A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling.

Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing under electrical pacing. The plastic platform enabled on-line noninvasive recording of passive tension, active force, contractile dynamics, and Ca2+ transients, as well as endpoint assessments of action potentials and conduction velocity. By combining directed cell differentiation with electrical field conditioning, we engineered electrophysiologically distinct atrial and ventricular tissues with chamber-specific drug responses and gene expression. We report, for the first time, engineering of heteropolar cardiac tissues containing distinct atrial and ventricular ends, and we demonstrate their spatially confined responses to serotonin and ranolazine. Uniquely, electrical conditioning for up to 8 months enabled modeling of polygenic left ventricular hypertrophy starting from patient cells.

Method for the Fabrication of Elastomeric Polyester Scaffolds for Tissue Engineering and Minimally Invasive Delivery.

Using the methods described herein, we have demonstrated how scaffolds can be designed for a number of applications including tissue engineering, biomedical devices and injectable tissues. Details on the methods of polymerization and physical and chemical characterization of poly(octamethylene maleate (anhydride) citrate (POMaC) are described. Two POMaC polymer recipes with different monomer ratios of maleic anhydride and citric acid were synthesized and compared. Mechanical testing was performed on scaffolds of two distinct anisotropic designs to show how scaffold design influences the apparent elasticity in the long and short axis. POMaC scaffolds of various patterns and geometries were fabricated to demonstrate: (1) scaffold function can be determined by scaffold design (e.g., inherent shape-memory or self-assembling tubular structures), and (2) the soft lithography approach to fabricating biodegradable elastomers described here can be used to suit a number of different potential applications.

Kinase inhibitor screening using artificial neural networks and engineered cardiac biowires.

Kinase inhibitors are often used as cancer targeting agents for their ability to prevent the activation of cell growth and proliferation signals. Cardiotoxic effects have been identified for some marketed kinase inhibitors that were not detected during clinical trials. We hypothesize that more predictive cardiac functional assessments of kinase inhibitors on human myocardium can be established by combining a high-throughput two-dimensional (2D) screening assay and a high-content three-dimensional (3D) engineered cardiac tissue (BiowireTM) based assay, and using human induced pluripotent stem cell-derived CMs (hiPSC-CMs). A subset (80) of compounds from the GlaxoSmithKline published kinase inhibitor set were tested on hiPSC-CM monolayers and significant effects on cell viability, calcium transients, and contraction frequency were observed. Artificial neural network modelling was then used to analyze the experimental results in an efficient and unbiased manner to select for kinase inhibitors with minimal effects on cell viability and function. Inhibitors of specific interest based on the modeling were evaluated in the 3D Biowire tissues. The three-dimensional Biowire platform eliminated oversensitivity in detecting both Ca2+ transient amplitude enhancements as well as the acute detrimental effects on cell viability due to the kinase inhibitor application as compared to the monolayer testing.

High-Content Assessment of Cardiac Function Using Heart-on-a-Chip Devices as Drug Screening Model.

Drug discovery and development continues to be a challenge to the pharmaceutical industry despite great advances in cell and molecular biology that allow for the design of better targeted therapeutics. Many potential drug compounds fail during the clinical trial due to inefficacy and toxicity that were not predicted during preclinical stages. The fundamental problem lies with the use of traditional drug screening models that still largely rely on the use of cell lines or animal cell monolayers, which leads to lack of predictive power of human tissue and organ response to the drug candidates. More physiologically relevant systems are therefore critical in relieving the burden of high failure rates. Emerging knowledge and techniques in tissue engineering and microfabrication have enabled the development of micro-engineered systems - collectively known as organs-on-chips - that may lead to a paradigm shift in preclinical drug screening assays. In this review we explore the technological advances and challenges in the development of heart-on-a-chip models, by addressing current assessment methods for drug-induced cardiotoxicity and providing a perspective on the modifications that should be implemented to realize the full potential of this system.

Highly Elastic and Moldable Polyester Biomaterial for Cardiac Tissue Engineering Applications.

Polyester biomaterials are used in tissue engineering as scaffolds for implantation of tissues developed in vitro. An ideal biodegradable elastomer for cardiac tissue engineering exhibits a relatively low Young's modulus, with high elongation and tensile strength. Here we describe a novel polyester biomaterial that exhibits improved elastic properties for cardiac tissue engineering applications. We synthesized poly(octamethylene maleate (anhydride) 1,2,4-butanetricarboxylate) (124 polymer) prepolymer gel in a one-step polycondensation reaction. The prepolymer was then molded as desired and exposed to ultraviolet (UV) light to produce a cross-linked elastomer. 124 polymer exhibited highly elastic properties under aqueous conditions that were tunable according to the UV light exposure, monomer composition, and porosity of the cured elastomer. Its elastomeric properties fell within the range of adult heart myocardium, but they could also be optimized for higher elasticity for weaker immature constructs. The polymer showed relatively stable degradation characteristics, both hydrolytically and in a cellular environment, suggesting maintenance of material properties as a scaffold support for potential tissue implants. When assessed for cell interaction, this polymer supported rat cardiac cell attachment in vitro as well as comparable acute in vivo host response when compared to poly(l-lactic acid) control. This suggests the potential applicability of this material as an elastomer for cardiac tissue engineered constructs.

Biomaterial based cardiac tissue engineering and its applications.

Cardiovascular disease is a leading cause of death worldwide, necessitating the development of effective treatment strategies. A myocardial infarction involves the blockage of a coronary artery leading to depletion of nutrient and oxygen supply to cardiomyocytes and massive cell death in a region of the myocardium. Cardiac tissue engineering is the growth of functional cardiac tissue in vitro on biomaterial scaffolds for regenerative medicine application. This strategy relies on the optimization of the complex relationship between cell networks and biomaterial properties. In this review, we discuss important biomaterial properties for cardiac tissue engineering applications, such as elasticity, degradation, and induced host response, and their relationship to engineered cardiac cell environments. With these properties in mind, we also emphasize in vitro use of cardiac tissues for high-throughput drug screening and disease modelling.