WO2013083078A1 - 一种x射线下可见的生物可降解支架及其制备方法 - Google Patents

一种x射线下可见的生物可降解支架及其制备方法 Download PDF

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Publication number
WO2013083078A1
WO2013083078A1 PCT/CN2012/086171 CN2012086171W WO2013083078A1 WO 2013083078 A1 WO2013083078 A1 WO 2013083078A1 CN 2012086171 W CN2012086171 W CN 2012086171W WO 2013083078 A1 WO2013083078 A1 WO 2013083078A1
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Prior art keywords
layer
developing
stent
biodegradable
biodegradable stent
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PCT/CN2012/086171
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English (en)
French (fr)
Inventor
陈树国
石秀凤
孟娟
罗七一
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上海微创医疗器械（集团）有限公司
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Publication of WO2013083078A1 publication Critical patent/WO2013083078A1/zh

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
    • 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
    • A61L31/18—Materials at least partially X-ray or laser opaque
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0076—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof multilayered, e.g. laminated structures
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2230/00—Geometry of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2230/0002—Two-dimensional shapes, e.g. cross-sections
    • A61F2230/0028—Shapes in the form of latin or greek characters
    • A61F2230/0054—V-shaped

Definitions

  • the invention relates to the field of medical devices. More specifically, the present invention relates to a biodegradable stent visible under X-rays and a method of preparing the same. Background technique
  • the stent As a mature interventional medical device for the treatment of luminal stenosis, the stent has been widely used. Taking a vascular stent as an example, during the treatment, the stent is delivered to the lesion (stenosis) by the catheter, and then the balloon is expanded or self-expanded to enlarge the diameter of the stent to expand the narrow blood vessel.
  • the surface layer of the stent is generally coated or doped with drugs that inhibit the proliferation of intima and smooth muscle cells, such as rapamycin, paclitaxel, etc., through the sustained release of these drugs in the blood. Inhibition of proliferation of intima and smooth muscle cells near the surface of the scaffold. Brackets made of metal materials are widely used, but they have the following drawbacks:
  • biodegradable stents can also interfere with surgical revascularization, hinder the formation of collateral circulation, inhibit positive remodeling of blood vessels, and require long-term antiplatelet therapy. Based on such problems, biodegradable stents have attracted widespread attention as a possible solution.
  • the biodegradable stent is made of a degradable material and can support the blood vessel in a short period of time after implantation in the lesion site. After the treatment is completed, the stent degrades into an organic substance that can be absorbed and metabolized by the human body in the human environment, and finally the stent disappears.
  • biodegradable stents such as magnesium metal, degradable polymers, etc.
  • materials for biodegradable stents are mostly X-ray permeable, have poor development performance under X-rays, and are not visible even under X-rays. Without the presence of markers, it is difficult to accurately position the stent.
  • Ray development determines the position of the stent and it is necessary to increase the X-ray visibility of the biodegradable stent.
  • Existing such techniques include 1 to add a development point (or development ring) to the stent; 2 to graft iodine atoms onto the stent material; 3 to apply X-ray contrast agents to the stent surface.
  • WO 2009099958 A1 discloses a method for developing a degradable stent which is attached to a body of a degradable stent with a degradable developing point carrier for mounting a fixed development point. Due to the limited number of carriers and development points, the development point can only show the local state of the stent. If other parts of the stent move or collapse, the development point cannot display it.
  • the method of grafting iodine atoms into the scaffold material can develop the scaffold under X-ray, but the grafting rate of iodine atoms is very low. Because of the low chemical reactivity of the molecular segment of the scaffold host material, the graft ratio of the contrast agent is generally About 7%, the development efficiency is very low.
  • the biocompatibility of iodine-containing units and vascular endothelial cells remains a concern: in the degradation process of scaffolds, the precipitation of iodine-containing units and endothelialization of blood vessels are always accompanied, and the scaffolds are completely degraded. It has been covered by a layer of new endothelial cells. Therefore, with the further degradation of the scaffold material, the iodine-containing unit on the surface or inside of the scaffold will be present in the envelope of vascular endothelial cells for a long time.
  • US20080009939 discloses a method of dip coating a developing coating on a surface of a stent, which is immersed in an aqueous solution containing an ionic contrast agent (ioxolol) or sprayed a solution of pVA containing iodixanol on a stent.
  • an ionic contrast agent ioxolol
  • the disadvantage of the method is: the developing coating is weakly combined with the main body layer of the stent, and the developing coating is easily detached from the main body layer of the stent during the crimping and expanding of the stent; the inner and outer surfaces of the stent are coated with the developing coating, wherein
  • the development coating on the outer surface of the stent directly oppresses the wall of the vessel, which tends to cause biocompatibility problems with the vessel wall; in addition, stent impregnation/spraying requires a long period of drying to remove the solvent. Therefore, it is necessary to find a way to enable the entire stent to be developed under X-rays.
