transplant stent

Abstract

The present invention relates to a biodegradable, absorbable stent comprising a skeletal structure made of a metallic alloy of magnesium and a transition metal and / or a rare earth element. The skeletal structure is coated with a polymer, and the coated skeletal structure has struts of stent elements, and the stent may be a valve support stent. Furthermore, the present invention relates to the use of a disclosed valveless stent, or a system comprising a corresponding stent, for implantation in congenital heart disease to open the pulmonary artery, to maintain patency of the ductus arteriosus (ductus of Botallo), to maintain patency of aortic isthmus stenosis, to stimulate growth in a hypoplastic pulmonary artery, or as an esophageal stent or ureteral support.

Description

Technical Field

[0001] The present invention relates to a stent for transplantation including a heart valve support stent, and particularly to a stent for transplantation to children.

Background Art

[0002] Congenital heart diseases are estimated to occur at a rate of 1 in 100 newborns. These heart malformations vary in severity and can affect various structures within the newborn's heart accordingly. The treatment of congenital heart diseases depends on the type and severity of the disease. Affected infants or children may require one or more surgeries to ensure that the heart or blood vessels function properly.

[0003] For example, stent insertion may be required. A stent refers to an intravascular prosthesis or "support" inserted during surgery, for example, to expand a narrowed blood vessel. Stents are also used for fixing heart valves in the vascular system. Due to the lack of products suitable for children, currently, permanent and non-absorbable stents developed for adult patients are being used.

[0004] A particular problem regarding stent transplantation in children, especially newborns, is that the stent cannot "grow" with the patient, and the physiological growth of surrounding structures such as blood vessels is hindered.

[0005] Conventional technology has revealed essentially two types of permanent stents: balloon-expandable stents and self-expanding stents. Balloon-expandable permanent stents have been the most frequently used in the treatment of vascular stenosis. Balloon-expandable stents are usually made of deformable metal or metal alloy. Self-expanding stents are usually made of nickel-titanium alloy (nitinol). Nitinol has properties such as pseudo-elasticity and shape memory. Balloon-expandable stents can be expanded as needed in growing children, thus achieving an increase in diameter. Expansion is not always possible (depending on the behavior of inward growth and the position of the stent). In some cases, it may damage or tear surrounding structures. Self-expanding stents do not expand. They usually open to approximately the specified final diameter depending on the radial force of the stent and the surrounding pressure of the vessel that opposes that radial force.

[0006] International Patent Application Publication WO2011 / 000354A2 discloses a stent in which a heart valve is sutured. This stent consists of a plurality of coaxially arranged crown elements, each crown element formed from a plurality of U-shaped arches having at least one base and two ends. According to the present invention, the base of a crown element is connected to the ends of other crown elements via a connecting bridge. A 3D droplet dosing technique is used to form a thin-walled sandwich structure in the manufacture of this valve stent. The present invention also relates to an apparatus suitable for applying a stent equipped with a positioning wire having a clamp at its end, the clamp of which can be connected by press-fit connection to a fixing hook at the end of the crown element.

[0007] International Patent Application Publication WO2016 / 071357A1 relates to an intraluminal vascular implant having a first hollow cylindrical vascular body and at least one second hollow cylindrical vascular body. The first and second vascular bodies are structurally separate vascular bodies, each having a first end, a second end and a longitudinal axis, and the first and second vascular bodies each comprise a vascular section. The vascular sections of the first vascular body and the vascular sections of the second vascular body are designed to be insertable into each other in part, forming a common stent section that does not contain prosthesis material.

[0008] International Patent Application Publication WO2016 / 055564A1 describes a vascular prosthesis system for insertion into and support within a patient's blood vessel, the vascular prosthesis system includes (i) a stent graft element having a hollow cylindrical body, the stent graft element comprising a meandering circumferential support and a prosthesis material attached to and connected to the support and forming a circumferentially covered stent graft element, and (ii) a stent element having a hollow cylindrical body, the stent element comprising a stent support structure without prosthesis material and forming an uncovered stent element. Furthermore, a strip-shaped prosthesis material section is provided to connect the stent graft elements and the stent elements to each other, the first end of the strip-shaped prosthesis material section being fixed only to the first proximal stent graft element end and the second end being fixed to the first proximal stent element end to form a prosthesis material bridge.

