Chronic Opioid Use Independently Increases Complications and Resource Utilization After Primary Total Joint Arthroplasty.

BACKGROUND: Current literature suggests a link between the chronic use of opioids and musculoskeletal surgical complications. Given the current opioid epidemic, the need to elucidate the effects of chronic opioid use (OD) on patient outcomes and cost has become important. The purpose of this study was to determine if OD is an independent risk factor for inpatient postoperative complications and resource utilization after primary total joint arthroplasty. METHODS: A total of 3,545,565 patients undergoing elective, unilateral, primary total hip (THA) and knee (TKA) arthroplasty for osteoarthritis from January 2016 to December 2019 were identified using a large national database. In-hospital postoperative complications, length of stay, and total costs adjusted for inflation in opioid + patients were compared with patients without chronic opioid use (OD). Logistic regression analyses were used to control for cofounding factors. RESULTS: OD patients undergoing either THA or TKA had a higher risk of postoperative complications including respiratory (odds ratio (OR): 1.4 and OR: 1.3), gastrointestinal (OR: 1.8 and OR: 1.8), urinary tract infection (OR: 1.1 and OR: 1.2), blood transfusion (OR: 1.5 and OR: 1.4), and deep vein thrombosis (OR: 1.7 and OR: 1.6), respectively. Total cost ($16,619 ± $9,251 versus $15,603 ± $9,181, P < .001), lengths of stay (2.15 ± 1.37 versus 2.03 ± 1.23, P < .001), and the likelihood for discharge to a rehabilitation facility (17.8 versus 15.7%, P < .001) were higher in patients with OD. CONCLUSION: OD was associated with higher risk for in-hospital postoperative complications and cost after primary THA and TKA. Further studies to find strategies to mitigate the impact of opioid use on complications are required.

Increased Risk of In-Hospital Complications and Costs After Total Hip Arthroplasty for Primary and Secondary Osteonecrosis.

BACKGROUND: An increasing proportion of patients are undergoing total hip arthroplasty (THA) for osteonecrosis (ON). Comorbid conditions and surgical risk factors are known to be greater in ON patients compared with patients who have osteoarthritis (OA) alone. The purpose of our study was to quantify the specific in-hospital complications and resource utilization associated with patients undergoing THA for ON versus OA. METHODS: A large national database was queried to identify patients undergoing primary THA from January 1, 2016 to December 31, 2019. A total of 1,383,880 OA, 21,080 primary ON, and 54,335 secondary ON patients were identified. Demographics, in-hospital complications, costs, lengths of stay, and discharge dispositions for primary and secondary ON cohorts were compared to OA only. Age, race, ethnicity, comorbidities, Medicaid, and income status were controlled with binary logistic regression analyses. RESULTS: The ON patients were often younger, African American or Hispanic, and had more comorbidities. Those undergoing THA for primary and secondary ON had a significantly higher risk of perioperative complications, including myocardial infarction, postoperative blood transfusion, and intraoperative bleeding. Total hospital costs and lengths of stay were significantly higher for both primary ON and secondary ON and both cohorts were less likely to be discharged home. CONCLUSION: While rates of most complications have decreased over recent decades in ON patients undergoing THA, the ON patients still have worse outcomes even when controlling for comorbidity differences. Bundled payment systems and perioperative management strategies for these different patient cohorts should be considered separately.

Inhospital Complications and Costs of Simultaneous Bilateral Total Knee Arthroplasty: The Case for Selection and Potential Cost Savings.