  • the degradation or metabolism of the developing material is completely discharged outside the body before the endothelium of the stent is prevented from being retained in the tissue for a long period of time, causing a problem of poor biocompatibility.
  • the present invention provides a biodegradable stent visible under X-rays, comprising a biodegradable stent body layer and a developing layer as an inner layer thereof, characterized in that:
  • the stent body layer and the developing layer are formed by two-layer melt extrusion; and the developing layer is composed of a biodegradable polymer material and a developing material visible under X-rays, and the developing material can be decomposed by metabolism in the body. Or directly excreted outside the body.
  • the developing material is a contrast agent or a degradable metallic material visible under X-rays.
  • the mass ratio of the developing material in the developing layer is between 5 and 70%, and the mass ratio of the biodegradable polymer material in the developing layer is between 95 and 30%.
  • the stent body layer is composed of a biodegradable polymer material selected from one or more of the following materials: polylactic acid (PLA), polyglycolic acid (PGA), Polylactic acid-glycolic acid copolymer (PLGA), polycaprolactone (PCL), polydioxanone (PPDO), polyanhydride, polytrimethylene carbonate (PTMC), polyesteramide, polybutylene Butylene glycolate (PBS), polyhydroxybutyrate (PHBV), polyacetylglutamic acid and polyorthoester (POE) and copolymers thereof, blends.
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PLGA Polylactic acid-glycolic acid copolymer
  • PCL polycaprolactone
  • PPDO polydioxanone
  • PTMC polytrimethylene carbonate
  • polyesteramide polyesteramide
  • PBS polybutylene Butylene glycolate
  • PHBV polyhydroxybutyrate
  • POE polyacety
  • the biodegradable polymer material in the developing layer is a biodegradable polymer material with rapid degradation rate (complete degradation time in vivo is less than 6 months), and the biodegradable polymer with faster degradation rate
  • the material is selected from one or more of the following materials: polylactic acid, polyglycolic acid, polyanhydride, polyester amide, polybutylene succinate (PBS), polyhydroxybutyrate (PHBV), poly Acetylglutamate and polyorthoester (POE) and their copolymers, blends.
  • the contrast agent is a contrast agent that can be used for blood angiography, and is characterized by: The thermal decomposition temperature is higher than 150 ° C or has a developing ability after thermal decomposition of the melt processing.
  • the contrast agent is selected from the group consisting of diatrizoic acid, iopromide, iohexol, sodium iodide, potassium iodide, and iodixanol.
  • the contrast agent is soluble in blood, can migrate from the degradable polymer material and dissolve in the blood within 1 month, and then is metabolized and excreted.
  • the degradable metallic material visible under X-rays is selected from the group consisting of: a degradable metal, a degradable metal alloy and a degradable metal compound, and a complex of an organic molecule and a metal.
  • the degradable metal includes, but is not limited to, a metal such as iron.
  • the shape of the degradable metallic material is a particle or a powder shape, and the particle diameter may be selected within a range of 10 ⁇ -100 ⁇ according to actual processes and requirements.
  • the material of the developing layer is formed by physically mixing a developing material such as a powder of a degradable metallic material with a degradable polymer material having a faster degradation rate, such as mechanical agitation mixing and melt blending;
  • a developing material such as a powder of a degradable metallic material
  • a degradable polymer material having a faster degradation rate such as mechanical agitation mixing and melt blending
  • the developing material (such as a degradable metal material) is degraded and metabolized with the degradable polymer material, thereby avoiding residual in the tissue after the endothelium of the stent.
  • the thickness of the stent body layer and the developing layer is adjusted according to actual development requirements and overall thickness requirements of the stent.
  • the thickness ratio of the developing layer to the stent body layer is generally controlled to be between 1:5-1:10.
  • the thickness of the developing layer is between 0.01 and 0.05 mm, and the thickness of the body layer of the stent is between 0.05 and 0.5 mm.
  • the present invention also provides a method for preparing a biodegradable stent visible under X-rays, the biodegradable stent comprising a biodegradable stent body layer and a development layer as an inner layer thereof, the method comprising :
  • the material of the stent body layer and the material of the development layer are double-layer melt extruded to form a tube;
  • the material of the developing layer comprises a biodegradable polymer material and a developing material visible under X-rays
  • the developing material can be decomposed or directly metabolized in the body by metabolism
  • the method is further excreted, and the method further comprises: physically mixing the developing material and the biodegradable polymer material to form a material of the developing layer before the two-layer melt extrusion.
  • the physical mixing comprises mechanical agitation mixing and melt blending.
  • the stent is then crimped onto a delivery system and sterilized after packaging. The stent is positioned and released during operation with an X-ray imaging device.
  • the biodegradable stent obtained by the method for producing a biodegradable stent according to the present invention has the following technical effects.
