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Historically, high-energy extremity injuries resulting in significant soft-tissue trauma and bone loss were often deemed unsalvageable and treated with primary amputation. With improved soft-tissue coverage and nerve repair techniques, these injuries now present new challenges in limb-salvage surgery. High-energy extremity trauma is pre-disposed to delayed or unpredictable bony healing and high rates of infection, depending on the integrity of the soft-tissue envelope. Furthermore, orthopedic trauma surgeons are often faced with the challenge of stabilizing and repairing large bony defects while promoting an optimal environment to prevent infection and aid bony healing. During the last decade, nanomedicine has demonstrated substantial potential in addressing the two major issues intrinsic to orthopedic traumas (i.e., high infection risk and low bony reconstruction) through combatting bacterial infection and accelerating/increasing the effectiveness of the bone-healing process. This review presents an overview and discusses recent challenges and opportunities to address major orthopedic trauma through nanomedical approaches.

Purpose As health care costs continue to rise, providers must increasingly identify and implement cost-effective practice measures without sacrificing quality of care. Corticosteroid injections are an established treatment for trigger finger; however, numerous clinical trials have documented the limited efficacy of these injections in the diabetic population. Furthermore, the most cost-effective treatment strategy for diabetic trigger finger has not been determined. The purpose of this study was to perform a decision analysis to identify the least costly strategy for effective treatment of diabetic trigger finger using existing evidence in the literature. Methods Four treatment strategies for diabetic trigger finger were identified: (1) 1 steroid injection followed by surgical release, (2) 2 steroid injections followed by surgical release, (3) immediate surgical release in the operating room, and (4) immediate surgical release in the clinic. A literature review was conducted to determine success rates of the different treatment strategies. Costing analysis was performed using our institutional reimbursement from Medicare. One-way sensitivity and threshold analysis was utilized to determine the least costly treatment strategy. Results The least costly treatment strategy was immediate surgical release in the clinic. In patients with insulin-dependent diabetes mellitus, this strategy results in a 32% and a 39% cost reduction when compared with treatment with 1 or 2 corticosteroid injections, respectively. For 1 or 2 corticosteroid injections to be the most cost-effective strategy, injection failure rates would need to be less than 36% and 34%, respectively. The overall cost of care for immediate surgical release in the clinic was $642. Conclusions Diabetic trigger finger is a common problem faced by hand surgeons, with a variety of acceptable treatment algorithms. Management of diabetic trigger finger with immediate surgical release in the clinic is the most cost-effective treatment strategy, assuming a corticosteroid injection failure rate of at least 34%. Type of study/level of evidence Economic/decision III.

Standardized clinical assessment and management plans (SCAMPs) are a novel quality improvement initiative shown to improve patient care, diminish practice variation, and reduce resource utilization. Unlike clinical practice guidelines, a SCAMP is a flexible algorithm that undergoes iterative updates based on periodic data collection and review. We recently implemented a SCAMP for the closed treatment of pediatric torus fractures. The purpose of this study is to analyze the effect of SCAMP implementation on resource utilization, practice variability, cost of care, and outcomes.This study was a retrospective review of prospectively collected data on 273 patients with pediatric torus fractures. The pre-SCAMP cohort included 116 subjects from 2008 to 2010. The SCAMP cohort included 157 subjects from 2011 to 2013. The pre-SCAMP cohort was treated according to the judgment of attending fellowship-trained pediatric orthopaedic surgeons. The SCAMP cohort was treated with a standardized algorithm including radiographs and splint application at initial presentation, with a single follow-up at 3 weeks. Patient demographics were analyzed to verify comparability between cohorts. Follow-up data including clinic visits, x-rays and practice variability was recorded. Costing analysis was conducted using time-derived activity-based costing methodology. Outcomes were compared using Poisson regression analysis. Incident rate ratios (IRR) with 95% confidence limits were estimated.No differences in clinical results were observed between the pre-SCAMP and SCAMP cohorts, and all patients demonstrated return to baseline activity at final follow-up. Patient demographics were comparable across cohorts. The SCAMP cohort had a 48% reduction in clinic visits [IRR, 0.52; 95% confidence interval (CI), 0.44-0.60; P0.001], 60% reduction in x-rays (IRR, 0.40; CI, 0.33-0.47; P0.001), and a 23% reduction in x-rays per clinic visit (IRR, 0.77; 95% CI, 0.65-0.91; P0.001). Furthermore, SCAMP implementation resulted in a 49% reduction in the overall cost of care.SCAMPs provide a novel alternative to CPGs to implement cost effective changes in Orthopaedic practice. For pediatric torus fractures, SCAMP implementation resulted in decreased practice variability, resource utilization, and overall cost of care while maintaining clinical outcomes.Level 3.

