CN113813893B - Method for preparing silk fibroin drug delivery capsule based on microfluidic chip - Google Patents
Method for preparing silk fibroin drug delivery capsule based on microfluidic chip Download PDFInfo
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- CN113813893B CN113813893B CN202111227824.9A CN202111227824A CN113813893B CN 113813893 B CN113813893 B CN 113813893B CN 202111227824 A CN202111227824 A CN 202111227824A CN 113813893 B CN113813893 B CN 113813893B
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Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/14—Polymerisation; cross-linking
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5052—Proteins, e.g. albumin
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a method for preparing a silk fibroin drug delivery capsule based on a microfluidic chip, which belongs to the technical field of drug preparation and prepares a water phase; crosslinking the water phase and the oil phase in a channel in the confocal micro-fluidic chip, and collecting and preparing oily drug drops wrapped by the water phase from an outlet of the channel to obtain a drug delivery microcapsule; the concentration of the water phase, the flow velocity of the water phase in the channel, the flow velocity of the oil phase in the channel and the geometric dimension of the confocal micro-fluidic chip are controlled, so that the regulation and control of the drug carrying capacity and the capsule wall thickness are realized. The method has the advantages of convenient operation and high preparation efficiency, oily medicine liquid drops with single distribution size can be prepared by controlling the concentration of the silk fibroin aqueous solution, the flow rates of the aqueous phase and the oil phase, the geometric dimension of the chip and other parameters, and the regulation and control of medicine carrying capacity, capsule wall thickness and the like can be realized; the capsule wall has high strength, high biocompatibility, better biodegradability and interfacial activity.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a method for preparing a silk fibroin medicine delivery capsule based on a microfluidic chip.
Background
Packaging and controlled delivery of bioactive materials is an important bottleneck in the design of current biomaterials. For example, in tumor therapy, how to disperse an effective drug in a stable carrier, selectively released at the lesion site to reduce adverse effects; or in biochemical reactions, individual cells are isolated in microreactors to isolate external disturbances.
Microcapsules of a size on the order of microns can provide complete barrier protection for bioactive materials and allow release thereof at a designed time or target location, and are ideal packaging delivery vehicles. In the daily chemical industry, microcapsule technology is used to separate the components in the product and prevent the interference between the different components. The preparation method of the microcapsules can be divided into two main types, namely top-down and bottom-up.
The production of a colloid consisting of microcapsules by stirring two incompatible phases at high speed, which is common in industrial production, is a top-down process under the action of an emulsifier. However, this drastic approach is not suitable for bioactive materials that are relatively sensitive to external stimuli and that have poor processability. In contrast, in microfluidic chips, the disturbance created by the flow field breaks one of the two incompatible liquid phases flowing continuously in the microchannel into droplets dispersed in the other continuous phase, a gentle, highly controllable, bottom-up approach.
The technology for preparing the microcapsule by using the liquid drop microfluidic chip only needs to use a trace amount of raw materials, and the preparation process of the microcapsule is accurately controlled by simple steps. Meanwhile, the microfluidic chip can be made of glass or resin materials with high transparency, and the microcapsule preparation process with high repeatability can realize complete real-time online observation. The channel size in a microfluidic chip is typically only a few times the microcapsule size. The channels, which are also of the order of micrometers, can be integrated or parallelized in large quantities, so that an efficient production of microcapsules is achieved while ensuring precise control. Digital PCR based on droplet microfluidic technology has been widely used to achieve absolute quantification of DNA molecules. In the future, the unique advantages of the droplet microfluidic technology can lead the technology to have huge application prospects in a plurality of hot fields such as a micro droplet reactor, drug transportation and release, tissue engineering, single cell package analysis and the like.
