Abstract
Despite improvements in pre-clinical drug testing models, predictability of clinical outcomes continues to be inadequate and costly due to poor evidence of drug metabolism. Humanized miniature organs integrating decellularized rodent organs with tissue specific cells are translational models that can provide further physiological understanding and evidence. Here, we evaluated 4-Flow cannulated rat hearts as the fundamental humanized organ model for cardiovascular drug validation. Results show clearance of cellular components in all chambers in 4-Flow hearts with efficient perfusion into both coronary arteries and cardiac veins. Furthermore, material characterization depicts preserved organization and content of important matrix proteins such as collagens, laminin, and elastin. With access to the complete vascular network, different human cell types were delivered to show spatial distribution and integration into the matrix under perfusion for up to three weeks. The feature of 4-Flow cannulation is the preservation of whole heart conformity enabling ventricular pacing via the pulmonary vein as demonstrated by noninvasive monitoring with fluid pressure and ultrasound imaging. Consequently, 4-Flow hearts surmounting organ mimicry challenges with intact complexity in vasculature and mechanical compliance of the whole organ providing an ideal platform for improving pre-clinical drug validation in addition to understanding cardiovascular diseases.
Highlights
With cardiovascular diseases as the leading cause of death worldwide, the demand for better cardiovascular treatments and predictions of therapeutic outcomes is a substantial challenge for translational research
The 4-Flow hearts were cannulated at the superior vena cava (SV), ascending aorta (AA), pulmonary artery (PA), and pulmonary vein (PV) while Langendorff hearts only have the AA cannulation
Under perfusion decellularization with constant pressure, after nine hours, the 4-Flow hearts were visually clear of cell matter in all chambers in contrast to the opaque atrial tissue remaining in the Langendorff cannulated hearts at 14 hours (Fig. 1A,B)
Summary
With cardiovascular diseases as the leading cause of death worldwide, the demand for better cardiovascular treatments and predictions of therapeutic outcomes is a substantial challenge for translational research. Current methods for harvesting rodent hearts for perfusion decellularization follow the Langendorff isolation method, intended for ex vivo experiments, by cannulating the ascending aorta and preserving aortic valve function to perfuse only through the coronary arteries[4,11,16,17]. We have developed a method - termed 4-Flow cannulation - optimized for isolating hearts for decellularization and recellularization to maintain heart physiology with a complete circulation and organ conformity. The versatility of the 4-Flow cannulation will be validated when compared to the current isolation method - Langendorff - which was adopted from ex vivo applications with only the aorta cannulation Techniques such as resin casting will be used to map the perfusion network of the whole organ and multiphoton imaging will illustrate three dimensional architecture of the preserved matrix. The objective is to highlight 4-Flow cannulated hearts as the humanized predictive model for translational research in cardiac drug development
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