Patent Application
20230181179
The present invention relates to an endoluminal delivery device, and in particular to a endoluminal delivery device for delivery of a substance to an extravascular or intramyocardial target site, according to the preamble of the independent claim.
Within the medical field, there is a growing trend towards minimally invasive techniques when accessing or treating specific sites within the body. Such techniques have many advantages over open surgery, as they involve less trauma to the body, resulting in less complications and shorter recovery time after the procedure. Minimally invasive techniques often use the vascular system to access specific sites or regions of the body, by inserting a catheter and/or guide wire assembly percutaneously through e.g. the femoral or radial artery, and subsequently steering through the vasculature to a specific site under the guidance of angiographic imaging. However, some sites within a body are not accessible, or difficult to access, using known techniques, due to the complexity and sizing of the vasculature.
Various techniques and devices are known for administration via the vascular system of substances to specific and localized target sites within the body. Examples of procedures where such techniques are used are in chemotherapy, treatment of various immunological conditions and stem cell treatments.
For example, U.S. Pat. No. 8,152,758 discloses a catheter assembly including a delivery cannula with multiple channels and an expandable distal portion, wherein two needles are threaded through channels and used for infusion of a substance into the vessel wall.
U.S. Pat. No. 5,464,395 shows an injection balloon catheter with side ports for needle injection into surrounding tissue.
US 2008/0319314 discloses an injection catheter with internal channels and a tip electrode, with a needle threaded through the assembly such that it can protrude out through the distal tip. Other catheter systems with injection needles are shown in e.g. U.S. Pat. Nos. 6,613,017B1 and 6,796,963B1.
These and other known systems are not adapted or suitable for access to the remote microvasculature due to their size and complexity.
Thus, the inventors of the present invention has identified a need for an improved endoluminal delivery device, which provides for enhanced access to remote locations in the body, especially via the microvasculature, as well as procedural efficiency in delivering substances to extravascular or intramyocardial target sites.
An object of the present invention is to provide an endoluminal delivery device which allows reliable access via the vasculature to more remote extravascular sites within the body.
A further object of the present invention is to provide an endoluminal delivery device which mitigates the problems of bleeding at the puncture site of the vessel wall during and after penetration and delivery to an extravascular or intramyocardial target site.
The above-mentioned objects are achieved by the present invention according to the independent claim. Preferred embodiments are set forth in the dependent claims.
According to a first aspect, an endoluminal delivery cannula, for delivery of a substance to an extravascular or intramyocardial target site via the vascular system of a human or animal is disclosed. The endoluminal delivery cannula comprises a cannula hub provided at a proximal end of the cannula and an elongated proximal portion having an outer diameter, wherein the outer diameter is being constant along essentially the entire length of the proximal portion as measured when the cannula is essentially straight. Further, the cannula comprises a tip portion arranged distally of the proximal portion and extending from the proximal portion to a distal tip of the cannula, and a continuous lumen extending from the proximal end of the cannula through the proximal portion and the tip portion to the distal tip. The tip portion has an opening at the distal tip to provide communication between the lumen and the exterior of the cannula. The tip portion is preferably tapered towards the distal tip by being provided at the proximal end of the tip portion with an outer diameter being essentially the same as the outer diameter of the elongated proximal portion, and an outer diameter at the distal tip being smaller than the outer diameter at the proximal end of the tip portion.
In some aspects, the endoluminal delivery cannula has a distal tip with a pointed tip section for penetrating tissue, wherein the pointed tip section comprises at least one primary facet and two secondary facets, wherein the two secondary facets are arranged proximally of said primary facet.
According to a further aspect, an endoluminal delivery assembly, for delivery of a substance to an extravascular or intramyocardial target site via the vascular system of a human or animal body is disclosed. The assembly comprises an endoluminal delivery cannula, a protective catheter adapted for insertion into the vascular system of a human or animal body, wherein a distal end of the assembly is configured to be guided to a position in the vascular system suitable for accessing the intended extravascular or intramyocardial target site. The assembly further comprises a proximal catheter hub provided at the proximal end of the protective catheter and adapted for guiding the catheter through the vascular system, wherein the proximal catheter hub is adapted for the endoluminal delivery cannula to be inserted therethrough and into said protective catheter.
