When synthesizing nanoscale liposomes, the ability to control vesicle size helps define their pharmaceutical properties. Conventional microfluidic liposome synthesis methods, however, are limited in terms of the sizes they can produce and the consistency of those sizes.
A new microfluidic vortex-focusing technique resolves those challenges, generating liposomes at precise sizes with negligible size variance. The method, which extends a related microfluidic technique outlined in the recently released book, Liposomes, can be used up to the laminar flow limit, for manufacturing-scale production.
Its developers, led by Don DeVoe, PhD, professor, associate chair of research & administration, University of Maryland, generated liposomes as small as 27 nm for lipids incorporating polyethylene glycol (PEG), and between 61 nm and 127 nm for those without PEG. Production rates exceeded 20g/hour, according to a paper in Nature Communications. Consequently, these small nano-sized liposomes can penetrate the skin as well as cross the blood-brain barrier. Their smaller size range can also enhance cell uptake for reduced toxicity when compared to larger nanoparticles.
Additive Manufacturing
Basically, the platform “combines hydrodynamic focusing and vortex-enhanced mixing in a single process,” the paper notes. Vortex focusing uses an aqueous buffer to sheath the lipid stream in a process similar to flow focusing. This “spatially constrains the mixing zone and significantly reduces the diffusive length scale during vortex mixing,” the researchers explained in the paper. The complex 3D geometry needed to generate the focusing zone and vortex field was created using high-resolution additive manufacturing. Specifically, stereolithography used a digital light processor to build the pattern layer-by-layer.
Key device features are a steep solubility gradient and vortex-enhanced mixing. Outcomes also depended on nozzle tip thickness, nozzle length, light intensity, the resin used and other elements.
Conventional microfluidic techniques can “generate exceptionally sharp solubility gradients and rapid mixing profiles that allow the resulting nanoparticle sizes to be precisely controlled. However, because of the inherently small channel dimensions in these systems, processing throughput has been limited,” DeVoe says.
The microfluidic vortex focusing method his lab has developed increases throughput “by many orders of magnitude” over conventional flow focusing, he says, and delivers tight size control in a continuous flow process. This “will allow biopharmaceutical manufacturers to use a single platform for all stages of nanomedicine development, from preclinical studies to pilot-scale production and beyond.”
It also reduces the number of manufacturing steps and increases process throughput, production agility and scalability for nanomedicines that are optimized to specific sizes. As DeVoe says, “By eliminating the need to change manufacturing methods at each stage, the development cycle can be accelerated.”
