CN110564009B - Composition for treating skin inflammation - Google Patents
Composition for treating skin inflammation Download PDFInfo
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- CN110564009B CN110564009B CN201910770951.XA CN201910770951A CN110564009B CN 110564009 B CN110564009 B CN 110564009B CN 201910770951 A CN201910770951 A CN 201910770951A CN 110564009 B CN110564009 B CN 110564009B
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- sodium
- cellulose derivative
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明实施例涉及一种组合物，所述组合物用作悬浮生物3D打印支持材料，所述组合物包括卡波姆、纤维素衍生物、钠离子和水。该组合物悬浮支持性能好、生物相容性好、易用性强、适用范围广。
Embodiments of the present invention relate to a composition for use as a suspension bio-3D printing support material, the composition comprising carbomer, a cellulose derivative, sodium ions and water. The composition has good suspension support performance, good biocompatibility, strong usability and wide application range.
Description
Technical Field
The invention belongs to the technical field of biological 3D printing, and particularly relates to a composition.
Background
Biological 3D printing is an important additive manufacturing technique for biological tissue engineering, drug testing, and regenerative medicine. The technology is used for positioning and assembling biological ink or other materials by using a biological 3D printer, finally constructing a biological structure with biomedical functions or activities, and manufacturing devices such as tissues and organs, medical instruments, transplants and the like.
Conventional biological 3D printing techniques typically print from bottom to top with support from the bottom of a container (e.g., a culture dish or multi-well plate) to form a biological structure. As biological structures manufactured by biological 3D printing become more complex, the traditional biological 3D printing technology cannot meet the manufacturing requirements of the biological structures.
In order to expand the application range of the biological 3D printing technology, the suspended biological 3D printing technology is developed and applied to the field, and the biological structure is constructed in a container filled with a suspended printing support material, so that a three-dimensional biological structure with a complex structure, such as a blood vessel and a blood vessel branch, an organ or tissue with a cavity or a complex grid, a slender or thin-walled structure and the like, can be manufactured. As a new biological 3D printing mode, the technology has great development potential. One key in the biological 3D printing technique of suspension lies in suspension printing supporting material, and suspension printing supporting material needs to have suitable holding power, guarantees that printing structure does not take place deformation and other unfavorable changes before printing process and taking out to can print the suitable time after the end and print the structure phase separation, should also possess the shear and thin fast, the performance of quick recovery after the shear stops.
Suspended biological 3D printing support materials commonly used in the prior art include gelatin, alginic acid, nanoclay, pluronic, and the like. These materials have major drawbacks: gelatin, pluronic and the like are temperature-sensitive materials, the temperature needs to be strictly controlled in the printing process, otherwise, the mechanical property of the materials is changed, and the printing effect is influenced; alginic acid is a chemical crosslinking material, has high requirements on solution components, can generate crosslinking interference if certain ions exist, and has narrow application range; the nano clay is inorganic silicate, has poor biocompatibility and is not beneficial to living cell printing. In summary, a support material for 3D printing of suspended organisms with good suspension support performance, good biocompatibility and wide application range is still lacking in the prior art.
Disclosure of Invention
In order to solve at least one of the above technical problems, embodiments of the present invention propose a composition.
<1> a composition for use as a suspended organism 3D printing support material, the composition comprising carbomer, a cellulose derivative, sodium ions and water.
<2> the composition as stated in <1>, the mass volume ratio of the carbomer is 0.5-2%, preferably 0.7-1.2%, more preferably 0.9%, and the mass volume ratio of the carbomer is the ratio of the mass of the carbomer to the total volume of the composition at normal temperature, and the unit is g/mL.
<3> the composition as stated in <1> or <2>, wherein said carbomer is one or more of Carbopol 940, Carbopol 941, Carbopol 934, Carbopol 1342, Carbopol 980, Carbopol ETD 2020, Carbopol AQUA SF-1, Carbopol Ultrez 21, Carbopol Ultrez 20.
