CN105617464A

CN105617464A - Macromolecule polymer scaffold material preparation method based on micro-fluidic technology

Info

Publication number: CN105617464A
Application number: CN201410629406.6A
Authority: CN
Inventors: 秦建华; 于跃; 张晓庆
Original assignee: Dalian Institute of Chemical Physics of CAS
Current assignee: Dalian Institute of Chemical Physics of CAS
Priority date: 2014-11-07
Filing date: 2014-11-07
Publication date: 2016-06-01

Abstract

The present invention provides a macromolecule polymer scaffold material preparation method based on a micro-fluidic technology. According to the method, a liquid droplet micro-fluidic device is used to rapidly produce a lot of uniform liquid droplets or spherical particles, and the liquid droplets or particles are adopted as the pore forming agent and are densely dispersed in an organic solvent with a dissolved macromolecule polymer so as to prepare the macromolecule polymer scaffold material with characteristics of specific morphology and uniform pore; the scaffold material prepared through the method has characteristics of uniform product, good repeatability, uniform pore distribution, uniform pore diameter, wide pore size adjustment range, controllable material shape, and the like; with the method, all preparation steps after the material feeding are completed by the one micro-fluidic device, the product collected from the micro-fluidic device terminal is the prepared final product, and the characteristics of full-automated preparation method and the like are provided; and the prepared scaffold material has the micron-scale size, is hopefully further amplified to the millimeter scale size even the centimeter scale size, and is suitable for being applied in micro-part tissue engineering.

Description

Preparation method based on the high molecular polymer timbering material of microflow control technique

Technical field

The invention belongs to the crossing domain of new material technology and microflow control technique, the preparation method being specifically related to a kind of high molecular polymer timbering material based on microflow control technique.

Background technology

The core of microflow control technique is micro-fluidic chip, also known as chip lab, refer to and the basic operation unit of Routine Test Lab is integrated on the chip of a piece several square centimeters (under even more), network is formed by microchannel, whole system is run through, in order to replace the various functions of Routine Test Lab with controlled fluid. In the last few years, microflow control technique had been widely used for micron order materials synthesis field. Material prepared by microflow control technique is utilized to have of a great variety, form of diverse, the features such as structure composition complexity is high and homogeneity is good, it has also become one of important method prepared by micron order material, there is vast potential for future development.

At first, in order to meet the needs of tissue engineering during the appearance of high molecular polymer timbering material. Seed cell is inoculated on timbering material and is transplanted to the internal injury repairing that realizes, or timbering material is directly filled in injury region, the three-dimensional environment of a self-regeneration is provided for injury region cell. This material is also used to build some bionical tissue models in vitro and provide support as bioreactor for a large amount of amplification cultivation of cell. Timbering material has hole through in a large number for growth and proliferation of cell more. Current timbering material is divided into natural and synthetic two kinds, and ideal has collagen, polylactic acid, Poly(D,L-lactide-co-glycolide, polyglycolic acid, hydroxyapatite etc. It is respectively used to structure and the reparation of particular organization's organ. Relative to natural polymeric material, the high molecular polymer of synthetic has definite ingredients, and physicochemical properties are adjustable, mechanical strength is good, non-immunogenicity, the advantage such as can be mass-produced, and obtains application widely in organizational project and regenerative medicine field.

Currently used high molecular polymer is prepared the method for timbering material and is broadly divided into phase inversion, thermally induced phase separation, melt spinning pulling method, nuclear track etching method. The porogen that these methods use also exists particle diameter and Density Distribution is uneven, aperture adjustable extent is limited, control the defects such as difficulty, cause that prepared timbering material distribution of pores and pore-size distribution are uneven, limit the further application of high molecular polymer timbering material to a certain extent.

Summary of the invention

The preparation method that it is an object of the invention to provide a kind of high molecular polymer timbering material based on microflow control technique. Relative to how empty timbering material prepared by traditional method, the features such as it has even pore distribution, and pore diameter is homogeneous, and aperture adjustable extent is wide, and material morphology is controlled, and preparation method is full-automatic. The timbering material size of preparation is at micron order, and is hopeful to be amplified to millimeter even Centimeter Level further. It is suitable for the application of some minute sites organizational projects.

The preparation method of the high molecular polymer timbering material of the uniform pores that the present invention introduces by means of the unique advantage of microfluidic platform, drop micro fluidic device is utilized to quickly generate a large amount of uniform drop or spheroidal particle, using drop or granule as porogen, intensive it is scattered in the organic solvent being dissolved with high molecular polymer, organic solvent is immersed in aqueous phase by recycling micro fluidic device mutually, make solvent diffuse, high molecular polymer precipitates out, after removing porogen, generate the timbering material with uniform pore.

Wherein spheroidal particle is by solidifying droplet formation, curing mode can be temperature or the phase in version of pH value induction, can also be light or thermocatalytic polyreaction, the removal of the former spheroidal particle can make convert return drop dissolution by adjustment temperature or pH value, and the removal of the latter's spheroidal particle can pass through chemical reaction or enzymatic degradation realizes.

When utilizing drop as porogen, it is necessary to add suitable surfactant, it is prevented that owing to solvent diffuse causes that liquor capacity shrinks, cause inner droplets to extrude and merge between the drop caused, cause pore failure. Drop or the small ball's diameter height prepared due to microfluidic methods are homogeneous, therefore also highly homogeneous using the hole of its porous support materials prepared as template. And its pore-size and porosity can be realized by size and the generating rate of adjustment drop or spheroidal particle, the size of drop and granule and generating rate can be realized by liquid flow rate in adjustment micro fluidic device easily. This control method and simply but highly effective. ,

When utilizing micro fluidic device to be immersed in aqueous phase mutually by organic solvent, organic solvent can be cut into drop mutually or be drawn into liquid stream, thus generating spherical or fibrous many empty timbering materials, the size of timbering material can be realized by liquid flow rate in the size of adjustment micro fluidic device and device, and the size range of the timbering material that can prepare is at micron order. And be hopeful to expand device structure further to prepare more large scale timbering material.

