WO2018107466A1

WO2018107466A1 - Biodegradable thrombus filter, and manufacturing method, application, and delivery device thereof

Info

Publication number: WO2018107466A1
Application number: PCT/CN2016/110385
Authority: WO
Inventors: 赵清华; 崔淑君; 石桂欣; 赵庆洪; 谷涌泉; 刘青
Original assignee: 北京阿迈特医疗器械有限公司
Priority date: 2016-12-16
Filing date: 2016-12-16
Publication date: 2018-06-21
Also published as: CN109963527B; CN109963527A

Abstract

A biodegradable thrombus filter (100, 200, 11), a manufacturing method and application thereof, and a delivery device for delivering the thrombus filter (100, 200, 11), and a thrombus filter system comprising the thrombus filter (100, 200, 11) and the delivery device. The biodegradable thrombus filter (100, 200, 11) comprises a filter body (101, 201) and a center line (102, 202, 12). The filter body (101, 201) comprises a porous tubular frame (103, 203) and two porous filter mesh (104, 204) positioned at two ends of the porous tubular frame body (103, 203). The porous tubular frame (103, 203) and porous filter mesh (104, 204) are seamlessly formed via deposition of a biodegradable polymer fiber according to a pre-designed model. The center line (102, 202, 12) is manufactured using a biodegradable polymer. The center line (102, 202, 12) has one end connected to a top portion of the porous filter mesh (104, 204), passes through an internal portion of the filter (100, 200, 11) and the top portion of another porous filter mesh (104, 204), and extends outside the filter (100, 200, 11). The center line (102, 202, 12) is provided with two or more locking positions (105, 205). The center line (102, 202, 12) and the locking positions (105, 205) realize expansion of the filter (100, 200, 11) through a pulling action and allow adjustment to the size of filter expansion. The thrombus filter (100, 200, 11) has an adjustable expansion coefficient, so is less likely to be displaced, or to damage or perforate a vein during use.

Description

Biodegradable thrombus filter, preparation method thereof, use and conveying device

Technical field

The present invention relates to the field of medical devices, and in particular to a biodegradable thrombus filter, a preparation method and use thereof, and a delivery device for delivering the thrombus filter and a thrombus filtration system including the thrombus filter and the delivery device . Among them, the thrombus filter belongs to an implantable device, and the delivery device belongs to an interventional device.

Background technique

Venous Thromboembolism (VTE) includes Deep Vein Thrombosis (DVT) and Pulmonary Thromboembolism (PTE).

After the diagnosis of VTE, according to the characteristics of patients, the current treatment methods are: 1, medical treatment, usually oral administration of vasoactive drugs such as dopamine, urokinase and other thrombolysis, followed by injection of heparin / oral warfarin for anticoagulation, the treatment Can only relieve symptoms, can not achieve the purpose of radical cure; 2, surgical treatment, including pulmonary thromboendothelial stripping and cardiopulmonary transplantation, the former is currently the only means to cure PTE, but the operation is difficult, high risk, China is currently at In the initial stage, the survival rate of the latter patients is less than 20% after 5 years of operation; 3. The interventional treatment of disintegration and aspiration thrombus is not very effective, and the broken small embolism is easy to cause re-embolization; 4 Inferior vena cava (IVC) interference, including IVC ligation and implantation of Vena Cava Filter (VCF), both can prevent PTE recurrence and lethal PTE, but IVC ligation is still 20% Patients can re-occur PTE through the collateral circulation. After IVC is blocked, blood reflux is limited, relatively serious complications occur, and postoperative mortality is also high. The VCF is a filter-like device that is deployed in blood vessels to physically intercept floating blood clots.

PTE is mostly asymptomatic, so the rate of misdiagnosis and missed diagnosis is high. Once developed into a symptomatic PTE, radical cure is difficult and the patient suffers a lot. Therefore, prevention of PTE is an important way to reduce the incidence and mortality of the disease. Implantation of VCF is an important means of preventing lethal PTE.

Currently, VCFs used in clinical practice are prepared by laser welding and/or laser cutting of non-degradable metals. However, laser welding and laser cutting processes are complicated and costly. On the product side, for permanent non-degradable metal filters, even when the PTE protection is no longer needed, even the perfectly designed filter has no effect on the hemodynamics of the filter itself, and the vena cava blood flow is slow. (15-30 cm/s), any factor that interferes with its hemodynamics can cause embolism. Temporary and Recyclable Non-Degradable Metal Filters There are a variety of complications during and without the evasion of the filter, including embolization caused by puncture and deployment, embolization of the instrument and blood vessel contact, etc. These embolic problems have a serious impact. Product safety and effectiveness.

Novel VCF-related patents with biodegradable features have been published internationally, such as US 6,267,776 B1 (2001, Paul T. O'Connell et al.), which discloses a filter having six parallel support portions. The wire, the end or the intermediate part is bound together by a confinement ring to form a conical or biconical structure, the confinement ring is made of a biodegradable material, and after the degradation, the filter can be converted into a stent to function; US 2009/0105747 A1 (2009) , Bard) discloses a filter comprising a stent portion and a filter portion at one end/both of the stent, the screen portion being woven with biodegradable suture; US 2010/0016881 A1 (2010, Cook) discloses a bio-available a degrading filter that is formed by concealing the free ends of four degradable fibers constrained at one end into rows of parallel diameter-increasing zig-zag structural rings; US 8236039 B2 (Abbott, 2012) discloses a funnel-shaped filter having a biodegradable wall and a blood vessel wall attached to the enlarged portion of the filter, and the wall hanging function is to separate the filter from the inner surface of the blood vessel, thereby suppressing the endothelialization of the filter. The filter requires surgery for recovery; US 2014/0188152 A1 (2014, Cook) discloses a filter that requires balloon expansion, the filter consisting of a stent and a tapered mesh portion, the end of the tapered filter is bio- The degraded confinement ring, after the confinement ring is degraded, the support site is adherent and endothelialized and gradually degraded and absorbed; the filter disclosed in EP 2845567 A1 (2015) comprises two upper and lower recyclable hooks, which are connected by a degradable center line and a support line. The recovery hook at one end is connected to the tapered filter screen, and after the support line and the center line are degraded, the filter is removed by recycling hooks at both ends.

