Systems and methods for controlling the flow of therapeutic agents delivered to an infusion catheter

Abstract

Described herein are devices, systems, and methods for treating a patient including at least one infusion catheter having a proximal end with a hub, a distal end with a distal tip, and a lumen extending from the proximal end to the distal tip. The device includes a connector body having a first connector for fluidly coupling and releasably connecting to the hub of the at least one infusion catheter, a second connector for fluidly coupling and releasably connecting to at least one manual syringe pump, and a passive pressure-controlled mechanical flow regulator for regulating the flow of fluid supplied to the infusion catheter by manual pumping action of the at least one manual syringe pump and delivered by the infusion catheter into the patient's vascular system. The mechanical flow regulator may be configured to deliver a therapeutic agent or a second fluid supplied under pressure by pumping action of the at least one manual syringe pump into and through the lumen of the infusion catheter at a desired infusion rate.

Description

[Technical Field]

[0001] This application claims priority to U.S. Patent Application No. 18 / 087,767, filed December 22, 2022, which is incorporated by reference in its entirety into this disclosure.

[0002] The present disclosure relates generally to systems and methods for delivering therapeutic agents into a patient's vasculature to treat disease in a target organ. [Background technology]

[0003] Infusion catheters are used to deliver therapeutic agents into a patient's vascular system to treat disease in a target organ. The infusion catheter has a hub for connecting to a source of therapeutic agent.

[0004] In situations requiring infusion under pressure and / or at a controlled flow rate, current systems typically use electronically controlled pumps to provide a constant flow of therapeutic agent for effective infusion. The operation of the electronically controlled pumps is governed by a control system configured to automatically control and regulate the flow of therapeutic agent through the infusion catheter. The use of electronically controlled pumps complicates the procedure by requiring extended tubing and personnel to handle the therapeutic agent outside of the sterile field. Summary of the Invention

[0005] This disclosure describes devices and systems for treating a patient that are used with or include at least one infusion catheter having a proximal end with a hub, a distal end with a distal tip, and a lumen extending from the proximal end to the distal tip. The device includes a connector body having a first connector for fluidly coupling and releasably connecting to the hub of the at least one infusion catheter, a second connector for fluidly coupling and releasably connecting to at least one manual syringe pump, and a mechanical flow regulator controlled by passive pressure supplied to the infusion catheter by manual pumping action of the at least one manual syringe pump to regulate the flow of fluid delivered by the infusion catheter into the patient's vascular system.

[0006] In some embodiments, the passive pressure-controlled mechanical flow regulator may be configured to deliver a therapeutic agent or second fluid supplied through the lumen of the infusion catheter under pressure by pumping action of at least one manual syringe pump at a desired infusion rate.

[0007] In some embodiments, the connector body may further include a first flow path extending through the first connector and fluidly coupled to a lumen of the infusion catheter in use, and a second flow path extending through the second connector and fluidly coupled to at least one manual syringe pump in use. A passive pressure controlled mechanical flow regulator may be fluidly coupled to both the first and second flow paths.

[0008] In some embodiments, the connector body may further include a third connector for fluidly coupling and removably connecting to at least one additional manual syringe pump, and a third flow path extending through the third connector and fluidly coupled to the at least one additional manual syringe pump during use. A passive pressure-controlled mechanical flow regulator may be fluidly coupled to the third flow path.

[0009] In some embodiments, the passive pressure controlled mechanical flow regulator comprises:

[0010] i) a first pressure relief valve having an inlet fluidly coupled to the second flow path and an outlet fluidly coupled to the first flow path;

[0011] ii) a second pressure relief valve having an inlet fluidly coupled to the first flow path and an outlet fluidly coupled to the third flow path;

[0012] iii) a third pressure relief valve having an inlet fluidly coupled to the third flow path and an outlet fluidly coupled to the first flow path; iv) a fourth pressure relief valve having an inlet fluidly coupled to the first flow path and an outlet fluidly coupled to the second flow path; may include:

[0013] The first and third pressure relief valves may be configured to open at a respective first preset supply pressure corresponding to a desired injection rate, and the second and fourth pressure relief valves may be configured to open at a respective second preset supply pressure higher than the first preset supply pressure.

[0014] In some embodiments, the first and second pressure relief valves may be configured to deliver therapeutic agent provided under pressure by pumping action of the at least one manual syringe pump into and through the lumen of the infusion catheter at a desired infusion rate and direct any excess flow into the at least one additional manual syringe pump, and the third and fourth pressure relief valves may be configured to deliver therapeutic agent provided under pressure by pumping action of the at least one additional manual syringe pump into and through the lumen of the infusion catheter at a desired infusion rate and direct any excess flow into the at least one manual syringe pump.

[0015] In some embodiments, the connector body may further include a passive flow restrictor coupled to the flow path downstream of the passive pressure-controlled mechanical flow regulator. The passive flow restrictor may be a fixed-size aperture or plug or other suitable passive flow control mechanism. The passive flow restrictor may be configured such that a slow flow rate of fluid through the connector body generates sufficient pressure to activate the first and second pressure relief valves.

[0016] In some embodiments, the connector body may further include a second connector for fluidly coupling and removably connecting to at least one additional manual syringe pump in a configuration that bypasses the passive pressure controlled mechanical flow regulator.

[0017] In some embodiments, the connector body may further include a first flow path extending through the first connector and fluidly coupled to a lumen of the infusion catheter in use, a second flow path extending through the second connector and fluidly coupled to at least one manual syringe pump in use, and an additional flow path extending through the second connector and fluidly coupled to at least one further manual syringe pump in use. A passive pressure-controlled mechanical flow regulator may be fluidly coupled to both the first and second flow paths, and the additional flow path may be fluidly coupled to the second flow path located downstream of the passive pressure-controlled mechanical flow regulator.

[0018] In some embodiments, the connector body may further include a check valve disposed between the passive pressure controlled mechanical flow regulator and the additional flow path.

[0019] In some embodiments, the connector body may be configured to deliver a therapeutic agent, supplied under pressure by pumping action of at least one manual syringe pump, into and through the lumen of the infusion catheter at a desired infusion rate, and the connector body may be further configured to deliver a second fluid, supplied under pressure by pumping action of at least one further manual syringe pump, into and through the lumen of the infusion catheter.

[0020] In some embodiments, a passive pressure-controlled mechanical flow regulator may include a chamber and a restrictor tube, the chamber having an inlet port leading into an interior space thereof, the restrictor tube extending into the interior space of the chamber, the restrictor tube including a restrictor inlet disposed within the interior space of the chamber and an annular elastomeric membrane positioned spaced apart from the restrictor inlet.

[0021] In some embodiments, the elastomeric membrane may be configured to deform or flex radially inward to regulate fluid flow through the restrictor tube.

[0022] In some embodiments, the restrictor tube may further include a bypass valve having an inlet in fluid communication with the interior space of the chamber and an outlet in fluid communication with the lumen of the restrictor tube. The bypass valve may be configured to open at a preset pressure within the interior space of the chamber that is greater than a pressure corresponding to a desired injection rate of fluid flow through the restrictor tube.

[0023] In some embodiments, a passive pressure controlled mechanical flow regulator may include a restrictor aperture of a fixed size corresponding to a desired injection rate.

[0024] In some embodiments, the size of the restrictor opening can be fixed based on the injection rate of a fluid of known viscosity delivered by a manual syringe pump of a preset size within a preset operating pressure range.

[0025] Related systems, kits and methods are also described and claimed. [Brief explanation of the drawings]

[0026] [Figure 1A] FIG. 1 is a diagram schematically illustrating a medical system according to a first embodiment of the present disclosure.

[0027] [Figure 1B]FIG. 1B is a schematic diagram of the connector body of the system of FIG. 1A.

[0028] [Figure 1C] FIG. 1C shows an example of a coil spring valve.

[0029] [Figure 1D-F] 1D to 1F are diagrams showing an example of a slit valve.

[0030] [Figure 1G] FIG. 1G shows an example of an elastomeric duckbill valve.

