Draft:Microengineering-Based Nanomedicine Formulations

• Comment: In accordance with the Wikimedia Foundation's Terms of Use, I disclose that I have been paid by my employer for my contributions to this article. Marketing-IMM (talk) 13:39, 18 June 2025 (UTC)

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Microengineering-based nanoparticle technology integrates microfabrication with the unique properties of nanoparticles, creating innovative devices and systems. This interdisciplinary field leverages microengineering's precision to manipulate nanoparticles for diverse applications, including medicine, diagnostics, electronics, and materials science. Recently, it has significantly advanced nanomedicine, offering scalable solutions for mRNA-based therapeutic formulation and supporting advanced drug delivery systems.

Microfluidic Approaches to Nanoparticle Formulation

Microengineering, particularly microfluidics, is essential for advanced nanoparticle (NP) formulation. Traditional bulk methods often struggle with controlling NP size and uniformity, hindering clinical translation due to the impact on drug delivery, biodistribution, and therapeutic efficacy. Microfluidics overcomes these limitations by enabling precise fluid manipulation at the microscale. This control allows for NPs with tailored properties (size, shape, encapsulation efficiency), leading to improved drug delivery and reduced toxicity. The continuous nature of microfluidic processes facilitates scalability and reduces batch-to-batch variability, crucial for clinical and commercial success. Microfluidics has enabled novel biomaterial discoveries, including clinically approved NPs, and promises to accelerate clinical translation.

1. Liposomes and Lipid Nanoparticles (LNPs)

Liposomes (unilamellar lipid vesicles with an aqueous core) and LNPs (lipid nanoparticles, often multilamellar or with a dense core containing nucleic acid/lipid complexes) benefit significantly from microfluidic formulation. Microfluidics enables controlled production, improving stability, drug loading, and targeted delivery of therapeutics like nucleic acids (siRNA, mRNA) for gene therapy and vaccines. Liposomes and LNPs are among the most clinically advanced NPs, representing a significant portion of FDA-approved NPs in clinical use. Traditional macroscale production methods, like extrusion for liposomal doxorubicin (Doxil®), have faced manufacturing challenges leading to drug shortages. Bulk mixing for LNPs often results in suboptimal particle sizes (>100 nm). Microfluidic approaches offer a solution for controlled liposome and LNP manufacturing.

2. Polymeric Nanoparticles

Biodegradable polymers are crucial in novel drug delivery systems for modulating drug release profiles (controlled, delayed, or programmed release). Solvent evaporation is a common bulk method for formulating polymeric NPs and microparticles, encapsulating hydrophobic or hydrophilic compounds. However, scaling up solvent evaporation with bulk stirring lacks precise emulsification control, resulting in heterogeneously sized NPs, increasing manufacturing costs due to additional processing and quality control. Microfluidics addresses these challenges, enabling precise control over NP parameters (size, polydispersity, drug loading, release kinetics) in polymer NP formulation.

3. Inorganic Nanoparticles

In nanomedicine, inorganic nanoparticles are used as therapeutic and imaging agents due to their unique responses to external stimuli (e.g., magnetic fields, infrared light). Bulk synthesis of metal nanoparticles (gold, silver, iron) involves chemical methods (nucleation and growth) requiring precise control over temperature, stirring rate, and reducing agent concentration. Microfluidic environments facilitate this control, ensuring a more homogenous process.

Micromixer Designs and Fabrication

Caterpillar Micromixers:

The Caterpillar Micromixer has internal bas-relief structures which induce recirculation flows transverse to the flow direction which result in efficient chaotic mixing. At very low Re numbers, e.g. for viscous flows at low flow rates, the mixing mechanism may change and a near-multilamellae type flow pattern arises which uses diffusion mixing in thin layers, in a split-and-recombine fashion. As they consist of a structured single channel, these devices may also be used successfully if precipitation occurs during the reaction or if fine slurries shall be processed.

The Caterpillar Micromixers are particularly suitable for applications where fast mixing at higher throughput is desired, providing highest performance for l/l-mixing as well as for g/l- or l/l dispersing. The scaled up mixers are used for pilot and industrial-scale production with enhanced mixing efficiency and compatibility with multi-phase systems. The higher flowrates enable production scales of a few up to about 100 tons per year with all the advantages of our micro mixers, such as mixing quality, availability of different housing materials and safety gains.

Star Lamination Mixers:

The Star Laminators create an alternate, interdigital-type feeding array which is generated by stacking thin foils with star-like through-holes. In this way, a finely dispersed injection of two fluid streams is achieved. The foil stack is inserted into the recess of a housing where it is tightened by applying compression. The novel Star Laminators are large capacity microstructured mixers reaching volume flows up to the m3/h domain. The apparatuses yield at higher flow rates a mixing efficiency which compares the high performance of today’s low-capacity (l/h) micromixers.

