CN117122724A - 3D printing cuttlebone elastic hemostatic support and construction method thereof - Google Patents
3D printing cuttlebone elastic hemostatic support and construction method thereof Download PDFInfo
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- CN117122724A CN117122724A CN202311142981.9A CN202311142981A CN117122724A CN 117122724 A CN117122724 A CN 117122724A CN 202311142981 A CN202311142981 A CN 202311142981A CN 117122724 A CN117122724 A CN 117122724A
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- hemostatic
- cuttlebone
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- elastic
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Classifications
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- A61L24/043—Mixtures of macromolecular materials
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
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- A61L24/001—Use of materials characterised by their function or physical properties
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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Abstract
The invention relates to a 3D printing cuttlebone elastic hemostatic stent and a construction method thereof. The existing hemostatic material has the problems of being effective only for mild to moderate bleeding, large in side effect, poor in biocompatibility, required to compress and seal wounds and the like. The method comprises the steps of dissolving polysebacic acid glycerol ester prepolymer and polycaprolactone in tetrahydrofuran to prepare a polymer solution, adding sodium chloride particles and cuttlebone powder, heating and stirring to obtain 3D printing ink; placing the sheet-shaped or block-shaped grid support into a 3D printer, and printing out the sheet-shaped or block-shaped grid support; placing the grid bracket into a vacuum drying oven for vacuum thermal crosslinking, immersing into distilled water for washing and desalting after crosslinking is finished, and freeze-drying to obtain the hemostatic bracket. The hemostatic scaffold is particularly suitable for bleeding wounds which are lacunar in systemic cavity and deep in bleeding site and difficult to rely on compression control, combines the degradable elastic biopolymer material with traditional hemostatic drug cuttlebone powder, and has the advantages of being porous, elastic memory, rapid in hemostasis, compressible and degradable.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to a 3D printing cuttlebone elastic hemostatic stent and a construction method thereof.
Background
At present, common hemostatic materials, besides gauze, bandages, gelatin sponge, zeolite and the like, also have been widely used, as well as novel materials such as fibrin glue, polysaccharide, oxidized cellulose and the like, which form a stable physical barrier at a bleeding part by enhancing the coagulation process, inhibiting the degradation of blood clots or interacting with blood and tissues, and prevent the blood from flowing out so as to promote hemostasis.
Most hemostatic materials are only effective for mild to moderate bleeding, and the hemostatic effect is insufficient to cope with large and uncontrollable vascular bleeding, and meanwhile, side effects such as high re-bleeding rate, embolism, tissue injury and the like exist, so that the further popularization and application are severely limited. In addition, hemostatic materials containing animal-derived components such as collagen, fibrinogen, thrombin, etc. may also be allergic or immunogenic when used in vivo, and may cause nerve damage or stress due to excessive swelling. In addition, in the early stage of general bleeding wounds, hemostatic devices such as tourniquets and hemostats are used, or hemostatic dressings are covered on wound surfaces to stop bleeding, so that the wound is often required to be compressed and closed, the device is not suitable for the bleeding wounds such as lacunar and deep incompressible wounds such as important viscera such as heart, liver and spleen, and bullet and burst wounds, and the device is low in efficiency, and a great amount of blood is lost in a short time, so that hemorrhagic shock is caused, and secondary injury, local necrosis of tissues, infection and the like are caused in the body. Therefore, a new hemostatic material needs to be proposed to overcome the above-mentioned clinical drawbacks of the existing hemostatic materials.
Disclosure of Invention
The invention aims to provide a 3D printing cuttlebone elastic hemostatic stent and a construction method thereof, which are used for solving the problems of the existing hemostatic material that the hemostatic material is effective only for mild to moderate bleeding, has large side effect and poor biocompatibility, needs to compress and seal wounds and the like.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the method for constructing the 3D printing cuttlebone elastic hemostatic scaffold comprises the following steps:
dissolving a polysebaceous glycerol ester prepolymer and polycaprolactone in tetrahydrofuran to prepare a polymer solution, adding sodium chloride particles and cuttlebone powder, heating and stirring to obtain pale yellow plasticine-like solid, namely 3D printing ink;
placing 3D printing ink into a 3D printer to print out a sheet-shaped and block-shaped grid support;
placing the grid bracket into a vacuum drying oven for vacuum thermal crosslinking, immersing into distilled water for washing and desalting after crosslinking is finished, and freeze-drying to obtain the hemostatic bracket.