The relevant VCF patents currently disclosed in China with biodegradable characteristics are 201280010783.0, 200910260085.6, 201310442071.2, 201110121164.6, 200910199830.0, 201210351175.8, 200720173001.1, 97211610.9, 201220645604.8, and 201420178084.3. These patents include fully degradable and partially degradable VCF, for The non-degradable part of the degradable VCF is mostly made of nickel-titanium or stainless steel.

The process for realizing the filter products of the prior art and the product structure described by the patent can be summarized into two types: the metal part is mostly prepared by laser welding or laser cutting technology, the process is complicated and the cost is high; the degradable part is mostly prepared by using a preparation process, The method is not suitable for mass production.

In addition, the existing VCF has poor swellability and cannot adapt to different vascular environments, and is likely to cause serious clinical accidents such as filter displacement, vein damage or perforation.

Summary of the invention

Accordingly, it is an object of the present invention to provide a biodegradable thrombus filter having a variable coefficient of expansion such that its cross-sectional size can be adaptively changed according to different blood vessel diameters, thereby being suitable for use. More extensive, filter displacement, venous damage or perforation are less likely to occur during use.

Another object of the present invention is to provide a method of preparing the biodegradable thrombus filter of the present invention which is simple and efficient and which can greatly reduce production costs.

Yet another object of the present invention is to provide a use of the biodegradable thrombus filter of the present invention.

It is still another object of the present invention to provide a delivery device for use with the thrombus filter of the present invention for delivering the thrombus filter.

It is still another object of the present invention to provide a thrombus filtration system.

The object of the present invention is achieved by the following technical solutions.

In one aspect, the present invention provides a biodegradable thrombus filter comprising a filter body and a centerline, the filter body comprising a porous tubular stent body and two porous filter meshes at opposite ends of the porous tubular stent body, The porous tubular stent body and the porous filter mesh are integrally formed from biodegradable polymer fibers deposited in a pre-designed form, the centerline being made of a biodegradable polymer; wherein one end of the centerline and one The top end of the porous filter is connected and extends through the inside of the filter through the top end of another porous filter to the outside of the filter. The center line is provided with more than two card positions, and the filter can be realized through the center line and the card position. The pulling is expanded and the expansion size of the filter is adjustable.

Preferably, the porous tubular stent body and the porous filter mesh and the centerline are integrally formed.

Preferably, the porous tubular stent body has a circular, polygonal or irregular pattern in cross section.

Preferably, the thrombus filter has a spherical shape, a rugby shape, a lantern shape, a centrifugal tube shape or an irregular shape, and the like.

Preferably, the pre-designed pattern is in the form of a petal.

Preferably, the petal form is deposited by a linear, zigzag and/or circular arc wire.

Preferably, the porous tubular stent body and/or the biodegradable polymer fiber of the porous filter mesh are combined with the fibers at right angles, acute angles, obtuse angles, curved rounded corners or Their combination.

Preferably, the cross-section of the porous tubular stent body and/or the porous filter web biodegradable polymer fiber is circular, polygonal or irregular.

Preferably, the porous tubular stent body and/or the porous filter web biodegradable polymer fiber has a fixed or varying diameter to accommodate different sites of degradation planning; preferably, the biodegradable polymer fiber The diameter is from 50 nm to 1 mm, and more preferably, the biodegradable polymer fiber has a diameter of from 100 μm to 500 μm.

The present invention may use any biodegradable thermoplastic polymer particles, powder, crumb, or a blend of two or more biodegradable thermoplastic polymers suitable for extrusion, injection molding, and Biodegradable inorganic particles/thermoplastic polymer composites, and the like.

Preferably, the biodegradable polymer is selected from one or more of the following: polylactic acid (PLA), L-polylactic acid (PLLA), D-polylactic acid (PDLA), polyethylene glycol-polyglycolic acid ( PGA), polycaprolactone (PCL), polyethylene glycol (PEG), polyanhydride, polyhydroxyalkanoate (PHA), polydioxanone, polyiminocarbonate, polyfumaric acid a copolymer or mixture of the above materials, and a mixture of one or more of the foregoing materials with other biodegradable polymeric materials.

Preferably, the porous tubular stent body and/or porous filter mesh has fixed size pores, varying size pores or a combination of both to accommodate different site degradation planning schemes.

Preferably, the biodegradable thrombus filter further comprises a gold wire wound thereon. The gold wire can function to stabilize the structure of the thrombus filter and can function to develop and fix the thrombus filter after the thrombus filter is implanted into the body.

Preferably, the thrombus filter is a vena cava filter.

Preferably, the surface or part of the surface of the biodegradable thrombus filter can be treated by biological, chemical, physical or a combination thereof to inhibit cell growth or promote thrombolysis.