Disclosure of Invention
The invention aims to provide a method for preparing a silk fibroin drug delivery capsule based on a microfluidic chip by using silk fibroin as a reliable wall material, so as to solve at least one technical problem in the background technology.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the invention provides a method for preparing a silk fibroin drug delivery capsule based on a microfluidic chip, which comprises the following steps:
Preparing an aqueous phase;
crosslinking the water phase and the oil phase in a channel in the confocal micro-fluidic chip, and collecting and preparing oily drug drops wrapped by the water phase from an outlet of the channel to obtain a drug delivery microcapsule; the concentration of the water phase, the flow velocity of the water phase in the channel, the flow velocity of the oil phase in the channel and the geometric dimension of the confocal micro-fluidic chip are controlled, so that the regulation and control of the drug carrying capacity and the capsule wall thickness are realized.
Preferably, the aqueous phase is an aqueous silk fibroin solution.
Preferably, the oil phase is n-hexadecane (the n-hexadecane is obtained by filtering edible soybean oil).
Preferably, the organic solvent is added to regulate the crystallinity of the silk fibroin, so as to realize the regulation of the degradation time of the drug delivery microcapsule.
Preferably, the preparation of the aqueous silk fibroin solution comprises: degumming silkworm cocoons, dissolving the degummed silkworm cocoons in a salt solution, and then desalting to obtain a silk fibroin aqueous solution.
Preferably, the silk cocoons are boiled by using sodium bicarbonate aqueous solution to degumm, the degummed silk cocoons are dissolved in lithium bromide aqueous solution, and lithium bromide salt is removed by a dialysis method to obtain silk fibroin aqueous solution.
Preferably, the preparation method of the confocal micro-fluidic chip comprises the following steps:
Preparing a water phase channel, an oil phase channel and a crosslinking channel on the substrate by adopting a soft lithography method, and sealing the cover plate on the substrate; the water phase channel and the oil phase channel are communicated with each other, the water phase and the oil phase enter the cross-linking channel through the water phase channel and the oil phase channel respectively, cross-linking occurs in the cross-linking channel, and the drug delivery microcapsule is obtained from the outlet of the cross-linking channel.
Preferably, the base sheet and the cover sheet are both made of a confocal resin PMMA.
Preferably, two pneumatic pumps are used for respectively driving the oil phase and the water phase, the absolute flow rate and the relative flow rate of the oil phase and the water phase are adjusted by adjusting the driving pressure of the pneumatic pumps, and when the liquid drops of the water phase and the oil phase reach balance in the channel, the liquid drops are collected from the outlet.
Preferably, the water phase and the oil phase are respectively arranged in two pneumatic pump pressure bins, a polytetrafluoroethylene guide pipe is used for respectively guiding the water phase and the oil phase to the water phase channel and the oil phase channel, the connecting end of the guide pipe and the channel is connected with a silica gel plug, and a plastic threaded connector is used for winding a raw rubber belt for encapsulation.
The invention has the beneficial effects that: the operation is convenient, the preparation efficiency is high, oily medicine liquid drops with single distribution size can be prepared by controlling the concentration of the silk fibroin aqueous solution, the flow rates of the aqueous phase and the oil phase, the geometric size of the chip and other parameters, and the regulation and control of medicine carrying capacity, capsule wall thickness and the like can be realized; the capsule wall has high strength, high biocompatibility, better biodegradability and interfacial activity.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for the description of the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
Fig. 1 is a block diagram of a confocal micro-fluidic chip according to an embodiment of the present invention.
Wherein: 1-an aqueous phase channel; 2-oil phase channels; 3-crosslinking channels; 4-a catheter; 5-a substrate; 6-cover plate.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to like or similar elements throughout or elements having like or similar functionality. The embodiments described below by way of the drawings are exemplary only and should not be construed as limiting the invention.
It will be understood by those skilled in the art that, unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the prior art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
As used herein, the singular forms "a", "an", "the" and "the" are intended to include the plural forms as well, unless expressly stated otherwise, as understood by those skilled in the art. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, and/or groups thereof.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
In order that the invention may be readily understood, a further description of the invention will be rendered by reference to specific embodiments that are illustrated in the appended drawings and are not to be construed as limiting embodiments of the invention.
It will be appreciated by those skilled in the art that the drawings are merely schematic representations of examples and that the elements of the drawings are not necessarily required to practice the invention.