Background As ≥30% of displaced pediatric forearm fractures demonstrate loss of reduction (LOR) following closed reduction (CR); radiographic follow-up is advocated at 1, 2, 4, and 6 weeks for detection of redisplacement. We hypothesized that there is minimal change in fracture alignment 2 weeks after CR, and consequently, that radiographs at 4 weeks add cost but little value to clinical care. Methods A total of 184 patients enrolled in a prospective study of pediatric forearm fractures including both distal and diaphyseal injuries were evaluated. All were treated with CR, casting, and radiographic evaluation at 1, 2, 4, and 6 weeks postinjury. Primary endpoint was radiographic LOR. Secondary endpoint was need for any intervention. A modified number-needed to treat analysis estimated the utility of the week 4 x-ray in predicting intervention. Relative value unit (RVU) costing, time-derived activity-based costing (TDABC), and billing totals were used for cost analysis. Results Seventy patients (38%) demonstrated radiographic LOR. Independent predictors of LOR were initial radius displacement >75% (OR=5.40; CI, 2.23-12.60), concomitant ulna fracture (OR=1.71; CI, 1.15-2.54), and dominant arm involvement (OR=2.87; CI, 1.40-5.87). Eighty percent of all LORs occurred within the first 2 weeks. There was no statistically significant change in radiographic alignment after week 2. Of 40 total interventions, all were performed within the first 2 weeks of follow-up. The 4-week x-ray did not influence decision to intervene, and at most, 1 in every 40 patients would require an intervention after week 2. Elimination of the 4-week x-ray would result in a savings of 4.8% (RVU method) to 11.9% (TDABC method) in the overall cost of nonoperative fracture care. Conclusions There is minimal change in fracture alignment 2 weeks following CR of pediatric forearm fractures, and all interventions are based on early radiographic follow-up. The week 4 x-ray adds little value to clinical decision making, and its elimination would result in savings up to 11.9% of the overall cost of nonoperative fracture care. Level of evidence Level II-prognostic.

We investigate the effectiveness of a comprehensive aseptic protocol in reducing surgical site infection (SSI) after knee arthroplasty in a single medical center with a high prevalence of MRSA. A database of all patients in a single center undergoing primary knee arthroplasty between 2005 and 2011 was reviewed for SSI using Centers for Disease Control criteria and AAOS guidelines. All patients were treated with an aseptic protocol consisting of the following: preoperative 2% mupirocin nasal ointment and 0.4% chlorhexidine surgical site wipes, modified instrument care, perioperative prophylactic vancomycin and cefazolin, and surgical site skin preparation with chlorhexidine, alcohol, and iodophor. We compare our protocol total knee arthroplasty SSI rate to our institutional historical control (2001-2004) and to contemporary literature. Among 1,224 patients, 70% were ASA class2 and 64% had a body mass index (BMI) 30 kg/m(2). We found an overall 0.49% infection rate, significantly lower than that of our institutional historical control (0.49 vs. 2.24%, p 0.001; odds ratio [OR], 0.21; number needed to treat [NNT], 145) and seven recently published reports (p 0.001-0.042; OR, 0.07-0.42). Compared with these reports, significantly more of our patients were ASA class 2, BMI 30 kg/m(2), immunosuppressed, or had rheumatoid arthritis. Our aseptic protocol decreases SSI in a high-risk population undergoing knee arthroplasty in a medical center and community with a high prevalence of MRSA.

