Abstract
Advances in the intratumor measurement of drug responses have included a pioneering biomedical microdevice for high throughput drug screening in vivo, which was further advanced by integrating a graded-index lens based two-dimensional fluorescence micro-endoscope to monitor tissue responses in situ across time. While the previous system provided a bulk measurement of both drug delivery and tissue response from a given region of the tumor, it was incapable of visualizing drug distribution and tissue responses in a three-dimensional (3D) way, thus missing the critical relationship between drug concentration and effect. Here we demonstrate a next-generation system that couples multiplexed intratumor drug release with continuous 3D spatial imaging of the tumor microenvironment via the integration of a miniaturized two-photon micro-endoscope. This enables optical sectioning within the live tissue microenvironment to effectively profile the entire tumor region adjacent to the microdevice across time. Using this novel microimaging-microdevice (MI-MD) system, we successfully demonstrated the four-dimensional imaging (3 spatial dimensions plus time) of local drug delivery in tissue phantom and tumors. Future studies include the use of the MI-MD system for monitoring of localized intra-tissue drug release and concurrent measurement of tissue responses in live organisms, with applications to study drug resistance due to nonuniform drug distribution in tumors, or immune cell responses to anti-cancer agents.
Highlights
A biomedical microdevice [1] has emerged as a promising tool for highthroughput screening of drugs in vivo for the treatment of complex diseases, such as cancers
A variety of 3D imaging methodologies have been adopted in biomedical research, such as confocal fluorescence microscopy for the imaging of E. coli nucleoid organization and dynamics [10] and transdermal delivery of avanafil [11], magnetic resonance imaging for multiphase steady-state imaging in pediatric congenital heart disease [12], X-ray computed tomography for the identification of mechanical stress distribution in suture and tendon applications [13] and the imaging of asthmatic human lungs [14], and near infrared spectroscopy for the investigation of glimepiride liposomal films [15]
The z scan is implemented by tuning the convergence or divergence of the incident laser beam, which is controlled by the electronically tunable lens (ETL) in conjunction with an offset lens
Summary
A biomedical microdevice [1] has emerged as a promising tool for highthroughput screening of drugs in vivo for the treatment of complex diseases, such as cancers. A variety of 3D imaging methodologies have been adopted in biomedical research, such as confocal fluorescence microscopy for the imaging of E. coli nucleoid organization and dynamics [10] and transdermal delivery of avanafil [11], magnetic resonance imaging for multiphase steady-state imaging in pediatric congenital heart disease [12], X-ray computed tomography for the identification of mechanical stress distribution in suture and tendon applications [13] and the imaging of asthmatic human lungs [14], and near infrared spectroscopy for the investigation of glimepiride liposomal films [15] These techniques are, not capable of directly measuring the heterogeneous intratumor drug concentration because of the limited penetration depth or insufficient resolution. Similar GRIN lens based confocal or multiphoton micro-endoscopy has been investigated [18,19,20,21,22,23,24,25], this is the first instance in which such a 3D imaging system is integrated with multiplexed drug delivery into tumors, representing an important advance toward realizing the simultaneous measurement of drug distribution and tissue effect without the need for tissue removal by biopsy
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