According to yet another aspect, a method for delivery of a substance to an extravascular or intramyocardial target site via the vascular system of a human or animal body is disclosed. The method comprises the steps of
Specific embodiments of the invention will now be described. However, it will be apparent to those skilled in the art that individual features may be combined in different manners, and the below disclosures are in no manner limiting.
The terms “proximal” and “distal” is herein used as is conventional in the art, i.e. as being in relation to a user, such that a proximal end of a device or assembly is the end directed towards the user, and a distal end is directed away from a user.
Further, the terms “cannula” and “needle” are used interchangeably herein, and both refer to an elongated tube, preferably made of a metal, which may have a sharpened tip adapted for penetration of tissue or the like.
To initiate a delivery procedure, a guide catheter 200 is typically used to reach a location near a defined target site 500 via the vascular system. Such a guide catheter 200 is typically a standard interventional catheter for vascular access, and may be provided together with the disclosed cannula 1 and protective catheter 150, or as a separate unit. On the right side in
The guide catheter 200 may be inserted percutaneously into a blood vessel 300 according to known techniques, e.g. using the Seldinger procedure or other known techniques, to access the vasculature via for instance the femoral artery or the radial artery. It should be noted that the devices and assemblies described herein are especially adapted for access to remote target sites in the body, i.e. for access into and via the microvasculature, and thus adapted to navigate very small vessels, as small as 1 mm or less in diameter, to reach sites within the body previously not accessible via standard techniques. However, they are also compatible for use with larger guide catheters and via larger blood vessels. The devices, assemblies and methods described herein are described in terms of reaching an extravascular target site; however, they may also similarly be used for intramyocardial delivery. Thus, a target site may be accessed via navigation through the vascular system and reached either via penetration of a blood vessel wall (for an extravascular site) or via penetration of the myocardium from e.g. inside the heart (for an intramyocardial target site).
The disclosed devices and assemblies may be used for targeted and localized delivery of one or a combination of cells, RNA, recombinant proteins, antibodies, high-dose chemotherapy, radiotherapy, or tumor-specific therapies. The specific target site 500 may be a tumor, an organ, a body cavity or a localized region of a specific tissue or body part. As further examples, disclosed devices and assemblies may be used for delivery of e.g. cell or RNA therapy for cardiometabolic regenerative therapies including the heart, liver, and kidney and for direct intra-tumor infusion.
When the guide catheter 200, which preferably has manoeuvrability and steerability properties, has been inserted via the vasculature such that the distal tip 201 of the guide catheter 200 is near the desired target site 500, the cannula 1 and protective catheter 150 are inserted via the guide catheter 200. As an alternative, the cannula 1 may be inserted into the guide catheter prior to inserting the assembly into the vasculature. In any case, the cannula 1 and protective catheter 150 are adapted to be navigated through the vascular system of a patient to a location near a target site 500 via the guide catheter 200. The cannula 1 and protective catheter 150 are directed towards the vessel wall 301, as seen in
During the insertion through the guide catheter 200 and out towards the vessel wall 301, the protective catheter 150 and cannula 1 are prevented from axial displacement in relation to each other by a locking function at the proximal end, which will be described further below. This is to prevent the potentially sharp tip of the cannula 1 from piercing or damaging the guide catheter or the blood vessel before reaching the desired location.
Once at the desired site at the vessel wall 301, the tip of the cannula 1 is advanced out of the protective catheter 150 towards the vessel wall and further distally, such that it penetrates the vessel wall and extravascular tissue to reach the target site 500, as shown in
Once at the target site 500, a substance to be injected into the target site is applied by syringe into the cannula via a proximal cannula hub, and ejected from the cannula via a distal opening at the tip of the cannula. In some aspects, the injected substance may be ejected both via the distal opening, and via side openings near the distal tip of the cannula. The administration of substance may be repeated a number of times, as needed. Further, the tip of the cannula may be retracted and repositioned if needed. Once administration is finished, the tip of the cannula is retracted from the vessel wall and back into the protective catheter.
