An electronic blood vessel, its preparation method and application

Abstract

This invention discloses an electronic blood vessel, its preparation method, and its application. The preparation method of the electronic blood vessel includes the following steps: liquefying liquid metal ink into a micro-electric field stimulation pattern on a PET film to prepare a PET film with patterned liquid metal ink; forming a polymer solution on the patterned liquid metal ink PET film, and then peeling it off to obtain a polymer composite film; fixing a PVDF film on the polymer composite film and bonding it to obtain the electronic blood vessel composite film; and rolling the electronic blood vessel composite film into a tubular shape to obtain the electronic blood vessel. The method of preparing electronic blood vessels according to this invention is simple to operate, and the prepared electronic blood vessels have a certain promoting effect on endothelial cell proliferation, good biocompatibility, and are compatible with the patient's own blood vessels.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to an electronic blood vessel, its preparation method, and its application. Background Technology

[0002] Cardiovascular disease is currently one of the leading causes of death worldwide, with coronary atherosclerosis (CAD) being one of the most challenging acquired diseases. CAD often results from plaque buildup in blood vessels, blocking blood flow to the heart and potentially causing myocardial infarction and sudden death. Coronary artery bypass grafting (CABG) involves transplanting a blood vessel to bridge the narrowed area; however, the body's own blood vessels are a limited resource. Current solutions primarily involve replacing autologous blood vessels with artificial ones. Large-diameter (>6mm) artificial blood vessels made of polytetrafluoroethylene (PTFE) have achieved excellent results in large-diameter vascular replacement surgeries, but small-diameter (<6mm) artificial blood vessels are still prone to blockage. Therefore, further optimization is needed in the fabrication of small-diameter artificial blood vessels to improve their patency.

[0003] Current methods for preparing small-diameter artificial blood vessels mainly include decellularized matrix, self-rolling artificial blood vessels, and biomimetic materials. The decellularized matrix method involves implanting a vascular mold subcutaneously into an animal for several months, then removing it for decellularization. The self-rolling artificial blood vessel method primarily involves preparing a polymer film and using a mandrel to roll the film into a tubular shape to form the artificial blood vessel. Biomimetic materials mainly utilize hydrogels and biodegradable polymers to form tubular artificial blood vessels through cross-linking. Recent clinical studies have shown that most methods are used as scaffolds directly implanted into the host tissue, forming patent artificial blood vessels through a remodeling process. However, the complex interaction between blood flow and the graft can cause inflammatory responses, leading to thrombosis, intimal hyperplasia, or smooth muscle accumulation, thus causing vascular occlusion. Postoperative vascular occlusion needs to be monitored promptly to maintain the patient's condition. There are reports of using external stents to monitor blood flow patency, but these are not used as vascular grafts; they only serve as external stents.

[0004] While methods for fabricating artificial blood vessels using decellularized matrix methods offer excellent biocompatibility, their long fabrication cycles hinder mass production and do not fully resolve patency issues. Self-coiling artificial blood vessels rely primarily on material biocompatibility but do not significantly improve patency. Artificial blood vessels made from biomimetic materials and polymers offer the advantage of mass production to meet future large-scale clinical needs, but patency issues still require resolution. Current surface-anticoagulant-treated blood vessels (such as those covalently grafted with heparin sodium) have not yielded satisfactory results, and electronic blood vessels stimulated by an external power source via micro-electric fields suffer from the reliance on external power and susceptibility to infection. Summary of the Invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the present invention proposes a method for preparing an electronic blood vessel.

[0006] The present invention also proposes an electronic blood vessel prepared by the above preparation method.

[0007] The present invention also proposes applications of the above-mentioned electronic blood vessels.

[0008] The present invention also proposes an artificial blood vessel.

[0009] In one aspect of the present invention, a method for preparing an electronic blood vessel is provided, comprising the following steps:

[0010] S1. Liquid metal ink is liquefied on a PET film to form a micro-electric field electrostimulation pattern, thereby preparing a PET film with patterned liquid metal ink;

[0011] S2. The polymer solution is formed on the PET film of patterned liquid metal ink, and the resulting composite film is peeled off from the PET film of patterned liquid metal ink to obtain a polymer composite film.