<4> the composition as stated in any one of <1> to <3>, wherein the cellulose derivative has a mass-to-volume ratio of 0.5 to 10%, preferably 1 to 3%, more preferably 1%, and the mass-to-volume ratio of the cellulose derivative is a ratio of the mass of the cellulose derivative to the total volume of the composition at ordinary temperature, and is expressed in g/mL.
<5> the composition as stated in any one of <1> to <4>, wherein the cellulose derivative is one or more of methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, wood pulp nanocellulose.
<6> the composition as stated in any one of <1> to <5>, wherein the cellulose derivative is a cellulose derivative having a degree of substitution of between 0.4 and 3, preferably 1.2 to 1.5.
<7> the composition as stated in any one of <1> to <6>, wherein the mass-to-volume ratio of sodium ions is 0.3 to 0.4%, and the mass-to-volume ratio of sodium ions is a ratio of the mass of sodium ions to the total volume of the composition at room temperature, and is in g/mL.
<8> the composition as stated in any one of <1> to <7>, wherein at least a part of the sodium ions is provided by sodium chloride, the mass volume ratio of the sodium chloride is 0.7-0.9%, and the mass volume ratio of the sodium chloride is the ratio of the mass of the sodium chloride at normal temperature to the total volume of the composition, and the unit is g/mL; preferably, the sodium ions are provided by one or more of sodium hydroxide, sodium bicarbonate, sodium carbonate and sodium chloride.
<9> the composition as claimed in any one of <1> to <8>, further comprising a first component, the first component being one or more of polyethylene glycol, polyvinyl alcohol, polysorbate, sodium hyaluronate.
<10> the composition according to <9>, wherein the mass-to-volume ratio of the first component is 0.5 to 40%, preferably 0.8 to 5%, more preferably 1 to 2%, and the mass-to-volume ratio of the first component is the ratio of the mass of the first component to the total volume of the composition at normal temperature, and is in g/mL.
<11> the composition as stated in <9> or <10>, the molecular weight of the polyethylene glycol is in the range of 200-3000, preferably 800-2000.
<12> the composition as stated in <9> or <10>, wherein the mass-to-volume ratio of the sodium hyaluronate is less than 2%, and the mass-to-volume ratio of the sodium hyaluronate is a ratio of a mass of the sodium hyaluronate to a total volume of the composition at room temperature, and is expressed in g/mL.
<13> the composition as claimed in any one of <1> to <12>, further comprising one or more of cell culture medium, buffer, xanthan gum.
<14> the composition as stated in <13>, wherein the cell culture medium is DMEM, RPMI, MEM or Ham's.
<15> the composition as stated in <13>, wherein the cell culture medium is a cell culture medium containing a phenol red indicator.
<16> the composition as <13>, wherein the buffer is used for maintaining the pH of the composition at 7.2-7.4.
<17> the composition as stated in <13>, wherein the buffer is a PBS phosphate buffer.
<18> the composition as stated in <13>, the mass volume ratio of the xanthan gum is 0.25-4%, and the mass volume ratio of the xanthan gum is the ratio of the mass of the xanthan gum to the total volume of the composition at normal temperature, and the unit is g/mL.
<19> the composition as set forth in any one of <1> to <18>, further comprising a cell culture additive.
<20> the composition of <19>, wherein the cell culture additive is one or more of ions, regulators, and nutrients.
<21> the composition as claimed in any one of <1> to <8>, which consists of carbomer, a cellulose derivative, sodium chloride and water.
<22> the composition as claimed in any one of <1> to <11>, which consists of carbomer, a cellulose derivative, sodium chloride, polyethylene glycol and water.
<23> the composition as set forth in any one of <1> - <11>, <13>, which consists of carbomer, cellulose derivative, sodium chloride, polyethylene glycol, cell culture medium and water.
