Microfluidics Technology for the Design and Formulation of Nanoparticles

Engineered Nanoparticles (NPs) are becoming essential to enhance drug delivery systems (DDSs) for both biomedical and pharmaceutical applications. Controlling the delivery of molecules of interest, increases their concentration in a desired location and lead to improved drug efficacy as well as minor adverse effects. NPs including lipid-based and polymeric NPs have been used over the years as nanocarriers of various bioactive molecules. Here, the authors have reviewed the conventional formulations and methods to manufacture polymeric and lipid-based NPs emphasizing their advantages and limitations. Although they are easy to master, these methods present multiple drawbacks, such as large particle size and high polydispersity index (PDI), besides the unreproducible formulation and high batch-to-batch variability. Therefore, novel approaches have emerged such as microfluidic-based NPs production, which may overcome these limitations and give rise to effective drug delivery system.

Comparison of manufacturing methods

The main reason for using NPs in medical applications is their essential characteristics, such as high mass-to-surface-area ratio, their ability to adsorb and function as carriers for other compounds, and their quantum properties. NPs possess a significantly large “functional” surface that can adsorb, bind, and carry different compounds, like proteins or other functional moieties. Depending on their chemical properties and morphology, NPs can be classified into several categories such as ceramic, carbon-based nanoparticles, semiconductor, metal, lipid-based, and polymeric NPs.

A. Conventional methods to produce nanocarriers

Lipid-based NPs formulations, including liposomes and solid lipid nanoparticles (SLN), have been manufactured using different methods. These methods directly affect the final quality of the NPs especially their size, PDI and morphology. Different lipid-based NPs manufacturing methods are listed but overall, most strategies to produce lipid-based NPs followed these basic steps: 1) Lipid dissolution in organic solvents; 2) Drying of the resulting compound; 3) Hydration of anhydrous lipids (by applying different aqueous solutions); 4) Separation of liposomal vesicles; 5) Quality control assay.

Methods to manufacture polymeric NPs can be categorized into two groups: two-step processes that need to prepare the emulsification system as the first step and then form NPs, and a one-step process that exempts the emulsification step.

A comparison between the different manufacturing method of polymeric NPs and lipid-based NP is depicted in Table 1.

B. Microfluidic-based methods to produce nanocarriers

The principal innovation of microfluidics is the ability to transfer the traditional bulk technique to microscale fluidic chips. Solvents can be mixed within microchannels by a pumping system in a continuous laminar flow manner. This type of flow offers a high mixing quality and enhances the performance of microscale devices. The possibility to adjust the flow rate ratio (FFR) and total flow ratio (TFR) allows the continuous production of monodisperse and homogenous NPs; Figure 1. Overall, this method offers high reproducibility and low batch-to-batch variations. In addition, the versatility of the method makes the encapsulation process faster while keeping the encapsulation efficiency high.

For lipid-based NPs, a pre-prepared lipid phase and an aqueous phase are pushed in separate channels and ultimately mixed in a continuous controlled mixing. Mixing causes a local diffusion of phospholipids in the aqueous phase, which promotes self-assembly of lipids and consequently produces liposomes.

The unique physicochemical properties of Lipid-based PNs (liposomes or solid core lipid nanoparticles) and their biocompatibility makes them excellent nanocarriers for drugs and food applications.

Figure 1: Schematic presentation of liposomes manufacturing using the microfluidic system

The production of polymeric NPs follow the same principle but using either hydrophobic polymers such as polycaprolactone (PCL), poly-lactic acid (PLA), poly-(lactic-co-glycolic acid) (PLGA) or hydrophilic polymers such as albumin, chitosan, gelatin, and alginate.

Polymeric NPs are more stable than liposomes and their preparation methods are “easy” to reproduce. They are commonly used to improve drug solubility while reducing drug toxicity and to control drug retention time.

C. Applications

Nanotechnology represents an active area for research to improve drug formulations, controlled drug release and targeted delivery. The application of NPs in nanomedicine, have been investigated in different areas, from controlled drug delivery to the diagnosis and prevention of diseases. In this review, the authors discuss emerging applications for NPs within the medical filed such as targeted small molecules delivery (nucleic acid-based treatment) and targeted chemotherapy delivery. Of note, the authors highlighted that nanocarriers have a broader scope than those mentioned in this article but was not space to be discussed.


In this paper, the authors have demonstrated the automation power of our sequential perfusion system ARIA together with its ability to be synchronized with a widefield (or other) microscope to perform multiplexed antibody The path from preclinical stage to industrial production of Nano-drug delivery systems is challenging. This is due to the difficulty to obtain a size-controlled, reproducible, stable formulation with high encapsulation efficiency and low batch-to-batch variability. Conventional manufacturing methods are not well-adapted to the production of NPs with small particle size and narrow size distribution. Advanced microfluidic design allows adjusting the process parameters in an automatic manner, making it more controllable and enhances the possibility to produce the optimum particle size and PDI. Future advancement of microfluidic systems can lead to the optimization of NP production, which will ultimately extend their use in therapy, and integrate them into new medical applications.

To learn more about this Microfluidics Technology for the Design and Formulation of Nanoparticles protocol, explore the article here: https://www.mdpi.com/2079-4991/11/12/3440/htm

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