CN117504137B - Cardiac pacemaker fixing device and preparation method thereof - Google Patents
Cardiac pacemaker fixing device and preparation method thereof Download PDFInfo
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- CN117504137B CN117504137B CN202410014062.1A CN202410014062A CN117504137B CN 117504137 B CN117504137 B CN 117504137B CN 202410014062 A CN202410014062 A CN 202410014062A CN 117504137 B CN117504137 B CN 117504137B
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/372—Arrangements in connection with the implantation of stimulators
- A61N1/375—Constructional arrangements, e.g. casings
- A61N1/37512—Pacemakers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/362—Heart stimulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/362—Heart stimulators
- A61N1/37—Monitoring; Protecting
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/372—Arrangements in connection with the implantation of stimulators
- A61N1/375—Constructional arrangements, e.g. casings
- A61N1/37518—Anchoring of the implants, e.g. fixation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/372—Arrangements in connection with the implantation of stimulators
- A61N1/375—Constructional arrangements, e.g. casings
- A61N1/3758—Packaging of the components within the casing
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Biophysics (AREA)
- Electrotherapy Devices (AREA)
Abstract
The invention discloses a cardiac pacemaker fixing device and a preparation method thereof, and belongs to the technical field of medical appliances. The cardiac pacemaker fixing device comprises a fixing wing body, a strain sensor and a medicine reservoir. The strain sensor is positioned at the middle part of the bottom of the hook body of the fixed wing body; the fixed wing body is provided with a double-sided groove, and the medicine storage warehouse comprises a medicine storage warehouse with double-sided grooves and a medicine coating layer on the surface of the fixed wing body. The medicine storage library consists of a chitosan carrier and endothelial growth factor; the drug coating consists of a polydopamine substrate and bioactive molecules. The strain sensor is favorable for monitoring the combination state of the cardiac pacemaker and the cardiac muscle, so that the cardiac pacemaker is accurately fixed; the surface bioactive molecules in the drug reservoir are beneficial to adsorbing endothelial cells, the endothelial growth factors can promote the adhesion and proliferation of the endothelial cells, the combined action of the two molecules is beneficial to promoting the endothelialization process, and the long-term fixation stability of the cardiac pacemaker is further improved.
Description
Technical Field
The invention relates to the technical field of medical appliances, in particular to a cardiac pacemaker fixing device and a preparation method thereof.
Background
Implantable cardiac pacemaker therapy is currently one of the most successful biomedical engineering treatment techniques today and has been widely used in clinical work. The cardiac pacemaker has the main indications of slow arrhythmia such as heart block, sick sinus syndrome and the like, and is also applied to a series of new indications such as hypertrophic obstructive cardiomyopathy, chronic heart failure, atrial fibrillation, orthostatic hypotension, vasovagal syncope and the like. Wherein the sinus node dysfunction disease and causing symptoms is a class I indication. With the awareness of cardiac pacemaker indications and the continued improvement of pacing engineering, patients in need of pacemaker therapy are increasing year by year.
In the existing implanted cardiac pacemakers, the number of the traditional cardiac pacemakers with the pulse generator of the subcutaneously implanted cardiac pacemakers connected with the electrode lead which is arranged through the vein is large, but the traditional cardiac pacemakers still have some limitations and defects, and the incidence rate of related complications in operation and after operation is high. Leadless cardiac pacemakers can reduce the capsular bag and lead related complications of venous system pacing, with significant advantages in clinic over conventional cardiac pacemakers. Nevertheless, there are still some disadvantages, if the implantation site is not fixed exactly, often resulting in a displacement of the leadless cardiac pacemaker, which may fall off to the pulmonary artery or right femoral vein, and serious cases may cause pulmonary embolism. The CN201180061312.8 patent provides a leadless cardiac pacemaker with a radial fixation mechanism that includes a fixation mechanism separate from the pacing electrode and having a diameter equal to or less than the outer diameter of the pacemaker that allows the pacemaker to be inserted into tissue over 2 rotations. The application number CN201611034171.1 provides a cardiac pacing device, a fixing method and a conveying system thereof, wherein the cardiac pacing device comprises a ring-shaped bracket and a cardiac pacemaker, the leadless pacemaker is at least partially arranged on the ring-shaped bracket, and the ring-shaped bracket has a first size under the condition that the rebound of the leadless pacemaker is limited by a first environment and expands to a second size under a second environment; the annular stent has self-expansion property, and can be tightly attached to the wall of a primary blood vessel, so that the fixation of the cardiac pacemaker device and the atrium is realized. Patent application number CN201811134030.6 discloses a cardiac pacemaker system and a pacemaker fixing device, which consists of an annular bracket and at least one receiving and releasing part, wherein the annular bracket is used for installing a leadless pacemaker so as to reliably fix the leadless pacemaker at a preset position in a body. The above patent adopts various mechanical designs to fix the cardiac pacemaker, enhances the firmness of the cardiac pacemaker to a certain extent, does not relate to monitoring the combination state of the cardiac pacemaker and cardiac muscle in the design process, and does not relate to promoting the rapid combination of organism tissues and a fixing device, so that the stability of long-term fixation cannot be ensured.
