Patent Application
20250017751
The present invention belongs to the technical field of implantable polymeric endoluminal support structures, e.g., stents and/or scaffolds for use, e.g., in regenerative cardiovascular interventions.
In particular, the present invention relates to a method of preforming an implantable polymer stent for delivery and deployment into a body, e.g., in a bodily lumen such as a blood vessel.
U.S. Pat. No. 10,813,777 B2 discloses a tubular stent which is made of a bioabsorbable network of polymeric fibers that can be rearranged upon expansion, accommodated for diameter enlargement without the need of a strut or strut pattern, and provide temporary support to a biological duct. Additionally, a stent is provided where the rearranged fibrous network, in its expanded state, can act as a scaffold for cell infiltration and promote autologous tissue formation.
In cardiovascular interventions, implantable endoluminal support structures such as stents may serve as minimally-invasively deliverable scaffolds.
For the purpose of delivery and deployment into a bodily lumen, it is known to use stents having an initial nominal configuration with a smaller diameter, which is then expanded after deployment (e.g., upon being inflated with a balloon).
Nevertheless, this known approach has the drawback that endoluminal support structures, especially polymeric stents, tend to recoil to their initial smaller nominal configuration after deployment and inflation.
As a solution, it is known to manufacture stents according to the size they should have and maintain after deployment at a target site within a bodily lumen (e.g., a blood vessel) and then crimp the stent down to smaller diameter for deployment purposes.
In particular, stents are subjected to a crimping procedure by using a crimping device that applies a radial compression that reduces the diameter of the stent.
Then, once the stent has been deployed at a desired target site into the bodily lumen, the diameter of the stent is radially expanded, e.g., by self-expansion or by inflating a balloon.
Crimping devices are known in the art and—in case of balloon expandable stents—commonly include a balloon of a catheter assembly inside the lumen to crimp the stent onto such balloon. The stent is placed at the center of the device and then crimping is performed by applying radial compression that allows to obtain a desired reduction of the diameter of the stent and to mount the stent firmly onto the balloon of the catheter assembly.
Delivery and deployment of a stent are commonly accomplished by positioning the stent around one end of a catheter, inserting said end of the catheter into a bodily lumen (e.g., a blood vessel), advancing the catheter to a target site, expanding the stent at the target site, and finally removing the catheter from the lumen (U.S. Pat. No. 8,298,466B1).
The stent must allow for crimping and expansion without incurring in any structural and/or functional damages to its structure.
Further, it is necessary that the stent maintains its size and shape after deployment at the target site, despite loads and forces acting on the same after deployment.
For instance, once deployed and expanded in a target site of a blood vessel, the stent needs to withstand the radial forces exerted by the walls of the vessel, further than the cyclic loading induced by the beating heart or movement of an artery in the body (especially in the leg or other peripherals).
U.S. Pat. No. 8,298,466B1 discloses a method of fabricating a stent having improved capability of mechanical support to walls of a bodily lumen, said method comprising: disposing a bioabsorbable polymer tube in a chamber; contacting the tube with a fluid at supercritical conditions, wherein the fluid is impregnated in the polymeric tube; adjusting conditions in the chamber so that the fluid is subcritical to form a porous structure in the tube; and reducing or preventing radial expansion of the tube during formation of the porous structure.
US2017348124A1 discloses a method of uniform crimping and expansion of a medical device such as a scaffold. A catheter balloon is pressurized at relatively high pressures prior to crimping to allow pre-arranged folds of the balloon to be substantially removed. Then, when the balloon reaches an inflated state, the scaffold is crimped to the balloon until the scaffold diameter has been reduced in size to about 50% (or more). At this point, the balloon pressure is relieved to avoid damage to the balloon and to achieve a small crossing profile.
US2017252191 (A1) discloses a method for crimping a polymeric coated stent on a balloon catheter. The stent can be either a metallic stent or a bioabsorbable polymeric stent having a coating that comprises a polymer and a rapamycin derivative drug. Crimping is conducted in an environment having a relative humidity of 45% to 55% and at a temperature greater than 25°, where humidity level is maintained until the stent is considered crimped and compressed on the balloon by a crimping apparatus.
However, there is still room for improvements.
