Electric Fields Regulate In Vitro Surface Phosphatidylserine Exposure of Cancer Cells via a Calcium-Dependent Pathway.

Cancer is the second leading cause of death worldwide after heart disease. The current treatment options to fight cancer are limited, and there is a critical need for better treatment strategies. During the last several decades, several electric field (EF)-based approaches for anti-cancer therapies have been introduced, such as electroporation and tumor-treating fields; still, they are far from optimal due to their invasive nature, limited efficacy and significant side effects.

Phosphatidylserine: The Unique Dual-Role Biomarker for Cancer Imaging and Therapy.

Cancer is among the leading causes of death worldwide. In recent years, many cancer-associated biomarkers have been identified that are used for cancer diagnosis, prognosis, screening, and early detection, as well as for predicting and monitoring carcinogenesis and therapeutic effectiveness. Phosphatidylserine (PS) is a negatively charged phospholipid which is predominantly located in the inner leaflet of the cell membrane.

Application of strain and calibration of Förster Resonance Energy Transfer (FRET) emission for in vitro live cell response to cytoskeletal deformation.

Cellular mechanotransduction is an integral part of many crucial physiological processes, but non-invasive tools for quantifying intracellular strain in vivo are not available for complex tissues such as bone. As a first step to address this gap, we have utilized a novel, non-invasive approach to quantify cellular strain in vitro by employing a transfected alpha-actinin Förster Resonance Energy Transfer (FRET) sensor. Following validation experiments, mouse fibroblasts transfected to express FRET sensors were seeded to a silicone membrane and subjected to up to 10% tensile strain mounted on a multi-photon microscope.

Diabetic wound healing in a MMP9-/- mouse model.

Reduced mobilization of endothelial progenitor cells (EPCs) from the bone marrow (BM) and impaired EPC recruitment into the wound represent a fundamental deficiency in the chronic ulcers. However, mechanistic understanding of the role of BM-derived EPCs in cutaneous wound neovascularization and healing remains incomplete, which impedes development of EPC-based wound healing therapies. The objective of this study was to determine the role of EPCs in wound neovascularization and healing both under normal conditions and using single deficiency (EPC) or double-deficiency (EPC + diabetes) models of wound healing.

Physiological Growth, Remodeling Potential, and Preserved Function of a Novel Bioprosthetic Tricuspid Valve: Tubular Bioprosthesis Made of Small Intestinal Submucosa-Derived Extracellular Matrix.

Background: Prosthetic valves currently used in children lack the ability to grow with the patient and often require multiple reoperations. Small intestinal submucosa-derived extracellular matrix (SIS-ECM) has been used successfully as a patch for repair in various tissues, including vessels, valves, and myocardium.

Objectives: This study sought to assess the remodeling potential of a tubular tricuspid valve (TV) bioprosthesis made of SIS-ECM by evaluating its growth, structure, and function in a growing ovine model.

Cross Talk between NOTCH Signaling and Biomechanics in Human Aortic Valve Disease Pathogenesis.

Aortic valve disease is a burgeoning public health problem associated with significant mortality. Loss of function mutations in NOTCH1 cause bicuspid aortic valve (BAV) and calcific aortic valve disease. Because calcific nodules manifest on the fibrosa side of the cusp in low fluidic oscillatory shear stress (OSS), elucidating pathogenesis requires approaches that consider both molecular and mechanical factors.

Review of molecular and mechanical interactions in the aortic valve and aorta: implications for the shared pathogenesis of aortic valve disease and aortopathy.

Aortic valve disease (AVD) and aortopathy are associated with substantial morbidity and mortality, representing a significant cardiovascular healthcare burden worldwide. These mechanobiological structures are morphogenetically related and function in unison from embryonic development through mature adult tissue homeostasis, serving both coordinated and distinct roles. In addition to sharing common developmental origins, diseases of the aortic valve and proximal thoracic aorta often present together clinically.

Nanofiber Microenvironment Effectively Restores Angiogenic Potential of Diabetic Endothelial Cells.

