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Start of funding 01.07.2017

Bioluminescent Human Mesenchymal Stem Cells for Regenerative Medicine

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Limited long-term efficacy of stem cell therapy for heart disease treatment stems mainly from poor viability of the implanted cells due to ischemia and inflammation. Application of insulinlike growth factors can be used as a countermeasure increasing stem cell proliferation. However, effective use of those agents is limited by their short half-life. This obstacle could be overcome by the use of drug delivery nanoparticles as agent reservoirs. In the funded work we will initiate the translation of promising results achieved with such particles in tissue culture to in vivo application. To this end we will elucidate the treatment efficacy by monitoring cell survival after implantation using genetically modified bioluminescence reporter stem-cells.

Final report:
Analytical photoacoustic spectroscopy for tailoring contrast agents

Photoacoustic imaging (PAI) combines the good contrast of optics with the penetration depth, temporal and spatial resolution of ultrasound. Biomedical PAI can use endogenous blood hemoglobin as a source for contrast. Beyond that, there is an increasing emphasis on exogenous, targetable contrast agents for molecular imaging like organic dyes, nanoparticles, or chromoproteins. The power of contrast agents is that they can be responsive to (patho-) physiological conditions. That is, their spectra change as a function of a biological stimulus. This change can then be interpreted by instrumentation specific to photoacoustic imaging.

The group of Dr. Jesse Jokerst lately showed a number of such functional PAI approaches including the quantification of heparin activity in blood using methylene blue [1] or detecting levels of oxidative stress (i.e. ROS) by functionalized cyanine dyes [2] or plasmonic materials [3]. While such probes can already provide impressive functional whole animal imaging, their reliable in vivo application could be boosted by engineering next generation dyes and nanoparticles tailored for PAI based on detailed understanding of their photophysics. However, this work requires high quality spectral information to integrate PAI, absorbance, and fluorescence spectra. The group of Dr. Andre Stiel develops PA-spectroscopy instrumentation able to deliver such data [4], [5]. In our mutual visits and discussion funded by the BaCaTeC program we charted a roadmap to further engineer and improve functional contrast agents for PAI. In a joined effort the Jokerst group covers in vivo imaging and the Stiel group adds spectroscopic studies. This work already commenced by measuring a range of dyes from the studies mentioned above and scaffolds suitable for new developments. Such work not only further populates the palette of functional PAI agents for life-science and pre-clinical studies but also aims at clinical translation for e.g. efficient in vivo diagnostics of ROS in infections allowing in turn for more targeted and effective therapeutic interventions.

[1] J. Wang et al., “A Mechanistic Investigation of Methylene Blue and Heparin Interactions and Their Photoacoustic Enhancement,” Bioconjug. Chem., vol. 29, no. 11, pp. 3768–3775, 2018.
[2] A. Hariri, E. Zhao, A. S. Jeevarathinam, J. Lemaster, J. Zhang, and J. V Jokerst, “Molecular imaging of oxidative stress using an LED-based photoacoustic imaging system.,” Sci. Rep., vol. 9, no. 1, p. 11378, Aug. 2019.
[3] T. Kim, Q. Zhang, J. Li, L. Zhang, and J. V. Jokerst, “A Gold/Silver Hybrid Nanoparticle for Treatment and Photoacoustic Imaging of Bacterial Infection,” ACS Nano, vol. 12, no. 6, pp. 5615–5625, 2018.
[4] P. Vetschera, kanuj Mishra, J.-P. Fuenzalida Werner, A. Chmyrov, V. Ntziachristos, and A. C. Stiel, “Characterization of reversibly switchable fluorescent proteins (rsFPs) in optoacoustic imaging,” Anal. Chem., Aug. 2018.
[5] J. P. Fuenzalida Werner et al., “Structure-Based Mutagenesis of Phycobiliprotein smURFP for Optoacoustic Imaging,” ACS Chem. Biol., 2019.