Anastasia Korolj

Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis

We report the fabrication of a scaffold (hereafter referred to as AngioChip) that supports the assembly of parenchymal cells on a mechanically tunable matrix surrounding a perfusable, branched, three-dimensional microchannel network coated with endothelial cells. The design of AngioChip decouples the material choices for the engineered vessel network and for cell seeding in the parenchyma, enabling extensive remodelling while maintaining an open-vessel lumen. The incorporation of nanopores and micro-holes in the vessel walls enhances permeability, and permits intercellular crosstalk and extravasation of monocytes and endothelial cells on biomolecular stimulation. We also show that vascularized hepatic tissues and cardiac tissues engineered by using AngioChips process clinically relevant drugs delivered through the vasculature, and that millimeter-thick cardiac tissues can be engineered in a scalable manner. Moreover, we demonstrate that AngioChip cardiac tissues implanted via direct surgical anastomosis to the femoral vessels of rat hindlimbs establish immediate blood perfusion.

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.

Organ-On-A-Chip Platforms: A Convergence of Advanced Materials, Cells, and Microscale Technologies

Significant advances in biomaterials, stem cell biology, and microscale technologies have enabled the fabrication of biologically relevant tissues and organs. Such tissues and organs, referred to as organ-on-a-chip (OOC) platforms, have emerged as a powerful tool in tissue analysis and disease modeling for biological and pharmacological applications. A variety of biomaterials are used in tissue fabrication providing multiple biological, structural, and mechanical cues in the regulation of cell behavior and tissue morphogenesis. Cells derived from humans enable the fabrication of personalized OOC platforms. Microscale technologies are specifically helpful in providing physiological microenvironments for tissues and organs. In this review, biomaterials, cells, and microscale technologies are described as essential components to construct OOC platforms. The latest developments in OOC platforms (e.g., liver, skeletal muscle, cardiac, cancer, lung, skin, bone, and brain) are then discussed as functional tools in simulating human physiology and metabolism. Future perspectives and major challenges in the development of OOC platforms toward accelerating clinical studies of drug discovery are finally highlighted.

Platform technology for scalable assembly of instantaneously functional mosaic tissues

A biodegradable polymer-based approach enables vertical and horizontal assembly of living tissues in a single step using a hook and look mechanism. Engineering mature tissues requires a guided assembly of cells into organized three-dimensional (3D) structures with multiple cell types. Guidance is usually achieved by microtopographical scaffold cues or by cell-gel compaction. The assembly of individual units into functional 3D tissues is often time-consuming, relying on cell ingrowth and matrix remodeling, whereas disassembly requires an invasive method that includes either matrix dissolution or mechanical cutting. We invented Tissue-Velcro, a bio-scaffold with a microfabricated hook and loop system. The assembly of Tissue-Velcro preserved the guided cell alignment realized by the topographical features in the 2D scaffold mesh and allowed for the instant establishment of coculture conditions by spatially defined stacking of cardiac cell layers or through endothelial cell coating. The assembled cardiac 3D tissue constructs were immediately functional as measured by their ability to contract in response to electrical field stimulation. Facile, on-demand tissue disassembly was demonstrated while preserving the structure, physical integrity, and beating function of individual layers.

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.

Human pluripotent stem cell-derived cardiomyocyte based models for cardiotoxicity and drug discovery.

