Biomedical research has relied on animal studies and conventional cell cultures for decades. Recently, microphysiological systems (MPS), also known as organs-on-chips, that recapitulate the structure and function of native tissues in vitro, have emerged as a promising alternative1. However, current MPS typically lack integrated sensors and their fabrication requires multi-step lithographic processes2. Here, we introduce a facile route for fabricating a new class of instrumented cardiac microphysiological devices via multi-material 3D printing. Specifically, we designed six functional inks, based on piezo-resistive, high conductance, and biocompatible soft materials that enable integration of soft strain gauge sensors within micro-architectures that guide the self-assembly of physio-mimetic laminar cardiac tissues. We validated that these embedded sensors provide non-invasive, electronic readout of tissue contractile stresses, inside cell incubator environments. We further applied these devices to study drug responses, as well as the contractile development of human stem cell derived laminar cardiac tissues over four weeks.

Inspired by the relatively simple morphological blueprint provided by batoid fish such as stingrays and skates, we create a biohybrid system that enables an artificial animal, a tissue-engineered ray, * Correspondence to: K.K.P. 29 Oxford Street, Pierce Hall Cambridge, MA 02130. kkparker@seas.harvard.edu. Phone: 617-495-2850, 617-835-5920. Fax: 617-496-1793 Bioinspired design, as applied to robotics, aims at implementing naturally occurring features such as soft materials, morphologies, gaits, and control mechanisms in artificial settings to improve performance (1-4). For example, recent soft-robotics studies raised awareness on the importance of material properties (3, 4), shifting the focus from rigid elements to soft materials, while other investigations report successful mimicry of gaits or morphological features inspired by insects (5, 6), fish (7,8), snake (9), salamanders (10) and cheetahs (11). While recent advances have the promise of bridging the performance gap with animals, the current soft-robotic actuators based on, for instance, electroactive polymers, shape memory alloys or pressurized fluids, are yet to mature to the point of replicating the high-resolution complex movements of biological muscles (3, 4).In this context, biosensors and bioactuators (12) are intriguing alternatives, since they can intrinsically respond to a number of control inputs (such as electric fields and optical stimulation). Thanks to recent advances in genetic tools (13) and tissue engineering (12), these responses can be altered and tuned across a wide range of time and length scales. Some pioneering studies have exploited these technologies for self-propulsion, developing miniaturized walking machines (14-16), and flagellar (17) or jellyfish inspired (18) swimming devices. These biohybrid systems operate at high energy efficiency and harvest power from energy dense, locally available nutrients, although at present they require specialized environments (physiological solutions) that may limit their applicability. Moreover and most importantly, these biohybrid locomotors lack of the reflexive control (9, 19) necessary to enable adaptive maneuvering and thus of the ability to respond to spatiotemporally varying external stimuli.Here, we design, build and test a tissue-engineered analog of a batoid fish such as stingrays and skates. By combining soft materials and tissue engineering with optogenetics, we created an integrated sensory-motor system that allowed for coordinated undulating fin movement and phototactically controlled locomotion, that is guided via light stimuli. We drew from fish morphology, neuromuscular dynamics and gait control to implement a living, bio-hybrid system that leads to robust and reproducible locomotion and turning maneuvers. Batoid fish are ideal biological models in robotics (8) because their nearly planar bauplan is characterized by a broad dorsoventral disk, with a flattened body and extended pectoral fins, that enhances stability against roll (20). They swim with high energy efficien...

Laboratory studies of the heart use cell and tissue cultures to dissect heart function yet rely on animal models to measure pressure and volume dynamics. Here, we report tissue-engineered scale models of the human left ventricle, made of nanofibrous scaffolds that promote native-like anisotropic myocardial tissue genesis and chamber-level contractile function. Incorporating neonatal rat ventricular myocytes or cardiomyocytes derived from human induced pluripotent stem cells, the tissue-engineered ventricles have a diastolic chamber volume of ~500 μL (comparable to that of the native rat ventricle and approximately 1/250 the size of the human ventricle), and ejection fractions and contractile work 50–250 times smaller and 104–108 times smaller than the corresponding values for rodent and human ventricles, respectively. We also measured tissue coverage and alignment, calcium-transient propagation and pressure/volume loops in the presence or absence of test compounds. Moreover, we describe an instrumented bioreactor with ventricular-assist capabilities, and provide a proof-of-concept disease model of structural arrhythmia. The model ventricles can be evaluated with the same assays used in animal models and in clinical settings.

Microphysiological systems and organs-on-chips promise to accelerate biomedical and pharmaceutical research by providing accurate in vitro replicas of human tissue. Aside from addressing the physiological accuracy of the model tissues, there is a pressing need for improving the throughput of these platforms. To do so, scalable data acquisition strategies must be introduced. To this end, we here present an instrumented 24-well plate platform for higher-throughput studies of engineered human stem cell-derived cardiac muscle tissues that recapitulate the laminar structure of the native ventricle. In each well of the platform, an embedded flexible strain gauge provides continuous and non-invasive readout of the contractile stress and beat rate of an engineered cardiac tissue. The sensors are based on micro-cracked titanium-gold thin films, which ensure that the sensors are highly compliant and robust. We demonstrate the value of the platform for toxicology and drug-testing purposes by performing 12 complete dose-response studies of cardiac and cardiotoxic drugs. Additionally, we showcase the ability to couple the cardiac tissues with endothelial barriers. In these studies, which mimic the passage of drugs through the blood vessels to the musculature of the heart, we regulate the temporal onset of cardiac drug responses by modulating endothelial barrier permeability in vitro.