Delivery catheter

Abstract

A delivery catheter 100 configured to deliver a composition to a target is disclosed. The delivery catheter includes a catheter tube 200 defining a first channel 250 and a second channel 270 in a catheter tube wall, the first channel containing a first pull wire 260 and the second channel containing a second pull wire 280, the first pull wire and the second pull wire being configured to cause a distal end of the catheter tube to deflect. A tip assembly (300) is connected to the catheter tube, the tip assembly comprising a tip electrode (310) and an electrode strip (320), where the tip electrode defines a delivery lumen. A control handle 400 is used to control deflection of the distal end of the catheter tube. An injection handle 500 is used to control the delivery of the composition. The needle assembly 600 includes a flexible needle 510 extending from a needle hub to deliver the composition.

Description

Technical Field

[0001] This disclosure generally relates to catheters. In particular, some embodiments of this disclosure relate to delivery catheters configured to deliver compositions (such as cellular compositions or gene therapy agents) to a target site. Background Technology

[0002] Catheters can be used to deliver therapeutic or diagnostic agents to patients. Targeted delivery of therapeutic or diagnostic agents to patients can improve treatment outcomes.

[0003] To ensure the safe and accurate delivery of therapeutic or diagnostic agents to patients, target mapping is typically performed. This may include using a map or model of a part of the patient's body, such as the heart, to help identify one or more treatment areas.

[0004] Any discussion of documents, actions, materials, devices, articles, etc., included in this specification is not an admission that any or all of these matters constitutes part of the prior art base existing prior to the priority date of each appended claim or common general knowledge in the field related to this disclosure.

[0005] Throughout this specification, the word “comprising” or variations thereof such as “including” or “having” shall be understood to imply inclusion of the mentioned element; integer or step; or group of element, integer or step, but not excluding any other element; integer or step; or group of element, integer or step. Summary of the Invention

[0006] Some embodiments relate to a delivery catheter configured to deliver a composition to a target site, the delivery catheter comprising:

[0007] The conduit fittings are defined as follows:

[0008] A first lumen extends between the proximal and distal ends of the catheter fitting, wherein the catheter fitting includes a flexible portion configured to deflect the distal end relative to the proximal end.

[0009] A first channel in the pipe wall, the first channel including a first pull wire, the first pull wire being configured to cause deflection of the distal end in a first direction;

[0010] A second channel in the pipe wall, the second channel including a second pull wire, the second pull wire being configured to cause deflection of the distal end in a second direction;

[0011] The end assembly is connected to the distal end of the catheter fitting, the end assembly including an end electrode and an electrode band, wherein the end electrode defines a delivery lumen in communication with a first lumen of the catheter fitting;

[0012] A control handle for controlling the deflection of the distal end of the catheter fitting, the control handle being connected to the proximal end of the catheter fitting;

[0013] An injection handle for controlling the delivery of the composition, the injection handle being connected to the control handle; and the injection handle comprising:

[0014] A cylinder defining an orifice extending between a first end and a second end of the cylinder;

[0015] A piston configured to slide within the orifice;

[0016] A spring, disposed in the hole and configured to resist sliding of the piston toward a first end of the cylinder;

[0017] A needle assembly comprising a flexible needle extending from a needle hub, the needle extending: (i) through the injection handle; (ii) through the control handle; (iii) through a first lumen of the catheter fitting; and (iv) into a delivery lumen of the end assembly;

[0018] The needle hub is connected to a piston on the injection handle such that sliding of the piston toward a first end of the barrel causes the needle to extend through the end assembly to deliver the composition; and

[0019] The injection handle is configured to retract a flexible needle into the end assembly after the composition has been delivered.

[0020] The control handle may include: a first pulley assembly connected to the first pull cable, wherein rotation of the first pulley assembly applies tension to the first pull cable to cause deflection of the distal end in the first direction; and a second pulley assembly connected to the second pull cable, wherein rotation of the second pulley assembly applies tension to the second pull cable to cause deflection of the distal end in the second direction.

[0021] The first channel and the second channel may be positioned at opposite radial locations along the wall of the pipe fitting.

[0022] The pipe wall may include: (i) a first ridge extending from the pipe wall into the first lumen to define the first channel; and (ii) a second ridge extending from the pipe wall into the first lumen to define the second channel.

[0023] The first direction and the second direction are opposite in relation to the deflection of the distal end.

[0024] Deflection of the distal end in the first direction can cause the flexible portion of the catheter fitting to have a first radius of curvature. Deflection of the distal end in the second direction can cause the flexible portion of the catheter fitting to have a second radius of curvature. The first radius of curvature and the second radius of curvature are not equal.

[0025] The delivery lumen can be centrally located within the end assembly.

[0026] The first pulley assembly and the second pulley assembly may include a lever arm device configured to: (i) amplify; or (ii) reduce the tension applied to the first and second cables, respectively, to cause deflection at the distal end. The lever arm device may include: (i) a linkage; or (ii) a gear system; or (iii) a linkage and gear system. The first pulley assembly and the second pulley assembly may be disposed on opposite lateral sides of the control handle.

[0027] The first and second pull wires can be positioned on opposite sides of the needle within the control handle.

[0028] The first and second pull wires may be disposed on opposite sides of the needle in the conduit fitting.

[0029] The injection handle may also include a rotatable needle actuator ring on the piston, the rotatable needle actuator ring being configured to restrict sliding of the piston within the orifice. Rotation of the rotatable needle actuator ring may be configured to cause the rotatable needle actuator ring to travel along the piston to shorten or lengthen the distance the piston can slide within the orifice.

[0030] The injection handle may further include a groove and a pin, the groove being formed on the piston and the pin being configured to engage the groove to: (i) restrict sliding of the piston within the orifice; and / or (ii) restrict rotation of the piston within the orifice. The pin may be configured to engage the groove to resist a spring force exerted on the piston by the spring.

[0031] Some embodiments relate to a delivery catheter configured to deliver a composition to a target site, the delivery catheter comprising:

[0032] The conduit fittings are defined as follows:

[0033] A first lumen extends between the proximal and distal ends of the catheter fitting, wherein the catheter fitting includes a flexible portion configured to deflect the distal end relative to the proximal end.

[0034] A first channel in the pipe wall, the first channel including a first pull wire, the first pull wire being configured to cause deflection of the distal end in a first direction;

[0035] A second channel in the pipe wall, the second channel including a second pull wire, the second pull wire being configured to cause deflection of the distal end in a second direction;

[0036] An end assembly connected to the distal end of the catheter fitting, the end assembly including an end electrode and an electrode band, wherein the end electrode defines a delivery lumen in communication with a first lumen of the catheter fitting;

[0037] A control handle for controlling the deflection of the distal end of the catheter fitting, the control handle being connected to the proximal end of the catheter fitting;

[0038] An injection handle for controlling the delivery of the composition;

[0039] A needle assembly connected to the injection handle and comprising a flexible needle extending from the needle hub, the needle extending: (i) through the injection handle; (ii) through the control handle; (iii) through a first lumen of the catheter fitting; and (iv) into a delivery lumen of the end assembly to deliver a composition;

[0040] The injection handle is configured to retract a flexible needle into the end assembly after the composition has been delivered.

[0041] Some embodiments relate to a delivery catheter configured to deliver a composition to a target site, the delivery catheter comprising:

[0042] The conduit fittings are defined as follows:

[0043] A first lumen extends between the proximal and distal ends of the catheter fitting, wherein the catheter fitting includes a flexible portion configured to deflect the distal end relative to the proximal end.

[0044] A first pull wire, configured to cause deflection of the distal end in a first direction;

[0045] A second pull wire, configured to cause deflection of the distal end in a second direction;

[0046] An end assembly connected to the distal end of the catheter fitting, the end assembly including an end electrode and an electrode band, wherein the end electrode defines a delivery lumen in communication with a first lumen of the catheter fitting;

[0047] A control handle for controlling the deflection of the distal end of the catheter fitting, the control handle being connected to the proximal end of the catheter fitting, and the control handle comprising:

[0048] A first pulley assembly, connected to the first draw cable, wherein rotation of the first pulley assembly applies tension to the first draw cable to cause deflection of the distal end in the first direction; and

[0049] A second pulley assembly, connected to the second pull cable, wherein rotation of the second pulley assembly applies tension to the second pull cable to cause deflection of the distal end in the second direction;

[0050] An injection handle for controlling the delivery of the composition;

[0051] A needle assembly connected to the injection handle and comprising a flexible needle extending from the needle hub, the needle extending: (i) through the injection handle; (ii) through the control handle; (iii) through a first lumen of the catheter fitting; and (iv) into a delivery lumen of the end assembly to deliver a composition;

[0052] The injection handle is configured to retract a flexible needle into the end assembly after the composition is delivered.

[0053] Some embodiments relate to a delivery catheter configured to deliver a composition to a target site, the delivery catheter comprising:

[0054] A catheter fitting defining a first lumen extending between a proximal and a distal end of the catheter fitting, wherein the catheter fitting includes a flexible portion configured to allow the distal end to deflect relative to the proximal end.