The inventive method completes from all preparation processes after reinforced by a micro fluidic device, has both been finished product to be prepared from the product collected by micro fluidic device terminal. Generation method is easy, and product is homogeneous, reproducible.

Accompanying drawing explanation

Fig. 1: micro fluidic device platform schematic diagram, mainly includes control system, sampling system, preparation system and monitoring system four part. The core that wherein prepared by execution material is micro-fluidic chip.

Fig. 2: drop micro-fluidic chip schematic diagram, is used for generating porogen drop or spheroidal particle, and forms polymer globules or fiber.

Fig. 3: generate the principle schematic of the high molecular polymer timbering material with homogeneous space.

Detailed description of the invention

Embodiment 1:

Do porogen with drop and prepare PLGA (PLGA) porous small ball

Preparation 2w/w%PVA aqueous solution, 1.5w/w%PLGA dichloromethane solution, and in PLGA solution, add 2w/w% surfactant Span80. Pure water is imported chip from porogen entrance, PLGA solution is imported chip from organic facies entrance, PVA solution is imported chip from aqueous phase entrance. At Microscopic observation and adjust each phase flow velocity, making pure water produce drop under the effect of PLGA solution, make PLGA solution produce drop under the effect of PVA solution, a large amount of pure water drops, much larger than pure water drop, are therefore wrapped in PLGA solution by PLGA solution droplets. Volatilization in making dichloromethane dissolve to PVA in microfluidic channel, PLGA precipitates out and solidify to form PLGA bead, due to the occupy-place effect of pure water drop, is internally formed hole at PLGA bead, pore size is proportional with the diameter of pure water drop, and porosity is proportional with the quantity of the pure water drop of parcel.

Embodiment 2:

Do porogen with microsphere and prepare polylactic acid (PLA) porous fibre

Preparation 7.5w/w% aqueous gelatin solution, 10w/w%PLA dichloromethane solution, the mixture of 1:1w/w glycerol and water. Aqueous gelatin solution is imported chip from porogen entrance, PLA solution is imported chip from organic facies entrance, glycerine water solution is imported chip from aqueous phase entrance. At Microscopic observation and adjust each phase flow velocity, making aqueous gelatin solution produce drop under the effect of PLGA solution, on chip, the position containing aqueous gelatin solution drop applies low temperature stimulation, is that aqueous gelatin solution is solidified into gelatin solid particle; PLA solution is made to form laminar flow under the effect of glycerine water solution, dichloromethane volatilization in passage, PLA is made to precipitate out precipitation, generate PLA fiber, owing to including a large amount of solid gelatinous granule inside PLA solution, therefore being formed hole by the position of gelatin particle in fiber forming process, pore size is proportional with the diameter of granule, and porosity is proportional with the quantity of the granule of parcel. Put it into after collecting PLA fiber in hot bath, be that gelatin particle is dissolved into liquid dissolution, obtain end-product.

Claims

1. the preparation method based on the high molecular polymer timbering material of microflow control technique, it is characterized in that: utilize drop micro fluidic device to quickly generate a large amount of uniform drop or spheroidal particle, using drop or granule as porogen, intensive it is scattered in the organic solvent being dissolved with high molecular polymer, organic solvent is immersed in aqueous phase by recycling micro fluidic device mutually, makes solvent diffuse, and high molecular polymer precipitates out, after removing porogen, generate the timbering material with uniform pore.

2. in accordance with the method for claim 1, it is characterized in that: described spheroidal particle is by solidifying droplet formation, curing mode can be temperature or the phase in version of pH value induction, can also be light or thermocatalytic polyreaction, the removal of the former spheroidal particle can make convert return drop dissolution by adjustment temperature or pH value, and the removal of the latter's spheroidal particle can pass through chemical reaction or enzymatic degradation realizes.

3. in accordance with the method for claim 1, it is characterized in that: when utilizing drop as porogen, it is necessary to add suitable surfactant, it is prevented that owing to solvent diffuse causes that liquor capacity shrinks, cause inner droplets to extrude and merge between the drop caused, cause pore failure.

4. in accordance with the method for claim 1, it is characterized in that: described in there is the timbering material of uniform pore, its pore-size and porosity can be realized by size and the generating rate of adjustment drop or spheroidal particle, the size of drop and granule and generating rate can realize by adjusting liquid flow rate in micro fluidic device easily, and the pore-size scope that can generate is the size range of drop that current drop microfluidic methods can be prepared or spheroidal particle.

5. in accordance with the method for claim 1, it is characterized in that: when utilizing micro fluidic device to be immersed in aqueous phase mutually by organic solvent, organic solvent can be cut into drop mutually or be drawn into liquid stream, thus generating spherical or fibrous many empty timbering materials, the size of timbering material can be realized by liquid flow rate in the size of adjustment micro fluidic device and device, and the size range of the timbering material that can prepare is at micron order.

6. in accordance with the method for claim 1, it is characterized in that: described in have the timbering material of uniform pore be that one-step method is formed, namely complete by a micro fluidic device from all preparation processes after reinforced, be both finished product to be prepared from the product collected by micro fluidic device terminal.