Disclosure of Invention
The invention provides a cardiac pacemaker fixing device and a preparation method thereof, which are used for solving the problems of lack of supervision on a fixed state and long-term stability of fixation in the current cardiac pacemaker system design and further reducing the probability of displacement of a cardiac pacemaker.
In order to achieve the technical aim, the invention provides a cardiac pacemaker fixing device, the main structure of which consists of a fixing wing body, a strain sensor and a medicine reservoir; the fixed wing body is provided with a double-sided groove, and the surface of the fixed wing body is provided with micropores; the fixed wing body consists of four hook bodies, and the strain sensor is positioned at the middle part of the bottom of the hook body of the fixed wing body; the medicine storage warehouse comprises a medicine storage warehouse positioned in the grooves on the two sides of the fixed wing body and a medicine coating positioned on the surface of the fixed wing body; the drug storage library consists of a chitosan carrier and endothelial growth factor, and the drug coating consists of a polydopamine substrate and bioactive molecules.
Further, the strain sensors are passive wireless strain sensors, the number of the strain sensors is four, and the strain sensors are respectively stuck in grooves in the middle part of the bottom of the hook body of the fixed wing body through adhesive; the passive wireless strain sensor consists of a resistance strain gauge, a radio frequency chip, a radio frequency antenna and a circuit board, and the sensing element is the resistance strain gauge; the wireless signal transceiver module in the pacemaker program control instrument sends out electromagnetic waves with certain frequency through the antenna, and when the radio frequency chip enters the working range of the transmitting antenna, induced current is generated inside the radio frequency chip and activated; after the resistance strain gauge is strained, the resistance variable quantity is converted into a voltage signal through the circuit board, then the voltage signal is transmitted to the radio frequency chip, information in the radio frequency chip is transmitted to a wireless signal receiving and transmitting module of the pacemaker program-controlled instrument through the radio frequency antenna, and the pacemaker program-controlled instrument processes and analyzes the received signal to monitor the strain of the fixed wing, so that whether the implantation state is reliable or not is further judged.
Further, the double-sided grooves are distributed on two sides of the fixed wing body, the positions of the double-sided grooves are opposite, the grooves are in a long strip shape, the length of each groove is 5-8 mm, the width of each groove is 100-300 mu m, and the depth of each groove is 20-50 mu m. Compared with the conventional drug-carrying coating, the drug-carrying coating in the groove not only can increase the drug-carrying capacity, but also can reduce the drug loss in the implantation process of the cardiac pacemaker.
Further, the viscosity of the chitosan is 100-400 mPa.s, and the endothelial growth factor is Vascular Endothelial Growth Factor (VEGF); the chitosan has good biodegradability, and the degradation product has no toxic or side effect on human body and tissues and has good biocompatibility; and can be swelled into gel under weak acid condition, and has extremely strong plasticity. The vascular endothelial growth factor can promote the division and proliferation of vascular endothelial cells and promote the repair after injury.
Further, the polydopamine substrate is polymerized by dopamine, and the bioactive molecule is arginine-glutamine-aspartic acid-valine (REDV) or arginine-glycine-aspartic acid (RGD); the polydopamine substrate has stronger interfacial bonding force, and is immersed into liquid medicine containing bioactive molecules to form a surface coating.
Further, the preparation method of the cardiac pacemaker fixing device comprises the following steps:
(1) Firstly, carrying out double-sided groove treatment on a fixed wing body through laser grooving;
(2) Carrying out microporation treatment on the surface of the fixed wing body by using a chemical pickling method;
(3) Preparing a drug coating: dissolving dopamine hydrochloride in Tris-HCl buffer solution, placing the fixed wing body treated in the step (2) in the solution, and reacting for 12-24 hours in a shaking table to form a polydopamine coating on the surface of the fixed wing body; dissolving bioactive molecules in PBS buffer solution, immersing the treated fixed wing body in the liquid medicine, standing at 4deg.C for 24 hr, taking out, washing with PBS for three times, and drying at room temperature;
(4) Placing the strain sensor in a groove at the middle part of the bottom of the hook body of the fixed wing body, and fixing the strain sensor by using an adhesive;
(5) Preparing a medicine storage warehouse: dissolving chitosan in acetic acid, stirring to obtain chitosan acetic acid solution, adjusting pH to 4-6, and then adding endothelial growth factor solution; dropwise adding sodium tripolyphosphate solution into the system, stirring at room temperature to obtain suspension, centrifuging at 4deg.C for 30min, collecting precipitate, dialyzing in PBS solution for 3 times, adding into a tablet press, pre-pressing, transferring into grooves of the fixed wing body, compacting again, and lyophilizing for 24 hr to obtain the fixed wing body with drug reservoir.
