Pulsating balloon catheter system and method of using the same

Abstract

We provide a pulsating balloon catheter system. [Solution] The system comprises a pulse generator and a balloon catheter assembly operably connected to the pulse generator. In the embodiment, the balloon catheter assembly comprises a proximal connector configured to operably connect the balloon catheter assembly to the pulse generator and convert a first pulse energy generated by the pulse generator into a second pulse energy, a distal balloon, and a catheter component, the catheter component comprising a fluid passage operably positioned between the proximal connector and the distal balloon, the fluid passage configured to propagate the second pulse energy from the proximal connector along the fluid passage to the distal balloon. The system, assembly, and kit find use in a variety of different applications, including balloon angioplasty applications.

Description

[Background technology]

[0001] This section provides background information relating to the present disclosure that is not necessarily prior art. This section also provides a general overview of the present disclosure and is not a comprehensive disclosure of its entire scope or all of its features.

[0002] Ischemic heart disease, the world's leading cause of death, is caused by the accumulation of atherosclerotic plaques in the human vascular system. Globally, these diseases account for 84.5% of cardiovascular deaths and 28.2% of all deaths. Ischemic heart disease develops through a mechanism called atherosclerosis, which is the accumulation of fatty and calcified materials that causes stenosis, or narrowing, of the lumen of the ductus arteriosus. Both coronary and peripheral arteries can be affected by atherosclerotic plaque accumulation.

[0003] Plaque buildup from atherosclerosis restricts blood flow through these arteries, potentially leading to major adverse cardiovascular events such as myocardial infarction, limb amputation, and death. In the early stages of atherosclerosis, plaque is soft and fatty, but as time and the disease progresses, these plaques become physically hardened or calcified. Calcified plaques (CPs), which develop in the innermost layer of the arterial wall, are the most frequently occurring. These CPs result from the deposition and reconstruction of calcium hydroxyapatite, a process that mimics bone formation. CP-loaded vessels have reduced vascular elasticity and impaired vascular perfusion. Due to this reduced extensibility and perfusion, CPs are associated with an increased risk of death and other adverse events.

[0004] While many patients with CP are asymptomatic, a significant number develop ischemia-related symptoms and signs and undergo endovascular or surgical repair. Given its lower mortality rate, the endovascular approach is generally preferred. However, CP-loaded vessels present special challenges for effective endovascular treatment. A range of devices are often used to treat CP-loaded vessels. The CP lesion is initially pre-inflated using balloon angioplasty (BA). During BA, the balloon advances into the affected artery and expands to inflate the plaque-loaded vessel and restore normal blood flow. This pre-inflation step must be successful before secondary therapies such as drug-coated balloons or stents can be successfully used. To achieve successful pre-inflation, BA must mechanically disrupt the CP to ensure long-term opening or patency of the vessel and re-establish the elasticity of the surrounding healthy vessel. Often, high-pressure, non-stretchable balloons are used to achieve success. However, due to the strength of the CP, sufficient balloon expansion is often limited, and the CP remains undisrupted. Without sufficient balloon dilation and CP fragmentation, the vessel will remain with residual stenosis that restricts downstream blood flow, indicating a high risk of poor outcomes, immediate or long-term complications, and the need for additional treatment. To ensure patency of the affected vessel, the high rupture strength of the CP must be overcome.

[0005] During a standard BA (vascular angioplasty), a pressurized catheter balloon is used to break up atherosclerotic plaque and expand the arterial wall to re-establish normal blood flow in the narrowed artery. Typically, the balloon is pressurized via a manually operated screw-driven syringe that translates the rotation of a handle facing the physician into the displacement of a syringe piston. The syringe handle is rotated by the clinician until the pressure in the system reaches the desired pressure or the physician senses that the calcified plaque is being broken up. During the procedure, the physician can sense whether the calcified plaque is being broken up in two ways: (1) from the balloon's contour under fluoroscopy, a medical imaging technique commonly used in cardiovascular procedures, and (2) from the decrease in pressure in the hydraulic system, indicated by a pressure gauge. During angioplasty, a radiopaque dye (i.e., contrast agent) is introduced into the balloon, which illuminates the balloon and the contour of the arterial wall under fluoroscopy. When the plaque is intact and the balloon is pressurized, the balloon adopts a characteristic dogbone shape, with the proximal and distal edges unrestricted to expand, but the center obstructed by the plaque. The dogbone shape informs the clinician of the severity and distribution of the plaque. A more uniformly expanded balloon indicates to the physician that the plaque has been treated. A second method used to sense plaque fragmentation is indicated by a pressure gauge attached to the balloon. When treating severe plaque and / or circumferentially distributed plaque, the pressure inside the balloon is increased until plaque fragmentation occurs. Prior to plaque fragmentation, the balloon maintains the dogbone shape described above. After fragmentation, the plaque no longer restricts the balloon's expansion, and the balloon expands the plaque into the elastic artery. This expansion of the balloon increases its volume, deforming it from a dogbone shape to a fully expanded cylindrical shape. This increase in volume lowers the pressure inside the balloon, causing a change that can be visualized or sensed from the connected pressure gauge.

[0006] To overcome the rupture strength of CPs, angioplasty balloons are often used off-label (i.e., without FDA approval) to aggressively dilate CP-loaded vessels. In these cases, the balloon is pressurized to a pressure exceeding the rated rupture pressure (i.e., >20–40 ATM) to achieve sufficient balloon dilation to dilate the artery. These invasive procedures increase the risk to patients, including balloon rupture in 21% of cases, vascular dissection in 76% of cases, and restenosis (i.e., post-procedure restenosis) in 20–30% of cases. Other treatment strategies that attempt to break up CPs include cutting and scoring balloons and shock wave lithotripsy. Cutting balloons, which are balloons surrounded by a sharp-tipped metal blade, and scoring balloons, which are balloons confined in a metal cage, are intended to create stress concentration for CP breakup. During balloon pressurization, the metal blade or cage can become embedded in soft tissue or the CP, potentially causing major procedural problems. Poor outcomes are associated with these balloons, including restenosis in 20–30% of cases and serious adverse events such as vascular perforation, myocardial infarction, or death in 6% of cases. Shock wave BA uses a low-pressure balloon with an implanted shock wave generating lithotripter. While the short-term efficacy and safety of lithotripsy devices have been demonstrated through clinical trials, recent case reports have shown that these >50 ATM cavitation ruptures can lead to dangerous arterial dissection and perforation. Another commonly used treatment for CP is atherectomy, a technique that uses grinding to debulk the CP. However, atherectomy is technically more difficult and can pulverize the CP and surrounding healthy tissue, potentially causing long-term vascular damage.

[0007] In addition to concerns about patient outcomes, endovascular procedures and surgeries can significantly impact the treating physician. Interventional cardiologists may be exposed to an estimated 50 mSv–200 mSv of ionizing radiation in the course of their work, which is equivalent to 2,500–10,000 chest X-rays. This level of radiation exposure exposes treating physicians to serious long-term health problems, including cancer, cataracts, cognitive impairment, and reproductive toxicity. To mitigate the risk of backscattering of ionizing radiation, physicians wear personal protective equipment (PPE) (e.g., heavy lead clothing) for protection. A statistically significant group of interventional cardiologists reported musculoskeletal injuries that may have a shortening effect on their physician careers as a result of this PPE.

[0008] One of the goals of modern medicine is to ensure high-quality care regardless of the patient's location. In certain locations, this care cannot be provided due to a shortage of experienced physicians or limited resources. Because cardiovascular procedures can be life-threatening, it is essential that all patients have equal access to treatment regardless of their location. For this reason, it is important that devices providing services to these patients can be operated remotely or from a different location.

[0009] Further improvements to balloon angioplasty devices and their usage are still needed. [Overview of the project]

[0010] A pulsating balloon catheter system is provided. The system includes a pulse generator and a balloon catheter assembly operably connected to the pulse generator. In an embodiment, the balloon catheter assembly includes a proximal connector configured to operably connect the balloon catheter assembly to the pulse generator and convert a first pulse energy generated by the pulse generator into a second pulse energy, a distal balloon, and a catheter component, the catheter component including a fluidic passage operably positioned between the proximal connector and the distal balloon, the fluidic passage configured to propagate the second pulse energy from the proximal connector along the fluid passage to the distal balloon. Also provided are embodiments of robotic and / or standalone balloon catheter systems. Balloon catheter assemblies and kits containing them are also provided. Systems and methods for evaluating vascular distensibility in vivo are also provided. Systems and methods for determining the system state of a balloon catheter system are also provided. The systems, assemblies, and kits find use in a variety of different applications, including balloon angioplasty applications. [Brief explanation of the drawing]

[0011] [Figure 1] This is a schematic diagram of a system according to one embodiment of the present invention. [Figure 2] This is a diagram of a catheter balloon assembly according to one embodiment of the present invention. [Figure 3A] This is a diagram of the proximal connector of a balloon catheter assembly according to one embodiment of the present invention. [Figure 3B] This is a diagram of the proximal connector of a balloon catheter assembly according to one embodiment of the present invention. [Figure 3C] This is a diagram of the proximal connector of a balloon catheter assembly according to one embodiment of the present invention. [Figure 3D] This is a diagram of the proximal connector of a balloon catheter assembly according to one embodiment of the present invention. [Figure 3E] It is a diagram of the proximal connector of the balloon catheter assembly according to an embodiment of the present invention. [Figure 3F] It is a diagram of the proximal connector of the balloon catheter assembly according to an embodiment of the present invention. [Figure 3G] It is a diagram of the proximal connector of the balloon catheter assembly according to an embodiment of the present invention. [Figure 3H] It is a diagram of the proximal connector of the balloon catheter assembly according to an embodiment of the present invention. [Figure 4A] It is a diagram of the handheld actuator of the pulse generator according to an embodiment of the present invention. [Figure 4B] It is a diagram of the handheld actuator of the pulse generator according to an embodiment of the present invention. [Figure 4C] It is a diagram of the handheld actuator of the pulse generator according to an embodiment of the present invention. [Figure 4D] It is a diagram of the handheld actuator of the pulse generator according to an embodiment of the present invention. [Figure 4E] It is a diagram of the handheld actuator of the pulse generator according to an embodiment of the present invention. [Figure 4F] It is a diagram of the handheld actuator of the pulse generator according to an embodiment of the present invention. [Figure 5] It is a diagram showing an example of the pressure-volume relationship for a balloon with an unrestricted diameter of 4 mm and a length of 20 mm. [Figure 6] It is a diagram showing two examples of the experimentally measured pressure inside the balloon of FIG. 5 and the force output from the balloon. [Figure 7A] It is a diagram showing the pressure-volume relationship under various physical constraints. [Figure 7B] Panels A - B are exemplary fluoroscopic X-ray images of local lesions (indicated by arrows). In Panels C - D, the balloon is inserted over the lesion and pressurized. Looking at Panel C, the balloon appears to be inflated. However, in the normal projection image (Panel D), the balloon inflation is insufficient. [Figure 7C] This figure shows an example of measuring changes in vascular distensibility obtained during treatment using the system according to the present invention. [Figure 8] This is a schematic diagram of a system according to one embodiment of the present invention, configured to evaluate vascular distension in vivo. [Figure 9A] This is a diagram of the proximal connector of a balloon catheter assembly according to one embodiment of the present invention, configured to evaluate vascular distensibility in vivo. [Figure 9B] This is a diagram of the proximal connector of a balloon catheter assembly according to one embodiment of the present invention, configured to evaluate vascular distensibility in vivo. [Figure 9C] This is a diagram of a proximal connector of a balloon catheter assembly according to another embodiment of the present invention. [Figure 10A] Figures 9A and 9B show examples of analytical and experimental relationships between membrane position, balloon volume, and Hall sensor output for a system like the one shown. [Figure 10B] Figure 9C shows the functional data for one embodiment. [Figure 11] This is a schematic diagram of an exemplary electronic circuit for monitoring the system state according to the present invention. [Figure 12A] This figure shows the result of operation of an exemplary electronic circuit for monitoring the system state according to the present invention. [Figure 12B] This figure shows exemplary behavior of pressure and volume measurements from a catheter of the system according to the present invention during treatment, provided that it is undamaged (i.e., leak-free). [Figure 12C] This figure shows exemplary behavior of pressure and volume measurements from a completely malfunctioning catheter in the system according to the present invention during treatment. [Figure 12D] This figure shows exemplary behavior of pressure and volume measurements from a leaking catheter in the system according to the present invention during treatment. [Figure 13A]This diagram shows a schematic representation of an elastic conduit (e.g., artery) with an implanted hardened material (e.g., calcified plaque) treated by dynamic balloon angioplasty (DBA) techniques and devices according to some embodiments of this instruction. [Figure 13B] Figure 13A is a schematic diagram of an elastic conduit having a DBA angioplasty balloon that is guided to the lesion site and pre-pressurized. [Figure 13C] Figure 13A is a schematic diagram of an elastic conduit having a DBA angioplasty balloon circulated at low pressure. [Figure 13D] Figure 13A is a schematic diagram of an elastic conduit having a DBA angioplasty balloon circulating under high pressure. [Figure 13E] Figure 13A is a schematic diagram of the elastic conduit in which the hardened material has been destroyed according to the principles of this instruction. [Figure 14] This figure shows a pulsation therapy plan according to one embodiment of the present invention. [Figure 15] This figure shows the procedure steps for autonomic angioplasty performed using embodiments of the present invention. [Figure 16A] Figure 15 illustrates a graphical user interface (GUI) that an operator may use during autonomic angioplasty according to an embodiment of the present invention. [Figure 16B] This figure shows a GUI according to another embodiment of the present invention. [Figure 17] This is a photograph of a balloon catheter assembly according to one embodiment of the present invention. [Figure 18A] Figure 17 is a photograph of the proximal connector of a balloon catheter assembly. [Figure 18B] Figure 17 is a photograph of the proximal connector of a balloon catheter assembly. [Figure 18C] Figure 17 is a photograph of the proximal connector of a balloon catheter assembly. [Figure 19] This is a diagram of a balloon catheter system according to one embodiment of the present invention. [Figure 20A]This figure shows a microcomputed tomography scan, which will be described in detail in the section on experiments below. [Figure 20B] This figure shows a microcomputed tomography scan, which will be described in detail in the section on experiments below. [Modes for carrying out the invention]

[0012] A pulsating balloon catheter system is provided. An embodiment of the system includes a pulse generator and a balloon catheter assembly operably connected to the pulse generator. In an embodiment, the balloon catheter assembly includes a proximal connector configured to operably connect the balloon catheter assembly to the pulse generator and to convert a first pulse energy generated by the pulse generator into a second pulse energy, a distal balloon, and a catheter component, the catheter component including a fluid passage operably positioned between the proximal connector and the distal balloon, the fluid passage configured to propagate the second pulse energy from the proximal connector along the fluid passage to the distal balloon. An embodiment of a robotic balloon catheter system is also provided. A balloon catheter assembly and a kit containing the same are also provided. The system, assembly, and kit find use in a variety of different applications, including balloon angioplasty applications.

[0013] Before the present invention is described in more detail, it should be understood that the present invention is not limited to the specific embodiments described and is therefore, of course, subject to change. Furthermore, since the scope of the present invention is limited only by the appended claims, it should also be understood that the terms used herein are merely for describing specific embodiments and are not intended to limit them.

[0014] Where a range of values ​​is provided, unless the context clearly indicates otherwise, it is understood that each intervening value up to one-tenth of the lower limit unit between the upper and lower limits of that range, and any other descriptive or intervening values ​​within the descriptive range, are included within the invention. The upper and lower limits of these smaller ranges may independently be included within the smaller range and are also included within the invention, subject to any specific excluded limitations within the descriptive range. Where a described range includes one or both of the limitations, a range excluding one or both of those included limitations is also included within the invention.

[0015] In this specification, certain ranges of numbers preceded by the term "approximately" are presented. The term "approximately" is used herein to provide literal support for the exact number it precedes, as well as for any number that is close to or nearly close to the number it precedes. In determining whether a number is close to or nearly close to a specifically listed number, a number that is close to or nearly close to an unlisted number may, in the context presented, provide a substantial equivalence to the specifically listed number.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention pertains. Furthermore, any methods and materials similar to or equivalent to those described herein may be used in carrying out or testing the present invention, but representative exemplary methods and materials are described below.

[0017] All publications and patents cited herein are incorporated herein by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference, and are incorporated herein by reference to disclose and describe methods and / or materials relating to the cited publications. Any citation of a publication is of its disclosure prior to the filing date, and the present invention should not be construed as acknowledging that the present invention does not have prior rights to such publication by features of the prior invention. Furthermore, the dates of the publications provided may differ from the actual publication dates which may need to be independently verified.

[0018] It should be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural nouns unless the context clearly indicates otherwise. It should also be noted that claims may be designed to exclude any optional elements. Therefore, this statement is intended to serve as a precedent for the use of exclusive terms such as “exclusively,” “only,” or “negative” restrictions in relation to the enumeration of elements of claims.

