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Robust manufacturing of lipid-polymer nanoparticles through feedback control of parallelized swirling microvortices.

ABSTRACT: A variety of therapeutic and/or diagnostic nanoparticles (NPs), or nanomedicines, have been formulated for improved drug delivery and imaging applications. Microfluidic technology enables continuous and highly reproducible synthesis of NPs through controlled mixing processes at the micro- and nanoscale. Yet, the inherent low-throughput remains a critical roadblock, precluding the probable applications of new nanomedicines for clinical translation. Here we present robust manufacturing of lipid-polymer NPs (LPNPs) through feedback controlled operation of parallelized swirling microvortex reactors (SMRs). We demonstrate the capability of a single SMR to continuously produce multicomponent NPs and the high-throughput performance of parallelized SMRs for large-scale production (1.8 kg d-1) of LPNPs while maintaining the physicochemical properties. Finally, we present robust and reliable manufacturing of NPs by integrating the parallelized SMR platform with our custom high-precision feedback control system that addresses unpredictable disturbances during the production. Our approach may contribute to efficient development and optimization of a wide range of multicomponent NPs for medical imaging and drug delivery, ultimately facilitating good manufacturing practice (GMP) production and accelerating the clinical translation.

SUBMITTER: Toth MJ

PROVIDER: S-EPMC5560772 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Robust manufacturing of lipid-polymer nanoparticles through feedback control of parallelized swirling microvortices.

Toth Michael J MJ Kim Taeyoung T Kim YongTae Y

Lab on a chip 20170801 16

A variety of therapeutic and/or diagnostic nanoparticles (NPs), or nanomedicines, have been formulated for improved drug delivery and imaging applications. Microfluidic technology enables continuous and highly reproducible synthesis of NPs through controlled mixing processes at the micro- and nanoscale. Yet, the inherent low-throughput remains a critical roadblock, precluding the probable applications of new nanomedicines for clinical translation. Here we present robust manufacturing of lipid-po ...[more]

PMID: 28726923

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Project description:We present a new, robust three dimensional microfabrication method for highly parallel microfluidics, to improve the throughput of on-chip material synthesis by allowing parallel and simultaneous operation of many replicate devices on a single chip. Recently, parallelized microfluidic chips fabricated in Silicon and glass have been developed to increase the throughput of microfluidic materials synthesis to an industrially relevant scale. These parallelized microfluidic chips require large arrays (>10,000) of Through Silicon Vias (TSVs) to deliver fluid from delivery channels to the parallelized devices. Ideally, these TSVs should have a small footprint to allow a high density of features to be packed into a single chip, have channels on both sides of the wafer, and at the same time minimize debris generation and wafer warping to enable permanent bonding of the device to glass. Because of these requirements and challenges, previous approaches cannot be easily applied to produce three dimensional microfluidic chips with a large array of TSVs. To address these issues, in this paper we report a fabrication strategy for the robust fabrication of three-dimensional Silicon microfluidic chips consisting of a dense array of TSVs, designed specifically for highly parallelized microfluidics. In particular, we have developed a two-layer TSV design that allows small diameter vias (d < 20 µm) without sacrificing the mechanical stability of the chip and a patterned SiO2 etch-stop layer to replace the use of carrier wafers in Deep Reactive Ion Etching (DRIE). Our microfabrication strategy allows >50,000 (d = 15 µm) TSVs to be fabricated on a single 4" wafer, using only conventional semiconductor fabrication equipment, with 100% yield (M = 16 chips) compared to 30% using previous approaches. We demonstrated the utility of these fabrication strategies by developing a chip that incorporates 20,160 flow focusing droplet generators onto a single 4" Silicon wafer, representing a 100% increase in the total number of droplet generators than previously reported. To demonstrate the utility of this chip for generating pharmaceutical microparticle formulations, we generated 5-9 µm polycaprolactone particles with a CV < 5% at a rate as high as 60 g/hr (>1 trillion particles/hour).

Dataset Information

Robust manufacturing of lipid-polymer nanoparticles through feedback control of parallelized swirling microvortices.

Publications

Robust manufacturing of lipid-polymer nanoparticles through feedback control of parallelized swirling microvortices.

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