[0012] S3. Place the PVDF film on the polymer composite film obtained in step S2 and fix it. After bonding, the electronic blood vessel composite film is obtained.

[0013] S4. Roll the electronic blood vessel composite film obtained in step S3 into a tubular shape to obtain the electronic blood vessel.

[0014] In some embodiments of the present invention, the liquid metal includes gallium and zinc.

[0015] In some embodiments of the present invention, the mass ratio of gallium to zinc is (5-25):1.

[0016] In some embodiments of the present invention, the mass ratio of gallium to zinc is (18-22):1.

[0017] In some embodiments of the present invention, the electrical stimulation pattern adopts an interdigital capacitor electrical stimulation pattern, and a uniform electric field is generated between parallel electrodes.

[0018] In some embodiments of the present invention, the polymer solution includes at least one of PLCL, PTMC, PLGA, PGA and PLA.

[0019] In some embodiments of the present invention, the mass fraction of the polymer solution is 0.8% to 1.5%.

[0020] In some embodiments of the present invention, the solvent used in the polymer solution includes dichloromethane. In some embodiments of the present invention, the PVDF film is a PVDF film that has undergone magnetron sputtering metallization.

[0021] In some embodiments of the present invention, the PVDF film is a PVDF film that has been treated with platinum, gold, silver or copper by magnetron sputtering.

[0022] In some embodiments of the present invention, the PVDF film is a PVDF film that has been treated with platinum by magnetron sputtering.

[0023] In some embodiments of the present invention, the magnetron sputtering conditions are: power 80-120W, sputtering gas pressure 2-6mT, DC deflection voltage 350-420V, metal deposition rate 3-7A / S, deposition time 4-6min, average metal deposition thickness 50-80nm, and average platinum metal deposition particle size 0.5-2nm.

[0024] In some embodiments of the present invention, the bonding is performed using a hot press.

[0025] In some embodiments of the present invention, the parameters of the hot press are 70-90℃ and 0.8-1.5MPa.

[0026] In some embodiments of the present invention, the area of ​​the PVDF is 1-220 mm². 2 .

[0027] In some embodiments of the present invention, the area of ​​the PVDF is 48-220 mm². 2 .

[0028] In some embodiments of the present invention, the thickness of the PVDF is 18-25 μm.

[0029] In a second aspect of the invention, an electronic blood vessel prepared by the above method is provided.

[0030] In some embodiments of the present invention, the diameter of the electronic blood vessel is 1-2.5 mm.

[0031] In a third aspect of the invention, the application of the above-mentioned electronic blood vessel is proposed, namely, its application in the preparation of vascular gene therapy materials, drug delivery materials, tissue engineering, biosensing, and optoelectronic materials.

[0032] In a fourth aspect of the invention, an artificial blood vessel is provided, the artificial blood vessel comprising the aforementioned electronic blood vessel.

[0033] In some embodiments of the present invention, the artificial blood vessel further includes a capacitive sensor.

[0034] In some embodiments of the present invention, the capacitive sensor includes a pyramid structure.

[0035] In some embodiments of the present invention, the pyramid structure is prepared by mixing a 0.5-2% mass fraction PLCL solution and a 0.5-2% mass fraction PTMC solution and then preparing the structure using a pyramid mold.

[0036] In some embodiments of the present invention, the base side length of the pyramid structure is 5, 10, or 20 μm.

[0037] In some embodiments of the present invention, the spacing between the pyramid structures is 5, 10, or 20 μm.

[0038] In some embodiments of the present invention, the volume ratio of PLCL solution to PTMC solution is 1:1.

[0039] In some embodiments of the present invention, the capacitive sensor is prepared by placing the pyramid structure described above at both ends of two parallel electrode lines extending from the electronic blood vessel.

