CN108273142B - Preparation method of degradable occluder with controllable degradation rate - Google Patents
Preparation method of degradable occluder with controllable degradation rate Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods
- A61B17/0057—Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods
- A61B17/12—Surgical instruments, devices or methods for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels or umbilical cord
- A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
- A61B17/12099—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder
- A61B17/12122—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder within the heart
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially resorbable by the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
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Abstract
The invention discloses a preparation method of a degradable stopper with controllable degradation rate, which comprises wires and a flow blocking film and is characterized in that a biocompatible coating is added on the surface of the wires to block the wires from contacting with water, so that the reduction speed and the degradation rate of the mechanical property of the degradable stopper are delayed, and the degradable stopper can be gradually degraded only after the degradable stopper is completely endothelialized in a human body; or any one or more of groups, peptide bonds, growth factors and medicines which can promote the endothelialization speed are introduced on the surfaces of the wire and the flow resisting membrane, so that the endothelialization can be completed more quickly after the occluder is implanted. The degradable occluder prepared by the invention has controllable degradation speed, slows down the degradation speed of the degradable occluder, can ensure that the degradable occluder starts to degrade after the heart septum is endothelialized when being applied to the heart septum, and avoids the problems of early falling off or fragment embolism and the like of the occluder.
Description
Technical Field
The invention relates to a preparation method of a degradable occluder with controllable degradation rate, belonging to the technical field of medical instruments.
Background
Amorphous polymers have three mechanical states, which are glassy, elastomeric and viscous. At the glass transition temperature TgThe high polymer is in a glass state, is a rigid solid and only has very small deformation under the action of external force; at the melting temperature TmIn the above, the high polymer is in a viscous state, the material gradually changes into a viscous fluid, and the deformation cannot be recovered at the moment; at the glass transition temperature TgAbove, melting temperature TmHereinafter, the high polymer is in a high elastic state, the amount of elastic deformation of the material is obviously increased, and the deformation is relatively stable in this temperature range. Many polymer materials have superelasticity, which utilizes the excellent properties of the polymer materials in the high elastic state.
The traditional occluder is woven by NiTi alloy wires with superelasticity and shape memory, and the biggest defect of the metal material is that the metal material is not degradable, and the problems of arrhythmia, conduction block, Ni ion precipitation, valve injury and the like exist after operation. After the implant is implanted into the heart of a patient, the patient needs to carry the implant for life, and the long-term safety of the patient to the human body is lack of data support. Particularly, the heart of children is continuously developed, and the long-term safety of the occluder is not proved by long-term follow-up data.
Currently, the biodegradable materials commonly used for making degradable occluders mainly include: polylactic acid series (PLA series, degradation curve of poly-L-lactic acid PLLA in buffer solution is shown in fig. 2), Polydioxanone (PDO), polyglycolic acid (PGA, degradation curve of polyglycolic acid PGA in buffer solution is shown in fig. 3), Polycaprolactone (PCL), Polyhydroxybutyrate (PHB), and the like. The glass transition temperature (Tg) of the PDO high polymer material is about-10 ℃, the glass transition temperature (Tg) is lower, the melting temperature (Tm) is about 100 ℃, and therefore the PDO high polymer material is in a high-elasticity state at room temperature (about 20 ℃), is relatively soft and is beneficial to weaving. PPO is a crystalline polymer, the crystallinity is about 37 percent, the melting point is about 110 ℃, and the PPO has good tensile strength, high strength retention rate in the degradation process, knotting strength and other properties. Although the PLA material has good biocompatibility, excellent mechanical property and slow degradation period, the glass transition temperature (Tg) is 50-60 ℃ and is slightly higher, so the PLA material is in a glass state at room temperature, is harder and is not beneficial to weaving, and is mostly used as a pipe material in the application of the degradable field, and the PLA material is processed and shaped by weaving through laser cutting, such as a degradable stent. The PGA material has the glass transition temperature of about 35 ℃, poor flexibility, high crystallinity, easy moisture absorption and degradation in air, difficult storage, high degradation rate, absorption starting after being implanted into tissues for 15 days, large amount of absorption after 30 days, complete absorption after 60-90 days, quick loss of mechanical properties and unsuitability for manufacturing stoppers (the degradation curve of polyglycolic acid in buffer solution is shown in figure 3). The glass transition temperature of Polycaprolactone (PCL) is low and is-60 ℃, the material is soft, but the degradation period is long, and the degradation is very slow. Only the molecular weight is reduced within 1 year, the material begins to be degraded into fragments in about 2 years, and the material is completely degraded in 3-5 years. FIG. 1 is a graph of molecular weight data of PCL in rats as a function of time.