Example 1
The embodiment 1 of the invention provides a method for preparing a drug delivery capsule by adopting a confocal micro-fluidic chip, which adopts a soft lithography method to process an autonomously designed confocal resin (PMMA) chip and uses the chip to prepare oily liquid drops wrapped by regenerated silk fibroin. By controlling the concentration of the silk fibroin aqueous solution, the flow rates of the aqueous phase and the oil phase, the geometric dimension of the chip and other parameters, oily medicine liquid drops with single distribution size can be prepared, and the regulation and control of medicine carrying capacity, capsule wall thickness and the like can be realized.
As shown in fig. 1, the confocal resin (PMMA) chip includes a base sheet 5, a cover sheet 6, and the cover sheet 6 is capped on the base sheet 5. The substrate 5 is provided with a water phase channel 1, an oil phase channel 2 and a crosslinking channel 3, the water phase channel 1 and the oil phase channel 2 are communicated with the crosslinking channel 3 together, and water phase solution and oil phase can enter the crosslinking channel through the water phase channel and the oil phase channel respectively.
In this example 1, the chip preparation method:
A piece of PMMA sheet with micro channels machined according to CAD drawing was sealed with a piece of unpatterned PMMA sheet. After sealing, the channel may allow fluid at a pressure of about 300kPa to pass.
In this example 1, the droplet preparation step:
Extracting regenerated silk fibroin aqueous solution by using a dried silkworm cocoon; the oil phase adopts soybean oil; two pneumatic pumps are used for respectively driving the oil phase and the water phase, and two-phase liquid drops quickly reach equilibrium in the channel.
The adjustment of the absolute flow rate and the relative flow rate of the oil-water two phases can be realized by adjusting the driving pressure of the pneumatic pump, and the liquid drops can be collected from the outlet after being balanced.
And (3) flow rate control: the flow rate of the water phase and the oil phase can be observed by adopting the pneumatic pump for driving and connecting a flow rate meter in series.
Example 2
The embodiment 2 of the invention provides a method for preparing a drug delivery capsule by adopting a confocal micro-fluidic chip, which comprises the following steps:
Preparing an aqueous phase;
crosslinking the water phase and the oil phase in a channel in the confocal micro-fluidic chip, and collecting and preparing oily drug drops wrapped by the water phase from an outlet of the channel to obtain a drug delivery microcapsule; the concentration of the water phase, the flow velocity of the water phase in the channel, the flow velocity of the oil phase in the channel and the geometric dimension of the confocal micro-fluidic chip are controlled, so that the regulation and control of the drug carrying capacity and the capsule wall thickness are realized.
In this example 2, the aqueous phase is an aqueous silk fibroin solution. The oil phase is soybean oil or n-hexadecane.
In the preparation process of the drug delivery microcapsule in this example 2, the regulation of the degradation time of the drug delivery microcapsule is achieved by regulating the crystallinity of silk fibroin by adding an organic solvent.
The preparation of the aqueous silk fibroin solution comprises the following steps: degumming silkworm cocoons, dissolving the degummed silkworm cocoons in a salt solution, and then desalting to obtain a silk fibroin aqueous solution.
Specifically, in this example 2, cocoons were boiled with an aqueous sodium bicarbonate solution to be degummed, and then the degummed cocoons were dissolved in an aqueous lithium bromide solution, and the lithium bromide salt was removed by dialysis to obtain an aqueous silk fibroin solution.
In this example 2, the molar concentration of the aqueous sodium bicarbonate solution used was 0.02M, and the molar concentration of the aqueous lithium bromide solution used was 9.3M.
As shown in fig. 1, in this embodiment 2, preparing a confocal microfluidic chip includes:
preparing a water phase channel, an oil phase channel and a crosslinking channel on the substrate 5 by adopting a soft lithography method, and sealing a cover plate 6 on the substrate 5; the water phase channel 1 and the oil phase channel 2 are communicated with the crosslinking channel 3 together, the water phase and the oil phase enter the crosslinking channel 3 through the water phase channel 1 and the oil phase channel 2 respectively, crosslinking occurs in the crosslinking channel 3, and the drug delivery microcapsule is obtained from the outlet of the crosslinking channel 3.