[0055] An end assembly connected to the distal end of a catheter fitting, the end assembly including an end electrode and an electrode band, wherein the end electrode defines a delivery lumen in communication with a first lumen of the catheter fitting;

[0056] A control handle for controlling the deflection of the distal end of the catheter fitting, the control handle being connected to the proximal end of the catheter fitting;

[0057] An injection handle for controlling the delivery of a composition, the injection handle being connected to a control handle, and the injection handle comprising:

[0058] A cylinder defining an orifice extending between a first end and a second end of the cylinder;

[0059] A piston configured to slide within a bore;

[0060] A spring, which is disposed in the hole and configured to resist the sliding of the piston toward the first end of the cylinder;

[0061] A needle assembly comprising a flexible needle extending from a needle hub, the needle extending: (i) through the injection handle; (ii) through the control handle; (iii) through a first lumen of the catheter fitting; and (iv) into a delivery lumen of the end assembly;

[0062] Wherein, the needle hub is connected to a piston of the injection handle, such that sliding of the piston toward a first end of the barrel causes the needle to extend through the end assembly to deliver the composition; and

[0063] The injection handle is configured to retract a flexible needle into the end assembly after the composition is delivered.

[0064] Some embodiments relate to a kit for a delivery catheter configured to deliver a composition to a target site, the kit comprising:

[0065] Conduit fittings;

[0066] An end assembly configured to connect to the distal end of a conduit fitting;

[0067] A control handle for controlling the deflection of the distal end of a catheter fitting, the control handle being configured to connect to the proximal end of the catheter fitting;

[0068] An injection handle for controlling the delivery of a composition, the injection handle being configured to connect to a control handle; and

[0069] A needle assembly for delivering a composition via a flexible needle extending from the end assembly, the needle assembly being configured to connect to an injection handle;

[0070] Among them, the conduit fittings are those described in this article.

[0071] Some embodiments relate to a kit for a delivery catheter configured to deliver a composition to a target site, the kit comprising:

[0072] Conduit fittings;

[0073] An end assembly configured to connect to the distal end of a conduit fitting;

[0074] A control handle for controlling the deflection of the distal end of a catheter fitting, the control handle being configured to connect to the proximal end of the catheter fitting;

[0075] An injection handle for controlling the delivery of a composition, the injection handle being configured to connect to a control handle; and

[0076] A needle assembly for delivering a composition via a flexible needle extending from the end assembly, the needle assembly being configured to connect to an injection handle;

[0077] The control handle is the control handle described in this article.

[0078] Some embodiments relate to a kit for a delivery catheter configured to deliver a composition to a target site, the kit comprising:

[0079] Conduit fittings;

[0080] An end assembly configured to connect to the distal end of a conduit fitting;

[0081] A control handle for controlling the deflection of the distal end of a catheter fitting, the control handle being configured to connect to the proximal end of the catheter fitting;

[0082] An injection handle for controlling the delivery of a composition, the injection handle being configured to connect to a control handle; and

[0083] A needle assembly for delivering a composition via a flexible needle extending from the end assembly, the needle assembly being configured to connect to an injection handle;

[0084] Wherein, the injection handle is the injection handle described herein; and

[0085] The needle assembly is the needle assembly described in this article.

[0086] The delivery catheters described herein, or the kits for delivery catheters described herein, can be configured to deliver: (i) cell compositions; or (ii) gene therapies. Attached Figure Description

[0087] The embodiments are described in more detail below by way of example with reference to the accompanying drawings, in which:

[0088] Figure 1A This is a top view of a catheter according to some embodiments;

[0089] Figure 1B According to some embodiments Figure 1A Side view of the catheter;

[0090] Figure 1C According to some embodiments Figure 1B A cross-sectional view of the conduit;

[0091] Figure 2A is an end view of a conduit fitting according to some embodiments;

[0092] Figure 2B This is a top view of the conduit fitting according to some embodiments of FIG2A;

[0093] Figure 2C This is a longitudinal sectional view of the conduit fitting according to some embodiments of FIG2A;

[0094] Figure 2D According to some embodiments Figure 2B A radial sectional view of the conduit fittings;

[0095] Figure 3 According to some embodiments Figure 1A A cross-sectional view of the distal segment of the catheter;

[0096] Figure 4A This is a top sectional view of a catheter control handle according to some embodiments;

[0097] Figure 4B According to some embodiments Figure 4A Exploded perspective view of the catheter control handle;

[0098] Figure 5A This is an exploded perspective view of a catheter injection handle according to some embodiments;

[0099] Figure 5B It is assembled according to some embodiments. Figure 5A Side view of the catheter injection handle;

[0100] Figure 5C It is assembled according to some embodiments. Figure 5B A cross-sectional view of the catheter injection handle;

[0101] Figure 6A This is an exploded perspective view of a catheter needle assembly according to some embodiments;

[0102] Figure 6B It is assembled according to some embodiments. Figure 6A A side view of the catheter needle assembly; and

[0103] Figure 6C It is assembled according to some embodiments. Figure 6B A cross-sectional view of the catheter needle assembly. Detailed Implementation

[0104] This disclosure generally relates to catheters. In particular, some embodiments of this disclosure relate to delivery catheters configured to deliver compositions such as cellular compositions or gene therapy agents to a target site. It will also be understood that delivery catheters include injection catheters, but for ease of reference, the term "delivery catheter" is used herein.

[0105] Figure 1A-1C An embodiment of a delivery catheter 100 configured to deliver a composition to a target site is shown. The delivery catheter 100 may include a catheter fitting 200, a terminal assembly 300, a control handle 400, an injection handle 500, and a needle assembly 600. Figure 1A This is a top view of the delivery catheter 100. Figure 1B This is a side view of the delivery catheter 100. Figure 1C It is along Figure 1B The delivery conduit 100 is cut along line BB marked in the middle.

[0106] Referring to Figures 2A-2D, the conduit fitting 200 may include a fitting wall 202 defining a first end 210 and a second end 220 of the conduit fitting 200, wherein the first end 210 and the second end 220 are located at opposite ends of the conduit fitting 200. Figure 2A is an end view of the conduit fitting 200. Figure 2B This is a top view of the conduit fitting 200. Figure 2C This is a longitudinal sectional view of the delivery catheter 100, cut along line AA marked in Figure 2A. Figure 2D It is along Figure 2B The radial cross-sectional view of the delivery conduit 100, cut along line BB (marked in the center). The conduit wall 202 may include multiple layers. In some embodiments, each layer of the conduit wall 202 comprises a combination of different materials. The conduit wall 202 may include a braided section to enhance its resistance to bending. The braided section may extend along a significant portion of the length of the conduit fitting 200. The braid may be made of 16 gauge thread. The thread braid may have a "one under two, over two" configuration or pattern. The thread braid may have a braid density of 28-30 programmable weft fibers (PPI) per inch.

[0107] The distance between the first end 212 located at the first end 210 and the second end 222 located at the second end 220 defines the total length of the conduit fitting 200. Figure 2C A longitudinal reference axis 230 is shown extending through the conduit fitting 200 between the first end 210 and the second end 220. The total length of the conduit fitting 200 can be measured along the longitudinal reference axis 230.

[0108] When the delivery catheter 100 is in use, as measured along the total length of the catheter fitting 220, a first end 210 of the catheter fitting 200 is closer to the target (and further away from the user), while a second end 220 is farther from the target (and closer to the user). Therefore, the first end 210 may alternatively be referred to as the distal end 210, and the second end 220 may alternatively be referred to as the proximal end 220. The catheter fitting 200 may define a first lumen 240 extending between the distal end 210 and the proximal end 220 of the catheter fitting. At least a portion of the catheter fitting 200 may be flexible. The catheter fitting 200 may include at least one flexible portion (not shown) configured to deflect the distal end relative to the proximal end. The flexible portion may be a connector connecting a separate segment of the catheter fitting. A separate segment of the catheter fitting 200 may be less flexible than the flexible portion. The entire catheter fitting 200 may be flexible. In some embodiments, the entire conduit fitting 200 is flexible, and some sections of the conduit fitting 200 are more flexible than other sections.

[0109] Turning Figure 2D In some embodiments, the catheter fitting wall 202 defines a first channel 250. The first channel 250 may be configured to receive a first pull wire 260. The first pull wire 260 may be configured to cause the distal end 210 of the catheter fitting 200 to deflect in a first direction.

[0110] In some embodiments, the catheter fitting wall 202 defines a second channel 270. The second channel 270 may be configured to receive a second drawwire 280. The second drawwire 280 may be configured to cause the distal end 210 of the catheter fitting 200 to deflect in a second direction. The first channel 250 and the second channel 270 may protect the respective drawwires 260, 280 from abrasion or damage. The first channel 250 and the second channel 270 may protect the respective drawwires 260, 280 from the influence of the needle (not shown) as the needle moves in and out of the catheter fitting 200 (during injection and retraction).

[0111] The fitting wall 202 may include a first ridge 204 extending from the inner surface of the conduit fitting 200 into the first lumen 240 to define a first channel 250. The fitting wall 202 may include a second ridge 206 extending from the inner surface of the conduit fitting 200 into the first lumen 240 to define a second channel 270.