As an alternative, or in addition to administrating a substance, the assembly may be used for taking samples from the target site via the tip of the cannula.
Due to a specific design of the cannula and its tip, essentially no bleeding of the vessel wall is seen. The details of the tip will described further below.
The cannula 1 further has a tip portion 5 arranged distally of the proximal portion 4 and extending from the proximal portion 4 to a distal tip 6 of the cannula 1. A continuous lumen 7 extends from an internal longitudinal channel 10 of the cannula hub at the proximal end 2 of the cannula through the proximal portion 4 and the tip portion 5 to the distal tip 6. The tip portion 5 has an opening 9 at the distal tip 6 to provide communication between the lumen 7 and the exterior of the cannula 1.
The encircled tip portion 5 in
In some aspects, the tip portion 5 and/or proximal portion 4 may preferably be provided with one or several radiopaque marker bands 11 at predefined distances from the distal end 6. One such example is schematically shown in
Further, in some aspects, also shown in
As is understood from the figures, and from the present disclosure, opening 9 at the distal tip 6 provides communication between the lumen 7 and the exterior of the cannula 1 and thus, when the substance to be delivered exits the cannula into the target site, the substance exits the cannula through this distal opening 9. Substance delivery is thus controlled and easily directed in the direction that the cannula is directed.
In some aspects, as illustrated in
As detailed in
The longitudinal length L2 of the proximal portion 4 may be within in the range of approximately 1000 mm to 2000 mm, preferably between 1200 mm to 1700, more preferably 1400 mm to 1500 mm.
In some aspects, the tapered tip portion 5 has a longitudinal length L3 of at least 5 mm, preferably within in the range of 100 mm and 300 mm, more preferably between 200 mm and 280 mm. In some aspects the longitudinal length L3 of the tapered tip portion 5 may be within the range of 5 mm to 50 mm, in other aspects the longitudinal length L3 may be within the range of 50 mm to 300 mm.
In one aspect, the total length L1 of the cannula 1 is approximately 1700 mm, wherein the proximal portion 4 has a longitudinal length L2 of approximately 1450 mm and the tip portion 5 has a longitudinal length L3 of approximately 250 mm.
In another aspect, the total length L1 of the cannula 1 is approximately 1700 mm, wherein the proximal portion 4 has a longitudinal length L2 of approximately 1695 mm and the tip portion 5 has a longitudinal length L3 of approximately 5 mm. Such a cannula would thus have essentially no or minimal tapered portion.
In yet another aspect, the total length L1 of the cannula 1 is approximately 500 mm, wherein the proximal portion 4 has a longitudinal length L2 of approximately 425 mm and the tip portion 5 has a longitudinal length L3 of approximately 75 mm. Such a size would be useful for paediatric use.
The proximal portion 4 of the cannula 1 preferably has a constant outer diameter D1 within the range of 0.15 mm to 0.50 mm, preferably between 0.20 mm and 0.35 mm, more preferably between 0.25 mm to 0.28 mm.
The inner lumen 7 preferably has an inner diameter D2 which is constant along essentially the entire length of the cannula 1, i.e. through the proximal portion 4 and the tip portion 5. Naturally, the inner diameter D2 must be adapted to a suitable outer diameter D1 of the cannula. The inner diameter D2 of the lumen is preferably within in the range of approximately 0.08 mm to 0.40 mm, preferably between 0.10 mm and 0.25 mm, more preferably between 0.12 mm and 0.16 mm.
As mentioned, the outer diameter D1 of the proximal portion 4 is preferably essentially constant along essentially the entire length of the proximal portion 4. Further, the part of the cannula where the proximal portion 4 adjoins the tip portion 5 has an outer diameter D3 being essentially the same as the outer diameter D1 of the elongated proximal portion 4. In other words, the cannula preferably has a smooth transition in outer diameter from the proximal portion 4 to the tip portion 5. Thereafter, the tip forms a gradual tapered tip towards the distal end 6, such that the outer diameter D4 at the distal end 6 is smaller than the outer diameters D3 and D1. This taper is preferably provided such that the outer diameter D4 at the distal tip 6 is preferably between 0.10 mm and 0.25 mm, and more preferably between 0.15 mm to 0.22 mm.