<24> the composition as stated in any one of <1> - <23>, which simultaneously satisfies the following conditions:
(1) the viscosity eta of the composition is not less than 20 Pa.s at 25 ℃ and under a static state,
(2) at 25 ℃, when the shear rate is switched from d (gamma)/dt < 0.251/s to d (gamma)/dt < 10001/s, the viscosity of the composition is reduced within 1s to eta <2 Pa.s;
(3) the viscosity of the composition is restored to above 20 Pa.s within 2s when the shear rate is reduced from d (gamma)/dt ≥ 10001/s to d (gamma)/dt ≤ 0.251/s at 25 ℃.
The embodiment of the invention has the following beneficial effects: the composition provided by the embodiment of the invention can be used for suspended organism 3D printing, and has the advantages of good suspension support performance, good biocompatibility, strong usability and wide application range.
Drawings
FIG. 1 shows the results of rheological measurements at 4 ℃ for the composition of example 9 according to the invention.
FIG. 2 shows the results of the rheological measurements at 25 ℃ of the composition of example 9 according to the invention.
FIG. 3 shows the results of the rheological measurements at 37 ℃ of the composition of example 9 according to the invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to specific embodiments below. Those skilled in the art will appreciate that the present invention is not limited to the drawings and the following examples.
The inventors have conducted a great deal of research to find suitable support materials for 3D printing of suspended organisms, and the present invention is based on the following findings of the inventors: carbomer can provide viscoelastic support, but the shearing healing speed is low, a gap is formed after the printing head moves in the carbomer, the carbomer cannot be quickly recovered, so that biological ink enters the gap due to capillary action, the capillary phenomenon is extremely unfavorable for biological 3D printing, and therefore the carbomer alone cannot meet the requirement of being used as a suspended biological 3D printing support material.
In the present invention, the term "mass-to-volume ratio" means the ratio of the mass of a certain component to the total volume of the composition at ordinary temperature (m/v) in g/mL.
Composition comprising a metal oxide and a metal oxide
Embodiments of the present invention provide a composition that can be used for biological 3D printing, the composition comprising carbomer, a cellulose derivative, sodium ions, and water. The composition can be used as a suspended organism 3D printing support material and is in a colloid shape.
In the composition according to the embodiment of the present invention, preferably, the mass volume ratio of the carbomer is 0.5 to 2%, preferably 0.7 to 1.2%, and more preferably 0.9%.
Such as one or more of Carbopol 940, Carbopol 941, Carbopol 934, Carbopol 1342, Carbopol 980, Carbopol ETD 2020, Carbopol AQUA SF-1, Carbopol Ultrez 21, Carbopol Ultrez 20, different types of carbomers having different rheological properties, and being adaptable to different printing materials and printing speeds. In the embodiment of the invention, the carbomer can be a single type of carbomer or a mixture of different types of carbomers. Carbomers of embodiments of the present invention are not limited to the above-mentioned types.
The carbomer provides a basic structure of suspending gel (gelbarh) for the composition, is a long-chain linear polymer, is interwoven into a net shape after absorbing water to form a supporting structure with certain viscoelasticity, so that the composition has low fluidity, the static state of the composition is maintained under a non-shearing state, and the suspending support property is provided for a printed biological structure.
According to the composition of the embodiment of the present invention, preferably, the cellulose derivative has a mass volume ratio of 0.5 to 10%, preferably 1 to 3%, and more preferably 1%.
The cellulose derivative is one or more of methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose and wood pulp nanocellulose. It should be noted that the term "cellulose derivative" in the present invention includes wood pulp nanocellulose. In the embodiment of the present invention, the cellulose derivative may be one cellulose derivative, or may be a mixture of a plurality of cellulose derivatives. The cellulose derivatives of the embodiments of the present invention are not limited to the above.
According to the composition of the embodiment of the present invention, preferably, the cellulose derivative has a degree of substitution of between 0.4 and 3, preferably 1.2 to 1.5.