[0019] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features that can be readily separated from or combined with any of the features of some other embodiments without departing from the scope or spirit of the invention. Any enumerated method may be performed in the order of the enumerated events, or in any other logically possible order.

[0020] Apparatus and methods have been, or will be, described with a functional description for grammatical fluidity, but unless explicitly stated under Section 112 of the United States Patent Act, the claims should not necessarily be interpreted as being limited by a “means” or “step” limitation, but should be granted the full scope of the meaning and equivalents of the definitions provided by the claims under the doctrine of legal equivalents, and if the claims are explicitly stated under Section 112 of the United States Patent Act, they should be granted the full legal equivalents under Section 112 of the United States Patent Act.

[0021] To further describe various aspects of the present invention, we will first describe the system and its components in more detail, and then consider the method of using the system and the kit for carrying out the subject method.

[0022] Pulsating balloon catheter system As summarized above, a pulsating balloon catheter system is provided. A pulsating balloon catheter system of an embodiment of the present invention is configured to provide a distal balloon that imparts pulsating energy to contacting internal tissue (e.g., luminal vascular tissue such as the inner wall of an artery) in the form of increasing and decreasing pressure applied to the contacting internal tissue at a desired frequency, duty cycle, and amplitude. As used herein, frequency is the number of total pressure pulse cycles (peak-to-peak) per unit time, duty cycle is the percentage of time allocated to the high-pressure segment of a single pressure cycle, and amplitude is the difference between the maximum and minimum pressures. Since the energy imparted to the internal tissue by the balloon is pulsating, it changes (e.g., increases and decreases) at a defined or determined frequency and duty cycle. During BA treatment, distal blood flow to the distal balloon may be obstructed, thereby limiting the treatment time. To successfully achieve treatment within this time, the pulsating frequency and amplitude must impart sufficient energy to the tissue to treat it. The frequency of the pulsating energy imparted to the associated tissue by the balloon can vary, but in some cases the frequency is high, in some cases ranging from 0 to 100 Hz, e.g., 0 to 25 Hz. Similarly, the duty cycle of the pulsating energy imparted to the tissue by the balloon can vary in some cases ranging from 10% to 100%, e.g., 60% to 80%. The amplitude of the pulsating energy imparted to the tissue by the balloon can vary in some cases ranging from 0 to 100 ATM, e.g., 0 to 30 ATM, within the range of the internal balloon pressure. As described below, during a given procedure, the frequency may change throughout the course of the procedure, i.e., it may not remain constant as desired.

[0023] Pulsating energy, when exposed to affected luminal vascular tissue, is effective in treating affected tissues such as CP tissue and mitigates adverse effects on surrounding healthy tissue. Key properties of pulsating energy for achieving therapeutic success may include the frequency and amplitude of the delivered pulsating energy. In embodiments, such pulsating energy can enable safe and controlled fatigue fracture of CP lesions. Fatigue fracture is the process of periodically loading a structure at a pressure below the pressure that would cause instantaneous fracture. While conventional treatments may apply dangerous high-pressure bursts to blood vessels, potentially causing dissection and perforation, pulsating angioplasty uses lower-pressure, high-frequency vibrations in an amplified balloon to initiate low-pressure fatigue fracture of CP lesions.

[0024] Input signal vs. output signal in mechanical systems The embodiments described are dynamic physical systems in which the system output (e.g., actual frequency, duty cycle, and amplitude) is controlled by the system input (e.g., desired frequency, duty cycle, and amplitude) and system characteristics (e.g., catheter length, friction, and flow path lumen diameter). Embodiments of the system are configured to generate controlled mechanical lithotripsy pulses within an angioplasty balloon so that the system output tracks a commanded input signal, or a desired input signal, with minimal attenuation in some examples. Signal attenuation is the reduction in the amplitude of the system output relative to the input due to the characteristics of the physical system. For successful treatment, minimal attenuation is required so that the output pulsating energy remains substantially similar to the input pulsating energy, for example, in terms of frequency, duty cycle, and / or amplitude, as it propagates from the system input (e.g., proximal connector) to the system output (e.g., distal balloon). Thus, in some examples, any change in frequency between the proximal connector and the distal balloon, if present, is 30% or less, for example, 5% or less. In some cases, any change in the amplitude of the pulsation energy between the proximal connector and the distal balloon is less than 30%, for example, less than 5%, if present. In some cases, any change in the duty cycle of the pulsation energy between the proximal connector and the distal balloon is less than 30%, for example, 5%, if present.

[0025] Prior art in this field (as described in, for example, WO2017 / 168145A1, US2019 / 0000491A1, US6348048B1, WO2001 / 010491A2, and US8574248B2) describes methods for generating pressure pulses within an angioplasty balloon. However, due to system characteristics, the prior art either requires operation at low frequencies to achieve the full pressure pulse or suffers from severe signal attenuation. In the case of low-frequency pressure pulses, the balloon does not generate sufficient pulses within the vessel to achieve improved treatment outcomes. In the case of high-frequency pressure pulses, the system output (i.e., balloon pulse) does not track the system input, and / or the system output is severely attenuated due to system characteristics, thereby rendering the treatment ineffective. In other cases, the system is designed so that the input pressure itself is generated with high frictional losses (e.g., piston pump systems) such that the high-frequency input pressure pulse is attenuated before it is transmitted to the proximal connector.

[0026] As summarized above, according to embodiments of the present invention, a pulsating balloon catheter system representing a mechanical system includes a pulse generator and a balloon catheter assembly operably connected to the pulse generator. The pulse generator of the system is a component configured to generate a first pulsating energy which can be converted into a second pulsating energy by the balloon catheter assembly, for example, as will be described in more detail below. The balloon catheter assembly is configured to receive the first pulsating energy provided by the pulse generator and convert the first pulsating energy into a second pulsating energy which can be received by the distal balloon, for example, for use in DBA or lithotripsy applications, and for use after the final inflation of a blood vessel, for example, for use in a single procedure including both applications, for example, for use in DBA or lithotripsy applications, and for use after the final inflation of a blood vessel, for example. That is, embodiments of the present invention can be used to first apply a pressure pulse to luminal tissue such as a blood vessel to crack calcium (i.e., CP-affected tissue), and then to dilate the blood vessel using a conventional non-stretchable balloon after inflation, for example, as will be described in more detail below. Here, we will examine the embodiments of the pulse generator and balloon catheter assembly in more detail.

[0027] pulse generator The first pulsating energy may vary as desired, and examples of the first pulsating energy include, but are not limited to, pulsating pressure energy, pulsating mechanical energy, and pulsating electromagnetic energy. Because the first pulsating energy is pulsating, the magnitude of the first energy changes or modulates over time, for example, according to a determined or known frequency, e.g., a predetermined frequency, according to the user, and / or according to the progress of the treatment (as described below). The frequency of the first pulsating energy may vary, but in some examples the frequency is high, and in some examples it is in the range of 0 to 100 Hz, e.g., 2 to 25 Hz. As described below, during a given procedure, the frequency amplitude and / or duty cycle may change during the course of the procedure, i.e., they may not be constant as desired (e.g., as described in conjunction with Figure 6 below). The frequency, amplitude, and / or duty cycle may also vary depending on the type of balloon catheter (e.g., balloon length and / or diameter, shaft length), treatment type, lesion stiffness, lesion density (e.g., obtained by computed tomography or intravascular imaging), or lesion morphology. The frequency, amplitude, and / or duty cycle may also vary in response to user input, negative feedback from measurements, and / or positive feedback from system modeling.

[0028] The pulse generator of an embodiment of the present invention includes a potential source configured to provide a pulsating mode of a first pulsating energy by providing energy which can be optionally adjusted by a regulator and an oscillator. Any convenient potential source may be used, and examples of potential sources include voltage sources, pressure sources, electromagnetic sources, electric field sources, chemical sources, laser sources, etc. In some embodiments, the potential source is a pressure source, and examples of suitable pressure sources include, but are not limited to, compressed gas cylinders and compressors. Optionally, the potential source may be operably coupled to a regulator, which plays a role in modulating the energy into a suitable form so that it can be further actuated by an oscillator. For example, if the potential source is a high-pressure gas source, the regulator may help in adjusting the gas pressure to a suitable value which can be input to the oscillator, for example, as can be done in a pneumatic pulse generator. In addition to the potential source and regulator, the pulse generator may include an oscillator. In such an example, the oscillator is used to modulate the magnitude and timing of the potential energy from the potential source to provide a desired first pulsating energy.

[0029] The different components of a pulse generator may reside within a single housing or be provided as two or more different, operably connected units. In some examples, at least some of the pulse generator components reside within a handheld unit. In such examples, the handheld component, e.g., a handheld actuator, is designed to be held and operated by a single adult human hand. The form factor of such a handheld unit may vary as desired, but in some examples, such a unit has a typical diameter and / or width in the range of 20–150 mm, e.g., 50–80 mm, a length in the range of 50–300 mm, e.g., 100–200 mm, and a mass in the range of 100–2000 g, e.g., 500–750 g. For example, a pulse generator may include a first console component housing a potential source and regulator, and a second handheld actuator including an oscillator and an actuator for the oscillator, e.g., an operable button. The handheld actuator may, as desired, include an electrical connector for providing electrical connections to various components of the balloon catheter assembly. For example, the electrical connector may be used to receive data regarding diaphragm position, memory, and / or pressure, and to supply power to these sensors, such examples of which are further described below.

[0030] In some examples, at least some of the pulse generator components reside in a mountable unit configured to be positioned or fixed on an operating table near the patient, so that the physician does not need to be physically present to treat the patient. In such cases, the mountable unit is designed to be easily clamped or fixed to the operating table, or to be independently stable on the operating table, and can be operated by a remote control unit. In such examples, the mountable unit may include a communicator that provides communication between the unit and a distal control unit, the communicator may be implemented by any desired hardware and / or software configuration, and may be configured to communicate using wired or wireless (e.g., Bluetooth® or radio frequency) protocols. The pulse generator used in the system of the present invention may be configured to be reusable or single-use, as desired. The pulse generator used in the system of the present invention may be configured to accept a sterile sleeve so that the generator can be used without contaminating the sterile field of the operating room. Further details relating to pulse generators and components thereof that may be used in embodiments of the present invention, such as potential sources, oscillators, regulators, etc., are provided in U.S. Patent Application Publication No. 2020 / 0046949 and pending PCT application serial number PCT / US2020 / 055458, the disclosures of which are incorporated herein by reference.

[0031] Balloon catheter assembly As summarized above, in addition to the pulse generator, the system of the present invention includes a balloon catheter assembly. The balloon catheter assembly is configured to receive a first pulsating energy from the pulse generator and convert the first pulsating energy into a second pulsating energy that can be propagated along the length of the assembly, for example, in a fluid, e.g., a liquid, along its passage to the distal balloon. When the balloon catheter assembly converts the first pulsating energy into the second pulsating energy, it changes the form of the pulsating energy in some way. Examples of changes to the form of energy that can be made by the proximal connector include, but are not limited to, a change in gas pressure and / or flow rate to liquid pressure and / or flow rate, a change in mechanical potential and / or kinetic energy to fluid pressure and / or flow rate, a change in optical potential and / or kinetic energy to fluid pressure and / or flow rate, a change in electric field potential and / or kinetic energy to fluid pressure and / or flow rate, and a change in magnetic potential and / or kinetic energy to fluid pressure and / or flow rate. For example, if the first pulsating energy is a first pneumatic pulsating energy, the balloon catheter assembly may be configured to convert the first pneumatic pulsating energy into a second hydraulic pulsating energy that can propagate from the proximal end of the balloon catheter assembly to the distal end, which is an example of gas-to-liquid conversion of pulsating energy. In some examples, the balloon catheter assembly propagates the second pulsating energy from the proximal end to the distal end with a weak attenuation, where attenuation exists, but the magnitude of the attenuation does not exceed a 30% reduction, and in some examples, with a weak attenuation of not more than 5%, as described above.

[0032] In some examples, a balloon catheter assembly comprises (i) a proximal connector configured to operably connect the balloon catheter assembly to a pulse generator and to convert a first pulse energy generated by the pulse generator into a second pulse energy; (ii) a distal balloon; and (iii) a catheter component including a fluid passage operably positioned between the proximal connector and the distal balloon.

[0033] A proximal connector is a component of an assembly positioned proximal within the assembly, for example, located at or near the proximal end, for example, within 1 cm of the proximal end or closer, and the proximal connector is configured to operably connect the assembly to a pulse generator, for example, as described above, and to convert a first pulsating energy into a second pulsating energy. A given type of connector may be a press-fit connector, latch connector, screw connector, threaded connector, magnetic connector, push-to-connect connector, yol-lock connector, claw-clamp connector, gasket connector, socket connector, flange connector, cam-and-groove socket, quick connector, etc., and may optionally use an aligner or stopper to provide a connection that repeatedly and precisely positions the proximal connector in relation to the pressure generator and / or electrical connector.

[0034] As discussed above, in some examples, the conversion is an energy conversion from fluid to fluid, for example, the first pulsating energy is pneumatic pulsating energy and the second pulsating energy is hydraulic pulsating energy. In such examples, the proximal connector may include a proximal chamber separated by a membrane and a distal chamber, for example, the membrane sealing the distal chamber from the proximal chamber. The proximal chamber may be configured to receive pneumatic pulsating energy from a pulse generator. The volume of the proximal chamber may vary in some examples from 0.1 mL to 100 mL, for example from 1 mL to 4 mL, and in some examples, the proximal chamber is occupied by gas. In a particular example, the proximal chamber forms a minimum volume chamber while being large enough to accommodate the volume change required to inflate the balloon. In this case, the time required to inflate this minimum volume chamber to a specific pressure can be minimized, increasing the frequency of procedures. The distal chamber is fluidically coupled to the fluid passageway of the catheter component. The volume of the distal chamber can vary in some cases from 0.1 mL to 100 mL, for example from 1 mL to 4 mL, and in some cases the distal chamber is occupied by a liquid.

[0035] The membrane separating the proximal and distal chambers is configured to move in response to a first pulsating energy, thereby generating a second pulsating energy within the distal chamber of the connector. The dimensions of the membrane may vary; in some examples, the membrane has an area of ​​100 mm². 2 ~5000mm 2 For example, 500mm 2 ~2000mm 2The membrane can be manufactured from any suitable elastic (e.g., flexible) material, in some examples the material has a hardness in the Shore 10A to Shore 90A range, e.g., Shore 50A, and a thickness of 0.5mm to 5mm, e.g., 1.0mm to 2.5mm. Suitable membrane materials include, but are not limited to, silicone and rubber, and may be reinforced by adding reinforcing components such as braids. A biasing component such as a spring may be provided as desired to provide a default or baseline membrane position. For example, a spring may be provided on the distal chamber side of the membrane to encourage the membrane to return to its initial position when the force is removed from the proximal chamber side of the membrane. In other examples the system may be controlled so that a pulse generator provides a constant pressure (but a low pressure such as 0.1 to 2 atm) to the proximal chamber to counteract the priming pressure. This reaction force allows the diaphragm to be set in the appropriate position to start treatment and measurement.

[0036] The configuration of the proximal connector in such embodiments can be modified, but in some examples, the proximal chamber is defined by a proximal flange, the distal chamber is defined by a distal flange, the proximal and distal flanges are positioned on either side of a membrane to define the proximal and distal chambers, and the proximal and distal chambers can be sealed (e.g., sealed) to each other by a separation membrane. In such examples, the proximal flange may include a proximal port perpendicular to the proximal flange (e.g., axially) configured to receive a first pulse energy generated by a pulse generator, e.g., pneumatic pulsation energy. The dimensions of the proximal port can vary as desired, but in some examples, the port has an outer diameter in the range of 1 mm to 30 mm, e.g., 3 mm to 8 mm, and an inner diameter in the range of 1 mm to 30 mm, e.g., 2 mm to 7 mm. In some examples where the proximal flange has the proximal port, the port may have a length in the range of 1 mm to 50 mm, e.g., 3 mm to 10 mm. In such examples, the distal flange may include a distal port that fluidly connects the distal chamber to the catheter's fluid passage. The dimensions of the distal port may vary as desired, but in some examples, the port has a lumen diameter ranging from 0.1 mm to 10 mm, for example, from 1 mm to 3 mm.

[0037] In examples where the proximal chamber includes a proximal port, the proximal port is fluidically coupled to the port. In such examples, the junction between the proximal port and the proximal chamber may include a nozzle and / or diffuser, which in some cases may be geometrically formed by a proximal flange. In such cases, the nozzle or diffuser may act to increase or decrease the flow velocity at the expense of fluid pressure. Such an increase or decrease in flow velocity may improve the characteristics of the energy conversion, such as the ramp-up time or smoothness of the energy conversion. In the case of airflow, the velocity of the gas may be high enough to induce compressible fluid phenomena, such as those occurring in sonic or supersonic flows. In such cases, the flow velocity can be optimized using special flow nozzles, such as convergent-divergent nozzles.

