# Microfluidic Flow-Focusing for Size-Controlled Formation of Cubosomes

## TL;DR

This paper introduces a microfluidic method to create cubosomes of controlled size for drug delivery applications.

## Contribution

A microfluidic flow-focusing technique is presented for tunable size control of cubosomes during solvent exchange.

## Key findings

- Cubosome sizes can be tuned from 195 nm to 125 nm by adjusting flow rate ratios.
- The method shows statistically significant size control compared to bulk solvent exchange.
- Polydispersity remains low-to-moderate despite some variability from pumping instability.

## Abstract

Cubosomescolloidal dispersions of lipid inverted bicontinuous
cubic phasesare promising nanosystems for advanced drug delivery
applications. Here, we report on a microfluidic hydrodynamic flow-focusing
approach for solvent exchange that enables the preparation of cubosomes
with tunable size. The approach involves a preliminary step where
the lipid phytantriol, the main building block, is first dissolved
in ethanol to create a precursor solution. This precursor is subsequently
flowed through the central channel of a cross-shaped microfluidic
device, where it is focused by two lateral streams of water containing
the stabilizer Pluronic F127. As water and ethanol mix, the polarity
shift forces phytantriol to self-assemble into cubosomes, while the
laminar-flow conditions imposed by the microchannels provide controlled
mixing conditions. By adjusting the flow rate ratio (Q

R
) between the water-F127 side streams
and the phytantriol-ethanol precursor, we control the width of the
precursor streamthe region through which solvent molecules
exchange. This manipulation thus directly governs the mixing time,
influencing the kinetics of lipid self-assembly, which ultimately
determines particle size. This technique allows for the tuning of
cubosome sizes from 195 nm down to 125 nm, with size decreasing monotonically
as QR
increases and the polydispersity
index remaining in the low-to-moderate range. Although variability
is still significant, largely due to pumping instability and the use
of a commercial microfluidic device not specifically designed for
this application, the trends are statistically significant for every
precursor-concentration series (p ≤ 0.011).
Further customization of the apparatus is expected to improve reproducibility
and scalability. The results obtained with this microfluidic method
differ markedly from those obtained by bulk solvent exchange, which
shows only a weak and generally nonsignificant trend toward larger
particle size at higher dilution ratios.