Intraluminal delivery cannula, assembly, and related methods

Abstract

It allows reliable access to more remote extravascular sites in the body via the vascular system. [Solution] The present invention relates to an intraluminal delivery cannula for delivering a substance to an extravascular target site via the vascular system of a human or animal body, the cannula comprising a proximal cannula hub, an elongated proximal, and a distal tip. The distal tip is tapered toward a distal tip that is preferably provided with a sharpened tip for penetrating tissue. The sharpened tip may comprise at least one primary facet and two secondary facets, the two secondary facets being located proximal to the primary facets. An intraluminal delivery assembly comprises the above-mentioned cannula, a protective catheter adapted for insertion into the vascular system of a human or animal body, and a proximal catheter hub provided at the proximal end of the catheter and engaged to guide the catheter through the vascular system.

Description

Technical Field

[0001] The present invention relates to an intraluminal delivery device, and more particularly to an intraluminal delivery device for delivering a substance to an extravascular or intramyocardial target site as described in the preamble of the independent claim.

Background Art

[0002] In the medical field, there is an increasing trend towards minimally invasive techniques when accessing a specific site in the body or during its treatment. Such techniques have many advantages over open surgery as they cause less trauma to the body, resulting in fewer complications and a shorter recovery time after the procedure. Minimally invasive techniques often use a catheter and / or a guidance wire assembly that is inserted percutaneously, for example, through the femoral artery or the radial artery, and then steered through the vasculature to a specific site under the guidance of angiographic images to access a specific site or region of the body. However, depending on the site within the body, it may be impossible or difficult to access using known techniques due to the complexity and sizing of the vasculature.

[0003] Various techniques and devices are known for administering substances via the vasculature to specific local target sites within the body. Examples of procedures using such techniques include chemotherapy, treatment of various immunological conditions, and stem cell therapy.

[0004] For example, U.S. Patent No. 8,152,758 discloses a catheter assembly including a delivery cannula having a plurality of channels and an expandable distal portion, through which two needles are passed and used for injecting substances into the blood vessel wall.

[0005] U.S. Patent No. 5,464,395 shows an infusion balloon catheter having a lateral port for needle infusion into the surrounding tissue.

[0006] U.S. Patent Application Publication 2008 / 0319314 discloses an infusion catheter with an internal channel and a tip electrode, through which a needle is passed through an assembly and made protruding from the distal tip. Other catheter systems with infusion needles are shown, for example, in U.S. Patents 6,613,017B1 and 6,796,963B1.

[0007] These systems, and other known systems, are unsuitable or inappropriate for accessing remote microvascular systems due to their size and complexity.

[0008] Therefore, the inventors of the present invention have identified a need for improved intraluminal delivery devices that enhance access to remote locations within the body via the microvascular system and improve the efficiency of deliveries of substances to extravascular or intramyocardial target sites. [Overview of the Initiative]

[0009] The objective of the present invention is to provide an intraluminal delivery device that enables reliable access to more distant extravascular sites within the body via the vascular system.

[0010] A further object of the present invention is to provide an intraluminal delivery device that reduces the problem of bleeding at the puncture site in the vascular wall during and after penetration and delivery to an extravascular or intramyocardial target site.

[0011] The above objectives are achieved by the present invention as described in the independent claims. Preferred embodiments are described in the dependent claims.

[0012] According to a first embodiment, an intraluminal delivery cannula is disclosed for delivering a substance to an extravascular or intramyocardial target site via the vascular system of a human or animal. The intraluminal delivery cannula comprises a cannula hub provided at the proximal end of the cannula and an elongated proximal portion having an outer diameter, the outer diameter being essentially constant along the entire length of the proximal portion when measured when the cannula is essentially straight. Furthermore, the cannula comprises an apical portion located distal to the proximal portion and extending from the proximal portion to the distal tip of the cannula, and a continuous lumen extending from the proximal end of the cannula through the proximal and apical portions to the distal tip. The apical portion has an opening at its distal tip, creating communication between the lumen and the outside of the cannula. Preferably, the tip portion has an outer diameter essentially the same as the outer diameter of the elongated proximal portion, and the outer diameter at the distal tip is smaller than the outer diameter at the proximal end of the tip portion, and is provided at the proximal end of the tip portion, thereby having a tapered shape toward the distal tip.

[0013] In some embodiments, the intraluminal delivery cannula has a distal tip with a sharpened tip section for penetrating tissue, the sharpened tip section comprising at least one primary facet and two secondary facets, the two secondary facets being located proximal to the aforementioned primary facet.

[0014] In a further embodiment, an intraluminal delivery assembly is disclosed for delivering a substance to an extravascular or intramyocardial target site via the vascular system of a human or animal body. The assembly comprises an intraluminal delivery cannula and a protective catheter adapted for insertion into the vascular system of a human or animal body, wherein the distal end of the assembly is configured to be guided to a position within 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 insertion of the intraluminal delivery cannula through it into the protective catheter.

[0015] In yet another embodiment, a method is disclosed for delivering a substance to an extravascular or intramyocardial target site via the vascular system of a human or animal body. This method is a) the step of providing an assembly disclosed herein, b) Navigating the distal end of the protective catheter to a location near the target site, either extravascular or intramyocardial; c) The step of orienting the distal end of the protective catheter toward the vessel wall along the general direction of the extravascular or intramyocardial target site, d) The step of advancing the distal tip of the intraluminal delivery cannula so that the tip of the intraluminal delivery cannula penetrates the myocardium or blood vessel wall and reaches a target site extravascular or intramyocardial; e) The step of injecting a substance into a target site extravascular or intramyocardium, f) The procedure includes the step of retracting the distal tip of the intraluminal delivery cannula into the protective catheter. [Brief explanation of the drawing]