[0009] International Patent Application Publication WO2000 / 062708A1 relates to a multi-part stent with a connecting structure that allows multiple stent sections to move and bend relative to each other. During deployment and positioning, the connecting structure connects the multiple stent sections, keeping them substantially stationary relative to each other. After deployment, the connecting structure allows the multiple stent sections to move relative to each other. The movable stent sections allow the stent to bend better during deployment in the body cavity, adapt flexibly to the shape of the body cavity, reduce pressure on the cavity wall, and lower the risk of trauma. After deployment, the various stent sections can be completely separated from each other. Alternatively, a configuration is possible in which they remain partially connected and move substantially independently of each other. The connecting structure may be designed to separate during deployment, for example, by rupturing or disintegrating in the body cavity.

[0010] International Patent Application Publication WO2019 / 052610A1 relates to an implantable valve prosthesis, particularly a valve prosthesis for preventing the backflow of blood from the atrium to a venous opening into the atrium. The present invention aims to provide an alternative means available for the treatment of mitral valve or tricuspid valve regurgitation. To solve this problem, the present invention provides an implantable valve prosthesis comprising (1) a generally tubular stent having a first end section having at least a first end opening and a second end section having a second end opening, and (2) a flexible tube having a first end section having at least one first end section having a first end opening and a second end section having a second end opening that can be closed by folding the tube, and the flexible tube is positioned on its outer surface over at least a portion of the second end section of the stent such that the tube protrudes beyond the second end opening of the stent together with its second end section and second end opening, and the second end opening of the tube is open when unpressurized.

[0011] German Patent Application Publication DE4222610A1 describes a stent for valves and closure organs, particularly a stent for cardiac valve prostheses. The stent comprises a base ring with at least two posts offset symmetrically from one another. These posts are essentially oriented in the direction of the ring's axis and are connected to one another by arched strips for attaching at least two flexible valve sails, thereby enabling the fabrication of a valve or closure organ, particularly a cardiac valve prosthesis. The valve or closure organ remains flexible within a limited range, only in specific regions, even under varying closure pressure differences, i.e., particularly under varying physiological stress conditions. Specifically, flexibility is maintained by the rigid design of the free ends of the posts and / or the restricted flexibility of the post base and / or the restricted flexibility of the strips.

[0012] U.S. Patent Application Publication US2009 / 0312834A1 relates to a stent structure with improved migration resistance. In particular, US2009 / 0312834A1 refers to mesh stents, such as braided stents and torsion stents, in which at least a portion of the stent is folded back to form a multilayer stent device. Among many other advantages, such multilayer structures improve migration resistance.

[0013] U.S. Patent Application Publication US2012 / 0290073A1 describes a bioabsorbable scaffold comprising at least partially a poly(L-lactic acid) composite. This composite comprises poly(4-hydroxybutyric acid) or poly(L-lactic acid)-β-polycaprolactone block copolymer to enhance the fracture toughness or tensile strength of the scaffold. The composite may also contain bioceramic particles, L-lactic acid monomer, or both, dispersed throughout the composite. The bioceramic particles enhance the radial strength and stiffness of the scaffold, while the L-lactic acid monomer is used to regulate the absorption rate of the scaffold.

[0014] International Patent Application Publication WO2016 / 127542A1 discloses a multilayer expandable vascular skeleton comprising at least two lattice-like skeletal walls made of magnesium alloy and an internal skeletal cavity. An expandable balloon is positioned inside the skeleton. During expansion of the multilayer expandable vascular skeleton, the skeletal wall near the outer layer exceeds the strain rate and ruptures due to relatively large expansion. According to WO2016 / 127542A1, by providing a multilayer lattice-like skeletal wall, it is possible to prevent the outer layer from rupturing during expansion of the vascular skeleton and thus prevent loss of skeletal function. Furthermore, outer layer rupture during expansion is also prevented, improving safety.