The cellulose derivative in the composition can enable the composition to be thinned rapidly when being sheared and recover rapidly after being sheared so as to reduce capillary phenomenon in biological 3D printing, and can play roles in thickening and reducing fluidity so as to enable the composition to be kept in a static state under a non-shearing state and provide suspension support.
According to the composition of the embodiment of the invention, preferably, the mass volume ratio of the sodium ions is 0.3-0.4%. More preferably, at least a part of the sodium ions is provided by sodium chloride, and the mass volume ratio of the sodium chloride is 0.7-0.9%. More preferably, the sodium ions can also be provided by one or more of sodium hydroxide, sodium carbonate and sodium bicarbonate and sodium chloride which are used as acidity regulators.
The sodium ions are used for maintaining the ion osmotic pressure of the composition within a range suitable for the cells to live, keeping the normal shape of the cells and preventing water absorption, swelling and breaking or water loss.
The composition provided by the embodiment of the invention can support a biological structure to be kept stable when the composition is static through the synergistic cooperation of the carbomer and the cellulose derivative, can be quickly thinned to contain the 3D printed biological structure when the printing head moves quickly, can be quickly restored to be static after the printing head moves, has small interlayer disturbance, and can be used as a support material for 3D printing of suspended organisms.
The composition according to the embodiment of the present invention, in a preferred embodiment, further includes a first component, and the first component is one or more of polyethylene glycol, polyvinyl alcohol, polysorbate, and sodium hyaluronate.
When the composition comprises the components such as polyethylene glycol, polyvinyl alcohol, polysorbate, sodium hyaluronate and the like, multiple technical effects can be brought: the composition can avoid the layering of a composition system and the uneven distribution of components, thereby improving the stability of the composition; the lubricating property of the composition can be improved, the viscosity of the composition during shearing is reduced, the movement resistance of a printing head is reduced, and the printing head can move smoothly in the composition during printing without stagnation or excessive adhesion of the composition; it also makes it possible to increase the transparency of the composition, thus facilitating the observation of biological structures and in particular of biological inks based on photocrosslinking; and also as a cosolvent when the suspension printing support material contains a poorly compatible pharmaceutical ingredient (such as phenobarbital, loratadine, etc.).
In the composition according to the embodiment of the present invention, preferably, the mass volume ratio of the first component is 0.5 to 40%, preferably 0.8 to 5%, and more preferably 1 to 2%.
In the composition according to the embodiment of the present invention, preferably, the first component is polyethylene glycol. The polyethylene glycol has the advantages of no toxicity, low cost, stable production process and good reagent consistency.
In the composition according to the embodiment of the present invention, the molecular weight of the polyethylene glycol is preferably in the range of 200-. In the embodiment of the invention, the polyethylene glycol can adopt polyethylene glycol with a certain molecular weight, and can also adopt a mixture of polyethylene glycols with different molecular weights.
In the composition according to the embodiment of the present invention, the polyvinyl alcohol may be a polyvinyl alcohol having a certain molecular weight or a mixture of polyvinyl alcohols having different molecular weights. The polyvinyl alcohol can serve as a cosolvent or a dispersant when the suspension printing support material contains a poorly soluble pharmaceutical ingredient (e.g., phenobarbital, loratadine, etc.).
According to the composition of the embodiment of the invention, the mass volume ratio of the sodium hyaluronate is preferably less than 2%. Sodium hyaluronate can provide a milder extracellular environment when printing certain cells, such as chondrocytes or keratocytes, etc.
The polysorbate can act as a co-solvent when the suspension printing support material contains a poorly dispersible pharmaceutical ingredient (e.g., a macromolecular protein drug).
In another preferred embodiment, the composition according to an embodiment of the present invention further comprises one or more of cell culture medium, buffer, xanthan gum.