[0016] [Figure 1] This specification outlines the use of the intraluminal delivery assemblies disclosed herein. [Figure 2A] This shows a first embodiment of an intraluminal delivery cannula. [Figure 2B] This shows a first embodiment of an intraluminal delivery cannula. [Figure 3A] Further embodiments of intraluminal delivery cannulas are shown. [Figure 3B] Further embodiments of intraluminal delivery cannulas are shown. [Figure 4A] This shows a cross-sectional view of the cannula hub. [Figure 4B] This shows a cross-sectional view of the cannula hub. [Figure 5A] This is a perspective view of an assembly equipped with an intraluminal delivery cannula. [Figure 5B] This is a side view of an assembly equipped with an intraluminal delivery cannula. [Figure 6A] This shows a cross-sectional view of a specific component of an assembly equipped with an intraluminal delivery cannula. [Figure 6B] A cross-sectional view of a specific part of an assembly with an intraluminal delivery cannula is shown. [Figure 7A] The reference plane and needle grinding angle of the cannula tip section are shown. [Figure 7B] The reference plane and needle grinding angle of the cannula tip section are shown. [Figure 7C] The reference plane and needle grinding angle of the cannula tip section are shown. [Figure 7D] The reference plane and needle grinding angle of the cannula tip section are shown. [Figure 7E] The reference plane and needle grinding angle of the cannula tip section are shown. [Figure 8] Perspective views of various cannula tips obtained as a result during an experiment for determining a suitable needle grinding of the cannula tip section are shown. [Figure 9] Perspective views of various cannula tips obtained as a result during an experiment for determining a suitable needle grinding of the cannula tip section are shown. [Figure 10] Perspective views of various cannula tips obtained as a result during an experiment for determining a suitable needle grinding of the cannula tip section are shown. [Figure 11] Perspective, top, and side views of a suitable cannula tip section are shown.

Mode for Carrying Out the Invention

[0017] Next, specific embodiments of the present invention will be described. However, it will be apparent to those skilled in the art that the individual features may be combined differently and that the following disclosure is not intended to be limiting.

[0018] As used herein, the terms “proximal” and “distal” are used as they are commonly used in the art, namely, in relation to the user, the proximal end of a device or assembly is the end oriented toward the user, and the distal end is oriented toward the user.

[0019] Furthermore, the terms "cannula" and "needle" are used interchangeably herein and both refer to elongated tubes, preferably made of metal, which may have a pointed tip adapted to penetrate tissue or the like.

[0020] Figure 1 shows an overview of the intraluminal delivery cannula 1 disclosed herein in use when positioned within a blood vessel 300. The cannula 1 is preferably provided in a kit or assembly 400 together with a protective catheter 150 and adapted to be inserted into the vascular system of a human or animal body via a guide catheter, as will be described in further detail below.

[0021] To initiate the delivery procedure, the guide catheter 200 is typically used to reach a location near a specified target site 500 via the vascular system. Such a guide catheter 200 is typically a standard intervention catheter for vascular access and may be provided together with the cannula 1 and protective catheter 150 of this disclosure, or as a separate unit. On the right side of Figure 1, a schematic cross-sectional view along plane B is shown, where the protective catheter 150 is preferably coaxially positioned around the cannula 1, and the guide catheter 200 is positioned around the protective catheter 150 within the blood vessel 300.

[0022] The guide catheter 200 can be percutaneously inserted into a blood vessel 300 by known techniques, such as the Seldinger procedure or other known techniques, to access the vascular system, for example, via the femoral artery or radial artery. The devices and assemblies described herein are specifically adapted for access to remote target sites within the body, i.e., for access within and through the microvascular system, and are therefore adapted to navigate very small blood vessels, approximately 1 mm or less in diameter, to reach parts of the body that were previously inaccessible by standard techniques. However, they are also compatible with use through larger blood vessels with larger guide catheters. The devices, assemblies, and methods described herein describe access to extravascular target sites, but they can also be used for intramyocardial delivery. Thus, target sites can be accessed via navigation through the vascular system, either by penetrating the blood vessel wall (in the case of an extravascular site) or by penetrating the myocardium from, for example, inside the heart (in the case of an intramyocardial target site).

[0023] The devices and assemblies of this disclosure may be used for targeted local 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, organ, body cavity, or a local area of ​​a specific tissue or body part. As further examples, the devices and assemblies of this disclosure may be used for cardiac metabolic regeneration therapy, including the heart, liver, and kidneys, and for the delivery of, for example, cell or RNA therapies for direct intratumor injection.

[0024] The guide catheter 200 is preferably maneuverable and easy to operate, but when the guide catheter 200 is inserted through the vascular system such that its distal tip 201 is near the desired target site 500, the cannula 1 and protective catheter 150 are inserted through the guide catheter 200. Alternatively, the cannula 1 may be inserted into the guide catheter prior to the insertion of the assembly into the vascular system. In either case, the cannula 1 and protective catheter 150 are adapted to be navigated through the patient's vascular system via the guide catheter 200 to a position near the target site 500. The cannula 1 and protective catheter 150 are oriented toward the vessel wall 301 as shown in Figure 1. In some embodiments, although not shown in Figure 1, a guide catheter 200 with a pre-formable and pre-bent tip 201 may be used, and when the tip is near the target site, the bent tip may further assist in guiding the assembly toward the vessel wall 301. Alternatively, or in combination, a controllable tip 201 is also envisioned to assist in fine-tuning the injection direction.

[0025] While being inserted toward the vessel wall 301 through the guide catheter 200, the protective catheter 150 and cannula 1 are prevented from axially displacing relative to each other by a locking mechanism at their proximal ends, which will be explained in more detail below. This is to prevent the potentially sharp tip of cannula 1 from puncturing or damaging the guide catheter or vessel before reaching the desired position.

[0026] As shown in Figure 1, once the tip of the cannula 1 reaches a desired site in the vessel wall 301, it exits the protective catheter 150 and advances distally through the vessel wall and extravascular tissue to reach the target site 500. In some embodiments, the tip of the cannula 1 may be provided with a depth limiting element, as will be described in more detail below. The advancement of the tip is preferably observed by providing one or more radiopaque markers near or at the tip, so that the tip can be positioned during the procedure using angiography or other imaging techniques.

