Abstract
Over the last decade, there has been a 62% rise in the number of therapeutic compounds under development
for cancers, diabetes, neurodegenerative diseases, and cardiovascular diseases, and the total expenditure has
nearly doubled. Despite the significant investment, the average number of new drugs approved by the Food and
Drug Administration (FDA) has declined since the 1990s, mainly due to the low success rate of human clinical
trials and the insufficient efficacy and/or excessive adverse (toxic) reactions associated with the candidate drugs.
Planar cell cultures and animal models used in drug testing often fail to accurately reflect human physiology and
pathology. Three-dimensional (3D) human cell-based organ-on-a-chip models, combined with advanced
vascularization and microfluidics technologies, have been increasingly used to improve drug testing, by
recapitulating important physiological parameters of their in vivo human counterparts. However, the
characterization of 3D vascularized organoid cultures is challenging with pure optical imaging methods that reach
only small depths (~1 mm) and/or lacks functional imaging capability. The organoids can reach 2–3 mm in all
dimensions, and the response to the drug treatment by cells at different locations may significantly vary due to
non-uniform tissue properties, limited molecular diffusion, and heterogeneous vascular arborization. To address
these issues, we propose to develop a novel integrated imaging-bioreactor platform that combines a miniaturized
photoacoustic tomography (mini-PAT) system (Aim 1) and a human vascularized organ-on-a-chip bioreactor
(Aim 2). Mini-PAT can be directly integrated onto the bioreactor and provide critical anatomical and functional
information about the 3D organoid’s development, vasculature function and metabolism. As proof of concept,
we will apply the integrated platform for on-chip, longitudinal, and volumetric imaging of the progression of
hepatocellular carcinoma (HCC) organoids, their multiscale vascularization, and their response to anti-
angiogenic drugs (Aim 3). Most importantly, both the mini-PAT and bioreactor are highly compact and low-cost
(~$200 per unit), so they can be readily multiplexed for monitoring a large array of organoids in parallel. The
highly heterogeneous drug-organoid interactions can thus be simultaneously studied in a statistically meaningful
manner. Ultimately, this proposal will provide a platform technology for a variety of applications that require
high-throughput pathological testing on human tissue models. More excitingly, it would pave the way for
personalized medicine screening using an array of patient-derived disease models.