According to the composition of the embodiment, preferably, the cell culture medium is, for example, DMEM, RPMI, MEM, Ham's, or the like. One skilled in the art will be able to select an appropriate cell culture medium as a component of an embodiment composition of the invention depending on the target biological structure to be printed. The cell culture medium can provide nutritional support for cells during biological 3D printing and simulate a growth environment.
In accordance with the compositions of the embodiments, the cell culture medium is preferably a cell culture medium containing a phenol red indicator. The pH of the composition can be indicated when a cell culture medium containing a phenol red indicator is used. The composition is reddish to red in color when the cell culture medium contains the phenol red indicator, colorless or yellowish in color when the phenol red indicator is not contained, and has good transparency when the composition contains the first component.
Preferably, the buffer is used to maintain the pH of the composition at 7.2-7.4 in the compositions according to embodiments of the present invention. Preferably, the buffer is PBS phosphate buffer. The buffer is used for maintaining a stable pH environment of the composition.
According to the composition of the embodiment of the invention, preferably, the mass volume ratio of the xanthan gum is 0.25-4%. The xanthan gum is a polysaccharide product obtained by fermenting xanthomonas campestris, is non-toxic, has better biocompatibility than carbomer, can be co-cultured with cells, can play a thickening role in the composition, enables the composition to be uniformly dispersed, has a stable system, and can improve the printing survival rate of the cells particularly when the cells with lower survival rate (such as stem cells or part of primary cells) are printed.
Compositions according to embodiments of the present invention, in another preferred embodiment, any of the foregoing compositions may further comprise cell culture additives, such as one or more of ions (e.g., zinc ions, selenium-containing ions), regulators (e.g., insulin, transferrin, ethanolamine), nutrients (e.g., glutamic acid, serum, sodium pyruvate, etc.).
Compositions according to embodiments of the present invention, in one preferred embodiment, consist of carbomer, a cellulose derivative, sodium chloride and water.
In another preferred embodiment, the composition according to the embodiments of the present invention consists of carbomer, a cellulose derivative, sodium chloride, polyethylene glycol and water.
In another preferred embodiment, the composition according to embodiments of the present invention consists of carbomer, a cellulose derivative, sodium chloride, polyethylene glycol, cell culture medium and water.
The composition according to the embodiment of the present invention preferably satisfies the following conditions at the same time:
(1) the viscosity eta of the composition is not less than 20 Pa.s at 25 ℃ and under a static state,
(2) at 25 ℃, when the shear rate is switched from d (gamma)/dt < 0.251/s to d (gamma)/dt < 10001/s, the viscosity of the composition is reduced within 1s to eta <2 Pa.s;
(3) the viscosity of the composition is restored to above 20 Pa.s within 2s when the shear rate is reduced from d (gamma)/dt ≥ 10001/s to d (gamma)/dt ≤ 0.251/s at 25 ℃.
The above components suitable as constituents of the compositions of the embodiments of the present invention are all commercially available products known to those skilled in the art and belonging to the prior art.
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited to these examples.
In the above table, "√" indicates that the corresponding components are added to the example.
In examples 1 to 11, the contents of carbomer, cellulose derivative, sodium ion, polyethylene glycol, polyvinyl alcohol, sodium hyaluronate, xanthan gum and polysorbate were all in terms of mass to volume ratio and the unit was g/mL. Wherein, the polyethylene glycol is a product of aladdin company; sodium hyaluronate is a product of TCI company and is obtained from rooster comb; xanthan gum is a product of Sigma company, 80 meshes; polysorbate is Polysorbate-80; the buffer solution is PBS phosphate buffer solution of BI company, and the pH value is 7.4; the cell culture medium is DMEM medium manufactured by GIBCO company.
In the above examples, the carbomer used in examples 1, 2, 4, 6, 8-11 was Carbopol 940, and the carbomer used in examples 3, 5, 7, 12 was Carbopol 941.
