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1. Microengineered 3D Tumor Models for Anti-Cancer Drug Discovery in Female-Related Cancers

   https://doi.org/10.1007/s10439-020-02704-9  

   Amirghasemi, Farbod ; Adjei-Sowah, Emmanuela ; Pockaj, Barbara A. ; Nikkhah, Mehdi ( January 2021 , Annals of Biomedical Engineering)

   The burden of cancer continues to increase in society and negatively impacts the lives of numerous patients. Due to the high cost of current treatment strategies, there is a crucial unmet need to develop inexpensive preclinical platforms to accelerate the process of anti-cancer drug discovery to improve outcomes in cancer patients, most especially in female patients. Many current methods employ expensive animal models which not only present ethical concerns but also do not often accurately predict human physiology and the outcomes of anti-cancer drug responsiveness. Conventional treatment approaches for cancer generally include systemic therapy after a surgical procedure. Although thismore »treatment technique is effective, the outcome is not always positive due to various complex factors such as intratumor heterogeneity and confounding factors within the tumor microenvironment (TME). Patients who develop metastatic disease still have poor prognosis. To that end, recent efforts have attempted to use 3D microengineered platforms to enhance the predictive power and efficacy of anti-cancer drug screening, ultimately to develop personalized therapies. Fascinating features of microengineered assays, such as microfluidics, have led to the advancement in the development of the tumor-on-chip technology platforms, which have shown tremendous potential for meaningful and physiologically relevant anti-cancer drug discovery and screening. Three dimensional microscale models provide unprecedented ability to unveil the biological complexities of cancer and shed light into the mechanism of anti-cancer drug resistance in a timely and resource efficient manner. In this review, we discuss recent advances in the development of microengineered tumor models for anti-cancer drug discovery and screening in female-related cancers. We specifically focus on female-related cancers to draw attention to the various approaches being taken to improve the survival rate of women diagnosed with cancers caused by sex disparities. We also briefly discuss other cancer types like colon adenocarcinomas and glioblastoma due to their high rate of occurrence in females, as well as the high likelihood of sex-biased mutations which complicate current treatment strategies for women. We highlight recent advances in the development of 3D microscale platforms including 3D tumor spheroids, microfluidic platforms as well as bioprinted models, and discuss how they have been utilized to address major challenges in the process of drug discovery, such as chemoresistance, intratumor heterogeneity, drug toxicity, etc. We also present the potential of these platform technologies for use in high-throughput drug screening approaches as a replacements of conventional assays. Within each section, we will provide our perspectives on advantages of the discussed platform technologies.« less
2. Three-dimensional microscale hanging drop arrays with geometric control for drug screening and live tissue imaging

   https://doi.org/10.1126/sciadv.abc1323  

   Ganguli, A. ; Mostafa, A. ; Saavedra, C. ; Kim, Y. ; Le, P. ; Faramarzi, V. ; Feathers, R. W. ; Berger, J. ; Ramos-Cruz, K. P. ; Adeniba, O. ; et al ( April 2021 , Science Advances)

   Existing three-dimensional (3D) culture techniques are limited by trade-offs between throughput, capacity for high-resolution imaging in living state, and geometric control. Here, we introduce a modular microscale hanging drop culture where simple design elements allow high replicates for drug screening, direct on-chip real-time or high-resolution confocal microscopy, and geometric control in 3D. Thousands of spheroids can be formed on our microchip in a single step and without any selective pressure from specific matrices. Microchip cultures from human LN229 glioblastoma and patient-derived mouse xenograft cells retained genomic alterations of originating tumors based on mate pair sequencing. We measured response to drugsmore »over time with real-time microscopy on-chip. Last, by engineering droplets to form predetermined geometric shapes, we were able to manipulate the geometry of cultured cell masses. These outcomes can enable broad applications in advancing personalized medicine for cancer and drug discovery, tissue engineering, and stem cell research.« less
3. Characterization and printability of Sodium alginate -Gelatin hydrogel for bioprinting NSCLC co-culture

   https://doi.org/10.1038/s41598-019-55034-9  

   Mondal, Arindam ; Gebeyehu, Aragaw ; Miranda, Mariza ; Bahadur, Divya ; Patel, Nilkumar ; Ramakrishnan, Subhramanian ; Rishi, Arun K. ; Singh, Mandip ( December 2019 , Scientific Reports)

   3D bioprinting improves orientation ofin vitrotumor models by offering layer by layer positioning of cancer cells and cancer associated fibroblasts (CAFs) which can replicate tumor microenvironment. Aim of this study was to develop a sodium alginate -gelatin (SA-GL) hydrogel by optimizing rheological parameters to print non-small cell lung cancer (NSCLC) patient derived xenograft (PDX) cells and lung CAFs co-cultures. SA-GL hydrogels were prepared, and rheological properties were evaluated. Both the cells were mixed with the hydrogel and printed using INKREDIBLE bioprinter. Hydrogels prepared with 3.25% and 3.5% (w/v) SA and 4% (w/v) GL showed higher printability and cell viability.more »A significant decline in viscosity with shear rate was observed in these hydrogels suggesting the shear thinning property of hydrogels. Spheroid size distribution after 15 days was in the diameter range of 50–1100 µm. Up-regulation of vimentin, α-SMA and loss of E-cadherin in co-culture spheroids confirmed cellular crosstalk. This study demonstrates that rheological optimization of SA-GL hydrogel enhances printability and viability of NSCLC PDX and CAF co-culture which allows 3D co-culture spheroid formation within the printed scaffold. Therefore, this model can be used for studying high throughput drug screening and other pre-clinical applications.