[0015] U.S. Patent Application Publication US2021 / 0338422A1 discloses a valve prosthesis with a mechanically coupled sail valve. Embodiments described herein relate to a centrally open valve prosthesis comprising a valve frame and a mechanically coupled valve. The described valve frame has projections configured to connect to the valve mounting area of ​​the valve. Some embodiments include a valve retaining device that engages with the projections of the valve frame and mounts the valve to the valve frame. Methods for manufacturing and using such valve prostheses are also described.

[0016] German Patent Application Publication DE102008040786A1 describes an implant comprising a base body composed entirely or partially of a biocorrosive metallic material, the material decomposing into alkaline products in an aqueous environment, the base body having a coating or cavity filler comprising a polymer matrix and at least one active substance embedded in the polymer matrix, wherein at least one polymer and at least one active substance of the matrix are adapted to each other such that the rate of release of the active substance from the matrix increases with increasing pH.

[0017] U.S. Patent Application Publication US2011 / 060401A1 relates to a tubular, growable support prosthesis having a mesh structure, the mesh structure comprising at least two structural rings connected to one another via connecting elements, arranged point-symmetrically about the longitudinal axis of the prosthesis, and the structural rings and / or connecting elements having at least one predetermined break point.

[0018] U.S. Patent Application Publication US2013 / 325102A1 discloses an absorbable vascular stent having a proximal and distal end. Between the proximal and distal ends, a tubular structure having a pattern is formed. The pattern structure comprises a plurality of support rods and connecting rods. The support rods or connecting rods have a straight, U-shaped, or S-shaped cross-section, and at least one support rod is provided with at least one through groove or through hole. The special structure of this vascular stent can improve the performance of iron vascular stents, and vascular stents made of other absorbable materials can be decomposed more rapidly.

[0019] With the absorbable stents described above, a challenge is to adjust or set the absorption time so as not to inhibit the growth of the heart and blood vessel portions treated by the stent. Foreign bodies (stents, occlusions, etc.) grow into the tissue, and the stent becomes fixed in place through adhesion, causing the tissue to take on the shape of the stent and remain in that position. Therefore, the use of conventional stents inhibits the growth of the treated heart and blood vessel portions.

[0020] Permanent stents are particularly disadvantageous in heart valve implantation in children. This is because the presence of the heart valve within the stent makes post-dilation even more difficult than with balloon-expandable stents that do not contain a valve. During post-dilation, the heart valve tissue can be compressed between the high-pressure balloon and the stent, potentially damaging the heart valve.

[0021] In 2007, Zartner et al. reported the first use of magnesium stents in pediatric patients with hypoplastic pulmonary arteries (Zartner, P., et al. Catheterization and Cardiovascular Interventions, 2007, 69(3), 443-446). However, a drawback of the stents described in this literature was that they dissolved rapidly, resulting in a lack of long-term effectiveness.

[0022] Also in 2007, Waksman published a paper summarizing the options for bioabsorbable stents (Waksman, R, Catheterization and Cardiovascular Interventions, 2007, 70(3), 407-414). The drawback of the stents described in this paper is that the absorption period is long, ranging from 6 to 24 months, which is too long for use in infants during their growth period.

[0023] Therefore, there is still a need for stents that can be used, especially in children. [Overview of the Initiative]

[0024] Therefore, the object of the present invention is to provide a blood supply stent that can adjust the absorption time of the biodegradable stent so as not to inhibit vascular growth. Such a stent is intended for use in neonates and children in particular.

[0025] The present invention discloses a biodegradable, absorbable stent comprising a framework made of a metallic alloy of magnesium and a transition metal and / or a rare earth element, wherein the framework is coated with a polymer, and the coated framework has struts for the stent elements.

[0026] In one embodiment, the stent element is diamond-shaped.

[0027] One embodiment of a stent relates to a stent in which the struts are flattened.

[0028] The present invention further defines that the struts of the stent element have slots.

[0029] In a further embodiment of the stent, the rare earth element is selected from the group of lanthanides including gadolinium, dysprosium, and yttrium.

[0030] The struts of the stent according to the present invention may have barbs (spikes).

[0031] Furthermore, it may be defined that the circumference comprises 24, 21, 18, 15, or 12 stent elements.

