Peter T. Masiakos

A biodegradable and biocompatible gecko-inspired tissue adhesive

There is a significant medical need for tough biodegradable polymer adhesives that can adapt to or recover from various mechanical deformations while remaining strongly attached to the underlying tissue. We approached this problem by using a polymer poly(glycerol-co-sebacate acrylate) and modifying the surface to mimic the nanotopography of gecko feet, which allows attachment to vertical surfaces. Translation of existing gecko-inspired adhesives for medical applications is complex, as multiple parameters must be optimized, including: biocompatibility, biodegradation, strong adhesive tissue bonding, as well as compliance and conformability to tissue surfaces. Ideally these adhesives would also have the ability to deliver drugs or growth factors to promote healing. As a first demonstration, we have created a gecko-inspired tissue adhesive from a biocompatible and biodegradable elastomer combined with a thin tissue-reactive biocompatible surface coating. Tissue adhesion was optimized by varying dimensions of the nanoscale pillars, including the ratio of tip diameter to pitch and the ratio of tip diameter to base diameter. Coating these nanomolded pillars of biodegradable elastomers with a thin layer of oxidized dextran significantly increased the interfacial adhesion strength on porcine intestine tissue in vitro and in the rat abdominal subfascial in vivo environment. This gecko-inspired medical adhesive may have potential applications for sealing wounds and for replacement or augmentation of sutures or staples.

Müllerian Inhibiting Substance Inhibits Ovarian Cell Growth through an Rb-independent Mechanism

Müllerian inhibiting substance (MIS), a transforming growth factor-β family member, causes regression of the Müllerian duct in male embryos. MIS overexpression in transgenic mice ablates the ovary, and MIS inhibits the growth of ovarian cancer cell lines in vitro, suggesting a key role for this hormone in postnatal development of the ovary. This report describes a mechanism for MIS-mediated growth inhibition in both a human epithelial ovarian cancer cell line and a cell line derived from normal ovarian surface epithelium, which is the origin of human epithelial ovarian cancers. MIS-treated cells accumulated in the G1phase of the cell cycle and subsequently underwent apoptosis. MIS up-regulated the cyclin-dependent kinase inhibitor p16 through an MIS type II receptor-mediated mechanism and inhibited growth in the absence of detectable or inactive Rb protein. Prolonged treatment with MIS down-regulated the Rb-related protein p130 and increased the Rb family-regulated transcription factor E2F1, overexpression of which inhibited growth. These findings demonstrate that p16 is required for MIS-mediated growth inhibition in ovarian epithelial cells and tumor cells and suggest that up-regulation of E2F1 also plays a role in this process.

Müllerian-inhibiting substance type II receptor expression and function in purified rat Leydig cells.

Mullerian-inhibiting substance (MIS), a gonadal hormone in the transforming growth factor-β superfamily, induces Mullerian duct involution during male sexual differentiation. Mice with null mutations of the MIS ligand or receptor develop Leydig cell hyperplasia and neoplasia in addition to retained Mullerian ducts, whereas MIS-overexpressing transgenic mice have decreased testosterone concentrations and Leydig cell numbers. We hypothesized that MIS directly modulates Leydig cell proliferation and differentiated function in the maturing testis. Therefore, highly purified rat Leydig and Sertoli cells were isolated to examine cell-specific expression, binding, and function of the MIS type II receptor. These studies revealed that this receptor is expressed abundantly in progenitor (21-day) and immature (35-day) Leydig cells as well as in Sertoli cells. Prepubertal progenitor Leydig cells exhibit high affinity (Kd = 15 nm), saturable binding of MIS. No binding, however, is detected with either peripubertal imm...

Clinical clearance of the cervical spine in blunt trauma patients younger than 3 years: A multi-center study of the american association for the surgery of trauma