Further, the specific operation of the chemical pickling method in the step (2) is as follows: ultrasonically cleaning the fixed wing body in acetone for 10min, and after the fixed wing body is dried, putting the fixed wing body with the clean surface into HNO with the volume fraction of 20% -40% 3 Soaking in the solution at 4 ℃ for 24 hours; respectively ultrasonic cleaning with deionized water and acetone for 10min, and dryingAnd (5) standby.
Further, in the step (3), the concentration of the dopamine hydrochloride solution is 2-8 mg/mL, the setting parameter of the shaking table is 37 ℃, the concentration of the bioactive molecule solution is 0.5-1 mug/mL, and the mass ratio of the bioactive molecule to the dopamine hydrochloride is 1:100-1:1000.
Further, in the step (5), the concentration of the chitosan acetic acid solution is 2.5-4 mg/mL, the mass ratio of the endothelial growth factor to the chitosan is 1:5000-1:500, and the mass ratio of the sodium tripolyphosphate to the chitosan is 1:3-1:6.
Compared with the prior art, the invention has the following beneficial effects:
1. the passive wireless strain sensor is arranged on the fixed wing body of the cardiac pacemaker, so that the strain condition of the fixed wing can be sensed, the combination condition of the fixed wing and the cardiac muscle is judged in a traction experiment, the hook bodies of more than two fixed wing bodies are ensured to be combined with the cardiac muscle in the implantation process of the cardiac pacemaker, and the probability of displacement is reduced.
2. The fixed wing body of the cardiac pacemaker is provided with the double-sided groove, and the medicine storage warehouse is arranged in the groove.
3. The vascular endothelial growth factor can promote the adhesion and proliferation of endothelial cells, and the chitosan can achieve the effects of slow release and controlled release by being used as a degradable drug carrier, so that the drug effect is better exerted, and the implanted cardiac pacemaker can be better fixed and combined with the organism.
4. In addition, the bioactive molecules loaded on the upper surface of the pacemaker fixing wing body are beneficial to the adsorption of endothelial cells by the pacemaker fixing wing, so that the endothelialization process is further accelerated.
In a word, the cardiac pacemaker fixing wing device can ensure that an implanted cardiac pacemaker can be firmly combined with cardiac muscle in an implantation process, and can induce adhesion and growth of endothelial cells so as to ensure long-term stability of fixation of the cardiac pacemaker and reduce probability of occurrence of cardiac pacemaker displacement.
Drawings
Fig. 1 is a schematic structural view of a cardiac pacemaker fixation device.
Fig. 2 is a schematic of drug release from a cardiac pacemaker drug reservoir.
FIG. 3 is a graph of the relative cell activities of the examples and comparative examples after 3 days of cell culture.
In the figure, a 1-fixed wing body, a 2-strain sensor, a 3-medicine storage warehouse and a 4-medicine coating are arranged.
Detailed Description
The following description of the embodiments of the present invention will be made more apparent and fully hereinafter with reference to the accompanying drawings, in which some, but not all embodiments of the invention are shown. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Fig. 1 shows a schematic structure of a cardiac pacemaker fixing device, and a main structure of the cardiac pacemaker fixing device comprises a fixing wing body 1, a strain sensor 2 and a medicine reservoir. The fixed wing body 1 is provided with double-sided grooves, and the strain sensor 2 is positioned in the groove at the middle part of the bottom of the hook body of the fixed wing body 1. The medicine storage warehouse comprises a medicine storage warehouse 3 positioned on the grooves on the two sides of the fixed wing body 1 and a medicine coating 4 positioned on the surface of the fixed wing body 1. The surface of the fixed wing body 1 is provided with micropores, the micropores are formed by a chemical acid washing method and are uniformly distributed on the surface of the fixed wing body 1, and the existence of the micropores is beneficial to improving the firmness of the surface coating. The double-sided grooves of the fixed wing body 1 are formed by machining in a laser grooving mode, the double-sided grooves are distributed on two sides of the fixed wing body 1 and are opposite in position, the length of each groove is 5-8 mm, the width of each groove is 100-300 mu m, and the depth of each groove is 20-50 mu m.