BACKGROUND: Published comparisons between bilateral and unilateral total knee arthroplasties (TKAs) remain biased, as most patients undergoing bilateral TKA are prescreened and healthier than average patients having unilateral procedures. Our objectives were to compare postoperative complications and resource utilization of patients having simultaneous bilateral TKAs with similar patients having unilateral procedures. METHODS: The Nationwide Inpatient Sample (NIS) database was used to identify patients undergoing primary elective TKA from 2002 to 2011. A total of 4,445,263 patients were identified. Of these, 190,783 (4%) were having same-day bilateral procedures. Patients with staged bilateral TKA during the same hospitalization were excluded. Complications and costs were compared to a matched cohort of patients having unilateral procedures. This cohort was matched based on age, gender, and 30 comorbid-defined elements in the NIS. RESULTS: A total of 172,366 (90%) simultaneous bilateral procedures were matched 1:1 to patients with unilateral procedures for the adjusted analysis. Patients with bilateral procedures were at an increased risk for many complications including postoperative anemia (OR: 2.3; 95% CI: 2.2-2.3, P < .001), cardiac (OR: 2.1; 95% CI: 2.0-2.3, P < .001), and inhospital mortality (OR: 3.3; 95% CI: 2.6-4.3). These patients also incurred in higher hospital costs ($19,343 vs $12,852, P < .001) and were discharged more commonly to a rehabilitation facility (70% vs 32%, P < .001). CONCLUSION: Patients undergoing simultaneous bilateral TKA are at an increased risk of developing important postoperative complications and mortality compared with unilateral cases. These data highlight the importance of patient selection and optimization for bilateral TKA and potential cost savings.

Increased Morbidity With Diagnosis and Treatment of Pulmonary Embolism After Total Joint Arthroplasty: A Matched Control Analysis of 30,000 Patients.

BACKGROUND: Currently, the risks associated with the diagnosis of pulmonary embolism (PE) and subsequent treatment are not well known. The purpose of our study is to quantify the specific in-hospital complications and resource utilization of patients with PE following total joint arthroplasty when compared to a matched cohort. METHODS: The Nationwide Inpatient Sample database was used to identify patients undergoing primary hip and knee arthroplasty from January 1993 to December 2008. PE was determined using International Classification of Diseases, Ninth Revision, Clinical Modification codes. In-hospital complications, costs, and length of stay for patients with PE were compared to patients without PE, matched on the basis of age, gender, procedure (total hip arthroplasty vs total knee arthroplasty), year of surgery, morbid obesity, and all 28 comorbid-defined elements of the Elixhauser Comorbidity Index. RESULTS: Of 8,634,038 procedures, 30,281 (0.4%) patients had a PE after total joint arthroplasty. In total, 29,917 (98%) were matched one-to-one with patients without PE. Patients with PE had a substantially higher risk of all postoperative in-hospital complications: deep vein thrombosis (odds ratio [OR] 17), peripheral vascular (OR 34), hematoma (OR 3.7), and gastrointestinal bleeding (OR 7.0) (all P < .001). Mortality was significantly higher in patients with PE compared to patients without PE (3.4% vs 0.1%, OR 30), along with total hospital costs, lengths of stay, and rates of discharge to rehabilitation facilities. CONCLUSION: After controlling for comorbidities patients with PE have a significantly higher risk for complications including in-hospital mortality and higher hospital costs when compared to patient without PE.

Survivorship and Outcomes of Femoral Neck Preserving Stems in Primary Total Hip Arthroplasty.

BACKGROUND: Short-stem femoral implants (SSFIs) promote the preservation of bone in the femoral neck, reduce soft tissue disruption, and facilitate minimally invasive surgical techniques. The purpose of this study was to report the revision rate, complication rate, patient satisfaction, patient-reported outcomes, and radiographic outcomes of patients who underwent total hip arthroplasty (THA) with the Alteon Neck Preserving Femoral Stem (ANPS). METHODS: A prospectively maintained database was reviewed which analyzed 92 THAs between the years 2016 and 2018. Patient-reported outcomes, patient satisfaction, complication rates, and radiographic outcomes were assessed at 2-5 years postoperatively. RESULTS: The final cohort consisted of 63 hips. Five patients (7.9%) underwent revision surgery and 2 (3.2%) had other complications not requiring revision. Survivorship when considering only the femoral component was 93.7% at an average of 41.4 months of follow-up. The average postoperative Oxford Hip Score (41.5 ± 8.3) and Harris Hip Score (77.9 ± 16.6) demonstrated significant improvement among our nonrevised patients, respectively (P < .001). Radiographs demonstrated spot welding in 56% of arthroplasties most commonly in Gruen Zones 2, 3, and 13 and that femur radiolucencies were visualized in 58% predominantly along the distal aspect of the stem. Radiographic femoral component subsidence was present in 9.7% of patients. CONCLUSION: The ANPS may be less reliable than previously reported. Our cohort's revision rate was unacceptably high with 6.3% requiring revision surgery for femoral component loosening in less than 5 years. Surgeons should consider the challenges and prohibitive failure rate associated with SSFIs before routine usage in THA.