The effect of chronic hyperglycemic exposure on endothelial cell (EC) phenotype, impaired wound neovascularization, and healing is not completely understood. The hypotheses are: 1) chronic exposure to diabetic conditions impairs the angiogenic potential of ECs and 2) this deficiency can be improved by an extracellular microenvironment of angiogenic peptide nanofibers. Angiogenic potential of microvascular ECs isolated from diabetic (db/db) and wild type (wt) mice was assessed by quantifying migration, proliferation, apoptosis, capillary morphogenesis, and vascular endothelial growth factor (VEGF) expression for cell cultures on Matrigel (Millipore, Billerica, MA) or nanofibers under normoglycemic conditions.

Asymmetric cell-matrix and biomechanical abnormalities in elastin insufficiency induced aortopathy.

Aortopathy is characterized by vascular smooth muscle cell (VSMC) abnormalities and elastic fiber fragmentation. Elastin insufficient (Eln (+/-)) mice demonstrate latent aortopathy similar to human disease. We hypothesized that aortopathy manifests primarily in the aorto-pulmonary septal (APS) side of the thoracic aorta due to asymmetric cardiac neural crest (CNC) distribution.

Angiogenic microenvironment augments impaired endothelial responses under diabetic conditions.

Diabetes-induced cardiomyopathy is characterized by cardiac remodeling, fibrosis, and endothelial dysfunction, with no treatment options currently available. Hyperglycemic memory by endothelial cells may play the key role in microvascular complications in diabetes, providing a potential target for therapeutic approaches. This study tested the hypothesis that a proangiogenic environment can augment diabetes-induced deficiencies in endothelial cell angiogenic and biomechanical responses.

Regulation of endothelial MAPK/ERK signalling and capillary morphogenesis by low-amplitude electric field.

Low-amplitude electric field (EF) is an important component of wound-healing response and can promote vascular tissue repair; however, the mechanisms of action on endothelium remain unclear. We hypothesized that physiological amplitude EF regulates angiogenic response of microvascular endothelial cells via activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. A custom set-up allowed non-thermal application of EF of high (7.

Diabetes alters intracellular calcium transients in cardiac endothelial cells.

Diabetic cardiomyopathy (DCM) is a diabetic complication, which results in myocardial dysfunction independent of other etiological factors. Abnormal intracellular calcium ([Ca(2+)](i)) homeostasis has been implicated in DCM and may precede clinical manifestation. Studies in cardiomyocytes have shown that diabetes results in impaired [Ca(2+)](i) homeostasis due to altered sarcoplasmic reticulum Ca(2+) ATPase (SERCA) and sodium-calcium exchanger (NCX) activity.

Maladaptive matrix remodeling and regional biomechanical dysfunction in a mouse model of aortic valve disease.

Aortic valve disease (AVD) occurs in 2.5% of the general population and often requires surgical intervention. Aortic valve malformation (AVM) underlies the majority of cases, suggesting a developmental etiology.

Tissue-engineered provisional matrix as a novel approach to enhance diabetic wound healing.

Inherent pathologies associated with diabetic wound microenvironment including increased proteolysis, inflammatory dysregulation, and impaired neovascularization prevent timely resolution of chronic diabetic ulcers. It is hypothesized that augmentation of local wound microenvironment with a stable provisional matrix formed by proteolysis-resistant angiogenic peptide nanofibers (NFs) will create permissive environment for attenuated inflammation, enhanced neovascularization, and improved diabetic wound healing. Using murine excisional wound healing models, full-thickness dorsal skin wounds were treated with either NFs or control solutions (phosphate buffered saline; hyaluronic acid) and analyzed for morphology, inflammatory response, neovascularization, and biomechanical properties.

Regulation of endothelial cell activation and angiogenesis by injectable peptide nanofibers.

RAD16-II peptide nanofibers are promising for vascular tissue engineering and were shown to enhance angiogenesis in vitro and in vivo, although the mechanism remains unknown. We hypothesized that the pro-angiogenic effect of RAD16-II results from low-affinity integrin-dependent interactions of microvascular endothelial cells (MVECs) with RAD motifs. Mouse MVECs were cultured on RAD16-II with or without integrin and MAPK/ERK pathway inhibitors, and angiogenic responses were quantified.

Neuromagnetic measures of word processing in bilinguals and monolinguals.

Objective: This study aimed to use magnetoencephalography (MEG) to examine the question of whether Mandarin-English bilingual speakers recruit the same cortical areas or develop distinct language-specific networks without overlaps for word processing.

Methods: Eight healthy Mandarin-English bilingual adults and eight healthy English monolingual adults were scanned while single-word paradigms were audio-visually presented.

