Scaffold biomaterials for nano-pathophysiology.

This review is intended to provide an overview of tissue engineering strategies using scaffold biomaterials to develop a vascularized tissue engineered construct for nano-pathophysiology. Two primary topics are discussed. The first is the biological or synthetic microenvironments that regulate cell behaviors in pathological conditions and tissue regeneration. Second is the use of scaffold biomaterials with angiogenic factors and/or cells to realize vascularized tissue engineered constructs for nano-pathophysiology. These topics are significantly overlapped in terms of three-dimensional (3-D) geometry of cells and blood vessels. Therefore, this review focuses on neovascularization of 3-D scaffold biomaterials induced by angiogenic factors and/or cells. The novel strategy of this approach in nano-pathophysiology is to utilize the vascularized tissue engineered construct as a tissue model to predict the distribution and subsequent therapeutic efficacy of a drug delivery system with different physicochemical and biological properties

The genesis of intramyocardial pressure

This dissertation explores the genesis of intramyocardial pressure (IMP), the positive oscillatory pressure measured within the contracting and relaxing walls of the heart. A wide variety of methods is critically reviewed and observed to yield peak values higher or lower than peak left ventricular pressure (LVP). All investigators have observed a strong radial gradient of IMP with maximum values at the endocardium. Three generations of mathematical models are developed herein to provide the physical mechanism responsible for the magnitude and distribution of IMP. Model predictions are compared to experimental findings and voluminous literature data. The first generation models examine solid elastic description of the left ventricle, with local IMP defined as the negative of the average of the three local time-varying orthogonal stresses. These models yield negative values for IMP, and lack a radial gradient contrary to experimental findings. The second generation models consider multi-layer design separated by thin fluid layers. Both tissue and fluid pressures exhibit a strong radial gradient; the latter being positive, never exceeding peak LVP. In view of myocardial morphology, it became apparent that the majority of pressure transducers are sensitive to both fluid pressure and fiber stress. Separation of IMP into two components of intramyocardial fluid pressure (IFP) and fiber stress (IFS) resolves methodological problems. A transducer, insensitive to fiber stress, yields peak IFP values below peak LVP that are sensitive to inotropic, mechanical, and neural interventions in canines, though LVP may not change. Experiments in empty beating hearts permitted decoupling of wall stress from LVP. Decompression was observed to modify but not obliterate phasic myocardial activity (IFP) as predicted by published formulas, derived to calculate ventricular wall stresses. Focusing attention on the muscle cell, intracellular fluid pressure in a contracting isolated skeletal myocyte of the giant barnacle is measured and observed to be dynamically related to shortening, but not to tension in isometric experiments. A mechanistic model of the myocyte, consisting of a fluid-filled cylindrical shell with axially arranged contractile filaments, manifests a positive transmural pressure during shortening, which is attributed to cell distortion. In the myocardium this imposes distortion of the interstitial spaces, thereby altering IFP. Intracellular pressure in the shortening myocyte acts as an internal load, resisting shortening and incurring metabolic costs formerly attributed solely to extracellular load. Transmural pressure developed during shortening is held responsible for cell relengthening during relaxation. Intramyocardial fluid pressure is concluded to be generated by shortening of primarily fluid filled fibers. Therefore, it is caused by an intrinsic wall mechanism, resulting in LVP development

New Dimensions in Vascular Engineering: Opportunities for Cancer Biology

Angiogenesis is a fundamental prerequisite for tissue growth and thus an attractive target for cancer therapeutics. However, current efforts to halt tumor growth using antiangiogenic agents have been met with limited success. A reason for this may be that studies aimed at understanding tissue and organ formation have to this point utilized two-dimensional cell culture techniques, which fail to faithfully mimic the pathological architecture of disease in an in vivo context. In this issue of Tissue Engineering, the work of Fischbach-Teschl's group manipulate such variables as oxygen concentration, culture three-dimensionality, and cell–extracellular matrix interactions to more closely approximate the biophysical and biochemical microenvironment of tumor angiogenesis. In this article, we discuss how novel tissue engineering platforms provide a framework for the study of tumorigenesis under pathophysiologically relevant in vitro culture conditions

Tracking of Endothelial Cell Migration and Stiffness Measurements Reveal the Role of Cytoskeletal Dynamics

Cell migration is a complex, tightly regulated multistep process in which cytoskeletal reorganization and focal adhesion redistribution play a central role. Core to both individual and collective migration is the persistent random walk, which is characterized by random force generation and resistance to directional change. We first discuss a model that describes the stochastic movement of ECs and characterizes EC persistence in wound healing. To that end, we pharmacologically disrupted cytoskeletal dynamics, cytochalasin D for actin and nocodazole for tubulin, to understand its contributions to cell morphology, stiffness, and motility. As such, the use of Atomic Force Microscopy (AFM) enabled us to probe the topography and stiffness of ECs, while time lapse microscopy provided observations in wound healing models. Our results suggest that actin and tubulin dynamics contribute to EC shape, compressive moduli, and directional organization in collective migration. Insights from the model and time lapse experiment suggest that EC speed and persistence are directionally organized in wound healing. Pharmacological disruptions suggest that actin and tubulin dynamics play a role in collective migration. Current insights from both the model and experiment represent an important step in understanding the biomechanics of EC migration as a therapeutic target