Traditional Laboratory Markers Hold Low Diagnostic Utility for Immunosuppressed Patients With Periprosthetic Joint Infections.

BACKGROUND: Although predictive laboratory markers and cutoffs for immunocompetent patients are well-studied, similar reference ranges and decision thresholds for immunosuppressed patients are less understood. We investigated the utility of typical laboratory markers in immunosuppressed patients undergoing aspiration of a prosthetic hip or knee joint. METHODS: A retrospective review of adult patients with an immunosuppressed state that underwent primary and revision total joint arthroplasty with a subsequent infection at our tertiary, academic institution was conducted. Infection was defined by Musculoskeletal Infection Society criteria. A multivariable analysis was used to identify independent factors associated with acute (<90 days) and chronic (>90 days) infection. Area under the receiver-operator curve (AUC) was used to determine the best supported laboratory cut points for identifying infection. RESULTS: We identified 90 patients with immunosuppression states totaling 172 aspirations. Mean follow-up from aspiration was 33 months. In a multivariate analysis, only synovial fluid cell count and synovial percent neutrophils were found to be independently correlated with both acute and chronic infection. A synovial fluid cell count cutoff value of 5679 nucleated cells/mm3 maximized the AUC (0.839) for predicting acute infection, while a synovial fluid cell count cutoff value of 1293 nucleated cells/mm3 maximized the AUC (0.931) for predicting chronic infection. CONCLUSION: Physicians should be aware of lower levels of synovial nucleated cell count and percentage of neutrophils in prosthetic joint infections of the hip or knee in patients with immunosuppression. Further investigation is necessary to identify the best means of diagnosing periprosthetic joint infection in this patient population.

In-Hospital Complications and Costs of Simultaneous Bilateral Total Hip Arthroplasty: The Case for Selection and Potential Cost Savings.

Background: Published comparisons between bilateral and unilateral total hip arthroplasty (THA) remain controversial regarding the potential risks and benefits. Our objectives were to compare (1) postoperative complications and (2) resource utilization of patients having simultaneous bilateral THA with patients having unilateral procedures. Methods: The Nationwide Inpatient Sample was used to identify patients undergoing primary elective THA from January 2016 to December 2019. Complications and costs were compared between unilateral and simultaneous bilateral patients. Binary logistic regression analysis controlling demographics, comorbidities, and the primary diagnosis was performed to compare the cohorts of unilateral and bilateral patients. Results: Nine thousand nine hundred fifty-five Bilateral procedures and 785,609 unilateral procedures were identified. Patients with bilateral procedures were at increased risk for many medical complications including gastrointestinal complications (OR: 4.1; 95% CI: 2.4-6.9, P < .01), postoperative blood transfusions (OR: 3.6; 95% CI: 3.3-3.9, P < .01), and pulmonary embolisms (OR: 3.2; 95% CI: 2.0-5.1, P < .01). Patients with bilateral procedures were also at increased risk for joint complications, including periprosthetic fractures (OR: 7.4; 95% CI: 5.2-10.5, P < .01) and other mechanical complications (OR: 27.0; 95% CI: 23-30, P < .01). These patients also incurred higher index hospitalization costs ($25,347 vs $16,757, P < .001) and were discharged more commonly to a rehabilitation facility (17.8% vs 13.4%, P < .001). Conclusions: Bilateral THA are at increased risk of developing postoperative complications despite being younger and having fewer comorbidities on average when compared with unilateral patients. While bilateral patients had a higher index hospitalization cost, the overall cost of one episode of care is lower than two separate hospitalizations.

Virtual Versus In-person Grand Rounds in Orthopaedics: A Framework for Implementation and Participant-reported Outcomes.

