High-throughput Synthesis And Screening Of Calcium Phosphate Biomaterials Based On Microfluidic Technology

The formation of biological minerals in nature is a naturally occurring and highly controlled complex process.One of its important characteristics is the nucleation and growth of inorganic minerals under the regulation of organic substrates,and then self-assembly to form a highly ordered multi-level structure with unique excellent properties.As the main inorganic mineral component of biological hard tissue,calcium phosphate is widely used as a biomedical material because of its good biocompatibility and bioactivity.Calcium phosphate with different morphologies and chemical compositions showed significant differences in physical and chemical properties.High-throughput experiments can provide a large amount of data in a short period of time,effectively shorten the experiment cycle and accelerate the process of material research and development.Microfluidic chip technology has attracted extensive discussion because of its small size,high efficiency,low cost and easy operation.In this paper,a highthroughput experimental platform for biomimetic synthesis of calcium phosphate was designed by using microfluidic chip technology,and the range of conditions for synthesis of calcium phosphate with different morphologies was quickly screened and determined.The main contents are as follows:Firstly,a microfluidic high-throughput on-film synthesis and screening platform with a6×6 array microreactor was established,which consists of PDMS chips and assist devices.The platform can construct a stable and reliable concentration gradient,and has the advantages of high experimental efficiency,wide screening range,low energy consumption and relatively independent experimental environment.A collagen film with a smooth surface and a dense structure was prepared by solution spin coating,which was used as the substrate for the biomimetic microfluidic reaction.Secondly,the Ca/P ratio gradient was constructed using the microfluidics platform to quickly determine the range of Ca/P ratio in which the morphology of calcium phosphate changed from three-dimensional flower clusters to long strip structures,and to explore the potential mechanism of collagen film substrate promoting the formation of micro-flower structures.The concentration gradients of acidic amino acids,neutral amino acids and basic amino acids were constructed to synthesize calcium phosphate with various morphologies,and the concentration ranges of acidic amino acids were determined in which the structure of calcium phosphate changed from long strips to micro-flower or block-like aggregates;The concentration range of neutral amino acids from flower clusters to long strips;The concentration range of basic amino acids from spherical to nanometer short rods.Finally,by simulating the reaction conditions of the microfluidic experiment,a scale-up experiment environment consistent with the microreactor was constructed.The self-made PDMS orifice was used to synthesize calcium phosphate with different morphologies under the control of aspartic acid and arginine on the surface of the collagen film.The material is consistent with the microfluidic experiment results in terms of morphology,elements,phase and chemical composition,which verifies that this microfluidic platform has excellent stability and accuracy.In this study,a new method for the synthesis of biomimetic calcium phosphate materials was proposed,which expanded the application of microfluidic high-throughput technology,provided a large number of data for the screening of inorganic mineral calcium phosphate,provided parameter support for the theoretical study of biomineralization,and enriched the database of biomaterials.The designed microfluidic platform is universal and can be applied to the batch synthesis of other materials,significantly improving the efficiency of material research and development.