Continuous fabrication of monodisperse polylactide microspheres by droplet-to-particle technology using microfluidic emulsification and emulsion–solvent diffusion

Abstract

Monodisperse polylactide (PLA) microspheres were continuously fabricated by microfluidic emulsification and subsequent dilution into water. The diameter was precisely tuned from 6 to 50 µm by changing the flow rate of the fluids in microfluidics or the PLA concentration in the dispersed phase. The use of amphiphilic oil-soluble poly(ethylene glycol)-b-polylactide (o-PEG-PLA) as a matrix resulted in a highly porous microsphere morphology, and the porosity was controlled by blending PLA. Therefore, monodisperse PLA microspheres with the predetermined surface porosity were continuously produced by just enough reagents and energy. Biodegradable polymeric microspheres have been developed for use in the chemical industry such as in coatings, inks, agrichemicals, foods, and drug delivery carriers. 1-3 In particular, polylactide (PLA) has attracted a great deal of attention all over the world in recent decades because it is producible from renewable resources. PLA is also well known for its biodegradability and biocompatibility. It breaks down into lactic acid units that are nontoxic to the human body. In general, PLA microspheres are prepared by the emulsion-solvent evaporation technique. 4-6 However, this technique has drawbacks such as the presence of toxic solvent residues in the end products, requirement for multi-step preparation, and polydispersity in the microsphere diameter. During emulsion preparation, although dichloromethane (DCM) is commonly used as the organic solvent because of good solubility of PLA and its high volatility, which facilitates easy evaporation from the emulsion droplets, it is harmful to human health so that complete removal of it from the products is required. Surfactants used for emulsification also should be eliminated because of these were non-essentials of human body. Multi-step preparation of microspheres results in greater equipment investment and the total production cost. Moreover, monodispersity in microsphere diameter enhances the quality of final products in all applications and saves further separation processes. In drug delivery applications, for example, monodisperse carriers decrease undesirable side effects and achieve precise control of drug release kinetics and encapsulation efficiency. In recent years, preparation methods for monodisperse microspheres have been developed. For example,

Fabrication of porous polymer microspheres by tuning amphiphilicity of the polymer and emulsion–solvent evaporation processing

“…Compared with nonporous ones, porous microspheres possess excellent permeability, relatively low density and high surface area, which are promising in the fields of gas storage, drug storage and delivery, catalysis, solid phase organic and peptide synthesis, and ion-exchange [1][2][3][4][5][6][7]. Many approaches for the fabrication of porous microspheres have been developed, including seeding emulsion, suspension or dispersion polymerization, internal phase-separation approach and microfluidics assisted route [8][9][10][11][12]. Porous polymer spheres with various structures at different scales can be generated by these methods.…”

Advanced materials and processing for drug delivery: The past and the future

“…A range of organic (PLA [151, 161] and PLGA [156, 157]) and inorganic (chitosan [172, 173], poly(N-isopropylacrylamide) pNIPAAM [133, 134, 152, 155], hydrogelator [153], silk protein [135], pectin [175], hydrazide and aldehyde-functionalized carbohydrates [158], dextranhydroxyethyl methacrylate (dex-HEMA) [166] and silica [154]) materials have been investigated for microparticle formation through generation of liquid precursor droplets in microfluidics prior to solidification by solvent extraction or induced polymerization (Figure 4b). Furthermore, porous microparticles are also fabricated with the help of microfluidics to facilitate drug release.…”

“…Furthermore, porous microparticles are also fabricated with the help of microfluidics to facilitate drug release. The use of poly(ethylene glycol)-b-polylactide (PEG–PLA), which is oil-soluble, as gel matrix in O/W emulsion leads to the formation of a reverse micelle structure with a small amount of water encapsulated within, creating pores upon freeze drying [151]. PEG has also been used as porogens during the formation of porous pNIPAAM microparticles [155].…”

PLA micro- and nano-particles

“…The polymer solution in the organic solvent is filled in a T-or Y-junction microfluidic device and then ejected into a large amount of stabilizing solution. The solvent is diffused from droplets into the water phase, and then the droplets are solidified to microspheres due to the relatively different solubility of the solvent in water [2,15,74,75]. When the polymer solution droplets are ejected into the stabilizing solution, the size of the particles are determined by properties of the solutions (density and viscosity), the flow rate of the polymer solution, the diameter of the nozzle, and the interfacial tension between the polymer solution and the nozzle tip.…”