INTRODUCTION: Grand rounds have been weekly gatherings at academic orthopaedic surgery programs across the country for decades. During the 50th year of grand rounds at our institution, the COVID-19 pandemic prompted the transformation of this in-person forum into a virtual setting. The purpose of this study was to detail this initiative and to report survey data providing participant-reported perceptions and satisfaction of virtual versus in-person grand rounds. MATERIALS AND METHODS: Once in-person meetings were discontinued, virtual grand rounds commenced using the Zoom video application. At the conclusion of the 2020 to 2021 academic year, a 30-item online survey was sent to all residents, faculty, and visiting faculty to assess their perspective and satisfaction. A five-point Likert scale ranging from 1 to 5, with 5 being extremely effective, was used. A 21-item follow-up survey was sent to all speakers as well. RESULTS: Thirty-six virtual grand rounds were successfully hosted. The response rate for the survey was excellent-80 of 86 (93.0%) surveys returned completed. Respondents found that virtual grand rounds were more convenient to attend, were more convenient to obtain Continuing Medical Education, and were more satisfied with virtual grand rounds. Respondents reported that in-person grand rounds were more effective for stimulating social collegiality and networking. Speakers found that virtual grand rounds were more effective for uploading the presentation and overall convenience, whereas they were less effective at retaining audience attention and receiving audience feedback. Improved faculty attendance after the switch to virtual grand rounds was also noted. CONCLUSION: This study found that respondents across all groups appreciated the convenience of attending and obtaining Continuing Medical Educations at virtual grand rounds while also noting the merits of in-person grand rounds for promoting peer interaction, camaraderie, and departmental identity. All respondents strongly recommended continuation of this program in a hybrid format. Virtual orthopaedic grand rounds are viable, readily implemented and demonstrate improved participant satisfaction.

Operative Versus Nonoperative Management of Displaced Midshaft Clavicle Fractures: A Cost-effectiveness Analysis.

To date, the optimal management of displaced midshaft clavicle fractures remains unknown. Operatively, plate or nail fixation may be used. Nonoperatively, the options are sling or harness. Given the equivocal effectiveness between approaches, the costs to the health care system and the patient become critical considerations. A decision tree model was constructed to study plate and sling management of displaced midshaft clavicle fractures. Primary analysis used 6 randomized controlled trials that directly compared open reduction and internal fixation with a plate to sling. Secondary analysis included 18 studies that studied either plate, sling, or both. Incremental cost-effectiveness ratios (ICERs) were calculated using quality-adjusted life-years (QALYs). Second-order Monte Carlo probabilistic sensitivity analysis (PSA) was subsequently conducted. In primary analysis, at a willingness-to-pay (WTP) threshold of $100,000, operative management was found to be less cost-effective relative to nonoperative management, with an ICER of $606,957/QALY (0.03 additional QALYs gained for an additional $16,120). In PSA, sling management was cost-effective across all WTP ranges. In secondary analysis, the ICER decreased to $75,230/QALY. Primary analysis shows that plate management is not a cost-effective option. In secondary analysis, the incremental effectiveness of plate management increased enough that the calculated ICER is below the WTP threshold of $100,000; however, the strength of evidence in secondary analysis is lower than in primary analysis. Thus, because neither option is dominant in this model, both plate and sling remain viable approaches, although the cost-conscious decision will be to treat these fractures with a sling until future data suggest otherwise. [Orthopedics. 2022;45(5):e243-e251.].

Clinical Characteristics and Multisystem Imaging Findings of COVID-19: An Overview for Orthopedic Surgeons.

The COVID-19 pandemic holds widespread implications for global public health, economies, societies, and the practice of orthopedic surgery. As our knowledge of the transmissibility of SARS-CoV-2 and the symptomatology and management of COVID-19 expands, orthopedic surgeons must remain up to date on the latest medical evidence and surgical perspectives. While COVID-19 primarily manifests with pulmonary symptoms, cardiovascular, neurologic, and other major organ systems may also be affected and present with hallmark imaging findings. This article reviews initial and emerging literature on clinical characteristics and imaging findings of COVID-19.

Correction to: Clinical Characteristics and Multisystem Imaging Findings of COVID-19: An Overview for Orthopedic Surgeons.

[This corrects the article DOI: 10.1007/s11420-020-09775-3.].

Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) Shows Efficacy Against Osteosarcoma.