In another aspect, the present invention provides a method of preparing a biodegradable thrombus filter of the present invention, wherein the method is carried out using a four-axis rapid prototyping system as a manufacturing apparatus, the four-axis rapid prototyping system comprising:

(i) a pedestal;

(ii) a three-axis X-Y-Z positioning system coupled to the base, wherein the X-Y-Z positioning system defines X, Y, and Z directions, respectively;

(iii) mounted on the X-Y-Z positioning system and moved by the X-Y-Z positioning system a dispensing system comprising an extrusion head;

(iv) a fourth shaft system coupled to the base, comprising a rotating rod coupled to the base below the extrusion head, wherein the rotating rod can be forward or reversed about the axis thereof Rotating; the central axis of the rotating rod is parallel to the Y axis;

(v) a computer control system that can accurately control the XYZ positioning system according to a set program to accurately control the movement of the extrusion head of the dispensing system in the X, Y, Z directions, and precisely control the fourth axis system Rotation of the rotating rod about its axis;

The method includes the following steps:

1) preparing a solid or hollow mold according to the shape and size of the filter to be prepared;

2) a program for designing a deposition pattern of biodegradable polymer fibers using a computer;

3) fixing the mold to the position of the rotating rod of the fourth shaft system of the four-axis rapid prototyping system, so that it can rotate in the forward or reverse direction with the fourth shaft rotating rod under the control of the computer control system And incorporating the biodegradable polymer into the dispensing system of the four-axis rapid prototyping system;

4) According to the procedure designed in step 2), the XYZ positioning system and the fourth axis system are controlled by the computer control system, so that the distribution system accurately extrudes the biodegradable polymer fiber according to the pre-designed deposition pattern of the biodegradable polymer fiber. Depositing a specific position of the mold that can be rotated on the fourth shaft or directly deposited on the rotating rod to prepare a filter body precursor having a specific size and structure;

5) removing the filter body precursor prepared in the step 4) from the mold, and stringing the two ends thereof with biodegradable polymer fibers to form the top of the porous filter, or one or two of the porous filters. The tip can also be formed directly on a four-axis rapid prototyping system, with one end of the centerline connected to the top of a porous filter, and the other end of the centerline extending through the interior of the filter through the top of the other porous filter to the filter. Externally, the center line is provided with more than two card positions, the tension expansion of the filter is realized by the center line and the card position, and the expansion size of the filter is adjustable, thereby obtaining a thrombus filter having a desired shape.

Preferably, the shape of the mold in step 1) is cylindrical, spherical, rugby-shaped, lantern-shaped, centrifugal tube-shaped, or irregular; preferably, the mold is processed by 3D printing technology or traditional techniques such as CNC machining. Method preparation.

Preferably, the mold is fixed using a clamp in step 3) or by a hollow mold placed over a rotating rod of the fourth shaft system.

Preferably, the fixing in step 3) is to replace the rotating rod of the fourth shaft system with the mold to receive the polymer, fix it on the fourth shaft system, and enable it to be in the computer control system Under the control of the forward or reverse rotation.

Preferably, in step 5), the top end of a porous filter is directly formed on a four-axis rapid prototyping system, and the other end of the filter body precursor is stringed together with biodegradable polymer fibers to form another porous filter. The top of the.

Preferably, the method further comprises the step of 6) winding the gold wire around the thrombus filter.

The preparation method of the present invention is further improved on the basis of the characteristics of the thrombus filter to be prepared, based on the four-axis rapid prototyping system in the applicant's published patent applications CN 102149859 A and CN 104274867 A. The extruded biodegradable polymer fibers are deposited on the mold at a set speed, pattern, and wire routing or deposited directly on the rotating rod. In order to better control the porosity, pore size and structure of the porous tubular stent body and/or the porous filter, either the feed arm or the rotating rod or both can be along the longitudinal direction (ie, the axial direction of the rotating rod). mobile. In addition to the longitudinal movement, the rotational speed of the rotating rod, the longitudinal movement speed of the feed arm and the rotating rod, and the outer dimensions of the mold also affect the size and density of the pore size of the porous tubular stent body and/or the porous filter, and ultimately affect the thrombus. The degradation scheme of the filter.

The pattern of the porous tubular stent body and/or the porous filter mesh of the thrombus filter of the present invention is designed by a computer program; the thickness of the fiber can be controlled by a computer program, or can be controlled by a rapid prototyping system, or both can be controlled at the same time; The pores of the stent body and the porous filter are controlled by computer programs and/or mold shapes.

The surface area, porosity and pore size of the porous tubular scaffold and/or porous filter of the biodegradable thrombus filter depend on the structural design of the thrombus filter, including the size and geometry of the fibers, the number of fibers per unit volume, and the fibers. The structure of the structure. In most cases, these factors are more controlled by certain aspects of the manufacturing equipment, such as by rotating rods, dies or extrusion heads.

The mold may be of a fixed diameter or a variable diameter to adapt to the inner diameter of the vena cava of the human body. The inner diameter of the vena cava is usually in the range of 18 to 32 mm, and the size of the mold is mainly based on the inner diameter of the vena cava and the needs of the thrombus filter. Designed with radial support.

In general, the diameter of the extruded biodegradable polymer fiber is determined by the inner diameter of the extrusion head, the extrusion speed, the moving speed of the extrusion head along the rotating rod, and the rotational speed of the rotating rod. Sometimes, it can also be programmed. Control, such as designing repeated wire runs in certain locations to form different or identical fiber diameters at different locations, allows different sites to be degraded according to a planned protocol.

The biodegradable thrombus filter of the present invention can be deployed in a desired location by intervention. During implantation into the body, the filter is placed in an unexpanded state, which facilitates the implementation of minimally invasive intervention, and after implantation into the blood vessel, the thrombus filter can be passed through the centerline and the card position according to the actual vessel diameter. The swell size is adjusted so that the filter fits better on the inner wall of the blood vessel, so that displacement is less likely to occur. The biodegradable thrombus filter has a mechanical properties and an absorbent plan that is determined by the filter material, style, and shape.

In still another aspect, the invention provides the use of a biodegradable blood thrombus filter of the invention in the manufacture of a device for the prevention or treatment of venous thromboembolism, such as deep vein thrombosis and pulmonary thromboembolism.

In another aspect, the invention provides the use of a biodegradable thrombus filter of the invention for the prevention or treatment of venous thromboembolism such as deep vein thrombosis and pulmonary thromboembolism.

Preferably, the biodegradable thrombus filter can be deployed in the IVC to capture a fatal large embolus before the embolus produced by deep vein thrombosis (DVT) reaches the lungs, preventing and reducing pulmonary thromboembolism (PTE). Or prevent and reduce PTE recurrence.

