The bioreactor system described in this project offers a unique environment to evaluate cellular metabolism and function utilizing the complementary features of MR and PET imaging. This in vitro platform technology will (1) enable the discovery of clinically translatable tissue biomarkers related to various diseases; (2) support screening and evaluation of new radiotracers and therapeutics; and (3) improve treatment planning through direct assessment of patient cells and tissue samples. The facile measurement of metabolic and functional changes in cells and tissue may be directly translated into patient-specific therapeutic management.
The goal of this research is to optimize a 5mm MR-compatible PET 3D cell/tissue culture bioreactor and test it by using a combination of hyperpolarized (HP) 13C MR and PET probes. Three-dimensional (3D) cell and tissue culture bioreactors provide a novel platform to investigate, in a very controlled and cost effective environment, cell and tissue metabolism and function as well as response to therapy. Combining HP 13C labeled MR probes with MR-compatible 3D tissue culture bioreactors has allowed the monitoring of metabolic fluxes with high temporal resolution (seconds) without background signals from the culture media. The addition of positron emission tomography (PET) imaging with an array of labeled tracers provides yet another dimension to understanding metabolic function, protein interaction, signaling pathways and drug pharmacokinetics/pharmacodynamics (PK/PD), in the bioreactor system. Both hyperpolarized 13C MR and PET have advantages and disadvantages, yet there is great interest in investigating their complimentary roles in the setting of providing companion imaging biomarkers for assessing new therapies. To accomplish this we will optimize a 5mm MR-compatible PET Bioreactor (aim 1) and use this platform to investigate the synergistic role of PET and HP MR (aim 2). The test studies aim to demonstrate the breadth of application of this cross- platform bioreactor system, spanning both multinuclear PET and MR. Adapting existing micro-engineered MR compatible 3D culture bioreactor designs for PET imaging studies represents a novel direction that will have a major impact on screening and evaluation of new radiotracers and therapeutics, and in identifying the synergistic role of HP MR and PET for future clinical applications. The proposed studies will also provide new information concerning the synergistic role of MR and PET probes. This optimized 5 mm bioreactor can be further micro-engineered to allow the study of smaller amounts of primary human cells and tissues, including biopsy samples, ultimately influencing patient management.