Cap-Drop: A Pre-Programmed, Self-Powered Capillary Microfluidic System for Passive Droplet Generation and 3D Cell Culture Modeling.

3D cell culture models and precision diagnostics have advanced significantly through microfluidic systems, yet their broad implementation remains limited by challenges in scalability, integration, and portability. Effective 3D cell culture models require systems that maintain sample integrity, minimize evaporation, and avoid crosstalk while handling various biofluids. However, current platforms often depend on active pumping, bulky components, and complex controls, which hinder portability, usability, and affordability. To address these challenges, the Capillary Droplet microfluidic (Cap-Drop) is presented, a novel capillary-driven platform that generates and immobilizes droplets with precision, eliminating the need for external pumps or intricate setups. Unlike conventional system, where moving droplets complicate tracking and identification, Cap-Drop ensures fixed droplet positioning, allowing seamless tracking and analysis. By integrating hydrophilic and hydrophobic materials with several innovative capillary elements -including passive vents (PV), pressure reducer (PR), stop valves (SV), delay channels, and bubble trap (BT)-Cap-Drop enables robust droplet formation (40 to 500 nL) for biofluids of varying properties. The pre-programmed design of PV in corporation with other capillary elements autonomously seals microwells (MWs), ensuring consistent sample digitization and supress risk of evaporation. Cap-Drop is optimized and offers a transformative platform for microfluidic technologies in mechanistic cellular studies, preclinical drug screening, and clinical diagnostics.