BACKGROUND Cervical spine clearance in the very young child is challenging. Radiographic imaging to diagnose cervical spine injuries (CSI) even in the absence of clinical findings is common, raising concerns about radiation exposure and imaging-related complications. We examined whether simple clinical criteria can be used to safely rule out CSI in patients younger than 3 years. METHODS The trauma registries from 22 level I or II trauma centers were reviewed for the 10-year period (January 1995 to January 2005). Blunt trauma patients younger than 3 years were identified. The measured outcome was CSI. Independent predictors of CSI were identified by univariate and multivariate analysis. A weighted score was calculated by assigning 1, 2, or 3 points to each independent predictor according to its magnitude of effect. The score was established on two thirds of the population and validated using the remaining one third. RESULTS Of 12,537 patients younger than 3 years, CSI was identified in 83 patients (0.66%), eight had spinal cord injury. Four independent predictors of CSI were identified: Glasgow Coma Score <14, GCSEYE = 1, motor vehicle crash, and age 2 years or older. A score of <2 had a negative predictive value of 99.93% in ruling out CSI. A total of 8,707 patients (69.5% of all patients) had a score of <2 and were eligible for cervical spine clearance without imaging. There were no missed CSI in this study. CONCLUSIONS CSI in patients younger than 3 years is uncommon. Four simple clinical predictors can be used in conjunction to the physical examination to substantially reduce the use of radiographic imaging in this patient population.

Extracorporeal Membrane Oxygenation for Nonneonatal Acute Respiratory Failure: The Massachusetts General Hospital Experience From 1990 to 2008

OBJECTIVE To determine the efficacy of extracorporeal membrane oxygenation (ECMO) for nonneonatal acute respiratory failure. DESIGN Single-institution, retrospective medical record review from February 1990 to March 2008. SETTING Tertiary care hospital. PATIENTS Eighty-one nonneonatal patients (mean age, 23 years; age range, 2 months to 61 years) with acute respiratory failure who had failed maximal ventilator support received ECMO therapy between 1990 and 2008. Patients were grouped into 6 categories based on diagnosis: sepsis (n = 8), bacterial or fungal pneumonia (n = 15), viral pneumonia (n = 9), trauma or burn (n = 10), immunocompromise (n = 15), and other (n = 24). Main Outcome Measure Survival to hospital discharge. RESULTS Overall survival was 53%. Survival was highest in patients with viral pneumonia (78%), followed by bacterial pneumonia (53%), sepsis syndrome (44%), and immunocompromise (40%). Patients treated following trauma or burns had the lowest survival (33%). The average age was 19 years for survivors as compared with 27 years for nonsurvivors. Survival was lower in patients with multiple organ failure as compared with those with single organ failure (33% vs 60%, respectively), in patients who experienced mechanical ventilation for longer than 10 days prior to the initiation of ECMO as compared with those who received ventilatory support for less than 10 days prior to the initiation of ECMO (31% vs 57%, respectively), and in patients requiring more than 400 hours of ECMO support as compared with those requiring less than 400 hours of ECMO support (42% vs 55%, respectively). CONCLUSIONS Therapy with ECMO may provide a survival benefit in carefully selected patients with nonneonatal acute respiratory failure who have failed maximal ventilator support. Nonneonatal survival with ECMO therapy is strongly dependent on diagnosis, with the highest survival seen in those with viral or bacterial pneumonia. Older age, multiple organ failure, prolonged ventilation prior to ECMO initiation, and long ECMO runs are associated with decreased survival.

A Highly Tunable Biocompatible and Multifunctional Biodegradable Elastomer

Biodegradable elastomers have emerged as promising materials for their potential to mimic the viscoelastic properties of several tissues and exhibit compliance with dynamic environments without damaging the surrounding tissue.[1, 2] Several elastomers have been recently proposed;[3–8] however, the development of highly tunable biodegradable elastomers that can effectively and controllably present biological and physical signals and withstand repeated cycles of physiologic loads, has remained elusive. Such materials should be useful for a broad range of clinically-relevant applications, such as cardiac therapy. For example, following myocardial infarction, the local controlled delivery of bioactive cues[9] or the physical support of the left ventricle wall[10] have been shown to improve cardiac function. The synergistic therapeutic effect of biochemical and biophysical cues has not yet been explored using degradable materials given the absence of materials that can simultaneously deliver bioactive cues and maintain mechanical integrity in a dynamic environment such as the beating heart. Here, we describe a novel biocompatible and mechanically tunable elastomer, poly(glycerol sebacate urethane) (PGSU), suitable for efficient encapsulation and controlled delivery of bioactive macromolecules and with the potential to be applied to cardiac drug delivery.

Cervical spine injury in young children: a National Trauma Data Bank review.

