Preparation Of PEGDA Microspheres Containing Concentration-gradient Drugs Based On A Microfluidic Droplet Chip

Drug microsphere is a novel pharmaceutical dosage form.Microspheres have an enormous impact on medical technology since they enable flexible delivery of drugs with improved performance during the drug delivery and release process.The size of microspheres strongly affects their drug release profile,biodistribution and administration route,and the desired release effect can be achieved by utilizing their size-dependent feature.Recently,co-delivery of different actives has attracted increasing interest.With microfluidic techniques,monodisperse microparticles with controlled size can be generated,and drugs with desired dose can be precisely encapsulated in the microparticles.Thus,actives can be released at desired sites with controllable rate.While drugs and target substances are loaded in the microspheres simultaneously,targeted release of the drug can be achieved.In this paper,a multi-channel chip for generating droplet array was designed,and a variety of concentration gradient combinations of different substances could be formed.Based on the chip,polymer microspheres containing different concentrations of two anticancer drugs were prepared for screening the optimum synergistic concentration of the drugs.In chapter 1,microfluidic methods for preparing multi-functional particles were reviewed,including photolithographic techniques,micromolding methods and droplet template methods.Then the materials and methods for preparing drug microspheres were introduced.The microfluidic concentration-gradient generation techniques used in drug screening and controlled release were also summarized.Finally,the purpose and design of this work were proposed.In chapter 2,a multilayered PDMS chip for generating concentration-gradient droplets was manufactured.With Poly(ethylene glycol)diacrylate(PEGDA)as a carrier material,doxorubicin hydrochloride and paclitaxel as model drugs,multiple microspheres containing different concentration combinations of drugs were prepared.The configuration of chip was designd and optimized in the experiment.The effects of channel shape,depth and flow-rate on droplet formation were investigated.The coefficients of variation of the droplet size in each channel were 2.6%-5.4%(n=50),while the coefficient of variation in 8 channels was 5.0%(n=400).The trend of concentration gradient in the chip was almost the same as theoretically calculated values.By preparing the two-fluorescence-labeled microspheres,it was demonstrated that two materials with different hydrophilicity could be simultaneously loaded in PEGDA microspheres.Finally,microspheres containing eight different concentration combinations of drugs were prepared for inducing apoptosis of HeLa,and the optimum synergistic activity of two drugs was screened.In chapter 3,the method established in this work for preparation of PEGDA microspheres containing concentration gradient drugs was summarized,and their application prospects in the future were predicted as well.