Fig. 2 is a schematic diagram of drug release of a cardiac pacemaker drug reservoir, wherein the drug reservoir 3 is composed of a chitosan carrier and endothelial growth factor, the viscosity of chitosan is 100-400 mpa·s, and the endothelial growth factor is Vascular Endothelial Growth Factor (VEGF). The drug coating 4 is composed of a polydopamine substrate and bioactive molecules, wherein the polydopamine substrate is polymerized by dopamine, and the bioactive molecules are arginine-glutamyl-aspartic acid-valine (REDV) or arginine-glycine-aspartic acid (RGD).
Example 1
The cardiac pacemaker fixing device is prepared by the following method:
(1) Firstly, carrying out double-sided groove treatment on a fixed wing body 1 through laser grooving, wherein the groove length is 6.5mm, the groove width is 200 mu m, and the groove depth is 35 mu m;
(2) Ultrasonically cleaning the fixed wing body 1 in acetone for 10min, drying, and then placing the fixed wing body 1 with clean surface into HNO with volume fraction of 30% 3 Soaking in the solution at 4 ℃ for 24 hours; respectively ultrasonically cleaning with deionized water and acetone for 10min, and drying for later use;
(3) Preparation of drug coating 4: 100mg of dopamine hydrochloride is weighed and dissolved in Tris-HCl buffer solution (pH=8.5) to prepare a solution of 5mg/mL, the fixed wing body 1 treated in the step (2) is placed in the solution, the solution is reacted for 18h (37 ℃ and 100 rmp) in a shaking table to oxidize and self-polymerize the dopamine, and a uniform polydopamine coating is formed on the surface of the fixed wing body 1. Dissolving 550 mug REDV in PBS buffer solution to prepare a liquid medicine with the concentration of 0.75 mug/mL, immersing the treated fixed wing body 1 in the liquid medicine, standing for 24 hours at the temperature of 4 ℃, taking out, flushing with PBS for three times, and drying at room temperature;
(4) The strain sensor 2 is placed in a groove at the middle part of the bottom of the hook body of the fixed wing body 1 and is fixed by using an adhesive;
(5) Preparation of drug depot 3: 200mg of chitosan (200-300 mPa.s) is weighed and dissolved in 65mL of acetic acid with volume fraction of 1%, and magnetically stirred for 2 hours to obtain 3.1mg/mL of chitosan acetic acid solution; to the above solution, 1mol/L NaOH solution was added dropwise to adjust the pH to 5, 40mL of 5.5. Mu.g/mL VEGF solution was prepared, and the solution was added dropwise to the chitosan acetic acid solution. 45mL of sodium tripolyphosphate solution with the concentration of 1mg/mL is dropwise added into the system, and stirring is carried out for 30min at room temperature; the obtained suspension was centrifuged at 4℃for 30min (15000 rmp/min), the precipitate was collected, dialyzed 3 times in PBS solution, and then added into a tablet press to be pre-pressed and formed, and then transferred into a groove of the stationary vane body 1 to be compacted again, and freeze-dried for 24h, thereby obtaining the stationary vane body 1 with a drug reservoir.
Example 2
The cardiac pacemaker fixing device is prepared by the following method:
(1) Firstly, carrying out double-sided groove treatment on a fixed wing body 1 through laser grooving, wherein the groove length is 5mm, the groove width is 100 mu m, and the groove depth is 20 mu m;
(2) Ultrasonically cleaning the fixed wing body 1 in acetone for 10min, drying, and then placing the fixed wing body 1 with clean surface into HNO with volume fraction of 20% 3 Soaking in the solution at 4 ℃ for 24 hours; respectively ultrasonically cleaning with deionized water and acetone for 10min, and drying for later use;
(3) Preparation of drug coating 4: 100mg of dopamine hydrochloride is weighed and dissolved in Tris-HCl buffer solution (pH=8.5) to prepare 2mg/mL solution, the fixed wing body 1 treated in the step (2) is placed in the solution, the solution is reacted for 12h (37 ℃ and 100 rmp) in a shaking table to oxidize and self-polymerize dopamine, and a uniform polydopamine coating layer is formed on the surface of the fixed wing body 1. Dissolving 100 mug REDV in PBS buffer solution to prepare a liquid medicine with the concentration of 0.5 mug/mL, immersing the treated fixed wing body 1 in the liquid medicine, standing for 24 hours at the temperature of 4 ℃, taking out, flushing for three times by PBS, and drying at room temperature;
(4) The strain sensor 2 is placed in a groove at the middle part of the bottom of the hook body of the fixed wing body 1 and is fixed by using an adhesive;
(5) The preparation of the drug depot 3 is then carried out: 200mg of chitosan (100-200 mPa.s) is weighed and dissolved in 50mL of acetic acid with volume fraction of 1%, and magnetically stirred for 2 hours to obtain 4mg/mL of chitosan acetic acid solution; to the above solution, a 1mol/L NaOH solution was added dropwise to adjust the pH to 4. 40mL of VEGF solution (1. Mu.g/mL) was prepared and added dropwise to the chitosan acetic acid solution. Adding 33mL of sodium tripolyphosphate solution with the concentration of 1mg/mL into the system dropwise, and stirring for 30min at room temperature; the obtained suspension was centrifuged at 4℃for 30min (15000 rmp/min), the precipitate was collected, dialyzed 3 times in PBS solution, and then added into a tablet press to be pre-pressed and formed, and then transferred into a groove of the stationary vane body 1 to be compacted again, and freeze-dried for 24h, thereby obtaining the stationary vane body 1 with a drug reservoir.
