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Simulation, Design, and Fabrication of a Droplet-Based Microfluidic Device to Study The Role of Tumor Microenvironment and Drug Effects on the Behavior of Multicellular Tumor Spheroids

Besanjideh, Mohsen | 2023

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  1. Type of Document: Ph.D. Dissertation
  2. Language: Farsi
  3. Document No: 56135 (08)
  4. University: Sharif University of Technology
  5. Department: Mechanical Engineering
  6. Advisor(s): Shamloo, Amir; Kazemzadeh Hannani, Siamak
  7. Abstract:
  8. Despite the extensive research conducted so far to treat cancer, this disease is still one of the main causes of death worldwide. The results of recent studies reveal the importance of the tumor microenvironment in the growth, proliferation, and invasion of the primary tumor. Most common models in cancer research, such as 2-dimensional in vitro models and xenografts, do not have sufficient ability to mimic the interaction of tumors with human stromal tissue. Therefore, the implementation of 3-dimensional in vitro models with the ability to replicate tumor microenvironments is essential. In this study, a microfluidic platform has been introduced to create parallel models of the tumor microenvironment. To this end, a droplet-based microfluidic device has been designed and built to generate alginate microgels with different concentrations ranging from 0.5% to 2% (w/v). using this device, the effect of alginate concentration, flow rate ratio, crosslinker flow rate, and the width of flow-focusing channel has been investigated. Also, the binary dripping and quasi-jetting regimes were detected in 1% to 2% alginate concentration. Then, using a numerical study, the effect of alginate concentration on the droplet formation process was investigated. It was observed that alginate concentration affects droplet size and droplet formation regime by changing the viscous dissipation rate. Moreover, to control the droplet size in high viscosity ratios, employing nanoparticles in the continuous phase was proposed. It was observed that using nanoparticles facilitates droplet size reduction up to 50% by increasing the viscosity of the continuous phase. In the next step of the present study, different microfluidic platforms have been designed and fabricated to trap microgels. Among them, a platform capable of trapping eleven microgels has been selected to construct parallel models of the tumor microenvironment. To establish crosstalks between tumor cells and other elements of the tumor microenvironment, a side channel has been connected to microfluidic traps through a set of microposts. According to numerical simulations, under dynamic conditions, microposts assist in mimicking shear stress distribution (10 mPa on average) and pressure gradient in spheroid edges similar to an in vivo model. The drug absorption process was also numerically investigated in different microfluidic configurations and it was found that by modifying the drug dose applied in vitro, the in vivo drug absorption process can be well mimicked under continuous infusion and bolus injection treatments. In the last step, the droplet-based microfluidic device was used to produce A549 tumor spheroids with an alginate concentration of 1% and an average size of 200 m. The generated spheroids were successfully established in the microfluidic traps. The results of live/dead assays after 72 hours and channel coating with vascular cells reveal the high capability of the proposed platform for tumor microenvironment modeling
  9. Keywords:
  10. Drug Delivery ; Tumor Microenvironment ; Porous Media ; Droplet-Based Microfluidics ; Multicellular Spheroids ; Vascular Cells ; Cancer Cells ; Microfluidic Chip

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