BACKGROUND Education in microvascular surgery is limited by variable experience, a difficult learning curve, and potentially catastrophic complications caused by failed anastomoses. Furthermore, utilization of live-animal training models can be difficult because of lack of access and high maintenance costs. The purpose of this study was to determine the effectiveness and cost of a self-directed microvascular training curriculum utilizing synthetic microvessels and nonliving models in an orthopaedic residency program. METHODS Twenty-five orthopaedic residents ranging from postgraduate year (PGY)-1 to PGY-4 were prospectively enrolled. The curriculum consisted of learning the basics of microsurgery on nonliving models and progressed to anastomoses on a 1-mm synthetic microvessel. Outcomes included Global Rating Scale (GRS) scores (5 to 25 points), patency, anastomosis time, comfort level (1 to 10 points), time to complete the curriculum, and curriculum utility (1 to 10 points). Blinded qualitative assessments (from 1 to 10 points) of pre-curriculum and post-curriculum anastomoses were made by 4 hand surgery faculty members. Outcome measures were obtained at baseline and post-curriculum. The curriculum cost was calculated as the setup cost and the maintenance cost per resident. Student t tests and Fisher exact tests were utilized for significance. RESULTS All residents successfully completed the curriculum. The mean anastomosis time (and standard deviation) decreased from 40 ± 3 minutes to 22 ± 4 minutes (p < 0.001). The mean GRS score improved from 12 ± 2 points to 18 ± 2 points (p < 0.01). Patency was achieved by 44% at baseline evaluation and by 96% at post-curriculum evaluation (p < 0.0001). The mean comfort level improved from 3 ± 1.2 points to 6 ± 1.7 points (p < 0.0001) on a scale of 1 to 10 points. Also on a scale of 1 to 10, the blinded mean qualitative anastomoses score improved from 4.8 ± 2.2 points (poor) to 8.0 ± 1.1 points (good) (p < 0.0001). The mean time to complete the curriculum was 5.5 ± 1.4 hours, and, on a scale of 1 to 10, curriculum utility was rated by the residents to be 8 ± 1.8 points. The cost of the initial setup was $1,795 with a yearly utilization cost per resident of $42. CONCLUSIONS The implementation of a self-directed curriculum utilizing synthetic microvessels and nonliving models demonstrated significant improvements in resident microvascular skill. This curriculum represents a modest startup cost and low yearly cost per resident.

Osteosarcoma (OS) is the most common primary malignancy of bone. We investigated the roles of insulin-like growth factor binding protein 5 (IGFBP5) domains in modulating OS tumorigenicity and metastasis. The N-terminal (to a lesser extent the C-terminal) domain inhibited cell proliferation and induced apoptosis while the C-terminal domain inhibited cell migration and invasion. The Linker domain had no independent effects. In vivo, the N-terminal domain decreased tumor growth without affecting pulmonary metastases while the C-terminal domain inhibited tumor growth and metastases. In summary, the N- and C-terminal domains modulated OS tumorigenic phenotypes while the C-terminal domain inhibited OS metastatic phenotypes.

Background: Outcome assessment for the management of Chiari malformation type 1 is difficult because of the lack of a reliable and specific surgical outcome assessment scale. Such a scale could reliably correlate postoperative outcomes with preoperative symptoms. Objective: We developed a novel scoring system and applied it retrospectively to 146 patients treated at our institution in order to create and verify a simple and quantifiable assessment of Chiari outcomes. Methods: The Chicago Chiari Outcome Scale (CCOS) uses 4 postoperative outcome categories (pain, nonpain symptoms, functionality, and complications) graded 1 to 4 for a total possible score of 16. As a comparison with current Chiari outcome methodology, each patient was also placed into a gestalt outcome group of “improved,” “unchanged,” or “worse” (I/U/W). Patients were stratified by CCOS scores and by I/U/W group. Results: Stratifying patients by total CCOS scores showed that patients who achieved CCOS scores between 13 and 16 were predominantly in the I/U/W improved group (n = 101, 69%); scores between 9 and 12 were predominantly I/U/W unchanged (n = 39, 27%), and scores between 4 and 8 were I/U/W worse (n = 6, 4%). Symptom subscore results provided insight into the specifics of the overall outcome in addition to the more quantitative nature of the 16-point scale. Conclusion: We describe a CCOS that assigns higher scores to patients judged improved by gestalt I/U/W ratings and lower scores to those who were unchanged or worse while defining outcome in 4 specific subcategories. As such, this CCOS should allow for a more unified and quantifiable outcome assessment after Chiari surgery.