[0038] Optionally, the proximal connector may include one or more sensors configured to provide data relating to one or more components of the connector and / or balloon catheter assembly. Any convenient type of sensor may be included in the proximal connector, where the sensor of interest includes, but is not limited to, pressure sensors, position sensors, displacement sensors, proximity sensors, flow sensors, temperature sensors, etc. In some examples, the proximal connector includes a pressure sensor operably coupled to the distal chamber. In such cases, the pressure sensor may detect the pressure in the fluid within the distal chamber and its changes. When a pressure sensor is included, any convenient type of pressure sensor may exist, and examples of possible pressure sensors include, but are not limited to, resistive, capacitive, piezoelectric, optical, and MEMS-based pressure sensors. In some cases, these pressure sensors may measure the pressure at the proximal connector, and in other cases, the pressure may be read in or along the balloon. To measure such pressure in the balloon, for example, an optical fiber-based sensor may be used. In some examples, the proximal connector includes a membrane position sensor configured to provide spatial data regarding the membrane's position over a given period of time, for example, during system use. Where a membrane position sensor is present, any convenient membrane position sensor may be used. In some examples, the membrane position sensor is a Hall sensor used in conjunction with one or more magnets (e.g., permanent magnets or electromagnets) located at a fixed location relative to the membrane, such as the fixed position of the proximal connector or pulse generator (e.g., a handheld actuator), where the one or more fixed magnets are positioned to modulate the voltage of the Hall sensor as the membrane moves. In other examples, the membrane position sensor may be an optical sensor, a field potential sensor, a resistance sensor, a magnetic sensor, an angle sensor, or an acceleration sensor. Furthermore, any combination of these sensors may be used to collect position data of the membrane or diaphragm. When a combination of membrane position sensors is used, for example, to ensure that the sensors provide accurate data over various frequencies, the sensor data may be combined via a "sensor fusion" technique, as known in the art.Membrane position sensors, if present, may be used for a variety of different purposes, such as evaluating the extensibility and therapeutic properties of blood vessels (as described below), evaluating the proper filling of balloon catheter assemblies, and determining whether a membrane has been stretched beyond a desired threshold. Methods for manufacturing membrane sensors may include, but are not limited to, adhesives, direct printing, welding, and embedding.

[0039] Optionally, the proximal connector may further include an electrical assembly. The electrical assembly may be configured to perform several functions, including, but not limited to, powering one or more sensors, controlling one or more sensors, storing data acquired from one or more sensors, transmitting sensor data from one or more sensors to another location, storing information about the balloon catheter assembly, writing and / or reading data. The electrical assembly may be modified and, in some examples, may include circuits and / or memory. The memory may store various different types of information, if present, including, but not limited to, information about the balloon catheter assembly and / or its components, such as information about the distal balloon, such as expiration date, batch number, balloon size (e.g., balloon diameter and length), balloon rated burst and nominal pressure, cycle limits (e.g., the number of allowable cycles for which the balloon is rated), and cycles used, allowable pulse frequency or duration, previous use, balloon reference pressure-volume curve, and / or instructions for use. The electrical assembly may further include, if present, a connector for operably connecting the electrical assembly to a pulse generator. The electrical assembly may exist in any convenient configuration, such as a printed circuit board including a flexible printed circuit board. In some cases, the sensor may transmit data wirelessly, such as via Bluetooth® RF.

[0040] Various components of the proximal connector may reside within a housing or overmolding, as described above, and may be configured to protect the proximal connector components, for example, during accidental drops or during packaging. The housing, if present, may be manufactured from a suitable rigid material, such as a polymer material, and may be transparent or opaque as desired.

[0041] As summarized above, a balloon catheter assembly may include a catheter component positioned between the proximal connector and the distal balloon. The catheter component is configured to propagate or transmit a second pulsating energy from the proximal connector to the distal balloon with minimal attenuation, if any, as described above. The catheter component includes a portion, e.g., a shaft, configured to be used as a catheter so that it can be introduced into the lumen of a human or another animal, e.g., a mammal. The dimensions of this portion may vary, but in some examples, this catheter portion has an outer diameter (OD) in the range of 1.50 mm to 2.50 mm, e.g., 1.75 mm to 2.20 mm.

[0042] While the structure of catheter components can vary, in some examples, the catheter component includes a proximal flexible tube, a distal catheter shaft (e.g., the catheter portion as described above), and a connector that connects the distal end of the proximal flexible tube to the proximal end of the distal catheter shaft. The proximal flexible tube is made of a flexible material, such as braided or unbraided polyvinyl chloride (PVC), silicone, or polycarbonate (PC), and the dimensions of the tube can vary. In some examples, the flexible tube has a lumen with a diameter ranging from 0.1 mm to 10 mm (e.g., 1 mm to 3 mm) and a wall thickness ranging from 0.1 mm to 5 mm (e.g., 0.5 mm to 2 mm). The length of the proximal flexible tube can also vary in some examples, ranging from 1 cm to 100 cm, for example, from 5 cm to 20 cm.

[0043] The distal catheter shaft may also vary. The distal catheter shaft may be manufactured from any suitable physiologically acceptable material, including but not limited to polyimide or polyimide-type materials such as polyimide braid. In some cases, the distal catheter shaft may have a length ranging from 10 cm to 1 m, for example, from 100 cm to 300 cm. The outer diameter of the distal catheter shaft may also vary in some examples, ranging from 1.50 to 2.50 mm, for example, from 1.75 mm to 2.20 mm. The distal catheter shaft may include a first fluid passage lumen, the dimensions of which may vary. In some examples, the diameter of this first fluid passage lumen may range from 1.3 to 2.2 mm, for example, from 1.6 to 2.1 mm. The first fluid passage may include one or more openings at the distal end to establish fluid communication between the inside of the fluid passage lumen and the inside of the distal balloon. One or more openings, when present, are configured to substantially not attenuate the second pulsating energy as it enters the balloon from the fluid passage, and in some examples, not attenuate the second pulsating energy at all. In some examples, these openings may be configured to be nozzles and / or diffusers. In some examples, the nozzles or diffusers may act to increase or decrease the flow velocity at the expense of fluid pressure. With such an increase or decrease in flow velocity, the balloon inflation characteristics, e.g., ramp-up time, impact, force, etc., may be altered. The distal catheter shaft may include a second guidewire lumen. If a second guidewire lumen is present, the dimensions of this second guidewire lumen may vary, and in some examples, the diameter of the guidewire lumen is in the range of 0.25–0.5 mm, e.g., 0.37–0.42 mm. The distal catheter shaft may be configured to traverse the entire length of the balloon or terminate at the proximal connection of the balloon catheter. If the distal catheter shaft spans the entire length of the balloon, a port may be formed in the distal catheter shaft to allow fluid communication between the inside of the catheter shaft and the balloon. Port formation can be performed using a laser process or other special machining process.The pattern or distribution of ports within the catheter shaft can be configured to ensure that the distal catheter shaft has the necessary rigidity to push through a narrow, calcified lesion, and also has the flexibility to traverse long, meandering lesions to prevent twisting. The holes formed in the ports may be 0.05–1 mm, for example, 0.2 mm. The holes may be patterned in a helical or linear pattern, or according to the internal braiding of the material. The number of holes may be 100–500, for example, 200. The total area of ​​the holes should exceed the cross-sectional area of ​​the flow path lumen. By forming ports along the entire length of the distal catheter shaft, the entire balloon surface receives an equal amount of pulsating energy during treatment. This configuration ensures that if one part of the balloon is deflated, that part and the other parts of the balloon receive an equal amount of energy. The disadvantage of this configuration is that the cross-sectional profile (i.e., the total diameter of the distal catheter shaft) is larger, making it more difficult to pass through narrow lesions. To narrow the distal catheter shaft, the distal catheter shaft may terminate at the proximal balloon connection. In this case, only the guidewire lumen traverses the length of the balloon. In this configuration, the balloon may have a proximal neck diameter matching the distal catheter shaft and a distal neck diameter matching the guidewire lumen. Since the guidewire lumen has a smaller diameter than the distal catheter shaft, the cross-profile of this configuration may be improved compared, for example, to the configuration described earlier. However, there is only one port for transferring fluid from the distal catheter shaft to the balloon, which can lead to uneven energy distribution to the balloon wall and calcified lesions. These two configurations can be used in different examples, such as different displays and anatomical locations.

[0044] The catheter components of these embodiments also include a connector that connects the distal end of the proximal flexible tube to the proximal end of the distal catheter shaft. The connector may vary as desired. In some cases, the connector includes a first branch configured to provide guidewire access to the guidewire channel of the catheter shaft, and a second branch configured to fluidly connect the lumen of the proximal flexible tube and the distal catheter shaft. A suitable example of a connector is a Y-connector.

[0045] As discussed above, the balloon catheter assembly further includes a distal balloon. Any suitable balloon can be used. Suitable balloons include, but are not limited to, standard angioplasty balloons such as distensible and non-distensible angioplasty balloons. In one embodiment, the balloon is a composite balloon comprising two distinct layers, a non-distensible layer and a distensible layer. To illustrate the improvement of this composite balloon structure over the prior art, the two layers of the composite balloon as individual units are described. Non-distensible angioplasty balloons are typically used in percutaneous procedures because the set diameter of the balloon evenly distributes force to the surrounding blood vessels without bulging into the less rigid, healthy tissue surrounding the stenosis. When the non-distensible balloon material is pressurized, the balloon is initially filled, resulting in a low-pressure, high-stretch state. When the non-distensible balloon reaches its nominal diameter, the balloon pressure increases correspondingly significantly for lower stretch. When the pressure is released within the balloon, the balloon remains at its nominal stretch due to the lack of elasticity of the balloon. This lack of elasticity is problematic for three reasons: (1) unless a vacuum is created, a depressurized balloon remains filled and can obstruct blood flow; (2) after treatment, it can be difficult to remove the balloon catheter through the sheath; and (3) during pulsation therapy, the balloon does not push fluid during the low-pressure phase, preventing the necessary stress relief in the surrounding tissue. Therefore, non-stretchable balloons are useful at high pressures but are limited at lower pressures. Extensible angioplasty balloons typically have a linear pressure-stretch curve. The use of these balloons is limited in percutaneous procedures because the balloon stretches unevenly around the hardened segment of the artery, thereby potentially causing damage to the healthy, soft tissue surrounding the hardened affected tissue. In extensible balloons, the balloon pressure typically increases linearly. Compared to non-stretchable balloons, extensible balloons have a "short" initial filling region, and therefore, when the pressure inside the balloon is released, the balloon returns to its initial stretched state without requiring additional vacuum.This return to the initial state is beneficial to the procedure because blood flow is immediately restored upon returning to the initial stretched state, and the balloon can be more easily retracted through the sheath. Furthermore, during pulsating angioplasty, the balloon's extensibility acts as a propulsive force to push fluid out of the balloon, and this propulsion is necessary to allow the surrounding tissue to relax with low stress during the low-pressure phase. Therefore, extensible balloons are useful at lower pressures, but their therapeutic capacity at high pressures is limited. Non-stretchable and stretchable angioplasty balloons are not optimal on their own for the various stages of pulsating and standard percutaneous transluminal angioplasty. However, using non-stretchable and stretchable angioplasty balloons together as a combination can meet the important needs of both treatments. In one embodiment of a composite balloon for composite angioplasty, the non-stretchable balloon is covered with an extensible sleeve to achieve pressurized stretching “indicated by arrows,” as further described, for example, in the pending PCT application serial number PCT / US2020 / 055458, the disclosure of which is incorporated herein by reference. The extensible layer may be rubber, silicone, polyurethane, or nitinol material, or another material that can be stretched to 100-500% before rupture, can withstand thousands of cycles before rupture, and minimizes plastic deformation even if plastic deformation occurs during expansion. In use, the exemplary composite balloon functions as follows: During the low-pressure phase, the extensible material dominates the response. The composite balloon follows the extensible material curve until the balloon stretch intersects with the stretch of the non-stretchable balloon. At this intersection and at higher pressures, the non-stretchable material dominates the balloon response. Immediately after the pressure is released, the balloon returns along the arrow-indicated response to the initial or zero stretch state. This exemplary composite balloon possesses the low-pressure advantages of a distensible angioplasty balloon and the high-pressure advantages of a non-distensible angioplasty balloon. Other advantages include balloon self-folding and deflation, mitigation of tears and pinholes, increased oscillation frequency during pulsating angioplasty, and improved balloon indentation while traversing the lesion.Further details relating to the composite angioplasty balloon used in embodiments of the present invention can be found in the pending PCT application serial number PCT / US2020 / 055458, the disclosures of which are incorporated herein by reference.

[0046] In other examples, the balloon may have external features that cause pulsating stress concentrations in the surrounding material. These features may be incorporated into the general balloon shape (i.e., the balloon takes on its original shape when pressurized) or through additional components surrounding the balloon (e.g., strips or cages). In certain examples, the additional components traverse the length of the balloon (i.e., from the proximal end to the distal end of the balloon). In this case, the stress concentration in the surrounding material occurs in such a way that radial cracks develop within the calcium structure. In other examples, the additional components traverse the balloon circumferentially so that longitudinal cracks develop within the calcium structure as the balloon stretches in each pulse. Furthermore, the additional components may be distributed orthogonally so that stress concentrations occur in both the radial and longitudinal directions within the surrounding material. This allows for the development of cracks in both the longitudinal and radial directions to completely pulverize the calcium.

[0047] A balloon catheter assembly may or may not be a "sealed" component. In some examples, the balloon catheter assembly is not sealed so that a fluid, e.g., liquid, may be introduced into the fluid passage of the assembly and / or gas may be removed from the assembly (e.g., via de-bubbling). In yet other examples, the balloon catheter assembly is a sealed or sealed assembly such that the fluid passage and balloon are pre-filled with liquid before use and the liquid is sealed within the assembly. In any example, the liquid introduced into the lumen and balloon of the assembly may vary, and in some examples, the liquid is saline. Optionally, the liquid may contain a suitable contrast agent, examples of which include radioactive contrast agents such as iodine contrast agents and barium contrast agents.

[0048] In some embodiments, the above embodiments may be configured so that the procedure can be performed entirely autonomously and / or remotely. In these cases, the balloon catheter may be inserted into the patient manually or using a robotic catheter placement system (described in published application WO2010 / 025338, the disclosure of which is incorporated herein by reference). Using this system, instruments such as a guidewire and balloon catheter can be advanced to the site of the lesion, and after reaching the lesion, the balloon can be inflated or deflated. In the embodiments described above, the balloon may be pre-filled with fluid so that the user does not need to inflate the balloon before pressurization. In other embodiments, a composite balloon embodiment may be used to ensure that the balloon deflates and rolls up after the procedure so that the balloon can be easily removed. In such embodiments, the operator may be located at a console to control the procedure, including pressure, frequency, and / or duty cycle. At the same time, the operator may be able to view X-ray imaging to visualize the inflated balloon and the effectiveness of the procedure. In some cases, feedback, such as visual, auditory, or tactile feedback, may be provided to the operator to indicate characteristics of the procedure, such as volume and / or pressure changes, frequency, duty cycle, balloon expansion, and balloon position in the balloon.

[0049] Balloon catheter assemblies may be configured for single or one-time use, making them disposable. Before use, balloon catheter assemblies may be sterilized as desired.

[0050] Various aspects of the present invention have been described in general terms above, and elements of the present invention will be further considered in the context of specific embodiments.

[0051] Specific Embodiments Figure 1 schematically shows a system according to an embodiment of the present invention for generating balloon vibrations for radiofrequency angioplasty. In some examples, the system may include a pulse generator having a potential energy source such as a high voltage or pressure source, a switching system for controlling, for example, a high potential source, and a balloon catheter assembly for converting the output of the pulse generator (i.e., first pulsating energy) into hydraulic vibrations of the angioplasty balloon (i.e., second pulsating energy). In the embodiment, the potential energy source acts to drive the balloon angioplasty vibration, the switching system controls the frequency, duty cycle, and / or amplitude of the energy output from the pulse generator, and the proximal connector of the balloon catheter assembly converts the output energy into hydraulic vibrations, thereby generating vibrations within the angioplasty balloon catheter, and a high-flow balloon catheter allows for pressure vibration input to the system and optimization in balloon output. Modifications of this system are provided in each of the following embodiments. The following embodiments are not intended to be an exhaustive list, but are intended to provide examples of various configurations of the overall system.