In still another aspect, the present invention provides a delivery device for delivering a thrombus filter of the present invention, comprising: a vascular sheath kit comprising an outer sheath and a push sheath, the outer sheath being provided with a joint at the end The end of the push sheath is provided with a sealing cap, and the pushing sheath is matched with the outer sheath so as to be insertable into the outer sheath, wherein the conveying device further comprises a loading tube, a positioning sheath and Pulling wire, where:

One end of the loading tube is configured to be insertable and fixable in a joint of the outer sheath, the loading tube being configured to load a thrombus filter in an unexpanded state, and inserted and fixed at an outer sheath at one end of the loading tube The connector can insert the push sheath therein and enable the push sheath to push the thrombus filter loaded therein into the outer sheath and through the outer sheath into the body;

The positioning sheath is wrapped outside the loading tube and is free to slide outside the device tube, the positioning sheath being provided with a scale or gear along its length, the scale or gear being configured to enable Determining a relative position of the loading tube and the positioning sheath, thereby determining an expanded size of the thrombus filter delivered to the body in vitro in combination with a pushing degree of the pushing sheath;

The pull wire is configured to connect the centerline of the thrombus filter during delivery of the thrombus filter and pass through the interior of the push sheath at the end of the push sheath by the closure cap, and in the thrombus filter body The above connection can be broken outside the body after reaching the desired swell size.

The term "vascular sheath kit" generally refers to a kit of devices that direct medical guidewires, balloons, and other instruments into the vascular lesion site during an interventional procedure. In the present invention, for the purpose of delivering a thrombus filter, the vascular sheath kit includes an outer sheath and a push sheath, and the portion according to the intended use The outer sheath and the push sheath may have different gauges, for example, having different lengths and diameters. Preferably, the diameter may be 2F-14F and the length may be a few centimeters to eighty centimeters.

In one embodiment of the invention, the push sheath is comprised of a pushable portion that is a portion of the push sheath that can be inserted into the outer sheath, the loading tube, and a positioning sheath, and the non-pushable portion After the pushable portion is fully inserted into the outer sheath, the loading tube and the positioning sheath, the non-pushable portion abuts the loading tube and/or the positioning sheath; wherein:

The length of the positioning sheath ≤ the length remaining after the loading tube is inserted into the joint,

The pushing sheath can push the length of the portion > the length of the outer sheath, and

The length remaining after the loading tube is inserted into the joint < the length difference between the push sheath pushable portion and the outer sheath < the length remaining after the loading tube is inserted into the joint + the length of the positioning sheath.

Preferably, wherein the loading tube and the positioning sheath are both cylindrical tubes.

Preferably, wherein the outer sheath, the push sheath, the loading tube and/or the positioning sheath are made of a material comprising polytetrafluoroethylene.

In one embodiment of the invention, the portion of the positioning sheath having the scale or gear is transparent, translucent or hollow to facilitate viewing of the relative position of the loading tube to the positioning sheath.

In a further aspect, the present invention provides a thrombus filtration system comprising the biodegradable thrombus filter of the present invention and the delivery device of the present invention.

In still another aspect, the present invention also provides a method of using the delivery device or thrombus filtration system of the present invention, comprising the steps of:

1. Loading the unexpanded thrombus filter with a loading tube;

2. Connecting the centerline of the thrombus filter with a pull wire and passing through the interior of the push sheath at the end of the push sheath by the closure cap;

3. Inserting and fixing one end of the loading tube into the joint of the outer sheath;

4. Insert the push sheath into the loading tube and push the thrombus filter in the loading tube into the outer sheath and through the outer sheath into the body;

5. determining the relative position of the loading tube and the positioning sheath by positioning the scale or gear on the sheath, thereby determining the expansion size of the thrombus filter delivered to the body in vitro in combination with the pushing degree of the pushing sheath;

6. After the thrombus filter reaches the desired swell size in the body, the wire is disconnected in vitro and the delivery device is withdrawn to the outside of the body.

In a preferred embodiment of the invention, the delivery device or thrombus filtration system of the invention The method of use includes first operating in vitro to determine that the thrombus filter is fully pushed out of the outer sheath and at different expansion sizes, the end of the loading tube that is not inserted into the joint is on the scale or gear on the positioning sheath, and then the thrombus is delivered During the filter to the body, the different states and gears that have been determined are in turn determined by the state in which the thrombus filter is delivered to the body and the size of the expansion.

Preferably, the method of using the delivery device or thrombus filtration system of the present invention comprises: first performing the following operations in vitro to determine that the thrombus filter is fully pushed out of the outer sheath and that the loading tube is not inserted into the end of the joint when in different expanded sizes The scale or gear on the positioning sheath:

1. Insert the unexpanded thrombus filter into the loading tube to expose the tail of the centerline of the thrombus filter;

2. Fixing the pull wire to the tail of the center line of the thrombus filter, such as the end hole, by, for example, activating the knot;

3. Pass the pulling wire from the tip of the push sheath and out through the end of the push sheath, and tighten the pull wire until the tip of the push sheath contacts the tail of the thrombus filter, tighten the cap and pull The wire is fixed, at this time, the push sheath and the loading tube are connected by the pulling wire and the thrombus filter;

4. Insert one end of the loading tube into the joint of the outer sheath;

5. Move the positioning sheath so that the scale 1 or gear 1 on the end reaches the end of the loading tube that is not inserted into the joint, and pushes the push sheath until the non-pushable portion of the push sheath is caught by the positioning sheath, at which point the thrombus filter is partially Launching the outer sheath;

6. Fix the push sheath, pull back the outer sheath so that the thrombus filter is just fully pushed out of the outer sheath, at this time the loading tube is not inserted into the end of the joint to reach the scale 2 or gear 2 on the positioning sheath;