  • the entire stent can be clearly developed under X-ray during implantation, which helps the doctor to judge the position of the stent and the stent expansion state, and prevent adverse events such as stent displacement and immediate collapse.
  • the developing layer is on the inner surface of the biodegradable stent.
  • the developing material in the developing layer is dissolved in the blood and metabolized before the endothelium of the stent, or is excreted from the body along with the biodegradable material in the developing layer, and does not remain in the vascular tissue. In the case of avoiding the long-term existence of foreign matter, the problem of poor biocompatibility.
  • FIG. 1 shows a schematic cross-sectional view of a two-layer melt extruded tube in accordance with an embodiment of the present invention
  • FIG. 2 shows the structure of a biodegradable stent in accordance with an embodiment of the present invention. detailed description
  • a polylactic acid scaffold capable of developing under X-rays was prepared, and the developed layer was PLGA blended iodixanol, wherein the PLGA had a weight average molecular weight of 100,000 and an in vivo degradation time of 6 months.
  • the material of the stent body layer is biodegradable L-polylactic acid (PLLA) with a weight average molecular weight of 300,000.
  • PLLA biodegradable L-polylactic acid
  • the PLGA and iodixanol are melt blended and extruded at a mass ratio of 50:50, and the temperature of the blending and extrusion is 90-140 ° C, and the obtained developing particles are white, because the processing temperature is lower than that of the iodogram.
  • the thermal decomposition temperature of salicol (180 ° C), iodixanol does not undergo significant thermal degradation.
  • the developing particles have a good developing ability under X-ray.
  • the obtained developing particles and PLLA particles were subjected to two-layer melt extrusion molding to obtain a tube.
  • the cross-sectional structure of the tube was as shown in Fig. 1, the inner layer 1 was a developing layer, and the outer layer 2 was a stent main layer.
  • the outer diameter of the pipe is 2.00 mm, the inner diameter is 1.66 mm, and the wall thickness is 0.170 mm, wherein the outer layer 2, that is, the wall thickness of the PLLA layer is 0.145-0.155 mm, and the inner layer 1 is the wall thickness of the developing particle layer.
  • the tube has good developability under X-rays.
  • the developing temperature of the developing particles is 90-130 ° C
  • the extrusion temperature of the L-polylactic acid is 180-200 ° C
  • the head temperature is 180. C.
  • the extruded tube is laser-cut according to the stent structure of Fig. 2 to obtain a stent, which is pressed on the balloon of the delivery system, sterilized after packaging, and sent to the stenotic lesion of the blood vessel through the delivery system during operation.
  • the balloon is filled and pressurized to expand the stent to expand the narrow blood vessel. Throughout the surgery, the clear outline of the entire stent can be seen by X-ray imaging.
  • the scaffold was found to be blurred under X-rays, indicating that the developing material began to migrate out from the developing layer; after 1 month of implantation, the stent was found to be no longer developed under X-rays, indicating that the developing material of the inner layer of the stent was It has been metabolized. During this month, no significant inflammatory response was observed in vascular tissue. After 6 months of stent implantation, the stent was endothelialized and some of the stent rods were wrapped by the vascular endothelium. At this point, the inner layer of the stent had been degraded.
  • Embodiment 2 Embodiment 2
  • a polylactic acid scaffold capable of developing under X-rays is prepared, and the developed layer is a polylactic acid-caprolactone copolymer blended with degradable iron powder (iron content >99.8%), wherein the weight average molecular weight of the polylactic acid-caprolactone copolymer 60,000, the body degradation time is 3 months.
  • the iron powder has a particle diameter of 10 to 100 ⁇ m.
  • the material of the stent body layer is biodegradable L-polylactic acid (PLLA) with a weight average molecular weight of 300,000.
  • the polylactic acid-caprolactone copolymer and the iron powder are melt-blended and extruded in a ratio of 95:5 by mass ratio, and the temperature of the blending extrusion is 120-150 ° C, and the obtained developing particles are black.
  • the developing particles have a good developing ability.
  • the developing particles and the L-polylactic acid particles are subjected to two-layer melt extrusion molding to obtain a pipe.
  • the cross-sectional structure of the pipe is as shown in FIG. 1.
  • the inner layer 1 is a developing layer
  • the outer layer 2 is a stent main layer
  • the outer diameter of the pipe is It is 5.0 mm
  • the inner diameter is 4.40 mm
  • the wall thickness is 0.30 mm
  • the outer layer 2 that is, the wall thickness of the PLLA layer is 0.245-0.255 mm
  • the inner layer 1, that is, the wall thickness of the developing particle layer is 0.045-0.055 mm.
  • the developing temperature of the developing particles is from 120 to 150.
  • PLLA has an extrusion temperature of 180-200 ° C and a head temperature of 180.
