A Computational Pitting Corrosion Model of Magnesium Alloys.

Controlling the corrosion rate of implants to maintain mechanical properties during tissue healing is significant in developing magnesium alloy implants. In addition to surface treatment and material properties, the study of geometric alteration and mechanical strength are also vital for implant development. In this study, we developed a three-dimensional model for semi-autonomous computational pitting corrosion. It is based on the Monte Carlo method, modeling magnesium alloy implants toward clinical application. The corrosion probability is based on the number of exposed surfaces to saline and the oxidation characteristics of the elements. The computational results are well compared with the experimental measurement using micro-computed tomography (micro-CT) in 500 h. Subsequently, the computational analysis is extended to 3,000 h of corrosion analysis. The 3D model appears promising to assist the development of biodegradable implants.

Identification of a distal RXFP1 gene enhancer with differential activity in fibrotic lung fibroblasts involving AP-1.

Relaxin/insulin-like family peptide receptor 1 (RXFP1) mediates relaxin's antifibrotic effects and has reduced expression in the lung and skin of patients with fibrotic interstitial lung disease (fILD) including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). This may explain the failure of relaxin-based anti-fibrotic treatments in SSc, but the regulatory mechanisms controlling RXFP1 expression remain largely unknown. This study aimed to identify regulatory elements of RXFP1 that may function differentially in fibrotic fibroblasts. We identified and evaluated a distal regulatory region of RXFP1 in lung fibroblasts using a luciferase reporter system. Using serial deletions, an enhancer upregulating pGL3-promoter activity was localized to the distal region between -584 to -242bp from the distal transcription start site (TSS). This enhancer exhibited reduced activity in IPF and SSc lung fibroblasts. Bioinformatic analysis identified two clusters of activator protein 1 (AP-1) transcription factor binding sites within the enhancer. Site-directed mutagenesis of the binding sites confirmed that only one cluster reduced activity (-358 to -353 relative to distal TSS). Co-expression of FOS in lung fibroblasts further increased enhancer activity. In vitro complex formation with a labeled probe spanning the functional AP-1 site using nuclear proteins isolated from lung fibroblasts confirmed a specific DNA/protein complex formation. Application of antibodies against JUN and FOS resulted in the complex alteration, while antibodies to JUNB and FOSL1 did not. Analysis of AP-1 binding in 5 pairs of control and IPF lung fibroblasts detected positive binding more frequently in control fibroblasts. Expression of JUN and FOS was reduced and correlated positively with RXFP1 expression in IPF lungs. In conclusion, we identified a distal enhancer of RXFP1 with differential activity in fibrotic lung fibroblasts involving AP-1 transcription factors. Our study provides insight into RXFP1 downregulation in fILD and may support efforts to reevaluate relaxin-based therapeutics alongside upregulation of RXFP1 transcription.

Three-dimensional diastolic blood flow in the left ventricle.

Three-dimensional blood flow in a human left ventricle is studied via a computational analysis with magnetic resonance imaging of the cardiac motion. Formation, growth and decay of vortices during the myocardial dilation are analyzed with flow patterns on various diametric planes. They are dominated by momentum transfer during flow acceleration and deceleration through the mitral orifice. The posterior and anterior vortices form an asymmetric annular vortex at the mitral orifice, providing a smooth transition for the rapid inflow to the ventricle. The development of core vortex accommodates momentum for deceleration and for acceleration at end diastolic atrial contraction. The rate of energy dissipation and that of work done by viscous stresses are small; they are approximately balanced with each other. The kinetic energy flux and the rate of work done by pressure delivered to blood from ventricular dilation is well balanced by the total energy influx at the mitral orifice and the rate change of kinetic energy in the ventricle.

Kinematic, Dynamic, and Energy Characteristics of Diastolic Flow in the Left Ventricle.

Blood flow characteristics in the normal left ventricle are studied by using the magnetic resonance imaging, the Navier-Stokes equations, and the work-energy equation. Vortices produced during the mitral valve opening and closing are modeled in a two-dimensional analysis and correlated with temporal variations of the Reynolds number and pressure drop. Low shear stress and net pressures on the mitral valve are obtained for flow acceleration and deceleration. Bernoulli energy flux delivered to blood from ventricular dilation is practically balanced by the energy influx and the rate change of kinetic energy in the ventricle. The rates of work done by shear and energy dissipation are small. The dynamic and energy characteristics of the 2D results are comparable to those of a 3D model.

Intramyocardial peptide nanofiber injection improves postinfarction ventricular remodeling and efficacy of bone marrow cell therapy in pigs.

BACKGROUND: Growing evidence suggests that intramyocardial biomaterial injection improves cardiac functions after myocardial infarction (MI) in rodents. Cell therapy is another promising approach to treat MI, although poor retention of transplanted cells is a major challenge. In this study, we hypothesized that intramyocardial injection of self-assembling peptide nanofibers (NFs) thickens the infarcted myocardium and increases transplanted autologous bone marrow mononuclear cell (MNC) retention to attenuate cardiac remodeling and dysfunction in a pig MI model. METHODS AND RESULTS: A total of 40 mature minipigs were divided into 5 groups: sham, MI+normal saline, MI+NFs, MI+MNCs, and MI+MNCs/NFs. MI was induced by coronary occlusion followed by intramyocardial injection of 2 mL normal saline or 1% NFs with or without 1×10(8) isolated autologous MNCs. NF injection significantly improved diastolic function and reduced ventricular remodeling 28 days after treatment. Injection of MNCs alone ameliorated systolic function only, whereas injection of MNCs with NFs significantly improved both systolic and diastolic functions as indicated by +dP/dt and -dP/dt (1214.5±91.9 and -1109.7±91.2 mm Hg/s in MI+NS, 1693.7±84.7 and -1809.6±264.3 mm Hg/s in MI+MNCs/NFs, respectively), increased transplanted cell retention (29.3±4.5 cells/mm(2) in MI+MNCs and 229.4±41.4 cells/mm(2) in MI+MNCs/NFs) and promoted capillary density in the peri-infarct area. CONCLUSIONS: We demonstrated that NF injection alone prevents ventricular remodeling, whereas cell implantation with NFs improves cell retention and cardiac functions after MI in pigs. This unprecedented combined treatment in a large animal model has therapeutic effects, which can be translated to clinical applications in the foreseeable future.