[0112] Ridges 204 and 206 defining channels 250 and 270 may be present at the distal end 210. Ridges 204 and 206 may extend from the distal end 210 and along the pipe wall 202 toward the proximal end 220. Ridges 204 and 206 may extend from the distal end 210 along the pipe wall 202 to the proximal end 220. Ridges 204 and 206 may extend from the distal end 210 along the pipe wall 202 into the proximal end 220.

[0113] For clarity, Figure 2D A considerable gap is shown between the draw wires 260, 280 and the interior of their respective channels 250, 270. However, in some embodiments, the gap may be smaller to reduce the amount of radial movement of the draw wires 260, 280 in their respective channels 250, 270. Figure 2D The diagram also shows a first channel 250 and a second channel 270 disposed at opposite radial positions along the pipe wall 202. In some embodiments, the first channel 250 and the second channel 270 are disposed at different radial positions along the pipe wall 202, but these different radial positions are not opposite to each other.

[0114] The first drawstring 260 and the second drawstring 280 can induce deflection within the same plane of motion. The first drawstring 260 and the second drawstring 280 can induce deflection within the same plane of motion but in opposite directions. For example, refer to... Figure 2C The first draw wire 260 can move the distal end 210 to the left relative to the longitudinal reference axis 230, while the second draw wire 280 can move the distal end 210 back toward the longitudinal reference axis 230. Conversely, the second draw wire 280 can move the distal end 210 to the right relative to the longitudinal reference axis 230, while the first draw wire 260 can move the distal end 210 back toward the longitudinal reference axis 230.

[0115] The first drawstring 260 and the second drawstring 280 can induce deflection in different planes of motion. For example, the first drawstring 260 can induce deflection in a first plane of motion. The second drawstring 280 can induce deflection in a second plane of motion, which may not be parallel to the first plane of motion.

[0116] Deflection of the distal end 210 in a first direction can cause the flexible portion of the catheter fitting 200 to have a first radius of curvature. Deflection of the distal end 210 in a second direction can cause the flexible portion of the catheter fitting 200 to have a second radius of curvature. In some embodiments, the first and second radii of curvature are not equal. For example, the catheter fitting 200 may bend more in the first direction (i.e., have a smaller radius of curvature) compared to the second direction.

[0117] The first pull wire 260 and the second pull wire 280 can induce deflection of different portions of the catheter fitting 200. Deflection of the catheter fitting 200, such as at the end, is caused by applying tension to at least one of the first pull wire 260 and the second pull wire 280. The control handle 400 may include mechanisms configured to apply tension to the first pull wire 260 and / or the second pull wire 280. Various mechanisms for applying tension to the first pull wire 260 and / or the second pull wire 280 are then described herein by way of example.

[0118] Figure 3An embodiment of the end assembly 300 is shown. The end assembly 300 is configured to connect to the distal end 210 of the conduit fitting 200. In some embodiments, the end assembly includes an end electrode 310 and an electrode strip 320, wherein the electrode strip 320 may also be referred to as an annular electrode 320. The end electrode 310 may be connected to an end electrode lead 330. The electrode strip 320 may be connected to an annular electrode lead 332. The end electrode lead 330 and the annular electrode lead 332 may be soldered to their respective electrodes.

[0119] In some embodiments, the end electrode 310 defines a delivery lumen 312. The delivery lumen 312 may be connected to a first lumen 240 of the catheter fitting 200. The delivery lumen 312 may be connected to a tube 340 disposed within the first lumen 240 and extending toward the end assembly 300. The tube 340 may receive an injection needle (not shown) and separate the injection needle from the end electrode lead 330 and the annular electrode lead 332. The tube 340 may insulate the injection needle (not shown) from at least one of the end electrode 310 and the electrode band 320. The tube 340 may be made of a polyamide material. The tube 340 may extend into the delivery lumen 312 and extend to the end of the end electrode 310. The delivery lumen 312 may be centrally located within the end assembly 300.

[0120] The end assembly 300 may further include a transition tube 350 disposed at the distal end 210 of the catheter fitting 200. The transition tube 350 may be configured to connect the end electrode 310 to the distal end 210 of the catheter fitting 200. The transition tube 350 may define a distal end 352 and a proximal end 354. The distal end 210 of the catheter fitting 200 may be slightly tapered or have a stepped portion to define a reduced diameter for fitting within the lumen of the transition tube 350.

[0121] The first pull wire 260 and the second pull wire 280 may extend through the first lumen 240 of the conduit fitting 200 to connect to the distal end 210. The first pull wire 260 and the second pull wire 280 may connect to the distal end 210 near the end assembly 300. In some embodiments, the first pull wire 260 and the second pull wire 280 terminate at the proximal end 354 of the transition tube 350.

[0122] The end electrode 310 is configured to be inserted into the distal end 352 of the transition tube 350. The end electrode 310 can be secured to the distal end 352 of the transition tube 350 using an adhesive such as Dymax 215. The end electrode 310 may include an end portion 314 and a plug portion 316, wherein the diameter of the plug portion 316 is smaller than the diameter of the end portion 314. The end electrode 310 may include a stepped transition between the diameter of the end portion 314 and the diameter of the plug portion 316, thereby defining a shoulder 318. The end electrode 310 may abut against the distal end 352 of the transition tube 350. An electrode band 320 may be fitted around the distal end 352 of the transition tube 350 and may also be disposed around the plug portion 316 of the end electrode 310. The electrode band 320 may be spaced apart from the distal end 352 of the transition tube 350. The electrode band 320 may be spaced apart from the shoulder 318 of the end electrode 310.

[0123] The distal assembly 300 can be used to provide the location of the catheter distal assembly 300 within the patient's body. The distal assembly 300 can be used in conjunction with an external positioning (GPS) and / or mapping system to position the distal assembly 300 relative to a target point within the patient's body. For example, the delivery catheter 100 can be used to deliver the composition to the patient's heart. The patient can use a cardiac mapping system, such as the EnSite Precision system manufactured by Abbott, which can generate a real-time mapping / model of the patient's heart and identify the condition of the cardiac tissue. The cardiac mapping system can also track the location of the delivery catheter 100 as it enters the patient's heart. The cardiac mapping system can generate a high-resolution model that provides an actual mapping of the condition of the cardiac tissue, thereby reducing or avoiding the need for interpolation between adjacent measurement points to obtain an estimate of the condition of the cardiac tissue at an intermediate location.

[0124] At least one of the terminal electrode 310 and the electrode band 320 is a mapping electrode that monitors the precise location of the terminal component 300 in the heart. The mapping electrode can help generate a high-resolution model that provides a realistic mapping of the condition of the heart tissue, as described above. At least one of the terminal electrode 310 and the electrode band 320 can be used to monitor electrical signals at target sites. For example, healthy tissue can provide strong electrical signals that can be detected by one of the terminal electrode 310 and the electrode band 320. Dead or diseased heart tissue can provide weak or absent electrical signals. Damaged or inflamed tissue areas can provide moderate-intensity electrical signals. By measuring the intensity of the electrical signals generated from the heart tissue, the terminal component 300 can identify areas of heart tissue that require treatment, such as by delivering a therapeutic composition.

[0125] The electrical signals measured by the end-effector 300 can be transmitted to a computer system (not shown) via the end-effector lead 330 and the loop electrode lead 332. The computer system processes the data and displays it to the catheter operator. The computer system can also communicate with an external cardiac mapping system.

[0126] The electrical signals measured by the distal assembly 300 can also be used to correlate and / or verify cardiac mapping generated by an external cardiac mapping system. For example, if the cardiac mapping indicates a strong electrical signal at a specific location in the heart (indicating healthy tissue), while the distal assembly 300 indicates otherwise, the catheter operator can combine the location data generated by the distal assembly and / or the cardiac mapping system to check whether the catheter tip is in the correct position.

[0127] The delivery catheter 100 offers the advantages of combining or integrating mapping and therapeutic functions. Combining mapping and therapeutic functions eliminates the need for separate mapping and therapeutic catheters. This simplifies the procedure for the catheter operator and reduces the risk of errors. Using a combined mapping and therapeutic catheter can reduce the time patients spend undergoing procedures, which can improve patient experience and well-being.

[0128] The end component 300 may be modular. In some embodiments, the end component 300 may be interchangeable to suit different applications. For example, in some embodiments, the end component 300 includes an end component adapted to monitor and / or treat tissue hypoxia. In some embodiments, the end component 300 is used to deliver electrical stimulation to a target site.

[0129] like Figure 1C As shown, the control handle 400 is configured to connect to the proximal end 220 of the catheter fitting 200 and can be adapted to control the deflection of the distal end 210 of the catheter fitting 200. In some embodiments, such as Figure 4AAs shown, the control handle 400 may include a tip 401A to which the proximal end 220 of the catheter fitting 200 is connected. The control handle 400 may be configured to control the deflection of the distal end 210 of the catheter fitting 200 via actuated cables (such as a first cable 260 and a second cable 280). Actuation of the cables may occur through various mechanisms. For example, actuation of the cables may be achieved through a lever system or a pulley system, wherein actuating a lever or pulley about a fulcrum or pivot point applies tension to one or more cables, thereby deflecting the distal end 210. In some embodiments, rotating or translating a dial or knob may apply tension to one or more cables, thereby deflecting the distal end 210. The actuation mechanism used may depend on the construction of the cables, as the cables transition from the control handle 400 to the catheter fitting. For example, in embodiments where the draw cables 260, 280 move within channels 250, 270 formed in the conduit fitting wall, the fitting wall and / or channels 250, 270 may end before the actuation mechanism, such as... Figure 4A As shown, this allows for more space to move the draw cables 260 and 280, and potentially reduces stress on the draw cables 260 and 280. An embodiment of the control handle 400, wherein deflection of the distal end 210 is actuated by tensioning the draw cables via a pulley system, is described in more detail subsequently by way of example. However, it will be understood that control handles that control the distal end deflection of the conduit fitting in other ways, such as those described above, may be used alternatively.