Example 3
(1) Firstly, carrying out double-sided groove treatment on a fixed wing body 1 through laser grooving, wherein the groove length is 8mm, the groove width is 300 mu m, and the groove depth is 50 mu m;
(2) Ultrasonically cleaning the fixed wing body 1 in acetone for 10min, drying, and then placing the fixed wing body 1 with clean surface into HNO with volume fraction of 40% 3 Soaking in the solution at 4 ℃ for 24 hours; respectively ultrasonically cleaning with deionized water and acetone for 10min, and drying for later use;
(3) Preparation of drug coating 4: 100mg of dopamine hydrochloride is weighed and dissolved in Tris-HCl buffer solution (pH=8.5) to prepare 8mg/mL solution, the fixed wing body 1 treated in the step (2) is placed in the solution, the solution is reacted for 24 hours (37 ℃ and 100 rmp) in a shaking table to oxidize and self-polymerize the dopamine, and a uniform polydopamine coating layer is formed on the surface of the fixed wing body 1. Dissolving 1000 mug REDV in PBS buffer solution to prepare a liquid medicine with the concentration of 1 mug/mL, immersing the treated fixed wing body 1 in the liquid medicine, standing for 24 hours at the temperature of 4 ℃, taking out, flushing with PBS for three times, and drying at room temperature;
(4) The strain sensor 2 is placed in a groove at the middle part of the bottom of the hook body of the fixed wing body 1 and is fixed by using an adhesive;
(5) The preparation of the drug depot 3 is then carried out: 200mg of chitosan (300-400 mPa.s) is weighed and dissolved in 80mL of acetic acid with volume fraction of 1%, and magnetically stirred for 2 hours to obtain 2.5mg/mL of chitosan acetic acid solution; to the above solution, a 1mol/L NaOH solution was added dropwise to adjust the pH to 6. 40mL of 10. Mu.g/mL VEGF solution was prepared and added dropwise to the chitosan acetic acid solution. 67mL of sodium tripolyphosphate solution with the concentration of 1mg/mL is added into the system dropwise, and stirring is carried out for 30min at room temperature; the obtained suspension was centrifuged at 4℃for 30min (15000 rmp/min), the precipitate was collected, dialyzed 3 times in PBS solution, and then added into a tablet press to be pre-pressed and formed, and then transferred into a groove of the stationary vane body 1 to be compacted again, and freeze-dried for 24h, thereby obtaining the stationary vane body 1 with a drug reservoir.
Example 4
The same as in example 1, except that the drug in step (3) was RGD.
Comparative example 1
And respectively ultrasonically cleaning the fixed wing body 1 in deionized water and acetone for 10min, and drying for later use. Unlike the examples, the comparative example did not proceed with the five-step manufacturing process of the fixed wing body 1.
Comparative example 2
(1) Firstly, carrying out double-sided groove treatment on a fixed wing body 1 through laser grooving, wherein the groove length is 4mm, the groove width is 50 mu m, and the groove depth is 15 mu m;
(2) Ultrasonically cleaning the fixed wing body 1 in acetone for 10min, drying, and then placing the fixed wing body 1 with clean surface into HNO with volume fraction of 10% 3 Soaking in the solution at 4 ℃ for 24 hours; respectively ultrasonically cleaning with deionized water and acetone for 10min, and drying for later use;
(3) Preparation of drug coating 4: 100mg of dopamine hydrochloride is weighed and dissolved in Tris-HCl buffer solution (pH=8.5) to prepare a solution of 1mg/mL, the fixed wing body 1 treated in the step (2) is placed in the solution, the solution is reacted for 8 hours (37 ℃ and 100 rmp) in a shaking table to oxidize and self-polymerize the dopamine, and a uniform polydopamine coating is formed on the surface of the fixed wing body 1. Dissolving 80 mug REDV in PBS buffer solution to prepare a liquid medicine with the concentration of 0.4 mug/mL, immersing the treated fixed wing body 1 in the liquid medicine, standing for 24 hours at the temperature of 4 ℃, taking out, flushing for three times by PBS, and drying at room temperature;
(4) The strain sensor 2 is placed in a groove at the middle part of the bottom of the hook body of the fixed wing body 1 and is fixed by using an adhesive;
(5) Preparation of drug depot 3: 200mg of chitosan (100-200 mPa.s) is weighed and dissolved in 100mL of acetic acid with volume fraction of 1%, and magnetically stirred for 2 hours to obtain 2mg/mL of chitosan acetic acid solution; to the above solution, 1mol/L NaOH solution was added dropwise to adjust the pH to 5, 40mL of a 0.5. Mu.g/mL VEGF solution was prepared, and the solution was added dropwise to the chitosan acetic acid solution. Dropwise adding 20mL of sodium tripolyphosphate solution with the concentration of 1mg/mL into the system, and stirring for 30min at room temperature; the obtained suspension was centrifuged at 4℃for 30min (15000 rmp/min), the precipitate was collected, dialyzed 3 times in PBS solution, and then added into a tablet press to be pre-pressed and formed, and then transferred into a groove of the stationary vane body 1 to be compacted again, and freeze-dried for 24h, thereby obtaining the stationary vane body 1 with a drug reservoir.