In this embodiment 2, the base sheet and the cover sheet are made of PMMA.
Polydimethylsiloxane (Polydimethylsiloxane) is a hydrophobic silicone material. The polysiloxane has application in various fields of medicines, daily chemicals, foods, buildings and the like, the derivatives of the polysiloxane are hundreds, and the common polysiloxanes mainly comprise: polydimethylsiloxanes, cyclomethylsiloxanes, aminosilicones, polymethylphenylsiloxanes, polyether polysiloxane copolymers, and the like. Among them, cyclomethicone is one of the commonly used polysiloxanes.
The chemical dimethyl silicone oil of the polydimethylsiloxane has the advantages of no smell, high transparency, heat resistance, cold resistance, small viscosity change along with temperature, water resistance, small surface tension, heat conductivity coefficient of 0.134-0.159W/(m.K), light transmittance of 100 percent, no toxicity and smell of the dimethyl silicone oil, and good chemical stability, and the appearance is changed from colorless transparent volatile liquid to extremely high viscosity liquid or silica gel according to different relative molecular masses. The electric insulation, weather resistance and hydrophobicity are good, and the anti-shearing capability is very high, and the anti-shearing agent can be used for a long time at the temperature of minus 50 ℃ to 200 ℃. The material has excellent physical properties, can be directly used for damp-proof insulation, damping, shock absorption, defoaming, lubrication, polishing and other aspects, and can be widely used as insulation lubrication, shock resistance, oil dust prevention, dielectric liquid and heat carrier. And can be used as defoaming agent, mold release agent, paint and daily chemical product additive.
The polydimethylsiloxane can be mixed with lanolin, stearyl alcohol, cetyl alcohol, glyceryl monostearate, tween, span, etc. to be used as emulsion matrix. The protective effect can be enhanced by adding film forming agent such as PVP, PVA, cellulose derivative, etc. The drug release and penetration into skin are faster than those of ragweed fat, lanolin and vaseline.
Polydimethylsiloxane can be used for electronic connectors and the like in the electrical and electronic industry; can be used for fiber and leather: water repellent, softener, hand feeling improver, defoamer for dyeing industry and lubrication of sewing thread. The emulsion can be applied to fatliquoring of leather, thereby enhancing the hydrophobicity, softness and comfort of leather. The leather surface treated with the said paint can raise wear resistance, waterproof performance and demolding performance. Can be used as a release agent for rubber or plastic products (brake plates, screw heads, plugs and the like) and EVA shoe materials, can be directly or diluted by 10-200 times by low-hardness water for use, and has high efficiency, stability and extremely wide application.
In this example 2, two pneumatic pumps were used to drive the oil phase and the water phase respectively, the absolute flow rate and the relative flow rate of the oil phase and the water phase were adjusted by adjusting the driving pressure of the pneumatic pumps, and the droplets of the water phase and the oil phase were collected from the outlet after they were equilibrated in the channel. The water phase and the oil phase are respectively arranged in two pneumatic pump pressure bins, a polytetrafluoroethylene guide pipe is used for guiding the water phase and the oil phase to the water phase channel and the oil phase channel respectively, the connecting end of the guide pipe and the channel is connected with a silica gel plug, and a plastic threaded joint is used for winding a raw rubber belt for encapsulation.
Example 3
The embodiment 3 of the invention provides a method for preparing a drug delivery microcapsule by adopting a confocal micro-fluidic chip, wherein a confocal resin (PMMA) chip is processed by adopting a soft lithography method, and oily liquid drops wrapped by regenerated silk fibroin are prepared by using the chip. By controlling the concentration of the silk fibroin aqueous solution, the flow rates of the aqueous phase and the oil phase, the geometric dimension of the chip and other parameters, oily medicine liquid drops with single distribution size can be prepared, and the regulation and control of medicine carrying capacity, capsule wall thickness and the like can be realized.