In particular, there is a need for enhancing the capability of an endoluminal support structure such as a stent to maintain its size and shape after deployment, and to improve adhesion of said structure to the walls of a bodily lumen, e.g., a blood vessel, thereby preventing the risk of unwanted displacement after deployment.
This object is achieved by the provision of a method of preforming an implantable endoluminal support structure according to claim 1.
Accordingly, a method of preforming an implantable polymeric endoluminal support structure for delivery and deployment into a body is provided, wherein the method comprises the following steps:
In particular, the present invention provides a method of preforming an implantable endoluminal support structure, for delivery and deployment into a body, in particular a bodily lumen such as a blood vessel.
The endoluminal support structure can be, for instance, a polymeric fibrillated stent.
The tubular structure is preferably made of a network of polymeric fibers in the micrometric or nanometric range. Reference is made especially to U.S. Pat. No. 10,813,777 B2.
In particular, the tubular structure can be a stent that is obtained through electrospinning.
The invention is based on the basic idea that, by providing an endoluminal support structure made of polymeric fibers, it is possible to obtain an improved implantable structure (e.g., a polymer stent) having an enhanced capability of maintaining its size and shape once deployed, regardless of loads and forces acting on it once in site. Said structure further shows an improved capability of adhering to the walls of a bodily lumen, e.g., a blood vessel, into which it is deployed.
In particular, the main idea is that the support structure, such as a stent structure, is crimped down from a larger first diameter to a second smaller diameter. Such stent structures as e.g. described in U.S. Pat. No. 10,813,777 B2 have a shape memory, i.e. they (can) return to their initial shape upon certain temperature and environmental factors such as the presence of water or other substances. Thereby, it shall be prevented a situation where, after implantation, the stent structure tends to return to it is initial configuration (which it had before being deployed and inflated so as to be attached to the inner vessel wall), which could also mean that the stent structure returns to a smaller diameter and therefore does no longer maintain its position within the vessel.
According to the basic idea of the invention, the stent is initially provided with its nominal length and diameter, then crimped down to a smaller diameter, which is then used for the deployment. While being deployed, the stent will return to its nominal diameter, i.e. its regular length and diameter. With this size and configuration, it is placed at the implantation site within the blood vessel. Further influence of temperature, water uptake and other influencing factors, which might cause that the stent structure returns to its nominal state and configuration cannot cause a shrinking of the stent anymore as the stent is in the implanted and deployed state already in its nominal state.
The inventors witnessed with fully polymeric fibrillated structures (stents) the issue of intrinsic stent recoil. Here, the stent (without being subject to the method according to the invention) was first made in small diameter configuration, inflated, and exposed to elevated physiological temperature (fever conditions). Then, stents went back to their nominal small diameter configuration. There appeared to be a short of “shape memory effect” in the stent, wanting to go back to nominal configuration when exposed to elevated physiological temperatures in an aqueous environment. This led to the problem that the stent became smaller after removing the balloon, for which the stent itself was providing a stenosis inside the artery. As a solution, the inventors realized that the stents should be provided in the size how they should be at the implantation site (the new nominal state). Then, the stent will be crimped and then when they will be inflated and exposed to elevated temperature, the stents want again to go back to their initial state, but this time the large diameter. In this way the stent will not shrink at the implantation site. This has already been seen and proven in the lab. This way, the structure can be influenced such that in any case the stent structure will return to the pre-crimping form, in case that the factors which cause a shape-memory effect apply. It also helps that no unwanted irreversible structure change or material change happens during the process.
Preferably, crimping is performed at or around glass transition temperature (Tg) of said polymeric fibers. In this temperature range the shape memory of the stent structure and its material can be set in a very good manner.
More preferably crimping is performed at room temperature.
For instance, crimping may be performed at a temperature ranging from 34° to 43°.
In particular, crimping may be preferably performed at about 37° (i.e., approximately the body temperature of a healthy human subject).
Temperature range at so-called normal physiological conditions are preferable for performing the method. This way, it is ensured that the material is treated with the method in temperature ranges, which will also apply after implantation.
Advantageously, crimping may be performed in an environment having humidity level of about 20% to 100%.
For example, crimping can be performed in an aqueous solution. However, it is also possible to perform the step of crimping at dry conditions without the presence of an aqueous solution.