Comparative example 3
(1) Firstly, carrying out double-sided groove treatment on a fixed wing body 1 through laser grooving, wherein the groove length is 9mm, the groove width is 400 mu m, and the groove depth is 60 mu m;
(2) Ultrasonically cleaning the fixed wing body 1 in acetone for 10min, drying, and then placing the fixed wing body 1 with clean surface into HNO with volume fraction of 40% 3 Soaking in the solution at 4 ℃ for 24 hours; respectively ultrasonically cleaning with deionized water and acetone for 10min, and drying for later use;
(3) Preparation of drug coating 4: 100mg of dopamine hydrochloride is weighed and dissolved in Tris-HCl buffer solution (pH=8.5) to prepare 10mg/mL solution, the fixed wing body 1 treated in the step (2) is placed in the solution, the solution is reacted for 36h (37 ℃ C., 100 rmp) in a shaking table to enable dopamine to oxidize and self-polymerize, and a uniform polydopamine coating is formed on the surface of the fixed wing body 1. Dissolving 1200 mug REDV in PBS buffer solution to prepare a liquid medicine with the concentration of 1.2 mug/mL, immersing the treated fixed wing body 1 in the liquid medicine, standing for 24 hours at the temperature of 4 ℃, taking out, flushing with PBS for three times, and drying at room temperature;
(4) The strain sensor 2 is placed in a groove at the middle part of the bottom of the hook body of the fixed wing body 1 and is fixed by using an adhesive;
(5) Preparation of drug depot 3: 200mg of chitosan (300-400 mPa.s) is weighed and dissolved in 40mL of acetic acid with volume fraction of 1%, and the solution is magnetically stirred for 2 hours to obtain 5mg/mL of chitosan acetic acid solution; to the above solution, a 1mol/L NaOH solution was added dropwise to adjust the pH to 5, and 40mL of a 12. Mu.g/mL VEGF solution was prepared and added dropwise to the above chitosan acetic acid solution. 70mL of sodium tripolyphosphate solution with the concentration of 1mg/mL is dropwise added into the system, and stirring is carried out for 30min at room temperature; the obtained suspension was centrifuged at 4℃for 30min (15000 rmp/min), the precipitate was collected, dialyzed 3 times in PBS solution, and then added into a tablet press to be pre-pressed and formed, and then transferred into a groove of the stationary vane body 1 to be compacted again, and freeze-dried for 24h, thereby obtaining the stationary vane body 1 with a drug reservoir.
1. In vitro Release test
The cardiac pacemaker system constructed in the fixing modes of the examples and the comparative examples is used for in vitro release experiments to test the fixing performance of the cardiac pacemaker fixing device. The accuracy of judgment of stable combination of the hook teeth and the cardiac muscle of the cardiac pacemaker fixing wing body 1 is compared, and the result is as follows:
| example 1 | Example 2 | Example 3 | Example 4 | Comparative example 1 | Comparative example 2 | Comparative example 3 | |
| Accuracy rate of | 100% | 100% | 100% | 100% | 70% | 100% | 100% |
Analyzing the reason: when the cardiac pacemaker system adopting the fixing modes of the embodiment, the comparative example 2 and the comparative example 3 is adopted, after the cardiac pacemaker reaches a preset position for release, a traction experiment is carried out later, when the hook body of the fixed wing body 1 hooks myocardial tissues, the traction action can cause the strain of the hook body of the fixed wing body 1, the strain sensor 2 arranged on the fixed wing in the embodiment can sense the strain state of each hook body of the fixed wing, the pacemaker program controller can analyze the strain state, thereby accurately judging whether each hook body can stably hook the myocardial, and when at least two hook bodies of the fixed wing body 1 stably hook the myocardial, the release and the installation of the cardiac pacemaker are considered to be successful, and the combination state of the fixed wing body 1 of the cardiac pacemaker and the myocardial is accurately judged due to the arrangement of the strain sensor 2.
