|Review done thanks to the support of the MaMi H2020-MSCA-ITN-2017-Action”Innovative Training Networks”
Grant agreement number: 766007
Emma Thomée, PhD candidate
Microfluidic Nanoparticle Synthesis: A short review
1. Introduction into nanoparticle synthesis by microfluidics
Nanoparticles are particles with a size smaller than 100 nm. They are made up of carbon, metal, metal oxides or organic matter . Nanoparticles present great potential for biomedical applications within various fields such as drug delivery, imaging and biosensing. Due to having a large surface area relative to their volume, nanoparticles exhibit unique properties at nanoscale. Importantly, the physiochemical properties of nanoparticles depend on their size and morphology . To take advantage of this phenomenon, nanoparticles must be synthesized with well-controlled size and shape. Nanoparticle synthesis in microfluidic devices has shown advantages over the conventional batch synthesis processes due to more precise control of size and shape, resulting in a narrower size distribution of particles . This short review presents an overview of microfluidic approaches to nanoparticle production, including advantages over the conventional batch synthesis and examples of applications of microfluidic-synthesized nanoparticles.
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2. Conventional nanoparticle synthesis in batch reactors
A number of batch reactor strategies have been adopted to synthesize nanoparticles including “bottom-up” approaches such as precipitation, sol-gel and pyrolysis and “top-down” approaches such as mechanical milling, nanolithography and thermal decomposition. Simply put, a process of nanoparticle formation can be broken down into the general stages: initiation of reaction by physical activation or mixing, nucleation, particle growth and particle formation . By changing the reaction parameters and conditions, nanoparticles of different sizes and morphologies can be formed. Because of the random nature in macro-environments, it is technically challenging to control mixing and separation of particles in a batch reactor. This results in variations in size of the nanoparticles and batch-to-batch variations . Issues with size distribution as well as scale-up difficulties have driven the development of microfluidic devices that can prepare nanoparticles in a reproducible and high-throughput manner. Microfluidics is an emerging research field providing efficient tools within multiple research areas. A review about other microfluidic applications is available here.
3. Nanoparticle production with microfluidics
Microfluidic devices are designed to manipulate fluids in channels on the microscale, and have widely been used in the field of nanotechnology. Nanoparticle synthesis in microfluidic systems is performed in microreactors that have inner dimensions usually smaller than 1 mm. Microreactors can be of tubular designs and perhaps more commonly of lab-on-chip designs. Chips are often fabricated in polymers such as PDMS or glass. Xu et al.  demonstrated the advantages of microfluidic devices over bulk synthesis in terms of reaction yield and improved size and shape distribution. Also various shapes of non-spherical particles can be synthesized with microfluidic systems .
Microfluidic systems for nanoparticle synthesis can be divided into two general categories:
1. Single-phase continuous flow systems
Figure 2. Schematic illustration of different nanoparticle synthesis approaches. (a) batch approach; (b) single-phase flow; (c) gas-liquid multiphase flow; (d) liquid-liquid multiphase flow. Image from Ma et al. “Controllable synthesis of functional nanoparticles by microfluidic platforms for biomedical applications” .
Single-phase continuous flow systems
The single-phase continuous flow system was the first type of microfluidic device utilized for nanoparticle fabrication. Various types of nanoparticles, such as metal colloids , quantum dots  and liposomes , have been effectively fabricated through self-assembly and nanoprecipitation in single-phase systems.
Figure 3. Picture of a single-phase continuous flow system for nanosynthesis. Image from Wang et al. ”A rapid pathway toward a superb gene delivery system: programming structural and functional diversity into a supramolecular nanoparticle library” 
In a single-phase system, continuous laminar flow streams of single or multiple fluids flow through microchannels where nucleation and growth take place. The system ensures a homogenous environment throughout the reaction, as well short distances for diffusion and fast mixing and stirring. Mixing occurs primarily through diffusion across laminar flow streams. The geometries of the microfluidic channel can be utilized to precisely control mixing and reaction times, resulting in reproducible formation of nanoparticles of desired size and shape. Single-phase systems offer continuous modification in terms of allowing subsequent addition of reagents throughout the reaction and multi-step synthesis. They can also be scaled up as multiple reactions can be carried out in parallel, even on the same chip.