Polymethyl methacrylate (polymethyl methacrylate), PMMA for short, is a high molecular polymer, also called acrylic or organic glass, has the advantages of high transparency, low price, easy machining and the like, and is a glass substitute material which is commonly used.
PMMA has a lower density than glass: PMMA has a density of about 1.15-1.19g/cm 3, which is one half of that of glass (2.40-2.80 g/cm 3), and 43% of metallic aluminum (which is a light metal).
The mechanical strength of PMMA is higher: the PMMA has a relative molecular weight of about 200 ten thousand, is a long-chain high molecular polymer, and forms a molecular chain very soft, so that the PMMA has relatively high strength and 7-18 times higher tensile and impact resistance than common glass. There is a kind of organic glass which is heated and stretched, and the molecular chain segments are arranged in a very orderly manner, so that the toughness of the material is obviously improved. The nail is used to drive the organic glass, and even if the nail penetrates, no crack is generated. The plexiglas does not break into fragments after breakdown by a bullet. Thus, the drawn PMMA can be used as a bullet-proof glass and also as a canopy on a military aircraft.
PMMA has a lower melting point, much lower than the high temperature of about 1000 degrees glass.
PMMA has higher light transmittance
(1) Visible light: PMMA is the best polymer transparent material at present, and the light transmittance reaches 92 percent, which is higher than that of glass.
(2) Ultraviolet light: quartz is completely transparent to ultraviolet rays, but is expensive, and common glass can only transmit 0.6% of ultraviolet rays. PMMA can effectively filter ultraviolet light with the wavelength smaller than 300nm, but has poor filtering effect between 300nm and 400 nm. Some manufacturers coat the PMMA surface to increase its effectiveness and properties in filtering 300nm to 400nm ultraviolet light. On the other hand, PMMA has better stability under the condition of ultraviolet irradiation than polycarbonate
(3) Infrared rays: PMMA allows Infrared (IR) light at wavelengths less than 2800nm to pass through. IR at longer wavelengths, less than 25,000nm, may be substantially blocked. There is a special colored PMMA that can transmit a specific wavelength IR while blocking visible light (applied to remote control or thermal induction, etc.).
(4) The glass transition temperature of PMMA is about 105 ℃.
Because of the relatively large branched chain and relatively high viscosity of polymethyl methacrylate, the thermal processing method has relatively low processing speed, and the organic glass can be cut by a lathe, drilled by a drilling machine, and bonded into various shapes by using acetone, chloroform and other instruments, and can be processed into various products such as aircraft cabins, dentures, dental brackets and the like by using plastic molding methods such as blow molding, injection, extrusion and the like.
Cyanoacrylate, methylene chloride, chloroform, or the like can slightly dissolve the organic glass, and then the two pieces of organic glass can be firmly bonded together.
About 2 kg of petroleum is required to produce 1 kg of PMMA. In the presence of oxygen, PMMA begins to burn at 458℃, and carbon dioxide, water, carbon monoxide and some low molecular compounds including formaldehyde are produced after combustion.
PMMA has the advantages of light weight, low cost, easy molding, etc. And the organic silicon dioxide is dissolved in an organic solvent such as anisole, so that a good film and a good dielectric property can be formed, and the organic silicon dioxide can be used as a dielectric layer of an organic field effect transistor.
Its shaping method includes casting, injection moulding, machining and thermal moulding. In particular, the injection molding can be realized in mass production, the manufacturing process is simple, and the cost is low. Therefore, the device is widely applied to instrument parts, automobile lamps, optical lenses and transparent pipelines.
Application of organic glass acrylic (acrylic) in construction industry in construction, the organic glass acrylic (acrylic) is mainly applied to the aspects of construction lighting bodies, transparent roofs, shed roofs, telephone kiosks, stairways, room wall protection boards and the like; the sanitary ware includes bathtub, washbasin, dressing table, etc. The application development of the lamp shade and the automobile lamp for highway and high-grade road illumination is quite rapid. The market growth of the lighting body, the bathtub, the street advertising lamp box, the telephone booth and the like of the building is faster, the development space in the future is larger, and the market prospect is very broad.