[0040] According to embodiments of the present invention, at least the following beneficial effects are achieved: The method for preparing electronic blood vessels according to the present invention is simple to operate. It utilizes flexible, biodegradable, self-powered electronic materials combined with piezoelectric materials to prepare self-powered electronic artificial blood vessels that can convert the mechanical energy (pulsation of blood flow) of the organism into electrical energy for micro-electric field stimulation, avoiding the infection problems caused by external power sources. Simultaneously, the biodegradable polymer material ensures slow degradation after implantation, exhibiting excellent biocompatibility. The capacitive sensor constructed by the method of the present invention can also wirelessly monitor blood flow, enabling real-time monitoring of the artificial blood vessel's blockage. The electronic blood vessels prepared according to the present invention have a certain promoting effect on endothelial cell proliferation, possess good biocompatibility, and are compatible with the patient's own blood vessels. Attached Figure Description

[0041] The present invention will be further described below with reference to the accompanying drawings and embodiments, wherein:

[0042] Figure 1 This is a circuit diagram of a self-powered blood vessel in Embodiment 1 of the present invention, wherein A is a circuit diagram of a self-powered blood vessel and B is a circuit diagram covering the upper surface of the PVDF.

[0043] Figure 2 The graph shows the results of the determination of the content and ratio of gallium and zinc liquid metals in Example 1 of the present invention.

[0044] Figure 3 This is a graph showing the screening results of polymer proportions in the test examples of this invention;

[0045] Figure 4 This is a diagram of the extracorporeal blood circulation device in the test example of the present invention;

[0046] Figure 5 This is a graph showing the voltage results generated by PVDFs of different areas and thicknesses in the test examples of this invention;

[0047] Figure 6 This is a graph showing the proliferation results of endothelial cells cultured in vitro in the test examples of this invention;

[0048] Figure 7 This is a graph showing the results of endothelial cells cultured in vitro for 2 days under different micro-electric field conditions in the test examples of this invention;

[0049] Figure 8 This is a diagram showing the design result of the dual-layer antenna in the test example of this invention;

[0050] Figure 9 This is a graph showing the screening results of different pyramid structures in the test examples of this invention, based on their dimensions and parameters.

[0051] Figure 10 These are signal detection result diagrams for different pyramid structures in the test examples of this invention. A is the signal result diagram generated by a pyramid with a size of 20 μm, B is the signal result diagram generated by a pyramid with a size of 10 μm, and C is the signal result diagram generated by a pyramid with a size of 5 μm.

[0052] Figure 11 This is a graph showing the change in capacitance under blood flow pulsation conditions in the test examples of this invention;

[0053] Figure 12 This is a diagram of a rabbit carotid artery replacement model used in the test examples of this invention.

[0054] Figure 13 This is an ultrasound image showing the results of implanted self-generating blood vessels in the test example of this invention after 2 years;

[0055] Figure 14 This is an arteriography result of the implanted self-generating blood vessel in the test example of this invention, 2 years later;

[0056] Figure 15 This is a colorimetric image of a vascular tissue section implanted with a self-generating blood vessel for 2 years in the test example of this invention. Detailed Implementation

[0057] The following will describe the concept and technical effects of the present invention clearly and completely with reference to embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

[0058] Example 1

[0059] This embodiment provides an electronic blood vessel, the preparation method of which is as follows:

[0060] (1) Design of micro-electric field electrical stimulation patterns

[0061] The micro-electric field stimulation pattern is designed using interdigital capacitors, generating a uniform electric field between parallel electrodes. The self-powered vascular circuit pattern is as follows: Figure 1 As shown, the electrical stimulation pattern of the interdigital capacitor is located in Figure 1 Below. Above the interdigital capacitor is the location where the polyvinylidene fluoride (PVDF) piezoelectric film is placed. The potential difference generated by the PVDF under pulsating blood flow is introduced onto the interdigital capacitor, thereby creating a micro-electric field to stimulate endothelial cells.

[0062] (2) Preparation of self-powered electron vascular composite film

[0063] 1) Liquid metals (gallium and zinc, mass ratio of which is measured by inductively coupled plasma (ICP)) are applied to a PET film using a screen printing stencil. Figure 2 As shown, the 20:1 ink is patterned into the micro electric field pattern designed in (1). The PET film with the patterned liquid metallic ink is placed in an oven at 80°C to dry.