Osteosarcoma (OS) is associated with poor prognosis due to its high incidence of metastasis and chemoresistance. It often arises in areas of rapid bone growth in long bones during the adolescent growth spurt. Although certain genetic conditions and alterations increase the risk of developing OS, the molecular pathogenesis is poorly understood. Recently, defects in differentiation have been linked to cancers, as they are associated with high cell proliferation. Treatments overcoming these defects enable terminal differentiation and subsequent tumor inhibition. OS development may be associated with defects in osteogenic differentiation. While early regulators of osteogenesis are unable to bypass these defects, late osteogenic regulators, including Runx2 and Osterix, are able to overcome some of the defects and inhibit tumor propagation through promoting osteogenic differentiation. Further understanding of the relationship between defects in osteogenic differentiation and tumor development holds tremendous potential in treating OS.

Cartilage tissue engineering holds great promise for treating cartilaginous pathologies including degenerative disorders and traumatic injuries. Effective cartilage regeneration requires an optimal combination of biomaterial scaffolds, chondrogenic seed cells, and biofactors. Obtaining sufficient chondrocytes remains a major challenge due to the limited proliferative capability of primary chondrocytes. Here we investigate if reversibly immortalized mouse articular chondrocytes (iMACs) acquire long-term proliferative capability while retaining the chondrogenic phenotype. Primary mouse articular chondrocytes (MACs) can be efficiently immortalized with a retroviral vector-expressing SV40 large T antigen flanked with Cre/loxP sites. iMACs exhibit long-term proliferation in culture, although the immortalization phenotype can be reversed by Cre recombinase. iMACs express the chondrocyte markers Col2a1 and aggrecan and produce chondroid matrix in micromass culture. iMACs form subcutaneous cartilaginous masses in athymic mice. Histologic analysis and chondroid matrix staining demonstrate that iMACs can survive, proliferate, and produce chondroid matrix. The chondrogenic growth factor BMP2 promotes iMACs to produce more mature chondroid matrix resembling mature articular cartilage. Taken together, our results demonstrate that iMACs acquire long-term proliferative capability without losing the intrinsic chondrogenic features of MACs. Thus, iMACs provide a valuable cellular platform to optimize biomaterial scaffolds for cartilage regeneration, to identify biofactors that promote the proliferation and differentiation of chondrogenic progenitors, and to elucidate the molecular mechanisms underlying chondrogenesis.

Background/Aims: Osteosarcoma (OS) is the most common primary bone malignancy in children and young adults. Molecular mechanisms underlying the pathogenesis of OS remain to be fully understood. Several members of the E-F hand calcium-binding S100 protein family are differentially expressed in human cancers. We previously showed that S100A6 is highly expressed in OS tumors. In this study, we investigated the role of S100A4 in regulating OS proliferation and osteogenic differentiation. Methods/Results: Endogenous S100 expression was examined by semi-quantitative PCR in human OS lines. Adenoviral vector-mediated overexpression and RNAi knockdown of S100A4 were used to assess S100A4's effects on cell proliferation, migration and invasion and osteogenic differentiation. Apoptosis was assessed by using anti-caspase-3 immunostaining and flow cytometry with annexin V staining. Early osteogenic marker alkaline phosphatase (ALP) and late markers osteocalcin (OCN) and osteopontin (OPN) were assessed to determine the status of osteogenic differentiation. We found that S100A4 was elevated in metastatic MG63.2 cells. S100A4 knockdown inhibited cell proliferation, prolonged cell doubling time, and induced significant apoptosis. Silencing S100A4 expression in OS cells delayed cell wounding closure and diminished the numbers of migrated OS cells in transwell invasion assay. Furthermore, silencing S100A4 expression stimulated ALP activity, as well as late markers OPN and OCN, in both OS cells and mesenchymal stem cells. Conclusion: Our results strongly suggest that S100A4 may promote OS tumor growth by regulating the cell cycle, reducing apoptosis, and inhibiting osteogenic differentiation. Thus, S100A4 may serve as a marker for tumorigenic potential, as well as a therapeutic target.