[0130] Turning Figure 4A The internal structure of a control handle 400 is shown. The control handle 400 may include a housing 402 ergonomically shaped for comfortable grip and operation by a user. The housing 402 may include a hollow portion. The housing 402 may define a control portion 404 and a handle portion 406. The control handle 400 may also include a rocker arm 408 configured to actuate a first pull cable 260 and a second pull cable 280. The rocker arm 408 may be rotatably connected to the control portion 404 to allow the rocker arm 408 to rock back and forth relative to the handle portion 406, thereby moving the first pull cable 260 and the second pull cable 280.

[0131] The first pull cable 260 and the second pull cable 280 can extend through the first cavity 240 of the conduit fitting 200 and enter the control handle 400. The housing 402 can be divided into two housing portions 402A and 402B, as shown below. Figure 4B As shown, Figure 4B yes Figure 4AAn exploded view of the control handle 400 is shown. Opening the two housing portions 402A and 402B facilitates maintenance, such as adjusting the tension of the first pull cable 260 and the second pull cable 280. The two housing portions 402A and 402B can be secured by screws 403 or alternative fastening systems (such as snap-locks). Similarly, the control portion 404 and the handle portion 406 can also be divided into two corresponding control portions 404A and 404B and two handle portions 406A and 406B.

[0132] Continue to refer to Figure 4A In some embodiments, the control handle 400 includes a first pulley assembly 410 connected to a first pull cable 260, wherein rotation of the first pulley assembly 410 applies tension to the first pull cable 260 to cause deflection of the distal end 210. The deflection of the distal end 210 may be along a first direction. In some embodiments, the control handle 400 includes a second pulley assembly 420 connected to a second pull cable 280, wherein rotation of the second pulley assembly 420 applies tension to the second pull cable 280 to cause deflection of the distal end 210. The deflection of the distal end 210 may be along a second direction.

[0133] The first pulley assembly 410 and the second pulley assembly 420 can directly apply tension to the respective pull lines 260, 280 by pulling them. The first pulley assembly 410 and the second pulley assembly 420 may each include a lever arm device 430. In some embodiments, the first pulley assembly 410 and the second pulley assembly 420 indirectly apply tension to the respective pull lines 260, 280 via the lever arm device 430, which can amplify the force applied by the user to the respective pull lines 260, 280. The mechanical advantage generated by the lever arm device 430 reduces the force required for user input. Conversely, the lever arm device 430 can be configured to generate a mechanical disadvantage. For example, this could mean that a large input at pulley assemblies 410, 420 results in a small deflection of the distal end 210 of the catheter fitting 200. This can provide the user with finer control over the movement of the distal end 210 of the catheter fitting 200, especially when small movements of the distal end 210 are required to meet small target points. This can improve the flexibility and control performance for the catheter operator. This can increase patients' sense of security.

[0134] In some embodiments, the lever arm device 430 includes a link, such as link 448 or link 450, wherein link 448 or 450 includes at least one member and at least one pivot, the at least one member being rotatable about the at least one pivot to apply an output force in response to an input force.

[0135] In some embodiments, the lever arm device 430 includes a gear system 440. The gear system 440 includes at least one gear defining a plurality of gear teeth. In some embodiments, the gear system 440 includes a plurality of gears. Each gear may have a different number of gear teeth and / or a different gear diameter.

[0136] The gear system 440 provides torque through the distance between each gear tooth and the gear axis or the pivot about which the gear rotates. The link 448 or 450 and / or the gear system 440 can be configured to proportionally adjust the input force or input motion provided by the user at the first pulley assembly 410 and the second pulley assembly 420. In some embodiments, the lever arm device 430 includes the link 448 or 450 and the gear system 440.

[0137] The rocker arm 408 can be configured to actuate the pull cables 260, 280 via a lever arm device 430. For example, the rocker arm 408 can engage a gear system 440 and / or a linkage 448 or 450, which in turn connect to the pull cables 260, 280.

[0138] The first pulley assembly 410 and the second pulley assembly 420 can be located on opposite sides of the control handle 400.

[0139] An exemplary embodiment of the lever arm device 430 will now be described in detail, wherein specific components of the gear system 440 and the connecting rods 448, 450 are described in relation to their interconnections.

[0140] Turning Figure 4B In some embodiments, the rocker arm 408 includes a disc-shaped body 408A defining a central aperture 408B. The rocker arm body 408A may include a first knob 408C and a second knob 408D. The first knob 408C and the second knob 408D may be disposed along the circumference of the disc-shaped body 408A to protrude therefrom. The rocker arm body 408A may also define a first arcuate recess 408E and a second arcuate recess 408F. In some embodiments, the first arcuate recess 408E and the second arcuate recess 408F are disposed away from the center of the disc-shaped body 408A and the central aperture 408B. The first arcuate recess 408E and the second arcuate recess 408F may follow the same circular path. The first arcuate recess 408E and the second arcuate recess 408F may be disposed between the circumference of the disc-shaped body 408A and the central aperture 408B.

[0141] A first arcuate groove 408E receives a first pivot pin 436, while a second arcuate groove 408F receives a second pivot pin 438. The first pivot pin 436 and the second pivot pin 438 are configured to maintain a fixed relationship with the control portion 404 and / or the handle portion 406. A rocker arm 408 is configured to rotate relative to the control portion 404 and / or the handle portion 406. The rocker arm 408 can rotate about a central reference axis 409 passing through a central aperture 408B. When the rocker arm 408 rotates, the first arcuate groove 408E and the second arcuate groove 408F move relative to the first pivot pin 436 and the second pivot pin 438. The rocker arm 408 can rotate in a first direction (e.g., clockwise) until the first pivot pin 436 and the second pivot pin 438 abut the ends of their respective grooves 408E, 408F, thereby preventing further rotation in the first direction. The rocker arm 408 can rotate in a second direction (e.g., counterclockwise) until the first pivot pin 436 and the second pivot pin 438 abut against the opposite ends of their respective recesses 408E, 408F, thereby preventing further rotation in the second direction. Rotation of the rocker arm 408 can be considered as causing relative travel / translation of the first pivot pin 436 and the second pivot pin 438 in their respective recesses 408E, 408F.

[0142] The rocker arm 408 engages with the gear system 440. The gear system 440 includes a lever gear 442, a first sector gear 444, and a second sector gear 446. The central aperture 408B of the rocker arm 408 can be shaped to receive and engage the lever gear 442, such that rotation of the rocker arm 408 also causes the lever gear 442 to rotate about the axis 409.

[0143] The first sector gear 444 and the second sector gear 446 have teeth that engage with the teeth on the lever gear 442. Turning the rocker arm 408 causes a corresponding rotation of the lever gear 442, which in turn causes rotation of the first sector gear 444 and the second sector gear 446. The first sector gear 444 rotates about a first pivot pin 436, and the second sector gear 446 rotates about a second pivot pin 438.

[0144] A first sector gear 444 engages with a first pulley or connecting rod 448. A second sector gear 446 engages with a second pulley or connecting rod 450. The first connecting rod 448 and the second connecting rod 450 may be configured to rotate about or with the first pivot pin 436 and the second pivot pin 438, respectively. Alternatively, or in conjunction with the first pivot pin 436 and the second pivot pin 438, the sector gears 444 and 446 may include features that engage with corresponding features on the connecting rods 448 and 450 to transmit torque. For example, the sector gears 444 and 446 may include ridges that engage with corresponding grooves on the connecting rods 448 and 450, such that rotation of the gears 444 and 446 causes a corresponding rotation of the connecting rods 448 and 450.

[0145] The first link 448 and the second link 450 can each rotate about the first pivot pin 436 and the second pivot pin 438, respectively. The first link 448 and the second link 450 can each include a wedge-shaped or triangular member. A first cable 260 can be connected to the first link 448 distal to the pivot pin 436. A second cable 280 can be connected to the second link 450 distal to the pivot pin 438. Rotation of the first link 448 and the second link 450 thus allows movement of the first cable 260 and the second cable 280.

[0146] Joystick knobs 408C and 408D facilitate user operation of the joystick 408. Joystick knobs 408C and 408D may include textured surfaces to improve grip. For example, to turn the joystick 408 clockwise, joystick knob 408C can be pushed toward the second end 220 of the conduit fitting 200, and joystick knob 408D can be pulled away from the second end 220 of the conduit fitting 200. The second end 220 of the conduit fitting 200 can be connected to the control handle 400 via a strain relief member 470. In some embodiments, the strain relief member 470 is configured to reduce bending strain of the conduit fitting 200 at its point of contact with the control handle 400. The strain relief member 470 may be an elongated member of a section of the conduit fitting 200 connecting the control handle 400 to the second end 220 to distribute force over a larger surface area. Bending of the conduit fitting 200 at the second end 220 can also cause the strain relief member 470 to bend. The strain relief element 470 may be elastically deformable and may include an elastic material such as rubber.