PDO/PPDO poly (p-dioxanone) is an abbreviation for polydioxanone. Surgical sutures with the trade name PDS were developed by Ethicon corporation in the end of the 20 th century, in the end of the 70 th century, as monofilament structures with special surface structures that resulted in less wound damage, good degradability, and flexibility superior to other poly GA sutures.
The degradation of PDO is a hydrolysis process, and the speed of hydrolysis depends in part on the ease with which water molecules interact with the ester linkage. The PDO fiber is degraded more slowly, and can maintain a better strength in the early degradation stage. As the hydrolysis progresses, the amorphous regions and the oriented structure of the material are destroyed, and the strength of the material is reduced sharply until finally the crystalline regions are degraded. PDO can be finally and completely decomposed into carbon dioxide and water in a human body, has no chemical residue, and is widely used in the catgut embedding and lifting operation of medical cosmetology.
At present, the degradable occluder developed by Shanghai shape memory alloy materials Co., Ltd is mainly made of the following materials: 1. braided wire (poly (p-dioxanone) PDO), 2. flow-resistant film (polylactic acid PLA series).
The PDO occluder had lost mechanical strength around 3 months and began to degrade. The endothelialization of the heart diaphragm needs 1-3 months, which can cause the problems of early falling off of the occluder or embolism of fragments and the like.
Although the experimental result of the current animal (the animal model is beagle dog) shows that the endothelialization of the degradable occluder is started after 1 month of implantation, the endothelialization is complete after 3 months, the occluder is obviously degraded after 6 months, the occluder is basically degraded after 12 months, and the occluder is completely degraded after 2-3 years. However, the rate of endothelialization in animals is faster than in humans and it may take longer in humans for 3 months, although endothelialization in the heart of animals is complete. If the endothelialization of the occluder is not finished after 3 months, the mechanical property of the occluder is rapidly reduced, the supporting force is reduced, and the PDO wire material begins to degrade. Under the scouring of the blood flow of the heart, the wire of the occluder is broken, the degradation fragments fall off, and thrombus can be caused, so that pulmonary embolism and even cerebral infarction are caused.
How to control the degradation rate of the degradable occluder which takes PDO degradable suture lines as wires and PDLLA as a flow-resistant film in vivo is a problem to be solved urgently.
Considering the biocompatibility, degradability, knittability, shapeability, shape memory and other properties of the material, the degradable suture PDO is used as a wire material, and the knitted degradable occluder is the most ideal manufacturing material in the aspect of the current engineering technology.
Although the animal experiment result shows that the degradation rate of the PDO degradable occluder is matched with the endothelialization rate, the endothelialization rate of a human body is slower than that of an animal, so that the risk that the occluder starts to degrade and the endothelialization is not complete exists, degraded fragments of the occluder are washed away by blood flow in the heart to fall off, and thrombus is caused.
Disclosure of Invention
The invention aims to solve the problems that: the problem of too high degradation speed of the existing degradable plugging device.
In order to solve the problems, the invention provides a preparation method of a degradable occluder with a controllable degradation rate, which comprises a wire and a flow-resisting film, and is characterized in that one or two of the following methods are adopted:
the method comprises the following steps: a biocompatible coating is added on the surface of the wire material to prevent the wire material from contacting with water, so that the reduction speed and the degradation rate of the mechanical property of the wire material are delayed, and the wire material can be gradually degraded only after the wire material is completely endothelialized in a human body;
the second method comprises the following steps: any one or more of groups, peptide bonds, growth factors and medicines which can promote endothelialization speed are introduced on the surfaces of the wire and the flow-resisting membrane, so that the endothelialization of the occluder can be completed more quickly after the occluder is implanted;
when two methods are adopted, the first method is implemented first, and then the second method is implemented.
Preferably, the first method specifically comprises the following steps: and dip-coating a degradable coating with a longer degradation period than that of the degradable occluder on the surfaces of the wire and the flow resisting film.