Therapeutic advances for osteosarcoma have stagnated over the past several decades, leading to an unmet clinical need for patients. The purpose of this study was to develop a novel therapy for osteosarcoma by reformulating and validating niclosamide, an established anthelminthic agent, as a niclosamide stearate prodrug therapeutic (NSPT). We sought to improve the low and inefficient clinical bioavailability of oral dosing, especially for the relatively hydrophobic classes of anticancer drugs. Nanoparticles were fabricated by rapid solvent shifting and verified using dynamic light scattering and UV-vis spectrophotometry. NSPT efficacy was then studied in vitro for cell viability, cell proliferation, and intracellular signaling by Western blot analysis; ex vivo pulmonary metastatic assay model; and in vivo pharmacokinetic and lung mouse metastatic model of osteosarcoma. NSPT formulation stabilizes niclosamide stearate against hydrolysis and delays enzymolysis; increases circulation in vivo with t 1/2 approximately 5 hours; reduces cell viability and cell proliferation in human and canine osteosarcoma cells in vitro at 0.2-2 µmol/L IC50; inhibits recognized growth pathways and induces apoptosis at 20 µmol/L; eliminates metastatic lesions in the ex vivo lung metastatic model; and when injected intravenously at 50 mg/kg weekly, it prevents metastatic spread in the lungs in a mouse model of osteosarcoma over 30 days. In conclusion, niclosamide was optimized for preclinical drug delivery as a unique prodrug nanoparticle injected intravenously at 50 mg/kg (1.9 mmol/L). This increased bioavailability of niclosamide in the blood stream prevented metastatic disease in the mouse. This chemotherapeutic strategy is now ready for canine trials, and if successful, will be targeted for human trials in patients with osteosarcoma.

Algorithm for Management of Periprosthetic Ankle Fractures.

BACKGROUND: Evidence on the management of and outcomes from periprosthetic fractures about a total ankle replacement (TAR) are limited. The purpose of this study was to develop an algorithm for the management of patients with postoperative periprosthetic fractures about a TAR. METHODS: This was a retrospective analysis of patients undergoing a TAR from 2007 through 2017 with a subsequent periprosthetic fracture >4 weeks from index surgery. Implant stability was defined radiographically and intraoperatively where appropriate. Univariate and multivariate analyses were used to identify differences in outcomes. Thirty-two patients were identified with a remote TAR periprosthetic fracture with an average follow-up of 26 months (range, 3-104 months). RESULTS: Most fractures were located about the medial malleolus (62.5%); the majority of fractures (75%) were deemed to have stable implants. Fractures of the talus always had unstable implants and always required revision TAR surgery (100%, P = .0002). There was no difference in patient-reported outcomes between stable and unstable fractures at an average of 36 months. In a multivariate analysis, fracture location (talus), less time to fracture, and implant type were found to be predictive of unstable implants ( P < .001). Implant stability was independently associated with the need for revision surgery ( P < .049). Nonoperative treatment was independently associated with treatment failure ( P < .001). CONCLUSION: The majority of stable fractures about a TAR required operative fixation. Management with immobilization was fraught with a high rate of subsequent surgical intervention. We found that fractures about the talus required revision TAR surgery or arthrodesis. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Impact of Gender Disparities on Short-Term and Long-Term Patient Reported Outcomes and Satisfaction Measures After Elective Lumbar Spine Surgery: A Single Institutional Study of 384 Patients.