For instance, crimping may include performing crimping of a wetted fibrillated tubular structure.
Adding an aqueous solution or performing the method at a certain humidity can influence to lower the glass transition temperature (Tg) of the material and thereby further enhance the structural features of the stent so obtained in terms of improved capability to crimp the stent.
In particular, said aqueous solution can be water. In trials, normal drinkable water has been used. It is also possible to use isotonic water, which matches with the physiological conditions of the solutes of a human, saline, or phosphate buffered saline.
The method may further include allowing the fibrillated tubular structure to rest in a crimped state after crimping, before release. This allows relaxing of the fibers from the crimping.
In case crimping is performed in an aqueous solution (e.g., water), said step of allowing the fibrillated tubular structure to rest in a crimped state can be performed while being immersed in said aqueous solution.
Further, in case crimping is performed in an aqueous solution at relatively high temperatures (e.g., ranging from 34° to 43°, preferably around) 37°, the method may include:
Then, the crimping load can be released and the fibrillated tubular structure is dried.
Alternatively, the fibrillated tubular structure can be dried before the crimping load is released.
For instance, drying of the electrospun tubular structure (either before or after releasing the crimping load) can be performed by using compressed air.
Support structures such a stents usually include a porous structure made of a polymer material that is hydrophobic.
Accordingly, when exposed to water or bodily fluids such as blood, air remains trapped in said porous structure and inhibits water or bodily fluids from penetrating.
The inventors have found that wetting of the fibrillated tubular structure prior to crimping is beneficial since it eases reorganization of the fibrous mesh and makes inflation simpler. Further, wetting of the structure of the material will enhance and ease cell infiltration into the structure, it will prevent embolisms of air being trapped in the structure and released after implantation, will support coating or can be used as carrier for pharmaceutical agents. Further, the wetting will help that the overall stent structure has a homogenous stent expansion characteristic.
It has been surprisingly found by the inventors that the stent structure made of polymeric fibers as described herein in this disclosure has a tendency to go back to the initial state and have this shape memory. This is inter alia related to the difference between “dry” glass transition temperature (Tg) and “wet” glass transition temperature (Tg). The used polymers have a Tg above body temperature. This means, that at body temperature the polymer is in a glass state, meaning the material is stiff, brittle, and strong. Since small fibers will be mainly used for the stent structure, water may have an intense effect on the hydration of the fibers used in the stent structures. This may lead to a rapid drop in the Tg of the polymer as water molecules start interfering with the polymer chains within the fibers. As it progresses, the Tg drops to reach physiological body temperature. Here, the polymer transits from a glass transition towards a rubbery state. This will enable the polymer chains to freely move again. What happens next is that because of this, the build up stresses and strains induced by deformation due to the crimping can dissipate by which it will go back to its initial strain and stress free (or more optimal) starting configuration.
This also explains why the stent structures will remain crimped as long as they are dry and exposed to temperatures below its Dry Tg. But as soon as the constructs become humid, the Tg drops and regains its “shape memory” effect.
To this end, the method may further include subjecting the fibrillated tubular structure to high centrifugal force while being immersed in an aqueous solution, preferably water prior to crimping, so that air is removed from the network of electrospun polymeric fibers and replaced with the aqueous solution.
In particular, said aqueous solution can be water.
The high centrifugal force can be applied for approximately 30 seconds at, for example, 15000×g, relative centrifugal force (RCF).
The crimping is performed while the tubular structure is already mounted around an expandable balloon of a catheter assembly. This way, the process of manufacturing a ready-to-implant and ready-to-deployment product is significantly enhanced. For placing the stent structure on the balloon anyhow a kind of crimping or the like is needed. So, there is only one crimping step which integrates the dimension setting and the placement on the balloon of the balloon catheter. So the crimping method can be used to mount the stent on a balloon catheter device. In any case it is important that the stent is firmly crimped on the balloon. Therefore, after crimping, the stent may not (gradually) expand during shelf life or delivery into the body. Also, it should be firmly fixed that it withstands sufficient “dislodgement force” by pushing it through tight, rough and calcified lesions or when advancing it though introducer devices. This is achieved with the method as explained above.
The invention further provides a fibrillated tubular structure having the features of claim 15.