[0147] If the rocker arm 408 rotates clockwise, the lever gear 442 also rotates clockwise. The clockwise rotation of the lever gear 442 causes the sector gears 444 and 446 to rotate counterclockwise. The counterclockwise rotation of the sector gears 444 and 446 causes the connecting rods 448 and 450 to rotate counterclockwise. The counterclockwise rotation of the connecting rod 448 causes a decrease in the tension of the first cable 260. The counterclockwise rotation of the connecting rod 450 causes an increase in the tension of the second cable 280.

[0148] Conversely, if the rocker arm 408 rotates counterclockwise, the lever gear 442 also rotates counterclockwise. The counterclockwise rotation of the lever gear 442 causes the sector gears 444 and 446 to rotate clockwise. The clockwise rotation of the sector gears 444 and 446 causes the connecting rods 448 and 450 to rotate clockwise. The clockwise rotation of the connecting rod 448 causes an increase in the tension of the first cable 260. The clockwise rotation of the connecting rod 450 causes a decrease in the tension of the second cable 280.

[0149] In some embodiments, the ease of rotation of the rocker arm 408 can be adjusted by a brake 452. The brake 452 is rotatably connected to a first control unit 404A and configured to frictionally engage the first control unit 404A. Frictional engagement can be adjusted by rotating the brake 452. The brake 452 may include a knob 454 connected to a plug 456. The knob 454 of the brake 452 may extend through the first housing portion 406A and through an opening 407 in the first housing portion 406A. A user can rotate the knob 454 to control the frictional engagement of the brake 452. The plug 456 may frictionally engage the surface of the first control unit 404A. The brake 452 may be aligned to rotate about an axis 409.

[0150] Brake 452 is connected to nut plate 458 via screw 460, which extends through first control portion 404A, through central aperture 408B of rocker arm 408, and through central hole formed in lever gear 442. First control portion 404A, rocker arm 408, and lever gear 442 are sandwiched between brake 452 and nut plate 458. Turning the brake knob 454 in a first direction tightens screw 460, thereby reducing the distance between brake plug 456 and nut plate 458, and causing increased frictional engagement between brake plug 456 and first control portion 404A. Conversely, turning the brake knob 454 in the opposite second direction loosens screw 460, thereby increasing the distance between brake plug 456 and nut plate 458, and causing decreased frictional engagement between brake plug 456 and first control portion 404A. Screw 460 may cooperate with one or more washers 462 to distribute force over a wider area and / or reduce friction by separating adjacent surfaces.

[0151] The control handle 400 may include a connector 480. The connector 480 is configured to be connected to one or more of the electrodes 310, 320 via a wire module 490. The wire module 490 can send signals to and / or receive signals from one or more of the electrodes 310, 320. The wire module 490 can supply electrical signals to one or more of the electrodes 310, 320. The wire module 490 may include a first wire connected to the end electrode 310, such as an end electrode lead 330. The wire module 490 may include a second wire connected to the electrode strip 320, such as a ring electrode lead 332. The wire module 490 may be connected to the connector 480 via a solder cup pin 482.

[0152] Connector 480 may include adapter 484 configured to surround connector 480 and solder cup pin 482. Adapter 484 may engage with the interior of control handle 400. Adapter 484 may include a two-part configuration, such as a first adapter portion 484A and a second adapter portion 484B, to facilitate access to solder cup pin 482. In some embodiments, adapter 484 defines a recess 486 configured to engage with a retaining feature 488 in control handle 400. Connector 480 may be connected to control handle 400 at a tail end 401B, which is distal to head end 401A.

[0153] The control handle 400 and the injection handle 500 can be connected via a tether cable 492. The tether cable 492 can be connected to the tail end 401B. The control handle 400 can receive a needle 510 extending from the injection handle 500. The needle 510 can enter the control handle 400 via the tether cable 492.

[0154] Figure 5A An embodiment of an injection handle 500 is illustrated. The injection handle 500 is configured to control the delivery of a composition via a needle 510. The injection handle 500 may be configured to control composition delivery by translating the needle 510 within the injection handle 500. The movement of the needle 510 can be managed in various ways. For example, the translation of the needle 510 can be achieved by a lever system or a pulley system, wherein rotation of a lever or pulley about a fulcrum or pivot point applies an input force to a carriage to cause the translation of the needle 510. In some embodiments, rotation or translation of a dial or knob applies an input force to a carriage to cause the translation of the needle 510. The injection handle 500 may include a biasing device to provide resistance to translation of the needle 510 toward the catheter tip. The biasing device can bias the needle away from the catheter tip when the input force is removed. By way of example, embodiments of the injection handle 500 in which the translation of the needle 510 is achieved by a sliding device are described in more detail thereafter. However, it will be understood that injection handles that control the translation of the needle 510 in other ways, such as as described above, may also be used alternatively. In some embodiments, such as Figure 5A As shown, the injection handle 500 includes a cylinder 520 defining an aperture 522 extending between a first end 524 and a second end 526 of the cylinder 520. The injection handle 500 may include a needle actuator hub 530 configured to receive a needle 510. The needle actuator hub 530 may be connected to a control handle 400 via a tether cable 492. The needle actuator hub 530 may be connected to the first end 524 of the cylinder 520. The needle actuator hub 530 may include a threaded connection 531 that engages with a corresponding threaded connection 523 inside the aperture 522 of the cylinder 520 to prevent movement of the needle actuator hub 530 relative to the cylinder 520.

[0155] The injection handle 500 may also include a piston 540 configured to slide within a bore 522. The injection handle 500 may also include a spring 550 configured to resist sliding of the piston 540 toward a first end 524 of the barrel 520. The spring 550 may be disposed within the bore 522. The spring 550 may contact a needle actuator hub 530. Since the needle actuator hub 530 may be fixed relative to the barrel, sliding of the piston 540 relative to the barrel 520 compresses the spring 550. The needle 510 may be received within a tube 560 (such as a Hypotube) to protect the needle 510 from the compression and extension of the spring 550. The piston 540 may be received in the injection handle 500 at a second end 526 of the barrel 520.

[0156] The injection handle 500 is configured to securely retain the needle 510 in the delivery catheter 100, for example, during injection. The injection handle 500 can be configured to retract the needle 510 into the end assembly 300 after composition delivery. A spring 550 can retract the needle 510 into the end assembly 300, from a position that covers and holds the needle 510, including its sharp points. The spring 550 can retract the needle 510 immediately after the actuation force on the piston 540 is released. This increases patient reassurance because the needle tip is not exposed when no composition is being delivered.

[0157] The needle assembly 600 is connected to the injection handle 500. In some embodiments, the needle assembly 600 is connected to the piston 540. In some embodiments, the needle assembly 600 is connected to the distal end 541B of the piston 540.

[0158] The needle assembly 600 is configured to deliver a composition to a target site. In some embodiments, the needle assembly 600 includes a flexible needle 510 extending from a needle hub 610. The needle hub 610 is configured to connect to a piston 540 of an injection handle 500. The needle 510 can extend through the injection handle 500. When the needle hub 610 is connected to the piston 540, the needle 510 can pass through a control handle 400, through a first lumen 240 of the catheter fitting 200, and into a delivery lumen 312 of the end assembly 300. Sliding of the piston 540 toward a first end of the barrel 520 can trigger the needle 510 to extend through the end assembly 300 to deliver the composition.

[0159] Subsequently Figures 6A-6C The needle hub 610 is described in more detail below.

[0160] Figure 5B A side view of the assembled injection handle 500 is shown. Figure 5C It is along Figure 5B A cross-sectional view of the injection handle 500 cut by the marked line.

[0161] The needle actuator hub 530 may include a body 532 and a sleeve 534. The diameter of the sleeve 534 may be smaller than the diameter of the body 532 to define a shoulder 536. A spring 550 may abut and sit on the shoulder 536 such that the sleeve 534 extends into the spring 550, which stabilizes the spring 550 and causes the spring to compress along its longitudinal axis without bending or buckling. The sleeve 534 defines a contact surface 538, which the proximal end 541A of the piston 540 may abut against to limit its stroke.

[0162] In some embodiments, the injection handle 500 further includes a needle actuator ring 542 on the piston 540. The needle actuator ring 542 may be configured to provide a grip to the user to move the piston 540 within the orifice 522, for example, for injecting a composition. The needle actuator ring 542 may be configured to limit the sliding / translation of the piston 540 within the orifice 522. This may correspondingly limit the amount by which the needle 510 can extend beyond the end assembly 300, which may improve patient comfort. In some embodiments, the diameter of the needle actuator ring 542 is larger than the diameter of the piston 540, such that when the piston 540 slides within the orifice 522 toward the first end 524 of the cylinder 520, the needle actuator ring 542 eventually abuts against the second end 526 of the cylinder 520, thereby preventing further translation of the piston 540.

