Timothy M. Maul

Characterization of the response of bone marrow-derived progenitor cells to cyclic strain: implications for vascular tissue-engineering applications.

One of the major failings in vascular tissue engineering is the limited capacity of autologous differentiated cells to reconstitute tissues. A logical solution is to use multipotent progenitor cells, which in vascular treatments have been underutilized. Although biochemical stimulation has been explored to differentiate bone marrow-derived progenitor cells (BMPCs) to smooth muscle cells (SMCs), the use of biomechanical forces in differentiation remains unexplored. The purpose of this work was to explore the effects of cyclic strain alone on BMPC morphology, proliferation, and differentiation. BMPCs were isolated from rat bone marrow and, after 7 days in culture, the cells grew in distinct multilayered colonies. BMPCs were stimulated with 10% strain at 1 Hz for 7 days. Observations showed that cyclic strain inhibited proliferation (p < 0.05) and caused alignment of the cells (p < 0.05) and of the F-actin cytoskeleton perpendicular to the direction of strain. In addition, cyclic strain resulted in expression by the cells of vascular smooth muscle alpha-actin and h1-calponin. This work demonstrates the potential of physiologic biomechanical stimulation in the differentiation of BMPCs to SMCs, and this could have important implications for vascular tissue engineering and other therapies in which cell sourcing is a major concern.

American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock

Objectives: The American College of Critical Care Medicine provided 2002 and 2007 guidelines for hemodynamic support of newborn and pediatric septic shock. Provide the 2014 update of the 2007 American College of Critical Care Medicine “Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock.” Design: Society of Critical Care Medicine members were identified from general solicitation at Society of Critical Care Medicine Educational and Scientific Symposia (2006–2014). The PubMed/Medline/Embase literature (2006–14) was searched by the Society of Critical Care Medicine librarian using the keywords: sepsis, septicemia, septic shock, endotoxemia, persistent pulmonary hypertension, nitric oxide, extracorporeal membrane oxygenation, and American College of Critical Care Medicine guidelines in the newborn and pediatric age groups. Measurements and Main Results: The 2002 and 2007 guidelines were widely disseminated, translated into Spanish and Portuguese, and incorporated into Society of Critical Care Medicine and American Heart Association/Pediatric Advanced Life Support sanctioned recommendations. The review of new literature highlights two tertiary pediatric centers that implemented quality improvement initiatives to improve early septic shock recognition and first-hour compliance to these guidelines. Improved compliance reduced hospital mortality from 4% to 2%. Analysis of Global Sepsis Initiative data in resource rich developed and developing nations further showed improved hospital mortality with compliance to first-hour and stabilization guideline recommendations. Conclusions: The major new recommendation in the 2014 update is consideration of institution—specific use of 1) a “recognition bundle” containing a trigger tool for rapid identification of patients with septic shock, 2) a “resuscitation and stabilization bundle” to help adherence to best practice principles, and 3) a “performance bundle” to identify and overcome perceived barriers to the pursuit of best practice principles.

Molecular aspects of vascular tissue engineering.

Cardiovascular disease remains the number one cause of death in the United States. Most current surgical procedures to alleviate this disease rely on the availability of suitable small diameter vascular grafts, which are constrained by several limitations. Tissue engineering brings new hope to this field, but still faces many challenges. This review focuses on the molecular aspects of the different components of vascular tissue engineering. The topics addressed include the cell type, extracellular matrix, and physical and biochemical stimulation with respect to their role in the development of a tissue engineered vascular graft.

Shock-related anxiety and sexual function in adults with congenital heart disease and implantable cardioverter-defibrillators

BACKGROUND An increasing number of adults with congenital heart disease (CHD) require implantable cardioverter-defibrillators (ICDs), yet little is known about their impact on psychological well-being and sexual function. OBJECTIVE To assess shock-related anxiety in adults with CHD and its association with depression and sexual function. METHODS A prospective, multicenter, cross-sectional study was conducted on adult patients with CHD with (ICD(+)) and without (ICD(-)) ICDs. The Florida Shock Anxiety Scale was administered to patients with ICD(+) and the Beck Depression Inventory-II to all patients. Men completed the Sexual Health Inventory for Men, and women completed the Female Sexual Function Index. RESULTS A total of 180 adults with CHD (ICD(+): n = 70; ICD(-): n = 110; median age 32 years [interquartile range 27-40 years]; 44% women) were enrolled. The complexity of CHD was classified as mild in 32 (18%), moderate in 93 (52%), and severe in 54 (30%) subjects. In ICD recipients, a high level of shock-related anxiety was identified (Florida Shock Anxiety Scale score 16; interquartile range 12-23.5), which was slightly higher than the median score for ICD recipients in the general population (P = .057). A higher level of shock-related anxiety was associated with poorer sexual function scores in both men (Spearmans ρ =-.480; P<.001) and women (Spearmans ρ =-.512; P<.01). It was also associated with self-reported depressive symptomatology (Spearmans ρ = .536; P< .001). CONCLUSIONS Adults with CHD and ICDs demonstrate a high level of shock-related anxiety, which is associated with lower sexual functioning scores in men and women. These results underscore the need for increased clinical attention related to ICD-related shock anxiety and impaired sexual function in this population.

