MilliTech Achieves Million-Scale Microsphere Throughput per Chip with Proprietary Twister Technology, Enabling Continuous High-Throughput Production

Production capacity bottlenecks are obstacles hindering the industrialization of microsphere preparation using microfluidic technology.

Specifically, traditional microfluidic chips typically employ a single-channel design, which severely limits their microsphere generation capacity, with a maximum hourly output of only 0.5 mL. This production level is clearly far removed from the industrial-scale demand for thousands to tens of thousands of liters, thus failing to meet the practical requirements of large-scale manufacturing.

In an interview with VCBeat, Dr. Han Linchen, founder of Milli Technology, stated, “In the long run, microfluidics technology is poised to become the mainstream technology in the field of microsphere production.”As an innovative enterprise in the field of microfluidic production chips, Hangzhou Milli Technology Co., Ltd., established in 2022, is committed to addressing capacity challenges by transforming microfluidic technology into a versatile production platform for microsphere materials, thereby providing solutions for performance enhancement and functional innovation in microsphere products.

Setting aside considerations of quality and cost, Han Linchen stated that there are two primary approaches to enhancing microfluidic production capacity: first, increasing the droplet generation speed per channel; and second, increasing the number of channels. He emphasized that scaling up the number of channels is not an infinitely viable solution, as it eventually encounters bottlenecks in cost control and equipment management.

Therefore, the team at Hangzhou Milli Technology Co., Ltd. decided to start by increasing the spheroid formation speed of single channels.In March 2022, Milli Technology began building a microfluidic chip platform for the digitalized, large-scale production of microspheres.

Initially, although the team could leverage mature MEMS processes, there were no reference standards for production-grade chip design. This necessitated fluid dynamics experts to meticulously design microfluidic channels within simulation software, modeling various fluid properties. Agarose became the first material targeted for breakthrough, and its complex fluidic characteristics posed significant challenges to the design process.

Reportedly, the flow channel pattern initially designed by the team was inspired by Athlon processors and featured nearly 1,000 independent fluid inlets and outlets, enabling high-throughput production. However, persistent issues with liquid path alignment forced the team to abandon this approach. During the manufacturing process, the team also needed to precisely control the resistance between the dispersed phase fluid, the flow channels, and the raw materials, while accurately calculating changes in polymer properties and their impact on subsequent cross-linking reactions to ensure that the microspheres’ particle size, pore size, and mechanical strength met the required standards.

This also means that, in addition to the chip, chemical, and pump-valve systems, the entire platform architecture requires support from temperature control, raw material pretreatment, alignment, and sensor systems. For mass-production models, automated control software and operational documentation are further required to ensure stable production.

After multiple iterations and optimizations,The team at Milli Technology has successfully developed Twister technology—a novel microdroplet spheroidization technique utilizing 3D-structured microfluidic chips. This technology not only increases the droplet generation frequency by two to three orders of magnitude compared to traditional cross-flow junction chips, but its unique hydrodynamic design also ensures stable system operation, resulting in microspheres with highly uniform and consistent particle sizes.

Currently, the team employs a single-channel chip to produce agarose microspheres. Notably, during the development of agarose microsphere production, this chip can operate at temperatures up to 250°C and withstand pressures up to 3.0 MPa, fully meeting the requirements for large-scale, stable production of high-viscosity, high-temperature agarose scaffold microspheres.

Moreover, the chip enables precise control over an extremely narrow particle size range of microspheres, ensuring that the particle size distribution remains within D50 ± 10%. Currently, agarose microspheres produced using this microfluidic chip exhibit a stable particle size variance of approximately 5% and achieve yields close to 100%.

“This breakthrough has opened up new possibilities for the production of microfluidic technology, making the entire commercialization process feasible.”Han Linchen stated.

Microfluidic technology for microsphere preparation not only requires the direct capability to produce microspheres with uniform particle size and narrow size distribution, but also possesses the customized ability to rapidly develop microspheres of varying sizes, materials, and structures, as well as to fabricate complex microspheres encapsulated with double or multiple layers of materials.

Currently, Milli Technology has completed the development of high-throughput microfluidic production prototypes for various types, achieving a highly digitalized production mode. It is compatible with multiple raw materials, including agarose, inorganic materials, and plastic polymers, enabling the rapid large-scale production of microspheres with different particle sizes and functionalities.

Specifically, Hangzhou Milli Technology Co., Ltd.'s product portfolio of chromatographic microspheres encompasses Protein A and Ni-NTA affinity chromatography resins, 4/6FF chromatography resins, and Epoxy chromatography resins. Among these, Protein A chromatography resin, as the most critical chromatographic medium, has achieved performance levels leading within China, while Ni-NTA features high dynamic binding capacity and low Ni²⁺Its elution characteristics make it the preferred choice for the purification of His-tag recombinant proteins; 4/6FF is widely used in the purification of biological macromolecules such as viruses, virus-like particles, and plasmids, and can withstand disinfection with 0.5–2 M NaOH; while Epoxy chromatography resins, with their unique spacer arm design and broad coupling requirements, are suitable for the capture of small-molecule and peptide ligands.

To further enhance production capacity, Milli Technology has spared no effort in building its manufacturing bases. The team has established a 2,000-liter chromatography microsphere production base in Hangzhou’s Binjiang District and a 10,000-liter-scale base sphere production base in Xiaoshan District, both equipped with GMP-compliant production environments, to directly provide pharmaceutical clients with comprehensive services spanning from R&D to commercial manufacturing.

However, Milli Technology’s ambitions extend far beyond this. The team is continuously iterating its technology to increase production capacity and reduce costs. Reportedly, Milli Technology has significantly shortened the R&D cycle for new microsphere products from the traditional 6–12 months to just 30 days, a breakthrough that will undoubtedly secure greater market advantages for the team.

“Microfluidics technology is bound to lead the transformation of future production methods; it is only a matter of time before it replaces traditional manufacturing processes,” stated Han Linchen with conviction. This assessment is based on several factors, the most critical being that microfluidics enables fully digitalized end-to-end production, a capability unmatched by conventional reaction methods. Traditional approaches rely heavily on manual labor and empirical experience, often resulting in poor reproducibility. In contrast, microfluidics ensures consistency of production parameters across different devices, thereby significantly enhancing product quality and stability.

However, seamlessly integrating microfluidics technology into existing industrial production chains is no easy feat.

Han Linchen emphasized,The microspheres produced by the new technology must fully meet the requirements of the final product, which means that the new technology must not only be stable and reliable but also form a perfect substitute for existing products.This process is far more complex than simply developing stable devices or microspheres, as it requires new technologies to be fully integrated into existing production environments and seamlessly interfaced with all operational stages.

To achieve this goal, market education and customer acceptance are particularly crucial. “Customers need to gain a deep understanding of the alternative logic behind microfluidics technology and the advantages offered by microspheres, and recognize how these advantages impact end products,” said Han Linchen. To this end, Hangzhou Milli Technology Co., Ltd. strives to achieve technological breakthroughs while actively seeking collaborations with industry leaders to set industry benchmarks, thereby further promoting the development of microfluidics technology in the field of microsphere preparation.