[0064] 2) Pour 15 mL of a 1% mass fraction PLCL (Evonik, Germany) and PTMC (Daigang, China) polymer mixture dissolved in dichloromethane (i.e., the mass ratio of PLCL to PTMC is 1:1) onto a dry PET film (a PET film with patterned liquid metal ink). After the solvent evaporates, peel the composite film formed by the polymer mixture on the PET film off the PET film.

[0065] 3) The PVDF film with a thickness of 18 μm was subjected to magnetron sputtering platinum deposition on both sides (treatment conditions: power 100W, sputtering gas pressure 4mT, DC deflection voltage 390V, deposition rate 5A / s, deposition time 4-6 min, average platinum deposition thickness 70nm, average platinum deposition particle size 1nm) to enhance electron transfer capability. Then, the composite film obtained in step 2) and peeled off from the PET film was unfolded face up, with an area of ​​1×1cm. 2 The PVDF film is placed in a specific location (the specific location is as follows). Figure 1 (The location described in the red box). Then, using a symmetrical composite film obtained from the PET film (step 2) containing a liquid metal film, peeled off, the PVDF (1×1cm) is applied. 2 The membrane is fixed in this position. Simultaneously, it is bonded tightly using a hot press (80℃, 1MPa) to prepare the electronic blood vessel composite film. That is, the charge generated on both sides of the PVDF in the electronic blood vessel composite film is led out from one side by the liquid metal circuit of the bottom layer, and the charge on the other side is led out from the liquid metal circuit covering the top layer, such as... Figure 1 As shown, a uniform electric field is formed at both ends of the electrical stimulation pattern of the interdigital capacitor.

[0066] (3) Roll the electronic blood vessel composite film obtained in step (2) into a tube with a diameter of 2 mm to obtain the electronic blood vessel.

[0067] Example 2

[0068] This embodiment provides an electronic blood vessel, the only difference between its preparation method and that of Embodiment 1 is that the PVDF film used in step (2) has a thickness of 18 μm and an area of ​​6 × 8 mm. 2 .

[0069] Example 3

[0070] This embodiment provides an electronic blood vessel, the only difference between its preparation method and that of Embodiment 1 is that the PVDF film used in step (2) has a thickness of 18 μm and an area of ​​12 × 16 mm. 2 .

[0071] Example 4

[0072] This embodiment provides an electronic blood vessel, the only difference between its preparation method and that of Embodiment 1 is that the PVDF film used in step (2) has a thickness of 25 μm and an area of ​​12 × 16 mm. 2 .

[0073] Comparative Example 1

[0074] This comparative example provides an electronic blood vessel, the preparation method of which differs from that of Example 1 only in that the polymer mixed solution in part 2) of step (2) is PTMC by default.

[0075] Comparative Example 2

[0076] This comparative example provides an electronic blood vessel, the preparation method of which differs from that of Example 1 only in that the mass ratio of PLCL to PTMC added in the polymer mixed solution in part 2) of step (2) is 4:1.

[0077] Comparative Example 3

[0078] This comparative example provides an electronic blood vessel, the preparation method of which differs from that of Example 1 only in that the mass ratio of PLCL to PTMC added in the polymer mixed solution in part 2) of step (2) is 2:1.

[0079] Comparative Example 4

[0080] This comparative example provides an electronic blood vessel, the preparation method of which differs from that of Example 1 only in that the mass ratio of PLCL to PTMC added in the polymer mixed solution in part 2) of step (2) is 1:2.

[0081] Comparative Example 5

[0082] This comparative example provides an electronic blood vessel, the preparation method of which differs from that of Example 1 only in that the mass ratio of PLCL to PTMC added in the polymer mixed solution in part 2) of step (2) is 1:4.

[0083] Comparative Example 6

[0084] This comparative example provides an electronic blood vessel, the preparation method of which differs from that of Example 1 only in that PLCL is omitted in the polymer mixed solution in part 2) of step (2).