7. Fix the outer sheath, push back the positioning sheath so that the pulling wire pulls the center line and expands the thrombus filter to different sizes defined by the different card positions, and records that the loading tube is not inserted into the end of the joint at this time. Reaching a specific scale or gear position on the positioning sheath, respectively;

Then, in the process of delivering the thrombus filter into the body, the above steps 1-7 are repeated, except that, in turn, the different scales and gear positions that have been determined are used to determine the state in which the thrombus filter is delivered to the body and The size of the expansion, after the thrombus filter is expanded to an appropriate size, the following steps are performed:

8. Fix the outer sheath and push the push sheath to restore the end of the loading tube that is not inserted into the joint to the position of the scale 2 or the position 2 on the positioning sheath. At this time, the slip of the pulling wire exposes the outer sheath, and the expansion of the thrombus filter The opening size has been fixed;

9. Unscrew the sealing cap, pull the pulling wire to open the slip joint, withdraw the pulling wire, and release the thrombus filter;

10. Retract the delivery device such as the sheath and sheath.

The present invention prepares a biodegradable thrombus filter having better swellability and different structures and shapes by using a bio-degradable raw material by using a four-axis rapid prototyping system. The biodegradable thrombus filter of the present invention and the preparation method thereof have the following advantages:

1. The biodegradable thrombus filter of the present invention has two kinds of filters, so that the emboli in the blood vessel can be better captured or suppressed, and the PTE can be temporarily prevented, which can temporarily protect the body and disappear after completing the mission. It does not produce adverse effects on the terminal organs as shown by the traditional VCF, and the indwelling time in the body is short, avoiding the embolic problem caused by the conventional permanent filter due to the filter itself, and the temporary and recyclable filter during the insertion and recovery process. A variety of complications.

2. The biodegradable thrombus filter of the present invention can achieve planned degradation in blood vessels by selecting raw materials, structural design, and shape treatment.

3. The biodegradable thrombus filter of the present invention has a variable coefficient of expansion, and thus its cross-sectional size can be adaptively changed according to different blood vessel diameters, thereby being more applicable. During implantation into the body, the filter is placed in an unexpanded state, which facilitates the implementation of minimally invasive intervention, and after implantation into the blood vessel, the thrombus filter can be passed through the centerline and the card position according to the actual vessel diameter. The swell size is adjusted so that the filter fits better on the inner wall of the blood vessel, so that displacement, vein damage or perforation is less likely to occur during use.

4. The innovative traction expansion design of the invention solves the problem of release of the filter prepared by the existing biodegradable material in the internal environment, and at the same time acts to fix the filter by expansion, preventing the occurrence of displacement and reducing the product risk.

5. The preparation method of the biodegradable thrombus filter of the present invention is simpler, faster and more efficient, easier to change, and lower in cost than the preparation process of the existing filter (such as laser welding, laser cutting and braiding technology). Suitable for mass production of products.

6. The delivery system of the present invention can not only realize the minimally invasive implantation of the thrombus filter of the present invention, but also can determine the delivery state and the expansion size of the thrombus filter during implantation in vivo in vitro, and the delivery method is simple and easy to operate. The conveying process is accurate and controllable. The present invention also enables a single type of delivery device that can be used to deliver a variety of length gauge thrombus filters, thereby reducing inventory.

BRIEF DESCRIPTION OF THE DRAWINGS

1 is a schematic plan view showing the development of a biodegradable thrombus filter prepared in Example 1 of the present invention;

Figure 2 is a perspective view of the biodegradable thrombus filter of Figure 1;

3 is a perspective view showing a biodegradable thrombus filter prepared in Example 2 of the present invention;

4A shows the composition and structure of the conveying device of Embodiment 3; FIG. 4B illustrates several methods for pulling the wire to tie the knot;

5A to 5E are views showing a loading method of the thrombus filter of Embodiment 3; wherein, Figs. 5A to 5E sequentially show that the thrombus filter is compressed into the loading tube, and is connected to the push sheath by the pulling wire. the process of;

6A to 6G are views showing sequentially a transport operation procedure of the thrombus filter of Embodiment 3; wherein, FIG. 6A shows a state diagram of a joint in which one end of the loading tube is inserted into the outer sheath; and FIG. 6B shows a push push sheath in FIG. a portion of the thrombus filter exposed in the blood vessel, the end of the loading tube in the D position of the positioning sheath; Figure 6C shows the fixed push sheath, pull back the outer sheath, so that the loading tube is not inserted into the end of the joint to reach the positioning sheath In the 0th position, the thrombus filter is exactly exposed to the state diagram of the blood vessel; Figure 6D shows the fixed outer sheath, and the push-back positioning sheath causes the loading tube to be inserted into the end of the joint to reach the positioning sheath 1 (can also be selected as needed) Different gear positions), there is a certain displacement between the loading tube and the push sheath, the thrombus filter expands a certain diameter, and is fixed by the card position on the center line; FIG. 6E shows the fixed outer sheath, the push push sheath A state diagram in which the slip of the pulling wire is exposed to the outer sheath, at which time the expanded diameter of the thrombus filter has been fixed; FIG. 6F shows that the sealing cap is unscrewed, pulling a pulling wire to open the nodule, releasing State diagram of the thrombus filter; Figure 6G shows The state of FIG retracement push sheath, the outer sheath of the delivery device and the like;

Figure 7 is a view showing the contrast of the biodegradable thrombus filter of the embodiment 1 of the present invention in the inferior vena cava implantation process of the animal. The four black spots in the figure are four gold wire marks, and the thrombus filter in the figure is not yet Fully expanded

Figure 8 is a view showing the contrast of the biodegradable thrombus filter of the embodiment 1 of the present invention in the inferior vena cava implantation process of the animal. In the figure, four black spots are four gold wire marks, and the thrombus filter is inflated. Open state

Figure 9 is a photographic diagram of the biodegradable thrombus filter of Example 1 of the present invention after 2 weeks of implantation in an animal. The four black spots in the figure are four gold wire marks, and the thrombus filter is inflated. In the open state, no migration occurred.