Further, the polysebacic acid glycerol ester prepolymer and polycaprolactone are dissolved in 500 ml of tetrahydrofuran according to the mass ratio of 4:1 to prepare a polymer solution.
Further, the sodium chloride particles are subjected to a milling screen prior to addition to the polymer solution, comprising:
the sodium chloride particles ground by the grinding machine are sieved by a 400-mesh sieve and a 500-mesh sieve, the sodium chloride particles which cannot penetrate through the 500-mesh sieve are collected, and the polymer solution is added according to the amount which is twice the total mass of the polysebacemate glycerol ester prepolymer and the polycaprolactone.
Further, cuttlebone powder is subjected to disinfection, grinding and screening before being added into a polymer solution, and comprises the following steps:
cutting cuttlebone into small pieces, washing with water, soaking in 80% ethanol solution for 30min, soaking in distilled water for ten min, drying, and grinding;
sieving with 500 mesh sieve to obtain cuttlebone powder, and adding polymer solution according to the ratio of total mass of polysebacemate and polycaprolactone to cuttlebone powder of 17:3.
Further, after adding sodium chloride particles and cuttlebone powder to the polymer solution, stirring was performed by heating with a magnetic stirrer at 60℃at a rotational speed of 450rpm/min overnight.
Further, put 3D printing ink into 3D printer, print out slice, massive net support, include:
sealing the 3D printing ink and cooling in an environment of-20 ℃;
adding the cooled 3D printing ink into a 3D printing system, wherein the printing parameters are set as follows: the temperature is 65 ℃, the air pressure is 0.35Mpa, the diameter of an extrusion head is 0.4mm, and the extrusion speed is 8mm/s;
printing a blocky grid bracket, wherein the filling rate is 20%, 30% and 40%, and the interlayer angle is 60 degrees multiplied by 2;
printing a sheet grid support, wherein the filling rate is 40%, and the interlayer angle is 60 degrees multiplied by 3;
and (5) airing overnight.
Further, placing the grid support into a vacuum drying oven for vacuum thermal crosslinking, immersing into distilled water for washing and desalting after the crosslinking is finished, and obtaining the hemostatic support after freeze-drying, wherein the method comprises the following steps of:
placing the grid support in a vacuum drying oven, and thermally crosslinking for 36h at 120 ℃ under the condition of 1.0 bar;
taking out the grid bracket, desalting in distilled water for 24h, washing, freezing at-20deg.C, and vacuum drying to obtain hemostatic bracket.
On the other hand, the 3D printing cuttlebone elastic hemostatic support constructed by the method is provided, the hemostatic support is of a sheet-shaped grid structure, the sheet-shaped grid structure comprises two layers of 3D printing line bodies which are mutually intersected to form a rhombic, rectangular or square grid, or comprises three layers of 3D printing line bodies which are mutually intersected to form a triangular grid.
On the other hand, the 3D printing cuttlebone elastic hemostatic support constructed by the method is provided, the hemostatic support is of a block grid structure, the block grid structure comprises a plurality of layers of sheet grid structures which are overlapped up and down, the sheet grid structure comprises two layers of 3D printing line bodies which are mutually intersected to form a rhombic, rectangular or square grid, or comprises three layers of 3D printing line bodies which are mutually intersected to form a triangular grid;
the 3D printed line bodies of the lamellar lattice structures are connected to each other.