[0031] [Figure 2] FIG. 2 is a flow chart illustrating a medical procedure using the system of FIG. 1A to treat a patient.

[0032] [Figure 3] FIG. 3 is a diagram showing a schematic diagram of an example of an injection catheter.

[0033] [Figure 4] FIG. 4 is a diagram schematically illustrating a medical system according to a second embodiment of the present disclosure.

[0034] [Figure 5] FIG. 5 is a diagram schematically illustrating a medical system according to a third embodiment of the present disclosure.

[0035] [Figure 6A] FIG. 6A is a schematic diagram of an example of a pressure-controlled mechanical flow regulator that may be part of the connector body of the system of FIG.

[0036] [Figure 6B-C] 6B and 6C are schematic diagrams illustrating different configurations of the annular elastomeric (flexible) membrane of the exemplary pressure-controlled mechanical flow regulator of FIG. 6A.

[0037] [Figure 7] FIG. 7 is a diagram schematically illustrating a medical system according to a fourth embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0038] In this disclosure, when referring to the human body and components of devices and systems intended to be manually operated by a user, the terms "proximal" and "distal" are defined relative to the user's hand. That is, unless otherwise specifically indicated, the term "proximal" means closer to the user's hand and the term "distal" means farther from the user's hand. The term "passive" is defined in reference to the flow rate adjustment mechanisms described in this disclosure, and "passive" means that the flow rate adjustment mechanism does not employ an electromotive force source.

[0039] 1A and 1B, a medical system 11 is provided that includes a connector body 13 having a first syringe connector 15A, a second syringe connector 15B, and a catheter hub connector 15C integral with the connector body 13. The first syringe connector 15A may be configured to be fluidly coupled and releasably connected to a first manual syringe pump 17A, for example, using a luer fitting 19A at the distal tip of the first manual syringe pump 17A as shown. The second syringe connector 15B may be fluidly coupled and releasably connected to a second manual syringe pump 17B, for example, using a luer fitting 19B at the distal tip of the second manual syringe pump 17B as shown. The first and second manual syringe pumps 17A, 17B may each be a conventional manual syringe pump including a piston with a proximal handle that slides axially within an annular pump body. The pump body defines a variable-sized reservoir for holding fluid therein for either exiting the open distal tip as the piston moves distally toward the open distal tip or for entering the reservoir as the piston moves proximally away from the open distal tip. The catheter hub connector 15C is configured to fluidly couple to and removably connect to the hub 21 of an infusion catheter, as shown. The infusion catheter may be configured to deliver a therapeutic agent and / or a second fluid (such as a contrast agent for vascular imaging and visualization, a bolus of saline or other non-therapeutic agent, or a different therapeutic agent) into the patient's vasculature for treatment of disease in a target organ. For example, the hub 21 may correspond to the hub 308 of the exemplary infusion catheter of FIG. 3 . Alternatively, other suitable infusion catheters may be used.

[0040] First syringe connector 15A and connector body 13 provide an internal flow path (channel) 23A that branches off and connects to two valves V1 and V4 integral with connector body 13. Specifically, one branch of flow path (channel) 23A is fluidly connected to the inlet of valve V1, and the other branch of flow path (channel) 23A is fluidly connected to the outlet of valve V4. Valves V1 and V4 are also fluidly connected to an internal flow path (channel) 23C that extends through connector body 13 and catheter hub connector 15C to hub 21. Specifically, the outlet of valve V1 is fluidly connected to internal flow path (channel) 23C, and the inlet V4 of valve V4 is fluidly connected to internal flow path (channel) 23C.

[0041] Similarly, second syringe connector 15B and connector body 13 provide an internal flow path (channel) 23B that branches off and connects to two valves V2 and V3 integral with connector body 13. Specifically, one branch of flow path (channel) 23B is fluidly coupled to the inlet of valve V3, and the other branch of flow path (channel) 23B is fluidly coupled to the outlet of valve V2. Valves V2 and V3 are also fluidly coupled to an internal flow path (channel) 23C that extends through connector body 13 and catheter hub connector 15C to hub 21. Specifically, the outlet of valve V3 is fluidly coupled to internal flow path (channel) 23C, and the inlet of valve V2 is fluidly coupled to internal flow path (channel) 23C.

[0042] FIG. 1B shows only the components integrated into connector body 13 (not connected to the two manual syringe pumps and catheter hub). In some embodiments, connector body 13 is handheld and may include one or more housing sections that enclose and / or mechanically support first syringe connector 15A, second syringe connector 15B, and catheter hub connector 15C, along with fluid channels 23A, 23B, and 23C and valves V1, V2, V3, and V4, as shown. Fluid channels 23A, 23B, and 23C may be embodied by tubing and associated fluid couplings or other suitable fluid transfer structures and devices. Valves V1, V2, V3, and V4 may be embodied by medical-grade pressure relief valves configured to control the flow of fluids therethrough without reacting with or contaminating the fluids.

[0043] For example, valves V1, V2, V3, and V4 can be coil spring valves, as shown in Figure 1C. The coil spring valves employ a spring bias that keeps the valve closed and blocks flow through the valve. The valves open to allow fluid flow through the valve when pressure at the valve inlet sufficiently exceeds the spring bias provided by the coil spring. Alternatively, the valves can employ leaf springs or other springs that provide a spring bias that keeps the valve closed.

[0044] In another example, valves V1, V2, V3, and V4 can be slit valves, as shown in Figures 1D-1F. Slit valves employ a resilient diaphragm or sealing gasket with a slit configured in a closed state to block flow through the valve, as shown in Figure 1E. The valves open to allow fluid flow through the valve when pressure at the valve inlet is sufficient to open the slit in the diaphragm or gasket, as shown in Figure 1F.

[0045] In another example, valves V1, V2, V3, and V4 can be elastomeric duckbill valves, as shown in Figure 1G. Elastomeric duckbill valves employ an elastomeric tapered body followed by an outlet configured in a closed state to block flow through the valve. When pressure at the valve inlet is sufficient to deform the elastomeric tapered body and open the valve outlet, it opens to allow fluid flow through the valve.

[0046] System 11 may be configured to maintain consistent delivery of the therapeutic agent and / or second fluid within the patient's vasculature in conjunction with user (physician) manual pumping of one or both of first and second manual syringe pumps 17A, 17B. In this manner, system 11 can significantly reduce treatment complexity while maintaining the favorable distribution and inoculation patterns seen at a desired infusion rate (or desired infusion rate window).

[0047] In some embodiments, valve V1 may be designed and configured to open at a preset supply pressure SPV1 that produces a desired infusion rate. Thus, when the pressure in flow path (channel) 23A coupled to the inlet of valve V1 falls below such preset supply pressure SPV1, valve V1 remains closed, blocking flow through valve V1 and into internal flow path (channel) 23C extending through connector body 13 and catheter hub connector 15C to hub 21. When the pressure in flow path (channel) 23A coupled to the inlet of valve V1 reaches or exceeds such preset supply pressure SPV1, valve V1 opens, allowing flow through valve V1 and into internal flow path (channel) 23C extending through connector body 13 and catheter hub connector 15C to hub 21.

[0048] In some embodiments, valve V2 may be designed and configured to open at a predetermined supply pressure above a preset supply pressure SPV1 for valve V1 to release excess pressure / flow and allow flow into the reservoir of second manual syringe pump 17B. Thus, when the pressure in flow path (channel) 23C coupled to the inlet of valve V2 falls below such predetermined supply pressure SPV2, valve V2 remains closed, blocking flow through valve V2 and into internal flow path (channel) 23B extending through connector body 13 and second syringe connector 15B to second manual syringe pump 17B. When the pressure in flow path (channel) 23C coupled to the inlet of valve V2 reaches or exceeds such preset supply pressure SPV2, valve V2 opens, allowing flow through valve V2 and into internal flow path (channel) 23C extending through connector body 13 and second syringe connector 15B to second manual syringe pump 17B.