More preferably, the degradable coating is made of polylactic acid (good in biocompatibility, slow in degradation speed, capable of beginning to degrade after being implanted for 6 months, and needing 3-5 years for complete degradation), polycaprolactone or organic silicon. On one hand, the high polymer materials have good biocompatibility and long degradation period, and on the other hand, the degradable occluder surface is coated with a layer of high polymer protective film, so that the wire is not directly contacted with moisture, and the degradation principle of the wire is mainly hydrolysis. Meanwhile, the degradation period of the high polymer materials is long, and even if the wire materials begin to degrade, the degradation products are wrapped by the high polymer films with longer degradation periods and cannot fall off, the high polymer films cannot enter blood in a short time, and the risk of causing thrombus is avoided. Finally, after the occluder is completely endothelialized, the coating on the surface of the occluder begins to degrade, so that degraded fragments of the wire material in the coating are released, and the occluder is wrapped by endothelial cells, so that the risk of thrombus caused by the peeling of the degraded fragments does not exist.
Preferably, the second method specifically comprises: any one or more of growth factors, short peptides and proteins which can promote the endothelialization speed are modified or dip-coated on the surfaces of the wire and the flow-resisting membrane.
More preferably, the growth factors are introduced to the surfaces of the wire and the flow-resisting membrane through a chemical method or a physical method, so that the rapid endothelialization of the occluder at the defect site is promoted; the chemical method comprises the following steps: the functional group is introduced through a chemical bond or the growth factor is chemically bonded.
Further, the growth factor is EGF, FGF or PDGF.
More preferably, the short peptide adopts the short peptide of the extracellular matrix functional protein, which can promote the adhesion of endothelial cells and avoid the defect of directly introducing natural extracellular matrix components.
Further, the short peptide is any one or two of a non-specific polypeptide and a specific polypeptide; the non-specific polypeptide is RGD or YIGSR, and the polypeptide can promote the adhesion of various cell types including endothelial cells; the specific polypeptide is REDV, CAG or SVVYGLR, and the polypeptide can selectively promote the adhesion and expansion of endothelial cells. The application of the polypeptide surface modification can specifically promote the endothelialization of the material. The combined application of several polypeptides or the combined application of specific polypeptides and other biological information molecules may be an ideal scheme for promoting the endothelialization of the cardiovascular implant material by applying polypeptide modification in the future.
More preferably, the protein is laminin, which is chemically or physically introduced to the surface of the wire and the flow-blocking membrane. Laminin has specific binding sites for endothelial cells, and can be rapidly endothelialized after the material is implanted into a human body.
Preferably, the wire is a PDO wire, and the current-blocking film is a PDLLA film.
The degradable occluder prepared by the invention has controllable degradation speed, slows down the degradation speed of the degradable occluder, can ensure that the degradable occluder starts to degrade after the heart septum is endothelialized when being applied to the heart septum, and avoids the problems of early falling off or fragment embolism and the like of the occluder.
Drawings
FIG. 1 is a graph of data showing the change in molecular weight of PCL in rats over time;
FIG. 2 is a graph showing the degradation curve of poly (L-lactic acid) in a buffer solution;
FIG. 3 is a graph showing the degradation curve of polyglycolic acid in a buffer solution.
Detailed Description
In order to make the invention more comprehensible, preferred embodiments are described in detail below.
Example 1
Weaving PDO wires, sewing a degradable stopper of the PDLLA flow-resistant membrane, soaking the degradable stopper into solutions of Polycaprolactone (PCL), poly (L-lactic acid) (PLLA), poly (racemic lactic acid) (PDLLA) (PCL), PLLA and PDLLA are used as solutes, and chloroform, dichloromethane, hexafluoroisopropanol and the like are used as solvents), soaking for 10min, taking out, airing in a fume hood, cleaning, sterilizing and packaging, and directly using after an operation.
Example 2
Weaving PDO wires, cleaning, sterilizing and packaging the degradable occluder sutured with the PDLA flow-resistant membrane, unpacking and packaging before operation, and infiltrating the occluder into sterile physiological saline in which growth factors such as EGF, FGF or PDGF are dissolved, wherein the concentration is about 1-5%, and the infiltration time is 3-10 min. And using the solution with the growth factor dissolved as the exhaust solution after the stopper is arranged.