Microfluidic devices with multiphase flows, also referred to as segmented flows or droplet microfluidics, comprise two or several immiscible fluids in segmented phases. The flow phases can be liquid-liquid flows (often water-in-oil or oil-in-water) or gas-liquid flows. The discrete segments act as small individual reaction chambers, where mixing is generated within each segment as the segments move inside the channels . Like in single-phase systems, the geometries of the microchannels are designed to optimize reaction time and mixing. The very small volume of the droplet, typically on the picoliter scale, favours efficient thermal exchange and high reaction speed.
Compartmentalisation of reactions reduces the risk of contamination and channel clogging, resulting in a highly reproducible nanoparticle production with a small size distribution . However, the multiphase systems are less flexible than the single-phase systems in terms of continuous modification, as it is difficult to add reagents to the encapsulated droplets. Like single-phase systems, multiphase systems can be parallelized to increase throughput.
Figure 4. Optical images of a device for gold nanoparticle synthesis; (1) Droplet formation, (2) Picoinjection, (3) Mixing and (4) Droplet collection. Image from Abalde-Cela et al. “Droplet microfluidics for the highly controlled synthesis of branched gold nanoparticles” .
4. Advantages of microfluidic nanoparticle production
Microfluidic systems have presented several advantages for nanoparticle production over conventional batch synthesis. A list of advantages and disadvantages of microfluidic devices for nanoparticle synthesis compared to conventional synthesis is summarized below .
|Advantages||Disadvantages / Challenges|
|+ High reproducibility of synthesis||- Risk of fouling and channel clogging|
|+ Low reagent consumption||- Nanoparticles can diffuse through PDMS matrix|
|+ Convenient control of experimental parameters||- Not fully automated – labour-intensive|
|+ Better mixing||- Complex device design|
|+ Potential integration of online optimization andfeedback control||- Sometimes requiring special equipment such ascleanroom facilities|
|+ Reduced synthesis time+ Scale-up potential|
Importantly, in flow systems the nucleation, growth and formation stages can be spatially separated to occur at different places, whereas in batch synthesis they occur simultaneously in the reactor. In batch reactors, agglomeration inevitably starts to occur at a certain point of growth due to lack of mixing and separation of particles, resulting in a wider size and shape distribution . Another advantage of separating the phases in microfluidic devices is that each part of the device can be adapted for the specific conditions of the synthesis phase that occurs there. This facilitates high-throughput and process scale-up.
Fine-tuning of parameters
In microfluidic systems various experimental parameters including temperature, pH, concentration of reagents and flow velocity can be conveniently controlled and fine-tuned to fabricate nanoparticles of desired characteristics . Due to the small dimensions of microfluidic devices, fast and efficient temperature changes or can be induced. An easy way of varying parameters enables better control of the reactions and the possibility for fast screening to find optimal reaction conditions. Microfluidic devices have also opened up for new possibilities of sensor integration and online characterisation, for process optimization and real-time feedback control.
Passive and active mixing are key concepts in microfluidic nanoparticle formation. As most microfluidic devices work at laminar flow, the primary mixing is diffusion between flow streams. The mixing time in a continuous microfluidic channel can be estimated from the equation:
where w is the channel width, D is the diffusivity of the solvent in the core stream, R is the ratio of the core stream rate to the total flow rate of surrounding streams . Hence mixing time can be controlled by appropriate chip design and manipulating flow rates. To improve mixing performance, single-phase systems often comprise structures such as t-junctions, y-junctions, capillary and coaxial tubes, hydrodynamic flow focusing, herringbone mixer and micro mixing-based reactors. Some of these mixing techniques are illustrated in figure 4.
Figure 4. Common microfludic mixing techniques (a) Y-shaped microfluidic device, image from  (b) T-shapred microfluidic device, image from  (c) Hydrodynamic flow focusing device, image from  (d) Herringbone micromixer, image from .
5. Application of nanoparticles synthesized in microfluidic systems
As previously mentioned, several types of organic and inorganic nanoparticles have successfully been fabricated in microfluidic devices. To illustrate the versatility and improved outcome of nanoparticles produced in microfluidic systems, a short selection of examples of their biomedical applications is presented here. Several comprehensive review articles have already been published on the topic, and the examples below relies on some of the sources presented therein [7, 15, 21].