[0027] At the target site 500, the substance to be injected into the target site is delivered into the cannula via a syringe through the proximal cannula hub and discharged from the cannula through the distal opening at the tip of the cannula. In some embodiments, the injected substance may be discharged through both the distal opening and a lateral opening near the distal tip of the cannula. The administration of the substance may be repeated multiple times as needed. Furthermore, if necessary, the tip of the cannula may be retracted and repositioned. Once administration is complete, the tip of the cannula is retracted from the vessel wall and returned into the protective catheter.

[0028] As an alternative to or in addition to substance administration, the assembly may be used to extract a sample from a target site via the tip of a cannula.

[0029] Due to the specific design of the cannula and its tip, bleeding from the blood vessel wall is essentially eliminated. Further details about the tip are described below.

[0030] Figure 2A schematically shows a longitudinal cross-sectional view of the intraluminal delivery cannula 1 of this disclosure. As described above, the cannula 1 is adapted to deliver a substance to an extravascular or intramyocardial target site via the vascular system of a human or animal body. The cannula 1 has a proximal end 2 configured to remain outside the body and a distal end 3 configured to be inserted into the body via the vascular system to access an extravascular target site. A cannula hub 8 is preferably provided at the proximal end 2 of the cannula 1. The majority of the longitudinal length L1 of the cannula consists of an elongated proximal portion 4, which has a constant outer diameter D1 along essentially its entire length. In particular, “constant diameter” as used herein means that the diameter is constant when measured, as bending can cause twisting of the diameter.

[0031] Cannula 1 is positioned distal to its proximal portion 4 and further has a tip portion 5 extending from the proximal portion 4 to the distal tip 6 of cannula 1. The continuous lumen 7 extends from the inner 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, creating communication between the lumen 7 and the external appearance of cannula 1.

[0032] The tip portion 5, enclosed in a circle in Figure 2A, is shown in an enlarged view and is illustrated in more detail in Figure 2B. The tip portion 5 has a tapered shape toward the distal tip 6, and therefore has an outer diameter D3 at the proximal end of the tip portion 5 and another smaller outer diameter D4 at the distal tip 6. The outer diameter D3 is essentially the same as the outer diameter D1 of the elongated proximal portion 4, and the outer diameter D4 is smaller than the outer diameter D3. In other words, the gradual taper is provided distally from the point where the proximal portion 4 transitions to the distal tip portion 5 to the distal tip 6.

[0033] In some embodiments, it is preferable that the tip 5 and / or proximal 4 be provided with one or more radiopaque marker bands 11 at a predetermined distance from the distal end 6. One such example is schematically shown in Figure 3A, which shows several radiopaque marker bands 11. Such marker bands can be clearly visualized using angiographic images during the procedure and are used to determine the precise location of the tip and the penetration depth to the target site. Figure 3A shows only one schematic example of providing radiopaque marker bands 11. In practice, the bands may be provided in any predetermined configuration and can be used for localizing the tip, in particular to guide the user and determine the penetration depth from the vessel wall to the target site.

[0034] Furthermore, in some embodiments, as also shown in Figure 3A, the tip 5 may be provided with one or more outwardly projecting depth-limiting elements 12, for example, in the form of a peripheral flange or a similar structure, so that the user can feel resistance when the depth-limiting elements 12 reach the blood vessel wall upon penetration. In one embodiment, the depth-limiting elements may conform to the transition from the tip 5 to the proximal 4. The cannula 1 may have either or both a radiopaque marker 11 or depth-limiting elements 12.

[0035] As can be understood from the drawings and this disclosure, the opening 9 at the distal tip 6 creates communication between the lumen 7 and the exterior of the cannula 1, so that when the substance to be delivered exits the cannula and enters the target site, the substance exits the cannula through this distal opening 9. Thus, the delivery of the substance is controlled and the cannula is easily directed in the direction to which it is directed.

[0036] In some embodiments, as shown in Figure 3B, the cannula may have one or more secondary lateral openings 9' near the distal opening 9 and distally to the radiopaque marker 11 and / or depth limiting element 12. Such lateral openings allow material to exit the cannula through the distal opening 9 and one or more lateral openings 9', enabling wider and / or faster distribution of material at the target site, as indicated by the dashed arrows in Figure 3B. The lateral openings 9' allow for radial discharge of the cannula in addition to the distal discharge provided by the distal opening 9. Depending on the intent of distribution, the lateral openings 9' may be adapted to a specific pattern and / or opening size. In one embodiment, one or more lateral openings 9' are provided along the periphery of the tip 5. The lateral openings 9' may be provided in a random pattern or a predetermined pattern. In some embodiments, the lateral openings 9' are located near the distal opening 9. Therefore, the embodiments described in relation to Figures 3A and 3B may be combined.

[0037] As detailed in Figure 2A and applicable to all cannulas in this disclosure, the cannula 1 may have a longitudinal total length L1 from the proximal end 2 to the distal end 3 in the range of approximately 300 mm to 2500 mm. In some embodiments, for use mainly in adult patients, the longitudinal total length L1 is preferably between 1200 mm and 1900 mm, and more preferably between 1650 mm and 1750 mm. However, for pediatric use, for example, a longitudinal total length L1 of approximately 300 mm to 800 mm is preferred.

[0038] The vertical length L2 of the proximal portion 4 is in the range of approximately 1000 mm to 2000 mm, preferably between 1200 mm and 1700 mm, and more preferably between 1400 mm and 1500 mm.

[0039] In some embodiments, the tapered tip portion 5 has a longitudinal length L3 of at least 5 mm, preferably in the range of 100 mm to 300 mm, and more preferably in the range of 200 mm to 280 mm. In some embodiments, the longitudinal length L3 of the tapered tip portion 5 may be in the range of 5 mm to 50 mm, and in other embodiments, the longitudinal length L3 may be in the range of 50 mm to 300 mm.

[0040] In one embodiment, the total length L1 of the cannula 1 is approximately 1700 mm, the proximal portion 4 has a longitudinal length L2 of approximately 1450 mm, and the apical portion 5 has a longitudinal length L3 of approximately 250 mm.

[0041] In another embodiment, the total length L1 of the cannula 1 is approximately 1700 mm, the proximal portion 4 has a longitudinal length L2 of approximately 1695 mm, and the apical portion 5 has a longitudinal length L3 of approximately 5 mm. Thus, such a cannula essentially has no tapered portion or only a minimal tapered portion.