In another aspect, there is provided the use of a 3D printed cuttlebone elastic hemostatic scaffold as described in the preparation of hemostatic material packed into a bleeding wound.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a hemostatic stent constructed by means of a 3D printing technology, which is particularly suitable for bleeding wounds which are lacunar in systemic cavity property and deep in bleeding site and difficult to rely on compression control, combines degradable elastic biopolymer materials with traditional hemostatic drug cuttlebone powder, has the advantages of being porous, elastic memory, quick in hemostasis and compressible, can be stuffed into the bleeding wounds after being compressed, can effectively compress vascular lacerations after being mixed with blood to quickly expand and rebound, and can activate a rapid blood coagulation process by absorbing blood in a 3D microchannel in the stent, activate a synergistic hemostatic mode of platelet concentration, physical expansion compression and calcium ion activation coagulation paths, and improve the convenience of rescue operation.
Meanwhile, the material can be naturally degraded in vivo, secondary injury and wound re-bleeding caused by later extraction are not needed, all the used raw materials have excellent biocompatibility, the risks of potential biosafety and side effects are eliminated in the experimental verification process, all the used raw materials have excellent blood compatibility, the hemolysis reaction is not caused, and the internal and external coagulation paths are not influenced.
The hemostatic stent construction method has the characteristics of standardization, commercialization and flow, and has wide military and civil prospects.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the invention, and that other embodiments of the drawings can be obtained according to these drawings without inventive effort for a person skilled in the art.
Fig. 1 is a flow chart of the method of the present invention.
FIG. 2 is a powder electron microscope contrast view of the hemostatic stent of the present invention.
Fig. 3 is a comparative image of a MicroCT three-dimensional reconstruction of a hemostatic stent of the present invention.
Fig. 4 is a graph comparing tensile deformation versus stress curves of a hemostatic stent of the present invention.
Fig. 5 is a graph comparing compression set versus stress curves for hemostatic stents of the present invention.
FIG. 6 is a graph of the in vitro coagulation assay contrast and BCI index of the hemostatic stent of the present invention.
Fig. 7 is a contrast image of a blood clot at different magnification for different hemostatic materials.
Fig. 8 is a graph showing the hemostatic effect and the hemostatic time quantitative comparison of the hemostatic stent of the invention applied to a rat liver injury model.
Fig. 9 is a graph showing the quantitative comparison of the blood loss and the hemostatic time of the application of the blocky hemostatic stent of the invention to a rabbit carotid hemorrhage model.
Fig. 10 is an in vivo degradation display of the hemostatic stent of the present invention.
Fig. 11 is a schematic view of a hemostatic stent of the present invention loaded from a capsule.
Figure 12 is a block diagram of a triangular Kong Pianzhuang hemostatic stent.
Figure 13 is a block diagram of a diamond Kong Kuaizhuang hemostatic stent.
Figure 14 is a block diagram of a rectangular hole curve hemostatic stent.
Figure 15 is a block diagram of a triangular-hole bar-shaped hemostatic stent.
Fig. 16 is a compressive deformation display of a blocky hemostatic stent of the present invention.
Figure 17 is a graph comparing the deformation ratio of a blocky hemostatic stent of the present invention.
Fig. 18 is a graph comparing the rate of recovery from deformation of a blocky hemostatic stent of the present invention.
Figure 19 is a graph of the deformation recovery time versus the blocky hemostatic stent of the present invention.
Detailed Description
In order that the invention may be readily understood, a more complete description of the invention will be rendered by reference to the appended drawings. The drawings illustrate preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
In the description of this patent, it is to be understood that all technical and scientific terms used have the same meaning as commonly understood by one of ordinary skill in the art to which this patent belongs. In case of conflict, the present specification, definitions, will control. Unless otherwise indicated, the technical means used in the examples are conventional means known to those skilled in the art, the reagents used in the examples are commercial products, the devices used in the examples are existing devices, and the limitations on the means, reagents or devices should not be interpreted as limitations on the present patent, and the same types of means, reagents or devices for solving the same technical problems are within the scope of protection of the present patent.
In the description of this patent, it should be understood that when an equivalent, concentration, or other value or parameter is expressed as a range, preferred range, or as a range bounded by a list of upper preferable values and lower preferable values, this should be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value with any lower range limit or preferred value, regardless of whether ranges are separately disclosed. When a numerical range is described herein, unless otherwise indicated, the range is intended to include its endpoints and all integers and fractions within the range.
