbani, Piul; Egaña-Gorroño, Lander; Quadri, Nosirudeen; Frye, Laura; Zhou, Boyan; Reverdatto, Sergey; Ramirez, Lisa S; Dansereau, Stephen; Pan, Jinhong; Li, Huilin; D'Agati, Vivette D; Ramasamy, Ravichandran; DeVita, Robert J; Shekhtman, Alexander; Schmidt, Ann Marie
[Figure: see text].
PMID: 34818060
ISSN: 1946-6242
CID: 5063702

Behind the scenes of extracellular vesicle therapy for skin injuries and disorders

Subhan, Bibi Sheleeza; Ki, Michelle; Verzella, Alexandra; Shankar, Shruthi; Rabbani, Piul
SIGNIFICANCE/CONCLUSIONS:Skin wounds and disorders compromise the protective functions of skin and patient quality of life. Though accessible on the surface, they are challenging to address due to paucity of effective therapies. Exogenous extracellular vesicles (EVs), cell-free derivatives of adult multipotent stromal cells (MSCs), are developing as a treatment modality. Knowledge of origin MSCs, EV processing and mode of action is necessary for directed use of EVs in preclinical studies and methodical translation. Recent advances: Nano to microscale EVs, though from non-skin cells, induce functional responses in cutaneous wound cellular milieu. EVs allow a shift from cell-based to cell-free/derived modalities by carrying the MSC beneficial factors but eliminating risks associated with MSC transplantation. EVs have demonstrated striking efficacy in resolution of preclinical wound models, specifically within the complexity of skin structure and wound pathology. CRITICAL ISSUES/RESULTS:To facilitate comparison across studies, tissue sources and processing of MSCs, culture conditions, isolation and preparations of EVs, and vesicle sizes require standardization as these criteria influence EV types and contents, and potentially determine the induced biological responses. Procedural parameters for all steps preceding the actual therapeutic administration may be the key to generating EVs that demonstrate consistent efficacy through known mechanisms. We provide a comprehensive review of such parameters and the subsequent tissue, cellular and molecular impact of the derived EVs in different skin wounds/disorders. FUTURE DIRECTIONS/CONCLUSIONS:We will gain more complete knowledge of EV-induced effects in skin, and specificity for different wounds/conditions. The safety and efficacy of current preclinical xenogenic applications will favor translation into allogenic clinical applications of EVs as a biologic.
PMID: 34806432
ISSN: 2162-1918
CID: 5063312

Browning of adipose tissue and increased thermogenesis induced by Methotrexate

Verma, Narendra; Perie, Luce; Corciulo, Carmen; Leucht, Philipp; Ramkhelawon, Bhama; Cronstein, Bruce N; Mueller, Elisabetta
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.
PMID: 34761170
ISSN: 2573-9832
CID: 5050652

Physician wellness in orthopaedic surgery : a multinational survey study

Mir, Hassan; Downes, Katheryne; Chen, Antonia F; Grewal, Ruby; Kelly, Derek M; Lee, Michael J; Leucht, Philipp; Dulai, Sukhdeep K
AIMS/OBJECTIVE:Physician burnout and its consequences have been recognized as increasingly prevalent and important issues for both organizations and individuals involved in healthcare delivery. The purpose of this study was to describe and compare the patterns of self-reported wellness in orthopaedic surgeons and trainees from multiple nations with varying health systems. METHODS:A cross-sectional survey of 774 orthopaedic surgeons and trainees in five countries (Australia, Canada, New Zealand, UK, and USA) was conducted in 2019. Respondents were asked to complete the Mayo Clinic Well-Being Index and the Stanford Professional Fulfillment Index in addition to 31 personal/demographic questions and 27 employment-related questions via an anonymous online survey. RESULTS:A total of 684 participants from five countries (Australia (n = 74), Canada (n = 90), New Zealand (n = 69), UK (n = 105), and USA (n = 346)) completed both of the risk assessment questionnaires (Mayo and Stanford). Of these, 42.8% (n = 293) were trainees and 57.2% (n = 391) were attending surgeons. On the Mayo Clinic Well-Being Index, 58.6% of the overall sample reported feeling burned out (n = 401). Significant differences were found between nations with regards to the proportion categorized as being at risk for poor outcomes (27.5% for New Zealand (19/69) vs 54.4% for Canada (49/90) ; p = 0.001). On the Stanford Professional Fulfillment Index, 38.9% of the respondents were classified as being burned out (266/684). Prevalence of burnout ranged from 27% for Australia (20/74 up to 47.8% for Canadian respondents (43/90; p = 0.010). Younger age groups (20 to 29: RR 2.52 (95% confidence interval (CI) 1.39 to 4.58; p = 0.002); 30 to 39: RR 2.40 (95% CI 1.36 to 4.24; p = 0.003); 40 to 49: RR 2.30 (95% CI 1.35 to 3.9; p = 0.002)) and trainee status (RR 1.53 (95% CI 1.15 to 2.03 p = 0.004)) were independently associated with increased relative risk of having a 'at-risk' or 'burnout' score. CONCLUSIONS: 2021;2(11):932-939.
PMID: 34766825
ISSN: 2633-1462
CID: 5050792