Activated partial thromboplastin time is a better trending tool in pediatric extracorporeal membrane oxygenation

Objectives: To determine whether activated partial thromboplastin times are a better heparin management tool than activated clotting times in pediatric extracorporeal membrane oxygenation. Design: A single-center retrospective analysis of perfusion and patient records. Setting: Academic pediatric tertiary care center. Patients: Pediatric patients (<21 yrs old) requiring extracorporeal membrane oxygenation support initiated at Children’s Hospital of Pittsburgh. Interventions: None. Measurements and Main Results: Point-of-care activated clotting time and activated partial thromboplastin time values, clinical laboratory activated partial thromboplastin time values, weight-normalized heparin administration (units/kg/hr), and reported outcomes were collected for pediatric patients treated for cardiac and/or respiratory failure with extracorporeal membrane oxygenation. Spearman’s ranked correlations were performed for each coagulation test compared to heparin dosage. The Bland–Altman test was used to determine the validity of the point-of-care activated partial thromboplastin time. Hazard analysis was conducted for outcomes and complications for patients whose heparin management was based on the clinical laboratory activated partial thromboplastin time or the activated clotting time. Only the clinical laboratory activated partial thromboplastin time showed a correlation (&rgr; = 0.40 vs. &rgr; = −0.04 for activated clotting time) with the heparin administration (units/kg/hr). Point-of-care activated partial thromboplastin time and activated partial thromboplastin time values correlated well (&rgr; = 0.76), with <5% of samples showing a difference outside 2 SDs, but differences in their absolute values (&Dgr;activated partial thromboplastin time = 100 secs) preclude them from being interchangeable measures. Furthermore, despite no effective change in the mean activated clotting time, cardiac patients showed a significantly improved correlation to heparin dose for all coagulation tests (e.g., point-of-care activated partial thromboplastin time &rgr; = 0.60). Management of patients with the clinical laboratory activated partial thromboplastin time did not significantly affect patient survival rates but did significantly reduce bleeding complications and significantly increased clotting in the extracorporeal membrane oxygenation circuit. A hazard analysis demonstrated that bleeding complications were associated with an increased risk of mortality, whereas clotting complications in the extracorporeal membrane oxygenation circuit were not. Conclusions: The activated clotting time is not an accurate monitoring tool for heparin management in pediatricextracorporeal membrane oxygenation. The point-of-care activated partial thromboplastin time correlates well with the clinical laboratory activated partial thromboplastin time but cannot be substituted for the clinical laboratory activated partial thromboplastin time values. Management of pediatric extracorporeal membrane oxygenation patients with the clinical laboratory activated partial thromboplastin time reduced bleeding complications which are associated with increases in mortality.

Optimization of ultrasound contrast agents with computational models to improve selection of ligands and binding strength

Diagnosis of cardiovascular disease is currently limited by the testing modality. Serum tests for biomarkers can provide quantification of severity but lack the ability to localize the source of the cardiovascular disease, while imaging technology such as angiography and ultrasound can only determine areas of reduced flow but not the severity of tissue ischemia. Targeted imaging with ultrasound contrast agents offers the ability to locally image as well as determine the degree of ischemia by utilizing agents that will cause the contrast agent to home to the affected tissue. Ultrasound molecular imaging via targeted microbubbles (MB) is currently limited by its sensitivity to molecular markers of disease relative to other techniques (e.g., radiolabeling). We hypothesize that computational modeling may provide a useful first approach to maximize microbubble binding by defining key parameters governing adhesion. Adhesive dynamics (AD) was used to simulate the fluid dynamic and stochastic molecular binding of microbubbles to inflamed endothelial cells. Sialyl LewisX (sLex), P‐selectin aptamer (PSA), and ICAM‐1 antibody (abICAM) were modeled as the targeting receptors on the microbubble surface in both single‐ and dual‐targeted arrangements. Microbubble properties (radius [Rc], kinetics [kf, kr], and densities of targeting receptors) and the physical environment (shear rate and target ligand densities) were modeled. The kinetics for sLex and PSA were measured with surface plasmon resonance. Rc, shear rate, and densities of sLex, PSA, or abICAM were varied independently to assess model sensitivity. Firm adhesion was defined as MB velocity <2% of the free stream velocity. AD simulations revealed an optimal microbubble radius of 1–2 µm and thresholds for

A biohybrid artificial lung prototype with active mixing of endothelialized microporous hollow fibers

k_{{\rm f}}^{{\rm in}}

A New Experimental System for the Extended Application of Cyclic Hydrostatic Pressure to Cell Culture

(>102 s−1) and

Platelet activation in ovines undergoing sham surgery or implant of the second generation PediaFlow pediatric ventricular assist device.

k_{{\rm r}}^{{\rm o}}

Assessment of the Cerebral Circulation in Adults with Coarctation of the Aorta

(<10−3 s−1) for firm adhesion in a multi‐targeted system. State diagrams for multi‐targeted microbubbles suggest sLex and abICAM microbubbles may require 10‐fold more ligand to achieve firm adhesion at higher shear rates than sLex and PSA microbubbles. The AD model gives useful insight into the key parameters for stable microbubble binding, and may allow flexible, prospective design, and optimization of microbubbles to enhance clinical translation of ultrasound molecular imaging. Biotechnol. Bioeng. 2010;107: 854–864.