[0042] In yet another embodiment, the total length L1 of the cannula 1 is approximately 500 mm, the proximal portion 4 has a longitudinal length L2 of approximately 425 mm, and the apical portion 5 has a longitudinal length L3 of approximately 75 mm. Such a size is useful for pediatric use.

[0043] The proximal portion 4 of the cannula 1 preferably has a constant outer diameter D1 in the range of 0.15 mm to 0.50 mm, preferably between 0.20 mm and 0.35 mm, and more preferably between 0.25 mm and 0.28 mm.

[0044] The internal lumen 7 preferably has a constant inner diameter D2 along essentially the entire length of the cannula 1, i.e., through the proximal portion 4 and the apical portion 5. Naturally, the inner diameter D2 must match the preferred outer diameter D1 of the cannula. The inner diameter D2 of the lumen is preferably in the range of about 0.08 mm to 0.40 mm, preferably between 0.10 mm and 0.25 mm, and more preferably between 0.12 mm and 0.16 mm.

[0045] As previously described, it is preferable that the outer diameter D1 of the proximal portion 4 is essentially constant along the entire length of the proximal portion 4. Furthermore, the portion of the cannula adjacent to the tip portion 5 of the proximal portion 4 has an outer diameter D3 that is essentially the same as the outer diameter D1 of the elongated proximal portion 4. In other words, it is preferable that the outer shape of the cannula transitions smoothly from the proximal portion 4 to the tip portion 5. Subsequently, the tip forms a gradually tapered tip toward 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 between 0.10 mm and 0.25 mm, more preferably between 0.15 mm and 0.22 mm.

[0046] In one embodiment, the outer diameter D1 of the proximal part 4 may be approximately 0.25 mm, the inner diameter D2 of the lumen 7 is approximately 0.134 mm, and the outer diameter D4 at the distal end 6 is 0.190 mm.

[0047] The progressively tapered tip 5 improves operability, followability, and the ability to primarily push the cannula tip in, and provides a progressive transition to a smaller distal tip. The smaller the tip size, the less trauma to the vessel wall during penetration, and the smaller tip diameter allows the vessel wall to close on its own after the tip is withdrawn, reducing post-delivery bleeding. Thus, the tip configuration reduces the need for any separate closure step at the penetration site of the vessel wall.

[0048] The elongated proximal portion 4 and tip portion 5 of the cannula are preferably made of any superelastic alloy, such as stainless steel or nitinol Fe-Co-Ni-Ti alloy. In one embodiment, the elongated proximal portion 4 and tip portion 5 are made entirely of nitinol or other nickel-titanium alloy. In another embodiment, the tip portion 5 may be made of nitinol and the proximal portion 4 may be made of stainless steel. In a further embodiment, the tip portion may be made of nitinol and the tip may be made of a suitable ceramic material. The superelasticity of nitinol results in excellent flexibility, improving navigation through small, winding blood vessels. Having a more rigid distal tip, such as a ceramic tip, on a superelastic tip further facilitates penetration of the distal tip.

[0049] As shown in Figures 2A and 3, the cannula 1 is provided with a proximal cannula hub 8. Such a cannula hub 8 is adapted to deliver material to the inner lumen 7 of the cannula from a syringe or via other adapters or connectors for further delivery to a target site at the distal end of the cannula 1. The devices and assemblies described herein are adapted in particular for the delivery of a variety of materials in very small quantities. As already mentioned above, the materials may include chemotherapy drugs, stem cells, RNA, orphan drugs, etc., and such materials are usually very expensive. Therefore, there is great value in achieving a delivery system adapted to minimize volume loss during delivery. A further advantage of providing a delivery system that minimizes dead volume within the system is to minimize the risk of releasing air bubbles into the target site and reduce air embolism, which can cause stroke or cardiac arrest depending on the location in the body.

[0050] Figure 4A shows a cross-sectional view along the longitudinal axis of a preferred embodiment of the cannula hub 8. In particular, Figures 4A and 4B are transverse cross-sectional views along the longitudinal axis of an essentially cylindrical or conical cannula hub. In other words, the cannula hub 8 preferably has a circular shape that is symmetrical in all radial directions from a perspective view, as also shown in Figures 5A and 5B. As seen in Figure 4A, the internal longitudinal channel 10 of the cannula hub 8 connects the lumen 7 of the proximal portion 4 of the cannula to the female connector 13 at the proximal end of the cannula hub 8. The female connector 13 may be a standard Luer female connector or other preferred connector. Prior to use in material delivery, the cannula hub 8 may be provided with a cap or stopper 14 to keep the internal area clean and free of contaminants.

[0051] The internal cavity 15 of the cannula hub 8 is preferably adapted to minimize dead volume during delivery when using a standard Luer connector 16, as shown in Figure 4B. “Dead volume” is used herein to mean, for example, the amount of material that does not leave the device during delivery, such as the amount that remains in the cannula hub (or the entire system) after the syringe has been pushed into the female connector 13 and the material 17 has been injected into the cannula via the syringe. In other words, the internal cavity 15 of the cannula hub 8 is configured such that when a standard male Luer connector 16 is connected to the cannula hub, it fits snugly along the inner wall of the cavity 15, minimizing the internal volume distal to the male connector 16. The shape of the internal volume is preferably as shown in Figures 4A and 4B. Therefore, the internal volume of the cannula hub 8 can be formed from a thin cylindrical disk distal to the male connector 16, a conical volume of the internal longitudinal channel 10, and a narrow cylindrical volume. The dead volume formed by the internal volume of the cannula hub 8 is preferably less than 0.45 ml, preferably in the range of 0.25 ml to 0.45 ml, and more preferably between 0.30 ml and 0.40 ml.

[0052] The overall dead volume of the delivery system includes the internal volume of the cannula hub 8, as described above, along with the internal volume of the remaining portion of the cannula 1. As seen when the male Luer connector is attached, a smaller dead volume of the delivery system minimizes the loss of material during delivery, which is particularly important when delivering expensive and / or scarce materials and reduces the risk of air embolism. Therefore, preferably, the total internal dead space of the cannula hub 8 and the cannula 1 is less than 0.50 ml, and more preferably less than 0.40 ml.