In this example 3, the chip preparation method: is prepared by adopting a soft lithography method.
A piece of PDMS sheet with micro channels machined according to CAD drawings was sealed with a piece of non-patterned PDMS sheet. After sealing, the channel may allow fluid at a pressure of about 300kPa to pass.
Soft lithography (SoftLithography), also known as soft etching, is a fundamental technology applied to fabrication and microfabrication, which uses a polymer elastomer as a mask, stamp or template to fabricate nano-scale structures. Soft lithography refers to a collection of various process technologies for pattern lithography using soft stamps, including microcontact printing (μcp), nanoimprint lithography (NIL), molding (REM), micro transfer molding (μtm), capillary micro-molding (MIMIC), solvent assisted micro-molding (SAMIM), and the like.
The soft lithography process flow is as follows:
1. mask preparation: printing graphics on transparent film using high resolution laser photocopiers
2. Photoresist coating
3. And pre-baking the substrate coated with the photoresist to solidify the photoresist. The mask is placed on a substrate for exposure, and an ultraviolet light source, such as a mercury lamp, is usually used as a light source.
4. Fixing and post baking are carried out after development to ensure the flatness and firmness of the graph, and a step instrument is used for measuring the recording height;
5. pouring the stirred PMMA onto a mold, and obtaining the PMMA with the pattern after the PMMA is completely solidified;
6. At this time, hydrophilic or hydrophobic treatment can be carried out on the water phase or oil phase channels according to the requirement;
7. And (5) thermally sealing the PMMA chip.
REM-replica molding: REM technology creates complex surfaces by replica molding with a deformed PDMS mold, i.e., allows the size and shape of the mold surface features to be changed in a controlled manner (by mechanical compression, bending, stretching, or a combination of these deformations), and creates complex structures from simple, regular structures in the plane.
Mu TM-micrometastasis moulding: micro transfer molding (mu TM) is to coat liquid polymer prepolymer on the surface of a PDMS elastic mold to fill the mold, cover the mold on a substrate after removing excessive liquid, and excite the polymer to polymerize and solidify by radiation or heating. Removal of the mold leaves behind the corresponding microstructure on the substrate. The biggest advantage of mu (TM) over other methods is that multi-layered microstructures can be built on complex patterned structures and microstructures can be fabricated on non-planar surfaces.
Capillary micro-molding (MIMIC): fine molding is another non-photolithographic method that can form complex microstructures on flat or curved surfaces.
Solvent assisted micro-molding (SAMIM): solvent assisted micro-molding is a technique that allows the fabrication of patterns and quasi-three-dimensional microstructures on the surface of a polymeric substrate.
Soft lithography techniques make fabrication of nanoscale three-dimensional structures possible.
The preparation step of liquid drops:
Extracting regenerated silk fibroin aqueous solution by using a dried silkworm cocoon; the oil phase adopts soybean oil; two pneumatic pumps are used for respectively driving an oil phase and a water phase, and two-phase liquid drops quickly reach balance in a channel; the absolute flow rate and the relative flow rate of the oil-water two phases can be adjusted by adjusting the driving pressure of the pneumatic pump; after the droplet generation is equilibrated, it can be collected from the outlet.
And (3) flow rate control: the pneumatic pump is adopted for driving, and the flowmeter can be connected in series.
The silk fibroin solution phase and the soybean oil phase were placed in two pneumatic pump pressure chambers, respectively, and the liquid was introduced from the pressure pump to the chip using a PTFE catheter having an outer diameter of 1/16 inch. The street at the end of the conduit chip is connected with a silica gel plug, and a plastic threaded joint is used for winding a raw rubber belt for packaging.
The collected microcapsules can be treated by adding organic solvents such as methanol and ethanol, so that the crystallinity of the silk fibroin can be regulated and controlled, and the degradation time of the microcapsules can be regulated and controlled.