In the description of this patent, it should be understood that, in describing the process, a plurality of steps are involved, and should not be construed as limiting the sequence of steps of the method, and the technical solution obtained by only changing the sequence of steps when solving the same technical problem is also within the protection scope of this patent.
The 3D printing technology is widely applied to the fields of tissue engineering technology and biological materials by virtue of the individuation and precision advantages thereof. The 3D printing processing and manufacturing of the hemostatic material are currently studied, and are mainly concentrated in the application field of the hydrogel material, but the hydrogel material has poor performance in the aspects of mechanical strength, elasticity and other mechanical properties, so that the practical application of the gel hemostatic material is limited.
To achieve a clinically rapid hemostasis, the ideal hemostatic material needs to meet the following requirements: a) Excellent liquid absorption capacity; b) Suitable mechanical properties to withstand blood pressure and compressive contact with surrounding tissue; c) The structural stability is kept under the stress condition, and the wound tissue is not damaged; d) Good biocompatibility; e) The operation is simple and quick. And is more demanding for controlling bleeding and treating specific wounds, especially for deep bleeding types where hemostasis by compression is difficult.
The invention provides a construction method of a 3D printing cuttlebone elastic hemostatic scaffold, which is especially suitable for bleeding wounds with systemic lacunarity, deep bleeding sites and difficult compression control. The method comprises the following steps:
s1: preparing 3D printing ink:
and dissolving the polysebaceous glycerol ester prepolymer and polycaprolactone in tetrahydrofuran to prepare a polymer solution, adding sodium chloride particles and cuttlebone powder, heating and stirring to obtain pale yellow plasticine-like solid, namely the 3D printing ink. The method specifically comprises the following steps:
s101: the polysebacic acid glycerol ester prepolymer and polycaprolactone are dissolved in 500 ml tetrahydrofuran according to the mass ratio of 4:1 to prepare a polymer solution. The preparation quality generally chosen is 4g of polysebacic acid glycerol ester prepolymer and 1g of polycaprolactone.
S102: sodium chloride particles were subjected to milling screening prior to addition to the polymer solution, comprising:
the sodium chloride particles ground by the grinding machine are sieved through 400 meshes and 500 meshes, the sodium chloride particles which cannot penetrate through 500 meshes, namely, the diameter of 30-38 microns, are collected, and the sodium chloride particles with the diameter range are added into the polymer solution according to the amount which is twice the total mass of the polysebacemate glycerol ester prepolymer and the polycaprolactone.
S103: the cuttlebone powder is sterilized, ground and screened before being added into a polymer solution, and comprises the following steps:
the whole cuttlebone is obtained from fresh adult cuttlefish without needle which is salvaged and captured in 4-8 months, the volume is 15cm long, 3cm wide and above, and the thickest part is more than 1cm. Cutting cuttlebone into small pieces, washing with water, soaking in 80% ethanol solution for 30min, soaking in distilled water for ten min, drying, and grinding;
sieving with 500 mesh sieve to obtain cuttlebone powder with particle diameter smaller than 30 μm, and adding polymer solution at ratio of total mass of polysebacemate glycerol ester prepolymer and polycaprolactone to cuttlebone powder of 17:3 (15% total mass).
S104: after adding sodium chloride particles and cuttlebone powder into the polymer solution, heating and stirring the mixture by a heating magnetic stirrer at 60 ℃ and a rotating speed of 450rpm/min for overnight, and fully volatilizing tetrahydrofuran.
S2:3D prints net support:
placing 3D printing ink into a 3D printer to print out sheet-shaped and block-shaped grid supports, comprising:
s201: sealing the 3D printing ink and cooling in an environment of-20 ℃ to reduce the surface viscosity, so that the 3D printing ink is convenient to transfer to a printing material cylinder;
s202: adding the cooled 3D printing ink into a 3D printing system, wherein the printing parameters are set as follows: the temperature is 65 ℃, the air pressure is 0.35Mpa, the diameter of an extrusion head is 0.4mm, and the extrusion speed is 8mm/s;
s203: printing a blocky grid bracket, wherein the filling rate is 20%, 30% and 40%, and the interlayer angle is 60 degrees multiplied by 2;
s204: printing a sheet grid support, wherein the filling rate is 40%, and the interlayer angle is 60 degrees multiplied by 3;
s205: air-dried overnight and further volatilize residual tetrahydrofuran.