When the cardiac pacemaker system of the fixing mode of the comparative example 1 is adopted, the state that the fixed wing body 1 is combined with the cardiac muscle can only be roughly judged by using the traditional radiography means in the implantation process, and in the traction experiment, the state is usually judged by the form change of the hook body, on one hand, the size of the hook body is smaller, and the change is not easy to observe; on the other hand, since the contrast of the image obtained by the imaging means is limited, even if the hook shape changes, stable combination of the hook and the cardiac muscle cannot be determined, for example, the hook shape can also change due to the fact that only the distal end of the hook is touched by tissues, so that the accuracy is limited.
2. In vitro cell experiments
Cell activity of Human Umbilical Vein Endothelial Cells (HUVECs) on the surface of cardiac pacemaker fixation devices was evaluated by MTT assay. Samples of the examples and comparative examples were taken, 3 replicates each, and placed into cell culture plates, with 20 μl of HUVECs cell suspension added to each well. Three days after addition of the cells of the corresponding cell culture medium, an additional 20. Mu.L of MTT solution (5 mg/mL) was added to each well and the incubation was continued for 4 hours at 37 ℃. The medium was then removed and dissolved in 150. Mu.L of DMSO and the absorbance of the solution was measured at 490nm using a microplate reader. Relative cell activity of each group of samples was calculated from absorbance using the cell culture plates as controls.
The relative cell activities after 3 days of incubation for the examples and comparative samples are shown in FIG. 3. From the graph, all the example surfaces show relatively high cell activity on HUVECs, more than 90%; the comparative example surface showed relatively slightly lower cell activity on the HUVECs surface, and the above results demonstrate that the cardiac pacemaker fixation device prepared by the method of the example was non-cytotoxic and beneficial to the growth of endothelial cells to some extent.
3. Animal experiment
Samples of example 1 and comparative example 1 were implanted into hearts of different pigs, and after 1 month and 2 months of implantation, the endothelialization degree of the pacemaker fixed wing body 1 was observed.
The implantation procedure fixation state monitoring procedure of example 1 is as follows: after the cardiac pacemaker reaches a preset position for release, carrying out a traction experiment, and when the program control instrument shows that the fixed wing body 1 has at least two hooks which can stably hook cardiac muscle, considering that the release and the installation of the cardiac pacemaker are successful; the implantation procedure of comparative example 1 was not effected by the monitoring system described above.
The number of hooks that hooked the myocardium during implantation and when the material was obtained was recorded, respectively, with the following results:
| implantation procedure 1 | Sampling Process 2 | Implantation procedure 2 | Sampling Process 2 | |
| Example 1 | 4 | 4 | 4 | 4 |
| Comparative example 1 | 4 | 4 | 4 | 3 |
From the above results, the cardiac pacemaker fixing device of embodiment 1 can accurately determine the combination state of the hook body of the fixation wing body 1 and the cardiac muscle, and the hook body does not fall off during the implantation window period; there are two possibilities for the reduction of the number of hooks that catch on the myocardium in the material drawing process 2 of comparative example 1: firstly, the number of hooks actually hooked on the cardiac muscle is 4 in the implantation process, the number of hooks is 3 in the material drawing process, and one hook falls off from cardiac muscle tissue in the implantation time period; another possibility is that the number of hooks actually catching the myocardium is 3 during the implantation procedure, but the condition judgment is wrong due to the lack of the monitoring system in the embodiment. The above effects show that the cardiac pacemaker fixing device is more reliable than the device of the comparative example.
Endothelialization results were as follows: example 1 complete endothelialization has been achieved at 1 month of implantation; whereas comparative example 1 had a lower degree of endothelialization at 1 month of implantation and achieved endothelialization at 2 months of implantation. The animal experiment result is consistent with the in-vitro cell experiment result, and the cardiac pacemaker fixing device is favorable for accelerating the endothelialization process, so that the stability of long-term fixation of the cardiac pacemaker fixing device is ensured.
