A PET-compatible tissue bioreactor for research, discovery, and validation of imaging biomarkers and radiopharmaceuticals: System design and proof-of-concept studies

Timothy D. Whitehead, Samuel T. Nemanich, Carmen Dence, Kooresh I. Shoghi

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Research and discovery of novel radiopharmaceuticals and targets thereof generally involves initial studies in cell cultures, followed by animal studies, both of which present several inherent limitations. The objective of this work was to develop a tissue bioreactor (TBR) enabling modulation of the microenvironment and to integrate the TBR with a small-animal PET scanner to facilitate imaging biomarker research and discovery and validation of radiopharmaceuticals. Methods: The TBR chamber is a custom-blown, water-jacketed, glass vessel enclosed in a circulating perfusion bath powered by a peristaltic pump, which is integrated within the field of view of the PET scanner. The chamber is in series with a gas exchanger and a vessel for degassing the system during filling. Dissolved oxygen/temperature probes and septa for injection or sampling are located at the inlet and outlet of the cell chamber. A pH probe is located at the chamber outlet. Effluent is collected in the fraction collector as mixedcup samples. In addition, both medium and tissue chamber can be sampled to investigate tissue and secretory products through multiscale analysis. As a proof of concept, we studied the effects of lipids on glucose uptake using HepG2 cells. To that end, we varied the nutrient substrate environment over a period of approximately 27 d, before and after the addition of lipids, and studied the effects of pioglitazone, a peroxisome proliferator-activated receptor γ agonist, on lipid and glucose uptake. In parallel, the TBR was imaged by PET in conjunction with 11C- palmitate in the presence and absence of lipids to characterize 11C-palmitate uptake. Results: The O2 consumption, glucose consumption, lactate production, and free fatty acid consumption and production rates were consistent in demonstrating the effects of lipids on glucose uptake. Pioglitazone exhibited improved glucose uptake within 3 d of treatment. Semiquantitative analysis suggested that lipids induced greater 11C-palmitate uptake. Conclusion: The integrated TBR offers a platform to monitor and modulate the tissuemicroenvironment, thus facilitating tissue-specific imaging and therapeutic biomarkers of disease, identification of molecular diagnostic markers, and validation of radiopharmaceuticals in both rodent and human cell lines. COPYRIGHT

Original languageEnglish
Pages (from-to)1812-1819
Number of pages8
JournalJournal of Nuclear Medicine
Volume54
Issue number10
DOIs
StatePublished - Oct 1 2013

Keywords

  • Biomarker discovery
  • Bioreactor
  • Imaging
  • Positron emission tomography (PET)
  • Tissue engineering

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