[0163] The needle actuator ring 542 can be configured to engage with the piston 540 to adjust the stroke of the piston 540 within the bore 522. The needle actuator ring 542 can slide along the piston 540 and lock at a specific point on the piston 540. In some embodiments, the needle actuator ring 542 includes a threaded portion 544 configured to allow the needle actuator ring 542 to rotate along a corresponding thread 546 disposed on the exterior of the piston 540. Rotating the needle actuator ring 542 to travel along the piston 540 can shorten or lengthen the distance the piston 540 can slide within the bore 522. A pin 548 can lock the needle actuator ring 542 in a predetermined position on the piston 540.

[0164] The injection handle 500 may also include a recess 570 and a pin 572. The recess 570 may be formed on the piston 540. The recess 570 may extend along the length of the piston 540. The pin 572 may be configured to engage the recess 570 to limit the sliding of the piston 540 within the orifice 522 to the length of the recess 570. The pin 572 may be configured to engage the recess 570 to limit rotation of the piston 540 within the orifice 522. The pin 572 may be configured to engage the recess 570 to resist a spring force exerted on the piston 540 by the spring 550. For example, the pin 572 may abut the end of the recess 570, thereby preventing further travel of the piston 540. The recess 570 and the pin 572 may limit the amount of travel that the piston 540 can take, thereby limiting the amount by which the needle 510 can extend beyond the end assembly 300, which can improve patient safety.

[0165] Figure 6A This is an exploded view of the needle component 600. Figure 6B This is a side view of the assembled needle assembly 600. Figure 6C It is along Figure 6B The marked line is cut Figure 6B A sectional view.

[0166] The needle assembly 600 includes a needle hub 610. The needle assembly 600 may also include a first tube 620 extending from the needle hub 610. The needle assembly 600 may also include a second tube 630. The second tube 630 is connected to the first tube 620. The second tube 630 may be fitted within the first tube 620. A needle 510 extends from the needle hub 610 through the first tube 620 and the second tube 630. As the first tube 620 and the second tube 630 extend over the needle 510, the diameters of the first tube 620 and the second tube 630 may decrease to distribute force over a longer length of the needle 510 in a manner similar to that of the strain relief element 470 and its interaction with the conduit fitting 200.

[0167] A needle 510 extends from a needle hub 610 through an injection handle 500, through a control handle 400, through a catheter fitting 200, and into an end-effector 300. A first pull cable 260 and a second pull cable 280 are disposed on opposite sides of the needle 510 within the control handle 400. The first pull cable 260 and the second pull cable 280 are disposed on opposite sides of the needle 510 within the catheter fitting 200.

[0168] The needle hub 610 may include a flange 612 for connection to a syringe or other fluid source containing a composition to be delivered using the delivery catheter 100. The needle hub 610 may define a lumen 614 for receiving the composition. The lumen 614 is in fluid communication with the needle 510 for delivery to a target site. The needle hub 610 may include a threaded connection 616 for a secure connection to a corresponding threaded connection of a piston 540. The piston 540 may be hollow. The threaded connection 616 may be securely connected to the distal end 541B of the piston 540. The needle hub 610 may include a shoulder 618 abutting against the distal end 541B of the piston 540 to indicate engagement along the entire length of the threaded connection 616.

[0169] A needle insert 640 may be provided to facilitate attachment of the syringe to the lumen 614. The outer surface 642 of the needle insert 640 may engage with the interior of the lumen 614 to facilitate positioning of the needle insert 640 relative to the lumen 614.

[0170] Some embodiments of the delivery catheter 100 may be provided in an assembled or unassembled form. Some embodiments may relate to a kit of the delivery catheter 100 for delivering a composition to a target site. The kit may include a catheter fitting 200, a tip assembly 300, a control handle 400, an injection handle 500, and a needle assembly 600.

[0171] Composition

[0172] Various compositions can be administered using the catheters disclosed herein. In one example, the composition is a biological composition. For example, the composition may include cell populations, such as mesenchymal lineage precursor cell populations or soluble factors derived therefrom, and / or extracellular vesicles isolated therefrom under culture conditions.

[0173] As used herein, the term "mesenchymal lineage precursor or stem cell (MLPSC)" refers to an undifferentiated pluripotent cell that possesses the capacity for self-renewal while maintaining pluripotency and the ability to differentiate into multiple cell types, which are either mesenchymal in origin, such as osteoblasts, chondrocytes, adipocytes, stromal cells, fibroblasts, and tendons, or non-mesenchymal in origin, such as hepatocytes, nerve cells, and epithelial cells. For the avoidance of doubt, "mesenchymal lineage precursor cell" refers to a cell capable of differentiating into mesenchymal cells, such as bone, cartilage, muscle, and adipocytes, as well as fibrous connective tissue.

[0174] The term "mesenchymal lineage precursor or stem cell" includes parental cells and their undifferentiated progeny. The term also includes mesenchymal precursor cells (MPCs), pluripotent stromal cells, mesenchymal stem cells (MSCs), perivascular mesenchymal precursor cells, and their undifferentiated progeny.

[0175] MLPSCs can be autologous, allogeneic, xenogeneic, syngeneic, or syngeneic. Autologous cells are isolated from the same individual and will be re-implanted. Allogeneic cells are isolated from a donor of the same species. Xenogeneic cells are isolated from a donor of another species. Syngeneic or syngeneic cells are isolated from organisms with the same genes, such as twins, clones, or highly inbred animal research models.

[0176] For example, MLPSCs are allogeneic. For example, allogeneic MLPSCs are cultured, amplified, and cryopreserved.

[0177] MLPSCs are primarily found in the bone marrow, but are also observed in a variety of host tissues, including, for example, umbilical cord blood and cord, adult peripheral blood, adipose tissue, cancellous bone, and dental pulp. They are also found in the skin, spleen, pancreas, brain, kidneys, liver, heart, retina, brain, hair follicles, intestine, lungs, lymph nodes, thymus, ligaments, tendons, skeletal muscle, dermis, and periosteum; and they can differentiate into germ layers such as mesoderm and / or endoderm and / or ectoderm. Thus, MLPSCs can differentiate into a wide range of cell types, including but not limited to adipose, bone, cartilage, elastic, muscle, and fibrous connective tissue. The specific lineage commitment and differentiation pathways of these cell types depend on various influences from mechanical effects and / or endogenous bioactive factors, such as growth factors, cytokines, and / or the local microenvironment conditions established by the host tissue.

[0178] As used herein, the terms “enriched,” “enriched,” or variations thereof are used to describe a cell population in which the proportion of a particular cell type or a certain number of cells of a particular type is increased compared to an untreated cell population (e.g., cells in their natural environment). In one example, an enriched population of MLPSCs contains at least about 0.1% or 0.5% or 1% or 2% or 5% or 10% or 15% or 20% or 25% or 30% or 50% or 75% of MLPSCs. In this respect, the term “cell population enriched with MLPSCs” is considered to provide explicit support for the term “cell population containing X% MLPSCs,” where X% is the percentage described herein. In some examples, MLPSCs can form clonal colonies, such as CFU-F (fibroblasts) or subsets thereof (e.g., 50% or 60% or 70% or 70% or 90% or 95%) may have this activity.

[0179] In one example, the MLPSCs of this disclosure are cultured and expanded from a population of STRO-1+ MLPSCs. In another example, the MLPSCs are cultured and expanded from a population of MLPSCs containing approximately 0.1% to 75% STRO-1+ cells. In yet another example, the MLPSCs are cultured and expanded from a population of MLPSCs containing approximately 0.5% to 75% STRO-1+ cells. In yet another example, the MLPSCs are cultured and expanded from a population of MLPSCs containing approximately 0.1% to 75% STRO-1+ cells. In yet another example, the MLPSCs are cultured and expanded from a population of MLPSCs containing approximately 0.1% to 75% STRO-1+ cells. In yet another example, the MLPSCs are cultured and expanded from a population of MLPSCs containing approximately 1% to 75% STRO-1+ cells. In yet another example, the MLPSCs are cultured and expanded from a population of MLPSCs containing approximately 0.1% to 75% STRO-1+ cells. In another example, MLPSCs were cultured and expanded from a population of MLPSCs containing approximately 10% to 75% STRO-1+ cells.

[0180] In one example of this disclosure, MLPSCs are mesenchymal stem cells (MSCs). MSCs can be a homogeneous composition or a mixed cell population rich in MSCs. A homogeneous MSC composition can be obtained by culturing adherent bone marrow or periosteum cells, and MSCs can be identified by specific cell surface markers recognized with unique monoclonal antibodies. For example, a method for obtaining a cell population enriched with MSCs is described in U.S. Patent 5,486,359. Alternative sources of MSCs include, but are not limited to, blood, skin, umbilical cord blood, muscle, fat, bone, and perichondrium. In one example, the MSCs are allogeneic. In one example, the MSCs are cryopreserved. In one example, the MSCs are cultured, expanded, and cryopreserved.

[0181] In another instance, MLPSCs are CD29+, CD54+, CD73+, CD90+, CD102+, CD105+, CD106+, CD166+, MHC1+MSCs.

[0182] Isolated or enriched MLPSCs can be amplified in vitro through culture. Isolated or enriched MLPSCs can be cryopreserved, thawed, and subsequently amplified in vitro through culture.