Example 3
Weaving PDO wires, soaking a degradable stopper with a PDLLA flow-resistant membrane in a PCL solution (PCL is a solute, chloroform, dichloromethane, hexafluoroisopropanol and other solvents) for 10min, taking out, airing in a fume hood, cleaning, sterilizing and packaging. Before an operation, in an operating room, the plugging device is soaked in sterile physiological saline in which growth factors, polypeptides and proteins for promoting endothelialization are dissolved, the concentration is about 1% -5%, and the soaking time is 3-10 min. And a solution dissolved with growth factors, polypeptides, proteins and the like is used as an exhaust solution after the stopper is installed.
Claims (10)
1. A preparation method of a degradable occluder with controllable degradation rate comprises a wire and a flow blocking film, and is characterized in that the following method is adopted, namely the first method is implemented firstly, and then the second method is implemented:
the method comprises the following steps: a biocompatible coating is added on the surface of the wire material to prevent the wire material from contacting with water, so that the reduction speed and the degradation rate of the mechanical property of the wire material are delayed, and the wire material can be gradually degraded only after the wire material is completely endothelialized in a human body;
the second method comprises the following steps: any one or more of groups, peptide bonds, growth factors and medicines which can promote endothelialization speed are introduced on the surfaces of the wire and the flow-resisting membrane, so that the endothelialization of the occluder can be completed more quickly after the occluder is implanted.
2. The method for preparing the degradable occluder with controllable degradation rate according to claim 1, wherein the first method is specifically as follows: and dip-coating a degradable coating with a longer degradation period than that of the degradable occluder on the surfaces of the wire and the flow resisting film.
3. The method for preparing the degradable occluder with controllable degradation rate according to claim 2, wherein the degradable coating is polylactic acid, polycaprolactone or silicone.
4. The method for preparing the degradable occluder with controllable degradation rate according to claim 1, wherein the second method is specifically as follows: any one or more of growth factors, short peptides and proteins which can promote the endothelialization speed are modified or dip-coated on the surfaces of the wire and the flow-resisting membrane.
5. The method for preparing the degradable occluder with controllable degradation rate according to claim 4, wherein the growth factor is introduced to the surface of the wire and the flow-resistant membrane by a chemical method or a physical method; the chemical method comprises the following steps: the functional group is introduced through a chemical bond or the growth factor is chemically bonded.
6. The method for preparing a degradable occluder with controllable degradation rate of claim 5 wherein the growth factor is EGF, FGF or PDGF.
7. The method for preparing the degradable occluder with controllable degradation rate according to claim 5, wherein the short peptide is a short peptide of extracellular matrix functional protein.
8. The method for preparing a degradable occluder with controllable degradation rate according to claim 7, wherein the short peptide is either or both of a non-specific polypeptide and a specific polypeptide; the nonspecific polypeptide is RGD or YIGSR; the specific polypeptide is REDV, CAG or SVVYGLR.
9. The method for preparing a degradable occluder with controllable degradation rate according to claim 4, wherein the protein is laminin, and is chemically or physically introduced to the surface of the wire and the flow-resistant membrane.
10. The method for preparing a degradable occluder with controllable degradation rate according to any one of claims 1-9 wherein the wire is a PDO wire and the flow-resistant film is a PDLLA film.
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| CN109464167B (en) * | 2018-12-11 | 2022-06-07 | 先健科技(深圳)有限公司 | Plugging device and preparation method thereof |
| CN109464168B (en) * | 2018-12-17 | 2020-09-29 | 先健科技(深圳)有限公司 | Plugging device |
| CN109498074A (en) * | 2019-01-04 | 2019-03-22 | 上海形状记忆合金材料有限公司 | Method Wholly-degradable plugging device dedicated driving means and its connect with plugging device |
| CN113769177B (en) * | 2021-08-26 | 2022-05-27 | 四川大学 | A kind of degradable occluder coating and preparation method thereof |
| CN114533969A (en) * | 2022-01-18 | 2022-05-27 | 深圳市儿童医院 | Preparation method and application of anti-streaming membrane for promoting endothelialization |
| CN115054307B (en) * | 2022-06-30 | 2024-08-23 | 上海微创医疗器械（集团）有限公司 | Occlusion implant and method for the production thereof |
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