bims-miftum 2020-09-06 papers

Issue of 2020–09–06
five papers selected by
Nidhi Menon, Virginia Tech

Lab Chip. 2020 Sep 01.

Modeling iontophoretic drug delivery in a microfluidic device.

Maryam Moarefian, Rafael V Davalos, Danesh K Tafti, Luke E Achenie, Caroline N Jones.

Iontophoresis employs low-intensity electrical voltage and continuous constant current to direct a charged drug into a tissue. Iontophoretic drug delivery has recently been used as a novel method for cancer treatment in vivo. There is an urgent need to precisely model the low-intensity electric fields in cell culture systems to optimize iontophoretic drug delivery to tumors. Here, we present an iontophoresis-on-chip (IOC) platform to precisely quantify carboplatin drug delivery and its corresponding anti-cancer efficacy under various voltages and currents. In this study, we use an in vitro heparin-based hydrogel microfluidic device to model the movement of a charged drug across an extracellular matrix (ECM) and in MDA-MB-231 triple-negative breast cancer (TNBC) cells. Transport of the drug through the hydrogel was modeled based on diffusion and electrophoresis of charged drug molecules in the direction of an oppositely charged electrode. The drug concentration in the tumor extracellular matrix was computed using finite element modeling of transient drug transport in the heparin-based hydrogel. The model predictions were then validated using the IOC platform by comparing the predicted concentration of a fluorescent cationic dye (Alexa Fluor 594®) to the actual concentration in the microfluidic device. Alexa Fluor 594® was used because it has a molecular weight close to paclitaxel, the gold standard drug for treating TNBC, and carboplatin. Our results demonstrated that a 50 mV DC electric field and a 3 mA electrical current significantly increased drug delivery and tumor cell death by 48.12% ± 14.33 and 39.13% ± 12.86, respectively (n = 3, p-value <0.05). The IOC platform and mathematical drug delivery model of iontophoresis are promising tools for precise delivery of chemotherapeutic drugs into solid tumors. Further improvements to the IOC platform can be made by adding a layer of epidermal cells to model the skin.

DOI: https://doi.org/10.1039/d0lc00602e

Nanomedicine. 2020 Aug 26. pii: S1549-9634(20)30148-9. [Epub ahead of print] 102294

The design and characterization of a gravitational microfluidic platform for drug sensitivity assay in colorectal perfused Tumoroid cultures.

Tao Wang, Ryan Green, Mark Howell, Taylor Martinez, Rinku Dutta, Subhra Mohapatra, Shyam Mohapatra.

The tumor microenvironment plays a critical role in tumor initiation, progression, metastasis, and drug resistance. However, models recapitulating the complex 3D structure, heterogeneous cell environment, and cell-cell interactions found in vivo are lacking. Herein, we report on a gravitational microfluidic platform (GMP) retrofitted with MEMS sensors, which is integrated with 3D nanofiber scaffold-aided tumoroid culture. The results showed that this GMP for tumoroid growth mimics the tumor microenvironment more precisely than static culture models of colon cancer, including higher drug resistance, enhanced cancer stem cell properties, and increased secretion of pro-tumor cytokines. In addition, the GMP includes integrated surface acoustic wave-based biosensing to monitor cell growth and pH changes to assess drug efficacy. Thus, this simple-to-use perfused GMP tumoroid culture system for in vitro and ex vivo studies may accelerate the drug development process and be a tool in personalized cancer treatment.

Keywords: Colorectal cancer; Fiber-inspired smart 3D scaffold; Microfluidic system; Perfused cultures; Tumoroids

DOI: https://doi.org/10.1016/j.nano.2020.102294

J Vis Exp. 2020 Aug 16.

Quantifying the Brain Metastatic Tumor Micro-Environment using an Organ-On-A Chip 3D Model, Machine Learning, and Confocal Tomography.

C Ryan Oliver, Trisha M Westerhof, Maria G Castro, Sofia D Merajver.

