Microfluidic PLGA Nanoparticles Synthesis

by PG Microfluidic Mixing System

Nanoparticles are at the leading edge of the rapidly developing field of nanotechnology. Their unique size-dependent properties make these materials superior and indispensable in many areas. It has been used in many industries, such as pharmaceutical, energy, and electronics. Nanoparticle synthesis is one of the key steps to enable nanoparticle applications. Since most applications utilize nanoparticle size properties, the size distribution, yield, and size reproducibility from batch to batch become very important target parameters for evaluation of different nanoparticle synthesis methods. Traditional batch mode synthesis method (mixing in a bulk solution) has poor quality when the method is implemented in scaled up production. The size distribution and reproducibility of nanoparticles is usually poor due to some uncontrollable factors such as aggregation, heterogeneous mixing. 
The microfluidic technology based miniaturized reactors enable the rapid mixing of reagents, the control of temperature, and the precise spatial-temporal manipulation of reactions. The controlled and homogeneous mixing in microfluidic synthesis methods results in smaller and uniform nanoparticles. The physicochemical properties of nanoparticles can be precisely controlled in a reproducible manner. The control of the reaction environment leads to improve the quality of nanoparticle size distribution, better size reproducibility, and eventually improve the preparation process yield of nanoparticles.
 
Different nanoparticle synthesis, such as semiconductor nanoparticles, metal nanoparticles, colloidal nanoparticles, and biomaterial nanoparticles, have been demonstrated in microfluidic devices in homogeneous and well controlled fashion [2]. Precigenome PG-MFC controller, as a precise pressure control instrument, is very suitable for these nanoparticle synthesis applications. 

 Benefits:​

  • ​​​Compact and portable design

  • Precise and accurate pressure/flow output

  • Fast response time

  • Controllable liquid flow rate output with external flow sensors

  • Standard connection. Easy connect to other components

  • OEM service and module integration available

System Setup:

The system is setup with PG-MFC pressure controller (PG-MFC-8CH or PG-MFC-4CH or PG-MFC-2CH light version) and high speed imaging system (PG-HSV-M) to visualize mixing and nanoparticle formation in microfluidic mixing chip as shown in the Figure below. Since flow rates in these experiments are large enough (milliliters per minute range), they can be estimated by weighing collected nanoparticle solutions within certain time period. Alternatively, flow sensors (PG-LFS-2000) can be used to monitor the flow rates. 
 
Microfluidic chips used in the experiments are microfluidic mixing chip (passive mixing, herringbone mixing). Solution A and Solution B are loaded in 50mL reservoir kits (PG-MRK-50ML). In PGLA synthesis experiments, Solution A is PLGA in acetone solution. Solution B is polyvinyl alcohol (PVA) in water solution. During experiments, preset pressures from PG-MFC pressure controller were applied to reservoir kits. Solutions in reservoir kits were pushed through tubings into the two inlets of a microfluidic chip and mixed inside the channel of the microfluidic chip. The mixed solution (nanoparticle solution) was collected from the outlet of the microfluidic chip. Users can optimize the mixing ratio, flow rates, and synthesis effect by changing the pressure settings using the pressure controller.

System Performance:

PreciGenome Nanoparticle Synthesis System PG-SYN has used in a variety of applications and demonstrated synthesis of PLGA nanoparticle, which is widely used in pharmaceutical companies as drug delivery vehicles [2].

 

We demonstrated the use of microfluidic mixing chip (passive mixing, herringbone mixing) for the synthesis of PLGA nanoparticles. In this work acetone is used as PLGA solvent and water (with 1-2% PVA) is used as the water phase to trigger nanoparticle precipitation. Fabrication of the PLGA nanoparticles using microfluidic chips and precisely controlled pressure results in substantial improvements in nanoparticle size distribution compared to conventional batch methods. Dynamic Light Scattering (DLS) is used to characterize the final product. The figure below shows the comparison data. The average particle size and PDI (heterogeneity index for particle size) using microfluidic method are significantly smaller than those using traditional bulk method.

Method: Bulk
Average size: 571.84nm

PDI: 0.939

Method: Microfluidic PG-SYN-1
Average size: 162.97
PDI:0.304

It demonstrates that we can obtain different sizes of nanoparticles by changing pressure/flow ratio of PLGA and water. The Figure below shows the trend. Increasing the pressure/flow of water phase could lead to larger PLGA size. There is also optimal oil to water ratio for lowest PDI in this device.
Since this mixing device is based on herringbone mixing mechanism, the larger flow rates the better mixing effect it gives. We tested PLGA synthesis at different total flow rates. The Figure below shows the size and PDI effect with different flow rates when the pressure/flow ratio was kept the same (1:1). The larger the pressure/flow is, the smaller particle size it gives. The effect on PDI by the speed of mixing is not very clear. We still need to investigate whether fast mixing helps increase the PDI.

References

  1. Hung, L-H and Lee, AP, Microfluidic Devices for the Synthesis of Nanoparticles and Biomaterials, Journal of Medical and Biological Engineering, 27(1):1-6

  2. Chiesa, E, et.al., The Microfluidic Technique and the Manufacturing of Polysacharide Nanoparticles, Pharmaceutics, 2018, 10:267-289

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