Stem cells are characterized by their capability to self-renew and terminally differentiate into multiple cell types. Somatic or adult stem cells have a finite self-renewal capacity and are lineage-restricted. The use of adult stem cells for therapeutic purposes has been a topic of recent interest given the ethical considerations associated with embryonic stem (ES) cells. Mesenchymal stem cells (MSCs) are adult stem cells that can differentiate into osteogenic, adipogenic, chondrogenic, or myogenic lineages. Owing to their ease of isolation and unique characteristics, MSCs have been widely regarded as potential candidates for tissue engineering and repair. While various signaling molecules important to MSC differentiation have been identified, our complete understanding of this process is lacking. Recent investigations focused on the role of epigenetic regulation in lineage-specific differentiation of MSCs have shown that unique patterns of DNA methylation and histone modifications play an important role in the induction of MSC differentiation toward specific lineages. Nevertheless, MSC epigenetic profiles reflect a more restricted differentiation potential as compared to ES cells. Here we review the effect of epigenetic modifications on MSC multipotency and differentiation, with a focus on osteogenic and adipogenic differentiation. We also highlight clinical applications of MSC epigenetics and nuclear reprogramming.

Promoting osteogenic differentiation and efficacious bone regeneration have the potential to revolutionize the treatment of orthopaedic and musculoskeletal disorders. Mesenchymal Stem Cells (MSCs) are bone marrow progenitor cells that have the capacity to differentiate along osteogenic, chondrogenic, myogenic, and adipogenic lineages. Differentiation along these lineages is a tightly controlled process that is in part regulated by the Bone Morphogenetic Proteins (BMPs). BMPs 2 and 7 have been approved for clinical use because their osteoinductive properties act as an adjunctive treatment to surgeries where bone healing is compromised. BMP-9 is one of the least studied BMPs, and recent in vitro and in vivo studies have identified BMP-9 as a potent inducer of osteogenic differentiation in MSCs. BMP-9 exhibits significant molecular cross-talk with the Wnt/ β-catenin and other signaling pathways, and adenoviral expression of BMP-9 in MSCs increases the expression of osteogenic markers and induces trabecular bone and osteiod matrix formation. Furthermore, BMP-9 has been shown to act synergistically in bone formation with other signaling pathways, including Wnt/ β-catenin, IGF, and retinoid signaling pathways. These results suggest that BMP-9 should be explored as an effective bone regeneration agent, especially in combination with adjuvant therapies, for clinical applications such as large segmental bony defects, non-union fractures, and/or spinal fusions.

Background: Osteosarcoma is the most common primary malignancy of bone with poorly characterized molecular pathways important in its pathogenesis. Increasing evidence indicates that elevated lipid biosynthesis is a characteristic feature of cancer. We sought to investigate the role of lysophosphatidic acid acyltransferase b (LPAATb, aka, AGPAT2) in regulating the proliferation and growth of human osteosarcoma cells. LPAATb can generate phosphatidic acid, which plays a key role in lipid biosynthesis as well as in cell proliferation and survival. Although elevated expression of LPAATb has been reported in several types of human tumors, the role of LPAATb in osteosarcoma progression has yet to be elucidated. Methodology/Principal Findings: Endogenous expression of LPAATb in osteosarcoma cell lines is analyzed by using semiquantitative PCR and immunohistochemical staining. Adenovirus-mediated overexpression of LPAATb and silencing LPAATb expression is employed to determine the effect of LPAATb on osteosarcoma cell proliferation and migration in vitro and osteosarcoma tumor growth in vivo. We have found that expression of LPAATb is readily detected in 8 of the 10 analyzed human osteosarcoma lines. Exogenous expression of LPAATb promotes osteosarcoma cell proliferation and migration, while silencing LPAATb expression inhibits these cellular characteristics. We further demonstrate that exogenous expression of LPAATb effectively promotes tumor growth, while knockdown of LPAATb expression inhibits tumor growth in an orthotopic xenograft model of human osteosarcoma. Conclusions/Significance: Our results strongly suggest that LPAATb expression may be associated with the aggressive phenotypes of human osteosarcoma and that LPAATb may play an important role in regulating osteosarcoma cell proliferation and tumor growth. Thus, targeting LPAATb may be exploited as a novel therapeutic strategy for the clinical management of osteosarcoma. This is especially attractive given the availability of selective pharmacological inhibitors.