  • the obtained pipe has excellent developability under X-rays.
  • the tube obtained by extrusion molding is laser-cut according to the stent structure shown in Fig. 2, and a stent is obtained, and the stent is pressed and held on the balloon of the delivery system, and the stent is delivered to the narrow lesion position of the blood vessel through the delivery system during surgery,
  • the balloon is filled and pressurized to expand the stent to expand the narrow blood vessel.
  • the entire contour of the stent can be seen by X-ray imaging throughout the surgery. One month later, it was found by X-ray imaging that the inner layer of the stent began to degrade.
  • a PLGA scaffold capable of developing under X-rays was prepared, and the developed layer was PPDO blended sodium iodide, wherein the weight average molecular weight of PPDO was 100,000.
  • the material of the stent body layer is a biodegradable polylactic acid-glycolic acid copolymer (PLGA) having a weight average molecular weight of 300,000.
  • the PPDO and sodium iodide are blended and extruded at a mass ratio of 70:30, and the temperature of the blending and extruding is 120-140 ° C, and the obtained developing particles are white, because the processing temperature is lower than that of sodium iodide. At the thermal decomposition temperature, sodium iodide does not undergo significant thermal degradation.
  • the developing particles have a good developing ability.
  • the developing particles and the PLGA particles are subjected to two-layer melt extrusion molding to obtain a pipe.
  • the cross-sectional structure of the pipe is as shown in Fig. 1.
  • the inner layer 1 is a developing layer
  • the outer layer 2 is a stent main layer.
  • the outer diameter of the pipe is 1.0. Mm, an inner diameter of 0.8 mm, a wall thickness of 0.1 mm, wherein the outer layer 2, that is, the PLGA layer has a wall thickness of 0.085-0.095 mm, and the inner layer 1, that is, the developed particle layer has a wall thickness of 0.005 to 0.015 mm.
  • the developing temperature of the developing particles was 120-140 ° C
  • the extrusion temperature of PLGA was 180-200 ° C
  • the head temperature was 180 ° C.