Results: Our results showed significantly stronger beta-band power suppression in the right inferior parietal lobe (IPL) covering the supramarginal gyrus (BA 40) and angular gyrus (BA 39) for bilinguals when processing Mandarin versus English.

Regional structure-function relationships in mouse aortic valve tissue.

Site-specific biomechanical properties of the aortic valve play an important role in native valve function, and alterations in these properties may reflect mechanisms of degeneration and disease. Small animals such as targeted mutagenesis mice provide a powerful approach to model human valve disease pathogenesis; however, physical mechanical testing in small animals is limited by valve tissue size. Aortic valves are comprised of highly organized extracellular matrix compartmentalized in cusp and annulus regions, which have different functions.

Elastin haploinsufficiency results in progressive aortic valve malformation and latent valve disease in a mouse model.

Rationale: Elastin is a ubiquitous extracellular matrix protein that is highly organized in heart valves and arteries. Because elastic fiber abnormalities are a central feature of degenerative valve disease, we hypothesized that elastin-insufficient mice would manifest viable heart valve disease.

Objective: To analyze valve structure and function in elastin-insufficient mice (Eln(+/-)) at neonatal, juvenile, adult, and aged adult stages.

Complex temporal regulation of capillary morphogenesis by fibroblasts.

Interactions between endothelial and stromal cells are important for vascularization of regenerating tissue. Fibroblasts (FBs) are responsible for expression of angiogenic growth factors and matrix metalloproteinases, as well as collagen deposition and fibrotic myocardial remodeling. Recently, self-assembling peptide nanofibers were described as a promising environment for cardiac regeneration due to its synthetic nature and control over physiochemical properties.

Self-assembling short oligopeptides and the promotion of angiogenesis.

Because an adequate blood supply to and within tissues is an essential factor for successful tissue regeneration, promoting a functional microvasculature is a crucial factor for biomaterials. In this study, we demonstrate that short self-assembling peptides form scaffolds that provide an angiogenic environment promoting long-term cell survival and capillary-like network formation in three-dimensional cultures of human microvascular endothelial cells. Our data show that, in contrast to collagen type I, the peptide scaffold inhibits endothelial cell apoptosis in the absence of added angiogenic factors, accompanied by enhanced gene expression of the angiogenic factor VEGF.

Injectable self-assembling peptide nanofibers create intramyocardial microenvironments for endothelial cells.

Background: Promoting survival of transplanted cells or endogenous precursors is an important goal. We hypothesized that a novel approach to promote vascularization would be to create injectable microenvironments within the myocardium that recruit endothelial cells and promote their survival and organization.

Methods And Results: In this study we demonstrate that self-assembling peptides can be injected and that the resulting nanofiber microenvironments are readily detectable within the myocardium.

Endothelial cells promote cardiac myocyte survival and spatial reorganization: implications for cardiac regeneration.

Background: Endothelial-cardiac myocyte (CM) interactions play a key role in regulating cardiac function, but the role of these interactions in CM survival is unknown. This study tested the hypothesis that endothelial cells (ECs) promote CM survival and enhance spatial organization in a 3-dimensional configuration.

Methods And Results: Microvascular ECs and neonatal CMs were seeded on peptide hydrogels in 1 of 3 experimental configurations: CMs alone, CMs mixed with ECs (coculture), or CMs seeded on preformed EC networks (prevascularized).

Osmotic loading to determine the intrinsic material properties of guinea pig knee cartilage.

Few methods exist to study cartilage mechanics in small animal joints due to the difficulties associated with handling small tissue samples. In this study, we apply an osmotic loading method to quantify the intrinsic material properties of articular cartilage in small animal joints. Cartilage samples were studied from the femoral condyle and tibial plateau of two-month old guinea pigs.

Direct measurement of the Poisson's ratio of human patella cartilage in tension.

Articular cartilage has been shown to exhibit large transverse contractions when loaded in tension, suggesting the existence of large values for the Poisson's ratio. Previous studies have suggested that this effect is dependent on amplitude of applied strain, so that a single Poisson's ratio may not be sufficient to describe cartilage behavior. In this study, the Poisson's ratio (v), toe region modulus (Eo), and linear region modulus (E) of human patellar articular cartilage were calculated in simple tension tests from optical analysis of the two-dimensional strain fields at equilibrium.