[0085] Test case

[0086] 1. Screening of polymer solutions

[0087] The electronic blood vessels prepared in Example 1 and the electronic blood vessels prepared in Comparative Examples 1-6 were mechanically characterized, and the Young's modulus and yield strength of the electronic blood vessels were measured respectively.

[0088] The results are as follows Figure 3 As shown in the figure, the maximum yield strength is achieved when the mass ratio of PLCL to PTMC is 1:1. Therefore, a mass ratio of PLCL to PTMC of 1:1 is preferred for further research.

[0089] 2. Screening of microelectric field conditions for endothelial cells

[0090] An extracorporeal circulation device simulating the heart's pumping action was constructed (such as...) Figure 4 As shown in the figure, the pulsation of rabbit blood circulation was simulated (pulsation frequency was 18 times / min). The voltage generated by the PVDF prepared in Examples 2-4 was measured using an electrochemical workstation.

[0091] The results are as follows Figure 5 As shown in the figure, PVDF can convert the mechanical energy of blood pulsation into electrical energy, generating a sufficiently strong voltage of 300mV, which meets the requirements for electrical stimulation of cell proliferation (>50mV).

[0092] Human umbilical vein endothelial cells were seeded onto interdigital capacitors. Then, PVDF electronic blood vessels of different areas prepared in Examples 1-4 were rolled into 2 mm tubes and connected to an extracorporeal circulation device. Micro-electric field strengths were set to 0, 20, 50, 100, and 270 mV mm, respectively. -1 The interval was 0.3s, and the proliferation of endothelial cells was measured 2 days later. The control group was measured using 0mV mm. -1 The voltage was processed, and the blank control group initial was human umbilical vein endothelial cells were seeded on the interdigital capacitor.

[0093] The results are as follows Figure 6-7 As shown, from Figure 6 It can be seen that, compared with the control group, the PVDF-equipped electronic blood vessels were able to promote endothelial cell proliferation and accelerate the endothelialization process. Figure 7 As can be seen, the optimal micro-electric field condition is 50mV / mm. -1 The pulsed electric field was used with an interval of 0.3s, and the optimal micro-electric field conditions were used for subsequent research.

[0094] 3. Determination of capacitance changes under pulsating blood flow conditions

[0095] The electronic blood vessel prepared in Example 1 of this invention forms an antenna device through two layers of liquid metal-polymer composite thin film (e.g.) Figure 8 As shown in the diagram, the two parallel electrode lines extending from the electrode form the capacitor. A schematic diagram of the capacitive sensor is shown below. Figure 9As shown, an antenna device is formed by two layers of liquid metal-polymer composite thin film, with the two extending parallel electrode lines constituting the capacitor portion. To enhance its sensitivity, an elastic polymer pyramid structure was prepared (obtained by using a pyramid mold with a 1% mass fraction of PLCL and PTMC dissolved in dichloromethane, with a volume ratio of 1:1). Polymer pyramid structures of different sizes with base side lengths of 5, 10, and 20 μm and spacings of 5, 10, and 20 μm were obtained through casting. These polymer thin films with pyramid structures of different sizes were used as the dielectric material for the capacitive sensor. The pyramid film was placed at both ends of the two parallel electrode lines, thus forming the capacitive sensor portion.

[0096] The capacitance change of the electronic blood vessel prepared in Example 1 was measured using an electrochemical workstation (the pulsation of the blood vessel causes a change in the thickness of the dielectric material, which in turn leads to a change in the capacitance value in the circuit). The polymer pyramid structure of the capacitance sensor used had a base side length of 5, 10, and 20 μm and a spacing of 5, 10, and 20 μm, respectively. The experiment was conducted using an extracorporeal circulation device that simulates the heart pumping blood.

[0097] Changes in the capacitance of blood vessels can be wirelessly monitored by a network vector analyzer using an external coil. Therefore, by converting the frequency of these capacitance changes into the frequency of blood vessel pulsation, it is possible to wirelessly monitor the flow of blood and determine if the vessel is blocked.