[0049] In some embodiments, valve V3 may be designed and configured to open at a preset supply pressure SPV3 that produces a desired infusion rate. Thus, when the pressure in flow path (channel) 23B coupled to the inlet of valve V3 falls below such preset supply pressure SPV3, valve V3 remains closed, blocking flow through valve V3 and into internal flow path (channel) 23C extending through connector body 13 and catheter hub connector 15C into hub 21. When the pressure in flow path (channel) 23B coupled to the inlet of valve V3 reaches or exceeds such preset supply pressure SPV3, valve V3 opens, allowing flow through valve V3 and into internal flow path (channel) 23C extending through connector body 13 and catheter hub connector 15C into hub 21.

[0050] In some embodiments, valve V4 may be designed and configured to open at a predetermined pressure SPV4 above a preset supply pressure SPV3 for valve V3 to release excess pressure / flow and allow flow into the reservoir of first manual syringe pump 17A. Thus, when the pressure in flow path (channel) 23C coupled to the inlet of valve V4 falls below such predetermined supply pressure SPV4, valve V4 remains closed, blocking flow through valve V4 and into the internal flow path (channel) 23A extending through connector body 13 and first syringe connector 15A to first manual syringe pump 17A. When the pressure in flow path (channel) 23C coupled to the inlet of valve V4 reaches or exceeds such preset supply pressure SPV4, valve V4 opens, allowing flow through valve V4 and into the internal flow path (channel) 23A extending through connector body 13 and first syringe connector 15A to first manual syringe pump 17A.

[0051] In the configuration of Figures 1A and 1B, valves V1, V2, V3, and V4 of connector body 14 provide a passive pressure-controlled mechanical mechanism for regulating the flow of therapeutic agent and / or second fluid supplied to the infusion catheter and delivered by the infusion catheter into the patient's vasculature at or near a desired infusion rate.

[0052] 1A and 1B may optionally include a passive flow restrictor FR coupled to the flow path downstream of valves V1, V2, V3, and V4. The passive flow restrictor FR is a device that regulates the rate of fluid flow through the flow path. The passive flow restrictor FR may be a fixed-size aperture or plug or other suitable passive flow-restricting mechanism. The passive flow restrictor may be configured to generate sufficient pressure to activate the first and second pressure relief valves V1 and V2 at low fluid flow rates through the connector body.

[0053] FIG. 2 illustrates the operation of system 11 of FIG. 1 during a medical procedure to deliver a therapeutic agent into a patient's vascular system. As part of such a medical procedure, an infusion catheter is introduced by a user (physician) into a target vessel in the vascular system. In some embodiments, the target vessel may extend within or near a tumor or other diseased tissue. The target vessel may feed or drain any of a variety of organs, such as, but not limited to, the pancreas, spleen, gastrointestinal tract, liver, lungs, uterus, prostate, or brain; the target vessel may also lead to tumors in the head and neck. The target vessel may also lead to other organs or tissues targeted for treatment in other parts of the body. In some embodiments, a treatment system of the present invention may be introduced within the target vessel or adjacent to the target vessel rather than intravascularly.

[0054] In block 201, a therapeutic agent is loaded into the reservoir of the first manual syringe pump 17A.

[0055] In block 203, the reservoir of the second manual syringe pump 17B is initially empty.

[0056] In block 205, the user (physician) manually activates the pumping action of the first syringe pump 17A.

[0057] In block 207, during the manual pumping of block 205, valve V1 is configured to open at a preset supply pressure that produces the desired infusion rate, and valve V2 is configured to open at a predetermined supply pressure above the preset supply pressure of V1 to vent all excess pressure / flow and allow excess therapeutic agent flow into the reservoir of second syringe pump 17B. In this configuration, manual pumping of first syringe pump 17A delivers therapeutic agent flow through valve V1 into flow path (channel) 23C and through flow path (channel) 23C and into and through catheter hub connector 15C for delivery by the infusion catheter at or near the desired infusion rate. All excess pressure and therapeutic agent flow into flow path (channel) 23C caused by manual pumping of first syringe pump 17A is diverted via valve V2 to the reservoir of second syringe pump 17B.

[0058] In block 209, the user pumping and delivery of therapeutic agent from the reservoir of the first syringe pump in blocks 205 and 207 continues until the reservoir of the first syringe pump is empty (or nearly empty), and operation continues to block 211 if the reservoir of the second syringe pump is not empty (or nearly empty).

[0059] In block 211, the user (physician) manually activates the pumping action of the second syringe pump 17B.

[0060] In block 213, during the manual pumping of block 211, valve V3 is configured to open at a preset supply pressure that produces the desired infusion rate, and valve V4 is configured to open at a predetermined supply pressure equal to or greater than the preset supply pressure of V3 to vent all excess pressure / flow and allow excess therapeutic agent flow into the reservoir of first syringe pump 17A. In this configuration, manual pumping of second syringe pump 17B delivers therapeutic agent flow through valve V3, into and through flow path (channel) 23C, and into and through catheter hub connector 15C for delivery by the infusion catheter at or near the desired infusion rate. All excess therapeutic agent pressure and flow into flow path (channel) 23C caused by manual pumping of second syringe pump 17B is diverted to the reservoir of first syringe pump 17A via valve V4.

[0061] The user's pumping action in block 215 and delivery of therapeutic agent from the second syringe pump reservoir in blocks 211 and 213 continues until the second syringe pump reservoir is empty (or nearly empty), at which point operation returns to block 205 if the first syringe pump reservoir is not empty (or nearly empty) in block 217. Treatment ends when both syringes have delivered their predetermined doses and are empty in block 219 (although either the first or second syringe can be configured to contain a preset amount of therapeutic agent).

[0062] In this manner, this treatment, in conjunction with manual pumping by the user (physician) of one or both of the first and second manual syringe pumps 17A, 17B (including alternating between the first and second manual syringe pumps 17A, 17B), allows for consistent delivery of the therapeutic agent into the patient's vasculature at or near the desired infusion rate until the infusion is complete. Additionally, the therapeutic agent may contain suspended particles (such as macroaggregated albumin, resin spheres, glass spheres, gel beads, other embolic particles, etc.) and / or normally immiscible emulsions (typically immiscible with Lipiodol). The regulated flow provided by the connector body 13 can maintain the suspended particles and / or emulsions uniformly dispersed in the flow through the connector body during administration.

[0063] In some embodiments, the desired infusion rate may range from 0.1 ml / sec to 4 ml / sec or more, with the resulting delivery pressure at the catheter hub ranging from 9 psi to 2000 psi. These delivery pressure values ​​can be used to design the valves and flow paths in the connector body for the desired infusion rate and to select a suitable manual syringe pump. Specifically, the maximum pressure of a manual syringe pump varies depending on the size of the syringe pump; therefore, the size of the manual syringe pump should be selected to have a maximum pressure that matches or exceeds the delivery pressure that provides the desired infusion rate. For example, if the desired infusion rate is 0.5 ml / sec with a delivery pressure of 90 to 99 psi, a manual syringe pump with a maximum pressure of over 100 psi (e.g., a conventional syringe pump of 10 cc or less) can be used for the treatment.

[0064] In the process of FIG. 2 , a high-pressure flow of a second fluid (e.g., a contrast agent for vascular imaging and visualization, a bolus of saline or other non-therapeutic agent, or a different therapeutic agent) can also be delivered through the infusion catheter of system 11 and into the patient's vasculature. For example, the second fluid can be loaded into a reservoir of an additional manual syringe pump (not shown), which can be a conventional manual syringe pump as described in this disclosure. The additional manual syringe pump is fluidly coupled to and removably connectable with one of the first and second syringe connectors (e.g., 15A), and the other of the first and second syringe connectors (e.g., 15B) is capped to block flow through the other syringe connector. A user (physician) manually activates the pumping action of the additional manual syringe pump to deliver the second fluid from the additional manual syringe pump into and through flow path (channel) 23C and then into and through catheter hub connector 15C for delivery via the infusion catheter into the patient's vasculature. In this configuration, the safety valve (V2 or V4) having an outlet leading to the capped syringe connector does not operate to release excess pressure / flow. Thus, manual pumping of the additional manual syringe pump can be used to deliver a second fluid flow into and through the infusion catheter and into the patient's vasculature at or above the desired infusion rate of the therapeutic agent. In some embodiments, after infusion of the therapeutic agent, manual pumping of the additional manual syringe pump can be used to deliver a second fluid flow into and through the infusion catheter and into the patient's vasculature, where such second fluid can be delivered at a high pressure / high flow rate above the desired infusion rate of the therapeutic agent such that the second fluid flow forces the therapeutic agent within the vasculature toward the diseased tissue.