The fibrillated tubular structure has a first configuration before crimping and a second configuration after crimping, wherein crimping is performed through the method described above.
In particular, said fibrillated tubular structure may distinguish:
The fibrillated network may be arranged according to a random fiber orientation scenario.
In this case, the first fiber dispersion is smaller than the second fiber dispersion.
Alternatively, the fibrillated network may be arranged according to a controlled fiber orientation scenario.
In this case, the first main angle difference is equal to or smaller than the second main angle difference.
Alternatively, the fibrillated network may be arranged according to a combination of a controlled fiber orientation and a random fiber orientation scenario.
Alternately the fibrillated network may be composed of multiple layers of a controlled fiber orientation or a random fiber orientation or a combination of both
Advantageously, in the first configuration before crimping, the polymeric fibers forming the network are arranged according to a circumferentially aligned configuration.
The same arrangement of the polymeric fibers is then obtained once the fibrillated tubular structure is re-expanded to its original state after deployment at the target site.
This allows to enhance the load bearing capacity of the fibrillated tubular structure and benefit native-like tissue formation. In particular, cells can align along the fibers of the structure and produce a tissue component (e.g., collagen) in the same direction, resembling the native configuration.
In the first configuration for before crimping, the fibrillated tubular structure may have an inner diameter of 100 mm or less.
In the second configuration after crimping, the fibrillated tubular structure may have an increased wall thickness than in the first configuration before crimping.
Then, the wall thickness of the fibrillated tubular structure is decreased again when it is re-expanded to its original state after deployment at the target site.
Further, in the second configuration after crimping, the fibrillated tubular structure may substantially have the same length as in the first configuration before crimping.
Thus, according to the invention, wall thickness of the fibrillated tubular structure may vary between the first and second configurations, while the length of the fibrillated tubular structure remains substantially unchanged.
The material for the implantable polymer stent can be biocompatible polymer. Biocompatible polymeric fiber materials can include inter alia, but not limited to it:
Advantageously, the polymeric fibers may include: poly(L-lactide), poly(D-lactide), polyglycolide or a combination thereof in the form of a co-polymer being either poly(DL-lactide), poly(lactide-co-glycolic acid) or poly(DL-lactide-co-glycolic acid).
In particular, said crystalline or semi-crystalline polymeric material may have a glass-transition temperature (Tg) above physiological core body temperature.
Further details and advantages of the present invention shall now be disclosed in connection with the drawings.
It is shown in:
The present invention provides a method of preforming an implantable polymeric endoluminal support structure 20 for delivery and deployment into a body, in particular a bodily lumen such as a blood vessel.
In the present example, said endoluminal support structure 20 is a stent 20.
For example, the stent 20 may be obtained by electrospinning.
For “stent”, it is intended a structure for providing structural support to a bodily lumen, e.g., a blood vessel, upon self-expansion or balloon expansion after deployment at a target site.
The method includes forming a fibrillated structure 10 made of a network of electrospun polymeric fibers, said tubular structure 10 having a first diameter. The method further includes crimping the fibrillated tubular structure 10 so obtained down to a second diameter, said second diameter being smaller than the first diameter.
The present invention allows obtaining an improved endoluminal support structure 20 such as a stent 20 having an enhanced capability of maintaining its size and shape after deployment, and which better adheres to the walls of a bodily lumen, e.g., a blood vessel once deployed, thereby preventing the occurrence unwanted displacement.
Crimping may be performed at temperatures below melt transition temperature (Tm) of said polymeric fibers, preferably at or around glass transition temperature (Tg) of said polymeric fibers, more preferably at room temperature.
In particular, crimping may be performed at a temperature ranging from 34° C. to 43° C., preferably at about 37° C.
Crimping may be performed in an environment having humidity level of about 20% to 100%.
In the present embodiment, crimping is performed in an aqueous solution.
In the present embodiment, said aqueous solution is water, for example water from the tap or drinkable water.
In particular, in the present embodiment, crimping is performed in said aqueous solution at a temperature ranging from 34° C. to 43° C.
Preferably, crimping is performed in said aqueous solution at about 37° C., i.e., at a temperature that is close to the body temperature of a healthy human.
The fibrillated tubular structure 10 is allowed to rest in a crimped state after crimping, before release.