BACKGROUND: There is a paucity of data determining the impact that gender disparities have on spine outcomes, particularly perception of health and satisfaction. The aim of this study was to determine whether there is a difference in 3-month and 1-year patient-reported outcomes and satisfaction after elective lumbar spine surgery. METHODS: This was a retrospectively analyzed study from a maintained prospective database of 384 patients who underwent elective lumbar spine surgery. Patients were categorized by gender (men, n = 199; women, n = 185). Patient-reported outcome instruments (Oswestry disability index, visual analogue scale-back pain/leg pain, EuroQol visual analogue scale, and EuroQol 5 dimensions questionnaire) were completed before surgery, then at 3 and 12 months after surgery along with patient satisfaction measures. RESULTS: Baseline patient demographics, comorbidities, and operative variables were similar between both cohorts. The female cohort had a slightly longer hospital stay than male cohort (P = 0.007). Baseline patient-reported outcome measures were different between both cohorts, with female patients having more Oswestry disability index (23.8 vs. 20.4; P ≤ 0.0001) and visual analogue scale-back pain (7.2 vs. 6.2; P = 0.0004), and a lower EuroQol 5 dimensions questionnaire (0.34 vs. 0.49; P = 0.0001) compared with the male cohort. At 1-year follow-up, the male cohort had a significantly more mean change in visual analogue scale-leg pain (-3.9 vs. -2.8; P = 0.04) and trended to have more mean change in visual analogue scale-back pain (-3.4 vs. -2.5; P = 0.06) and EuroQol visual analogue scale (8.6 vs. 3.4; P = 0.054) scores compared with the female cohort. At 1-year a significantly more portion in the male cohort found that surgery met their expectations compared with the female cohort (65.0% vs. 49.5%; P = 0.02). CONCLUSIONS: Our study suggests that there may be differences in perception of health, pain, and disability between men and women at baseline, short-term and long-term follow-up that may influence overall patient satisfaction.

Post-operative delirium is an independent predictor of 30-day hospital readmission after spine surgery in the elderly (≥65years old): A study of 453 consecutive elderly spine surgery patients.

In the last decade, costs of U.S. healthcare expenditures have been soaring, with billions of dollars spent on hospital readmissions. Identifying causes and risk factors can reduce soaring readmission rates and help lower healthcare costs. The aim of this is to determine if post-operative delirium in the elderly is an independent risk factor for 30-day hospital readmission after spine surgery. The medical records of 453 consecutive elderly (≥65years old) patients undergoing spine surgery at Duke University Medical Center from 2008 to 2010 were reviewed. We identified 17 (3.75%) patients who experienced post-operative delirium according to DSM-V criteria. Patient demographics, comorbidities, and post-operative complication rates were collected for each patient. Elderly patients experiencing post-operative delirium had an increased length of hospital stay (10.47days vs. 5.70days, p=0.009). Complication rates were similar between the cohorts with the post-operative delirium patients having increased UTI and superficial surgical site infections. In total, 12.14% of patients were re-admitted within 30-days of discharge, with post-operative delirium patients experiencing approximately a 4-fold increase in 30-day readmission rates (Delirium: 41.18% vs. No Delirium: 11.01%, p=0.002). In a multivariate logistic regression analysis, post-operative delirium is an independent predictor of 30-day readmission after spine surgery in the elderly (p=0.03). Elderly patients experiencing post-operative delirium after spine surgery is an independent risk factor for unplanned readmission within 30-days of discharge. Preventable measures and early awareness of post-operative delirium in the elderly may help reduce readmission rates.

Risk Factors and Independent Predictors of 30-Day Readmission for Altered Mental Status After Elective Spine Surgery for Spine Deformity: A Single-Institutional Study of 1090 Patients.

BACKGROUND: Altered mental status (AMS) has been associated with inferior surgical outcomes. The factors leading to AMS after spine surgery are unknown. The aim of this study is to determine the risk factors and independent predictors of 30-day readmission for AMS in patients with spine deformity after undergoing elective spine surgery. METHODS: The medical records of 1090 adult (≥18 years old) patients with spine deformity undergoing elective spine surgery at a major academic institution from 2005 to 2015 were reviewed. We identified 18 patients (1.65%) who had AMS as the primary driver for 30-day readmission after surgery. Patient demographics, comorbidities, and intraoperative and postoperative complication rates were collected for each patient. The primary outcome investigated in this study was risk factors associated with 30-day readmission for AMS. RESULTS: Patient demographics and comorbidities were similar between both groups, with the AMS cohort being significantly older than the no-AMS cohort (70.11 vs. 61.93; P = 0.003). There were no significant differences in intraoperative variables and complication rates within the cohorts. The AMS cohort had a significantly higher proportion of patients transferred to the intensive care unit (AMS, 61.11% vs. no-AMS, 19.76%; P = 0.0002) and rate of pulmonary embolism (AMS, 11.11 vs. no-AMS, 0.93; P = 0.02) after surgery. Other postoperative complication rates were similar between the cohorts. In a multivariate stepwise regression analysis, age (P = 0.013) and ICU transfer (P = 0.0002) were independent predictors of 30-day readmission for AMS. CONCLUSIONS: Our study suggests that increasing age and intensice care unit transfer are independent predictors of 30-day readmission for AMS after spine surgery in patients with spine deformity.