[0053] As shown in Figures 4A and 4b, a further effect of the specific internal volumetric shape of the cannula hub cavity is that the thin cylindrical disk smoothly transitions into the internal longitudinal channel 10 via a short conical shape, resulting in reduced turbulence in the solution during substance injection. This is particularly important when using delicate substances, such as solutions containing living cells, e.g., stem cells, or other unstable cells or molecules.

[0054] Cannula 1 and cannula hub 8 are preferably used together with protective catheter 150 and catheter hub 160. One such assembly 400 is shown as a perspective view in Figure 5A and as a side view in Figure 5B. The protective catheter 150 is integrated with or attached to the catheter hub 160 at its distal end. In Figures 5A and 5B, the protective catheter 150 is shown in a cross section, but it extends to cover the entire cannula 1 to its distal end. Figure 6A shows a cross section of the catheter hub 160 along its longitudinal axis. Figure 6B shows the catheter hub 160 shown in Figure 6A with cannula 1 inserted.

[0055] Cannula 1 is fitted to be inserted through the opening 161 from the proximal end of the catheter hub 160. A locking mechanism 162 is fitted to be used to lock 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 mechanism 162 is locked, any axial movement between the protective catheter 150 and cannula 1, and consequently between the cannula hub 8 and the catheter hub 160, is prevented. Prior to the delivery procedure, cannula 1 is inserted into the catheter 150 via the catheter hub 160 by the user or during the manufacture of the assembly, so that the distal tip 6 of cannula 1 is protected by the distal end of the protective catheter 150 (not shown). In particular, the distal end of the protective catheter is not shown in Figures 5A and 5B to show that the cannula is located inside the catheter. Furthermore, only the short proximal portions of both the cannula and the protective catheter 150 are shown in Figures 5A and 5b.

[0056] As shown in Figures 5A and 5B, the catheter hub 160 may be equipped with a lateral port 170, which can be used to flush the system with saline or other suitable solution before, during, or after the delivery procedure.

[0057] As shown in the cross-sectional view of Figure 6A, the catheter hub 160 includes an internal channel 163 that extends along the longitudinal axis from the proximal opening 161 into the protective catheter 150 at the distal end of the catheter hub 160. As seen in Figure 6B, the internal channel 163 is adapted to accommodate the insertion of the cannula 1.

[0058] The locking mechanism 162 may include any preferred mechanism capable of locking the cannula in place when inserted into the catheter hub. Preferably, the locking mechanism 162 is adapted to allow reversible switching between a locked state and an unlocked state. Non-limiting examples include screw locks, snap locks, friction locks, and lever-base locks. Figures 5A and 5B, and Figures 6A and 6B, show examples of the locking mechanism 162. At the proximal end of the catheter hub 160, a locking wheel 164 is provided with an extension of an inner channel 163. The locking wheel 164 is provided with an inner thread 165a, which is adapted to cooperate with an outer thread 165b of the catheter housing. When the locking wheel 164 is screwed distally, an inner locking gasket 166 is compressed, and the inner channel 163 is compressed within the gasket 166. Therefore, as shown in Figure 6B, when the cannula 1 is located within the inner channel 163, the gasket 166 is compressed and grips the cannula 1. Thus, the cannula 1 is held in place by the gasket 166, preventing any relative axial movement between the catheter hub 160 and the cannula 1, and in this way, also preventing any axial movement between the catheter 150 and the cannula 1. After the cannula 1 is released by loosening the screw of the lock wheel 164, it can be repositioned and optionally locked again. Thus, the relative axial position of the cannula 1 in relation to the catheter 150 can be adjusted by using the locking means 162. Furthermore, when locked in relation to each other, the entire assembly can be operated and manipulated as a single unit.

[0059] As described above, by employing the assembly 400 of the protective catheter 150 with the catheter hub 160 attached and the cannula 1 with the cannula hub 8 attached, the guide catheter is usually positioned within a blood vessel so that the distal end of the guide catheter is as close as possible to the target site. As shown in Figure 1, the assembly 400 is inserted into the guide catheter 200 and pressed or guided to a position where the distal end of the catheter 150 protrudes from the guide catheter 200. During this step, the cannula 1 and the protective catheter 150 are locked in a manner that prevents axial movement between them. This prevents the potentially sharp tip of the cannula 1 from puncturing or damaging the guide catheter 200 during insertion and prevents damage to the blood vessel before reaching the desired position. Preferably, the distal end of the assembly 400 is positioned so that the longitudinal axis at the tip of the cannula 1 is oriented toward the target site 500 as shown in the figure. In some embodiments, this can be achieved using a guide catheter 200 having a pre-formed bent tip and / or a maneuverable tip 201, as is known in the art.

[0060] Once the distal tip 201 is directed toward the vessel wall and target site 500, the assembly 400 is advanced distally to the outside of the guide catheter 200. At this stage, the distal tip 6 of the cannula 1 remains within the protective catheter 150 to avoid unintentional damage to the vessel.

[0061] Subsequently, the locking mechanism 162 of the catheter hub 160 is released, and the tip of the cannula 1 exits the protective catheter 150 and moves toward the blood vessel wall, advancing further distally, penetrating the blood vessel wall and extravascular tissue, and reaching the target site. This movement is achieved by moving the proximal cannula hub 8 closer to the proximal end of the catheter hub 160, for example, by moving the cannula hub 8 distally while keeping the catheter hub 160 stationary.

[0062] In some embodiments, a stopping element may be provided to prevent the distal tip from advancing prematurely before reaching the desired position. Such a stopping element may be a stopping ring or similar arrangement provided around the cannula 1 between the cannula hub 8 and the catheter hub 160, and may be manually removed prior to penetration of the vessel wall. As an alternative to, or in combination with, a marker may be provided on the cannula 1 at a location visible between the locking means 162 of the cannula hub 8 and 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 the user with a visual parallax when the sharp tip is in a retracted protective position within the protective catheter, and is useful both during initial tip positioning and during repositioning of the intraluminal delivery device.