[0032] The present invention also relates to an embodiment of a stent in which the barbs have a diameter of 20 to 50 μm.

[0033] The barbs of the stent according to the present invention may be bent inward at an angle of 45° to 90° with respect to the struts of the stent.

[0034] In a further embodiment of the stent according to the present invention, the polymer of the coating is biodegradable, and it is defined that the polymer is poly(DL-lactide-co-glycolide).

[0035] According to the present invention, in one embodiment, it is defined that the stent is a valve-supporting stent.

[0036] In a valve-supporting stent, a number of stent elements divisible by 3 are provided on the circumference of the skeleton, and it is defined that the skeleton has 24, 21, 18, 15, or 12 stent elements.

[0037] In one embodiment of the valve-supporting stent, the heart valve is attached to the barbs of the struts.

[0038] Another object of the present invention is a system for implanting a stent, which includes an apparatus for implanting a stent as described above.

[0039] Furthermore, the present invention relates to the use of the valveless stent or system described above for implanting a stent in congenital heart disease to open the pulmonary artery, to maintain patency of the ductus arteriosus, to maintain patency of aortic isthmus stenosis, to stimulate growth in hypoplastic pulmonary arteries, or as an esophageal stent or ureteral support. [Brief explanation of the drawing]

[0040] The present invention will be described with reference to the drawings. The embodiments and aspects of the present invention shown in the drawings are merely illustrative, as will be obvious to those skilled in the art, and do not limit in any way the scope of protection of the claims. The present invention is defined by the claims and their equivalents. It will be understood that features of one aspect or embodiment of the present invention can be combined with features of other aspects or other embodiments.

[0041] [Figure 1] This figure schematically illustrates one embodiment of the structure of the stent according to the present invention.

[0042] [Figure 2] This is a schematic diagram of a tubular stent.

[0043] [Figure 3] This is a schematic diagram illustrating one embodiment of a barb. [Modes for carrying out the invention]

[0044] The technical problem of the present invention is solved by the independent claim. The dependent claims relate to further embodiments of the present invention.

[0045] In the context of this invention, the term "biodegradable" refers to the property of a metal alloy, polymer, or polymer mixture that can be biologically broken down in the body of a human or animal without endangering human or animal health.

[0046] The problems described above and underlying the present invention are solved by a biodegradable, absorbable stent for valve support, made by combining a metal alloy of magnesium and rare earth elements with a polymer mixture coating. The entire stent made from the metal alloy and polymer coating is biodegradable, and in the context of this disclosure, biodegradability means that it is chemically broken down into smaller molecules, compounds, and even elements by biological processes. An example of a biodegradable polymer in the sense of this disclosure is poly(DL-lactide-co-glycolide).

[0047] The structure of the stent is based on a series of continuously arranged struts, which form the so-called stent elements. These stent elements can be, for example, diamond-shaped, and are also referred to as diamond-shaped in the context of this invention. In one embodiment, the struts of the stent are used to fix a heart valve. This means that the same number of diamonds must be provided for each of the three valve lobules. Thus, the number of diamonds on the circumference of the stent is a number divisible by 3, preferably 24 or 21, or 18, 15, or 12 for stents with a small target diameter. The number of strut elements divisible by 3 stems from the fact that a point-symmetric trilobed valve needs to be sewn / attached to the center of the stent, and all valve lobules are the same size. Thus, the same number of fixing struts are required for each of the three valve lobules.

[0048] Stents cut from a tube are manufactured with barbs (spikes) for securing a heart valve in place (heart valve holder). According to the present invention, stents are envisioned to include having only one row of rhombuses on the circumference, having multiple rows of rhombuses arranged adjacent to each other and connected to one another, or having multiple rhombuses on the circumference connected to one another by struts.

[0049] Another element of the present invention, in one embodiment, is an integrated barb (so-called spike) which, with its assistance, fixes, for example, a heart valve made of pericardium within the stent.