As one of the most common malignancies, colon cancer is initiated by abnormal activation of the Wnt/β-catenin pathway. Although the treatment options have increased for some patients, overall progress has been modest. Thus, there is a great need to develop new treatments. We have found that bisbenzylisoquinoline alkaloid tetrandrine (TET) exhibits anticancer activity. TET is used as a calcium channel blocker to treat hypertensive and arrhythmic conditions in Chinese medicine. Here, we investigate the molecular basis underlying TET's anticancer activity. We compare TET with six chemotherapy drugs in eight cancer lines and find that TET exhibits comparable anticancer activities with camptothecin, vincristine, paclitaxel, and doxorubicin, and better than that of 5-fluorouracil (5-FU) and carboplatin. TET IC50 is ≤5 μM in most of the tested cancer lines. TET exhibits synergistic anticancer activity with 5-FU and reduces migration and invasion capabilities of HCT116 cells. Furthermore, TET induces apoptosis and inhibits xenograft tumor growth of colon cancer. TET treatment leads to a decrease in β-catenin protein level in xenograft tumors, which is confirmed by T-cell factor/lymphocyte enhancer factor and c-Myc reporter assays. It is noteworthy that HCT116 cells with allelic oncogenic β-catenin deleted are less sensitive to TET-mediated inhibition of proliferation, viability, and xenograft tumor growth. Thus, our findings strongly suggest that the anticancer effect of TET in colon cancer may be at least in part mediated by targeting β-catenin activity. Therefore, TET may be used alone or in combination as an effective anticancer agent.

Protein drugs have low bioavailability after oral administration, which is due in part to fast transit of the drugs or drug delivery vehicles through the gastrointestinal tract. Increasing the time that the drugs spend in the intestine after dosing would allow for greater absorption and increased bioavailability. We developed a formulation strategy that can be used to prolong intestinal retention of drug delivery vehicles without substantial alterations to current polymeric encapsulation strategies. A model drug, insulin, was encapsulated in negatively-charged poly(lactic-co-glycolic acid) (PLGA) microparticles, and the microparticles were subsequently mixed with positively-charged micromagnets, whose size will prevent them from being absorbed. Stable complexes formed through electrostatic interaction. The complexes were effectively immobilized in vitro in a model of the mouse small intestine by application of an external magnetic field. Mice that were gavaged with radio-labeled complexes and fitted with a magnetic belt retained 32.5% of the 125I-insulin in the small intestine compared with 5.4% for the control group 6 hours after administration (p=0.005). Furthermore, mice similarly gavaged with complexes encapsulating insulin (120 Units/kg) exhibited long-term glucose reduction in the groups with magnetic belts. The corresponding bioavailability of insulin was 5.11% compared with 0.87% for the control group (p=0.007).

Nanoparticle (NP) size has been shown to significantly effect the biodistribution of targeted and non-targeted NPs in an organ specific manner. Herein we have developed NPs from carboxy-terminated poly (d,l-lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-b-PEG-COOH) polymer and studied the effects of altering the following formulation parameters on the size of NPs, including: 1) polymer concentration, 2) drug loading, 3) water miscibility of solvent, and 4) the ratio of water to solvent. We found that NP mean volumetric size correlates linearly with polymer concentration for NPs between 70 and 250 nm in diameter (linear coefficient = 0.99 for NPs formulated with solvents studied). NPs with desirable size, drug loading, and polydispersity were conjugated to the A10 RNA aptamer (Apt) that binds to the Prostate Specific Membrane Antigen (PSMA), and NP and NP-Apt biodistribution was evaluated in a LNCaP (PSMA+) xenograft mouse model of PCa. The surface functionalization of NPs with the A10 PSMA aptamer significantly enhanced delivery of NPs to tumors vs. equivalent NPs lacking the A10 PSMA aptamer (a 3.77-fold increase at 24 hrs; NP-Apt 0.83% ± 0.21% vs. NP 0.22% ± 0.07% of injected dose per gram of tissue; mean ± s.d., n = 4, p = 0.002). The ability to control NP size together with targeted delivery may result in favorable biodistribution and development of clinically relevant targeted therapies.