The best way to implement the invention

The present invention will be further described in detail below with reference to the following examples, which does not mean Limit the invention.

Example 1

Biodegradable thrombus filter for the inferior vena cava, using polycaprolactone as a raw material, the specific processing steps are as follows:

1) using a 3D printing technique to prepare a cylindrical mold having outer diameters of 20 mm, 25 mm, and 30 mm, respectively;

2) using a computer designed biodegradable polymer fiber to be deposited into a petal form by a circular arc-like method; wherein the top end of the porous filter is designed to be directly formed on a four-axis rapid prototyping system;

3) fixing the mold on the rotating rod of the fourth shaft system of the four-axis rapid prototyping system, so that it can rotate forward or reverse with the fourth shaft rotating rod under the control of the computer control system; Adding polycaprolactone to the distribution system of the four-axis rapid prototyping system;

4) According to the procedure designed in step 2), the XYZ positioning system and the fourth axis system are controlled by the computer control system, so that the distribution system accurately extrudes the polymer fiber according to the pre-designed deposition pattern of the biodegradable polymer fiber, and deposits it in the first a specific position of the mold that can be rotated on the four axes to prepare a porous filter body precursor;

5) The cooled filter body precursor prepared in step 4) (the planar development view is shown in Fig. 1) is taken out from the mold, and the other end of the filter body precursor is stringed with polycaprolactone fibers to form another porous The top end of the filter 104. One end of the centerline 102 is coupled to the top end of a porous filter screen 104, and the other end of the centerline 102 extends through the interior of the filter 100 through the top end of another porous filter screen 104 to the exterior of the filter 100, wherein the centerline 102 Three latching positions 105 are provided thereon, the pulling expansion of the filter 100 is achieved by the center line 102 and the latching position 105, and the expansion size of the filter 100 is adjustable, thereby obtaining a thrombus filter 100 having a desired shape (see a perspective view thereof). figure 2).

6) The four portions shown by the arrows in Fig. 2 are respectively ligated and fixed by the gold wire 110, and the length of the exposed gold wire 110 is determined according to the thickness of the vein wall. The gold wire 110 can function to stabilize the thrombus filter 100 and can function to develop and fix a thrombus filter after being implanted in the body.

As shown in FIG. 2, the thrombus filter 100 includes a filter body 101 and a centerline 102, the filter body 101 including a porous tubular stent body 103 and two porous filter screens 104 at both ends of the porous tubular stent body 103, More than two card positions are arranged on the center line 102 105.

Example 2

A biodegradable thrombus filter using polylactic acid as a raw material, the specific processing steps are as follows:

1) preparing a rugby-shaped hollow mold by using 3D printing technology;

2) The computer designed biodegradable polymer fiber is deposited into a petal form by a zigzag wire; wherein the tops of the two porous filters are directly formed on the four-axis rapid prototyping system;

3) fixing the mold on the rotating rod of the fourth shaft system of the four-axis rapid prototyping system, so that it can rotate forward or reverse with the fourth shaft rotating rod under the control of the computer control system; Adding polylactic acid to the distribution system of the four-axis rapid prototyping system;

5) The filter body precursor prepared in the step 4) after cooling is taken out from the mold. One end of the centerline 202 is coupled to the top end of a porous filter screen 204, and the other end of the centerline 202 extends through the interior of the filter 200 through the top end of another porous filter screen 204 to the exterior of the filter 200, wherein the centerline 202 A card slot 205 is disposed thereon, and the tension expansion of the filter 200 is achieved by the center line 202 and the card position 205 and the expansion size of the filter 200 is adjusted, thereby obtaining a thrombus filter 200 having a desired shape (the perspective view thereof is shown in FIG. 3).

As shown in FIG. 3, the thrombus filter 200 includes a filter body 201 and a centerline 202, the filter body 201 including a porous tubular stent body 203 and two porous filter screens 204 at opposite ends of the porous tubular stent body 203, Two or more card positions 205 are disposed on the center line 202.

Example 3

Biodegradable thrombus filter delivery device and method of use thereof:

The delivery device used consisted of a 10F vascular sheath kit (available from COOK Medical) (including outer sheath 1 and push sheath 2), a 10F loading tube 3, a positioning sheath 4, and a 0.3 mm diameter nylon pull wire 5 (see Figure 4A). .

Vascular sheath material: sheath 6: polytetrafluoroethylene, barium sulfate; hemostatic valve 7: high density polyethylene, silica gel; side arm connecting tube 8: polyvinyl chloride; joint 9: polycarbonate. Loading tube 3 material: polytetrafluoroethylene. Positioning sheath 4 material: polytetrafluoroethylene.

Before the thrombus filter 11 is implanted, the vena cava angiography is first performed, and the inner diameter of the target site is measured to determine the thrombus filter size. Depending on the length of the thrombus filter to be delivered, it is first operated in vitro to determine the scale or position of the end of the loading tube that is not inserted into the sheath when the thrombus filter is fully pushed out of the sheath and at different expansion sizes. .

In use, the thrombus filter 11 needs to be loaded into the loading tube 3 first, and FIGS. 5A to 5E show schematic views of the loading method of the thrombus filter. The specific operation is to compress the thrombus filter 11 into the loading tube 3 to expose the tail of the thrombus filter center line 12. The pulling wire 5 is fixed in the trailing end hole 13 of the thrombus filter center line 12 by means of activating the knot (as shown in Fig. 4B). The drawing wire 5 is inserted into and out of the pushing sheath 2, and the pulling wire 5 is tightened until the tip end of the pushing sheath is attached to the tail of the thrombus filter 11, and the sealing cap 14 is screwed to fix the pulling wire 5, which At this time, the push sheath 2 and the loading tube 3 are integrally connected by the pulling wire 5 and the thrombus filter 11.