In the above examples, the cellulose derivative used in examples 1, 3, 5, 7, 10 and 12 was hydroxypropylmethylcellulose, the hydroxypropylmethylcellulose was a product of aladdin, examples 2, 4, 6, 8, 9 and 11 were carboxymethyl cellulose, the carboxymethyl cellulose was a product of aladdin, carboxymethyl cellulose II, and the degree of substitution was 1.2.
In the above examples, the molecular weight of the polyethylene glycol used in examples 2 to 4 and 9 was 2000, and the molecular weight of the polyethylene glycol used in example 12 was 1000.
The experimental results show that the compositions obtained in examples 1 to 12 are all suitable as support materials for suspended biological 3D printing. The compositions of examples 2-12 were in a transparent or translucent state.
Method for preparing composition
In one embodiment, a method of formulating a composition of an embodiment of the present invention comprises the steps of:
-deionized water is mixed with carbomer or sodium chloride aqueous solution is mixed with carbomer to make carbomer uniformly distributed;
-deionized water is thoroughly mixed with the cellulose derivative or an aqueous sodium chloride solution is thoroughly mixed with the cellulose derivative to uniformly distribute the cellulose derivative;
-if necessary, adjusting the pH value using an acid-base modifier, such as one or more of sodium hydroxide, sodium carbonate or sodium bicarbonate, to maintain the pH value in the range of 7.2-7.4, i.e. in the neutral to slightly alkaline range;
-pre-calculating the total sodium ion concentration such that the sodium ion concentration is maintained within a range close to physiological conditions, the acidity regulator providing a deficiency in the content of sodium ions, supplemented with sodium chloride.
When the composition comprises one or more of polyethylene glycol, polyvinyl alcohol, polysorbate, sodium hyaluronate, such components are typically added last to aid in the thorough mixing of the other components.
When the composition comprises a cell culture medium, it may be mixed uniformly with the cellulose derivative solution and then with the other components, and the sodium ions in the cell culture medium are counted when calculating the sodium ion concentration.
In particular, when the compositions of the present embodiments are used for suspended organism 3D printing of living cells, contamination should be avoided when formulating the compositions so as to affect the printing results, sterilization steps of the containers, materials should be included when formulating, and the formulating process should be performed aseptically.
Mode of use of the composition
When printing a target biological structure, using the composition as a suspension printing support material, placing a printing head in the composition, printing according to a preset printing mode, extruding biological ink in the composition, and gradually accumulating the biological ink to form the biological structure; and after the biological ink is crosslinked to form a stable biological structure, taking the biological structure out of the composition, flushing the composition for dissolving the surface of the biological structure by using normal saline or a cell culture medium, and culturing the cleaned biological structure in a cell culture system.
Rheological Properties of the composition
With reference to fig. 1-3, the rheological parameters of the composition of example 9 of the present invention were determined.
The apparatus used was: antopa MCR302 rotational rheometer.
The rotor model: CP50-1/TG-SN 24764; d is 0.099 mm.
And (3) testing conditions are as follows: 4 ℃/25 ℃/37 ℃ and normal pressure.
The test method comprises the following steps: the 3iTT test, 3iTT test, is a common test for thixotropy of materials, where a polymeric material is first tested for low shear rate (or static) viscosity, then suddenly changed to a high shear rate after a period of time, and then returned to the low shear rate (or static) after a period of time, and this test is used to observe the change in viscosity of the polymeric material at different shear rates, and the rheological properties of the composition of example 9 are tested using this method.
The test results were as follows:
in fig. 1 to fig. 3, the ordinate represents viscosity values, where η 0 represents the viscosity value at a shear rate d (gamma)/dt of 0.251/s, η 1 represents the viscosity value at a shear rate d (gamma)/dt of 10001/s, η 2 represents the viscosity value at a shear rate d (gamma)/dt of 20001/s, and η 3 represents the viscosity value at a shear rate d (gamma)/dt of 30001/s.
