From Bench To Scale: Comparing Microfluidic Mixing With DIANT’s Turbulent Jet Approach For Lipid Nanoparticles
Lipid nanoparticles (LNPs) are now firmly established as the leading non-viral delivery vehicles for nucleic acids, supporting the development of mRNA vaccines and gene therapies. Their success rests not only on lipid composition and nucleic acid design but also on the manufacturing process, where mixing technology plays a pivotal role. Subtle differences in mixing dynamics can affect particle size, encapsulation efficiency, and internal structure, ultimately shaping clinical performance and regulatory compliance.
This article examines a comparative study of two mixing approaches: microfluidic mixing, which has been widely adopted for preclinical work, and DIANT Pharma’s coaxial turbulent jet technology, designed to deliver robust, scalable manufacturing. Using a systematic design-of-experiments framework, the study highlights how each technology influences key particle attributes and evaluates their suitability across different stages of drug development.
Microfluidic Mixing and Its Role in Early Development
Microfluidic mixing remains a valuable tool in discovery and preclinical formulation. By relying on laminar flows in micrometer-scale channels, this approach allows precise control over mixing conditions at very small volumes. It is well suited for high-throughput screening, where multiple formulations can be tested efficiently with minimal consumption of nucleic acid and lipid materials.
However, microfluidic systems have inherent limitations when the goal shifts toward manufacturing robustness. Their reliance on diffusion-driven mixing under low Reynolds number conditions means they are sensitive to variations in flow rate or formulation parameters. This sensitivity often results in broader size distributions, variable encapsulation efficiency, and challenges in reproducibility at larger scales.
DIANT’s Turbulent Jet Technology and Robust Manufacturing
In contrast, DIANT’s coaxial turbulent jet mixing introduces a fundamentally different regime. By operating at high Reynolds numbers, the system achieves rapid convective mass transport, producing highly efficient mixing in a continuous process. This turbulence-driven approach inherently tolerates a wider design space, meaning that modest shifts in flow rates or lipid ratios have less impact on the final product.
The implications for process robustness are significant. The study showed that DIANT’s technology consistently yielded smaller, more uniform LNPs—typically in the 50–80 nanometer range—with narrow polydispersity. Encapsulation efficiency exceeded 85 percent across most formulations, demonstrating reliable payload incorporation even under varied experimental conditions. Such performance is advantageous not only for product consistency but also for cost efficiency, particularly when working with expensive therapeutic mRNA.
Structural analysis by cryogenic electron microscopy and small-angle X-ray scattering revealed more frequent bleb features and less ordered cores compared with microfluidic products. While these features are noteworthy, they did not undermine the advantages of particle uniformity and encapsulation efficiency delivered by turbulent jet mixing. For many applications, especially those moving toward regulatory submission and commercialization, process reliability outweighs minor differences in structural ordering.
Comparative Outcomes for Different Payloads
When applied to antisense oligonucleotide formulations, the distinction between the two technologies was most pronounced. DIANT’s turbulent jet system delivered both superior size control and encapsulation efficiency, while microfluidic systems produced larger, more variable particles with less consistent payload incorporation.
For mRNA formulations, particle sizes and encapsulation efficiencies were more comparable between the two mixers. Nonetheless, DIANT’s technology maintained its advantage in reproducibility, a factor of critical importance when advancing into later clinical stages.
Implications for Scale-Up and Control Strategies
The findings suggest that while microfluidic mixing retains value in early-stage research, DIANT’s turbulent jet mixing represents a more robust pathway for scaling into clinical and commercial manufacturing. Its tolerance to process variability reduces the burden on manufacturing control strategies, enabling more straightforward compliance with quality-by-design principles. In addition, the continuous mode of operation aligns with industry trends toward intensified, smaller footprint biomanufacturing systems.
By contrast, microfluidic mixing faces challenges when scaling due to minimum volume constraints and sensitivity to operational parameters. This limits its utility beyond preclinical screening and formulation optimization.
The comparative study highlights the central role of mixing technology in determining LNP attributes and manufacturing robustness. Microfluidic mixing offers precision at small scale and may generate more ordered internal structures, making it useful in discovery phases. However, DIANT’s turbulent jet technology demonstrated higher reproducibility, scalability, and encapsulation efficiency—qualities that align directly with the demands of clinical development and commercial production.
As the field of nucleic acid therapeutics continues to expand, DIANT’s approach offers a practical and reliable solution for bridging the gap between preclinical innovation and large-scale manufacturing, ensuring that promising therapies can be delivered consistently and at scale.