Claims (8)
1. The cardiac pacemaker fixing device is characterized in that the main body structure consists of a fixed wing body, a strain sensor and a medicine reservoir; the fixed wing body is provided with a double-sided groove, and the surface of the fixed wing body is provided with micropores; the strain sensors are positioned in grooves in the middle parts of the bottoms of the four hook bodies of the fixed wing body; the medicine storage warehouse comprises a medicine storage warehouse positioned in the grooves on the two sides of the fixed wing body and a medicine coating positioned on the surface of the fixed wing body; the drug storage library consists of chitosan and endothelial growth factor, and the drug coating consists of a polydopamine substrate and bioactive molecules; the strain sensors are passive wireless strain sensors, the number of the strain sensors is four, and the strain sensors are respectively stuck in grooves in the middle part of the bottom of the hook body of the fixed wing body through an adhesive; the passive wireless strain sensor consists of a resistance strain gauge, a radio frequency chip, a radio frequency antenna and a circuit board; the working flow is as follows: when the cardiac pacemaker reaches a preset position and is released, a traction experiment is carried out, when the hook body of the fixed wing body hooks myocardial tissues, the traction action can cause the strain of the hook body of the fixed wing body, a strain sensor arranged on the fixed wing body can sense the strain state of each hook body, the resistance strain gauge is a sensing element, after the strain occurs, the resistance change quantity is converted into a voltage signal through the circuit board and then the voltage signal is transmitted to the radio frequency chip, the information in the radio frequency chip is transmitted to a wireless signal receiving and transmitting module of the pacemaker program-controlled instrument through the radio frequency antenna, and the pacemaker program-controlled instrument processes and analyzes the received signals, so that whether each hook body can stably hook the cardiac muscle is accurately judged, and the monitoring of the strain of the fixed wing body and the implantation state of the pacemaker is realized.
2. The cardiac pacemaker fixing apparatus according to claim 1, wherein the double-sided grooves are distributed on both sides of the fixed wing body at opposite positions, the grooves are in a long shape, the length of the grooves is 5-8 mm, the width of the grooves is 100-300 μm, and the depth of the grooves is 20-50 μm.
3. The cardiac pacemaker fixing apparatus according to claim 1, wherein the viscosity of the chitosan is 100-400 mPa-s, and the endothelial growth factor is vascular endothelial growth factor.
4. The cardiac pacemaker fixation device of claim 1 wherein the polydopamine base is polymerized from dopamine and the bioactive molecule is arginine-glutamine-aspartic acid-valine or arginine-glycine-aspartic acid.
5. A method of making a cardiac pacemaker fixation device as described in any one of claims 1-4 comprising the steps of:
(1) Firstly, carrying out double-sided groove treatment on a fixed wing body through laser grooving;
(2) Carrying out microporation treatment on the surface of the fixed wing body by using a chemical pickling method;
(3) Preparing a drug coating: dissolving dopamine hydrochloride in Tris-HCl buffer solution to obtain dopamine hydrochloride solution, placing the fixed wing body treated in the step (2) in the solution, and reacting for 12-24 hours in a shaking table to form a polydopamine coating on the surface of the fixed wing body; dissolving bioactive molecules in PBS buffer solution to obtain bioactive molecule solution, immersing the treated fixed wing body in the bioactive molecule solution, standing at 4deg.C for 24 hr, taking out, washing with PBS for three times, and drying at room temperature;
(4) Burying a strain sensor in a groove at the middle part of the bottom of a hook body of a fixed wing body, and fixing the strain sensor by using an adhesive;
(5) Preparing a medicine storage warehouse: dissolving chitosan in acetic acid, stirring to obtain chitosan acetic acid solution, regulating pH to 4-6, and adding endothelial growth factor solution; dropwise adding sodium tripolyphosphate solution into the solution, stirring at room temperature to obtain suspension, centrifuging at 4deg.C for 30min, collecting precipitate, dialyzing in PBS solution for 3 times, adding into a tablet press, pre-pressing, transferring into grooves of the fixed wing body, compacting again, and lyophilizing for 24 hr to obtain the fixed wing body with drug reservoir.
6. A cardiac pacemaker fixation device as claimed in claim 5The preparation method is characterized in that the specific operation of the chemical pickling method in the step (2) is as follows: ultrasonically cleaning the fixed wing body in acetone for 10min, and after the fixed wing body is dried, placing the fixed wing body with a clean surface into HNO with a volume fraction of 20% -40% 3 Soaking in the solution at 4 ℃ for 24 hours; and respectively ultrasonically cleaning with deionized water and acetone for 10min, and drying for later use.
7. The method for preparing a cardiac pacemaker fixing device according to claim 5, wherein the concentration of the dopamine hydrochloride solution in the step (3) is 2-8 mg/mL, the setting parameter of the cradle is 37 ℃,100rmp, the concentration of the bioactive molecule solution is 0.5-1 μg/mL, and the mass ratio of the bioactive molecule to the dopamine hydrochloride is 1:100-1:1000.
8. The method for manufacturing a cardiac pacemaker fixing apparatus according to claim 5, wherein in the step (5), the concentration of the chitosan acetic acid solution is 2.5-4 mg/mL, the mass ratio of the endothelial growth factor to the chitosan is 1:5000-1:500, and the mass ratio of the sodium tripolyphosphate to the chitosan is 1:3-1:6.
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