In one aspect, the outer diameter D1 of the proximal portion 4 may be approximately 0.25 mm, the inner diameter D2 of the lumen 7 approximately 0.134 mm and the outer diameter D4 at the distal end 6 is 0.190 mm.
The gradual tapered tip portion 5 provides improved manoeuvrability, trackability and mainly pushability of the cannula tip, as well as providing a gradual transition to a smaller size distal tip. A smaller size tip inflicts less trauma on the vessel wall during penetration, and the small diameter of the tip allows the vessel wall to close in on itself after withdrawal of the tip, such that less bleeding is experienced after delivery. Thus, the configuration of the tip portion mitigates the need for any separate closure steps of the penetration site of the vessel wall.
The elongated proximal portion 4 and tip portion 5 of cannula 1 may preferably be made of stainless steel, nitinol, or any alloy with superelastic properties, such as Fe—Co—Ni—Ti alloys. In one aspect, the elongated proximal portion 4 and tip portion 5 are made entirely of nitinol or other nickel-titanium alloy. In another aspect, the tip portion 5 may be made of nitinol and the proximal portion 4 made of stainless steel. In further aspects, the tip portion may be made of nitinol with a tip made of a suitable ceramic material. Nitinol's superelastic properties resulting in superior flexibility provides improved navigation through small and tortuous vessels. Having a more rigid distal tip, such as a ceramic tip on a superelastic tip portion, improves the ease of penetration of the distal tip.
As seen in
A cross-sectional view along a longitudinal axis of a preferred aspect of a cannula hub 8 is illustrated in
The inner cavity 15 of the cannula hub 8 is preferably adapted for minimal dead volume during delivery when using a standard Luer connector 16, as shown in
The dead volume of the delivery system as a whole comprises the inner volume of the cannula hub 8, as described above, together with the inner volume of the rest of the cannula 1. A small dead volume of the delivery system, as seen when a male Luer connector is attached, allows minimal loss of substance during delivery, which is particularly important when delivering expensive and/or rare substances, and minimizes the risk of creating air embolisms. Thus, preferably the total inner deadspace of the cannula hub 8 and cannula 1 is below 0.50 ml, more preferably below 0.40 ml.
A further advantage of the particular inner volume shape of the cavity of the cannula hub as shown in
The cannula 1 and cannula hub 8 are preferably used together with a protective catheter 150 and catheter hub 160. One such assembly 400 is illustrated in
The cannula 1 is adapted to be inserted from the proximal end of the catheter hub 160 through opening 161. A locking means 162 is adapted to be used to lock the cannula 1 in place after insertion of the cannula into the protective catheter 150 and during different stages of the delivery procedure. When the locking means 162 is in a locked state, all axial movement between the protective catheter 150 and the cannula 1, and thus also the cannula hub 8 and the catheter hub 160, is prevented. Before a delivery procedure, the cannula 1 is inserted into the catheter 150 via the catheter hub 160 either by the user, or during manufacture of the assembly, such that the distal tip 6 of the cannula 1 is protected by a distal end of the protective catheter 150 (not illustrated). Notably, in
As seen in
As is shown in the cross-sectional view of
The locking means 162 may comprise any suitable mechanism to be able to lock the cannula in place when inserted into the catheter hub. Preferably, the locking means 162 is adapted to reversibly alternate between a locked state and an unlocked state. Non-limiting examples include screw locks, snap locks, friction locks and lever-based locks.