[0063] At any desired point during material delivery, such as when the tip of the cannula protrudes from the tip of the catheter, the cannula 1 and catheter 150 can be locked in a relative axial position by, for example, the engaging locking means 162. After delivery, or when the tip of the cannula is repositioned, this procedure is reversed so that the tip of the cannula is once again protected by the tip of the catheter, and then optionally repeated if there are other delivery volumes.

[0064] As described above, in some embodiments, it is preferable that the distal tip portion 5 has a progressively tapered shape toward the distal tip portion 6.

[0065] Furthermore, in some embodiments, the distal tip 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. In particular, as used herein, such a tip section is shown on a cannula 1 for delivering substances via the vascular system. However, similar pointed tips may also be used on other devices for similar applications, such as microneedles for intramuscular or intradermal injection.

[0066] Figures 7A to 7E show the grinding angles used to form the primary and secondary facets. In particular, Figures 7A to 7E and subsequent figures schematically show only the last approximately 1-3 millimeters of the tip section 100, and therefore the progressive tapered shape of the distal tip 5 of the cannula is not visible in these figures. Furthermore, in Figures 7A, 7B, 7C, and Figures 8 to 11, when perspective or side views are shown, the left side of the figure is oriented approximately distally, and the right side of the figure is oriented approximately proximal to the cannula. In Figure 7D, a top view of the tip section 100 is shown, where the top of the figure corresponds to the distal direction of the tip. In Figure 7E, the tip section 100 is viewed along the longitudinal axis A.

[0067] In needle grinding, that is, in the process of forming a sharp tip from a hollow cylindrical cannula, the distal end of the cannula is ground and polished with a grinding wheel or other grinding medium. Typically, the grinding wheel is stationary, and the needle or cannula is given a fixed angle in relation to the grinding surface. The resulting facet or bevel is thus formed within one or more planes that can be defined in relation to the geometry of the cannula itself.

[0068] Figure 7A shows a schematic perspective view of the tip section 100 prior to grinding any facets. The cylindrical cannula tip section 100 is shown having two reference planes, indicated as a first plane P1 and a second plane P2, which are arranged along the longitudinal axis A, and the first and second planes P1 and P2 are orthogonal to each other. These reference planes P1 and P2 are used herein to define the angles and arrangement of the planes that define the facets of the resulting tip section 100. For ease of understanding, the first plane P1 may be considered a horizontal plane and the second plane P2 may be considered a vertical plane.

[0069] Figure 7B shows a side view of the tip section 100 shown in Figure 7A after facet grinding. As will be described in detail below, a perspective view of the tip section 100 is shown in Figure 7C, showing the planes that form the facets in relation to the reference plane. In the first embodiment, as best shown in Figure 7B, the primary facet F1 of the tip is formed by needle grinding on a third plane P3, the third plane P3 is positioned at an angle theta θ with respect to the first plane P1. Preferably, the third plane P3 is positioned symmetrically with respect to the second plane P2 so that the third plane P3 intersects the first plane P1 in the extension perpendicular to the second plane P2. In other words, the sharp tip 6 is formed distally. An example of the tip obtained after the first grinding is shown in Figure 8, which will be described further below.

[0070] After forming the primary facet F1 and the two secondary facets F2 and F3, grinding is performed on the fourth and fifth surfaces P4 and P5 by needle grinding at the distal tip, as shown in Figure 7C. The arrangement of the fourth and fifth surfaces P4 and P5 will be further explained in Figures 7D and 7E.

[0071] Figure 7D shows a top view, i.e., a view of the tip section 100 from a direction perpendicular to surface P1 after the first grinding on the third surface P3. Figure 7E shows the tip section 100 from the distal direction along the vertical axis A.

[0072] The fourth and fifth faces P4 and P5 are arranged in pairs of symmetrical combination angles, and are symmetrical with respect to the longitudinal axis and also to the first and second faces P1 and P2. Thus, the symmetrical angles of the fourth and fifth faces P4 and P5 consist of two combination angles measured from different faces or viewpoints. As seen in Figure 7D, when the tip section 100 is viewed from a top view or along face P2, the first angle phi φ may be measured on either side of the second face P2 on the first face P1.

[0073] As shown in Figure 7E, the second component of the arrangement of the fourth and fifth faces P4 and P5 is the rotation angle omega ω around the longitudinal axis A. Figure 7E shows the tip section 100 as viewed along the longitudinal axis A. The fourth and fifth faces P4 and P5 are defined by two opposite rotations in relation to the reference plane. Thus, these two angles phi φ and omega ω together indicate the arrangement of the fourth and fifth faces P4 and P5, and consequently the angles that define the two secondary facets F2 and F3. Several examples of tips obtained after different grinding steps are shown in Figures 9 and 10 and will be further described in the following experimental section.

[0074] As is clear from the above and as can be seen from the drawings, the two secondary facets F2 and F3, together with the outer mantle surface of the tip section 100, form the distal tip 6. Therefore, the sharpness of the distal tip may be controlled by both phi φ and omega ω, thereby exhibiting the ability to optimize sharpness and, for example, finding the most effective penetration of the tissue.

[0075] The inventors discovered that a more favorable geometry is obtained when phi φ is greater than theta θ. However, when phi φ is greater than 45 degrees, the tip becomes too blunt.

[0076] Furthermore, as mentioned above, when providing one primary facet F1 at angle theta θ and two secondary facets F2 and F3 at angles phi φ and omega ω, it is clear that in order to obtain a usable tip, theta must be low, preferably less than 30 degrees. However, as will be explained in the experiments below, when theta θ is less than 10 degrees, the stiffness of the tip becomes insufficient.

[0077] Therefore, through extensive testing, calculations, and investigations of the resulting tips, the inventors have concluded that the following indicators are preferable for obtaining a needle tip suitable for a variety of penetration procedures, which is improved to minimize trauma and bleeding during penetration of blood vessel walls and surrounding tissues, and consequently during removal. A needle tip section having one primary facet F1 and two secondary facets F2 and F3 is preferably provided with a primary facet angle theta θ between 10.0 and 20.0 degrees, and secondary facets provided with ±phi φ angles between 15.0 and 20.0 degrees and ±omega ω angles between 25.0 and 90.0 degrees.