[0065] FIG. 3 shows an exemplary infusion catheter 101 including a flexible tubular body 302 having a proximal end 304 and a distal end 306. The tubular body 302 has a length of 2 to 8 feet and an outer diameter of 0.67 to 3 mm (corresponding to a catheter size of 2 to 12 French). The tubular body 302 preferably includes an inner liner, an inner braid, and an outer coating. By way of example, the liner may be a fluorinated polymer such as polytetrafluoroethylene (PTFE) or fluorinated ethylene propylene (FEP). By way of example, the braid may be made of a metal such as stainless steel or a nickel-titanium alloy, or a polymer such as polyethylene terephthalate (PET) or a liquid crystal polymer. By way of example, the outer coating may be made of a polyether block amide-based thermoplastic elastomer membrane such as Pebax®, polyurethane, polyamide, polyamide copolymer, polyester, polyester copolymer, fluorinated polymer such as PTFE or FEP, polyimide, polycarbonate, or other suitable material, or other standard or specialized materials used in the manufacture of catheters used within the bloodstream.

[0066] The proximal end 304 of the tubular body 302 preferably includes a hub 308. An infusion lumen 320 extends through the interior of the hub 308 and through the interior of the tubular body 302 to the distal end 306 and exits at an open distal tip or orifice 307. The hub 308 and infusion lumen 320 are configured to deliver a therapeutic agent from outside the patient's body into the patient's vascular system (artery or vein) for treatment of disease in a target organ. The hub 308 may also be configured to facilitate the passage of a guidewire through the infusion lumen 320. Any hub 308 suitable for at least facilitating the delivery of a therapeutic agent into the infusion lumen may be utilized.

[0067] An occluder 308 is preferably coupled to the distal end 306 of the tubular body 302. The occluder prevents backflow of therapeutic agent between the vessel wall and the catheter into untreated tissue during delivery. The occluder may be either static or dynamic during use. Static occluders include inflatable balloons. Dynamic occluders include microvalves that expand and contract within the vessel in response to changes in ambient fluid pressure. When therapeutic agent is injected, the microvalves open, contact the vessel wall, and block backflow of therapeutic agent that might otherwise occur due to vascular resistance. In a preferred embodiment, the occluder 308 includes multiple elastic strands 322, each of which includes a proximal portion 324, a central portion 326, and a distal portion 328. The proximal portion 324 is attached to the periphery of the outer surface 30 of the tubular body 302 at a location proximal to the open distal tip or aperture 307. The central portion 326 extends radially outward and toward the open distal tip or aperture 307. The distal section 328 is folded back into the occluder 308 and circumferentially bonded around the outer surface 330. The proximal and central sections 324, 326 are coated with a polymeric filter coating 334 that extends between the strands 322. The distal sections 28 of the strands 22 are uncoated. The infusion catheter 301 is manufactured and sold by Trisalus Life Sciences, Inc. of Westminster, Colorado as the TRINAV® Infusion System. In use, the infusion catheter 301 can be deployed to a target vascular location from an introducer sleeve (shown diagrammatically as 336), although the use of the introducer sleeve is not required. The infusion system can be advanced over a guidewire without the introducer sleeve and, in fact, provides superior deliverability. Once deployed within a vessel, the valve occluder 308 dynamically operates in synchronization with the patient's cardiac cycle, providing the intended retrograde blockage of therapeutic agents while maintaining greater than 70% of antegrade blood flow through the microvalve occluder within the vessel. Furthermore, the design allows for non-traumatic increase in therapeutic agent infusion pressure into local resistant tumor vessels, enabling deeper perfusion delivery of therapeutic agents.In another embodiment, one or more injection catheters can be used as part of the systems and methods described in this disclosure.

[0068] 4 illustrates another embodiment of a medical system 11′ similar to the embodiment described with reference to FIGS. 1A and 1B, but further including a second syringe connector 25 and a check valve CV integral with the connector body 13. The second syringe connector 25 may be capped to block flow through the second connector 25 during pumping of the first and / or second manual syringe pumps 17A, 17B. Alternatively, the second syringe connector 25 may be fluidly coupled and removably connected to an additional manual syringe pump (not shown) whose reservoir is filled with a second fluid (e.g., a contrast agent for vascular imaging and visualization, a bolus of saline or other non-therapeutic agent, or a different therapeutic agent). The second syringe connector 25 and connector body 13 provide an internal flow path that is fluidly coupled to an internal flow path (channel) 23C that extends through the connector body 13 and catheter hub connector 15C to the hub 21, as shown. Check valve CV is located upstream from the flow path leading to second connector 25 as shown and fluidly coupled to flow path (channel) 23C, which is located downstream from the flow path leading to valves V1, V2, V3, and V4. In this configuration, check valve CV allows flow in one direction (i.e., toward catheter hub connector 15C) and blocks flow in the opposite direction, thereby blocking second fluid flow back toward valves V1, V2, V3, and V4 and first and second manual syringe pumps 17A and 17B. An optional passive flow restrictor FR is coupled to the flow path downstream from valves V1, V2, V3, and V4. The passive flow restrictor FR is a device that regulates the rate of fluid flow through the flow path. The passive flow restrictor FR can be a fixed-size aperture or plug or other suitable passive flow-restricting mechanism. The passive flow restrictor FR may be configured to generate sufficient pressure to activate first and second pressure relief valves V1 and V2 at slow fluid flow rates through connector body 13. In other embodiments, the check valve CV and passive flow restrictor FR may be provided as a single device configured as both a check valve and a passive flow restrictor as described in this disclosure.

[0069] System 11' can be used to implement the steps of FIG. 2 described herein. Additionally or alternatively, manual pumping of an additional manual syringe pump fluidly coupled to second syringe connector 25 can provide a second fluid flow into and through flow path (channel) 23C and then into and through catheter hub connector 15C for delivery via the infusion catheter into the patient's vasculature. In this configuration, check valve CV blocks the second fluid flow upstream of valves V1, V2, V3, and V4, preventing safety valves V2 and V4 (whose outlets lead to syringe connectors 15A and 15B) from operating to release excess pressure / flow. Manual pumping of the additional syringe pump can be used to deliver a second fluid flow into and through the infusion catheter into the patient's vasculature at pressures at or above the desired infusion rate of the therapeutic agent. In some embodiments, after infusion of the therapeutic agent, manual pumping of an additional syringe pump can be used to deliver a second fluid flow into and through the infusion catheter and into the patient's vasculature, and such second fluid delivery can be performed at a high pressure / flow rate above the desired infusion rate of the therapeutic agent such that the flow of the second fluid (e.g., a bolus of saline) forces the therapeutic agent within the vasculature toward the diseased tissue. In other embodiments, manual pumping of an additional syringe pump can be used to deliver the second fluid at a different infusion rate below or above the desired infusion rate of the therapeutic agent.

[0070] Referring to FIG. 5, a medical system 511 is provided that includes a connector body 513 having a syringe connector 515A and a catheter hub connector 515C integral therewith. The syringe connector 515A may be configured to be fluidly coupled and removably connected to a manual syringe pump 517, for example, using a luer fitting 519 at the distal tip of the manual syringe pump 517, as shown. The manual syringe pump 517 may be a conventional manual syringe pump as described herein. The catheter hub connector 515C may be fluidly coupled and removably connected to an infusion catheter hub 521, as shown. The infusion catheter may be configured to deliver a therapeutic agent and / or a second fluid (e.g., a contrast agent for vascular imaging and visualization, a bolus of saline or other non-therapeutic agent, or a different therapeutic agent) into a patient's vasculature for treatment of a disease of a target organ. For example, the hub 521 may correspond to the hub 308 of the exemplary infusion catheter of FIG. 3. Alternatively, other infusion catheters may be used.