[0183] In one instance, at 50,000 live cells / cm² 2Isolated or enriched MLPSCs were seeded into a medium (serum-free or serum-supplemented), such as α-minimum essential medium (αMEM) supplemented with 5% fetal bovine serum (FBS) and glutamine, and allowed to adhere to the culture vessel overnight at 37°C and 20% O2. The medium was then changed and / or modified as needed, and the cells were cultured for an additional 68 to 72 hours at 37°C and 5% O2.

[0184] As those skilled in the art will understand, cultured MLPSCs are phenotypically different from cells in vivo. For example, in one embodiment, they express one or more of the following markers: CD44, NG2, DC146, and CD140b. Cultured MLPSCs are also biologically different from cells in vivo, exhibiting a higher proliferation rate than the main non-circulating (dormant) cells in vivo.

[0185] In one instance, a cell population is enriched from a cell preparation containing STRO-1+ cells in an optional form. In this regard, the term "optionally form" should be understood to mean that cells express markers that allow selection of STRO-1+ cells (e.g., cell surface markers). The marker may be STRO-1, but it does not have to be. For example, as described and / or illustrated herein, cells expressing STRO-2 and / or STRO-3 (TNAP) and / or STRO-4 and / or VCAM-1 and / or CD146 and / or 3G5 (e.g., mesenchymal precursor cells (MPCs)) also express STRO-1 (and may be STRO-1bright). Therefore, the indication that cells are STRO-1+ does not imply selection of cells solely by STRO-1 expression. In one instance, cells are selected based on at least STRO-3 expression, for example, they are STRO-3+ (TNAP+). For example, MPCs can be isolated from bone mononuclear cells using an anti-STRO-3 antibody.

[0186] Reference regarding the selection of cells or populations of them does not necessarily require selection from a specific tissue source. As described herein, STRO-1+ cells can be selected from, isolated from, or enriched from a wide variety of broad sources. Nevertheless, in some instances, these terms support selection from any tissue containing STRO-1+ cells (e.g., mesenchymal precursor cells) or vascularized tissue or containing pericytes (e.g., STRO-1+ pericytes) or any one or more of the tissues described herein.

[0187] In one instance, the cell expression used herein is selected individually or collectively from one or more markers in the group consisting of TNAP+, VCAM-1+, THY-1+, STRO-2+, STRO-4+ (HSP-90β), CD45+, CD146+, 3G5+, or any combination thereof.

[0188] "Individually" means that the invention includes separately described marks or groups of marks, and although individual marks or groups of marks may not be listed separately herein, the appended claims may separate and divisibly define such marks or groups of marks from one another.

[0189] "Commonly" means that the invention includes any number or combination of the marked objects or groups of marked objects described, and although such number or combination of marked objects or groups of marked objects may not be specifically listed herein, the appended claims may separate and severably define such combinations or sub-combinations from any other combinations of marked objects or groups of marked objects.

[0190] As used herein, the term “TNAP” is intended to include all isotypes of tissue-nonspecific alkaline phosphatase. For example, the term includes liver isotype (LAP), bone isotype (BAP), and kidney isotype (KAP). In one example, TNAP is BAP. In one instance, TNAP as used herein refers to a molecule capable of binding to an antibody against STRO-3 produced by a hybridoma cell line deposited on December 19, 2005, at the ATCC under the Budapest Treaty with accession number PTA-7282.

[0191] In addition, in one instance, STRO-1+ cells were able to produce clonal CFU-F.

[0192] In one instance, a significant proportion of STRO-1+ cells are capable of differentiating into at least two distinct germ layers. Unrestricted examples of lineages that STRO-1+ cells may commit to include bone progenitor cells; hepatocyte progenitor cells that are pluripotent for both bile duct epithelial cells and hepatocytes; neurally restricted cells capable of producing glial cell precursors that progress to oligodendrocytes and astrocytes; neural progenitors that progress to neurons; cardiac and cardiomyocyte precursors; and pancreatic β-cell lineages that secrete insulin in response to glucose. Other lineages include, but are not limited to, odontoblasts, odontoblasts, and chondrocytes, as well as the following precursor cells: retinal pigment epithelial cells, fibroblasts, skin cells such as keratinocytes, dendritic cells, hair follicle cells, renal tubular epithelial cells, smooth muscle and skeletal muscle cells, testicular progenitor cells, vascular endothelial cells, tendons, ligaments, cartilage, adipocytes, fibroblasts, bone marrow stromal cells, cardiac muscle, smooth muscle, skeletal muscle, pericytes, blood vessels, epithelial cells, glial cells, nerve cells, astrocytes, and oligodendrocytes.

[0193] In one instance, MLPSCs are obtained from a single donor or multiple donors, where the donor samples or MLPSCs are subsequently pooled and then cultured for amplification.

[0194] The MLPSCs included in this disclosure can also be cryopreserved prior to administration to a subject. In one instance, the MLPSCs were cultured, amplified, and cryopreserved prior to administration to a subject.

[0195] In one instance, this disclosure includes MLPSCs and their progeny, soluble factors derived therefrom, and / or extracellular vesicles isolated therefrom. In another instance, this disclosure includes MLPSCs and extracellular vesicles isolated therefrom. For example, the MLPSCs of this disclosure may be cultured and expanded over a period of time under conditions suitable for secreting extracellular vesicles into a cell culture medium. The secreted extracellular vesicles can then be obtained from the culture medium for therapeutic purposes.

[0196] As used in this article, the term "extracellular vesicle" refers to lipid particles that are naturally released from cells and range in size from about 30 nm to 10 micrometers, although they are typically smaller than 200 nm. They may contain proteins, nucleic acids, lipids, metabolites, or organelles from the releasing cell (e.g., mesenchymal stem cells; STRO-1+ cells).

[0197] As used in this article, the term "exosome" refers to an extracellular vesicle, typically ranging in size from about 30 nm to about 150 nm, originating from the endosomal chambers of mammalian cells, from which it is transported to the cell membrane and released. They may contain nucleic acids (e.g., RNA; microRNA), proteins, lipids, and metabolites, and play a role in intercellular communication by being secreted from one cell and absorbed by other cells to deliver their cargo.

[0198] As used herein, the term "culture conditions" refers to cells grown in culture. In one instance, culture conditions refer to a population of actively dividing cells. For example, such cells may be in an exponential growth phase. In another instance, cells may be in a quiescent phase. In one instance, soluble factors and / or extracellular vesicles obtained from cells grown under culture conditions are obtained after at least two or three days of culture. In another instance, soluble factors and / or extracellular vesicles are obtained after approximately 30 to 84 hours of co-culture.

[0199] Other examples of biological compositions include gene therapy products. In the context of this document, such gene therapy products function by transferring genetic material into cells (cells in the heart of the subject to be treated). Those skilled in the art will appreciate that such gene therapy products can be provided using their own delivery systems, such as cell populations, liposomes, etc.

[0200] Those skilled in the art will recognize that many changes and / or modifications can be made to the above embodiments without departing from the broad overall scope of this disclosure. Therefore, the present embodiments should be considered exemplary and not restrictive in all respects.

[0201] This application claims priority to U.S. Provisional Application US63 / 587,583, filed October 3, 2023, the disclosure of which is incorporated herein by reference.

[0202] All publications discussed and / or referenced herein have their entire contents incorporated herein.

[0203] Any discussion of documents, actions, materials, devices, articles, etc., included in this specification is for the purpose of providing context for this disclosure only. It should not be construed as an admission that any or all of these matters constitute part of the prior art as existing prior to the priority date of each claim of this application or as common general knowledge in the relevant field.

Claims

1. A delivery catheter configured to deliver a composition to a target site, the delivery catheter comprising: The conduit fittings are defined as follows: A first lumen extends between the proximal and distal ends of the catheter fitting, wherein the catheter fitting includes a flexible portion configured to deflect the distal end relative to the proximal end. A first channel in the pipe wall, the first channel including a first pull wire, the first pull wire being configured to cause deflection of the distal end in a first direction; A second channel in the pipe wall, the second channel including a second pull wire, the second pull wire being configured to cause deflection of the distal end in a second direction; The end assembly is connected to the distal end of the catheter fitting, the end assembly including an end electrode and an electrode band, wherein the end electrode defines a delivery lumen in communication with a first lumen of the catheter fitting; A control handle for controlling the deflection of the distal end of the catheter fitting, the control handle being connected to the proximal end of the catheter fitting; An injection handle for controlling the delivery of the composition, the injection handle being connected to the control handle, and the injection handle comprising: A cylinder defining an orifice extending between a first end and a second end of the cylinder; A piston configured to slide within the orifice; A spring, disposed in the hole and configured to resist sliding of the piston toward a first end of the cylinder; A needle assembly comprising a flexible needle extending from a needle hub, the needle extending: (i) through the injection handle; (ii) through the control handle; (iii) through a first lumen of the catheter fitting; and (iv) into a delivery lumen of the end assembly; The needle hub is connected to a piston on the injection handle such that sliding of the piston toward a first end of the barrel causes the needle to extend through the end assembly to deliver the composition; and The injection handle is configured to retract a flexible needle into the end assembly after the composition has been delivered.