Silk fibroin solution extraction: boiling silkworm cocoons by using a low-concentration sodium bicarbonate aqueous solution to degumm the silkworm cocoons, dissolving the degummed silkworm cocoons in a high-concentration lithium bromide aqueous solution, and removing lithium bromide salt by a dialysis method to obtain a regenerated silk fibroin aqueous solution with the highest concentration of 35% in mass fraction.
In this example 3, the molar concentration of the aqueous sodium bicarbonate solution used was 0.02M, and the molar concentration of the aqueous lithium bromide solution used was 9.3M.
The foregoing description of the preferred embodiments of the present disclosure is provided only and not intended to limit the disclosure so that various modifications and changes may be made to the present disclosure by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present disclosure should be included in the protection scope of the present disclosure.
While the foregoing embodiments of the present disclosure have been described in conjunction with the accompanying drawings, it is not intended to limit the scope of the disclosure, and it should be understood that, based on the technical solutions disclosed in the present disclosure, various modifications or variations may be made by those skilled in the art without requiring any inventive effort, and are intended to be included in the scope of the present disclosure.
Claims (4)
1. A method for preparing a silk fibroin drug delivery capsule based on a microfluidic chip, comprising:
preparing an aqueous phase; the water phase is a silk fibroin water solution;
the crystallinity of the silk fibroin is regulated and controlled by adding an organic solvent, so that the degradation time of the drug delivery microcapsule is regulated and controlled;
Crosslinking the water phase and the oil phase in a channel in the confocal micro-fluidic chip, and collecting and preparing oily drug drops wrapped by the water phase from an outlet of the channel to obtain a drug delivery microcapsule; the concentration of the water phase, the flow velocity of the water phase in the channel, the flow velocity of the oil phase in the channel and the geometric dimension of the confocal micro-fluidic chip are controlled, so that the drug carrying capacity and the capsule wall thickness are regulated and controlled;
The microfluidic chip is made of high-transparency glass or resin material, and realizes complete real-time online observation on the highly repeatable microcapsule preparation process;
the preparation method of the confocal micro-fluidic chip comprises the following steps:
preparing a water phase channel, an oil phase channel and a crosslinking channel on the substrate by adopting a soft lithography method, and sealing the cover plate on the substrate; the water phase channel and the oil phase channel are communicated with each other together, the water phase and the oil phase enter the cross-linking channel through the water phase channel and the oil phase channel respectively, cross-linking occurs in the cross-linking channel, and the drug delivery microcapsule is obtained from the outlet of the cross-linking channel;
two pneumatic pumps are used for respectively driving the oil phase and the water phase, the absolute flow rate and the relative flow rate of the oil phase and the water phase are adjusted by adjusting the driving pressure of the pneumatic pumps, and when the liquid drops of the water phase and the oil phase reach balance in a channel, the liquid drops are collected from an outlet;
the water phase and the oil phase are respectively arranged in two pneumatic pump pressure bins, a polytetrafluoroethylene guide pipe is used for guiding the water phase and the oil phase to the water phase channel and the oil phase channel respectively, the connecting end of the guide pipe and the channel is connected with a silica gel plug, and a plastic threaded joint is used for winding a raw rubber belt for encapsulation;
The oil phase is n-hexadecane.
2. The method for preparing a silk fibroin drug delivery capsule based on a microfluidic chip of claim 1, wherein the preparation of the silk fibroin aqueous solution comprises: degumming silkworm cocoons, dissolving the degummed silkworm cocoons in a salt solution, and then desalting to obtain a silk fibroin aqueous solution.
3. The method for preparing a silk fibroin drug delivery capsule based on a microfluidic chip according to claim 2, wherein the silk cocoons are boiled with sodium bicarbonate aqueous solution to be degummed, the degummed silk cocoons are dissolved in lithium bromide aqueous solution, and lithium bromide salt is removed by dialysis to obtain silk fibroin aqueous solution.
4. The method for preparing a silk fibroin drug delivery capsule based on a microfluidic chip according to claim 1, wherein the substrate and the cover sheet are both made of confocal resin PMMA.
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