[0050] The present invention is based on a combination of a polymer mixture and fluorinated or non-fluorinated compounds (alloys) from the group of lanthanides, such as magnesium, transition metals, and rare earth elements, including gadolinium, dysprosium, and yttrium. Magnesium has a short absorption time. Therefore, the stent according to this disclosure proposes that the absorption time can be precisely controlled by combining a small amount of polymer with a framework made of magnesium and rare earth elements as materials. The combination of magnesium and rare earth elements has proven advantageous in terms of the controllability of absorption time. The stent consists of a framework formed in a mesh-like structure, for example, a diamond shape, made of a mesh of metallic rare earth element alloys, and this mesh is coated with a polymer. In one embodiment, flattened metal struts are connected to each other in a diamond shape.

[0051] It will be apparent to those skilled in the art that the advantage of adjustable absorption time allows for better synchronization with vascular growth.

[0052] In one embodiment, the struts of the stent element may be flattened and have recesses on their surface, thereby providing slots in the struts that form the honeycomb-like stent element. One section of the honeycomb-like mesh structure composed of struts is connected to another section of the honeycomb-like mesh structure, for example, a diamond-shaped one, via lateral struts. This design allows the size of the stent to be adjusted in both width and length depending on the application.

[0053] The stent structure is coated with a polymer. This polymer coating ensures that the stent's absorption time is set to a predetermined period (targeting 3 to 6 months).

[0054] The stent struts may have barbs ranging in diameter from 20 to 50 μm. After the magnesium alloy polymer stent is cut, polished, and coated, the spikes are bent at an angle of 45 to 90° toward the lumen (inside the stent), thereby protruding into the interior of the stent.

[0055] After fabricating a heart valve from the patient's own tissue, a stent can be fitted over the valve according to a corresponding design. The barb punctures the pericardium and is fixed there. In this way, the heart valve is secured to the stent with only a few safety sutures, eliminating the need for further suturing. Since the process of suturing the heart valve to the stent usually accounts for a significant portion of the heart valve stent fabrication time (40-60 minutes based on experience), the invention of the barb saves valuable intervention time and, consequently, the anesthesia time for the patient.

[0056] The heart valve stent is inserted using a delivery system that includes a balloon catheter, thereby allowing the Mg / rare earth element / polymer stent to be fixed in a child with congenital heart valve defects.

[0057] The stent according to the present invention is a balloon-expandable stent, and its struts may be provided with slots filled with polymer. The polymer-coated struts may also be designed as a double T-beam to obtain higher mechanical stability.

[0058] The shape of the stent is selected according to the site of use. When used in the pulmonary valve site, the stent consists of diamonds with a diamond shape in length and circumference, although this shape is not mandatory. Each diamond is connected to an adjacent diamond at its four corners. This means that all diamonds have a closed configuration (see Figures 1 and 2). When used in the aortic valve site, a diamond ring (crown) is formed at the top, followed by a long, longitudinally curved strut at the commissure, and then a conical skirt consisting of two rows of diamonds in the left ventricular outflow tract region.

[0059] According to the present invention, application fields that do not use heart valves are also conceivable. For example, when used in aortic hypoplasia (aortic isthmus stenosis), a stent is manufactured with many short struts, i.e., a small diamond shape. All struts are connected to each other by connectors, thereby enabling the stent to achieve both high radial force and low longitudinal shortening.

[0060] When used in the pulmonary artery, fewer long struts are used. Not all diamonds (squares surrounded by struts) are connected to all other diamonds via connectors. This improves the longitudinal deformability of the stent, enhances maneuverability, and prevents stent breakage.

[0061] For applications other than the cardiovascular system, the stent according to the present invention can be designed to meet specific requirements, such as the required radial force, planned implantation time, and required diameter. The advantage of the present invention is that the stent can be adapted to a variety of requirements.

[0062] A further advantage and improvement over known state-of-the-art stents is that the use of an alloy of magnesium and rare earth elements allows for time-controlled stent dissolution behavior. This enables precise treatment of blood vessels over a defined period, allowing for continued growth of the treated area of ​​the blood vessels and heart. This is particularly advantageous for neonates, infants, and young children, whose hearts and blood vessels grow rapidly. It has been empirically observed that conventional stent and prosthesis treatments often result in rapid stenosis in children and neonates. In contrast, the biodegradable stent according to the present invention allows for normal blood vessel growth in children and neonates.