[0071] Syringe connector 515A and connector body 513 provide an internal flow path (channel) 523 that extends through connector body 513 and catheter hub connector 515C to hub 521. Internal flow path (channel) 523 includes a passive pressure-controlled mechanical flow regulator 525 that is supplied to the infusion catheter and configured to regulate the flow of therapeutic agent delivered by the infusion catheter into the patient's vasculature at or near a desired infusion rate.

[0072] In some embodiments, connector body 513 may be hand-held and may include one or more housing sections that enclose and / or mechanically support syringe connector 515A and catheter hub connector 515C along with flow paths (channels) 523 and controls 525. Flow paths / channels 523 may be embodied by tubing and associated fluid couplings or other suitable fluid transfer structures and devices.

[0073] System 511 may be configured to maintain consistent delivery of a therapeutic agent and / or a second fluid (e.g., contrast agent for vascular imaging and visualization, a bolus of saline or other non-therapeutic agent, or a different therapeutic agent) into both patients' vasculature in conjunction with user-operated manual pumping of one or more manual syringe pumps. In this manner, system 511 significantly reduces the complexity of treatment while maintaining favorable distribution and inoculation patterns observed at a desired infusion rate (or desired infusion rate window). The therapeutic agent may include suspended particles (e.g., macroaggregated albumin, resin spheres, glass spheres, gel beads, other embolic particles, etc.) and / or normally immiscible emulsions (typically immiscible with Lipiodol). Furthermore, the regulated flow provided by system 511 can be calibrated to a range of flow rates based on syringe size and the resistance of the selected catheter.

[0074] FIG. 6A illustrates an exemplary embodiment of a passive pressure-controlled mechanical flow regulator 525′ suitable for use as the controller 525 in the system 511 of FIG. 5. The controller 525′ includes a hollow body (or chamber) 601 having an inlet port 603 extending therethrough. The body 601 further supports or defines a restrictor tube 607 that extends into an interior volume 605 of the chamber. One end of the restrictor tube 607 defines a restricted inlet port 609 located within the interior volume 605. The opposite end of the restrictor tube 607 defines an outlet port 611 extending from the body 601. The restrictor tube 607 defines a lumen 613 that extends from the restricted inlet port 609 to the outlet port 611, a portion of the lumen 613 being defined by an annular elastomeric (flexible) membrane 615 configured as a pressure-controlled, variable-sized restrictor aperture. The inlet port 603 and the outlet port 611 can be fluidly coupled to an internal flow path (channel) 523 extending through the connector body 513 of FIG. 5 . In this configuration, therapeutic agent delivered to the flow path (channel) 523 fills the interior space 605 of the body 601. The restrictor inlet port 609 is configured to provide a pressure drop between the interior space 605 and the lumen 613. This pressure drop causes the annular elastomeric membrane 615 to elastically deform or deflect inward toward the central axis of the lumen 613, acting as a restrictor opening for the flow of therapeutic agent through the lumen 613 and out the outlet port 613, as indicated by arrows 617A and 617B. In some embodiments, the elastic deformation or deflection of the elastomeric membrane can occur radially inward, although such deformation or deflection is not limited to this configuration. For example, the elastomeric membrane 615 can be designed to be straight, pinched downward between two surfaces, or pinched downward between a rigid surface. The deformation or deflection of the annular elastomeric membrane 615, and therefore the size of the restrictor aperture, varies with pump pressure. The restrictor inlet can be smaller than the lumen of the infusion catheter and can be configured to provide an initial flow restriction at relatively low pressures. The annular elastomeric membrane 615 provides a secondary flow restriction at higher pressures.

[0075] 6B shows the configuration of annular elastomeric membrane 615 in an initial high-pressure state, where pressure P1 in interior space 605 is greater than or equal to pressure P2 in lumen 613 located upstream of annular elastomeric membrane 615, which is greater than pressure P3 in lumen 613 located downstream of annular elastomeric membrane 615. In this configuration, P1 > P2>P3 and annular elastomeric membrane 615 undergoes a deformation proportional to the magnitude of the pressure difference between P1 and P2 relative to P3. In this manner, annular elastomeric membrane 615 of restrictor tube 607 regulates the flow of therapeutic agent supplied to the infusion catheter and delivered by the infusion catheter into the patient's vasculature at or near a desired infusion rate.

[0076] 6C shows the configuration of annular elastomeric membrane 615 in a low-pressure state where pressure P1 in interior space 605 is approximately equal to pressure P2 in lumen 613 located upstream of annular elastomeric membrane 615, which in turn is approximately equal to pressure P3 in a lumen located downstream of annular elastomeric membrane 615. In this configuration, P1 is approximately equal to P2, which is approximately equal to P3, and annular elastomeric membrane 615 experiences minimal deformation or deflection. The flow of therapeutic agent is then controlled by restrictor inlet 609 and the resistance of the infusion system.

[0077] The restrictor tube 607 may also include an optional bypass valve 619 disposed downstream from the annular elastomeric membrane 615. The bypass valve 619 may be designed and configured to open at a preset supply pressure within the interior space 605 that exceeds the actuation pressure for desired flow through the restrictor aperture provided by the membrane 615 to the outlet port 611. In this manner, when the pressure within the interior space 605 falls below such preset supply pressure, the bypass valve 619 remains closed, blocking flow through the bypass valve 619 and into the lumen 613 extending through the restrictor tube 607 to the outlet port 611. When the pressure within the interior space 605 reaches or exceeds the preset supply pressure, the bypass valve 619 opens, permitting flow through the bypass valve 619 and into the lumen 613 extending through the restrictor tube 607 to the outlet port 611, as indicated by arrows 621 and 617B. The bypass valve 619 may be embodied by a pressure relief valve configured to control the flow of fluid therethrough without reacting with and contaminating the fluid flow as described in this disclosure.

[0078] In some embodiments, the connector 515A of the system of FIGS. 5 and 6 can be coupled to a first manual syringe pump 517 having a reservoir filled with a therapeutic agent. The first manual syringe pump 517 can be a conventional manual syringe pump as described herein. The catheter hub connector 515C can be fluidly coupled to and configured for releasable connection with an infusion catheter hub 521, as shown. For example, the hub 521 can correspond to the exemplary infusion catheter hub 308 of FIG. 3. The syringe connector 515A and connector body 513 provide an internal flow path that is fluidly coupled to an internal flow path (channel) 523 that extends through the connector body 513 and catheter hub connector 515C to the proximal hub 521 of the infusion catheter, as shown. The first manual syringe pump 517 is manually actuated to deliver the therapeutic agent into and through the internal flow path (channel) 523. The restrictor 525' of Figure 6 is provided on the infusion catheter to regulate the flow of therapeutic agent delivered by the infusion catheter into the patient's vasculature at or near a desired infusion rate.

[0079] Additionally or alternatively, connector 515A of the systems of FIGS. 5 and 6 can be coupled to an additional manual syringe pump (e.g., a second manual syringe pump similar to 517) whose reservoir is filled with a second fluid (e.g., a contrast agent for vascular imaging and visualization, a bolus of saline or other non-therapeutic agent, or a different therapeutic agent). The additional manual syringe pump can be a conventional manual syringe pump as described herein. Catheter hub connector 515C is fluidly coupled to an infusion catheter hub 521 as shown, and may be configured for releasable connection. In this configuration, syringe connector 515A and connector body 513 provide an internal flow path that is fluidly coupled to an internal flow path (channel) 523 that extends through connector body 513 and catheter hub connector 515C to the proximal hub 521 of the infusion catheter, as shown. The additional syringe pump is manually actuated to deliver a therapeutic agent into and through internal flow path (channel) 523. The bypass valve 619 of the restrictor tube 607 may be configured to open and permit flow at a predetermined pressure and infusion rate desired for infusion of a second fluid through the bypass valve 619 and into the lumen 613 extending through the restrictor tube 607 to the outlet 611. In this configuration, manual pumping of an additional syringe pump can be used to deliver a flow of the second fluid into and through the infusion catheter into the patient's vasculature at a pressure at or above the desired infusion rate of the therapeutic agent. In some embodiments, after infusion of the therapeutic agent, manual pumping of an additional syringe pump can be used to deliver a flow of the second fluid into and through the infusion catheter into the patient's vasculature, and such delivery of the second fluid can be performed at a high pressure / flow rate above the desired infusion rate of the therapeutic agent so that the flow of the second fluid (e.g., a bolus of saline) forces the therapeutic agent within the vasculature toward the diseased tissue. In other embodiments, manual pumping of an additional syringe pump can be used to deliver a second fluid at a different infusion rate, either below or above the desired infusion rate of the therapeutic agent.

