Optical imaging in microfluidic bioreactors enables oxygen monitoring for continuous cell culture

Sud, Dhruv; Mehta, Geeta; Mehta, Khamir; Linderman, Jennifer J.; Takayama, Shuichi; Mycek, Mary Ann

doi:10.1117/1.2355665

Cited by 80 publications

(63 citation statements)

References 11 publications

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“…An optical oxygen sensor was developed based on the oxygen-sensitive fluorescence of a ruthenium dye (SI Appendix, Fig. S20E) (52). Characterization of the optical oxygen sensor was performed in media containing a series of nitrogen and air concentrations.…”

Section: Significancementioning

confidence: 99%

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Zhang

Aleman

Shin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

595

571

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Organ-on-a-chip systems are miniaturized microfluidic 3D human tissue and organ models designed to recapitulate the important biological and physiological parameters of their in vivo counterparts. They have recently emerged as a viable platform for personalized medicine and drug screening. These in vitro models, featuring biomimetic compositions, architectures, and functions, are expected to replace the conventional planar, static cell cultures and bridge the gap between the currently used preclinical animal models and the human body. Multiple organoid models may be further connected together through the microfluidics in a similar manner in which they are arranged in vivo, providing the capability to analyze multiorgan interactions. Although a wide variety of human organ-on-a-chip models have been created, there are limited efforts on the integration of multisensor systems. However, in situ continual measuring is critical in precise assessment of the microenvironment parameters and the dynamic responses of the organs to pharmaceutical compounds over extended periods of time. In addition, automated and noninvasive capability is strongly desired for long-term monitoring. Here, we report a fully integrated modular physical, biochemical, and optical sensing platform through a fluidics-routing breadboard, which operates organ-on-a-chip units in a continual, dynamic, and automated manner. We believe that this platform technology has paved a potential avenue to promote the performance of current organ-on-a-chip models in drug screening by integrating a multitude of real-time sensors to achieve automated in situ monitoring of biophysical and biochemical parameters.organ-on-a-chip | microbioreactor | electrochemical biosensor | physical sensor | drug screening D rug discovery is a lengthy process associated with tremendous cost and high failure rate (1). On average, less than 1 in 10 drug candidates are eventually approved by the Food and Drug Administration (2), during which successful transition ratios to next phases are roughly 65, 32, and 60% for phase I, phase II, and phase III, respectively (3). Among the primary causes of failure, nonclinical/ clinical safety (>50%) and efficacy (>10%) stand out in the front, more than all other factors (e.g., strategic, commercial, operational) combined (3, 4). These two major causes not only contribute to the low success rates during the drug development but also lead to the withdrawal of approved drugs from the market. Among all of the drug attritions, it is estimated that safety liabilities related to the cardiovascular system account for 45%, whereas 32% are due to hepatotoxicity (5, 6). These high failure/attrition ratios of drugs SignificanceMonitoring human organ-on-a-chip systems presents a significant challenge, where the capability of in situ continual monitoring of organ behaviors and their responses to pharmaceutical compounds over extended periods of time is critical in understanding the dynamics of drug effects and therefore accurate prediction of human organ reacti...

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Section: Significancementioning

confidence: 99%

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Zhang

Aleman

Shin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

595

571

View full text Add to dashboard Cite

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“…24 In addition, this system had a large temporal dynamic range ͑750 ps to ϱ͒, 50 ps lifetime discrimination, and spatial resolution of 1.4 m, which made it very suitable for studying a variety of endogenous and exogenous fluorophores in biological samples. 2,4,[25][26][27][28] Fluorescence lifetime maps were determined by first acquiring fluorescence intensity images at four delays and then calculating the lifetime values from the intensity images on a pixel-by-pixel basis ͑described in Sec. 3.2͒.…”

Section: Time-gated Flimmentioning

confidence: 99%

Enhancing precision in time-domain fluorescence lifetime imaging

Chang

Mycek

2010

J. Biomed. Opt.

Self Cite

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Abstract. In biological applications of fluorescence lifetime imaging, low signals from samples can be a challenge, causing poor lifetime precision. We demonstrate how optimal signal gating ͑a method applied to the temporal dimension of a lifetime image͒ and novel total variation denoising models ͑a method applied to the spatial dimension of a lifetime image͒ can be used in time-domain fluorescence lifetime imaging microscopy ͑FLIM͒ to improve lifetime precision. In time-gated FLIM, notable fourfold precision improvements were observed in a low-light example. This approach can be employed to improve FLIM data while minimizing sample light exposure and increasing imaging speed.

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“…The lifetime of typical phosphorescence sensors for pO 2 range between hundreds of ns to several hundred μs. In simple biological samples that do not require 3D imaging, single-photon wide field phosphorescence lifetime imaging has been implemented efficiently [47][48][49][50]. However, 3D PLIM using point scanning confocal or multiphoton excitation is always slow since the required pixel residence time must be substantially longer than the phosphorescence lifetime (as long as a fraction of a millisecond).…”

Section: Demonstration Of 3d Phosphorescence and Fluorescence Lifetimmentioning

confidence: 99%

3D-resolved fluorescence and phosphorescence lifetime imaging using temporal focusing wide-field two-photon excitation

Choi¹,

Tzeranis²,

Won³

et al. 2012

Opt. Express

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Fluorescence and phosphorescence lifetime imaging are powerful techniques for studying intracellular protein interactions and for diagnosing tissue pathophysiology. While lifetime-resolved microscopy has long been in the repertoire of the biophotonics community, current implementations fall short in terms of simultaneously providing 3D resolution, high throughput, and good tissue penetration. This report describes a new highly efficient lifetime-resolved imaging method that combines temporal focusing wide-field multiphoton excitation and simultaneous acquisition of lifetime information in frequency domain using a nanosecond gated imager from a 3D-resolved plane. This approach is scalable allowing fast volumetric imaging limited only by the available laser peak power. The accuracy and performance of the proposed method is demonstrated in several imaging studies important for understanding peripheral nerve regeneration processes. Most importantly, the parallelism of this approach may enhance the imaging speed of long lifetime processes such as phosphorescence by several orders of magnitude. 291-295 (1996). 6. K. König, P. T. So, W. W. Mantulin, B. J. Tromberg, and E. Gratton, "Two-photon excited lifetime imaging of autofluorescence in cells during UVA and NIR photostress," J. Microsc. 183(Pt 3), 197-204 (1996). 7. J. R. Lakowicz, "Emerging applications of fluorescence spectroscopy to cellular imaging: lifetime imaging, metal-ligand probes, multi-photon excitation and light quenching," Scanning Microsc. Suppl. 10, 213-224 (1996 high-resolution measurements reveal a lack of correlation," Nat. Med. 3(2), 177-182 (1997). 14. I. P. Torres Filho, M. Leunig, F. Yuan, M. Intaglietta, and R. K. Jain, "Noninvasive measurement of microvascular and interstitial oxygen profiles in a human tumor in SCID mice," Proc. Natl. Acad. Sci. U.S.A. French, "Excitation-resolved hyperspectral fluorescence lifetime imaging using a UV-extended supercontinuum source," Opt. Lett. 32(23), 3408-3410 (2007). 32.

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Optical imaging in microfluidic bioreactors enables oxygen monitoring for continuous cell culture

Cited by 80 publications

References 11 publications

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Enhancing precision in time-domain fluorescence lifetime imaging

3D-resolved fluorescence and phosphorescence lifetime imaging using temporal focusing wide-field two-photon excitation

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