  • the obtained pipe has excellent developability under X-rays.
  • the extruded tube is laser-cut according to the stent structure shown in Fig. 2, and the stent is obtained.
  • the stent is pressed and held on the balloon of the delivery system, and the stent is delivered to the narrow lesion position of the blood vessel through the delivery system during surgery.
  • the capsule is filled and pressurized to expand the stent to expand the narrow blood vessel.
  • the entire contour of the stent can be seen by X-ray imaging throughout the surgery.

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Abstract

一种在X射线下可见的生物可降解支架，包括生物可降解支架主体层（2）和作为内层的显影层（1）。所述支架主体层（2）和显影层（1）以双层熔融挤出方式形成。显影层（1）由生物可降解高分子材料和在X射线下可见的显影材料组成，所述显影材料能够在体内通过新陈代谢分解或直接被排泄到体外。一种用于制备在X射线下可见的生物可降解支架的方法，包括：将所述支架主体层（2）和显影层（1）进行双层熔融挤出，以形成管材；将所述管材进行激光切割，以形成支架。

Description

一种 X射线下可见的生物可降解支架及其制备方法 技术领域
本发明涉及医疗器械领域。 更具体而言， 本发明涉及一种 X射线 下可见的生物可降解支架及其制备方法。 背景技术
血管、 输尿管、 食道等人体内的重要的管腔组织会因为各种原因 而发生狭窄。 支架作为一种成熟的治疗管腔狭窄的介入医疗器械， 已 经得到了广泛的应用。 以血管支架为例， 治疗过程中， 支架被导管输 送到病变 （狭窄） 部位， 然后以球囊扩张或者自膨胀的方式， 将支架 直径变大， 撑开狭窄的血管。 为了防止治疗后的血管出现再狭窄的问 题， 支架表层一般涂覆或掺有抑制内膜和平滑肌细胞增生的药物， 如 雷帕霉素、 紫杉醇等， 通过这些药物在血液中的缓释， 来抑制在支架 表层附近的内膜和平滑肌细胞的增生。 金属材料制成的支架被广泛使用， 但是其存在如下缺陷：
1 )在治疗完成以后永久存留在人体内， 金属支架的永久性植入将 削弱血管的 MRI或是 CT影像效果；
2 ) 金属支架还会干扰外科血运重建， 阻碍侧枝循环的形成， 抑制 血管正性重塑， 需要进行长期抗血小板治疗。 基于这样的问题， 生物可降解支架作为可能的解决方案， 引起了 广泛的关注。 生物可降解支架由可降解的材料做成， 在植入病变位置 后可以在短期内起到支撑血管的作用。 在治疗完成以后， 支架在人体 环境内降解成为可被人体吸收、 代谢的有机物， 最终支架消失。 然而 用于生物可降解支架的材料如金属镁、 可降解聚合物等， 多数是 X线 可透性的， 在 X射线下的显影性能都不好， 甚至于 X射线下不可见。 没有标志物存在，很难对支架进行准确定位。为了在手术过程中通过 X 射线显影确定支架位置， 增加生物可降解支架的 X射线可见性是非常 必要的。 现有的此类技术包括①给支架增加显影点 （或显影环） ； ②将碘 原子接枝到支架材料上；③将 X射线造影剂涂在支架表面这几类方法。
WO2009099958A1 公布了一种使可降解支架显影的方法， 它在可 降解支架的主体上连接有可降解的显影点托载体， 用于安装固定显影 点。 因托载体及显影点的个数有限， 显影点只能显示支架的局部的状 态， 如果支架的其它部位发生移动或者塌陷， 显影点就无法将其显示 出来。 给支架材料中接枝碘原子的方法可以使支架在 X射线下显影， 但 是碘原子接枝率很低， 由于支架主体材料分子链段的化学反应活性较 低， 一般造影剂的接枝率在 7%左右， 显影效率很低。 并且， 含碘单元 和血管内皮细胞的生物相容性仍是一个值得关注的问题： 在支架的降 解过程中， 总是会伴随着含碘单元的析出和血管内皮化的发生， 支架 在完全降解前已被一层新生内皮细胞所覆盖， 因此随着支架材料的进 一步降解， 支架表面或者内部的含碘单元就会长期存在于血管内皮细 胞的包围内。
