Graphically-Encoded Biodegradable Microspheres with Hydrogel Shell for Sustained Release of Drugs at Controlled Rates

Biodegradable microparticles have been widely used as an efficient drug delivery platform. Several biocompatible and biodegradable polymers, including polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), and polycaprolactone (PCL), have been used as matrix materials to encapsulate lipophilic drugs and control their release. To create microparticles containing the drugs, polymers are dissolved in a volatile organic solvent in conjunction with drugs, then emulsified and consolidated. Lipophilic drugs are released from the microparticles over a sustained period of time. As the polymer matrices biodegrade from the surface by the hydrolysis of ester groups in the backbones of the polymers, the microparticles impede an initial burst of drugs which can exert damaging effects on the biological integrity of the protein.<br/>These microparticles are generally in the form of oil-in-water emulsion templated microbeads. When the polymeric microbeads are implanted into tissue, however, the surfaces can undergo uneven degradation and the rate of drug release will vary particle by particle. It deteriorates the controllability over a consistent rate of release.<br/>Here, we microfluidically produce PLA microspheres enclosed by a hydrogel shell for sustained release at controlled rates. As the PLA microspheres do not directly contact with other microspheres due to the presence of the hydrogel shell, it reduces particle-by-particle variation regarding the degradation rate. Also, the hydrogel shell slows down the release rate as the degradation of the PLA core proceeds only by slow diffusion through the hydrogel shell. In this regard, we control the density of the hydrogel shell to elaborately alter the degradation rate of PLA. As the density of the hydrogel shell increases, the rate of degradation decreases so that the encapsulants can be released for an extended period of time. Therefore, the release rate can be adjusted to suit the type and dose of the drugs. To distinguish each microsphere with a different concentration of encapsulants and shell density, we graphically encode the PLA microspheres with different types of photolithographically featured SU-8 particles. These particles work as an indicator to readily recognize the content of the PLA microspheres and the release behavior of the drugs with the naked eye.<br/>Using a glass capillary microfluidic device, monodisperse oil-in-water-in-oil (O/W/O) double-emulsion droplets are produced. PLA and alpha-tocopherol (aTOC), which is an antioxidant that supports the immune system and reduces the risk of blood clots, are dissolved in toluene and used as the innermost phase of double-emulsion droplets. As the toluene evaporates completely, PLA is consolidated to form a solid microsphere. To enclose the PLA microspheres with a hydrogel, an aqueous solution of biocompatible sodium alginate and a complex of calcium-ethylenediaminetetraacetic acid (Ca-EDTA) is used as the middle water phase. When the double-emulsion droplets are collected in the mineral oil containing acetic acid, alginate is crosslinked by calcium ions dissociated from the Ca-EDTA complexes, forming the hydrogel shell. To further crosslink the alginate gel and make the hydrogel shell denser, the microcapsules are transferred to an aqueous solution of calcium chloride which can provide additional calcium ions to the alginate chains.<br/>We disperse different types of alphabet-shaped SU-8 particles in the innermost phase depending on the concentration of aTOC in the core and calcium chloride in the aqueous medium. For example, the microcapsules containing 1, 5, and 10 w/w% of aTOC in the core are encoded with ‘a’, ‘b’ and ‘c’ particles, respectively. When the microcapsules are transferred to 0, 20, 50 w/w% of aqueous calcium chloride solutions, they are encoded with ‘A’, ‘B’ and ‘C’ particles. Therefore, we can easily and precisely differentiate the composition and release rate of each microcapsule even if they are all mixed.