[0080] As noted above, the maximum pressure of a manual syringe pump varies depending on the size of the syringe pump. Therefore, the size of the manual syringe pump can be selected to have a maximum pressure consistent with the supply pressure that provides the desired injection rate for each of the therapeutic agent and the second fluid. For example, if the desired injection rate for the therapeutic agent is 0.5 ml / sec at a supply pressure of 90-99 psi and the desired injection rate for the second fluid is 1 ml / sec at a supply pressure of 155-180 psi, a manual syringe pump (e.g., a conventional 10 cc syringe pump) with a maximum pressure of 100 psi or greater but not exceeding 155-185 psi can be used for injecting the therapeutic agent, and a manual syringe pump with a maximum pressure of 155-185 psi or greater can be used for injecting the second fluid. In this example, bypass valve 619 can be configured to open and allow flow through bypass valve 619 at pressures in the 155-180 psi supply pressure range for injecting the second fluid.

[0081] Referring to FIG. 7 , a medical system 711 is provided that includes a connector body 713 having an integral syringe connector 715A and a catheter hub connector 715C. The syringe connector 715A may be configured to be fluidly coupled and releasably connected to a manual syringe pump 717, for example, using a luer fitting 719 at the distal tip of the manual syringe pump 717, as shown. The catheter hub connector 715C may be fluidly coupled and releasably connected to an infusion catheter hub 721, as shown. The infusion catheter may be configured to deliver a therapeutic agent and / or a second fluid (e.g., a contrast agent for vascular imaging and visualization, a bolus of saline or other non-therapeutic agent, or a different therapeutic agent) into a patient's vasculature for treatment of a disease of a target organ. For example, the hub 721 may correspond to the hub 308 of the exemplary infusion catheter of FIG. 3 .

[0082] The syringe connector 715A and connector body 713 provide an internal flow path (channel) 723 that extends through the connector body 713 and catheter hub connector 715C to the hub 721. The internal flow path (channel) 723 includes a fixed-size restrictor aperture 724 that is configured as a passive pressure-controlled mechanical flow regulator that supplies the infusion catheter and regulates the flow of a therapeutic agent or second fluid delivered by the infusion catheter into the patient's vasculature at or near a desired infusion rate. An optional pressure gauge can measure and display the pressure of the fluid supplied to the flow path (channel) 723. This pressure measurement display can be used as feedback to the user (physician) when operating the manual syringe pump 717 to ensure that manual pumping is performed within the desired operating pressure range.

[0083] In some embodiments, connector body 713 may be hand-held and / or may include one or more housing portions that enclose and / or mechanically support syringe connector 715A and catheter hub connector 715C along with flow paths (channels) 723 and fixed size restrictor apertures 724. Flow paths / channels 723 and fixed size restrictor apertures 724 may be embodied by tubing and associated fluid couplings or other suitable fluid transfer structures and devices.

[0084] System 711 may be configured to maintain consistent delivery of a therapeutic agent and / or a second fluid (such as a contrast agent for vascular imaging and visualization, a bolus of saline or other non-therapeutic agent, or a different therapeutic agent) into both patients' vasculature in conjunction with user (physician)-operated manual pumping of one or more manual syringe pumps. In this manner, system 711 can significantly reduce the complexity of treatment while maintaining favorable distribution and inoculation patterns seen at a desired infusion rate (or desired infusion rate window). Additionally, the therapeutic agent may contain suspended particles (such as macroaggregated albumin, resin spheres, glass spheres, gel beads, other embolic particles, etc.) and / or normally immiscible emulsions (typically immiscible with Lipiodol).

[0085] In some embodiments, the fixed size d of the opening of restrictor aperture 724 can be designed to regulate the flow of therapeutic agent or second fluid through flow path (channel) 723 at or near a desired infusion rate when the fluid viscosity and catheter lumen diameter are of known viscosity and diameter, and manual pumping of the syringe pump is performed within a preset pressure range. This flow, shown as arrow 728, continues through catheter hub connector 713C to the infusion catheter and is delivered by the infusion catheter into the patient's vasculature at or near the desired infusion rate.

[0086] In some embodiments, a kit of connector bodies 713 is provided, each connector body of the kit configured with a fixed restrictor orifice 724 opening size d to support a desired infusion rate of fluid through different manual syringe pumps with different fluid viscosities and / or different catheter lumen diameters and / or different operating pressure ranges. For example, a first connector body of the kit may be configured with a fixed restrictor orifice 724 opening size d1 to support a desired infusion rate of a first therapeutic agent of known viscosity (e.g., medium viscosity) through a 3 cc syringe pump operating at a pressure range of approximately 200-250 psi with a first preset catheter lumen diameter (e.g., 0.021 inch). In another example, a second connector body of the kit may be configured with a fixed restrictor orifice 724 opening size d2 to support a desired infusion rate of a second therapeutic agent of known viscosity (e.g., high viscosity) through a 10 cc syringe pump operating at a pressure range of approximately 100-125 psi with a second preset catheter lumen diameter (e.g., 0.025 inch). In yet another example, the third connector body of the kit may be configured with a fixed restrictor aperture 724 opening size d3 that supports a desired infusion rate for a saline fluid of known viscosity (e.g., low viscosity) through a 1 cc syringe pump operating at a pressure range of approximately 500-750 psi with a third preset catheter lumen diameter (e.g., 0.019 inches). The different connector bodies of the kit may be labeled with visible markers or color-coded with a preset color scheme to assist the user in selecting the connector body of the kit that matches the infusion system and treatment being used for the patient's treatment. The pressure measurement displayed by the optional pressure gauge 726 can be used to provide feedback to the user (physician) to operate the manual syringe pump 717 to ensure that manual pumping is performed within the desired operating pressure range.

[0087] The connector body of the kit that matches the infusion system and treatment used to treat the patient can be facilitated by a look-up table. Table 1 is an example of a connector body look-up table.

[0088] [Table 1]

[0089] The lookup table can be provided on a printed card packaged or distributed with the kit, or the lookup table can be provided via a graphical user interface from a software application running on a computing device. For example, the lookup table can be displayed as part of a graphical user interface provided by a web browser application or smartphone application.

[0090] This disclosure has described and illustrated embodiments of systems and methods for therapeutic agent delivery, as well as embodiments of pressure-enabled therapeutic agent delivery. While specific embodiments have been described, the invention is not limited thereto. The invention is intended to be as broad as technically possible, and this disclosure should be construed accordingly. Thus, while the systems and methods of the present invention are primarily suited to therapeutic treatment of humans, they have also been demonstrated in porcine tissues and organs and can be used for general mammalian treatment. Both humans and animals are considered "patients" for purposes of this disclosure. Furthermore, the therapeutic agents delivered in this disclosure may be a single therapeutic agent or a combination of multiple therapeutic agents. Accordingly, those skilled in the art will recognize that the present invention can be further modified without departing from the scope of the claims.