[0063] Until now, no conventional stent has been known in which the fixation of heart valve tissue within the stent is achieved by barbs.

[0064] Figure 3 schematically shows one embodiment of a stent barb according to the present invention.

[0065] The biodegradable stent according to the present invention can be used as a vascular support in various congenital heart diseases, for example, to open pulmonary artery atresia, to maintain patency of the ductus arteriosus (ductus of Botallo), to maintain patency of aortic isthmus stenosis, or to stimulate growth ("artificial growth") in hypoplastic pulmonary arteries.

[0066] Furthermore, the stent according to the present invention has potential applications beyond cardiovascular medicine, such as in esophageal stents, ureteral supports, and urethral valves.

[0067] The present invention also relates to a system comprising a stent and an apparatus for implanting the stent described above. Such an apparatus, for example, described in German Patent Application Publication DE102013224298A1, comprises an apparatus for transluminal insertion and placement of a self-expanding stent, in particular a cardiac valve stent, into a luminal organ. In this apparatus, the stent is positioned in a compressed state at the distal end of a tubular flexible implantation catheter and comprises a tubular outer catheter, a tubular inner catheter, and a tubular ring-shaped coil spring positioned between the outer catheter and the inner catheter at least at the distal end of the implantation catheter. The coil spring supports the proximal end of the stent at its distal end, and by retracting the outer catheter relative to the coil spring, the stent deploys at the implantation site and engages with the luminal organ.

[0068] The above description of preferred embodiments of the present invention is provided for illustrative and explanatory purposes only. It is not exhaustive and does not limit the invention to the disclosed forms themselves, and may be modified and altered in light of the above teachings or through the practice of the invention. The above embodiments have been selected and described to illustrate the principles of the present invention and examples of their practical applications, so that those skilled in the art may utilize the invention in various embodiments suitable for their particular use. The scope of the present invention shall be defined by the appended claims and their equivalents. The entire above document is incorporated herein by reference. [Explanation of Symbols]

[0069] A pocket flap cavity area B Trigonum intervalvular region C barb D Stent strut E Stent area near the outflow channel Slots within the F, G, H, I, K, L struts J Small hole for attaching sutures M Eyelet Relocation device using N storage system

Claims

1. A biodegradable, absorbent stent comprising a skeletal structure made of a metallic alloy of magnesium and a transition metal and / or a rare earth element, wherein the skeletal structure is coated with a polymer, and the coated skeletal structure has struts of stent elements.

2. The stent according to claim 1, wherein the stent element has a diamond shape.

3. The stent according to claim 1 or 2, wherein the strut is flattened.

4. The stent according to any one of claims 1 to 3, wherein the strut of the stent element has a slot.

5. The stent according to any one of claims 1 to 4, wherein the rare earth element is selected from the group of lanthanides including gadolinium, dysprosium, and yttrium.

6. The stent according to any one of claims 1 to 4, wherein the strut has a barb.

7. The stent according to claim 5, wherein the barb has a diameter in the range of 20 to 50 μm.

8. The stent according to any one of claims 1 to 6, wherein the barb is bent inward at an angle of 45° to 90° with respect to the strut of the stent.

9. The stent according to any one of claims 1 to 7, wherein the polymer is poly(DL-lactide-coglycolide).

10. The stent according to any one of claims 1 to 8, wherein the stent is a valve support stent.

11. The stent according to claim 9, wherein the circumference of the skeletal body has a number of stent elements that is divisible by 3.

12. The stent according to claim 11, wherein the skeletal body has 24, 21, 18, 15, or 12 stent elements.

13. The stent according to any one of claims 9 to 11, wherein a heart valve is attached to the barb of the strut.

14. A system for implanting a stent, comprising an apparatus for implanting a stent and a stent according to any one of claims 1 to 12.

15. A method of using a stent according to any one of claims 1 to 8 or a system according to claim 13 in a congenital heart disease for the purpose of implanting the stent to open the pulmonary artery, to maintain patency of the ductus arteriosus (Botalo's duct), to maintain patency of an aortic isthmus stenosis, to stimulate growth in a hypoplastic pulmonary artery, or as an esophageal stent or as a ureteral support.

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