This allows for relaxation of the polymeric fibers from the crimping.
In the present embodiment, the step of allowing the fibrillated tubular structure 10 to rest in a crimped state is performed while being immersed in said aqueous solution.
In particular, in the present embodiment, crimping is performed in said aqueous solution at a relatively high temperature.
In particular, in the present embodiment, the method further includes:
For “relatively high temperature” it is intended a temperature ranging from 34° C. to 43° C., preferably about 37° (i.e., the body temperature of a healthy human subject).
For “room temperature” it is intended a temperature of about 20°.
Wetting of the fibrillated tubular structure 10 before crimping can be beneficial since it cases reorganization of the fibrous mesh and makes inflation simpler.
In particular, in the present embodiment, the fibrillated tubular structure 10 is subjected to high centrifugal force while being immersed in an aqueous solution, preferably water before crimping, so that air is removed from the polymeric fibers and replaced with the aqueous solution.
In the shown embodiment (
For example, that said high centrifugal force can be applied for approximately 30 seconds at about 15000×g relative centrifugal force
The fibrillated tubular structure 10 is then maintained in the vial 12 until reaching a state where it is sunk to the bottom of the vial 12, this meaning that air present in the fibers has been almost completely replaced with the aqueous solution (
The present invention further provides a fibrillated tubular structure 10 having a first configuration before crimping and a second configuration after crimping, where crimping is obtained by implementing the above described method.
According to the invention, said fibrillated tubular structure distinguishes:
In one embodiment, the polymeric fibers may be arranged according to a random fiber orientation scenario (
The first fiber dispersion is smaller than the second fiber dispersion.
In particular, in the first configuration before crimping, the tubular structure 10 has an enlarged diameter where fibers are aligned. The directionality histogram describes a narrowed peak area surrounding one preferred orientation (
When deployed at the target site within a bodily lumen, the stent 20 is re-expanded (either naturally or upon inflation with a balloon) to its original state where fibers are substantially aligned.
In an alternative embodiment, the polymeric fibers may be arranged according to a controlled fiber orientation scenario (
In the first configuration for pre-deployment (
Advantageously, in the first configuration before crimping, the polymeric fibers may be arranged according to a circumferentially aligned configuration.
The same arrangement of the polymeric fibers is then obtained once the stent 20 is re-expanded to its original state after deployment at the target site.
In said first configuration before crimping, the fibrillated tubular structure 10 may have an inner diameter of 100 mm or less.
In the second configuration after crimping, the fibrillated tubular structure 10 has an increased wall thickness than in the first configuration before crimping.
Furthermore, in the second configuration after crimping, the fibrillated tubular structure has substantially the same length as in the first configuration before crimping. This is apparent by observing the stent 20 before and after crimping, as shown in
That is, the wall thickness of the tubular structure 10 varies between the first and second configurations (according to a “sponge effect”), while the length of the tubular structure 10 remains substantially unchanged.
Advantageously, the polymeric fibers may include: poly(L-lactide), poly(D-lactide), polyglycolide or a combination thereof in the form of a co-polymer being either poly(DL-lactide), poly(lactide-co-glycolic acid) or poly(DL-lactide-co-glycolic acid). The stent 20 may be mounted over the balloon of a balloon catheter.
Then, once the stent 20 is deployed at a target site within a bodily lumen, the balloon is inflated to re-expand the diameter of the stent 20 to its original configuration.
As the balloon is deflated, the stent 20 maintains its expanded configuration without shrinking.
Alternatively, the stent 20 may be self-expandable.
Also in this case, once re-expanded to its original configuration, the stent 20 maintains the expanded configuration without shrinking.
Here, the stent 100 is provided as e.g. described in the prior art and made of a electrospun polymer material. Its diameter in in the initial state (cf. left part of
At 37 degrees the stent 100 will maintain its shape (cf. upper right part of
In case that the temperature is above 37 degrees, then the stent 100 can show the problem of recoiling to its initial diameter, i.e. it shows a tendency to go to its initial state (cf. lower right part of
As shown in the left part of
| Number | Date | Country | Kind |
|---|---|---|---|
| 21210116.6 | Nov 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/081263 | 11/9/2022 | WO |