[0078] As an example, Figure 11 shows a needle tip section having a theta angle of 12.5 degrees, a phi angle of ±18.0 degrees, and an omega angle of ±30.0 degrees.

[0079] Another example of a suitable tip section is one having a theta angle of 15.0 degrees, a phi angle of ±20.0 degrees, and an omega angle of ±30.0 degrees.

[0080] Thus, the inventors, through a combined effect of controlling the intersection between F2 and F3 by both phi φ and omega ω as described herein, result in a triangulation point with optimal sharpness, minimizing bleeding and, for example, enabling effective tissue penetration.

[0081] The dimensions and configuration of the tip section 100 described above, in combination with the overall tapered tip portion 5 of the cannula 1, may be configured to achieve penetration with minimal trauma to the blood vessel wall, thereby reducing the need to provide any specific sealing means, such as closing or stopping the hole made in the blood vessel wall at the penetrating tip.

[0082] experiment Experiments were conducted to determine the optimal shape of the needle tip for optimal rigidity.

[0083] The diagrams showing the needle tip (Figures 8 to 11) are based on the fact that the catheter has an inner diameter (ID) of 0.147 mm and an outer diameter (OD) of 0.190 mm at the distal end, and is tapered due to grinding over a length of 25 cm. Based on the dimensions of the catheter, the optimal grinding angle was mathematically modeled to determine the low penetration force and buckling, i.e., rigidity of the needle tip.

[0084] First grinding angle theta The first grinding angle theta was evaluated for angles between 10° and 35°. As shown in Figure 8, these grinding angles produced a soft, rounded tip, which had low rigidity in the vertical direction but good rigidity in the lateral direction.

[0085] Second and third grinding files To improve tip sharpness and vertical rigidity, two symmetrical grinds at an angle of phi relative to the catheter axis were evaluated, as shown in Figure 9. However, during these grinds, the tip inevitably underwent cleavage. Furthermore, at certain angles, when the tip cleavage was greater than 0.3 mm, the tip cleavage resulted in a tip with a vertical edge rather than a triangular point. This reduced sharpness.

[0086] The combined effect of theta and phi on 0.1 mm tip cutting. As shown in Figure 10, the effects of theta and phi were investigated by setting a fixed tip cut of 0.1 mm to maintain a minimum tip cut. From this model, it can be seen that a lower theta value allows for more tip cut, and that phi must be greater than theta for a suitable geometry. Also, theta must be low to create a usable tip. Values ​​of 30° or 45° are not recommended.

[0087] The combined effect of theta and phi when no tip cutting is involved. High-precision grinding options allow for limiting tip cutting. As a result, the effects of theta and phi were evaluated for ideal conditions for a more suitable range of theta and phi. In this model, all needle facets coincide at a single point, so all tips are sharp. When phi ≤ theta, the inner diameter (ID) surface is cut by facets 2 and 3, as shown in Figure 9, creating a thin tongue-like portion. However, when phi is slightly greater than theta, facets 2 and 3 do not intersect the inner surface, thus improving tip stiffness, i.e., bending strength in the vertical direction.

[0088] The effects of OmegaTilt As shown in Figure 7D, facets 2 and 3 can be tilted by rotating the catheter by an angle of 100m. As a result, the catheter was rotated by ±100m when grinding facets 2 and 3, respectively.

[0089] As shown in Figure 10, the corners between facets 1 and 2 and 2 and 3 cannot be removed by tilt grinding with a 0.1 mm tip cut when theta and phi are set to 20° and 30°, respectively.

[0090] Area of ​​good design To determine the geometry useful for limiting the corners where facets meet, we set the omega to 30° and, after constructing and investigating a series of different geometries, were able to identify domains of good design. At theta < 10°, the needle tip exhibited low stiffness. At phi > 45°, the tip was not sharp.

[0091] Stiffness analysis Next, comparing the modeled angle with that of the ground needle tip, the grinding angle of the ground needle tip was very close to the intended value calculated by the model. By setting the elastic constant E = 80 GPa and the value of 0.3 to Poisson's ratio (common to most metals), the force required to flex the tip was calculated. It was found that cutting the tip by grinding angles 2 and 3 (phi angles) had a significant effect on tip stiffness.

[0092] Discovery of the optimal design After performing a series of calculations, it was determined that to construct the contour of the buckling force required to deflect the outermost tip upward to the full outer diameter of the cannula, theta was set to a range of 10° to 20°, phi to a range of 15° to 20°, omega to 30°, and tip cutting to 0.0 to 0.1 mm.

[0093] To find the angles for optimal rigidity, we constructed the limits for the best design, which were found to be theta = 12.5°, phi = 18°, omega = 30°, and a tip cut of 0.1 mm. As detailed above, the proposed optimal design is shown in Figure 11.

[0094] The present invention is not limited to the preferred embodiments described above. Various substitutions, modifications, and equivalents may also be used. Accordingly, the above embodiments should not be considered to limit the scope of the invention, which is defined by the appended claims.