[0052] In some embodiments schematically shown in Figure 1, the system includes two components: a pulse generator 70 (to the left of the dashed line) which may be configured to be reusable, and a balloon catheter assembly 1 (to the right of the dashed line) which may be configured for single use. The terms “reusable” and “disposable” as used elsewhere in this specification and description are used for convenience in describing embodiments of the invention shown in Figure 1. However, the invention is not limited thereto. Thus, any part of the device may be configured for single use or for multiple use, as desired. In the embodiment shown in Figure 1, the pulse generator 70 includes a potential source 870, a potential regulator 880, and a controller 72. The pulse generator also includes a switch or oscillator (such as a solenoid) 14 which may be located in a handheld component or actuator of the pulse generator, as desired. Also shown is a balloon catheter assembly 1 which includes a membrane 30, a pressure and / or flow transducer 31, an electrical connector 13, a high-flow catheter 16, and a proximal connector 400 including a balloon 2. The input to the pulse generator 70 may include feedback from a sensor such as a pressure or flow transducer 31, or feedback from a user input such as a button or switch. The output from the pulse generator 70 may include power, logic, and / or regulated potential energy 880 or unregulated potential energy 870, such as obtained from a high-pressure fluid or voltage in the form of a first pulsating energy, and is transmitted to the balloon catheter assembly 1. The balloon catheter assembly 1 converts the first pulsating energy output into hydraulic vibrations in the fluid communication path 35, and the hydraulic vibrations are output to the high-flow catheter 16 and balloon 2.

[0053] Figure 2 provides a diagram of a balloon catheter assembly 200 according to one embodiment of the present invention, which may be used in a system as schematically shown in Figure 1. The balloon catheter assembly 200 includes a proximal connector 210 having a proximal port 212 for operably connecting to the pneumatic output of a pulse generator (not shown), a proximal flexible tube 220 coupled to the distal port 214 of the proximal connector, a distal catheter shaft 240 having an angioplasty balloon such as a composite balloon 250 positioned at the distal end of the distal catheter shaft 240, and a Y connector 230 connecting the distal end of the proximal flexible tube 220 to the proximal end of the distal catheter shaft 240. Also shown is an optional valve 260 positioned between the distal end of the proximal flexible tube 220 and the Y connector 230. The proximal flexible tube 220, if present, acts as a tension-relieving element between the proximal connector 210 and the Y connector 230, the distal catheter shaft 240, and the angioplasty balloon 250. Valve 260, if present, may be used to introduce fluid into the fluid passage of the balloon catheter assembly. In some examples, valve 260 is absent. For example, as described above, the balloon catheter assembly may be a sealed or occluded system provided to the user, pre-filled with, for example, a suitable contrast agent containing fluid. In such examples, since fluid priming is not required to use the assembly in the system of the present invention, valve 260 may not be provided. In other examples, valve 260 is a tee connector having a one-way valve protruding from one of the tee connectors. This one-way valve allows for easy priming, in contrast to a three-way valve. In other tee connectors, the connection of tube 220 and y-connector 230 is made using a rotary luer to allow for easy positioning of the catheter and valve relative to the handle.

[0054] Figures 3A to 3D provide different diagrams of the proximal connector of a balloon catheter assembly according to embodiments of the present invention. Figure 3A provides a cutaway side view of the proximal connector 300. The proximal connector 300 includes a proximal flange 310 separated by a membrane 330 and a distal flange 350. The proximal flange 310 defines the proximal chamber 315, accessed by the proximal port 320. The distal flange 350 defines the distal chamber 355, accessed by the distal port 360. A pressure transducer 325 is operably coupled to the distal port 360 and the distal chamber 355. The proximal and distal flanges 310 and 350 are held together by screws, as indicated by the screws 370. Alternatively, the flanges can be fixed by any other suitable assembly method such as adhesive, welding, or other means. In other examples, the flanges can be manufactured as a single component by a multi-stage injection molding or overmolding process around the flexible membrane and electronics. Also shown are a Hall sensor 335, a permanent magnet 448 (which may be located within a handheld actuator 400), an electrical connector 390, and a flexible printed circuit board 397. The threaded portion 398 at the distal end of the distal port serves as the interface between the proximal flexible tube and the distal flange. Figure 3B provides an end view of the proximal flange 310 of the proximal connector 300. As seen in Figure 3B, the thread 370 is circumferentially positioned around the flange to provide a connection to the distal flange (not shown). Also shown are the proximal port 320 and the electrical connector 390, which provide an operable electrical connection to a pulse generator (not shown). Figure 3C shows an outer side view of the proximal connector 300, showing the proximal and distal flanges 310, 350 joined together by the thread 370. Also shown is a memory 395, which is electrically coupled to a flexible printed circuit board 397, which is electrically coupled to the electrical connector 390. Similarly, the pressure sensor 325 is electrically coupled to the flexible printed circuit board 397. Figure 3D shows a perspective view of the proximal connector 300.Figure 3E provides a diagram of a proximal connector 300 with an overmolded 380 made from a rigid, opaque material that helps protect various components of the proximal connector, such as circuits and sensors. The proximal connector can be connected to a common handheld actuator, while having different diameters and widths to accommodate different balloon types. For example, in the case of peripheral or coronary balloons, the proximal connector may have dimensions to accommodate volume changes of 1 to 20 ml. For larger balloons, such as valve repair balloons, the proximal connector can be enlarged to accommodate volume changes of up to 50 to 100 ml.

[0055] The flexible printed circuit board 397 connects various sensors on the assembly to the proximal flange, enabling connection to the handle regardless of the size of the proximal connector, and is further illustrated in Figures 3F to 3H, which provide front, rear, and isometric views of the flexible printed circuit board 397. This embodiment allows the size of the proximal connector to be changed (for example, as described above) without completely redesigning the electronic equipment, simply by increasing the length of the flexible PCB. Prox This is the length required between the electrical connector 390 and the bend in the diaphragm for the Hall sensor 335. Distal This is the length from the electrical connector 390 to the pressure transducer 325. These two lengths can be adjusted to accommodate changes in the size of the proximal connector. The memory 395 is also shown.

[0056] Figures 4A to 4C provide different diagrams of a handheld component, sometimes called an actuator, of a pulse generator according to an embodiment of the present invention. Figure 4A provides a side view of a handheld actuator 400, which is configured to be held in an adult's hand and includes a gripping area 410, a distal connector 420, a proximal tension-relaxing area 405, a pulse generator connector 406, and an actuator button 430. The gripping area 410 may be configured to be easily grasped by adjusting its shape to fit the human hand, for example, by using a soft plastic (e.g., rubber, silicone, thermoplastic elastomer (TPE)) overmolding.

[0057] Figure 4B provides an end view of the connector 420 of the actuator 400. As seen in Figure 4B, the connector 420 includes an electrical connector 430 and a pneumatic connector 440 for establishing a connection with the proximal port of a proximal connector (not shown). The connector 420 also includes a retaining clip to ensure a proper, reliable, and repeatable connection of the proximal connector. A release plate 445 with a release button 446 may be used to release the proximal port of the proximal connector 300 from the pneumatic connector 440.

[0058] Figure 4C provides a cutaway view of the actuator 400. Within the actuator 400, an electromagnetic 3 / 2-way solenoid 470 may be used. The solenoid 470 includes a pressure inlet port 471, an outlet port 472, an electromagnetic coil 473, a valve poppet, a spring assembly 474, and an exhaust port 475. The actuator may have additional space for an electronic passage or printed circuit board 485 and a pneumatic passage 486. Furthermore, in some examples, a permanent magnet 448 may be located within the connector 420 of the actuator 400 to induce voltage and / or current in a Hall effect sensor, and the Hall effect sensor is mounted on a film of the proximal connector (not shown). This electromagnet may also be located in the proximal connector. The 3 / 2-way solenoid 470 operates in two states: on and off. While in the ON state, the valve poppet and spring assembly 474 is actuated by energizing the electromagnetic coil 473, allowing the high-pressure flow from the inlet 471 to proceed to the outlet 472 and proximal connector (not shown) to pressurize the balloon. In the OFF state, the electromagnetic coil 473 is de-energized, and the valve poppet and spring assembly 474 is closed, allowing the pressurized fluid from the proximal connector (not shown) to be discharged through the inlet 472 to the exhaust port 475. To reduce noise, a noise suppressor (not shown) may be used at the exhaust port 475. Various electrical connectors may be used to transport signals and power to and from the pulse generator console (not shown) and to transport electrical contacts 430, actuator button 430, and electromagnetic coil 486, and may be located in area 485. Pneumatic connections may be transported and connected within the pneumatic connector area 486. Figure 4D provides a top view of the actuator button 430. The actuator button 430 may be a membrane-type switch or any similar type of button configuration, as known in the art. The switch may be impermeable to liquids or cleaning fluids. In some examples, the actuator button 430 may include an on / off switch 490, an on / off LED configuration 491, a control manipulator button 492, and a control manipulator LED 493.

[0059] Figures 4E and 4F respectively provide an exploded view and an assembled view of the actuator 400 coupled to the proximal connector 300 via the connector 420. The electrical connector 430 can be spring retained to account for any tolerances or movement that occur during repeated connection and disconnection of the proximal connector.

[0060] Model The mathematical model of the vibration system will be described below. This model has several purposes, including the purpose of controlling the system in real time (e.g., for a state space controller). The mathematical model describes the system of FIG. 1 in which a high potential source is converted into fluid pressure oscillations within the catheter and within the balloon. The input oscillation can be modeled as an instantaneous step input of pressure, P input The oscillations flow along the catheter of radius 2r and length l to the angioplasty balloon. The fluid responds rapidly to the step input, but as the balloon is pressurized, the fluid pressure gradient decays to balance the input step pressure. The volume-pressure relationship of the balloon determines the corresponding pressure generated within the balloon for a given volume and balloon stretch. After the step input, the pressure gradient is treated as quasi-static for small time steps and independent of time. The flow through the lumen of the catheter is modeled using the Navier-Stokes equations for pipe flow.

[0061]

Number

[0062] The system parameters are specified in Table 1.

[0063] The tube is assumed to have rigidity and result in one-way flow (v r = v θ = 0). The contrast agent mixture is modeled as an incompressible fluid, resulting in the following.

[0064]

Number

[0065] The effect of gravity is ignored. The pressure gradient is treated as quasi-static for small time steps, i.e., as follows:

[0066]

number

[0067] Applying these assumptions, equation (1) is transformed into the following equation:

[0068]

number

[0069] [Table 1]

[0070] The dimensionless parameters include the dimensionless radial position ξ described below.

[0071]

number

[0072] In the formula, r is the radius of the tube, and v is the velocity in the z direction. z It can be expressed by the following equation:

[0073]

number

[0074] During the ceremony,

[0075]

number

[0076] θ is the pressure gradient along the tube, φ(ξ) is the dimensionless velocity along the radius of the tube, and τ is the dimensionless time.

[0077]

number

[0078] Therefore, equation (2) becomes as follows:

[0079]

number

[0080] Assume the following equation. φ = 1 - ξ 2 -Ψ (6)

[0081] Therefore, the non-slip boundary condition is Ψ = 1 - ξ at τ = 0. 2 This is the result. Solving (3) by separating the variables gives the following equation.

[0082]

number

[0083] Here, J0 is the 0th and 1st type Bessel function, and α n θ is zero. When the fluid is initially at rest (φ=0 at τ=1), the following equation is given.

[0084]

number

[0085] Next, the speed profile is defined.

[0086]

number

[0087] Volumetric flow rate is expressed by the following equation:

[0088]

number

[0089] Instead, the fluid is at an average velocity

[0090]

number

[0091] If there is a fully developed velocity having τ=0, then the initial condition is that

[0092]

number

[0093] It will be corrected as, or

[0094]

number

[0095] Therefore, the following equation is given.

[0096]

number

[0097] In the case of a coaxial catheter shaft, the volumetric flow rate is corrected using a scaling factor to account for additional frictional losses at the inner wall, where k=R i It is / R (Papanastasiu, 1999).

[0098]

number

[0099] System parameters are identified for use in real-time control or treatment planning with this model. These system parameters include step input characteristics, balloon dimensions, catheter structure and dimensions, and balloon pressure-volume relationship.

[0100] Step input characteristics are system-dependent and can be measured (e.g., during the manufacturing process) and incorporated into the system. Similarly, using various sensor measurements incorporated into the system, in certain embodiments, the system can measure the step input response generated by a pressure generator.

[0101] In certain embodiments, the dimensions of the balloon and the structure and dimensions of the catheter can be preloaded into the balloon catheter memory. These dimensions include the length, diameter, and shape of the balloon. The catheter structure and dimensions include the shape of the cross-section of the catheter lumen (e.g., coaxial, co-extruded, etc.), and details such as the length of the catheter, outer diameter, inner diameter, and the ratio of the flow path area to the guidewire channel area. In certain embodiments, the pressure-volume relationship of the balloon can be measured and preloaded into the balloon catheter memory. An example of the pressure-volume relationship of an unconstrained balloon with a diameter of 4 mm and a length of 20 mm is shown in Figure 5.

[0102] Using these measured system characteristics and the model derived above, the system can be controlled in real time (e.g., using negative feedback control and / or feedforward control) to ensure that the pressure amplitude, duty cycle, and frequency are appropriately set during treatment. Two examples of experimentally measured pressure in a balloon and force output from the balloon are shown in Figure 6. This model accurately predicts the experimental measurements, as derived above. Using such a predictive model and feedback from system measurements, treatment characteristics (frequency, pressure input, and duty cycle) can be adjusted to maximize the therapeutic effect.

[0103] The pressure-volume relationship in Figure 5 and the “unrestrained balloon” in Figure 6 represent the relationship between the pressure and volume of the balloon when the balloon is not restrained by external constraints (e.g., rigid stenosis embedded in the blood vessel wall). When the balloon is restrained by healthy tissue, this pressure-volume relationship is different. In certain cases where the balloon is restrained, the curve has a steeper slope (i.e., for smaller volumes of fluid, the pressure increases at a higher rate). Thus, the pressure-volume curve is case-dependent and may be steeper in more severely affected tissue. Because this curve is case-dependent, the pressure-volume curve must be generated case-by-case, within the patient (i.e., in-situ), during treatment. In the described embodiment of the system, both the pressure and volume within the system can be measured in-situ using various inputs to the system. For example, at the start of a procedure, according to the above embodiment, the pressure in the balloon may be increased to a known value while the volume within the balloon is measured (e.g., using the described position sensor) to generate an in-situ pressure-volume curve (cycle 1 in Figure 7). In certain cases, this treatment-based pressure-volume curve may, in some cases, be compared to an unconstrained pressure-volume curve, which is an indicator of treatment success, or a curve measured during treatment progression (cycle 1000 or cycle 10000 in Figure 7). Comparing pressure-volume curves in this way can be used to provide repeatable measures of outcomes, such as treatment success, insufficient balloon diameter, or insufficient balloon expansion, even during pulsating balloon angioplasty. In other cases, if treatment is unsuccessful at a certain pressure level over the course of treatment (i.e., the balloon volume remains substantially the same, indicating insufficient balloon expansion and non-extensible / untreated vessels), the system may gradually increase the pressure within a safe range until the balloon volume increases. Alternatively, the system may provide feedback (auditory, visual, tactile, etc.) to the operator to indicate that the pulse pressure amplitude is not high enough. In other cases, the system is configured to detect insufficient expansion in a single plane, one example of which is shown in Figure 7B (panels A-D). Figure 7B (Panels A-B) shows fluoroscopic images of localized lesions that restrict blood flow.A standard balloon angioplasty (BA) is performed to treat a lesion by inserting a balloon across the lesion and increasing the pressure inside the balloon. In one fluoroscopic plane, after increasing the pressure, the balloon expands as shown in Figure 7B (Panel C). However, as seen in a normal fluoroscopic image plane (Figure 7B (Panel D)), the balloon remains under-expanded, which can be overlooked by the physician. In the embodiment described above, the system can measure when the balloon is under-expanded without requiring multiple projection fluoroscopic images. The advantages of this are reduced procedure time, radiation exposure to the physician and patient, and reduced injection of contrast agent.

[0104] Measurement of vascular extensibility As will be explained in detail below, vascular distensibility is a measurable characteristic of a vessel, calculated based on the ratio of the change in vascular volume to a given change in pressure. Vascular distensibility is an important feature to observe because improving it is a prerequisite for the definitive treatment of certain fundamental vascular disease conditions, such as atherosclerosis. Changes in vascular distensibility are seen in the different pressure-volume curves shown in Figure 7A, described above. In Figure 7A, the pressure-volume characteristics of the treated vessel, i.e., the vascular distensibility characteristics, change as a result of treatment from cycle 1 to cycle 1000 to cycle 10000. It should be noted that the values ​​shown in Figure 7A are illustrative and do not necessarily represent an actual treatment plan that may be implemented. For a given treatment plan, the actual values ​​may differ from those shown in Figure 7A, for example, being larger or smaller, depending on several different factors of the given treatment plan, including but not limited to the type of lesion, balloon, and specific parameters.

