An organ-on-a-chip model for pre-clinical drug evaluation in progressive non-genetic cardiomyopathy.

Angiotensin II (Ang II) presents a critical mediator in various pathological conditions such as non-genetic cardiomyopathy. Osmotic pump infusion in rodents is a commonly used approach to model cardiomyopathy associated with Ang II. However, profound differences in electrophysiology and pharmacokinetics between rodent and human cardiomyocytes may limit predictability of animal-based experiments. This study investigates the application of an Organ-on-a-chip (OOC) system in modeling Ang II-induced progressive cardiomyopathy. The disease model is constructed to recapitulate myocardial response to Ang II in a temporal manner. The long-term tissue cultivation and non-invasive functional readouts enable monitoring of both acute and chronic cardiac responses to Ang II stimulation. Along with mapping of cytokine secretion and proteomic profiles, this model presents an opportunity to quantitatively measure the dynamic pathological changes that could not be otherwise identified in animals. Further, we present this model as a testbed to evaluate compounds that target Ang II-induced cardiac remodeling. Through assessing the effects of losartan, relaxin, and saracatinib, the drug screening data implicated multifaceted cardioprotective effects of relaxin in restoring contractile function and reducing fibrotic remodeling. Overall, this study provides a controllable platform where cardiac activities can be explicitly observed and tested over the pathological process. The facile and high-content screening can facilitate the evaluation of potential drug candidates in the pre-clinical stage.

Beyond Polydimethylsiloxane: Alternative Materials for Fabrication of Organ-on-a-Chip Devices and Microphysiological Systems.

Polydimethylsiloxane (PDMS) is the predominant material used for organ-on-a-chip devices and microphysiological systems (MPSs) due to its ease-of-use, elasticity, optical transparency, and inexpensive microfabrication. However, the absorption of small hydrophobic molecules by PDMS and the limited capacity for high-throughput manufacturing of PDMS-laden devices severely limit the application of these systems in personalized medicine, drug discovery, in vitro pharmacokinetic/pharmacodynamic (PK/PD) modeling, and the investigation of cellular responses to drugs. Consequently, the relatively young field of organ-on-a-chip devices and MPSs is gradually beginning to make the transition to alternative, nonabsorptive materials for these crucial applications. This review examines some of the first steps that have been made in the development of organ-on-a-chip devices and MPSs composed of such alternative materials, including elastomers, hydrogels, thermoplastic polymers, and inorganic materials. It also provides an outlook on where PDMS-alternative devices are trending and the obstacles that must be overcome in the development of versatile devices based on alternative materials to PDMS.

A well plate-based multiplexed platform for incorporation of organoids into an organ-on-a-chip system with a perfusable vasculature.

Owing to their high spatiotemporal precision and adaptability to different host cells, organ-on-a-chip systems are showing great promise in drug discovery, developmental biology studies and disease modeling. However, many current micro-engineered biomimetic systems are limited in technological application because of culture media mixing that does not allow direct incorporation of techniques from stem cell biology, such as organoids. Here, we describe a detailed alternative method to cultivate millimeter-scale functional vascularized tissues on a biofabricated platform, termed 'integrated vasculature for assessing dynamic events', that enables facile incorporation of organoid technology. Utilizing the 3D stamping technique with a synthetic polymeric elastomer, a scaffold termed 'AngioTube' is generated with a central microchannel that has the mechanical stability to support a perfusable vascular system and the self-assembly of various parenchymal tissues. We demonstrate an increase in user familiarity and content analysis by situating the scaffold on a footprint of a 96-well plate. Uniquely, the platform can be used for facile connection of two or more tissue compartments in series through a common vasculature. Built-in micropores enable the studies of cell invasion involved in both angiogenesis and metastasis. We describe how this protocol can be applied to create both vascularized cardiac and hepatic tissues, metastatic breast cancer tissue and personalized pancreatic cancer tissue through incorporation of patient-derived organoids. Platform assembly to populating the scaffold with cells of interest into perfusable functional vascularized tissue will require 12-14 d and an additional 4 d if pre-polymer and master molds are needed.