BACKGROUND Blunt cervical spine injury (CSI) is rare in the pediatric population. The objective of this study was to better characterize the incidence and type of CSI in young children (age <3 years) using a large, trauma center-based data set. METHODS The National Trauma Data Bank (NTDB) was reviewed for the period January 2001 to December 2005 for patients younger than 3 years of age with a blunt CSI (International Classification of Diseases, Ninth Revision, 805x, 806x, 952x). Demographic, injury, and outcome information were reviewed. Data management was performed using SAS (SAS, Cary, NC) and Stata (Stata Corp, College Station, TX). Patients with CSI were compared to patients without CSI of similar age. Means were compared with the Wilcoxon rank sum test, medians were compared with a nonparametric test, and count data were compared with the chi(2) test, with significance set at <.05. RESULTS For the period of review, 95,654 young children (age <3 years) with blunt trauma were identified in the NTDB. The overall population had a median Injury Severity Score (ISS) of 4, and most patients (77.01%) had a Glasgow Coma Score (GCS) of 15. There were 1523 (1.59%) patients with a CSI (spinal cord and/or column), including 366 patients (0.38%) with a spinal cord injury (with or without column injury) and 182 (0.19%) with an isolated spinal cord injury (SCIWORA). The CSI and non-CSI populations did not differ regarding median GCS (15 for both groups), but the CSI population had a significantly higher median ISS (14 vs 4, respectively; P < .001). Compared to patients without CSI, the CSI population was more likely to die in the emergency department (2.04% vs 1.25%; P = .007) or be admitted to the intensive care unit (45.3% vs 16.9%; P < .001). Nearly half of all cervical spine fractures (48%) and more than half of cervical spinal cord injuries (53%) were in the lower cervical spine (C5-7). MVCs were the most common injury mechanism (66%) followed by falls (15%). A CSI was observed in 3.2% of all motor vehicle crashes (MVCs). CONCLUSIONS In this trauma center population, these findings confirm the infrequency of blunt CSI in the youngest (age <3 years) trauma patients. The frequency of injuries to the lower cervical spine is higher than previously appreciated. MVCs are the most likely injury mechanism for this potentially devastating injury.

Nonoperative Management of Perianal Abscess in Infants Is Associated With Decreased Risk for Fistula Formation

OBJECTIVE. We sought to determine the frequency of progression in infants of perianal abscess with and without surgical drainage to fistula in ano to optimize a treatment plan for these children. METHODS. A retrospective cohort study was conducted of all patients who were ≤1 year of age and presented with perianal abscess to 2 pediatric tertiary care institutions during a 10-year period (January 1995 to February 2005, inclusive). Patients were divided into those who underwent surgical drainage and those who did not, and the rate of subsequent fistula formation was determined. RESULTS. Of 165 children initially identified, follow-up was available for 140. Ninety-four percent of children were male. Mean age was 4.2 ± 3.1 months. Of the 140 patients, 83 abscesses were drained and 57 were not drained. Of patients who underwent surgical drainage, 50 developed a fistula, whereas of those who did not undergo drainage only 9 developed a fistula. Synchronous administration of antibiotics (intravenous or oral) used in 57 of 58 patients from 1 institution was associated with an even greater decrease in fistula formation (12.5%) in the undrained population. CONCLUSIONS. Perianal abscess formation in infants who are younger than 12 months is a separate entity from abscess formation in older age groups. In this largest study to date, a combined center series of patients who presented to 2 academic pediatric hospitals with infantile perianal abscess, local hygiene and systemic antibiotics without surgical drainage minimized formation of fistula in ano.

The economic cost of firearm-related injuries in the United States from 2006 to 2010

BACKGROUND Estimates of the number of firearm-related injuries widely vary. Although focus has been primarily on deaths, the societal cost of caring for victims of these injuries is largely unknown. Our goal was to estimate the economic impact of nonfatal, firearm-related injuries in the United States based on recent, publically available data. METHODS We queried several national registries for hospital and emergency department (ED) discharges from 2006 to 2010 to estimate the annual incidence of firearm-related injuries. The cost of direct medical services and lost productivity from firearm-related injuries were extrapolated from recently published estimates. To identify potentially important trends, we compared the economic impact and payor mix for firearm-related injuries in 2006 with those in 2010. RESULTS During the 5-year analytic period, we identified 385,769 (SE = 29,328) firearm-related ED visits resulting in 141,914 (SE = 14,243) hospital admissions, costing more than

Tissue-engineered cells producing complex recombinant proteins inhibit ovarian cancer in vivo

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