The 3D printer may be a PCPrinterBR151S type printing system of particle cloud biotechnology limited.
S3: processing and preparing a hemostatic support:
placing the grid stent obtained in the step S2 into a vacuum drying oven for vacuum thermal crosslinking, immersing into distilled water for washing and desalting after the crosslinking is finished, and obtaining the hemostatic stent after freeze-drying, wherein the method comprises the following steps of:
s301: placing the grid support in a vacuum drying oven, and thermally crosslinking for 36h at 120 ℃ under the condition of 1.0 bar;
s302: taking out the grid bracket, desalting in distilled water for 24h, washing, freezing at-20deg.C, and vacuum drying to obtain hemostatic bracket.
According to the method, traditional hemostatic traditional Chinese medicine cuttlebone powder rich in calcium ions, chitosan and chitin is combined with a 3D printing technology, and the elastic hemostatic 3D elastic sponge bracket with shape memory performance and an ordered pore structure is reconstructed by relying on PGS (polyglycerol sebacate, polysebacemate)/PCL (Polycaprolactone) printing raw materials with good biocompatibility. Based on the material, the physical compression setting of the elastic support can be realized by optimizing the printing structure, and the ballistically expanding compression and high-coagulation hemostatic material is developed. According to the invention, cuttlebone powder is loaded in the hemostatic bracket, and is directly added into 3D printing ink instead of being loaded on the surface or micropores of a 3D structure, and is fully mixed and crosslinked with other 3D printing raw materials, so that the superiority of the finally obtained hemostatic bracket space structure is greatly improved.
The hemostatic bracket with different structural forms can be constructed by the method, the shape, thickness, length, width, hole shape and the like of the hemostatic bracket can be flexibly adjusted according to clinical specific use requirements and wound conditions, printing can be designed in real time, and cutting can be performed on the basis of the existing printed finished product to obtain the required structural form. Both block and plate structural limitations are described in the embodiments, but may not be limited thereto as desired.
The 3D printing cuttlebone elastic hemostatic support can be of a block grid structure and used as hemostatic sponge to be filled in a bleeding wound. The block grid structure comprises a plurality of layers of sheet grid structures which are overlapped up and down, and 3D printing line bodies of the sheet grid structures are connected with each other. The sheet-like mesh structure comprises two layers of 3D printing line bodies which are mutually intersected to form a diamond-shaped, rectangular or square mesh, or three layers of 3D printing line bodies which are mutually intersected to form a triangular mesh. As shown in fig. 13, the hemostatic scaffold is a rhombus Kong Kuaizhuang hemostatic scaffold, and comprises a multi-layer sheet-shaped grid structure, wherein each sheet-shaped grid structure comprises two layers of 3D printing line bodies which are mutually intersected, the interlayer angle is 60 degrees x 2, and the holes are rhombus and are suitable for deep non-compressible hemostatic wounds. As shown in fig. 14, the hemostatic support is a rectangular hole curve block hemostatic support and comprises a multi-layer sheet-shaped grid structure, each sheet-shaped grid structure comprises two layers of 3D printing line bodies which are mutually intersected, the holes are rectangular or square, the compression capacity is small, and the hemostatic support is suitable for deep and large wounds on the body surface. As shown in fig. 15, the hemostatic support is a triangular hole bar-shaped block hemostatic support, is integrally bar-shaped, has smaller compression capacity, is suitable for long and narrow wounds of body surfaces, and comprises a multi-layer sheet-shaped grid structure, wherein each sheet-shaped grid structure comprises three layers of 3D printing line bodies which are mutually intersected, the interlayer angle is 60 degrees x 3, and the holes are triangular. According to specific requirements, the number of layers, the shape of the holes and the like can be arranged and combined to obtain various design schemes, so that different types of hemostatic stents are formed.