Claims

1. 1. An apparatus for use with at least one infusion catheter for treatment of a patient, the at least one infusion catheter having a proximal end with a hub, a distal end with a distal tip, and a lumen extending from the proximal end to the distal tip; The device includes a first connector for fluidly coupling and removably connecting to a hub of the at least one infusion catheter, a second connector for fluidly coupling and removably connecting to at least one manual syringe pump, and a connector body having a passive pressure-controlled mechanical flow regulator that regulates the flow of fluid supplied to the infusion catheter by manual pumping action of the at least one manual syringe pump and delivered by the infusion catheter into the vascular system of a patient.

2. 10. The device of claim 1, wherein the passive pressure-controlled mechanical flow regulator is configured to deliver a therapeutic agent or a second fluid supplied under pressure by pumping action of the at least one manual syringe pump through a lumen of the infusion catheter at a desired infusion rate.

3. 2. The device of claim 1, wherein the connector body further includes a first flow path extending through the first connector and fluidly coupled to a lumen of the infusion catheter in use, and a second flow path extending through the second connector and fluidly coupled to at least one manual syringe pump in use, and wherein the passive pressure controlled mechanical flow regulator is fluidly coupled to both the first and second flow paths.

4. 4. The device of claim 3, wherein the connector body further includes a third connector for fluidly coupling and removably connecting to at least one additional manual syringe pump, and a third flow path extending through the third connector and fluidly coupled to the at least one additional manual syringe pump during use, the passive pressure controlled mechanical flow regulator being fluidly coupled to the third flow path.

5. The passive pressure control mechanical flow regulator comprises: i) a first pressure relief valve having an inlet fluidly coupled to the second flow path and an outlet fluidly coupled to the first flow path; ii) a second pressure relief valve having an inlet fluidly coupled to the first flow path and an outlet fluidly coupled to the third flow path; iii) a third pressure relief valve having an inlet fluidly coupled to the third flow path and an outlet fluidly coupled to the first flow path; iv) a fourth pressure relief valve having an inlet fluidly coupled to the first flow path and an outlet fluidly coupled to the second flow path; The apparatus of claim 4 , comprising:

6. the first and third pressure relief valves are each configured to open at a first preset supply pressure corresponding to a desired injection rate; 6. The apparatus of claim 5, wherein the second and fourth pressure relief valves are each configured to open at a second preset supply pressure that is higher than the first preset supply pressure.

7. the first and second pressure relief valves are configured to deliver therapeutic agent provided under pressure by pumping action of the at least one manual syringe pump into and through a lumen of the infusion catheter at a desired infusion rate and to direct any excess flow into the at least one additional manual syringe pump; 7. The device of claim 6, wherein the third and fourth pressure relief valves are configured to deliver therapeutic agent supplied under pressure by pumping action of the at least one additional manual syringe pump into and through the lumen of the infusion catheter at a desired infusion rate and to direct any excess flow into the at least one manual syringe pump.

8. 6. The apparatus of claim 5, wherein the connector body further comprises a passive flow restrictor located downstream of the first, second, third and fourth pressure relief valves.

9. 10. The device of claim 1, wherein the connector body further comprises a second connector for fluidly coupling and removably connecting to at least one additional manual syringe pump configured to bypass the passive pressure controlled mechanical flow regulator.

10. 10. The device of claim 9, wherein the connector body further comprises a first flow path extending through the first connector and fluidly coupled to a lumen of the infusion catheter in use, a second flow path extending through the second connector and fluidly coupled to the at least one manual syringe pump in use, and an additional flow path extending through the second connector and fluidly coupled to the at least one further manual syringe pump in use, wherein the passive pressure controlled mechanical flow regulator is fluidly coupled to both the first flow path and the second flow path, and the additional flow path is fluidly coupled to the second flow path located downstream of the passive pressure controlled mechanical flow regulator.

11. The device of claim 10 , wherein the connector body further comprises a check valve disposed between the passive pressure-controlled mechanical flow regulator and the additional flow path.

12. the connector body is configured to deliver a therapeutic agent supplied under pressure by pumping action of the at least one manual syringe pump into and through a lumen of the infusion catheter at a desired infusion rate; 10. The device of claim 9, wherein the connector body is further configured to deliver a second fluid supplied under pressure by pumping action of the at least one additional manual syringe pump into and through a lumen of the infusion catheter.

13. 2. The device of claim 1, wherein the passive pressure controlled mechanical flow regulator includes a chamber and a restrictor tube, the chamber having an inlet port leading into an interior space thereof, the restrictor tube extending into the interior space of the chamber, the restrictor tube including a restricted inlet disposed within the interior space of the chamber and an annular elastomeric membrane positioned spaced apart from the restricted inlet.

14. The device of claim 13 , wherein the elastomeric membrane is configured to deform or flex radially inward to regulate fluid flow through the restrictor tube.

15. 14. The device of claim 13, wherein the restrictor tube further comprises a bypass valve having an inlet in fluid communication with the interior space of the chamber and an outlet in fluid communication with the lumen of the restrictor tube.

16. 16. The device of claim 15, wherein the bypass valve is configured to open at a preset pressure within the interior space of the chamber that is greater than a pressure corresponding to a desired injection rate of fluid flow through the restrictor tube.

17. 10. The device of claim 1, wherein the passive pressure controlled mechanical flow regulator includes a restrictor aperture of a fixed size corresponding to a desired injection rate.

18. 18. The device of claim 17, wherein the size of the restrictor aperture is fixed based on the injection rate of a fluid of known viscosity delivered by a manual syringe pump of a preset size within a preset operating pressure range.

19. 1. A system for treating a patient, comprising: at least one infusion catheter for treatment of a patient, the infusion catheter having a proximal end with a hub, a distal end with a distal tip, and a lumen extending from the proximal end to the distal tip, through which a first fluid is infused into the patient; a first connector for fluidly coupling to and removably connecting to a hub of the at least one infusion catheter; a second connector for fluidly coupling to and removably connecting to at least one manual syringe pump containing a first fluid; and a connector body having a passive pressure-controlled mechanical flow regulator that regulates the flow rate of the first fluid supplied to the infusion catheter by manual pumping action of the at least one manual syringe pump and delivered by the infusion catheter into the vascular system of a patient.

20. 20. The system of claim 19, wherein the passive pressure-controlled mechanical flow regulator is configured to deliver a first fluid supplied under pressure by pumping action of the at least one manual syringe pump through a lumen of the infusion catheter at a desired infusion rate.

21. 20. The system of claim 19, wherein the connector body further includes a first flow path extending through the first connector and fluidly coupled to a lumen of the infusion catheter in use, and a second flow path extending through the second connector and fluidly coupled to the at least one manual syringe pump in use, and wherein the passive pressure controlled mechanical flow regulator is fluidly coupled to both the first flow path and the second flow path.

22. 22. The system of claim 21, wherein the connector body further includes a third connector for fluidly coupling and removably connecting to the at least one additional manual syringe pump, and a third flow path extending through the third connector and fluidly coupled to the at least one additional manual syringe pump during use, the passive pressure controlled mechanical flow regulator being fluidly coupled to the third flow path.

23. The passive pressure control mechanical flow regulator comprises: i) a first pressure relief valve having an inlet fluidly coupled to the second flow path and an outlet fluidly coupled to the first flow path; ii) a second pressure relief valve having an inlet fluidly coupled to the first flow path and an outlet fluidly coupled to the third flow path; iii) a third pressure relief valve having an inlet fluidly coupled to the third flow path and an outlet fluidly coupled to the first flow path; iv) a fourth pressure relief valve having an inlet fluidly coupled to the first flow path and an outlet fluidly coupled to the second flow path; 23. The system of claim 22, comprising:

24. 24. The system of claim 23, wherein the connector body further includes passive flow restrictors located downstream of the first, second, third, and fourth pressure relief valves.

25. the first and third pressure relief valves are each configured to open at a first preset supply pressure corresponding to a desired injection rate; 24. The system of claim 23, wherein the second and fourth pressure relief valves are each configured to open at a second preset supply pressure that is higher than the first preset supply pressure.

