Effect of Manufacturing Tolerance of Microfluidic Device on the Physicochemical Properties of Nanoparticles for Nanomedicine Applications

• Nanocomposite molds improved microhardness by 2.5 times and reduced friction coefficient by 2 times. • Ni-PTFE reduced adhesive wear and enabled defect-free demolding of COC cartridges. • Pure Ni molds caused notable channel shrinkage/expansion; Ni-PTFE minimized it. • CFD analysis revealed depth deviations affected micromixing more than width,. • Ni-PTFE-molded cartridges enabled smaller, more uniform LNPs via improved mixing. Microfluidic cartridges enable scalable lipid nanoparticle (LNP) production, yet the impact of demolding defects and dimensional tolerances on mixing and downstream LNP quality remains poorly understood, compromising device reliability and batch-to-batch LNP consistency. In this work, we investigate how demolding defects and dimensional tolerances during manufacturing influence microfluidic mixing and the resulting LNP physicochemical properties—two critical parameters for consistent nanomedicine synthesis. Microfluidic cartridges were fabricated by micro injection molding using two electroformed molds: a conventional nickel mold and a lubricating Ni-PTFE nanocomposite mold; followed by solvent-assisted thermal bonding. Dimensional deviations in channel width and height were quantified after demolding and bonding. Results showed Ni-PTFE mold yielded enhanced channel integrity and tighter tolerances (0.60% width expansion; 1.68% depth decrease) compared with Ni molds (3.09% width shrinkage; 3.66% depth increase). After bonding, cartridges produced from Ni mold showed higher dimensional change in width due to thermal stress release. Computational fluid dynamics simulation shows mixing performance is highly sensitive to depth variations, while width changes have a smaller effect. Finally, these findings were validated by LNP synthesis, and Ni-PTFE molded cartridges produced LNPs with a smaller particle size and a lower polydispersity index. This work establishes the first direct correlation between mold/material choice, fabrication tolerances, microfluidic mixing performance, and resultant nanoparticle quality, underscoring the importance of dimensional control in microfluidic manufacturing for reliable and scalable nanomedicine synthesis.