(1) The composition continuously maintained a high viscosity at 4 ℃ at a shear rate d (gamma)/dt ═ 0.251/s, with viscosity values fluctuating between 52.1 and 52.6 Pa.s; the composition continuously maintained a high viscosity at 25 ℃ at a shear rate d (gamma)/dt ═ 0.251/s, the viscosity number fluctuating between 40.0 and 41.7 Pa.s; at 37 ℃ and a shear rate d (gamma)/dt of 0.251/s, the composition continuously maintained a high viscosity, the viscosity value fluctuating between 40.0 and 40.4 Pa.s.
(2) At 4 ℃, the shear rate is switched from d (gamma)/dt ═ 0.251/s to d (gamma)/dt ═ 10001/s, the composition is thinned rapidly (namely, the viscosity is reduced), the viscosity change response time is less than or equal to 0.5s, the viscosity is kept stable during shearing, and the viscosity value fluctuates between 0.353 and 0.356 Pa.s; at 25 ℃, the shear rate is switched from d (gamma)/dt (0.251/s) to d (gamma)/dt (10001/s), the composition is thinned rapidly, the viscosity change response time is less than or equal to 0.5s, the viscosity is kept stable during shearing, and the viscosity value fluctuates between 0.305 and 0.308 Pa.s; at 37 ℃, the shear rate is switched from d (gamma)/dt ═ 0.251/s to d (gamma)/dt ═ 10001/s, the composition becomes thin rapidly, the viscosity change response time is less than or equal to 0.5s, the viscosity remains stable during shearing, and the viscosity value fluctuates between 0.280 and 0.281Pa · s.
(3) At 4 ℃, the shear rate is switched from d (gamma)/dt ═ 0.251/s to d (gamma)/dt ═ 20001/s, the composition is thinned rapidly, the viscosity change response time is less than or equal to 0.5s, the viscosity is kept stable during shearing, and the viscosity value fluctuates between 0.227 and 0.228Pa · s; at 25 ℃, the shearing rate d (gamma)/dt is 0.251/s and is switched to d (gamma)/dt is 20001/s, the composition is thinned rapidly, the viscosity change response time is less than or equal to 0.5s, the viscosity is kept stable during shearing, and the viscosity value fluctuates between 0.197 and 0.198 Pa.s; at 37 ℃, the shearing rate d (gamma)/dt is 0.251/s and is switched to d (gamma)/dt is 20001/s, the composition is thinned rapidly, the viscosity change response time is less than or equal to 0.5s, the viscosity is kept stable during shearing, and the viscosity value fluctuates between 0.180 Pa.182 Pa.s.
(4) At 4 ℃, the shear rate is switched from d (gamma)/dt ═ 0.251/s to d (gamma)/dt ═ 30001/s, the composition is thinned rapidly, the viscosity change response time is less than or equal to 0.5s, the viscosity is kept stable during shearing, and the viscosity value is stabilized at 0.178 Pa.s; at 25 ℃, the shear rate is switched from d (gamma)/dt ═ 0.251/s to d (gamma)/dt ═ 30001/s, the composition is thinned rapidly, the viscosity change response time is less than or equal to 0.5s, the viscosity is kept stable during shearing, and the viscosity value is stabilized at 0.153 Pa.s; at 37 ℃, the shear rate is switched from d (gamma)/dt ═ 0.251/s to d (gamma)/dt ═ 30001/s, the composition becomes thin rapidly, the viscosity change response time is less than or equal to 0.5s, the viscosity remains stable during shearing, and the viscosity value is stable at 0.141 pas.
(5) When the shear rate is switched from d (gamma)/dt (10001/s), 20001/s and 30001/s to d (gamma)/dt ≤ 0.251/s at 4 deg.C, 25 deg.C and 37 deg.C, the viscosity of the composition is restored to 10 pas or more in 1s, to 20 pas or more in 1.5 s and to 30 pas or more in 5 s.