[0105] The system according to the present invention can be configured to assess vascular distensibility by obtaining in vivo measurements of volume changes at different pressures (or changes in pressure) applied to the blood vessel. Figure 7C provides an example of measurements of changes in vascular distensibility obtained during treatment using the system according to the present invention. As will be described in detail below, embodiments of the present invention enable the measurement of relative changes in luminal tissue (i.e., blood vessels) in real time during the application of the system according to the present invention to provide pulsating intravascular lithotripsy treatment. The system according to the present invention may be configured to measure and update treatment parameters based on changes in vascular distensibility. For example, after calcium cracking (i.e., destruction of CP tissue), the luminal tissue (i.e., blood vessels) and balloon may show significant dilation, contributing to a large gain in distensibility, as measured by the system. However, after the blood vessel has fully dilated, the changes in distensibility measured by the system may subside. Identification of such a condition may indicate that treatment can be stopped because not much further luminal gain has occurred.

[0106] The system can be configured to measure pressure in any convenient manner. In some examples, embodiments of the system according to the present invention may include a pressure gauge, as described herein, for measuring the pressure in the fluid passage and distal balloon of a balloon catheter assembly, for example, including a balloon catheter assembly according to the present invention. In some examples, the pressure gauge may be configured to measure the pressure in the distal chamber of the proximal connector, for example, as seen in the pressure transducer 325 of Figure 3A. In other examples, the pressure in the balloon may be measured using a pressure sensor, for example, an optical fiber or a piezoelectric resistance sensor.

[0107] The system may be configured to measure changes in the volume of a blood vessel in any convenient manner. In some examples, embodiments of the system according to the present invention may be configured such that a change in the position of a membrane separating the proximal and distal chambers of a proximal connector reflects a change in the volume of the distal balloon. The change in the volume of the distal balloon reflects a change in the cross-sectional area of ​​the blood vessel and therefore reflects a change in the volume of the blood vessel. Such embodiments may further include a Hall sensor and one or more permanent magnets for measuring changes in the position of such a membrane. The Hall sensor refers to a sensor configured to sense the presence or change of a magnetic field, i.e., by the use of the Hall effect. The permanent magnet may be composed of any convenient magnetic material or electromagnet, as desired, such that a change in the relative position of the Hall sensor with respect to the permanent magnet is detected by the Hall sensor. Using sensors such as the Hall sensor and permanent magnets described above, changes in the volume of the distal balloon, as well as the rate at which the distal balloon inflates, i.e., the rate of change in blood vessel volume, can be measured.

[0108] Figure 8 shows a system according to an embodiment of the present invention shown in Figure 1, further configured to evaluate vascular distensibility according to an embodiment of the present invention. Elements of the system shown in Figure 8, which are identical to the elements shown in Figure 1, have been described above in relation to Figure 1. The Hall sensor 805 is positioned on the membrane 30 such that a change in the position of the membrane 30 relative to a permanent magnet 810 positioned on the proximal connector 400 causes a change in the output of the Hall sensor 805. Such a change in the output of the Hall sensor 805 indicates a change in the volume of the distal balloon 2. As described in relation to Figure 1, a pressure or flow transducer 31 is configured to measure the pressure applied to the catheter 16 and balloon 2. Measurements of volume change based on the Hall sensor 805 and the permanent magnet 810, and pressure change based on the pressure gauge 31, are used to measure vascular distensibility in vivo. Such measurements of vascular distensibility can be performed during treatment. Such measurements are used to create a pressure-volume curve 815 that shows the pressure-volume relationship during the treatment phase. The pressure-volume curve 815 can be generated at different stages of treatment and can be used to evaluate the effectiveness of treatment, compare treatments across different settings, or modify or otherwise adjust treatment to optimize its effectiveness. In embodiments, the pressure-volume curve 815 may be similar to, for example, the pressure-volume curve described in Figure 7A described above or in Figure 16 described below. The data used from these pressure-volume curves can be collected and batched and ultimately used to predict (i) the success or failure of treatment, (ii) the need to adjust or attenuate the energy used in future treatment of a population or similar vessels, (iii) complex conditions such as circumferential calcium versus 270-degree or eccentric calcium, or (iv) the location of regions within relatively fixed arterial biostructures or regions undergoing significant torsion or bending.An exemplary embodiment for measuring vascular distensibility according to the present invention is shown in Figure 8 in the context of the system described in relation to Figure 1. However, it should be understood that the techniques for measuring vascular distensibility according to the present invention are not limited thereto and may be applied to other balloon-based systems, such as the system shown in Figure 820, including, for example, laser-based techniques, ultrasound-based techniques, cavitation-based techniques, pulsating balloon-based techniques such as those described herein, or plain balloon angiogenesis-based techniques. It should also be understood that data collected when the system is applied in connection with treatment, such as pressure-volume data as described above, may be used to apply various algorithms for machine learning. Such machine learning applications may be trained to make predictions, for example, regarding the success or failure of treatment, the need to change the treatment modality such as the applied energy, the presence of complex conditions, or the basic biomimetic modality of the subject or population of subjects, as described above. Any convenient machine learning algorithm or technique or model may be applied, for example, algorithms or techniques that apply supervised learning, unsupervised learning, semi-supervised learning, reinforcement learning, or dimensionality reduction. In embodiments, the machine learning technique of interest may include convolutional neural networks, or artificial neural networks that include deep learning techniques, decision trees, support vector machines, regression analysis, Bayesian networks, or other methods of applying genetic algorithms. The machine learning technique of interest may be implemented in software so that it can run on a general-purpose processor, e.g., a commercially available general-purpose processor, or a special-purpose processor, e.g., a graphics processor, e.g., a commercially available graphics processor, or it may be implemented on dedicated hardware.

[0109] Figure 9A shows an isometric view of a proximal connector 900 according to an embodiment of the present invention configured to measure vascular distensibility, and Figure 9B shows a cutaway view of the proximal connector 900. The proximal connector 900 includes a proximal flange 910 separated by a membrane 920 and a distal flange 915. The proximal flange 910 defines a proximal chamber 925 accessed by a proximal port 930. The distal flange 915 defines a distal chamber 935 accessed by a distal port 940. A pressure transducer 945 is operably coupled to the distal chamber 935 defined by the distal port 940 and the distal flange 915. The pressure transducer 945 is configured to observe changes in pressure applied to a distal balloon connected via the distal flange 915. A permanent magnet 950 is connected to the proximal flange 910 and configured to remain in relative position to the fixed position of the membrane 920. The Hall sensor 955, fixed to the membrane 920, is configured to move with the membrane 920 relative to a permanent magnet 950, which enables observation and measurement of changes in the volume of the distal balloon.

[0110] Distance 955 is the furthest left position (X) that the membrane 920 can move within the proximal chamber 925. l ) represents the furthest right position (X) that the membrane 920 can move within the distal chamber 935. Distance 960 is the furthest right position (X r The distance 960 represents the position (x) of the film 920 shown in Figure 9B. The Hall sensor 955 and the permanent magnet 950 are configured to sense changes in the position of the film 920 between the left end distance 955 and the right end position 960.

[0111] Figure 10A shows plot 1005 of the calculated, i.e., analytical output of a Hall sensor fixed to a film, such as the configuration of the Hall sensor 955 and a single permanent magnet 950 shown in the schematic diagrams in Figures 9A and 9B, and plot 1010 of experimental results confirming the analytical results of plot 1005. The analytical calculation of the magnetic flux density B, i.e., the magnitude of the effect of the magnetic field along the axis of symmetry of a permanently axially magnetized ring magnet, such as the configuration of the permanent magnet 950 shown in the schematic diagrams in Figures 9A and 9B, is expressed by the following equation.

[0112]

number

[0113] Here, B r is the residual field of the magnet independent of the magnet's shape, z is the distance from the pole surface on the magnet's axis, D is the thickness of the ring, and R and D is the thickness of the ring. a R is the outer radius of the ring. i is the inner radius of the ring. The magnitude of the magnetic flux density induces a measurable voltage change in the Hall effect sensor, depending on the distance z from the permanent magnet to the Hall effect sensor.

[0114] The x-axis 1015 of plot 1005 shows the distance of the membrane from a reference position (i.e., the position of the permanent magnet), such as membrane distances 955, 960, and 965 in Figure 9B. The y-axis 1020 of plot 1005 relates to the magnetic flux density, i.e., the magnitude of the effect of the magnetic field associated with the permanent magnet at different distances from the permanent magnet. Plot 1005 shows the leftmost possible membrane position at position 1025 and the rightmost possible membrane position at position 1030 (where "right" and "left" refer to the membrane positions seen in Figure 9B as described above). The results of the analysis of the effect of the magnetic field with respect to distance from the permanent magnet are shown in curve 1035. Curve 1035 shows that the effect of the magnetic field changes within the operable range of the membrane, particularly between positions 1025 and 1030, confirming that a Hall sensor, such as the membrane-mounted Hall sensor and permanent magnet configuration shown in Figures 9A and 9B, is a viable solution for measuring membrane position, and therefore the volume of the distal balloon (and thus the change in vascular volume).

[0115] The x-axis 1037 of plot 1010 represents the change in distal balloon volume based on different membrane positions. The y-axis 1040 of plot 1010 represents the voltage level generated by the Hall sensor as the Hall sensor moves a different distance from the permanent magnet. Curve 1045 reflects the voltage data collected from the Hall sensor, such as in the membrane-mounted Hall sensor and permanent magnet configurations shown in Figures 9A and 9B. Curve 1045 shows different voltage values ​​for each balloon volume value shown on the x-axis 1037 (associated with different membrane positions or distances between the membrane and the permanent magnet). That is, each membrane position, and therefore balloon volume, results in a different voltage level generated by the Hall sensor. In other words, the function represented by curve 1045 provides a unique solution such that each voltage corresponds to a different membrane position (diaphragm distance from the permanent magnet) related to the balloon volume. The maximum change in measured voltage (plotted on the y-axis 1040 in plot 1010) occurs between volume displacement measurements of approximately 0 mL and approximately 2.75 mL, enabling accurate volume measurement through the balloon volume between 0 mL and 2.75 mL in the operating region of interest. These results confirm that membrane-mounted Hall sensors are a viable approach for monitoring distal balloon volume changes in vivo and during treatment.

[0116] To measure minute volume changes occurring during a given treatment according to embodiments of the present invention, a highly sensitive and linear volume sensor may be used. A specific embodiment of the Hall effect volume system described above, capable of producing linear measurements over the balloon filling range, is shown in Figure 9C. As shown in Figure 9C, two permanent axial ring magnets 970 and 975 are fixed within an amplifier assembly, one fixed to the proximal and one to the distal flange, respectively. In this embodiment, the same poles of the magnets face each other (south facing south), but this configuration can be changed depending on the bias (null) voltage introduced into the internal differential amplifier of the Hall sensor. A Hall sensor 955, mounted on a flexible printed circuit board and centered on a flexible diaphragm 920, moves with the center of the diaphragm during treatment. The movement of the diaphragm affects the volume change in the balloon and thus provides a measure of balloon expansion. A small buffer distance is required between the proximal and distal limits of the diaphragm to prevent sensor saturation. As an example, two axially polarized NdFeB N42 ring magnets with an outer diameter of 1 / 2 inch × inner diameter of 1 / 4 inch × thickness of 1 / 8 inch were used with an analog Hall sensor (A1324, Allegro MicroSystems) and assembled in the configuration shown in Figure 9C. The total voltage range was 0.5 to 4 V and measured over a total volume range of 2.25 ml. A 6 × 60 mm balloon has an operating volume of approximately 2.0 ml. The results are shown in Figure 10B. The sensitivity of this sensor allows for the detection of changes of less than 1% of the balloon volume. Deviations from linearity occur at both ends of the curve. However, these ends are not important for the overall volume measurement, as practical changes in extensibility are expected to occur in the intermediate volume range.

[0117] As described above, measurements of changes in vascular volume combined with changes in vascular pressure can be used to assess vascular distensibility. The systems and techniques described herein enable the assessment of vascular distensibility in vivo and during treatment. Changes in vascular distensibility, including changes during, before, or after treatment, can be used to assess the effectiveness of treatment and / or adjust vascular treatment. For example, changes in vascular distensibility can be used to adjust the intensity and / or duration of treatment. Understanding and collecting treatment-related data, such as measurements of vascular volume and pressure, can be used in future predictive algorithms so that treatment is performed at a variable frequency and / or vibration frequency to reduce the time required for treatment and to more accurately predict the energy required before performing treatment. Such aspects of treatment, for example, the frequency and / or vibration frequency of the system, can be adjusted by the operator or, in other cases, automatically adjusted based on machine learning and / or other predictive algorithms, for example, as described herein.

[0118] As will be described in detail below, the systems and techniques for measuring vascular distensibility according to this disclosure may be further configured to acquire simultaneous measurements of vascular volume (i.e., absolute changes in vascular volume in addition to relative changes in vascular volume), such as intra-arterial cross-sectional imaging, in order to generate absolute vascular distensibility measurements. For example, imaging techniques such as ultrasound, angiography, computed tomography, intravascular ultrasound (IVUS) and / or optical coherence tomography (OCT) can be used to image treated vessels before and after treatment to obtain absolute vascular distensibility values. Such absolute vascular distensibility measurements can be compared between treatment groups.

[0119] Figures 8, 9A, 9B, and 10 illustrate configurations for measuring vascular distensibility in relation to a pulsating balloon catheter system according to the present invention; however, such presentations are illustrative only, and the disclosure is not limited to such embodiments. It should be understood that the described techniques for measuring vascular distensibility, including, for example, in vivo measurements during treatment by measuring volume using a Hall sensor and permanent magnet in conjunction with a pressure gauge, may also be applicable to other balloon-based systems and methods, such as other balloon-based systems and methods for treating diseased blood vessels.

[0120] Measurement during processing for system control For example, balloon angiogenesis systems, such as a pulsating balloon catheter system according to the present invention, can benefit from being configured to monitor the safe and effective operation of the system. Systems according to the present invention may be configured to monitor one or more measurable characteristics to ensure safe and effective operation and treatment. For example, in some embodiments of the system of the present invention, the energy output pulse should correspond to an expected value such as the energy input pulse or the threshold amplitude of the energy pulse. Such embodiments may be configured to ensure distensibility by measuring or comparing, or otherwise monitoring, the energy output pulse in order to ensure distensibility. In other embodiments of the system of the present invention, the input pressure applied to the system should correspond to a peak pressure measured within the system. In yet another embodiment, the input pressure applied to the catheter component needs to correspond to a target threshold pressure. "Corresponding to an expected value" means that, in each case, the measured value is greater than the expected value, or in other cases, the measured value is less than the expected value, depending on the configuration of the system. In another example, in some embodiments of the system of the present invention, the input pressure applied to the system should correspond to a minimum change, maximum change, or tolerance change in the volume of the distal balloon.

[0121] More generally, the system according to the present invention may be configured to detect a system state. The system state may refer to a normal operating state or a fault operating state of the system. Fault operation may mean that the system is in any undesirable system state, such as an unexpected pressure drop, system leak, balloon burst, or any other unsafe or disabled state.

[0122] This aspect of the present invention relates to a simple, effective, and fast technique for detecting a system state and providing a warning signal indicating such a system failure, as described above. Furthermore, this aspect of the system can also be used to predict how much vibration or energy will be rapidly required after the earliest data regarding extensibility has been collected. In a pulsating balloon catheter system, the system state can be determined by configuring the system to compare measured characteristics of the system, such as catheter pressure, including peak catheter pressure or distal balloon volume, with expected thresholds, i.e., target pressure or target volume, or their minimum or maximum expected values. Catheter pressure can be measured using any convenient pressure sensor, such as a pressure gauge, as described above. In some cases, the pressure sensor can be integrated into the distal chamber of the proximal connector in embodiments of the system according to the present invention. In such cases, the pressure sensor can be configured to measure the pressure applied to the distal balloon, for example, by measuring the fluid pressure in the distal chamber that is in fluid communication with the distal balloon. The distal balloon volume can be measured using any convenient sensor, such as a membrane position sensor or displacement sensor, or other sensor configured to measure changes in the volume of the distal balloon. In some cases, the membrane position sensor is a Hall sensor and magnet located at a fixed position of the membrane of the proximal connector, configured to measure the change in volume corresponding to the distal balloon, as described above.

[0123] In embodiments, electronic circuits may be configured to determine system states. In such embodiments, sensors configured to measure system characteristics as described herein may be further configured to output electronic signals based on the measured characteristics. Those skilled in the art will understand that any desired measurable system characteristic may be measured by appropriately configured sensors. In embodiments, sensors configured to measure system characteristics, such as a pressure sensor configured to measure system pressure or a membrane position sensor configured to measure distal balloon volume, may be further configured to output electronic signals based on the measured characteristics, such as the measured pressure or the measured volume. Such electronic signals may change based on the output of the sensor, i.e., the measured system characteristic, for example, the amount of pressure measured by the pressure sensor or the volume of the distal balloon measured by the membrane position sensor. The electronic signals corresponding to the measured system characteristics may be digital or analog signals. If the signal is an analog signal, its voltage or current, or other characteristics of the signal such as frequency, may change based on different measurements observed by the sensor. An electronic circuit may be configured to compare a measured system characteristic, such as a measured pressure signal or a measured volume signal, to a target pressure or target volume (i.e., a minimum or maximum value or tolerance range of the system characteristic) in any convenient manner. For example, a measured signal may be compared to a target threshold, such as a target pressure or target volume, using a comparator circuit to compare the measured system characteristic to a reference voltage corresponding to the target threshold. Any convenient comparator circuit may be applied that can compare the differences between the characteristics of the signals, such as comparing the voltage or current of the signals and generating a digital (i.e., binary) output indicating the result of the comparison, for example, which signal is larger. In some cases, the comparator circuit may be an analog comparator circuit, such as a differential amplifier, for example, a high-gain differential amplifier. In other cases, the comparator circuit may be a digital circuit, such as an adder circuit or a more complex or specialized digital logic circuit.

