Tubing-free Portable Microfluidic Cell Culture Arrays Driven by Braille Displays for Multiplex Drug Screening

Abstract

Personalized drug screening technologies have gained increasing attention as a promising strategy for overcoming the limitations of conventional chemotherapy, particularly in heterogeneous cancers such as chronic myelogenous leukemia (CML). Despite advances in in vitro screening techniques, most conventional drug testing platforms still rely heavily on either static multi-well plates or microfluidic devices with external tubing and pressure controllers. These setups introduce significant challenges in terms of system portability, scalability, and long-term operation in clinically relevant environments. The complexity of the supporting infrastructure, including pneumatic or electronic control systems, often restricts the practical deployment of microfluidic systems in personalized medicine workflows. This thesis presents the development of a tubing-free, programmable microfluidic platform designed for dynamic drug stimulation and long-term cell culture, driven entirely by a commercially available Braille display. The system eliminates the need for external pneumatic or electronic actuation by integrating micropump and microvalve functions directly into the microfluidic chip via physical alignment with piezoelectric Braille pins. These actuators enable dynamic control of fluid flow through localized vertical displacements without the need for any electrical or air tubing. Unlike prior Braille- integrated microfluidics that relied on hybrid setups with external tubing or pressure sources, the proposed system is fully self-contained and portable. The microfluidic chip consists of a multilayer PDMS structure featuring an upper fluidic layer with channels and dead-end cell culture chambers, and a thin lower membrane layer interfaced with Braille pins. Each chamber is connected to inlet and outlet microchannels whose flow paths are gated by the pin-driven actuators. The dead-end chamber architecture enables media and drug exchange via diffusion, thereby minimizing shear stress on cells while maintaining a quiescent environment. The modular nature of the chip design allows flexible reconfiguration of pump–valve–chamber units and supports multiplexed experiments across up to eight fluidic lanes. To validate the performance of the system, drug response experiments were conducted using K562 CML cells under various delivery conditions. Imatinib (IM) and Ponatinib (PO), two tyrosine kinase inhibitors commonly used in CML treatment, were selected as representative drugs. Continuous dosing experiments were performed to estimate the IC50 values for each drug within the system. These values were then used as reference concentrations for pre-mixed (1:1 and 2×) co-administration studies, as well as alternating dosing schemes in which IM and PO were delivered sequentially at time intervals of 24, 12, 6, 3, 1, and 0.5 hours. Interval dosing experiments were also conducted, in which drugs and fresh media were alternately administered to explore the effect of washout dynamics on cell response. Cell proliferation and apoptosis were monitored using bright-field and fluorescence microscopy at 24-hour intervals. Imaging data were quantified using an AI-based segmentation algorithm, and statistical analyses were performed to extract IC50 values, normalized viability, and death ratios. The Braille-actuated pumps demonstrated stable and reproducible flow chosen as the experimental condition to allow full 48-hour operation using a 1000 μL pipette tip. This choice ensured minimal reagent waste and streamlined setup in constrained environments such as incubators or microscope stages. Experimental results showed that the chip reliably supported long-term culture of K562 cells without contamination or leakage, and that the drug response profiles were consistent with known pharmacological behavior. IC50 values for both drugs fell within expected ranges, and alternating administration showed comparable or slightly enhanced apoptosis effects compared to continuous dosing. Notably, 6-hour alternation intervals demonstrated the most robust drug effect among short- cycle protocols. Pre-mixed drug studies suggested potential limitations in fixed-ratio co-administration compared to dynamically modulated regimens. Furthermore, in interval dosing trials, 1-hour cycles showed ambiguous effects that required a 72-hour extension for clearer evaluation, while 3-hour, 6- hour, and 12-hour intervals yielded distinct and interpretable viability profiles. The portability of the device, made possible by the complete elimination of tubing, and its ability to perform programmable drug delivery protocols autonomously, positions it as a strong candidate for integration into decentralized clinical screening environments. The compact form factor, reliance on off-the-shelf components, and software-defined actuation further enhance its applicability in translational research settings. From an engineering perspective, this work presents a paradigm shift in microfluidic system design. Whereas the miniaturization of electronic systems tends to improve both portability and functionality, miniaturized fluidic systems often retain bulky external infrastructure such as syringe pumps, pressure regulators, or valve controllers. By eliminating these constraints, the proposed Braille- actuated microfluidic system aligns microfluidic device development more closely with the core principles of miniaturization and integration in mechanical engineering. It redefines Braille pins not as auxiliary control elements, but as central enabling components for portable, self-contained bioanalysis platforms. In summary, this study introduces a novel microfluidic platform that leverages Braille display actuation for tubing-free, programmable cell culture and drug testing. Through detailed validation experiments using CML-relevant drugs, the system demonstrates its potential for personalized screening applications and sets the foundation for further development of modular, scalable, and clinically applicable microfluidic devices.