Brain metastases are the most lethal cancer lesions; 10-30% of all cancers metastasize to the brain, with a median survival of only ~5-20 months, depending on the cancer type. To reduce the brain metastatic tumor burden, gaps in basic and translational knowledge need to be addressed. Major challenges include a paucity of reproducible preclinical models and associated tools. Three-dimensional models of brain metastasis can yield the relevant molecular and phenotypic data used to address these needs when combined with dedicated analysis tools. Moreover, compared to murine models, organ-on-a-chip models of patient tumor cells traversing the blood brain barrier into the brain microenvironment generate results rapidly and are more interpretable with quantitative methods, thus amenable to high throughput testing. Here we describe and demonstrate the use of a novel 3D microfluidic blood brain niche (µmBBN) platform where multiple elements of the niche can be cultured for an extended period (several days), fluorescently imaged by confocal microscopy, and the images reconstructed using an innovative confocal tomography technique; all aimed to understand the development of micro-metastasis and changes to the tumor micro-environment (TME) in a repeatable and quantitative manner. We demonstrate how to fabricate, seed, image, and analyze the cancer cells and TME cellular and humoral components, using this platform. Moreover, we show how artificial intelligence (AI) is used to identify the intrinsic phenotypic differences of cancer cells that are capable of transit through a model µmBBN and to assign them an objective index of brain metastatic potential. The data sets generated by this method can be used to answer basic and translational questions about metastasis, the efficacy of therapeutic strategies, and the role of the TME in both.

DOI: https://doi.org/10.3791/61654

ACS Nano. 2020 Sep 03.

Three-Dimensional Human Liver-Chip Emulating Premetastatic Niche Formation by Breast Cancer-Derived Extracellular Vesicles.

Junyoung Kim, Chaeeun Lee, Inun Kim, Jooyoung Ro, Jungmin Kim, Yoohong Min, Juhee Park, Vijaya Sunkara, Yang-Seok Park, Issac Michael, Young-Ae Kim, Hee Jin Lee, Yoon-Kyoung Cho.

The liver is one of the most common sites of breast cancer metastasis and is associated with high lethality. Although the interaction between tumor cells and their microenvironment at metastatic sites has been recognized as a key regulator of tumor progression, the underlying mechanism is not fully elucidated. Here, we describe a three-dimensional (3D) microfluidic human liver-on-a-chip (liver-chip) that emulates the formation of a premetastatic niche to investigate the roles of breast cancer-derived extracellular vesicles (EVs) in liver metastasis. We demonstrate that breast cancer-derived EVs activate liver sinusoidal endothelial cells (LSECs) in the liver-chip, inducing endothelial to mesenchymal transition and destruction of vessel barriers. In addition, we show that transforming growth factor β1 (TGFβ1) in breast cancer-derived EVs upregulates fibronectin, an adhesive extracellular matrix protein, on LSECs, which facilitates the adhesion of breast cancer cells to the liver microenvironment. Furthermore, we observed that EVs isolated from triple-negative breast cancer (TNBC) patients with liver metastasis contain higher TGFβ1 levels and induce adhesion of more breast cancer cells to the 3D human liver-chip than do EVs isolated from healthy donors or nonmetastatic TNBC patients. These findings provide a better understanding of the mechanisms through which breast cancer-derived EVs guide secondary metastasis to the liver. Furthermore, the 3D human liver-chip described in this study provides a platform to investigate the mechanisms underlying secondary metastasis to the liver and possible therapeutic strategies.

Keywords: extracellular vesicles; liver microenvironment; metastasis; organ-on-a-chip; premetastatic niche

DOI: https://doi.org/10.1021/acsnano.0c04778

Sci Rep. 2020 Sep 04. 10(1): 14669

3D-bioprinted all-inclusive bioanalytical platforms for cell studies.

Roya Mazrouei, Vanessa Velasco, Rahim Esfandyarpour.

Innovative drug screening platforms should improve the discovery of novel and personalized cancer treatment. Common models such as animals and 2D cell cultures lack the proper recapitulation of organ structure and environment. Thus, a new generation of platforms must consist of cell models that accurately mimic the cells' microenvironment, along with flexibly prototyped cell handling structures that represent the human environment. Here, we adapted the 3D-bioprinting technology to develop multiple all-inclusive high throughputs and customized organ-on-a-chip-like platforms along with printed 3D-cell structures. Such platforms are potentially capable of performing 3D cell model analysis and cell-therapeutic response studies. We illustrated spherical and rectangular geometries of bio-printed 3D human colon cancer cell constructs. We also demonstrated the utility of directly 3D-bioprinting and rapidly prototyping of PDMS-based microfluidic cell handling arrays in different geometries. Besides, we successfully monitored the post-viability of the 3D-cell constructs for seven days. Furthermore, to mimic the human environment more closely, we integrated a 3D-bioprinted perfused drug screening microfluidics platform. Platform's channels subject cell constructs to physiological fluid flow, while its concave well array hold and perfused 3D-cell constructs. The bio-applicability of PDMS-based arrays was also demonstrated by performing cancer cell-therapeutic response studies.

DOI: https://doi.org/10.1038/s41598-020-71452-6