[0124] In some cases, a signal corresponding to a measured system characteristic, such as measured pressure or measured volume, can be inverted and summed with a signal corresponding to a target value or threshold, such as target pressure or target volume. The summation result can then be applied to a comparator circuit to compare it with a threshold representing the tolerance or expected difference between the measured system characteristic and the target threshold (e.g., measured pressure and target pressure or measured volume and target volume). Such a configuration, where the difference between the measured system characteristic and the target value of the system characteristic (e.g., measured pressure and target pressure or measured volume and target volume) is compared with a threshold, can allow for a buffer around the expected system characteristic, thereby allowing, in some cases, noise or other signals that do not represent the system state to be accounted for.

[0125] In embodiments, the result of a comparator circuit may be a digital signal (or may be converted to a digital signal), and the logical value of the digital signal indicates whether the measured system characteristic (such as measured pressure or measured volume) is an expected or unexpected reading. For example, the circuit may be configured so that the comparator generates a digital high signal, i.e., logic 1, when the measured system characteristic (e.g., measured pressure or measured volume) is outside the expected range, and a digital low signal, i.e., logic 0, when the measured system characteristic is within the expected range. Such digital signals may be stored in memory. Any convenient electronic circuit capable of storing digital logic signals may be applied. In some cases, the memory may consist of a flip-flop circuit, for example, a flip-flop capable of storing a single bit. In such a case, the output value of the flip-flop reflects the system state. For example, the output of the flip-flop may indicate logic 0 when the system state is normal, and logic 1 when the system state is a fault state. The output of such a flip-flop may be treated as an alarm signal, such that when an alarm signal is issued, it may become unsafe or ineffective to continue using the system. Such a signal may be communicated to the system operator in any convenient manner. For example, in some cases, the system status may be communicated to the operator via a warning signal such as a warning light, sound, or vibration. In other cases, the system status may cause the system to automatically perform an action, such as automatically turning off the system.

[0126] In certain embodiments, it may be desirable that system state values ​​stored in memory, for example, values ​​stored in a flip-flop, reflect a comparison of the maximum or minimum values ​​of measured system characteristics, such as a comparison of measured pressure at the peak amplitude of measured pressure, or a comparison of measured distal balloon volume at the peak amplitude of measured volume. That is, in embodiments, the system state reflects the peak catheter pressure or peak distal balloon volume. This digital data can be used to understand population and anatomical variables, as well as the required pressure and energy, and can also be used to predict the required energy and the best therapeutic energy to apply in relation to machine learning techniques, such as training data for machine learning models. In such embodiments, the system state may reflect whether the peak measurement of a system characteristic is greater than or equal to the target measurement of the system characteristic, for example, whether the peak amplitude of the measured pressure or measured distal balloon volume is greater than or equal to the target pressure or volume, respectively, at the expected time. In such embodiments, when the peak value of a measured characteristic does not rise to the level of the expected target value at the expected time, for example, an unexpected pressure drop may be indicated. In some embodiments, the system may be configured to continuously monitor system characteristics such as catheter pressure or distal balloon volume and to continuously compare such measurements with target values. In such cases, in order for the flip-flop output state to accurately reflect the system state, the system may be configured so that the results of the comparator circuit are written to the flip-flop at a time corresponding to the time the catheter is expected to be exposed to peak measurements, e.g., peak pressure or peak volume. That is, the flip-flop write operation is coordinated with the time the system is expected to exhibit peak measurements, e.g., peak pressure or peak volume. Any convenient technique may be applied to synchronize the sensor readings to the appropriate time. In some cases, the flip-flop write operation can be synchronized by setting the flip-flop clock signal to an inverting control signal used to control the input pressure to the catheter.In such a case, the rising edge of the flip-flop clock signal corresponds to the time when the control signal turns off the pressure on the catheter, which in turn corresponds to the time when the pressure is applied to the catheter for the longest period, i.e., the peak catheter pressure. Those skilled in the art will understand that alternative configurations with a similar effect can be used, such as using a falling-edge trigger flip-flop without inverting the pressure control signal.

[0127] When a configuration such as those described above is applied to synchronize the flip-flop write operation with a peak value of a system characteristic, such as peak system pressure or peak distal balloon volume, the logical value of the memory device, i.e., the system state reflected in the flip-flop, reflects the measured system characteristic, for example, the peak value of peak pressure or peak volume. Therefore, the system state may indicate that the system is unable to reach the peak measurement at any point during the pulsating cycle in which pressure is applied to the distal balloon and then removed, and thus the system is not functioning safely or effectively, or otherwise not functioning as expected.

[0128] Figure 11 shows a schematic diagram of an exemplary electronic circuit 1102 for monitoring system conditions via catheter pressure according to an aspect of the present invention. While the diagram shown in Figure 11 relates to the measurement of catheter pressure, those skilled in the art will understand that similar configurations may be used to measure other system characteristics, such as distal balloon volume. As seen in Figure 11, the measured pressure 1105 is the input signal to circuit 1102. As described herein, the measured pressure signal may be an analog or digital signal ultimately generated by a pressure sensor attached to an embodiment of the system and used to measure energy applied to the system, such as catheter pressure. The target pressure 1110 is another electronic signal, which is the input signal to circuit 1102. The target pressure signal 1110 may be wired to a specified value or may be configurable based on different types of therapeutic strategies, including different types of distal balloons, the amount of pressure expected to be applied to the catheter. The measured pressure 1105 and the target pressure 1110 are sent to a totaling circuit 1115 configured to calculate the difference between the measured pressure 1105 and the target pressure 1110. In other words, in the embodiment shown in Figure 11, the totalizing circuit 1115 is configured to add the target pressure 1110 to the negative value of the measured pressure 1105.

[0129] The total result 1120 of the summing circuit 1115 is compared to a threshold 1125. Both the total result 1120 and the threshold 1125 are inputs to the comparator circuit 1130. The threshold 1125 is an input signal to circuit 1102 and may be a wired value or, in either case, a configurable value that reflects the tolerance between the measured pressure 1105 and the target pressure 1110. The comparator circuit 1130 is configured to produce a comparator result 1135 that is a digital low value, i.e., a logic 0, if the result of the comparator circuit 1130 is within the tolerance range, and to produce a digital high value, i.e., a logic 1, if the result of the comparator circuit 1130 is outside the tolerance range. That is, for example, if the measured pressure signal 1105 is unacceptably low, the total result 1120 will also be unacceptably low, and the comparator result 1135 will be a digital high value or a logic 1. The comparator result 1135 is connected to the data import of the flip-flop 1140, which is used to store the system state, and in this case, it is in the form of a 1-bit digital logic value.

[0130] The solenoid trigger signal 1145 is a pressure control signal used to control the solenoid that turns on pressure to the catheter. That is, when the solenoid trigger signal 1145 is high, the solenoid is controlled so that pressure is input to the catheter (not shown in Figure 11) and therefore applied to the distal balloon (not shown in Figure 11). When the embodiment is configured in this way, the pressure is applied to the catheter for the longest time on the trailing edge (i.e., falling edge) of the solenoid trigger signal 1145. Since the catheter is exposed to pressure for the longest time on the trailing edge of the solenoid trigger signal 1145, the catheter pressure is expected to be at its peak amplitude at that time. That is, the maximum catheter pressure is expected on each trailing edge of the solenoid trigger signal 1145.

[0131] The solenoid trigger signal 1145 is inverted using the inverter 1150 before being sent to the flip-flop clock input signal. For example, any convenient inverter circuit or digital logic NOT gate can be applied to logically reflect the inverted solenoid trigger signal 1145 to the inverter output 1155, such that the rising edge 1170 of the inverter output 1155 corresponds to the trailing edge 1160 of the solenoid trigger signal 1145, and the falling edge 1175 of the inverter output 1155 corresponds to the rising edge 1165 of the solenoid trigger signal. Thus, if the flip-flop 1140 is a positive-edge triggered flip-flop, i.e., configured so that the stored value is written on each rising edge of the flip-flop clock signal, the comparator result 1135 is written to the flip-flop 1140 on each trailing edge of the solenoid trigger signal 1145. When the comparator result 1135 is written to the trailing edge of the solenoid trigger signal 1145, the comparator result 1135 reflects a comparison of the measured pressure 1105 at the peak amplitude of the pressure applied to the distal balloon via the catheter.

[0132] In the embodiment shown in Figure 11, the flip-flop output signal 1180 reflects the system state. The electronic circuit 1102 is configured such that when the system is functioning normally, the flip-flop output signal 1180 is digital low or logic 0, meaning that the measured pressure appears to be within the acceptable threshold of the target pressure and no unexpected pressure drop is detected. The electronic circuit 1102 is configured such that when the system is in a fault condition, the flip-flop output signal 1180 is digital high or logic 1, meaning that the measured pressure appears to be outside the acceptable threshold of the target pressure and an unexpected pressure drop is detected.

[0133] Figure 12A shows the results of the operation of an exemplary electronic circuit used to monitor the system state according to the present invention, such as the operation of the electronic circuit 1102 shown in Figure 11 and described above. Plot 1205 is a graph of pressure 1210 shown on the y-axis of plot 1205 over time 1215 shown on the x-axis of plot 1205. The pressure measured in the system, i.e., the catheter pressure, is shown in the plot on curve 1220. Since the pressure applied to the catheter pulsates, i.e., is pulsating, the measured pressure 1220 forms a waveform with periodic maximum and minimum amplitudes. The target pressure for the system, i.e., the maximum expected pressure, is shown by a line 1225 on plot 1205 that shows an exemplary target pressure. A threshold for the tolerance of the difference from the target pressure 1225 is shown as a pressure band 1230 that reflects the range of tolerance of the pressure value from the target pressure 1225. The system state signal 1235 reflects a logical value of 0 or 1, where logical value 0 indicates normal operation of the system and logical value 1 indicates a system failure.

[0134] Plot 1205 shows normal system operation during period 1240, which lasts approximately 0 to 0.4 seconds. During period 1240, the peak measured pressure consistently rises to the target pressure 1225 and remains consistently within the acceptable threshold 1230 of the target pressure 1225. Since the catheter pressure remains consistently within the acceptable pressure range during this time, the electronic circuitry configured to monitor the system status consistently shows normal system operation. This result is reflected in the system status signal 1235, which remains at logic 0 during time period 1240.

[0135] Furthermore, plot 1205 shows a system failure period during time 1245, which is approximately 0.4 to 1 second. During time 1245, the peak measured pressure consistently fails to rise to the target pressure 1225 and consistently remains outside the acceptable threshold 1230 for the target pressure 1225. During this time, since the peak catheter pressure is consistently outside the acceptable pressure range, the electronic circuitry configured to monitor the system status consistently indicates a system failure due to the measured pressure drop. This result is reflected in the system status signal 1235, which rises to logic 1 during time period 1245 and remains at logic 1.

[0136] Catheter burst detection The system according to the present invention may be configured to detect whether a catheter is intact, whether a catheter is completely broken, or whether a catheter is leaking.

[0137] Figure 12B shows exemplary behavior of pressure and volume measurements from an intact (i.e., leak-free) catheter of the system according to the present invention during treatment. In Figure 12B, the peak pressure and trough pressure remain substantially the same throughout the treatment, and the volume involved in the treatment does not decrease.

[0138] Figure 12C shows exemplary behavior of pressure and volume measurements from a completely failed catheter in a system according to the present invention during treatment. A completely failed catheter can cause lumen damage and damage to the amplifier assembly. Using catheter pressure and volume changes, a burst catheter can be detected within a treatment time of less than 0.05 to 2 seconds, e.g., less than 0.1 seconds. In the figure above, the volume sensor measures the volume drop and triggers a system warning to stop treatment. The volume drop may be in the range of 0.01 to 10 mL / second, e.g., 0.5 mL / second. Peak pressure also decreases during bursts, but delays the volume change.

[0139] Figure 12D shows exemplary behavior of pressure and volume measurements from a leaking catheter of the system according to the present invention during treatment. A leaking catheter can cause a fluid ejection that damages the vessel wall. Using catheter pressure and volume changes measured by one embodiment of the present invention, catheter leakage can be detected by measuring an increase in trough pressure during a pressure cycle, along with a decrease in volume within the catheter. The trough pressure increase may be in the range of 0.1 to 10 atm, e.g., 1 to 2 atm. The volume decrease may be in the range of 0.01 to 10 mL / sec, e.g., 0.1 mL / sec. In certain embodiments, a software-based scheme can be used to detect combinations of these conditions and immediately shut down the system during pulsating intravascular lithotripsy.

[0140] method The system of the present invention is used in a variety of applications. In some examples, the system is used to break up hardened materials embedded in elastic conduits. With respect to the embodiments presented herein, this disclosure describes applications related to the treatment of atherosclerotic calcification deposits in arterial conduits such as coronary arteries or peripheral arteries. However, the system and teachings are not limited to atherosclerotic calcification deposits or arterial conduits and may be applied to other applications in general, as determined by those skilled in the art. This is especially true in cases involving medical interventions such as situations that alter arterial distensibility (arterial vascular distensibility, as described above) or when occlusion occurs later due to the previous presence of a stent. Vascular distensibility is altered by the placement of previous stents in the lumen. Vascular distensibility curve data and feedback may be used in relation to future treatments, as well as data and feedback from predictive techniques such as machine learning techniques described herein.

[0141] In some examples, various embodiments of the systems described herein are used in dynamic balloon angioplasty (DBA), a technique for effectively and safely fragmenting calcified lesions during angioplasty using pressure vibrations with a generalized waveform (in some embodiments, harmonic vibrations or frequency-specific pressure waveform vibrations). The concept of DBA for treating arterial calcified plaques is shown in Figures 13A–13E. In DBA, a catheter 16 with a balloon 2 is deployed into a vessel 1300 having a calcified deposit 1350 (Figure 13B) with the help of a guidewire using, for example, any convenient protocol known in the art. Through the angioplasty balloon, the plaque is subjected to high-frequency pressure vibrations (Figures 13C–13D). In the low-pressure phase of the vibration (Figure 13C), the balloon pressure is reduced to the minimum pressure required to achieve balloon inflation, typically around 1–2 atm. In the high-pressure phase of the vibration (Figure 13D), the balloon is inflated to a peak pressure that may be set by the physician or system. Typical peak expansion pressures can extend beyond the low-pressure range up to the balloon's maximum rated pressure, which can be 25 atm or higher. Such pressure circulation in the balloon induces periodic loading of the calcified plaque 1350 below the fracture stress of the calcified plaque within the plastic deformation zone. The heterogeneity within the calcified plaque consists of numerous microfractures with sharp angles. Through the fracture mechanism described herein, the circulating load described in Figures 13A–13E generates circulating stresses near these sharp angles and irregular surfaces of the plaque microfractures. These circulating stresses cause these sharp angles to grow, expanding the microfractures into larger macroscopic fragments. The growth of these microfractures leads to more complete fracture of the plaque at lower expansion pressures compared to the static pressure. Higher frequency pressure cycles and higher pressure differences between cycles are expected to enhance the effectiveness of this crack growth mechanism.By generating controlled high-frequency pressure cycles within an angioplasty balloon, DBA reduces the balloon pressure required to fragment calcified plaques (e.g., by 1–50%, e.g., 20–30%, in some cases compared to a suitable non-DBA control), improves stent deployment, enhances drug delivery of drug-coated balloons, reduces stress on soft lipid core atherosclerotic plaques, expands calcified restenosis within stents, fragments calcified deposits on affected heart valve leaflets, and improves balloon-base expansion and prosthesis and device deployment. Further details regarding embodiments of DBA methods in which the system described herein may be used are provided in U.S. Patent Application Publication No. 2020 / 0046949 and pending PCT Application Serial No. PCT / US2020 / 055458, the disclosures of which are incorporated herein by reference.