US20080009939 公布了一种将显影涂层浸涂在支架表面的方法， 其将支架浸渍在含有离子型造影剂 (碘克沙醇)的水溶液中， 或将含有碘 克沙醇的 PVA溶液喷涂在支架表面， 该方法的缺点是： 显影涂层与支 架主体层结合薄弱， 显影涂层在支架压握和扩张的过程中容易从支架 主体层脱落； 支架内外表面均被显影涂层涂覆， 其中， 支架外表面的 显影涂层直接压迫接触血管壁， 容易导致与血管壁之间的生物相容性 问题； 另外， 支架浸渍 /喷涂需要较长时间干燥以脱除溶剂。 因此需要找到一种方法， 既能让整个支架在 X射线下显影， 又能 在支架内皮化之前显影材料全部降解或代谢被排出机体外， 避免其长 期滞留在组织中而引起生物相容性差的问题。 发明内容
为了解决上述技术问题， 本发明提供一种在 X射线下可见的生物 可降解支架， 包括生物可降解的支架主体层和作为其内层的显影层， 其特征在于：
所述支架主体层和所述显影层以双层熔融挤出方式形成； 并且 显影层由生物可降解高分子材料和在 X射线下可见的显影材料组 成， 所述显影材料能够在体内通过新陈代谢分解或直接被排泄出体外。 优选地， 所述显影材料为造影剂或 X射线下可见的可降解金属性 材料。 优选地， 显影材料在显影层中的质量比率在 5-70%之间， 生物可 降解高分子材料在显影层中的质量比率在 95-30%之间。 优选地， 所述支架主体层由生物可降解高分子材料组成， 所述生 物可降解高分子材料选自下列材料中的一种或多种： 聚乳酸 （PLA) 、 聚乙醇酸（PGA)、聚乳酸-乙醇酸共聚物（PLGA)、聚己内酯（PCL)、 聚对二氧环己酮 （PPDO) 、 聚酸酐、 聚三亚甲基碳酸酯 （PTMC ) 、 聚酯酰胺、 聚丁二酸丁二醇酯 （PBS ) 、 聚羟基丁酸戊酯 （PHBV) 、 聚乙酰谷氨酸和聚正酯 （POE) 及其共聚物、 共混物。 优选地， 所述显影层中的生物可降解高分子材料为降解速度较快 的生物可降解高分子材料 （体内完全降解时间小于 6 个月） ， 所述降 解速度较快的生物可降解高分子材料选自下列材料中的一种或多种： 聚乳酸、 聚乙醇酸、 聚酸酐、 聚酯酰胺、 聚丁二酸丁二醇酯 （PBS ) 、 聚羟基丁酸戊酯 （PHBV) 、 聚乙酰谷氨酸和聚正酯 （POE) 及其共聚 物、 共混物。 优选地， 所述造影剂是能够用于血液造影的造影剂， 其特征为： 热分解温度高于 150°C， 或者在熔融加工热分解后依然具有显影能力。 优选地， 所述造影剂选自泛影酸、 碘普罗胺、 碘海醇、 碘化钠、 碘化 钾、 碘克沙醇。 所述造影剂可溶于血液， 在 1 个月内能从可降解高分 子材料中迁移出来并溶解于血液， 然后被代谢排出体外。 优选地， X 射线下可见的可降解金属性材料选自： 可降解金属， 可降解金属合金和可降解金属化合物， 以及有机分子与金属结合的络 合物。 优选地， 所述可降解金属包括但不限于铁等金属。 优选地， 所 述可降解金属性材料的形状为粒子或粉末形状， 粒径可根据实际工艺 和需求在 10ηηι-100μηι的范围内进行选择。 优选地， 显影层的材料是通过将显影材料 （诸如可降解金属性材 料的粉末） 与降解速度较快的可降解高分子材料进行物理混合 （诸如 机械搅拌混合和熔融共混） 来形成的； 而在显影层的可降解高分子材 料降解时， 显影材料 （诸如可降解金属性材料） 随着可降解高分子材 料降解并代谢排出体外， 从而避免了在支架内皮化后残留于组织中。 所述支架主体层和显影层的厚度根据实际显影需求和支架整体厚 度要求调节。 所述显影层与所述支架主体层的厚度比例一般控制在 1 :5-1 : 10之间。 优选地， 显影层的厚度在 0.01-0.05mm之间， 支架主体 层的厚度在 0.05-0.5mm之间。 本发明还提供了一种用于制备在 X射线下可见的生物可降解支架 的方法， 所述生物可降解支架包括生物可降解的支架主体层和作为其 内层的显影层， 所述方法包括：
将所述支架主体层的材料与所述显影层的材料进行双层熔融挤 出， 以形成管材； 以及
对所述管材进行激光切割， 以形成支架，
其中， 所述显影层的材料包括生物可降解高分子材料和在 X射线 下可见的显影材料， 所述显影材料能够在体内通过新陈代谢分解或直 接被排泄出体外 优选地， 所述方法在双层熔融挤出之前还包括： 将显影材料和生 物可降解高分子材料进行物理混合， 以形成所述显影层的材料。 其中， 所述物理混合包括机械搅拌混合和熔融共混。 所述支架随后被压握到输送系统上， 包装后灭菌。 手术时借助 X 射线影像设备对支架进行定位和释放。 利用根据本发明的生物可降解支架的制备方法所得到的生物可降 解支架具有如下技术效果。 整个支架在植入过程中能够在 X射线下清晰显影， 有助于医生判 断支架位置和支架扩张状态， 防止支架位移、 即刻塌陷等不良事件发 生。 显影层在生物可降解支架的内表面， 显影层中显影材料在支架内 皮化之前即溶于血液并代谢排出体外， 或随同显影层中生物可降解材 料降解代谢被排出体外， 不残留在血管组织中， 避免异物的长期存在 而导致的生物相容性差的问题。 附图说明
为了更清楚地描述本发明的技术方案， 下面将结合附图作简要介 绍。 显而易见， 这些附图仅是本申请记载的一些具体实施方式。 根据 本发明的包括但不限于以下这些附图。 图 1 示出了根据本发明的实施例的双层熔融挤出成型的管材的截 面示意图； 以及
图 2示出了根据本发明的实施例的生物可降解支架的结构。 具体实施方式