2. The delivery catheter according to claim 1, wherein, The control handle includes: A first pulley assembly, connected to the first draw cable, wherein rotation of the first pulley assembly applies tension to the first draw cable to cause deflection of the distal end in the first direction; and A second pulley assembly, connected to the second pull line, wherein rotation of the second pulley assembly applies tension to the second pull line to cause deflection of the distal end in the second direction.

3. The delivery catheter according to claim 1 or 2, wherein, The first channel and the second channel are positioned at opposite radial locations along the wall of the pipe fitting.

4. The delivery catheter according to any one of claims 1 to 3, wherein, The pipe wall includes: (i) a first ridge extending from the pipe wall into the first lumen to define a first channel; and (ii) a second ridge extending from the pipe wall into the first lumen to define a second channel.

5. The delivery catheter according to any one of claims 1 to 4, wherein, The first direction and the second direction are opposite in relation to the deflection of the distal end.

6. The delivery catheter according to any one of claims 1 to 5, wherein: The deflection of the distal end in the first direction causes the flexible portion of the conduit fitting to have a first radius of curvature; The deflection of the distal end in the second direction causes the flexible portion of the conduit fitting to have a second radius of curvature; Wherein, the first radius of curvature and the second radius of curvature are not equal.

7. The delivery catheter according to any one of claims 1 to 6, wherein, The delivery lumen is centrally located within the end assembly.

8. The delivery catheter according to claim 2 or any one of claims 3 to 7 when claim 2 is referenced, wherein, The first pulley assembly and the second pulley assembly include a lever arm device configured to: (i) amplify; or (ii) reduce the tension applied to the first and second pulleys, respectively, to cause deflection at the distal end.

9. The delivery catheter according to claim 8, wherein, The lever arm device includes: (i) a link; or (ii) a gear system; or (iii) a link and a gear system.

10. The delivery catheter according to claim 2 or any one of claims 3 to 9 when claim 2 is referenced, wherein, The first pulley assembly and the second pulley assembly are disposed on opposite lateral sides of the control handle.

11. The delivery catheter according to any one of claims 1 to 10, wherein, The first pull wire and the second pull wire are disposed on opposite sides of the needle in the control handle.

12. The delivery catheter according to any one of claims 1 to 11, wherein, The first pull wire and the second pull wire are disposed on opposite sides of the needle in the conduit fitting.

13. The delivery catheter according to any one of claims 1 to 12, wherein, The injection handle also includes a rotatable needle actuator ring on the piston, wherein the rotatable needle actuator ring is configured to restrict the sliding of the piston within the orifice.

14. The delivery catheter according to claim 13, wherein, The rotation of the rotatable needle actuator ring is configured to cause the rotatable needle actuator ring to travel along the piston, thereby shortening or increasing the distance the piston can slide within the orifice.

15. The delivery catheter according to claim 13 or 14, wherein, The injection handle also includes a groove and a pin, the groove being formed on the piston and the pin being configured to engage the groove to: (i) restrict the sliding of the piston within the orifice; And / or (ii) restrict the rotation of the piston within the orifice.

16. The delivery catheter according to claim 15, wherein, The pin is configured to engage with the groove to resist the spring force exerted on the piston by the spring.

17. A delivery catheter configured to deliver a composition to a target site, the delivery catheter comprising: The conduit fittings are defined as follows: A first lumen extends between the proximal and distal ends of the catheter fitting, wherein the catheter fitting includes a flexible portion configured to deflect the distal end relative to the proximal end. A first channel in the pipe wall, the first channel including a first pull wire, the first pull wire being configured to cause deflection of the distal end in a first direction; A second channel in the pipe wall, the second channel including a second pull wire, the second pull wire being configured to cause deflection of the distal end in a second direction; An end assembly connected to the distal end of the catheter fitting, the end assembly including an end electrode and an electrode band, wherein the end electrode defines a delivery lumen in communication with a first lumen of the catheter fitting; A control handle for controlling the deflection of the distal end of the catheter fitting, the control handle being connected to the proximal end of the catheter fitting; An injection handle for controlling the delivery of the composition; A needle assembly connected to the injection handle and comprising a flexible needle extending from the needle hub, the needle extending: (i) through the injection handle; (ii) through the control handle; (iii) through a first lumen of the catheter fitting; and (iv) into a delivery lumen of the end assembly to deliver a composition; The injection handle is configured to retract a flexible needle into the end assembly after the composition has been delivered.

18. A delivery catheter configured to deliver a composition to a target site, the delivery catheter comprising: The conduit fittings are defined as follows: A first lumen extends between the proximal and distal ends of the catheter fitting, wherein the catheter fitting includes a flexible portion configured to deflect the distal end relative to the proximal end. A first pull wire, configured to cause deflection of the distal end in a first direction; A second pull wire, configured to cause deflection of the distal end in a second direction; An end assembly connected to the distal end of the catheter fitting, the end assembly including an end electrode and an electrode band, wherein the end electrode defines a delivery lumen in communication with a first lumen of the catheter fitting; A control handle for controlling the deflection of the distal end of the catheter fitting, the control handle being connected to the proximal end of the catheter fitting, and the control handle comprising: A first pulley assembly, connected to the first draw cable, wherein rotation of the first pulley assembly applies tension to the first draw cable to cause deflection of the distal end in the first direction; and A second pulley assembly, connected to the second pull cable, wherein rotation of the second pulley assembly applies tension to the second pull cable to cause deflection of the distal end in the second direction; An injection handle for controlling the delivery of the composition; A needle assembly connected to the injection handle and comprising a flexible needle extending from the needle hub, the needle extending: (i) through the injection handle; (ii) through the control handle; (iii) through a first lumen of the catheter fitting; and (iv) into a delivery lumen of the end assembly to deliver a composition; The injection handle is configured to retract a flexible needle into the end assembly after the composition is delivered.

19. A delivery catheter configured to deliver a composition to a target site, the delivery catheter comprising: A catheter fitting defining a first lumen extending between a proximal and a distal end of the catheter fitting, wherein the catheter fitting includes a flexible portion configured to allow the distal end to deflect relative to the proximal end. An end assembly connected to the distal end of a catheter fitting, the end assembly including an end electrode and an electrode band, wherein the end electrode defines a delivery lumen in communication with a first lumen of the catheter fitting; A control handle for controlling the deflection of the distal end of the catheter fitting, the control handle being connected to the proximal end of the catheter fitting; An injection handle for controlling the delivery of a composition, the injection handle being connected to a control handle, and the injection handle comprising: A cylinder defining an orifice extending between a first end and a second end of the cylinder; A piston configured to slide within a bore; A spring, which is disposed in the hole and configured to resist the sliding of the piston toward the first end of the cylinder; A needle assembly comprising a flexible needle extending from a needle hub, the needle extending: (i) through the injection handle; (ii) through the control handle; (iii) through a first lumen of the catheter fitting; and (iv) into a delivery lumen of the end assembly; The needle hub is connected to a piston on the injection handle such that sliding of the piston toward a first end of the barrel causes the needle to extend through the end assembly to deliver the composition; and The injection handle is configured to retract a flexible needle into the end assembly after the composition is delivered.

20. A kit for a delivery catheter configured to deliver a composition to a target site, the kit comprising: Conduit fittings; An end assembly configured to connect to the distal end of a conduit fitting; A control handle for controlling the deflection of the distal end of a catheter fitting, the control handle being configured to connect to the proximal end of the catheter fitting; An injection handle for controlling the delivery of a composition, the injection handle being configured to connect to a control handle; and A needle assembly for delivering a composition via a flexible needle extending from the end assembly, the needle assembly being configured to connect to an injection handle; Wherein, the conduit fitting is the conduit fitting according to claim 1.

21. A kit for a delivery catheter configured to deliver a composition to a target site, the kit comprising: Conduit fittings; An end assembly configured to connect to the distal end of a conduit fitting; A control handle for controlling the deflection of the distal end of a catheter fitting, the control handle being configured to connect to the proximal end of the catheter fitting; An injection handle for controlling the delivery of a composition, the injection handle being configured to connect to a control handle; and A needle assembly for delivering a composition via a flexible needle extending from the end assembly, the needle assembly being configured to connect to an injection handle; The control handle is the control handle according to claim 1.

22. A kit for a delivery catheter configured to deliver a composition to a target site, the kit comprising: Conduit fittings; An end assembly configured to connect to the distal end of a conduit fitting; A control handle for controlling the deflection of the distal end of a catheter fitting, the control handle being configured to connect to the proximal end of the catheter fitting; An injection handle for controlling the delivery of a composition, the injection handle being configured to connect to a control handle; and A needle assembly for delivering a composition via a flexible needle extending from the end assembly, the needle assembly being configured to connect to an injection handle; Wherein, the injection handle is the injection handle according to claim 1; and The needle assembly is the needle assembly according to claim 1.

23. The delivery catheter according to any one of claims 1 to 19, or the kit for delivery catheter according to any one of claims 20 to 22, wherein, The delivery catheter is configured to deliver: (i) a cell composition; or (ii) a gene therapy.

24. Steps, features, integers, compositions and / or compounds disclosed herein or individually or collectively indicated in this application specification, and any and all combinations of two or more of said steps and features.

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