[0142] In some examples, the system of the present invention is used in a manner sufficient to achieve a four-part pulsating treatment plan, as illustrated in Figure 14, as described above, which provides safe and controlled expansion of hardened plaque and surrounding healthy soft tissue. To treat these multi-component vessels, a four-part treatment algorithm may be used, which comprises the following steps: (1) a soft tissue low-stress expansion stage 3800 via the Mullins effect, (2) a plastic deformation stage 3700 in the calcified plaque until plaque fragmentation, (3) an immediate pressure reduction stage 3600 for plaque fragmentation detection and reduction of surrounding tissue stress, and (4) a soft tissue low-stress expansion stage 3500 via the Mullins effect for post-calcification of the soft tissue. An embodiment in which force is applied to the vessel over time by this four-part algorithm is shown in Figure 6. Due to significant attenuation throughout the catheter and the lack of pressure control in the prior art approach, the input pressure to the catheter is not successfully transmitted to the balloon (system output). Therefore, in conventional systems, tissue stress does not return to a low state during high-frequency vibration (i.e., there is no tissue relaxation period), limiting the effect of Mullins' stress circulation. Through damping minimization and pressure control, the system induces pressure vibration in a balloon (system output) following a pressure input from a proximal source where the pressure vibration is 0-50 ATM, the frequency is 0-25 Hz, and the duty cycle is 60-80%. This improvement is important for two reasons: (1) it allows tissue to relax during the decompression cycle (following the Mullins effect), and (2) it allows sufficient vibration to be applied to the blood vessel within the limited time before the artery is occluded during treatment. Further details regarding how embodiments of the present invention may be used can be found in the pending PCT application serial number PCT / US2020 / 055458, the disclosures of which are incorporated herein by reference.

[0143] In certain specific cases, embodiments of the present invention can be applied to evaluate vascular distensibility. Blood vessels are naturally distensible and elastic structures. Vascular distensibility is necessary to convert pulsating flow from the heart into a stable flow within the capillaries. However, over time, aging and the atherosclerotic process can reduce vascular distensibility, decrease the luminal area, and cause flow mismatch and additional stress in the vascular system. Vascular distensibility is particularly reduced during and after the formation of intima and medial calcified plaques in the vessel walls.

[0144] Improving vascular distensibility is a prerequisite for a clearer treatment of atherosclerosis. See Dattilo R, Himmelstein SI, Cuff RF. The COMPLIANCE 360° Trial: a randomized, prospective, multicenter, pilot study comparing acute and long-term results of orbital atherectomy to balloon angioplasty for calcified femoropopliteal disease. J Invasive Cardiol. 2014;26(8):355-360. http: / / www.ncbi.nlm.nih.gov / pubmed / 25091093. To maximize vascular wall distensibility after calcium accumulation, angioplasty or endovascular lithotripsy can be used to break up the intima and inner calcium rings, exposing the more elastic elements of the tubular vessels and freeing them from mummified calcium. As described above, embodiments of the present invention can be used to apply pulsating endovascular lithotripsy, which allows for both calcium cracking (i.e., cracking of CP tissue as shown in Figure 13), and to apply final post-inflation of the vessel. In some cases, embodiments of the present invention can be used for both applications in a single treatment: cracking of CP tissue and applying final post-inflation of the tissue. That is, embodiments of the present invention can also be used to crack CP tissue by first applying DBA to pulse the vessel, and then to dilate the vessel using, for example, conventional non-stretchable balloon post-inflation.

[0145] Vascular distensibility refers to a measurable quantity defined by the following relationship:

[0146]

number

[0147] In the equation, ΔV is the change in vascular volume in response to a given change in pressure ΔP. Due to the incompressibility of tissue, vascular volume can be converted to area by dividing by the length of the vessel. Because the pressure-volume relationship within arteries is nonlinear, extensibility is often defined in terms of a given pressure or volume.

[0148] Simultaneous in vivo measurement of pressure change ΔP and changes in vascular cross-sectional area or volume, ΔA or ΔV, can be difficult, making it challenging to obtain vascular distensibility. The system according to the present invention is used to address this difficulty by accurately evaluating vascular distensibility in vivo, as described below.

[0149] As discussed above, the proximal connector of the catheter balloon assembly may include a membrane position sensor, such as a Hall sensor, which provides data on the spatial position of the membrane at any given time, and a pressure gauge for measuring the pressure in the fluid passage and distal balloon of the balloon catheter assembly. In such an example, the system may be used to evaluate the volume expansion of the balloon in real time and / or to evaluate the vascular distensibility at the site of the balloon.

[0150] By measuring the diaphragm (i.e., membrane) position, the change in volume within the balloon can be evaluated in real time, and the corresponding balloon pressure can be measured. That is, the system is configured to pressurize the balloon-based catheter while simultaneously reading the pressure and volume within the catheter system. This volume-pressure relationship can provide a measure of vascular distensibility, as vascular distensibility is the ratio of the change in vascular volume to the change in pressure, as described above. To enable this measurement, the balloon volume-pressure relationship can be measured when the balloon is not constricted by the surrounding blood vessels. When placed in a rigid blood vessel, the balloon requires a higher pressure for equivalent balloon volume in an unconstricted baseline state. Therefore, the balloon can be used to measure vascular distensibility. The ability to accurately record the diaphragm position (a surrogate measurement of balloon volume) and balloon pressure allows for easy in vivo measurement of vascular distensibility. This distensibility measure can be used as a measure of therapeutic success, with lower distensibility indicating appropriate or therapeutic balloon dilation and therapeutic success. In some examples, the system is used in a manner similar to that described in U.S. Publication No. 2015 / 0080747 (the disclosure of which is incorporated herein by reference), where membrane displacement is used as a measure of balloon volume.

[0151] The system and method for measuring vascular distensibility according to the present invention can be configured to acquire pressure-volume measurements before, during, and after treatment. The data obtained during these measurements can be used to acquire changes in vascular distensibility and determine the effectiveness of the treatment. Changes in vascular distensibility can also be used to adjust the intensity and / or duration of the treatment.

[0152] In addition, embodiments of the present invention can be used to generate pressure-volume (i.e., distensibility curves) in various cases during treatment. Relative changes in distensibility before and after treatment can be obtained. These changes can be compared between similar vascular segments to understand the appropriate level of distensibility change.

[0153] Furthermore, the method according to the present invention may also include obtaining associative measurements of intra-arterial cross-sections using other available measurement techniques such as ultrasound, angiography, computed tomography, intravascular ultrasound (IVUS), and / or optical coherence tomography (OCT). In some examples, the system according to the present invention may be configured to incorporate information obtained from such measurements, i.e., sensor fusion techniques. Volume and / or area measurements obtained through such visualization techniques can be combined with pressure and volume readings (i.e., measurements of change or relative volume and / or pressure) from embodiments of the balloon system according to the present invention to generate accurate absolute vascular distensibility measurements. Such absolute distensibility measurements can then be used to compare treatments across vascular beds to optimize treatment for both short-term and long-term success. Furthermore, absolute measurements of vascular distensibility curves can be obtained and compared across treatment groups.

[0154] Systems and methods for measuring vascular distensibility are described in the context of the pulsating balloon catheter system according to the present invention, but such systems and methods for measuring vascular distensibility may also be applied to other systems such as static balloon angioplasty, pulsating endovascular lithotripsy, cavitation-based endovascular lithotripsy, and / or systems configured to deliver externally applied lithotripsy pulses.

[0155] Figure 15 shows the procedure steps of an autonomous angioplasty performed using the embodiment described above. To initiate this autonomous procedure, a physician or technician in a sterile field may connect the proximal connector to the actuator of the embodied system. This step may involve some human interaction with the patient, but fluoroscopy can be paused to minimize operator exposure. In this embodiment, a robotic catheter device (such as those known in the art) may be used to insert the angioplasty balloon into the lesion. This step may involve fluoroscopic imaging and radiation, but can be performed from a shielded laboratory, eliminating operator radiation exposure. After the appropriate balloon has crossed the lesion, the operator may select the appropriate treatment setting and initiate the treatment. Before, during, or after the procedure, the operator may visualize fluoroscopic images and compare them with measured pressure-volume data. If the treatment is unsuccessful, the procedure may be continued using the same or different settings. If the treatment fails, the balloon catheter can be removed by the robot. During these steps, the operator may remain inside a shielded laboratory and be protected from radiation. In some cases, pre-filled and / or spring-fastened balloon catheters and / or composite balloons can be used to minimize the operator's radiation exposure. In such cases, the operator does not need to fill the catheter with contrast agent, nor does they need to remove and fold the balloon upon completion of the procedure. Once all these steps are performed and fluoroscopy is no longer required, the procedure can be terminated.

[0156] Figure 16A shows a graphical user interface (GUI) that an operator may interact with during an autonomic angioplasty procedure. In this embodiment, the GUI may have several information zones, including a treatment characteristics zone, a balloon characteristics zone, and a plot zone. The treatment characteristics zone displays key treatment characteristics used by the operator during the procedure. Such characteristics include pressure, frequency, duty cycle, number of cycles, and treatment time. Some or all of these characteristics may be updated or modified by the system and / or by the user. The balloon characteristics zone may contain information about a balloon attached to a handheld actuator. Information that may be displayed may include the balloon's diameter, length, nominal pressure, and rated pressure, as well as other balloon characteristics such as whether the balloon is drug-coated or stent-covered. Furthermore, balloon catheter connection information (i.e., whether the balloon is connected or not) may be included in this section. The plot zone may display various treatment plots, including a distensibility plot and a treatment plot. The distensibility plot may include a nominal pressure-volume curve that may be provided with the balloon. Furthermore, a pressure-volume curve measured in situ during the procedure may be plotted and updated throughout the procedure. The operator can use this plot to determine the therapeutic effect as a measure of extensibility or efficacy. The pressure plot may include a display of pressure over time. Other information that may be included in the GUI (not shown) may include the treatment status and intensity, on / off switches, indicator LEDs, etc.

[0157] Figure 16B shows an exemplary GUI screen according to another embodiment, in which the GUI screen provides balloon and treatment information. The balloon section includes information on various balloon characteristics such as diameter and length, characteristics at low and high intensity, and priming conditions, which provides the user with information on proper catheter assembly. The treatment section includes information on treatment intensity (low or high), treatment mode (pulsating or static), treatment time, treatment status, cycle count, gas pressure level, and status messages.

[0158] The system can be used to apply pulsating energy to any number of different internal tissue locations of an object. In many embodiments, the object is a “mammal” or “mammalian,” and these terms are used to broadly describe organisms within mammals, including carnivores (e.g., dogs and cats), rodents (e.g., mice, guinea pigs, and rats), and primates (e.g., humans, chimpanzees, and monkeys). In some cases, the object is a human.

[0159] kit Furthermore, kits containing a system, or one or more of its components, are also provided, for example, as described above. Thus, a kit may, in some examples, include one or more of the following: a balloon catheter assembly, a pulse generator, or its components, such as its handheld actuator, which may or may not be pre-filled. The kit components may, if desired, be contained in sterile packaging.

[0160] The kit may also include instructions for using the kit components. These instructions may be recorded on a suitable recording medium. For example, they may be printed on a substrate such as paper or plastic. Thus, the instructions may reside within the kit as a package insert, or on the labeling of the kit or its component containers (i.e., associated with the package or sub-package). In other embodiments, the instructions may reside as an electronic data file on a suitable computer-readable storage medium, such as a portable flash drive, DVD, or CD-ROM. The instructions may take any form, including a complete instruction manual on how to use the device, or a website address where instructions posted on the World Wide Web can be accessed.

[0161] The following examples are provided for illustrative purposes only and are not intended to limit you. [Examples]

[0162] I. Devices Figure 17 provides a diagram of a balloon catheter assembly according to one embodiment of the present invention. Figure 18 shows the assembly process of the proximal connector of the balloon catheter assembly shown in Figure 17. The first step of the assembly process is to secure the electronic flexible printed circuit board assembly to the diaphragm and pressure sensor. For example, epoxy and solder may be used, respectively. The pressure sensor and diaphragm may be secured to the distal flange. The proximal flange may be secured to the distal flange using appropriate fastening techniques (e.g., fasteners, welding, etc.). The electronic connector may be secured to the front of the proximal flange using epoxy to provide a reliable connection to a handheld actuator, for example. Figure 6 shows the described embodiment and tests performed on the physical assembly. It is shown that as the pressure increases, the force in the distal balloon also increases. The force generated during vibration is consistent with the force generated during static expansion, showing minimal damping by the system during pulsation.

[0163] Figure 19 provides a diagram of a balloon catheter system according to an embodiment of the present invention, such as a balloon catheter system including an embodiment of the balloon catheter assembly shown in Figure 17.

[0164] Embodiments of the present invention offer several advantages, including, but are not limited to, the following: - In the embodiments of pre-filled balloon catheters and composite balloons, the operator does not need to fill the balloon catheter with a contrast agent / saline mixture, which is an improvement because the amount of fluid that can be introduced by the clinician during treatment may not be constant, which can lead to errors in volume injection, bubble removal, deflation, etc. - If the balloon is not pre-filled, the diaphragm tracking mechanism provides a method for determining the appropriate volume inserted into the system. - In embodiments of pre-filled balloon catheters and composite balloons, the volume-pressure relationship within the balloon can be measured in advance and used to make decisions during treatment. - The embodiment enables the performance of angioplasty pressurization with minimal physician interaction, thereby limiting the physician's exposure to hazardous X-rays from fluoroscopy. - The balloon may have internal memory that informs the rest of the system of its potential therapeutic properties.

[0165] II. In vitro demonstration of pulsating intravascular lithotripsy (P-IVL) for controlled fragmentation of calcified plaques in a cadaver model. A. Background The treatment of calcified plaques (CPs) remains an unmet clinical need in interventional cardiology. We invented pulsatile intravascular lithotripsy (P-IVL), a novel balloon-based technique for treating calcified tissue. This study demonstrates P-IVL's ability to controllably fragment the CP microstructure in cadaveric CPs.

[0166] B. Method P-IVL therapy uses a high-frequency vibrating balloon to controllably induce microcracks within the CP structure. Six sections of calcified tibial artery with a lumen diameter of 2–3 mm were excised from fresh cadavers. A P-IVL balloon (diameter-to-vascular ratio 1.1:1) (Pulse® device (shown in Figure 19), Amplitude Vascular Systems, Ann Arbor, MI) was placed throughout the lesion, and P-IVL therapy (Pulse, Amplitude Vascular Systems) was performed for 60 seconds. CP structure and lumen diameter were measured before and after treatment using co-registered 3D microcomputed tomography (μCT) and 2D contrast-enhanced radiography of the vascular segments.

[0167] C. Results Figure 21 shows a representative experiment. With P-IVL treatment, the mean acute lumen gain was 0.6 ± 0.2 mm and the mean residual stenosis was 38% ± 10%. No signs of vascular damage were observed in overall vascular pathology. μCT showed axial and longitudinal fragmentation of the CP structure (Figure 20). Even with extensive CP fragmentation settings, minimal overstretching of the elastic arterial wall was observed.

[0168] conclusion P-IVL therapy is an effective technique for treating CP that induces fragmentation within the CP microstructure. The mechanism of action against this fragmentation involves controlled fatigue-based growth induced in the CP structure.

[0169] III. Evaluation of pulsating intravascular lithotripsy for controlled fragmentation of calcified plaques in perfused cadaver models A. Background Vascular calcification deposits remain a therapeutic challenge in percutaneous interventions. This study evaluated a novel balloon-based pulsatile intravascular lithotripsy (P-IVL) technique to dilate peripheral arterial calcification lesions in a controlled manner within a perfused cadaver model.

[0170] B. Method P-IVL therapy uses a high-frequency vibrating balloon to induce controlled microcracks in vascular calcified deposits. Target specimens were fresh (or frozen for less than 6 months) cadaveric legs from patients with a history of coronary or peripheral atherosclerosis, diabetes, or smoking, and who had vascular calcified deposits on screening X-rays. Six legs, corresponding to 12 affected segments with vascular diameters of 3.0–6.0 mm, were treated with P-IVL therapy. (As shown in Figure 19) P-IVL balloons (diameter-to-vascular ratio 1.1:1) were placed across the entire lesion, and P-IVL therapy (Pulse, Amplitude Vascular Systems) was performed at low intensity (and additional high intensity in two cases of persistent lesions) for 30–90 seconds. Calcified plaque structure and lumen diameter were measured before and after treatment using fluoroscopy and optical coherence tomography (OCT). Treated arterial segments and adjacent untreated arterial segments were resected, and microcomputed tomography (μCT) analysis was performed by a blinded reviewer to evaluate calcium fracturing.

[0171] C. Results Quantitative coronary angiography (QCA) analysis of P-IVL treatment showed a reduction in diameter stenosis of 31.7±13.4%, a mean residual stenosis of 9.4±7.9%, and an acute lumen gain of 1.9±0.9 mm. OCT analysis showed a mean total area gain of 101.6±99.5%. Each vessel showed excellent angiographic dilation without adjuvant therapy. OCT revealed extensive calcium cracks, and μCT of the resected vessels confirmed deep and widespread calcium fragmentation. Calcium fragmentation is shown as in Figure 20B. Fragmentation occurred longitudinally (cracks traversing from left to right) and circumferentially (cracks traversing around the structure) as a result of the therapy.