为了进一步理解本发明， 下面将结合实施例对本发明的优选方案 进行描述。 这些描述只是举例说明本发明的特征和优点， 而非限制本 发明的保护范围。 实施例一
制备能够在 X射线下显影的聚乳酸支架， 显影层为 PLGA共混碘 克沙醇， 其中 PLGA的重均分子量为 10万， 体内降解时间 6个月。 支 架主体层的材料是生物可降解的左旋聚乳酸 (PLLA)， 重均分子量为 30 万。 将 PLGA和碘克沙醇按照质量比 50:50的比例熔融共混挤出造粒， 共混挤出的温度为 90- 140°C， 得到的显影粒子呈白色， 由于加工温度 低于碘克沙醇的热分解温度 (180°C)， 碘克沙醇不发生明显热降解。 显 影粒子在 X光下具有很好的显影能力。 将得到的显影粒子和 PLLA粒子进行双层熔融挤出成型， 以得到 管材， 管材的截面结构如图 1所示， 内层 1 为显影层， 外层 2为支架 主体层。 该管材的外径为 2.00mm， 内径为 1 .66mm， 壁厚为 0.170mm， 其中外层 2也就是 PLLA层的壁厚为 0.145-0.155mm， 内层 1也就是显 影粒子层的壁厚为 0.015-0.025mm。所述管材在 X射线下具有很好的显 影性。 其中， 显影粒子的挤出温度为 90- 130°C， 左旋聚乳酸的挤出温 度为 180-200°C， 机头温度为 180。C。 将挤出成型的管材按照图 2的支架结构进行激光切割， 得到支架， 将支架压握在输送系统的球囊上， 包装后灭菌， 手术时通过输送系统 将支架送到血管的狭窄病变位置， 对球囊进行充盈加压以扩张支架， 从而撑开狭窄的血管。 在整个手术过程中，通过 X射线成像可看到整个支架的清晰轮廓。 植入 1周后， 发现支架在 X射线下变得模糊， 说明显影材料开始从显 影层迁移溶出； 植入 1个月后， 发现支架在 X射线下不再显影， 说明 支架内层的显影材料已经代谢完毕。 在此一个月中， 未发现血管组织 有明显的炎症反应。 支架植入 6 个月后， 观察到支架内皮化， 部分支 架波杆被血管内皮包裹， 此时支架内层已经降解完毕。 实施例二
制备能够在 X射线下显影的聚乳酸支架，显影层为聚乳酸-己内酯 共聚物共混可降解铁粉 (铁含量>99.8%)， 其中聚乳酸-己内酯共聚物的 重均分子量 6万， 体内降解时间 3个月。 铁粉的粒径为 10-100μηι。 支 架主体层的材料是生物可降解的左旋聚乳酸 (PLLA)， 重均分子量为 30 万。 将聚乳酸 -己内酯共聚物和铁粉按照质量比 95:5 的比例熔融共混 挤出造粒， 共混挤出的温度为 120-150°C， 得到的显影粒子呈黑色。 显 影粒子具有很好的显影能力。 将显影粒子和左旋聚乳酸粒子进行双层熔融挤出成型， 以得到管 材， 管材的截面结构如图 1所示， 内层 1为显影层， 外层 2为支架主 体层， 该管材的外径为 5.0mm， 内径为 4.40mm， 壁厚为 0.30mm， 其 中， 外层 2也就是 PLLA层的壁厚为 0.245-0.255mm， 内层 1也就是显 影粒子层的壁厚为 0.045-0.055mm。 其中， 显影粒子的挤出温度为 120-150。C， PLLA的挤出温度为 180-200°C， 机头温度为 180。C。 得到 的管材在 X射线下具有很好的显影性。 将挤出成型所得的管材按照图 2所示的支架结构进行激光切割， 得到支架， 将支架压握在输送系统的球囊上， 手术时通过输送系统将 支架输送到血管的狭窄病变位置， 对球囊进行充盈加压以扩张支架， 从而撑开狭窄的血管。 在整个手术过程中， 通过 X射线成像能够看到整个支架的清晰轮 廓。 1个月后，通过 X射线成像发现支架内层开始发生降解。 3个月后， 通过 X射线成像发现支架内层完全降解， 显影材料被排出体外， 并且 支架在 X射线下变得不可见。 支架植入 6个月后， 血管完全内皮化， 病理观察发现没有明显炎症反应， 6〜18个月内没有血栓并发症， 无不 良事件发生， 病理检查证实局部血管壁无炎症反应， 平滑肌细胞无明 显增殖。 实施例三
制备能够在 X射线下显影的 PLGA支架， 显影层为 PPDO共混碘 化钠， 其中 PPDO的重均分子量 10万。 支架主体层的材料是生物可降 解的聚乳酸-乙醇酸共聚物 (PLGA), 重均分子量为 30万。 将 PPDO和碘化钠按照质量比 70:30的比例共混挤出造粒， 共混 挤出的温度为 120-140°C， 得到的显影粒子呈白色， 由于加工温度低于 了碘化钠的热分解温度， 碘化钠不发生明显热降解。 显影粒子具有很 好的显影能力。 将显影粒子和 PLGA粒子进行双层熔融挤出成型， 以得到管材， 管材的截面结构如图 1所示， 内层 1为显影层， 外层 2为支架主体层， 该管材的外径为 1.0mm， 内径为 0.8mm， 壁厚为 0.1mm, 其中外层 2 也就是 PLGA层的壁厚为 0.085-0.095mm， 内层 1也就是显影粒子层的 壁厚为 0.005-0.015mm。其中，显影粒子的挤出温度为 120-140°C， PLGA 的挤出温度为 180-200°C， 机头温度为 180°C。 得到的管材在 X射线下 具有很好的显影性。 