Nanoscale physico-mechanical properties of an aging resistant ZTA composite

Benalcázar Jalkh, E B; Coelho, P G; Witek, L; Bergamo, E T P; Lopes, A C O; Monteiro, K N; Cesar, P F; Genova, L A; Lisboa-Filho, P N; Abreu, J L B; Campos, T M B; Canteenwala, A; Bonfante, E A
OBJECTIVE:To characterize the effects of aging on the nanomechanical properties and 3D surface topographical parameters of an experimental Zirconia Toughened Alumina (ZTA) composite compared to its respective individual counterpart materials. METHODS:), while X-ray diffraction (XRD) and scanning electron microscope (SEM) assessed the crystalline content and microstructure. All tests were performed before and after simulated aging (134°C, 2.2 bar, 20 h). Statistical analyses were performed using linear mixed-model and least square difference pos-hoc tests (α = 5%). RESULTS:yielded the highest H and E values (H:21 GPa, E: 254 GPa), followed by ZTA 70/30 (H: 13 GPa, E: 214 GPa) and Zpex (H:11 GPa, E: 167 GPa), all significantly different (p < 0.03). CONCLUSION/CONCLUSIONS:presented high hydrothermal stability with respect to all evaluated variables, where artificial aging significantly increased the monoclinic content and surface roughness of Zpex.
PMID: 34385065
ISSN: 1878-0180
CID: 4999352

A Level 1 Trauma Center's response to the COVID-19 pandemic in New York City: a qualitative and quantitative story

Fisher, Nina D; Bi, Andrew S; Aggarwal, Vinay; Leucht, Philipp; Tejwani, Nirmal C; McLaurin, Toni M
BACKGROUND:The purpose of this study is to describe a Level 1 Trauma Center's orthopedic response to the COVID-19 pandemic, and to compare outcomes of acute fracture patients pre-COVID versus during the COVID-19 pandemic. METHODS:All inpatient fracture cases performed over a 5-month period were identified and retrospective chart review performed. Patients were divided into pre- and COVID-era groups based on when surgery was performed relative to March 16, 2020 (the date elective operations were ceased), and groups were statistically compared. Patients with a COVID test result were further sub-divided into COVID negative and positive groups, and statistically compared. Statistical analysis was performed using independent t-test for continuous variables and chi-square analysis for categorical variables. RESULTS:One hundred and nineteen patients were identified, 38% females with average age of 58 years. Average length of stay was 7 days with average time from injury to surgery of 3 days and average time from admission to surgery of 1.3 days. Overall in-hospital complication rate was 29.4%, and 30-day mortality and readmission rates were 2.5% and 5%, respectively. Sixty-nine patients comprised the pre-COVID group, and 50 in the COVID-era group. There was no significant difference with respect to length of stay, time from injury to surgery, time from admission to surgery, need for post-operative ICU stay, in-hospital complication rate, 30-day mortality rate and 30-day readmission rate. Thirty-four patients had COVID testing, with 24 negative and 10 positive. COVID-positive patients had longer time from injury to surgery (8.5 days vs. 2 days, p = 0.003) and longer time from admission to surgery (2.7 days vs. 1.2 days, p = 0.034). While more COVID-positive patients required ICU admission post-operatively (60% vs. 21%, p = 0.036), there was no difference in overall complication rate. CONCLUSIONS:Orthopedic care of acute fracture patients was not affected by a global pandemic. The response of our Level 1 Trauma Center's orthopedic department can guide other hospitals if and when new surges in COVID cases arise, in order to prevent compromising appropriate orthopedic care. LEVEL OF EVIDENCE/METHODS:Prognostic III.
PMID: 33616766
ISSN: 1633-8065
CID: 4794242