Project Summary The goal of this R01 proposal is to develop an ultra-soft, fully implantable, wireless label-free cardiac mapping and modulation system and apply it to identify chronic electrophysiological and metabolic changes and their links during heart failure (HF) development, progression, and pacing treatment in unrestrained conscious animals at cellular and whole heart levels. To achieve this, a miniaturized, mechanically compliant platform that integrates high-density, high-resolution sensing and modulation channels with wireless energy harvesting, storage, control, and data communication module is proposed. The resulting systems will greatly reduce motion artifacts and allow bidirectional high-content electrical and metabolic mapping and pacing in live animals. Those devices are innovative because they directly address the current limitations in chronically quantifying the individual roles and interplay between vital cardiac biophysical parameters during heart disease pathogenesis and will be used to fundamentally investigate the complex disease mechanisms involved in pathophysiological conditions leading to lethal HF and its therapeutic treatment. Once realized, this technology will be highly valuable to the cardiac research community. In the long term this work will enable closed-loop multiparametric cardiac mapping and pacing systems and offer new approaches to study the precise mechanisms and optimize the diagnostic and therapeutic strategies of other life-threatening heart diseases beyond HF. The three specific aims are: Aim 1 will establish ultra-soft multimodal cardiac systems for label-free cellular-resolution mapping of the excitation-contraction-metabolic waves and cardiac pacing. The mechanically compliant highly stretchable systems consist of high-density arrays (~300 channels in total) of (1) transparent microelectrodes for electrical mapping and stimulation; (2) multicolor micro-light-emitting diodes, and micro-photodetectors to excite and measure the autofluorescence of major endogenous fluorescent markers of cellular energy metabolism. Aim 2 will develop fully implantable wireless schemes for power harvesting, storage, control, and data communication to chronically operate the platforms in Aim 1 within a closed thoracic cavity in freely behaving small animals, which is beyond any possibility supported by current techniques. Graphical user interfaces will be developed for device configuration, real-time bidirectional control, data acquisition and processing. The integrated systems will be characterized, validated, and optimized by iterative benchtop measurements. Aim 3 will systematically investigate the precise mechanisms of HF pathogenesis and therapy using a battery of tests in rat models of HF. The functions of the proposed systems will be assessed in both ex vivo and in vivo studies. The implantable cardiac devices will identify the individual roles and links between local metabolic and electrical properties during...