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4. Growth of tumor emboli within a vessel model reveals dependence on the magnitude of mechanical constraint

   https://doi.org/10.1093/intbio/zyaa024  

   Kulwatno, Jonathan ; Gearhart, Jamie ; Gong, Xiangyu ; Herzog, Nora ; Getzin, Matthew ; Skobe, Mihaela ; Mills, Kristen L ( January 2021 , Integrative Biology)

   ABSTRACT Tumor emboli—aggregates of tumor cells within vessels—pose a clinical challenge as they are associated with increased metastasis and tumor recurrence. When growing within a vessel, tumor emboli are subject to a unique mechanical constraint provided by the tubular geometry of the vessel. Current models of tumor emboli use unconstrained multicellular tumor spheroids, which neglect this mechanical interplay. Here, we modeled a lymphatic vessel as a 200 μm-diameter channel in either a stiff or soft, bioinert agarose matrix to create a vessel-like constraint model (VLCM), and we modeled colon or breast cancer tumor emboli with aggregates of HCT116 or SUM149PT cells,more »respectively. The stiff matrix VLCM constrained the tumor emboli to the cylindrical channel, which led to continuous growth of the emboli, in contrast to the growth rate reduction that unconstrained spheroids exhibit. Emboli morphology in the soft matrix VLCM, however, was dependent on the magnitude of mechanical mismatch between the matrix and the cell aggregates. In general, when the elastic modulus of the matrix of the VLCM was greater than the emboli (EVLCM/Eemb > 1), the emboli were constrained to grow within the channel, and when the elastic modulus of the matrix was less than the emboli (0 < EVLCM/Eemb < 1), the emboli bulged into the matrix. Due to a large difference in myosin II expression between the cell lines, we hypothesized that tumor cell aggregate stiffness is an indicator of cellular force-generating capability. Inhibitors of myosin-related force generation decreased the elastic modulus and/or increased the stress relaxation of the tumor cell aggregates, effectively increasing the mechanical mismatch. The increased mechanical mismatch after drug treatment was correlated with increased confinement of tumor emboli growth along the channel, which may translate to increased tumor burden due to the increased tumor volume within the diffusion distance of nutrients and oxygen.« less
5. Microscale Collagen and Fibroblast Interactions Enhance Primary Human Hepatocyte Functions in Three-Dimensional Models

   https://doi.org/10.3727/105221620X15868728381608  

   Kukla, David A. ; Crampton, Alexandra L. ; Wood, David K. ; Khetani, Salman R. ( June 2020 , Gene Expression)

   Human liver models that are three-dimensional (3D) in architecture are indispensable for compound metabolism/toxicity screening, to model liver diseases for drug discovery, and for cell-based therapies; however, further development of such models is needed to maintain high levels of primary human hepatocyte (PHH) functions for weeks to months. Therefore, here we determined how microscale 3D collagen I presentation and fibroblast interaction affect the longevity of PHHs. High-throughput droplet microfluidics was utilized to generate reproducibly sized (∼300-μm diameter) microtissues containing PHHs encapsulated in collagen I ± supportive fibroblasts, namely, 3T3-J2 murine embryonic fibroblasts or primary human hepatic stellate cells (HSCs); self-assembled spheroids andmore »bulk collagen gels (macrogels) containing PHHs served as controls. Hepatic functions and gene expression were subsequently measured for up to 6 weeks. We found that microtissues placed within multiwell plates rescued PHH functions at 2- to 30-fold higher levels than spheroids or macrogels. Further coating of PHH microtissues with 3T3-J2s led to higher hepatic functions than when the two cell types were either coencapsulated together or when HSCs were used for the coating instead. Importantly, the 3T3-J2-coated PHH microtissues displayed 6+ weeks of relatively stable hepatic gene expression and function at levels similar to freshly thawed PHHs. Lastly, microtissues responded in a clinically relevant manner to drug-mediated cytochrome P450 induction or hepatotoxicity. In conclusion, fibroblast-coated collagen microtissues containing PHHs display high hepatic functions for 6+ weeks and are useful for assessing drug-mediated CYP induction and hepatotoxicity. Ultimately, microtissues may find utility for modeling liver diseases and as building blocks for cell-based therapies.« less