[0098] The detection signal diagrams of capacitive sensors with different sizes of pyramid structures are shown in the figure. Figure 10 As shown, from Figure 10 As can be seen, a 5μm size is optimal; the results of capacitance changes under blood flow pulsation are as follows: Figure 11 As shown, from Figure 11 As can be seen, the 5μm pyramid structure capacitive sensor is more sensitive, and the S11 changes more significantly.

[0099] 4. Long-term implantation and functional verification in vivo

[0100] The 2mm coiled electronic blood vessel prepared in Example 1 was implanted into a rabbit carotid artery model (e.g., Figure 12 (As shown). Two years after long-term implantation in the blood vessel, the morphology of the electronic blood vessel was examined by ultrasound and arterial angiography in rabbits. Tissue samples were taken, and the endothelialization process of the blood vessel graft was assessed by HE, Masson staining, and immunofluorescence staining.

[0101] The results are as follows Figure 13-15 As shown, from Figure 13-15As can be seen, the electronic blood vessel prepared by this invention can be implanted for a long time and has good biocompatibility. Figure 15 In this study, HE staining represents the distribution of cells and their nuclei; Masson staining is used to show the fiber distribution in the artificial blood vessel graft; CD31 is a marker of endothelial cells, used to mark their distribution; ColI is type I collagen, and Col III is type III collagen, both of which are abundant collagen types in vascular tissue. Staining these markers shows that the electronic blood vessels prepared in this embodiment of the invention underwent a better tissue remodeling process after transplantation, and cell regeneration and migration better promoted vascular degradation. Simultaneously, the abundant regeneration of collagen and fibers provides a good microenvironment and mechanical properties. The results indicate that, compared with the control group without PVDF (the only difference between the control group and Example 1 is the absence of PVDF), the self-powered electrically stimulated electronic blood vessels have better patency and can improve their endothelialization process.

[0102] The embodiments of the present invention have been described in detail above with reference to the accompanying drawings. However, the present invention is not limited to the above embodiments, and various changes can be made within the scope of knowledge possessed by those skilled in the art without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof can be combined with each other unless otherwise specified.

Claims

1. A method for preparing an electronic blood vessel, characterized in that, Includes the following steps: S1. Liquid metal ink is liquefied on a PET film to form a micro-electric field electrostimulation pattern, thereby preparing a PET film with patterned liquid metal ink; S2. The polymer solution is formed on the PET film of patterned liquid metal ink, and the resulting composite film is peeled off from the PET film of patterned liquid metal ink to obtain a polymer composite film. S3. Place the PVDF film between two symmetrical polymer composite films obtained in step S2 and fix them together to obtain the electronic blood vessel composite film. S4. Roll the electronic blood vessel composite film obtained in step S3 into a tubular shape to obtain the electronic blood vessel. The electrical stimulation pattern is an interdigital capacitor electrical stimulation pattern. The electronic blood vessel also includes a capacitive sensor; the capacitive sensor can wirelessly monitor blood flow and monitor the blockage of the artificial blood vessel.

2. The preparation method according to claim 1, characterized in that, The polymer solution includes at least one of PLCL, PTMC, PLGA, PGA, and PLA.

3. The preparation method according to claim 1, characterized in that, The polymer solution has a mass fraction of 0.8-1.5%.

4. The preparation method according to claim 1, characterized in that, The PVDF film is a PVDF film that has been treated with platinum, gold, silver or copper by magnetron sputtering.

5. The preparation method according to claim 1, characterized in that, The PVDF has a thickness of 18-25 μm and an area of ​​1-220 mm². 2 .

6. The preparation method according to claim 1, characterized in that, The capacitive sensor includes a flexible polymer pyramid structure, which can enhance the sensitivity of the capacitive sensor.

7. An electronic blood vessel, characterized in that, Prepared by the method according to any one of claims 1-6.

8. The electronic blood vessel according to claim 7, characterized in that, The diameter of the electronic blood vessel is 1-2.5 mm.

9. The application of the electronic blood vessel according to claim 7 or 8 in the preparation of vascular gene therapy materials, drug delivery materials, tissue engineering, biosensing, and optoelectronic materials.

10. An artificial blood vessel, characterized in that, The artificial blood vessel includes the electronic blood vessel as described in claim 7 or 8.

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