Claims

1. An intraluminal delivery cannula (1) for delivering a substance to an extravascular or intramyocardial target site via the vascular system of a human or animal body, The cannula (1) has a proximal end (2) configured to remain outside the body and a distal end (3) configured to be inserted into the body via the vascular system and to access a target site outside the blood vessel or within the myocardium, and the cannula (1) has a longitudinal length (L) from the proximal end (2) to the distal end (3). １ ) has, and the cannula (1) is A cannula hub (8) is provided at the proximal end (2) of the cannula (1), Vertical length (L) ２ ) and outer diameter (D １ An elongated proximal portion (4) having the outer diameter (D １ ) When measured when the cannula is essentially straight, the proximal portion (4) is essentially constant along its entire length, A tip portion (5) is positioned at the tip of the proximal portion (4) and extends from the proximal portion (4) to the distal tip (6) of the cannula (1), The inner diameter (D) extends from the proximal end (2) to the distal end (6) of the cannula through the proximal portion (4) and the tip portion (5), along the entire length of the cannula (1). ２ It comprises a continuous lumen (7) having ), The tip portion (5) has a primary opening (9) at the distal tip (6), creating communication between the lumen (7) and the outside of the cannula (1). The tip portion (5) is tapered along its entire length in the distal direction from the point where the elongated proximal portion (4) transitions to the distal tip portion (6) to the distal tip portion (6). The tapered tip portion (5) is formed such that, at its proximal end, the outer diameter (D ３ ), is substantially the same as the outer diameter (D １ ) of the elongated proximal portion (4), and the outer diameter (D ４ ) at the distal tip (6) is smaller than the outer diameter (D ３ ) at the proximal end of the tip portion (5), and the tip portion (5) includes a sharp tip section (100) for penetrating tissue. The tapered tip portion (5) has a vertical length (L) of at least 100 mm. ３ ) has, The pointed tip section (100) has at least one primary facet (F １ ) and two secondary facets (F ２ F ３ ) comprises, wherein the at least one primary facet (F1) and two secondary facets (F2, F3) are formed on a portion of the tapered tip portion (5) located on the distal tip (6) side, and the two secondary facets (F ２ F ３ ) is the primary facet (F １ It is located proximal to ) The pointed tip section (100) further comprises a lumen which is part of the continuous lumen (7). Intraluminal delivery cannula (1).

2. The entire length in the longitudinal direction (L) from the proximal end (2) to the distal end (3) １ The intraluminal delivery cannula (1) according to claim 1, wherein the length is in the range of approximately 300 mm to 2500 mm.

3. The outer diameter D at the distal tip (6) ４ The intraluminal delivery cannula (1) according to claim 1 or 2, wherein the diameter is in the range of 0.10 mm to 0.25 mm.

4. The intraluminal delivery cannula (1) according to any one of claims 1 to 3, wherein one or more radiopaque marker bands (11) are provided on the tapered tip (5) and / or proximal (4) at a predetermined distance from the distal tip (6).

5. The intraluminal delivery cannula (1) according to any one of claims 1 to 4, wherein the tapered tip portion (5) is provided with one or more protruding depth limiting elements (12).

6. The intraluminal delivery cannula (1) according to any one of claims 1 to 5, wherein the tapered tip (5) is further provided with one or more lateral openings (9') along at least a portion of the tapered tip (5).

7. The intraluminal delivery cannula (1) according to any one of claims 1 to 6, wherein the cannula hub (8) is provided with an internal longitudinal channel (10) and a female connector (13) at its proximal end, the internal longitudinal channel (10) is configured to create communication between the continuous lumen (7) of the cannula and the female connector (10), and both the internal longitudinal channel (10) and the female connector (13) have a total internal volume of less than 0.45 ml when the corresponding male connector is attached to the female connector (13).

8. The aforementioned pointed tip section (100) is A first surface (P) is arranged along the central vertical axis (A). １ ) and a second surface (P) arranged along the vertical axis (A). ２ ) and the first and second planes (P １ , P ２ )and, The first surface (P １ A third surface (P) positioned at an angle theta (θ) relative to ) ３ ) and the second surface (P ２ The third surface (P ３ )and, A fourth face (P) arranged by a pair of symmetrical angles ４ ) and the fifth face (P ５ ) and the symmetry angle is the first and second planes (P １ , P ２ The fourth plane (P) is symmetrical with respect to each of the other planes. ４ ) and the fifth surface (P ５ ) and, The aforementioned angle of symmetry is the first plane (P １ ) the second surface (P ２ This is a combination angle comprising a first angle phi (φ) measured from ) and a second angle omega (ω) which is the rotation angle around the vertical axis (A), The primary facet (F) of the pointed tip section (100) １ ) is the third surface (P ３ ) is established in The two secondary facets (F ２ F ３ ) each has the fourth and fifth surfaces (P ４ , P ５ An intraluminal delivery cannula (1) provided in any one of claims 1 to 7.

9. The two secondary facets (F ２ F ３ The intraluminal delivery cannula (1) according to claim 8, wherein the distal tip (6) is formed together with the outer mantle surface of the pointed tip section (100).

10. The intraluminal delivery cannula (1) according to any one of claims 8 or 9, wherein the angle phi (φ) is greater than the angle theta (θ).

11. An intraluminal delivery cannula according to any one of claims 8 to 10, wherein the one primary facet (F1) and the two secondary facets (F2, F3) are provided with a primary facet angle theta (θ) between 10.0 and 20.0 degrees, and secondary facets provided with angles of ±phi (φ) between 15.0 and 20.0 degrees and ±omega (ω) between 25.0 and 90.0 degrees.

12. An intraluminal delivery assembly (400) for delivering a substance to an extravascular or intramyocardial target site via the vascular system of a human or animal body, An intraluminal delivery cannula (1) according to any one of claims 1 to 11, A protective catheter (150) adapted for insertion into the vascular system of a human or animal body, The distal end of the assembly is configured to be guided to a position within the vascular system suitable for accessing the intended extravascular or intramyocardial target site, The system comprises a proximal catheter hub (160) provided at the proximal end of the protective catheter (150) and adapted to guide the protective catheter (150) through the vascular system, The proximal catheter hub (160) is fitted to an intraluminal delivery assembly (400) through which the intraluminal delivery cannula (1) is inserted into the protective catheter (150).

13. The intraluminal delivery assembly (400) according to claim 12, wherein the catheter hub (160) further comprises a locking means (162) adapted to be reversibly changed between a locked state and an unlocked state, the locking means (162) configured to prevent axial movement between the protective catheter (150) and the intraluminal delivery cannula (1) in the locked state.

14. The intraluminal delivery assembly (400) according to claim 13, wherein the locking means (162) comprises a locking wheel (164) having an internal thread (165a) cooperating with an external thread (165b) of the catheter hub, and the locking means is fitted such that when the locking means is driven, an internal locking gasket (166) is compressed to grip the proximal end of the intraluminal delivery cannula.

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