The 3D printing cuttlebone elastic hemostatic support can also be of a sheet-shaped grid structure and can be directly applied as hemostatic membrane. The sheet grid structure is a three-layer 3D printing film-shaped bracket which is intersected with each other to form a triangular grid. As shown in fig. 12, the hemostatic scaffold is a triangle Kong Pianzhuang hemostatic scaffold, which comprises three layers of 3D printed wire bodies intersecting each other, wherein the interlayer angle is 60 degrees×3, and the holes are triangular.
The 3D printing line body can be a straight line or a curve, and when the curve form is adopted, the overall elasticity is better.
The block grid structure can be in a regular shape or an irregular shape, the edge can be a straight line or a curve, the shape and the depth can be flexibly adjusted to adapt to wounds, and even a plurality of block grid structures can be combined for use.
As shown in fig. 11, the hemostatic support of the invention can be constructed in a windmill shape, and after being loaded into a gelatin capsule shell, the hemostatic support for filling with regular and uniform shape and size is formed, the capsule is more convenient to carry, the manufacturing process is more programmed, and better effects of expanding and compressing and absorbing blood to promote blood coagulation can be achieved.
The hemostatic scaffold constructed by the invention has excellent elasticity, compressibility, biocompatibility, degradability and the like, and has obvious advantages in deeper bleeding wound treatment, and the specific performance test results are analyzed as follows:
1. sample preparation:
for the block elastic compressible sponge bracket, a diamond hole structure is selected, and the block elastic compressible sponge bracket is cut into a structure with X of 5mm multiplied by Y of 1.2cm multiplied by Z of 5mm, and is compressed at the temperature of minus 20 ℃ along the Y-axis direction, so that the stable folding structure cube bracket can be obtained, and the volume is reduced to 1/4 before compression, and the stable folding structure cube bracket is used as a block sample. For the sheet hemostatic stent, a large-area printing finished product is cut by using a circular cutter with the diameter of 8mm, so that a circular sheet hemostatic stent is obtained and used as a sheet sample. A flow chart and various form bracket views are shown in fig. 1.
2. Cuttlebone powder loading observation:
the presence or absence of cuttlebone powder loading was divided into 0% CB (no cuttlebone powder loading) and 15% CB groups according to Cuttlebone (CB) powder content. The surface morphology of different sheet samples and the morphology of cuttlebone powder are observed through a scanning electron microscope, and the sheet samples loaded and unloaded with cuttlebone powder are scanned and three-dimensionally reconstructed through a micro CT (computed tomography) so as to verify the loading condition of cuttlebone powder. As a result, as shown in FIG. 2 and FIG. 3, the content and distribution of cuttlebone powder under the microstructure are shown in the graph, and the 0% CB group tablet can be seen to densely distributed with micro-connected pores of 30-50 μm. In the 15% CB group, a large amount of cuttlebone powder can be seen to be densely distributed on the surface of the pore inner support under a high-power microscope, and the size and distribution of pores cannot be affected by the addition of the cuttlebone powder. The loading content of cuttlebone powder can be displayed by three-dimensional reconstruction through a Micro-CT scanning bracket, as shown in figure 3. The 0% CB group sheet sample has no high density development, the development degree is obviously improved along with the improvement of the cuttlebone powder content, and the cuttlebone powder is uniformly distributed in the whole printed bracket grid.
3. Mechanical properties:
the sheet samples were subjected to tensile and compressive tests and the block elastic compressible sponge scaffold samples were subjected to cyclic loading compression fatigue resistance tests as shown in fig. 4, 5 and 9. The tensile and compressive results showed a significant increase in both tensile and compressive strength with the addition of cuttlebone powder (increasing the elasticity and compressibility exhibited in the following section).
4. Shape memory capability of the stent:
fig. 16 is a representation of compression set of a block elastic compressible sponge scaffold lattice scaffold. The high volume stent can be expanded for volume compression at low temperature (4 < ℃) and kept shape fixed at room temperature. Upon contact with a liquid (water, blood, etc.), rapid expansion (within 4 seconds) is achieved by absorbing the liquid. As shown in fig. 17 to 19, quantitative analysis of deformability (deformation ratio), deformation recovery time, deformation recovery ratio was performed for different filling ratios, and all of them were excellent.