Microfluidic synthesis of nanoparticles for imaging
Metallic nanoparticles are of great interest in biomedical imaging due to their optical and plasmonic properties. Their potential has been realized for applications in fluorescence imaging or as contrast agents in magnetic resonance imaging (MRI). The common approach to microfluidic metal nanoparticle synthesis has been mixing streams of a metal salt with a reducing agent. Wagner et al.  synthesized gold nanoparticles in a microfluidic device using a single-phase flow, from the reagents gold salt (HAuCl4) and a reducing agent (ascorbic acid). The device allowed convenient optimisation of parameters to obtain a narrower size distribution compared to conventional batch synthesis. Another group, Hassan et al. , first reported a proof-of-concept for continuous multistep microfluidic self-assembly of fluorescent, plasmonic, and magnetic nanoparticles. Their device was made up of two coupled Y-shaped glass microreactors (figure 5.). They observed a reduced synthesis time from hours in batch synthesis to a few minutes with the microfluidic device.
Figure 5. Illustration of a multistep device for continuous-flow synthesis of magnetic and fluorescent nanoparticles. Image from Hassan et al. “Multistep continuous-flow microsynthesis of magnetic and fluorescent gamma-Fe2O3@SiO2 core/shell nanoparticles .
Microfluidic synthesis of nanoparticles for drug delivery
Biodegradable polymers that release a drug after their degradation have been widely used for drug delivery . Microfluidic-synthesized nanoparticles have shown better drug loading capabilities compared to batch-synthesized nanoparticles . The first polymeric drug loaded nanoparticles fabricated in microfluidic devices, were synthesized by precipitation in a hydrodynamic flow focusing chip in PDMS by the group Farokhadz et al. . Their method has been used to fabricate various types of nanoparticle. Also, lipid-polymer nanoparticles, which are problematic to synthesize with batch-approaches, have been fabricated with desired characteristics in microfluidic devices . The recently emerging field “organ-on-a-chip” has introduced a new type of platforms for evaluation and screening of drug delivery systems. Organ-on-a-chip platforms are a group of microfluidic systems that aim to mimic specific functions of one or multiple organs. They can be used for fast screening to study the performance of drug delivery systems, aiming to accelerating the clinical translation of drug delivery nanoparticles .
Microfluidic synthesis of nanoparticles for biosensing
Introducing nanomaterials to biosensing applications has led to enhanced performance in terms of increased sensitivity, lower detection limits and broad detection ranges. Plasmonic nanoparticles (often gold or silver) has lately been a subject of interest, due to their localized surface plasmon resonance (SPR) phenomena which can be utilized for biosensing. As their SPR frequency is dependent on size, shape and local atmosphere of the particles (among other factors), particle size and shape must be precisely controlled during synthesis.
Microfluidic synthesis of these metal nanoparticles have shown advantages over the conventional synthesis methods, including better size and shape control, increase in reaction yield, and rapid mixing . Polydiacetylene is another type of nanomaterial that has been used for biosensing as it experiences a change in colour in response to various factors such as variations in pH and temperature. Baek et al.  successfully synthesized polydiacetylene nanoparticles in a microfluidic chip with high reproducibility and adjustable size by varying the flow rate (figure 6).
Figure 6. Illustration of the experimental setup for single-phase continous flow synthesis of polydiacetylene nanoparticles for sensing applications in a herringbone mircomixer microfluidic chip. Image from Baek et al. ”Nanoscale diameter control of sensory polydiacetylene nanoparticles on microfluidic chip for enhanced fluorescence signal” .
6. Conclusions on microfluidics nanoparticle synthesis
Microfluidic systems have demonstrated great potential as platforms for synthesis of both organic and inorganic nanoparticles with well-controlled size and shape. Improved techniques for synthesis resulting in higher quality of produced nanoparticles is expected to accelerate the research of nanoparticles for biomedical applications. The obvious challenge of microfluidic nanoparticle production lies in the translation of proof-of-concept stage to clinical and industrial practice. Other practical challenges in fabrication, automation and channel clogging must also be addressed. Nevertheless, microfluidic systems are very promising for solving some of the current challenges and speed up the development of up-scale, cost-effective nanoparticle synthesis.
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