As described above, before employing the assembly 400 of protective catheter 150 with attached catheter hub 160, and cannula 1 with attached cannula hub 8, a guide catheter is usually placed in a vessel such that the distal end of the guide catheter is as close to the target site as possible. The assembly 400 is inserted into the guide catheter 200 and pushed or guided into a position such that the distal end of the catheter 150 protrudes from the guide catheter 200, as seen in
Once the distal tip 201 is directed towards the vessel wall and the target site 500, the assembly 400 is advanced distally out of the guide catheter 200. At this stage, the distal tip 6 of the cannula 1 is still contained within the protective catheter 150, to avoid any unintended damage to the vessel.
Thereafter locking means 162 of the catheter hub 160 is released, and the tip of the cannula 1 is advanced out of the protective catheter 150 towards the vessel wall and further distally, such that it penetrates the vessel wall and extravascular tissue to reach the target site. This movement is performed by moving the proximal cannula hub 8 closer to the proximal end of the catheter hub 160, by e.g. holding the catheter hub 160 still and moving the cannula hub 8 distally.
In some aspects, a stop element may be provided to prevent premature advancement of the distal tip before reaching a desired location. Such a stop element could be a stop ring or similar arrangement around the cannula 1 between the cannula hub 8 and the catheter hub 160, that may be manually removed before penetration of the vessel wall. As an alternative, or in combination with a stop element, a marker may be provided on the cannula 1 at a location such that it can be seen between the cannula hub 8 and locking means 162 of the catheter hub 160 when the distal tip 6 of the cannula is protected by the distal tip of the protective catheter 150. Such a marker provides a user with a visual indication of when the sharp tip is in a retracted and protected position within the protective catheter, and is useful both during initial positioning of the tip and when repositioning the endoluminal delivery device.
At any desired time during delivery of a substance, such as when the cannula tip protrudes from the catheter tip, the cannula 1 and catheter 150 may be locked in a relative axial arrangement, e.g. by engaging locking means 162. After delivery, or if the cannula tip is to be repositioned, the procedure may be reversed such that the cannula tip is once more protected by the catheter tip, and thereafter optionally repeated for another delivery dose.
As described above, in some aspects the distal tip portion 5 is preferably gradually tapered towards the distal tip 6.
Further, in some aspects, the distal tip portion 5 of the cannula is preferably provided with a pointed tip section 100 for penetrating tissue formed by at least one primary facet F1 and two secondary facets F2 and F3. Notably, herein such a tip section is shown on a cannula 1 for delivery of a substance via the vasculature. However, it is also conceivable to use a similar pointed tip for other devices with similar use, such as micro-needles for intramuscular or intradermal injections.
In the context of needle grinding, i.e. forming a sharpened tip from a hollow cylindrical cannula, the distal end of the cannula is ground down and sharpened against a grinding wheel or other grinding media. Normally, the grinding wheel is stationary, and the needle or cannula is applied at a fixed angle in relation to the grinding surface. The resulting facets or bevels are thus formed in one or several planes which may be defined in relation to the geometry of the cannula itself.
Following the formation of the primary facet Fi, two secondary facets, F2 and F3, are formed by a needle grinding of the distal tip in a fourth and fifth plane, P4 and P5, respectively, as is illustrated in
The fourth and fifth planes P4, P5 are arranged at a set of two symmetrical and combined angles, such that the fourth and fifth planes P4, P5 are symmetrically arranged in relation to the longitudinal axis, and also to the first and second planes P1, P2. The symmetrical angles of the fourth and fifth planes P4, P5 are thus comprised of two combined angles measured in different planes or views. As seen in
The second component of the arrangement of the fourth and fifth planes P4, P5 is a rotational angle omega ω around longitudinal axis A, as illustrated in
As is evident from the above and seen in the figures, the two secondary facets F2, F3 form the distal tip 6 together with an outer mantle surface of the tip section 100. Hence, the sharpness of the distal tip may be controlled by both phi φ and omega ω, thereby offering the ability to optimize sharpness and finding the most effective penetration of e.g. a tissue.
It has been found by the inventors that if phi φ is larger than theta θ, a more suitable geometry is obtained. However, if phi φ is larger than 45 degrees, the tip becomes too blunt.