26. the first and second pressure relief valves are configured to deliver a first fluid supplied under pressure by pumping action of the at least one manual syringe pump into and through a lumen of the infusion catheter at the desired infusion rate and to direct any excess flow into the at least one additional manual syringe pump; 26. The system of claim 25, wherein the third and fourth pressure relief valves are configured to deliver a first fluid supplied under pressure by pumping action of the at least one additional manual syringe pump into and through a lumen of the infusion catheter at the desired infusion rate and to direct any excess flow into the at least one manual syringe pump.

27. 20. The system of claim 19, wherein the connector body further comprises a second connector for fluidly coupling and removably connecting to at least one additional manual syringe pump configured to bypass the passive pressure controlled mechanical flow regulator.

28. 28. The system of claim 27, wherein the connector body further comprises a first flow path extending through the first connector and fluidly coupled to a lumen of the infusion catheter in use, a second flow path extending through the second connector and fluidly coupled to the at least one manual syringe pump in use, and an additional flow path extending through the second connector and fluidly coupled to the at least one further manual syringe pump in use, wherein the passive pressure controlled mechanical flow regulator is fluidly coupled to both the first flow path and the second flow path, and the additional flow path is fluidly coupled to the second flow path located downstream of the passive pressure controlled mechanical flow regulator.

29. 30. The system of claim 28, wherein the connector body further comprises a check valve disposed between the passive pressure controlled mechanical flow regulator and the additional flow path.

30. the connector body is configured to deliver a first fluid, supplied under pressure by pumping action of the at least one manual syringe pump, into and through a lumen of the infusion catheter at a desired infusion rate; 28. The system of claim 27, wherein the connector body is further configured to deliver a second fluid supplied under pressure by pumping action of the at least one additional manual syringe pump into and through a lumen of the infusion catheter.

31. 20. The system of claim 19, wherein the passive pressure controlled mechanical flow regulator includes a chamber and a restrictor tube, the chamber having an inlet port leading into an interior space thereof, the restrictor tube extending into the interior space of the chamber, the restrictor tube including a restrictor inlet disposed within the interior space of the chamber and an annular elastomeric membrane positioned spaced apart from the restrictor inlet.

32. 32. The system of claim 31, wherein the elastomeric membrane is configured to deform or flex radially inward to regulate fluid flow through the restrictor tube.

33. 32. The system of claim 31, wherein the restrictor tube further comprises a bypass valve having an inlet in fluid communication with the interior space of the chamber and an outlet in fluid communication with the lumen of the restrictor tube.

34. 34. The system of claim 33, wherein the bypass valve is configured to open at a preset pressure within the interior space of the chamber that is greater than a pressure corresponding to a desired injection rate of fluid flow through the restrictor tube.

35. 20. The system of claim 19, wherein the passive pressure controlled mechanical flow regulator includes a restrictor aperture of a fixed size corresponding to a desired injection rate.

36. 34. The system of claim 33, wherein the size of the restrictor aperture is fixed based on the injection rate of a fluid of known viscosity delivered by a manual syringe pump of a preset size within a preset operating pressure range.

37. 20. The system of claim 19, wherein the infusion catheter includes an occluder at its distal end to prevent backflow of the first fluid.

38. 38. The system of claim 37, wherein the occluder is a dynamic occluder.

39. 39. The system of claim 38, wherein the dynamic occluder is a microvalve.

40. 20. The system of claim 19, wherein the first fluid is a therapeutic agent or a second fluid.

41. 1. A kit for use with at least one infusion catheter for treating a patient, the at least one infusion catheter having a proximal end with a hub, a distal end with a distal tip, and a lumen extending from the proximal end to the distal tip; The kit includes a plurality of connector bodies, each having a first connector for fluidly coupling and releasably connecting to a hub of the at least one infusion catheter, a second connector for fluidly coupling and releasably connecting to at least one manual syringe pump, and a passive pressure-controlled mechanical flow regulator supplied by manual pumping action of the at least one manual syringe pump to regulate the flow of fluid delivered by the infusion catheter into the patient's vascular system, wherein the passive pressure-controlled mechanical flow regulators of the plurality of connector bodies include restrictor openings of different fixed sizes corresponding to desired infusion rates of a plurality of different fluids.

42. 38. The kit of claim 37, wherein the various fixed sizes are fixed based on injection rates of fluids of known viscosity delivered by manual syringe pumps of preset sizes within different preset operating pressure ranges.

43. 1. A method of treating a patient, the method comprising: A system is provided, the system including an infusion catheter and a connector body, the infusion catheter having a proximal end with a hub, a distal end with a distal tip, and a lumen extending from the proximal end to the distal tip, the connector body having a first connector for fluidly coupling and releasably connecting to the hub of the infusion catheter, a second connector for fluidly coupling and releasably connecting to at least one manual syringe pump, and a passive pressure controlled mechanical flow regulator; fluidly and removably connect a first connector of the connector body to a hub of the infusion catheter; fluidly and removably connect a second connector of the connector body to a first manual syringe pump; manually operating the first manual syringe pump to pump fluid into the infusion catheter, wherein the passive pressure-controlled mechanical flow regulator of the connector body regulates the flow of fluid into and through the infusion catheter for delivery by the infusion catheter into the patient's vascular system. A method comprising:

44. 44. The method of claim 43, wherein the connector body is configured to deliver a therapeutic agent into and through a lumen of the infusion catheter at a desired infusion rate, the therapeutic agent being supplied to the connector body under pressure by manual pumping action of the first manual syringe pump.

45. 45. The method of claim 44, wherein the connector body further includes a first flow path extending through the first connector and fluidly coupled to a lumen of the infusion catheter in use, and a second flow path extending through the second connector and fluidly coupled to a first manual syringe pump in use, and wherein the passive pressure controlled mechanical flow regulator is fluidly coupled to both the first flow path and the second flow path.

46. the connector body further includes a third connector for fluidly coupling and removably connecting to at least one additional manual syringe pump, and a third flow path extending through the third connector and fluidly coupled to the at least one additional manual syringe pump during use, the passive pressure controlled mechanical flow regulator being fluidly coupled to the third flow path; The passive pressure controlled mechanical flow regulator comprises: i) a first pressure relief valve having an inlet fluidly coupled to the second flow path and an outlet fluidly coupled to the first flow path; ii) a second pressure relief valve having an inlet fluidly coupled to the first flow path and an outlet fluidly coupled to the third flow path; iii) a third pressure relief valve having an inlet fluidly coupled to the third flow path and an outlet fluidly coupled to the first flow path; iv) a fourth pressure relief valve having an inlet fluidly coupled to the first flow path and an outlet fluidly coupled to the second flow path; Including, 46. ​​The method of claim 45, wherein the method includes fluidly coupling and removably connecting a third connector of the connector body to a second manual syringe pump separate and different from the first manual syringe pump.

47. the first and third pressure relief valves are each configured to open at a first preset supply pressure corresponding to a desired injection rate; 47. The method of claim 46, wherein the second and fourth pressure relief valves are each configured to open at a second preset supply pressure that is higher than the first preset supply pressure.

48. the first and second pressure relief valves are configured to deliver therapeutic agent supplied under pressure by manual pumping of the first syringe pump into and through a lumen of an infusion catheter at a desired infusion rate and to direct any excess flow into the second manual syringe pump; 48. The method of claim 47, wherein the third and fourth pressure relief valves are configured to deliver therapeutic agent provided under pressure by manual pumping of the second manual syringe pump into and through the lumen of the infusion catheter at a desired infusion rate and to direct any excess flow into the first manual syringe pump.

49. the connector body further includes a second connector for fluidly coupling and removably connecting to at least one additional manual syringe pump configured to bypass the passive pressure controlled mechanical flow regulator; 44. The method of claim 43, wherein the method includes fluidly coupling and removably connecting a second connector of the connector body to a second manual syringe pump.

50. the connector body is configured to deliver therapeutic agent supplied under pressure by pumping action of the first manual syringe pump into and through a lumen of an infusion catheter at a desired infusion rate; 50. The method of claim 49, wherein the connector body is further configured to deliver a second fluid, supplied under pressure by pumping action of a second manual syringe pump, into and through the lumen of the infusion catheter.

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