5. Hemostatic effect:
the results of the in vitro related coagulation experiment verification of the sheet sample, including dynamic whole blood coagulation test and bracket blood clot electron microscope observation, show that the sheet sample can effectively absorb blood and induce erythrocyte aggregation in the blood, promote the generation of a large amount of thrombin by blood platelets so as to induce the generation of fibrin, accelerate the aggregation and adhesion of blood cells and form blood clots, thereby having strong hemostatic capability.
The sheet sample and the block elastic compressible sponge bracket sample are respectively used for an animal in-vivo hemostatic model. The flaky sample is applied to an SD rat liver injury model, the result shows that the hemostatic effect of the injection after the compression of the massive elastic compressible sponge bracket sample is applied to a New Zealand rabbit carotid artery hemorrhage model as shown in figure 8, and the result shows that the hemostatic effect is better than that of a commercial gauze control group as shown in figure 9.
5. Biocompatibility and degradability:
in vivo degradation and biosafety experiments were performed using sheet samples, which were further cut to a size of 5mm×2mm, and embedded in the liver middle lobe of SD rats, and the results of histological staining were shown in fig. 10. The result shows that the stent material can be naturally degraded in vivo, and the biological toxicity can not be generated according to the liver and kidney function verification result.
The invention combines the degradable biological polymer material with excellent elastic memory function with the traditional Chinese medicine hemostatic, prepares the expandable filling hemostatic material by means of the 3D printing technology, and is a better choice for emergency hemostasis of wounds difficult to compress and stop bleeding. The high-molecular material with excellent mechanical property and good biocompatibility can be degraded in vivo without secondary extraction, so that pain and re-bleeding risk of patients are reduced.
The printing bracket has the advantages that the cuttlebone powder with high-efficiency coagulation effect is added into the printing raw material, so that the target bracket can obtain high-efficiency coagulation effect. The aim of guiding the bone regeneration membrane is to shield connective tissue, the filling rate is high, the compact membranous structure is difficult to permeate blood, the loaded procoagulant component is limited to be contacted with blood, the printing filling rate of the target stent is controlled between 30% and 40%, and the target stent is fully contacted with the loaded cuttlebone powder while the proper pore size allows blood flow to pass through, so that the hemostatic effect is further improved. Meanwhile, the internal ordered pore canal structure of the bracket can quickly absorb liquid, so that local shape recovery is realized. In addition, the temperature is reduced to 120 ℃ in the thermal crosslinking process, the time is adjusted to 36 hours, and the aim of protecting organic matters (chitosan, chitin and the like) in cuttlebone powder is achieved, and meanwhile, the target stent has enough mechanical strength and shape memory performance.
The foregoing description of the invention has been presented for purposes of illustration and description, and is not intended to be limiting. Several simple deductions, modifications or substitutions may also be made by a person skilled in the art to which the invention pertains, based on the idea of the invention.
Claims (10)
1.3D prints cuttlebone elasticity hemostasis support's construction method, its characterized in that:
the method comprises the following steps:
dissolving a polysebaceous glycerol ester prepolymer and polycaprolactone in tetrahydrofuran to prepare a polymer solution, adding sodium chloride particles and cuttlebone powder, heating and stirring to obtain pale yellow plasticine-like solid, namely 3D printing ink;
placing 3D printing ink into a 3D printer to print out a sheet-shaped and block-shaped grid support;
placing the grid bracket into a vacuum drying oven for vacuum thermal crosslinking, immersing into distilled water for washing and desalting after crosslinking is finished, and freeze-drying to obtain the hemostatic bracket.
2. The method for constructing the 3D printed cuttlebone elastic hemostatic scaffold according to claim 1, which is characterized in that:
the polysebacic acid glycerol ester prepolymer and polycaprolactone are dissolved in 500 ml tetrahydrofuran according to the mass ratio of 4:1 to prepare a polymer solution.
