CN108273142B - Preparation method of degradable occluder with controllable degradation rate - Google Patents

Abstract

Translated fromChinese

本发明公开了一种降解速率可控的可降解封堵器的制备方法，所述可降解封堵器包括丝材和阻流膜，其特征在于，采用在丝材的表面增加生物相容性涂层，阻隔丝材与水接触，延缓其力学性能降低速度和降解速率，使其能够在人体内完全内皮化之后才开始逐步降解；或者在丝材和阻流膜的表面引入能促进内皮化速度的基团、肽键、生长因子和药物中的任意一种或几种，使封堵器植入后更快的完成内皮化。采用本发明制备的可降解封堵器使封堵器的降解速度可控，减缓可降解封堵器的降解速度，其应用于心脏隔膜时，能确保心脏隔膜内皮化后才开始降解，避免了封堵器在早期脱落或碎片栓塞等问题。The invention discloses a preparation method of a degradable occluder with a controllable degradation rate. The degradable occluder includes a wire material and a flow blocking film, and is characterized in that the surface of the wire material is used to increase biocompatibility. Coating, which blocks the contact of the wire with water, delays the reduction rate and degradation rate of its mechanical properties, and enables it to gradually degrade after complete endothelialization in the human body; Any one or more of speed groups, peptide bonds, growth factors and drugs can make the occluder complete the endothelialization faster after implantation. The degradable occluder prepared by the invention can control the degradation speed of the occluder and slow down the degradation speed of the degradable occluder. When the degradable occluder is applied to the cardiac diaphragm, it can ensure that the cardiac diaphragm begins to degrade after endothelialization, avoiding the need for Problems such as early occlusion or fragmentation of the occluder.

Description

Preparation method of degradable occluder with controllable degradation rate

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 T_gThe 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 T_mIn 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 T_gAbove, melting temperature T_mHereinafter, 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)

Translated fromChinese

1.一种降解速率可控的可降解封堵器的制备方法，所述可降解封堵器包括丝材和阻流膜，其特征在于，采用以下方法，先实施方法一，再实施方法二：1. a preparation method of a degradable occluder with a controllable degradation rate, the degradable occluder comprises a wire material and a blocking film, it is characterized in that, adopt the following method, first implement method one, then implement method two :方法一：在丝材的表面增加生物相容性涂层，阻隔丝材与水接触，延缓其力学性能降低速度和降解速率，使其能够在人体内完全内皮化之后才开始逐步降解；Method 1: Add a biocompatible coating on the surface of the wire to block the contact of the wire with water, delay the reduction rate of its mechanical properties and the degradation rate, and enable it to gradually degrade after complete endothelialization in the human body;方法二：在丝材和阻流膜的表面引入能促进内皮化速度的基团、肽键、生长因子和药物中的任意一种或几种，使封堵器植入后更快的完成内皮化。Method 2: Introduce any one or more of groups, peptide bonds, growth factors and drugs that can promote endothelialization on the surface of the wire and the blocking membrane, so that the endothelium can be completed faster after the occluder is implanted change.2.如权利要求1所述的降解速率可控的可降解封堵器的制备方法，其特征在于，所述方法一具体为：在丝材和阻流膜的表面浸涂降解周期比可降解封堵器长的可降解涂层。2. The method for preparing a degradable occluder with a controllable degradation rate as claimed in claim 1, wherein the method one is specifically: dip-coating on the surface of the wire material and the blocking film, the degradation cycle ratio is degradable The long biodegradable coating of the occluder.3.如权利要求2所述的降解速率可控的可降解封堵器的制备方法，其特征在于，所述可降解涂层采用聚乳酸、聚己内酯或有机硅。3 . The method for preparing a degradable occluder with a controllable degradation rate according to claim 2 , wherein the degradable coating adopts polylactic acid, polycaprolactone or silicone. 4 .4.如权利要求1所述的降解速率可控的可降解封堵器的制备方法，其特征在于，所述方法二具体为：在丝材和阻流膜的表面修饰或浸涂能促进内皮化速度的生长因子、短肽和蛋白中的任意一种或几种。4. The method for preparing a degradable occluder with a controllable degradation rate according to claim 1, wherein the second method is specifically: surface modification or dip coating on the wire material and the blocking film can promote endothelial Any one or more of growth factors, short peptides and proteins that can accelerate the speed of growth.5.如权利要求4所述的降解速率可控的可降解封堵器的制备方法，其特征在于，所述生长因子通过化学方法或物理方法引入到丝材和阻流膜的表面；所述化学方法为：通过化学键引入官能团或化学键结合生长因子。5. The method for preparing a degradable occluder with a controllable degradation rate according to claim 4, wherein the growth factor is introduced into the surface of the wire material and the blocking film by a chemical method or a physical method; the The chemical method is: introducing functional groups through chemical bonds or combining growth factors with chemical bonds.6.如权利要求5所述的降解速率可控的可降解封堵器的制备方法，其特征在于，所述生长因子为EGF、FGF或PDGF。6 . The method for preparing a degradable occluder with a controllable degradation rate according to claim 5 , wherein the growth factor is EGF, FGF or PDGF. 7 .7.如权利要求5所述的降解速率可控的可降解封堵器的制备方法，其特征在于，所述短肽采用细胞外基质功能蛋白的短肽。7 . The method for preparing a degradable occluder with a controllable degradation rate according to claim 5 , wherein the short peptide is a short peptide of extracellular matrix functional protein. 8 .8.如权利要求7所述的降解速率可控的可降解封堵器的制备方法，其特征在于，所述短肽为非特异性多肽和特异性多肽中的任意一种或两种；非特异性多肽为RGD或YIGSR；特异性多肽为REDV、CAG或SVVYGLR。8. The method for preparing a degradable occluder with a controllable degradation rate according to claim 7, wherein the short peptide is any one or both of a non-specific polypeptide and a specific polypeptide; The polypeptide is RGD or YIGSR; the specific polypeptide is REDV, CAG or SVVYGLR.9.如权利要求4所述的降解速率可控的可降解封堵器的制备方法，其特征在于，所述蛋白为层粘连蛋白，其通过化学方法或物理方法引入到丝材和阻流膜的表面。9 . The method for preparing a degradable occluder with a controllable degradation rate according to claim 4 , wherein the protein is laminin, which is introduced into the silk material and the blocking membrane by a chemical method or a physical method. 10 . s surface.10.如权利要求1-9任意一项所述的降解速率可控的可降解封堵器的制备方法，其特征在于，所述丝材为PDO丝材，所述阻流膜为PDLLA膜。10 . The method for preparing a degradable occluder with a controllable degradation rate according to claim 1 , wherein the wire material is a PDO wire material, and the flow blocking film is a PDLLA film. 11 .

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