6A to 6G sequentially show the transporting operation of the thrombus filter: one end of the loading tube 3 is inserted into the outer sheath 1 to the end of the luer 9 (see Fig. 6A). The positioning sheath 4 is moved so that the D position reaches the end of the loading tube 3 that is not inserted into the joint, and the push sheath 2 is advanced until it is caught by the positioning sheath 4, at which time 1/3 of the thrombus filter 11 is exposed in the blood vessel (see Fig. 6B). . The push sheath 2 is fixed, and the outer sheath 1 is pulled back so that the end of the loading tube 3 not inserted into the joint reaches the 0 position of the positioning sheath 4, at which time the thrombus filter 11 is completely exposed to the blood vessel (see Fig. 6C). The outer sheath 1 is fixed, and the positioning sheath 4 is pushed back so that the end of the loading tube 3 not inserted into the joint reaches the first gear such as the positioning sheath 4 (the different gear positions can be selected as needed), and the card position on the center line 12 is pulled. The tail end of the thrombus filter 11 is pulled out of the thrombus filter 11, and the thrombus filter 11 is thereby expanded to a certain diameter (see Fig. 6D). The outer sheath 1 is fixed, and the push sheath 2 is advanced to expose the slip of the pull wire 5 to the outer sheath 1 (see Fig. 6E). The sealing cap 14 is unscrewed, one of the pulling wires 5 is pulled, the nodule is opened, the pulling wire 5 is withdrawn, and the thrombus filter 11 is released (see Fig. 6F). The delivery device such as the push sheath 2 and the outer sheath 1 is withdrawn (see Fig. 6G).

Example 4

In vivo experiments with biodegradable thrombus filters were performed using a porcine inferior vena cava model. The specific process is as follows:

The experiment selected a healthy adult Chinese miniature pig model (purchased from the Experimental Animal Center of China Agricultural University), established a venous access through the common femoral vein, and then underwent inferior vena cava angiography to determine blood. The plug filter specification and the implant site are used to implant the thrombus filter into the designated site according to the method of use of the delivery device.

In the process of implanting the body, the thrombus filter is first placed in an unexpanded state, and after reaching the position to be placed, the thrombus filter is gradually expanded by pulling the center line, and different card positions on the center line are utilized. Fix the centerline to adjust the shape and size of the thrombus filter so that the thrombus filter fits more closely with the vessel wall.

The thrombus filter was used to evaluate the lumen patency of the thrombus implant site after embolization. Two weeks later, the experimental pigs underwent an inferior vena cava angiography to see if the thrombus filter was still in its original position and remained in an expanded state.

7 is a contrast diagram of the biodegradable thrombus filter of Example 1 implanted in the inferior vena cava of an animal. The four black spots in the figure are four gold wire marks, and the thrombus filter is not yet in the figure. Fully expanded. Figure 8 shows a contrast image of the thrombus filter in an expanded state. After the thrombus filter was implanted in the animal for 2 weeks, the angiogram is shown in Fig. 9. It can be seen that the thrombus filter is still in an expanded state, and no migration occurs, and the blood vessel is not damaged or perforated.

Claims

A biodegradable thrombus filter comprising a filter body and a centerline, the filter body comprising a porous tubular stent body and two porous filter meshes at opposite ends of the porous tubular stent body, the porous tubular stent body and porous The filter mesh is integrally formed from a biodegradable polymer fiber deposited in a pre-designed form, the centerline being made of a biodegradable polymer;

Wherein one end of the centerline is connected to the top end of a porous filter and extends through the inside of the filter through the top end of another porous filter to the outside of the filter, and the center line is provided with more than two card positions. The tension expansion of the filter can be achieved by the center line and the card position and the expansion size of the filter can be adjusted.
The biodegradable thrombus filter according to claim 1, wherein the porous tubular stent body has a circular, polygonal or irregular pattern in cross section.
The biodegradable thrombus filter according to claim 1, wherein the thrombus filter has a spherical shape, a rugby shape, a lantern shape, a centrifuge tube shape, or an irregular shape.
The biodegradable thrombus filter according to claim 1, wherein said pre-designed pattern is in the form of a petal, preferably, said petal form is formed by a straight line, a zigzag shape and/or a circular arc shape. Deposited

Preferably, the porous tubular stent body and/or the biodegradable polymer fiber of the porous filter mesh are combined with the fibers at right angles, acute angles, obtuse angles, rounded corners, or combinations thereof;

Preferably, the cross section of the porous tubular stent body and/or the porous filter web biodegradable polymer fiber is circular, polygonal or irregular;

Preferably, the porous tubular stent body and/or the biodegradable polymer fiber of the porous filter mesh have a fixed or varying diameter, preferably, the biodegradable polymer fiber has a diameter of 50 nm to 1 mm. More preferably, the biodegradable polymer fiber has a diameter of from 100 micrometers to 500 micrometers.
The biodegradable thrombus filter according to any one of claims 1 to 4, wherein the biodegradable polymer is selected from one or more of the group consisting of polylactic acid (PLA) and L-polylactic acid (PLLA). ), D-polylactic acid (PDLA), polyethylene glycol-polyglycolic acid (PGA), polycaprolactone (PCL), polyethylene glycol (PEG), polyanhydride, polyhydroxyalkanoate (PHA) , poly-p-dioxanone, polyiminocarbonate, polyfumaric acid, copolymer or mixture of the above materials And a mixture of one or more of the above materials with other biodegradable polymeric materials.
The biodegradable thrombus filter according to any one of claims 1 to 5, wherein the porous tubular stent body and/or the porous filter mesh has a fixed size pore, a variable size pore or a combination of the two.
The biodegradable thrombus filter according to any one of claims 1 to 6, further comprising a gold wire wound thereon.
The biodegradable thrombus filter according to any one of claims 1 to 7, wherein the thrombus filter is a vena cava filter.
A method of producing the biodegradable thrombus filter of any one of claims 1 to 8, wherein the method is performed using a four-axis rapid prototyping system as a manufacturing apparatus, the four-axis rapid prototyping system comprising:

(i) a pedestal;

(ii) a three-axis X-Y-Z positioning system coupled to the base, wherein the X-Y-Z positioning system defines X, Y, and Z directions, respectively;

(iii) a dispensing system mounted on the X-Y-Z positioning system and moving by the X-Y-Z positioning system, the dispensing system comprising an extrusion head;

(iv) a fourth shaft system coupled to the base, comprising a rotating rod coupled to the base below the extrusion head, wherein the rotating rod can be forward or reversed about the axis thereof Rotating; the central axis of the rotating rod is parallel to the Y axis;

(v) a computer control system that can accurately control the XYZ positioning system according to a set program to accurately control the movement of the extrusion head of the dispensing system in the X, Y, Z directions, and precisely control the fourth axis system Rotation of the rotating rod about its axis;

The method includes the following steps:

1) preparing a solid or hollow mold according to the shape and size of the filter to be prepared;

2) a program for designing a deposition pattern of biodegradable polymer fibers using a computer;

3) fixing the mold to the position of the rotating rod of the fourth shaft system of the four-axis rapid prototyping system, so that it can rotate in the forward or reverse direction with the fourth shaft rotating rod under the control of the computer control system And incorporating the biodegradable polymer into the dispensing system of the four-axis rapid prototyping system;

4) According to the procedure designed in step 2), the XYZ positioning system and the fourth axis system are controlled by the computer control system, so that the distribution system accurately extrudes the biodegradable polymer fiber according to the pre-designed deposition pattern of the biodegradable polymer fiber. a mold that can be rotated on the fourth axis a specific position of the tool or deposited directly on the rotating rod to prepare a filter body precursor having a specific size and structure;

5) removing the filter body precursor prepared in the step 4) from the mold, and stringing the two ends thereof with biodegradable polymer fibers to form the top of the porous filter, or one or two of the porous filters. The tip can also be formed directly on a four-axis rapid prototyping system, with one end of the centerline connected to the top of a porous filter, and the other end of the centerline extending through the interior of the filter through the top of the other porous filter to the filter. Externally, the center line is provided with more than two card positions, the tension expansion of the filter is realized by the center line and the card position, and the expansion size of the filter is adjustable, thereby obtaining a thrombus filter having a desired shape.
The method according to claim 9, wherein the shape of the mold in the step 1) is a cylindrical shape, a spherical shape, a football shape, a lantern shape, a centrifugal tube shape, or an irregular shape; preferably, the mold is 3D printed. Technical or CNC machine tool processing methods;

Preferably, in step 3), the mold is fixed by using a jig, or by fixing the hollow mold on the rotating rod of the fourth shaft system; or

Preferably, the fixing in step 3) is to replace the rotating rod of the fourth shaft system with the mold to receive the polymer, fix it on the fourth shaft system, and make it under the control of the computer control system. Rotate in the forward or reverse direction;

Preferably, the method further comprises the step of 6) winding the gold wire around the thrombus filter.
Use of a biodegradable thrombus filter according to any one of claims 1 to 8 in the manufacture of a device for the prevention or treatment of venous thromboembolism.
A delivery device for delivering the thrombus filter of any one of claims 1 to 8, comprising: a vascular sheath kit comprising an outer sheath and a push sheath, the outer sheath being provided with an end a connector, the end of the push sheath is provided with a sealing cap, and the pushing sheath is matched with the outer sheath so as to be insertable into the outer sheath, wherein the conveying device further comprises a loading tube and a positioning sheath And pulling the wire, where:

One end of the loading tube is configured to be insertable and fixable in a joint of the outer sheath, the loading tube being configured to load a thrombus filter in an unexpanded state, and inserted and fixed at an outer sheath at one end of the loading tube The connector can insert the push sheath therein and enable the push sheath to push the thrombus filter loaded therein into the outer sheath and through the outer sheath into the body;

The positioning sheath is wrapped outside the loading tube and is free to slide outside the device tube, the positioning sheath being provided with a scale or gear along its length, the scale or gear being configured to enable Determining a relative position of the loading tube and the positioning sheath, thereby combining push The degree of pushing of the sheath determines the expanded size of the thrombus filter delivered to the body in vitro;

The pull wire is configured to connect the centerline of the thrombus filter during delivery of the thrombus filter and pass through the interior of the push sheath at the end of the push sheath by the closure cap, and in the thrombus filter body The above connection can be broken outside the body after reaching the desired swell size.
The delivery device according to claim 12, wherein said push sheath is composed of a pushable portion and a non-pushable portion, said pushable portion being a portion of the push sheath that can be inserted into the outer sheath, the loading tube, and the positioning sheath, After the pushable portion is fully inserted into the outer sheath, the loading tube and the positioning sheath, the non-pushable portion abuts the loading tube and/or the positioning sheath; wherein:

The length of the positioning sheath ≤ the length remaining after the loading tube is inserted into the joint,

The pushing sheath can push the length of the portion > the length of the outer sheath, and

The length remaining after the loading tube is inserted into the joint < the length difference between the push sheath pushable portion and the outer sheath < the length remaining after the loading tube is inserted into the joint + the length of the positioning sheath.
The delivery device of claim 12, wherein the loading tube and the positioning sheath are both cylindrical tubes.
The delivery device of claim 12, wherein the outer sheath, the push sheath, the loading tube, and/or the positioning sheath are made of a material comprising polytetrafluoroethylene.
The delivery device of claim 12, wherein the portion of the positioning sheath having a scale or gear is transparent, translucent or hollowed out to facilitate viewing of the loading tube relative to the positioning sheath position.
A thrombus filtration system comprising the biodegradable thrombus filter of any one of claims 1 to 8 and the delivery device of any one of claims 12 to 16.