Research On The Formation Mechanism And Drug Release Property Of Calcium Alginate Microspheres Based On Microfluidic Method

Chronic diseases usually require long-term treatments by direct injection or oral administration of drugs,which can cause great physical and psychological pain to patients,and drugs reaching the focal area through the blood system can result in low drug utilization and side effects to the human body.Calcium alginate is an FDA-approved biocompatible material for biopharmaceutical applications,and its complex gel network structure facilitates drug storage and release,making calcium alginate microspheres an important application in the field of controlled drug release.Calcium alginate microspheres as drug carriers should have the property of high sphericity,good monodispersity,and uniform size,which are conducive to the sustained and stable release of drugs.It is important to study different morphology,size,and structure of microspheres and explore the corresponding drug release pattern and drug delivery mode to meet the therapeutic needs of different kinds of diseases.At present,the microspheres prepared by traditional technologies(spray drying technology,technology,emulsification/gel technology,etc.)are not uniform in size and poor in morphological controllability;microfluidic technology can prepare uniform size of sodium alginate droplets,but the technical defects in the gelation process cause the microspheres to be easily deformed.To meet the requirements of intravenous drug delivery(microsphere size should be smaller than red blood cells),there is a lack of research on the regulation of microsphere size(<10μm)of calcium alginate microspheres and the corresponding drug release pattern.If calcium alginate microspheres were encapsulated by other layer,the drug release time could be increased.Besides,single emulsion microfluidic device can not prepare multiple emulsified droplets.To address the above problems,this paper investigates the preparation process of calcium alginate microspheres with different morphology,size,and structure based on microfluidic technology,and explores the drug release pattern and drug delivery mode of the corresponding microspheres.Firstly,an oil phase gelation reaction system for calcium alginate microspheres was proposed,and the calcium alginate microspheres with high sphericity were fabricated by adjusting the concentration of calcium ions in a microfluidic chip.We investigated the swelling and drug release properties of different types of calcium alginate microspheres and selected high sphericity microspheres suitable for intradermal drug delivery.The therapeutic effect of high sphericity drug-delivery microspheres on a mouse model of acute kidney injury was investigated by subcutaneous injection into the kidney,and the results showed that our method could improve the kidney function in mice.Then,the microfluidic channel structure was designed using AutoCAD software,and the PDMS microfluidic chip was prepared by photolithographic processing,chemical etching,and ion bonding processes.Based on this microfluidic chip and the above calcium alginate microsphere gel reaction system,calcium alginate microspheres with size less than 10μm were successfully prepared.We controlled the size of microspheres from about 3μm to 7μm by the flow rate ratio of internal and external phases and the concentration of sodium alginate.We studied the swelling and drug release properties of calcium alginate microspheres.The use of intravenous injection for the treatment of mice with acute kidney injury showed that the kidney function had improved considerably.Finally,a controlled phase separation system was designed to achieve the preparation of complex structured calcium alginate-based composite microspheres in a simple single emulsion microfluidic chip while achieving the encapsulation of calcium alginate microspheres.The phase separation process of droplets was analyzed,and the structure of microspheres was controlled by the phase separation time.The drug release experiments showed that the drug release time of encapsulated calcium alginate microspheres was greatly prolonged and different structures of microspheres had different drug release patterns.In addition,the combination of graphene oxide and near-infrared light enabled the active regulation of the drug release pattern of the microspheres,and the type of microspheres suitable for oral drug delivery was selected Oral feeding experiments of drug-loaded microspheres on diabetic mice showed that the microspheres could protect insulin from destruction by gastric acid and release insulin continuously in intestinal fluid,which had a significant effect on blood glucose reduction.