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 (1.8kg/d) 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.

Microengineered human blood–brain barrier platform for understanding nanoparticle transport mechanisms

“…4a). Microfluidic parallelization technology that integrates multiple devices while preserving advantages of the microscale organ-ona-chip engineering will further provide higher throughput system 64 . We believe that our human BBB model could provide a widely useful tool for translational medicine research in particular for the modeling of neuroinflammation and reactive gliosis in neurological disorders.…”

3D-Printed Concentration-Controlled Microfluidic Chip with Diffusion Mixing Pattern for the Synthesis of Alginate Drug Delivery Microgels

“…Microfluidic platforms can precisely control over fluid flow in the microchannels [18]. Microfluidic chips have synthesized nano/micro-hydrogels, which have a wide range of biological and medical applications, such as enzyme-catalyzed reactions [19], cell manipulation [20], tumor screening [21] and microparticle synthesis [22,23,24,25]. Hydrodynamic flow focusing in straight or modular microfluidic platforms was mostly utilized for producing microparticles.…”

Polymeric Nanoparticles Controlled by On‐Chip Self‐Assembly Enhance Cancer Treatment Effectiveness

“…Fabrication of SMR Chip: The SMR uses two inlets and a single outlet, with a height of 50 mm, outlet width of 2 mm, inlet width of 1mm, and channels with the dimensions 0.2 mm × 0.2mm, (mixing efficiency was 0.92, volumetric average in a SMR). [8] To fabricate the SMR with the PDMS, elastomer and curing agent with a 10:1 mass ratio were poured www.advancedsciencenews.com www.advhealthmat.de on a patterned silicon wafer and cured at 80°C overnight. The molded SMR chip was torn off and bonded to glass slides using plasma cleaner (PDC-32G, Harrick Plasma, Ithaca, NY) for 60 s.…”

“…We used our SMR device that shows a high mixing efficiency of 92% to synthesize MVPs with the two ratios of 2 and 4 ( Figure 1a). [8] The MVPs showed much narrower size distributions and smaller sizes than BMPs (Figure 1b and S2b, Supporting Information), and the higher size uniformity was con-firmed in MVPs than in BMPs with the spherical shape of the NPs (Figure 1c). BMPs were considerably heterogeneous in size, but MVPs were highly homogeneous ( Figure 1d).…”

“…A major driving force of self-assembly was formation of phenylboronic ester bond between diol of DOX and PBA of pPBA, the strength of which is reversibly correlated to the pH. [8,12] The phenylboronic ester is stable at physiological pH 7.5 but it readily dissociates at an acidic condition, that is, pH 5.0. Our NPs has the acid-labile property of phenylboronic ester bond with which drugs can be released favorably in tumor-targeted drug delivery, as well as intracellular drug release, thanks to the acidic conditions of tumor microenvironment and intracellular endosomes.…”