The test shows that: 1. the composition has a high viscosity at rest or under low shear and a low viscosity change at low shear, providing sufficient, stable suspension support; 2. when the temperature is changed within the range of 4-37 ℃, the viscosity value of the composition is stable, the composition is insensitive to the temperature, and the requirement on temperature control of biological printing is lower; 3. when the low-speed shearing state (D (gamma)/dt is less than or equal to 0.251/s) or the static state is switched to the high-speed shearing state (D (gamma)/dt is more than or equal to 10001/s), the composition can be thinned quickly, the viscosity can be recovered quickly when the high-speed shearing state is switched to the low-speed shearing state or the static state, the viscosity change response time is short, the capillary phenomenon of the biological ink during 3D printing of suspended organisms can be greatly reduced, the form of a biological structure can be stabilized, the retardation phenomenon of the printing head moving in the composition can be reduced due to quick reduction of the viscosity, and the adhesion of the composition on the printing head can be reduced; 4. when the shear rate is changed, the viscosity change value of the composition is basically irrelevant to the temperature, and when the shear rate is switched at different temperatures, the composition can be quickly thinned and quickly recovered, and the requirement on temperature control during bioprinting is low.
Biocompatibility of the composition
Illustratively, the present invention takes the composition of example 9 as an example to verify its biocompatibility.
Using the composition of example 9 as a suspension printing support material, a bio-ink (SunP Gel G1, SunP Biotech, main component Gel-MA) having a mass volume ratio of photo-curable gelatin of 10% was added to the bio-ink with xanthan gum having a mass volume ratio of 0.5% to thicken it, to increase the printing speed. The printer is a Sunp Biomaker bio 3D printer. Mixing the biological ink with human non-small cell lung cancer cells (A549), and printing a 0.9cm double-layer square grid-shaped biological structure for 30 min. And after printing, using blue light to irradiate and crosslink to obtain a solidified Gel-MA biological structure body, taking the biological structure body out of the suspension printing support material, washing and soaking the biological structure body by a DMEM culture medium, and culturing at the constant temperature of 37 ℃.
The biological structure can be stably suspended in the composition during printing using the composition of example 9 of the present invention as a suspension printing support material, and the biological structure is kept intact in shape during the movement of the printing head.
After 5 days (120h) and 10 days (240h) of culture of the biological structure, the survival condition of the cells and the structure is good. In addition, the migration and aggregation proliferation of cells in the biological structure can be observed by optical microscope observation. Calcein-AM/PI living and dead staining is carried out on cells in the biological structure, the cells are observed by using a laser confocal microscope, the cell activity is good and the survival rate is more than 85 percent according to the judgment of static and three-dimensional images, and the composition disclosed by the embodiment 9 of the invention has good biocompatibility and is suitable for being used as a support material for 3D printing of suspended organisms.
The invention creatively selects a plurality of common agents as the components of the composition, and the obtained composition has the performance far superior to various support materials mentioned in the background technology when being used for suspending the support materials for biological 3D printing. The composition of the embodiment of the invention has the following technical effects of good suspension support performance; the ink has good biocompatibility and no toxic or side effect on cells, is suitable for printing biological ink containing living cells, and has wide application range; the rapid shear thinning and the stop shear rapid recovery can keep the target structure in situ static without dislocation in the printing process, ensure the integrity of the biological structure body and reduce the capillary phenomenon of the biological ink; when polyethylene glycol and other components are added, the transparency is high, the photocuring time is short, and the requirements on the illumination intensity and the illumination wavelength are looser; the ink can be compatible with various common cell culture media, supports printing of various common living cells, and is also suitable for complex structures containing no cell ink; various other cell culture additives can be added to meet individual requirements; the viscosity is slightly changed by temperature, and when the shear rate is changed, the change value of the viscosity is basically irrelevant to the temperature, so that the method is suitable for chemical crosslinking and temperature crosslinking of biological ink; has no pungent odor.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (33)
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