3. The method for constructing the 3D printed cuttlebone elastic hemostatic scaffold according to claim 2, which is characterized in that:
sodium chloride particles were subjected to milling screening prior to addition to the polymer solution, comprising:
the sodium chloride particles ground by the grinding machine are sieved by a 400-mesh sieve and a 500-mesh sieve, the sodium chloride particles which cannot penetrate through the 500-mesh sieve are collected, and the polymer solution is added according to the amount which is twice the total mass of the polysebacemate glycerol ester prepolymer and the polycaprolactone.
4. The method for constructing the 3D-printed cuttlebone elastic hemostatic scaffold according to claim 3, wherein the method comprises the following steps:
the cuttlebone powder is sterilized, ground and screened before being added into a polymer solution, and comprises the following steps:
cutting cuttlebone into small pieces, washing with water, soaking in 80% ethanol solution for 30min, soaking in distilled water for ten min, drying, and grinding;
sieving with 500 mesh sieve to obtain cuttlebone powder, and adding polymer solution according to the ratio of total mass of polysebacemate and polycaprolactone to cuttlebone powder of 17:3.
5. The method for constructing the 3D-printed cuttlebone elastic hemostatic scaffold according to claim 4, which is characterized in that:
after adding sodium chloride particles and cuttlebone powder into the polymer solution, heating and stirring the mixture by a heating magnetic stirrer at 60 ℃ and a rotating speed of 450rpm/min for overnight.
6. The method for constructing the 3D-printed cuttlebone elastic hemostatic scaffold according to claim 5, which is characterized in that:
placing 3D printing ink into a 3D printer to print out sheet-shaped and block-shaped grid supports, comprising:
sealing the 3D printing ink and cooling in an environment of-20 ℃;
adding the cooled 3D printing ink into a 3D printing system, wherein the printing parameters are set as follows: the temperature is 65 ℃, the air pressure is 0.35Mpa, the diameter of an extrusion head is 0.4mm, and the extrusion speed is 8mm/s;
printing a blocky grid bracket, wherein the filling rate is 20%, 30% and 40%, and the interlayer angle is 60 degrees multiplied by 2;
printing a sheet grid support, wherein the filling rate is 40%, and the interlayer angle is 60 degrees multiplied by 3;
and (5) airing overnight.
7. The method for constructing the 3D-printed cuttlebone elastic hemostatic scaffold according to claim 6, wherein the method comprises the following steps:
placing the grid bracket into a vacuum drying oven for vacuum thermal crosslinking, immersing into distilled water for washing and desalting after the crosslinking is finished, and obtaining the hemostatic bracket after freeze-drying, wherein the method comprises the following steps of:
placing the grid support in a vacuum drying oven, and thermally crosslinking for 36h at 120 ℃ under the condition of 1.0 bar;
taking out the grid bracket, desalting in distilled water for 24h, washing, freezing at-20deg.C, and vacuum drying to obtain hemostatic bracket.
8. The 3D printed cuttlebone elastic hemostatic stent constructed by the method of claim 7, wherein:
the hemostatic support is of a sheet-shaped grid structure, and the sheet-shaped grid structure comprises two layers of 3D printing line bodies which are mutually intersected to form a diamond-shaped, rectangular or square grid, or three layers of 3D printing line bodies which are mutually intersected to form a triangular grid.
9. The 3D printed cuttlebone elastic hemostatic stent constructed by the method of claim 7, wherein:
the hemostatic support is of a block grid structure, the block grid structure comprises a plurality of layers of sheet grid structures which are overlapped up and down, the sheet grid structure comprises two layers of 3D printing line bodies which are mutually intersected to form a rhombic, rectangular or square grid, or three layers of 3D printing line bodies which are mutually intersected to form a triangular grid;
the 3D printed line bodies of the lamellar lattice structures are connected to each other.
10. Use of a 3D printed cuttlebone elastic hemostatic scaffold as defined in claim 8 or 9 for the preparation of hemostatic material packed into a bleeding wound.
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