Synthesis Of Calcium Alginate Micro/nanogels Based On 3D-printed Microfluidic Technology And Its Application In Drug Delivery

In recent years,alginate micro/nanogels has been widely used in the field of drug delivery due to its advantages of good biocompatibility,low toxicity and environmental responsiveness.Ionic crosslinking between alginate and CaCl₂ is the most common and simple method to prepare calcium alginate micro/nanogels.Gelation rate is a critical factor of controlling formation of calcium alginate micro/nanogels.However,high solubility of calcium ions in aqueous solution will lead to poorly controlled preparation of alginate hydrogels.In order to solve these problems,the paper prepared calcium alginate micro/nanogels based on a microfluidic chip with diffusion mixing pattern.Microfluidic technology,3D printing technology,computer software simulation technology and other technical are applied.Finally,the calcium alginate micro/nanogels were used in the delivery of anti-tumor drugs.In this paper,the microfluidic chip was fabricated by 3D printing technology firstly.The studies found that the microfluidic chip in this paper can achieve diffusion mixing with laminar flow structure under different regulatory parameters.Secondly,the diffusion efficiency and mixing efficiency were calculated by simulation software.Then particle size distribution of the products was measured by dynamic light scattering.The regulatory factors are initial concentration of the reactants,total flow rate,flow ratio and length of the channels.When the channel length and flow rate ratio increased,the diffusion rate increased,and the average particle size increased.However,the initial concentration and total flow rate have little effect on the mixing efficiency,diffusion rate and particle size distribution of the products.In this paper,calcium alginate micro/nanogels based on microfluidic were used in drug delivery.Doxorubicin and sanguinarine were wrapped.After the doxorubicin was wrapped,the particle size distribution of calcium alginate increased.The drug loading rate was maintained above 80%.The drug delivery system had pH-controlled release.At the cellular level,there was not toxicity of calcium alginate micro/nanogels to MCF-10A and MCF-7cells.After 72 hours,Dox-loaded CaA micro/nanogels significantly enhanced the cell killing rate against human breast cancer cell?MCF-7?with relative cell viability of 10.5%,while free Dox only inhibits the cell growth by 40%.Finally,the study realized loading of sanguinarine.The cell lethality of sanguinarine delivered calcium alginate micro/nanogels against human breast cancer cells?MDA-MB-231 cells?was 66.98%,which slightly higher than pure sanguinarine solution.In this paper,we successfully prepared calcium alginate micro/nanogels by microfluidic chip with diffusion mixing pattern based on microfluidic technology,3D printing technology and hydrogel technology.The core problem is cross-linking rate between alginate and free cation(such as Ca²⁺).The controllability of ion crosslinking rate and particle size were explored.The cell killing effect of calcium alginate micro/nanogels on breast cancer cells was also studied.The calcium alginate prepared by the microfluidic chip can efficiently load anti-tumor drugs.The drug delivery system has pH-controlled release performance and can enhance the lethality of doxorubicin or sanguinarine to tumor cells.The concentration-controlled 3D printing microfluidic chip to prepare calcium alginate micro/nanogels will have a wider range of biological applications.