Titanium surface characteristics, including topography and wettability, alter macrophage activation.

Biomaterial surface properties including chemistry, topography, and wettability regulate cell response. Previous studies have shown that increasing surface roughness of metallic orthopaedic and dental implants improved bone formation around the implant. Little is known about how implant surface properties can affect immune cells that generate a wound healing microenvironment. The aim of our study was to examine the effect of surface modifications on macrophage activation and cytokine production. Macrophages were cultured on seven surfaces: tissue culture polystyrene (TCPS) control; hydrophobic and hydrophilic smooth Ti (PT and oxygen-plasma-treated (plasma) PT); hydrophobic and hydrophilic microrough Ti (SLA and plasma SLA), and hydrophobic and hydrophilic nano-and micro-rough Ti (aged modSLA and modSLA). Smooth Ti induced inflammatory macrophage (M1-like) activation, as indicated by increased levels of interleukins IL-1ß, IL-6, and TNFα. In contrast, hydrophilic rough titanium induced macrophage activation similar to the anti-inflammatory M2-like state, increasing levels of interleukins IL-4 and IL-10. These results demonstrate that macrophages cultured on high surface wettability materials produce an anti-inflammatory microenvironment, and this property may be used to improve the healing response to biomaterials. STATEMENT OF SIGNIFICANCE: Metals like titanium (Ti) are common in orthopaedics and dentistry due to their ability to integrate with surrounding tissue and good biocompatibility. Roughness- and wettability-increasing surface modifications promote osteogenic differentiation of stem cells on Ti. While these modifications increase production of osteoblastic factors and bone formation, little is known about their effect on immune cells. The initial host response to a biomaterial is controlled primarily by macrophages and the factors they secrete in response to the injury caused by surgery and the material cues. Here we demonstrate the effect of surface roughness and wettability on the activation and production of inflammatory factors by macrophages. Control of inflammation will inform the design of surface modification procedures to direct the immune response and enhance the success of implanted materials.

Persistent and high-level expression of human liver prolidase in vivo in mice using adenovirus.

Human liver prolidase, a metal-dependent dipeptidase, is being tested as a potential catalytic bioscavenger against organophosphorus (OP) chemical warfare nerve agents. The purpose of this study was to determine whether persistent and high-levels of biologically active and intact recombinant human (rHu) prolidase could be introduced in vivo in mice using adenovirus (Ad). Here, we report that a single intravenous injection of Ad containing the prolidase gene with a 6× histidine-tag (Ad-prolidase) introduced high-levels of rHu prolidase in the circulation of mice which peaked on days 5-7 at 159 ± 129 U/mL. This level of prolidase is ~120 times greater than that of the enzyme level in mice injected with Ad-null virus. To determine if all of Ad-prolidase-produced rHu prolidase was exported into the circulation, enzyme activity was measured in a variety of tissues. Liver contained the highest levels of rHu prolidase on day 7 (5647 ± 454 U/g) compared to blood or any other tissue. Recombinant Hu prolidase hydrolyzed DFP, a simulant of OP nerve agents, in vitro. In vivo, prolidase overexpression extended the survival of 4 out of 6 mice by 4-8h against exposure to two 1× LD(50) doses of DFP. In contrast, overexpression of mouse butyrylcholinesterase (BChE), a proven stoichiometric bioscavenger of OP compounds, protected 5 out of 6 mice from DFP lethality and surviving mice showed no symptoms of DFP toxicity. In conclusion, the results suggest that gene delivery using Ad is capable of introducing persistent and high levels of human liver prolidase in vivo. The gene-delivered prolidase hydrolyzed DFP in vitro but provided only modest protection in vivo in mice, delaying the death of the animals by only 4-8h.