将挤出成型的管材按照图 2所示的支架结构进行激光切割， 得到 支架， 将支架压握在输送系统的球囊上， 手术时通过输送系统将支架 输送到血管的狭窄病变位置， 对球囊进行充盈加压以扩张支架， 从而 撑开狭窄的血管。 在整个手术过程中， 通过 X射线成像能够看到整个支架的清晰轮 廓。 植入 1周天后， 通过 X射线成像发现支架在 X射线下的显影性明 显降低， 支架在 X射线下变得模糊。 植入 1个月后， 通过 X射线成像 发现支架在 X射线下不显影， 说明支架内层的显影材料已经代谢完毕。 在此一个月中， 未发现明显的炎症反应。 支架植入 6 个月后， 观察到 血管内皮化， 部分支架波杆被血管内皮包裹， 此时支架内层已经降解 完毕， 没有对内皮细胞产生不良影响。 以上实施例的说明只是用于帮助理解本发明的核心思想。 应当指 出， 对于本领域的普通技术人员而言， 在不脱离本发明原理的前提下， 还可以对本发明进行若干改进和修饰， 但这些改进和修饰也落入本发 明权利要求请求保护的范围内。

Claims

1. 一种在 x射线下可见的生物可降解支架， 包括生物可降解的支 架主体层和作为其内层的显影层， 其特征在于：
所述支架主体层和所述显影层以双层熔融挤出方式形成； 并且 显影层由生物可降解高分子材料和在 X射线下可见的显影材料组 成， 所述显影材料能够在体内通过新陈代谢分解或直接被排泄出体外。
2. 根据权利要求 1所述的生物可降解支架， 其中， 所述显影材料 为造影剂或 X射线下可见的可降解金属性材料。
3. 根据权利要求 1所述的生物可降解支架， 其中， 在所述显影层 中， 所述显影材料的质量比率在 5-70%之间，所述生物可降解高分子材 料的质量比率在 95-30%之间。
4. 根据权利要求 1所述的生物可降解支架， 其中， 所述支架主体 层由生物可降解高分子材料组成。
5. 根据权利要求 4所述的生物可降解支架， 其中， 组成所述支架 主体层的所述生物可降解高分子材料选自下列材料中的一种或多种： 聚乳酸（PLA) 、 聚乙醇酸（PGA) 、 聚乳酸-乙醇酸共聚物 （PLGA) 、 聚己内酯 （PCL) 、 聚对二氧环己酮 （PPDO ) 、 聚酸酐、 聚三亚甲基 碳酸酯 （PTMC ) 、 聚酯酰胺、 聚丁二酸丁二醇酯 （PBS ) 、 聚羟基丁 酸戊酯 （PHBV) 、 聚乙酰谷氨酸和聚正酯 （POE) 及其共聚物、 共混 物。
6. 根据权利要求 1所述的生物可降解支架， 其中， 所述显影层中 的生物可降解高分子材料在体内完全降解时间小于 6个月。
7. 根据权利要求 6所述的生物可降解支架， 其中， 所述显影层中 的生物可降解高分子材料选自下列材料中的一种或多种： 聚乳酸、 聚 乙醇酸、 聚酸酐、 聚酯酰胺、 聚丁二酸丁二醇酯 （PBS ) 、 聚羟基丁酸 戊酯 （PHBV) 、 聚乙酰谷氨酸和聚正酯 （POE) 及其共聚物、 共混物。
8. 根据权利要求 2所述的生物可降解支架， 其中， 所述造影剂是 能够用于血液造影的造影剂， 其特征为： 热分解温度高于 150°C， 或者 在熔融加工热分解后依然具有显影能力。
9. 根据权利要求 8所述的生物可降解支架， 其中， 所述造影剂选 自泛影酸、 碘普罗胺、 碘海醇、 碘化钠、 碘化钾、 碘克沙醇。
10. 根据权利要求 2所述的生物可降解支架， 其中， 所述 X射线 下可见的可降解金属性材料选自： 可降解金属， 可降解金属合金和可 降解金属化合物， 以及有机分子与金属结合的络合物。
1 1. 根据权利要求 10所述的生物可降解支架， 其中， 所述可降解 金属为铁。
12. 根据权利要求 2 所述的生物可降解支架， 其中， 所述可降解 金属性材料的形状为粒子或粉末形状，粒径在 10ηηι-100μηι的范围内进 行选择。
13. 根据权利要求 1 所述的生物可降解支架， 其中， 显影层的材 料是通过将所述显影材料与所述生物可降解高分子材料进行物理混合 来形成。
14. 根据权利要求 1 所述的生物可降解支架， 其中， 所述显影层 与所述支架主体层的厚度比例控制在 1 :5-1 : 10之间。
15. 根据权利要求 14所述的生物可降解支架， 其中， 所述显影层 的厚度在 0.01-0.05mm之间， 支架主体层的厚度在 0.05-0.5mm之间。
16. 一种用于制备在 X射线下可见的生物可降解支架的方法， 所 述生物可降解支架包括生物可降解的支架主体层和作为其内层的显影 层， 所述方法包括：
将所述支架主体层的材料与所述显影层的材料进行双层熔融挤 出， 以形成管材； 以及
对所述管材进行激光切割， 以形成支架，
其中， 所述显影层的材料包括生物可降解高分子材料和在 X射线 下可见的显影材料， 所述显影材料能够在体内通过新陈代谢分解或直 接被排泄出体外。
17. 根据权利要求 16所述的方法， 所述方法在双层熔融挤出之前 还包括： 将显影材料和生物可降解高分子材料进行物理混合， 以形成 所述显影层的材料。
18. 根据权利要求 17所述的方法， 其中， 所述物理混合包括机械 搅拌混合和熔融共混。
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