Preparation method and device of micro-fluidic dual-aqueous-phase monodisperse calcium alginate microspheres

Abstract

The invention discloses a preparation method of micro-fluidic dual-aqueous-phase monodisperse calcium alginate microspheres. The preparation method comprises the following steps: taking a polyethyleneglycol water solution as an outer aqueous phase, and glucan and a sodium alginate water solution as an inner aqueous phase; generating dual-aqueous-phase sodium alginate liquid drops at a conical sharp point through a coaxial capillary tube device; wherein the outer aqueous phase is continuous sample feeding; the inner aqueous phase is periodicity and intermittence sample feeding; introducing thedual-aqueous-phase sodium alginate liquid drops into a calcium chloride water solution to generate the needed monodisperse calcium alginate microspheres. According to the preparation method disclosedby the invention, sodium alginate or dual aqueous phases do not need to be subjected to a complicated pre-treatment process and a production manner is simple and rapid and has good biocompatibility;the formed microspheres are stable and the size of the microspheres is controllable; a device has the advantages of simple structure, flexibility and convenience for production, accuracy in operationand control and easiness for batch production.

Description

technical field [0001] The invention relates to a preparation method and device of calcium alginate microspheres, in particular to a preparation method and device of microfluidic two-phase monodisperse calcium alginate microspheres. Background technique [0002] Alginate gel microspheres have the characteristics of good biodegradability, biocompatibility, and non-toxicity. They can be used as carriers for encapsulating cells and drugs, and are widely used in drug delivery, drug release, enzyme engineering reactions, and 3D cell culture. ; At present, most of the traditional processes produce calcium alginate microspheres by dripping method, electrospray method, inkjet printing method, etc.; in 2016, Gu Xiaolong et al. Although this method can produce microspheres of uniform size, the size of the microspheres is large and cannot be adjusted; 2013 Alessandri et al. (Alessandri, Proceedings of the National Academy of Sciences of the United States of America, 2013,37,14843) Pra...

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Problems solved by technology

[0002] Alginate gel microspheres have the characteristics of good biodegradability, biocompatibility, and non-toxicity. They can be used as carriers for encapsulating cells and drugs, and are widely used in drug delivery, drug release, enzyme engineering reactions, and 3D cell culture. ; At present, most of the traditional processes produce calcium alginate microspheres by dripping method, electrospray method, inkjet printing method, etc.; in 2016, Gu Xiaolong et al. Although this method can produce microspheres of uniform size, the size of the microspheres is large and cannot be adjusted; 2013 Alessandri et al. (Alessandri, Proceedings of the National Academy of Sciences of the United States of America, 2013,37,14843) Practical inkjet printing method to produce alginate microgels, but the size of the produced alginate microgels is not uniform and the size is uncontrollable; in 2015 Nguyen et al. (Duy Khiem Nguyen, Advanced Healthcare Materials, 2015,10,1537) used Electrospray method is used to produce calcium alginate microgels, but the high-voltage electric field in this equipment can damage cells, and cells cannot be directly wrapped for subsequent operations, which limits the use of microgels

[0003] In recent years, single-size and controllable alginic acid microspheres can be produced using emerging microfluidic technology, but most microfluidic methods mainly use oil-water two-phase to generate water-in-oil alginic acid droplets to produce microspheres; Although this type of method can produce microspheres with good monodispersity, due to the introduction of oil phase and surfactant, the biocompatibility of microspheres can be reduced (Marcoux, Colloids and Surfaces A:Physicochemical and Engineering Aspects, 2011,377 ,54); In addition, when the oil-water sodium alginate droplet is introduced into the chip for cross-linking, the droplet will be deformed due to various unbalanced forces during the process of falling into the receiving liquid and when passing through the oil-water interface of the receiving liquid , the generated microspheres often have a "tail", which is in the shape of teardrops or tadpoles (Yung-Sheng Lin, Electrophoresis, 2013, 34, 425), and the sphericity is not good, which will affect the drug release effect

[0004] Aqueous solutions of polyethylene glycol and dextran at a certain concentration can spontaneously separate phases to form a two-phase aqueous system. Due to the good biocompatibility and selective distribution of this system, it is often used as a base for biological macromolecules such as proteins and nucleic acids. Separation and extraction; in recent years, the research on the preparation of calcium alginate microspheres by microfluidics has focused on the preparation of oil-water droplets, but few people have studied the preparation of calcium alginate microspheres with good biocompatibility two-water phase ; The reason is that the low surface tension and shear force between the two water phases are difficult to directly form stable droplets of water-in-water; sodium alginate needs to be pretreated, and the operation is cumbersome; 2017 Liu et al. (Yang Liu, Biomedical Microdevices, 2017, 19, 55) Aqueous two-phase calcium alginate microspheres can be prepared through PDMS microfluidic chips; however, this method not only needs to modify sodium alginate, but also uses oxidizing agents that affect biocompatibility and Catalase, while producing microspheres of non-uniform size

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