As for any microstructured mixer, the feeding section is most sensitive to particles and fouling. However, owing to their simple reversible assembly, which is a mounted foil stack, these micromixers can be cleaned in a straightforward manner, in case of fouling. Furthermore, the particles are not be detrimental because of the macroscopic dimensions of circular outlet channel.

Interdigital Micromixers:

It combine the regular flow pattern created by multi-lamination with geometric focussing which speeds up liquid mixing.

Due to this double-step mixing, the slit mixers are amenable to wide variety of processes such as mixing, emulsification, single-phase and multiphase organic synthesis. Extensive knowledge on hydrodynamics, mixing performance and reaction engineering for diverse applications of these mixers has been documented worldwide. Suitable for small-scale, high-throughput screening.

Fabrication Techniques: Lithography techniques are fundamental in micromixer fabrication. Photolithography uses masks and UV light to pattern photoresists, enabling high-resolution, complex designs, followed by etching or deposition. Electron beam lithography (EBL) offers even higher resolution through direct writing but is slower and primarily used for creating master molds. Soft lithography employs these master molds to replicate microstructures in elastomers like PDMS, providing a cost-effective approach for prototyping. These lithographic methods are often combined with etching techniques (wet or dry) to create the microchannels themselves.  Wet etching uses chemical solutions for material removal, while dry etching, including reactive ion etching (RIE), utilizes plasmas or reactive gases for more controlled etching.

Other fabrication methods include micromachining (CNC or laser) for precise material removal, 3D printing (stereolithography, selective laser sintering, fused deposition modeling, inkjet) for layer-by-layer construction of complex geometries, and bonding techniques (thermal, anodic, adhesive, PDMS) to join microchannel substrates.

Choice of fabrication technique

The choice of fabrication technique depends on several factors, including:

• Materials: The materials used for the micromixer (e.g., silicon, glass, polymers, metals).
• Design complexity: The complexity of the microchannel design.
• Resolution requirements: The required feature size and tolerances.
• Throughput: The desired production volume.
• Cost: The cost of the fabrication process.

Often, a combination of techniques is used to fabricate a single micromixer. For example, photolithography might be used to create a master mold, which is then used in a soft lithography process to create the final device.

Advantages of Microengineering Technology

1.    Scalability and Efficiency: Enables smooth transition from small-scale experiments to large-scale production. Parallelized microchannels and high-performance pumps enable scalable production, while process intensification reduces reaction times and enhances particle quality.

2.    Enhanced Product Quality: Precise parameter control ensures consistent particle size and encapsulation efficiency. Real-time monitoring allows for immediate adjustments, resulting in higher quality and more reliable products.

3.    Regulatory Compliance: Platforms can be designed to adhere to Good Manufacturing Practices (GMP) and incorporate Process Analytical Technology (PAT) principles, facilitating regulatory approval and market access.

4.    Precise Manipulation: Microfluidic devices precisely control fluid flow and manipulate individual cells or nanoparticles, enabling targeted drug delivery and controlled release.

5.    Miniaturization and Integration: Enables miniaturized devices for lab-on-a-chip systems and implantable devices, allowing for point-of-care diagnostics and personalized medicine.

6.    Controlled Microenvironment: Creates controlled microenvironments mimicking physiological conditions for studying cell behavior and drug responses.

Applications

Medicine and Diagnostics:

• Drug delivery: Controlled drug encapsulation and release.
• mRNA Therapeutics and Vaccines: Scalable production of mRNA-LNP formulations.
• Biosensing: Integration of nanoparticles into microfluidic sensors.
• Lab-on-a-chip devices: Miniaturized biological assays.
• Theranostics: Magnetic nanoparticle-assisted tracing for drug delivery and imaging.
• Sensors: Detection of physical and chemical signals.

Materials Science:

• Materials synthesis: Controlled nanoparticle synthesis.
• Materials assembly: Assembling nanoparticles into complex structures.

Challenges and Future Prospects

Scalability: Scaling up microengineered nanoparticle production.

Integration: Developing robust methods, AI/ML integration for process optimization, and GMP-compliant manufacturing facilities. Expanding into non-therapeutic applications.

Characterization: Developing advanced process analytical techniques (PAT).

Microengineering-based nanoparticle technology is a rapidly evolving field with significant potential across industries. Continued research will lead to more sophisticated and impactful devices.

References

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