The drug development process, from discovery to safety studies, aims to bring efficacious and safe drugs to market. Unfortunately, this ambition is often thwarted by unanticipated adverse effects that are not detected by the current drug-testing paradigm. Cardiotoxicity ranks as one of the primary causes of drug recalls, an extraordinarily costly event in terms of both the manufacturer’s bottom line and the negative patient outcomes [1]. As such, developing more predictive cardiotoxicity assessments is a main focus of research. Currently, preclinical cardiac assessments mainly consist of animal studies and heterologous expression systems of human cardiac ion channel in noncardiac cell lines. Animal models provide valuable in vivo pharmacodynamic and pharmacokinetic data, and their genes can be precisely manipulated for mechanistic investigations. However, species–species differences hinder their applicability as a model of human patients. For example, rodents have heart rates 3–10 times faster than humans [2], virtually no delayed rectifier potassium IKr (human ether-a-gogo-related gene [hERG]) current, and animal ion channel expression and action potential profiles are generally distinct from those of humans [3]. Human-specific drug screening data have been obtained using primary heart cells and tissue, tumor-derived immortalized mammalian cardiac cell lines, and heterologous expression systems in which noncardiac cells (Chinese Hamster Ovary or Human Embryonic Kidney) are transfected to express an individual human ion channel, most commonly the hERG channel. Most of the cardiotoxicity/arrhythmia safety screens performed to date have employed the latter as a means of assessing the potential for acute drug-induced electrocardiogram (ECG) abnormalities. These human-specific models are limited by genetic instability and the absence of important cardiac cell characteristics. Taken as a whole, the preclinical paradigm is able to predict 70–90% [1] of human patient drug effects, yet many promising drugs are triaged early in development and some cardiotoxic drugs still enter the market. To minimize the use of animal models and to improve the precision of risk prediction, various alternative platforms have been developed for drug safety evaluation. Here, we discuss the current challenges to the cardiotoxicity and drug discovery fields, the state of the art and we envision a more predictive human cardiac model.

Advances in organ-on-a-chip engineering

Predicting the effects of drugs before human clinical trials is at the heart of drug screening and discovery processes. The cost of drug discovery is steadily increasing owing to the limited predictability of 2D cell culture and animal models. The convergence of microfabrication and tissue engineering gave rise to organ-on-a-chip technologies, which offer an alternative to conventional preclinical models for drug screening. Organ-on-a-chip devices can replicate key aspects of human physiology crucial for the understanding of drug effects, improving preclinical safety and efficacy testing. In this Review, we discuss how organ-on-a-chip technologies can recreate functions of organs, focusing on tissue barrier properties, parenchymal tissue function and multi-organ interactions, which are three key aspects of human physiology. Specific organ-on-a-chip systems are examined in terms of cell sources, functional hallmarks and available disease models. Finally, we highlight the challenges that need to be overcome for the clinical translation of organ-on-a-chip devices regarding materials, cellular fidelity, multiplexing, sensing, scalability and validation.Organ-on-a-chip devices can recreate key aspects of human physiology in vitro, offering an alternative to animal models for preclinical drug testing. This Review examines how tissue barrier properties, parenchymal tissue function and multi-organ interactions can be recreated in organ-on-a-chip systems and applied for drug screening.

Cardiovascular disease models: A game changing paradigm in drug discovery and screening

Cardiovascular disease is the leading cause of death worldwide. Although investment in drug discovery and development has been sky-rocketing, the number of approved drugs has been declining. Cardiovascular toxicity due to therapeutic drug use claims the highest incidence and severity of adverse drug reactions in late-stage clinical development. Therefore, to address this issue, new, additional, replacement and combinatorial approaches are needed to fill the gap in effective drug discovery and screening. The motivation for developing accurate, predictive models is twofold: first, to study and discover new treatments for cardiac pathologies which are leading in worldwide morbidity and mortality rates; and second, to screen for adverse drug reactions on the heart, a primary risk in drug development. In addition to in vivo animal models, in vitro and in silico models have been recently proposed to mimic the physiological conditions of heart and vasculature. Here, we describe current in vitro, in vivo, and in silico platforms for modelling healthy and pathological cardiac tissues and their advantages and disadvantages for drug screening and discovery applications. We review the pathophysiology and the underlying pathways of different cardiac diseases, as well as the new tools being developed to facilitate their study. We finally suggest a roadmap for employing these non-animal platforms in assessing drug cardiotoxicity and safety.