In addition, especially when providing the one primary facet F1 at angle theta θ and two secondary facets F2 and F3, at angles phi φ and omega ω as described above, it is apparent that theta must be low, preferably under 30 degrees, to obtain a usable tip at all. However, as is described in the experiments below, if theta θ is under 10 degrees, then the tip will have an unsatisfactory rigidity.
Thus, through extensive testing, calculation and inspection of resulting tips the present inventors have reached the conclusion that in order to obtain an improved tip for penetration of a blood vessel wall and surrounding tissue with minimal trauma, leading to minimal bleeding on removal, as well as a needle tip suitable for multiple penetration procedures, the following criteria are preferable. A needle tip section with one primary facet F1 and two secondary facets F2 and F3 is preferably provided at primary facet angle theta θ being between 10.0 and 20.0 degrees, and secondary facets provided at +/− phi φ angles between 15.0 and 20.0 degrees, and +/− omega ω angles between 25.0 and 90.0 degrees.
As one example, a needle tip section is shown in
Another example of a suitable tip section would be a tip having theta θ angle 15.0 degrees, phi φ angle +/−20.0 degrees, omega angles +/−30.0 degrees.
It has thus been found by the inventors, that the combined effect of controlling the intersection between F2 and F3 by both phi φ and omega ω as described herein results in a triangular point with optimum sharpness and effective penetration of e.g. tissue, with minimal bleeding.
The above described dimensions and configuration of a tip section 100 works in combination with the overall tapered tip portion 5 of the cannula 1, such that a less-traumatic penetration of a vessel wall may be achieved, mitigating the need to provide any specific closure measures, such as plugging or stopping the hole made by the penetrating tip in the vessel wall.
Experiments were performed to determine the preferred shape of needle tip for optimal rigidity.
The figures illustrating a needle tip (
The first grinding angle, theta, was evaluated for angles between 10° and 35°. These grinding angles, as illustrated in
To improve the tip sharpness and to improve vertical rigidity, two symmetric grindings at angle phi to the catheter axis were evaluated, as illustrated on
By setting a fixed truncation of 0.1 mm to maintain minimal truncation, the effects of theta and phi were explored, as shown in
With the option of high precision grinding, truncation can be limited. As a result, the effect of theta and phi was evaluated for an ideal situation for more suitable ranges of theta and phi. In this modelling, the tips are all sharp as all the needle facets meet in a point. When phi<=theta, the ID (inner diameter) surface is cut by facets 2 and 3 and produces a thin tongue, as seen in
Facets 2 and 3 can be tilted by rotating the catheter by an angle, omega, as shown in
The corners between facets 1&2 and 2&3 cannot be removed by the tilted grinding with a truncation of 0.1 mm when theta and phi are set at 20° and 30° respectively as shown in
To determine a beneficial geometry to limit corners where the facets meet, omega was set to 30°, and a series of different geometries was constructed and inspected, after which a domain of good design could be identified. Theta<10° produced a needle tip with low rigidity. When phi>45°, the tip will not become sharp.
The modelled angles were then compared to the ground needle tip, and the grinding angles of the ground needle tip were very close to the intended values calculated by the modelling. By setting an elastic constant of E=80 GPa and a value of 0.3 to Poisson's ratio (common for most metals), the force necessary to deflect the tip was calculated. It was discovered that the truncation by grinding 2 and 3 (phi angles) had a major impact on the tip rigidity.
A series of calculations was performed where theta ranged between 10° and 20°, phi ranged between 15° and 20°, omega was set at 30°, and truncation was 0.0 to 0.1 mm to construct contour lines of buckling forces needed to deflect the outermost tip upwards a complete outer diameter of the cannula.
A limit of good design was constructed to find the angles for optimal rigidity and found to be theta=12.5°, phi=18°, omega=30° and a truncation of 0.1 mm. The suggested optimum design is shown in
The present invention is not limited to the above-described preferred embodiments. Various alternatives, modifications and equivalents may be used. Therefore, the above embodiments should not be taken as limiting the scope of the invention, which is defined by the appending claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2050580-6 | May 2020 | SE | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/SE2021/050443 | 5/11/2021 | WO |