[0172] conclusion P-IVL therapy is a promising technique for treating intravascular calcification deposits. The mechanism of action for calcium treatment using P-IVL involves fatigue-based fragmentation induced in the calcification deposits via controlled balloon vibrations directed towards the surrounding tissue.

[0173] Notwithstanding the attached claims, this disclosure is also defined by the following appendix:

[0174] 1. A pulsating balloon catheter system, (a) A pulse generator and (b) A balloon catheter assembly operably connected to a pulse generator and It is equipped with, The balloon catheter assembly (i) A proximal connector configured to operably connect the balloon catheter assembly to a pulse generator and to convert the first pulse energy generated by the pulse generator into a second pulse energy, (ii) distal balloon and (iii) A catheter component comprising a fluid passage operably positioned between a proximal connector and a distal balloon, configured to propagate a second pulse energy along the fluid passage from a proximal connector to a distal balloon, and A pulsating balloon catheter system equipped with this system. 2. The pulsating balloon catheter system as described in Appendix 1, wherein the proximal connector comprises a proximal chamber and a distal chamber separated by a membrane. 3. The pulsating balloon catheter system described in Appendix 2, wherein the proximal chamber is defined by the proximal flange and the distal chamber is defined by the distal flange. 4. The pulsating balloon catheter system according to Appendix 3, wherein the proximal flange comprises a proximal port configured to receive a first pulse energy generated by a pulse generator. 5. A pulsating balloon catheter system according to any one of the appendices 2 to 4, wherein the distal flange has a distal port that fluidly connects the distal chamber to a fluid passage.

[0175] 6. A pulsating balloon catheter system as described in any one of the appendices 2 to 5, wherein the proximal chamber contains gas and the distal chamber contains liquid. 7. A pulsating balloon catheter system according to any one of the appendices 2 to 6, further comprising a pressure sensor operably coupled to the distal chamber by a proximal connector. 8. A pulsating balloon catheter system according to any one of the appendices 2 to 7, wherein the proximal connector comprises a membrane position sensor configured to detect changes in the membrane position of the membrane. 9. The pulsating balloon catheter system described in Appendix 8, wherein the membrane position sensor is a Hall sensor. 10. The pulsating balloon catheter system as described in Appendix 9, comprising a fixed magnet positioned to modulate the voltage of a Hall sensor during membrane movement.

[0176] 11. A pulsating balloon catheter system according to any one of the appendices 1 to 10, wherein the proximal connector further comprises an electrical assembly. 12. A pulsating balloon catheter system as described in Appendix 11, wherein the electrical assembly comprises a circuit. 13. A pulsating balloon catheter system as described in Appendix 11 or 12, wherein the electrical assembly includes memory. 14. A pulsating balloon catheter system as described in Appendix 13, wherein the memory includes distal balloon information. 15. A pulsating balloon catheter system as described in Appendix 14, wherein the distal balloon information includes one or more of the following: expiration date, batch number, balloon size, balloon rated burst and nominal pressure, cycle limit, and cycles used.

[0177] 16. A pulsating balloon catheter system according to any one of appendices 11 to 15, wherein the proximal connector further comprises an electrical connector that electrically connects the electrical assembly to the pulse generator. 17. Catheter components, Proximal flexible tube and Distal catheter shaft and A pulsating balloon catheter system according to any one of the appendices 1 to 16, comprising a connector that connects the distal end of a proximal flexible tube to the proximal end of a distal catheter shaft. 18. The pulsating balloon catheter system according to Appendix 17, wherein the connector comprises a first branch configured to provide guidewire access to a guidewire channel of the catheter shaft, and a second branch configured to fluidly connect the lumen of the proximal flexible tube and the distal catheter shaft. 19. The pulsating balloon catheter system described in Appendix 18, wherein the connector is a Y-connector. 20. A pulsating balloon catheter system as described in any one of the appendices 1 to 19, wherein the distal balloon is equipped with a composite balloon.

[0178] 21. The pulsating balloon catheter system described in Appendix 20, wherein the composite balloon comprises an extensible component and a non-extensible component. 22. A pulsating balloon catheter system according to any one of the appendices 1 to 21, wherein the balloon catheter assembly comprises a sealed assembly filled with a predetermined volume of liquid. 23. A pulsating balloon catheter system as described in Appendix 22, wherein the liquid contains a contrast agent. 24. A pulsating balloon catheter system as described in any one of the appendices 1 to 23, wherein the pulse generator is configured to generate pneumatic pulse energy. 25. A pulsating balloon catheter system according to any one of the appendices 1 to 24, wherein the pulse generator comprises a handheld actuator operably connected to the proximal connector.

[0179] 26. A pulsating balloon catheter system described in any one of the appendices 1 to 25, wherein the pulse generator is reusable. 27. A pulsating balloon catheter system as described in any one of the appendices 1 to 26, wherein the balloon catheter assembly is configured for single use. 28. A pulsating balloon catheter system as described in Appendix 1, configured to generate pressure pulses having an amplitude selected based on therapeutic efficacy. 29. A pulsating balloon catheter system as described in Appendix 28, in which therapeutic effectiveness is evaluated by volume changes in the balloon. 30. A pulsating balloon catheter system as described in Appendix 28, wherein the change in volume within the balloon is determined by the diaphragm position.

[0180] 31. A pulsating balloon catheter system as described in any one of the appendices 1 to 30, further configured to evaluate vascular distensibility. 32. The pulsating balloon catheter system according to Appendix 31, further comprising a membrane position sensor configured to detect changes in the position of the membrane, and further configured to evaluate vascular distension based on changes in pressure detected by a pressure sensor and changes in volume based on changes in the position of the membrane. 33. The pulsating balloon catheter system as described in Appendix 32, wherein the membrane position sensor is a Hall sensor. 34. The pulsating balloon catheter system as described in Appendix 33, further comprising a fixed magnet positioned to modulate the voltage of the Hall sensor during membrane movement. 35. A pulsating balloon catheter system as described in any one of the appendices 31-34, further configured to assess vascular distensibility in virtually real time during treatment.

[0181] 36. A pulsating balloon catheter system as described in any one of the appendices 31-35, further configured to evaluate vascular distensibility before and after treatment. 37. A pulsating balloon catheter system described in any one of the appendices 31-36, the therapeutic effect of which is evaluated based on changes in vascular distensibility. 38. A pulsating balloon catheter system as described in any one of the appendices 1 to 37, further configured to detect the system state. 39. The pulsating balloon catheter system as described in Appendix 38, further comprising an electronic circuit configured to detect the system state. 40. A pulsating balloon catheter system as described in Appendix 39, wherein the electronic circuit is configured to compare the measured system characteristics with a target threshold.

[0182] 41. A pulsating balloon catheter system as described in Appendix 40, wherein the measured system characteristics include pressure. 42. A pulsating balloon catheter system as described in Appendix 41, wherein the measured pressure is the catheter pressure. 43. A pulsating balloon catheter system as described in Appendix 42, wherein the measured catheter pressure is the maximum amplitude of the pulsating catheter pressure. 44. A pulsating balloon catheter system as described in Appendix 41, wherein the measured system characteristics include volume. 45. A pulsating balloon catheter system as described in Appendix 44, wherein the measured volume is the distal balloon volume.

[0183] 46. ​​The pulsating balloon catheter system described in Appendix 45, wherein the measured distal balloon volume is the maximum distal balloon volume. 47. Electronic circuits, A comparator circuit configured to compare measured system characteristics with a target threshold, A flip-flop configured to store the result of a comparator circuit, Clocked based on pressure control signals, The data values ​​stored in a flip-flop reflect the system state of the flip-flop and A pulsating balloon catheter system comprising any one of the features described in Appendix 40 to 46. 48. The pulsating balloon catheter system as described in Appendix 47, wherein the circuit is configured to write the results of the comparator circuit to a flip-flop such that the results of the comparator circuit substantially correspond to a comparison of the maximum amplitude catheter pressure or the maximum distal balloon volume. 49. A pulsating balloon catheter system as described in Appendix 47 or 48, wherein the pressure control signal is based on a catheter pressure control signal. 50. The pulsating balloon catheter system described in Appendix 49, wherein the catheter pressure control signal is a solenoid trigger signal.

[0184] 51. The pulsating balloon catheter system described in Appendix 50, wherein the circuit is configured to write the result of the comparator circuit to a flip-flop when the solenoid trigger signal falls. 52. A pulsating balloon catheter system as described in any one of the appendices 38 to 51, wherein the detected system condition is one or more of the following: abnormal pressure, system leak, or balloon burst.

[0185] 53. A method for applying pulsating energy to a luminal tissue location, Deploy the pulsating balloon catheter system described in any one of the appendices 1 to 52 so that the distal balloon is adjacent to the luminal tissue, The system is activated to apply pulsating energy to the location of the luminal tissue. Methods that include... 54. The method described in Appendix 53, which is a method for performing dynamic balloon angioplasty. 55. Methods for evaluating vascular distensibility, as described in Appendices 53 and 54.

[0186] 56. A method for evaluating the vascular distensibility of luminal tissue locations using a balloon catheter system, The balloon catheter system has a distal balloon connected to a catheter component. The method is The balloon catheter system is deployed so that the distal balloon is adjacent to the luminal tissue, Operate the balloon catheter system to apply pressure to the distal balloon via the catheter component, To detect changes in the volume of the distal balloon and to detect changes in pressure applied to the distal balloon via the catheter component substantially simultaneously, Based on the detected changes in volume and pressure, the vascular distensibility of the luminal tissue is evaluated. A method for evaluating vascular distensibility, including the following. 57. A method for evaluating vascular distensibility as described in Appendix 56, wherein the vascular distensibility of the luminal tissue location is measured substantially in real time during treatment. 58. A method for evaluating vascular distensibility according to Appendix 56 or 57, further comprising measuring the vascular distensibility of the luminal tissue at different time points during treatment. 59. A method for evaluating vascular distensibility as described in Appendix 56, further comprising evaluating the vascular distensibility of the luminal tissue location before and after treatment. 60. A method for evaluating vascular distensibility as described in any one of the appendices 56 to 59, further comprising measuring the absolute vascular distensibility of the luminal tissue location.

[0187] 61. A method for evaluating vascular distensibility as described in Appendix 60, wherein absolute vascular distensibility is determined based on measuring the cross-sectional area of ​​the luminal tissue. 62. A method for evaluating vascular distensibility as described in Appendix 61, comprising measuring the cross-sectional area of ​​the luminal tissue by applying one or more of the following techniques: X-ray fluoroscopy, intravascular ultrasound, or optical coherence tomography.

[0188] 63. A balloon catheter assembly, (a) A proximal connector configured to operably connect the balloon catheter assembly to a pulse generator and to convert the first pulse energy generated by the pulse generator into a second pulse energy, (b) distal balloon and (c) A catheter component comprising a fluid passage operably positioned between a proximal connector and a distal balloon, configured to propagate a second pulse energy along the fluid passage from a proximal connector to a distal balloon, and A balloon catheter assembly equipped with the following features. 64. The balloon catheter assembly according to Appendix 63, wherein the proximal connector comprises a proximal chamber and a distal chamber separated by a membrane. 65. The balloon catheter assembly described in Appendix 64, wherein the proximal chamber is defined by a proximal flange and the distal chamber is defined by a distal flange. 66. The balloon catheter assembly according to Appendix 65, wherein the proximal flange comprises a proximal port configured to receive a first pulse energy generated by a pulse generator. 67. A balloon catheter assembly according to any one of the appendices 64 to 66, wherein the distal flange comprises a distal port that fluidly connects the distal chamber to a fluid passage.

[0189] 68. A balloon catheter assembly according to any one of the appendices 64 to 67, wherein the proximal chamber contains gas and the distal chamber contains liquid. 69. A balloon catheter assembly according to any one of the appendices 64 to 68, further comprising a pressure sensor operably coupled to a distal chamber by a proximal connector. 70. A balloon catheter assembly according to any one of the appendices 64 to 69, wherein the proximal connector comprises a membrane position sensor configured to detect changes in the membrane position of the membrane. 71. The balloon catheter assembly described in Appendix 70, wherein the membrane position sensor comprises a Hall sensor. 72. A balloon catheter assembly according to any one of the appendices 63 to 71, wherein the proximal connector further comprises an electrical assembly.

[0190] 73. The balloon catheter assembly described in Appendix 72, wherein the electrical assembly comprises a circuit. 74. The balloon catheter assembly according to Appendix 72 or 73, wherein the electrical assembly includes memory. 75. A balloon catheter assembly as described in Appendix 74, wherein the memory includes distal balloon information. 76. A balloon catheter assembly as described in Appendix 75, wherein the distal balloon information includes one or more of the following: expiration date, batch number, balloon size, balloon rated burst and nominal pressure, cycle limit, and cycles used. 77. A balloon catheter assembly according to any one of appendices 72 to 76, wherein the proximal connector further comprises an electrical connector that electrically connects the electrical assembly to a pulse generator.

[0191] 78. The catheter component comprises a proximal flexible tube, a distal catheter shaft, and a connector connecting the distal end of the proximal flexible tube to the proximal end of the distal catheter shaft and is the pulsating balloon catheter system according to any one of Appendices 63 to 77. 79. The connector comprises a first branch configured to provide guide wire access to the guide wire channel of the catheter shaft and a second branch configured to fluidly couple the lumens of the proximal flexible tube and the distal catheter shaft, and is the balloon catheter assembly according to Appendix 78. 80. The connector is a Y-connector, and is the balloon catheter assembly according to Appendix 79. 81. The distal balloon comprises a composite balloon, and is the balloon catheter assembly according to any one of Appendices 63 to 80. 82. The composite balloon comprises a stretchable component and a non-stretchable component, and is the balloon catheter assembly according to Appendix 81.

[0192] 83. The balloon catheter assembly according to any one of Appendices 63 to 82 comprises a sealed assembly filled with a liquid of a predetermined volume. 84. The liquid contains a contrast agent, and is the balloon catheter assembly according to Appendix 83. 85. The balloon catheter assembly according to any one of Appendices 63 to 84 is configured for single use. 86. The balloon catheter assembly according to any one of Appendices 63 to 85 is further configured to evaluate vascular extensibility. 87. The system further comprises a membrane position sensor configured to detect a change in the position of the membrane, and the system is further configured to evaluate vascular extensibility based on a change in volume based on a change in pressure detected by a pressure sensor and a change in the position of the membrane, and is the balloon catheter assembly according to Appendix 69.

[0193] 88. The balloon catheter assembly described in Appendix 87, wherein the membrane position sensor comprises a Hall sensor. 89. The balloon catheter assembly described in Appendix 88, further comprising a fixed magnet positioned to modulate the voltage of the Hall sensor during membrane movement. 90. A balloon catheter assembly described in any one of the appendices 86-89, further configured to assess vascular distension in virtually real time during treatment. 91. A balloon catheter assembly as described in any one of the appendices 86-90, further configured to evaluate vascular distension before and after treatment. 92. A balloon catheter assembly described in any one of the appendices 86-91, whose therapeutic effectiveness is evaluated based on changes in vascular distensibility.

[0194] 93. A balloon catheter assembly as described in any one of appendices 63 to 92, further configured to detect the system state. 94. The balloon catheter assembly described in Appendix 93, further comprising an electronic circuit configured to detect the system state. 95. The balloon catheter assembly described in Appendix 94, wherein the electronic circuit is configured to compare the measured system characteristics with a target threshold. 96. The balloon catheter assembly described in Appendix 95, wherein the measured system characteristics, including pressure, are those of the balloon catheter assembly described in Appendix 95. 97. The balloon catheter assembly described in Appendix 96, wherein the measured pressure is the catheter pressure.

[0195] 98. The balloon catheter assembly described in Appendix 97, wherein the measured catheter pressure is the maximum amplitude of the pulsating catheter pressure. 99. The balloon catheter assembly described in Appendix 95, wherein the measured system characteristics include volume. 100. The measured volume is the distal balloon volume, as described in Appendix 99 of the balloon catheter assembly. 101. The balloon catheter assembly described in Appendix 100, wherein the measured distal balloon volume is the maximum distal balloon volume. 102. Electronic circuits, A comparator circuit configured to compare measured system characteristics with a target threshold, A flip-flop configured to store the result of a comparator circuit, Clocked based on pressure control signals, The data values ​​stored in a flip-flop reflect the system state of the flip-flop and A balloon catheter assembly comprising any one of the items described in Appendix 95 to 101.

[0196] 103. The balloon catheter assembly described in Appendix 102, wherein the circuit is configured to write the results of the comparator circuit to a flip-flop such that the results of the comparator circuit substantially correspond to a comparison of the maximum amplitude catheter pressure or the maximum distal balloon volume. 104. A balloon catheter assembly as described in Appendix 102 or 103, wherein the pressure control signal is based on a catheter pressure control signal. 105. The balloon catheter assembly described in Appendix 104, wherein the catheter pressure control signal is a solenoid trigger signal. 106. The balloon catheter assembly described in Appendix 105, wherein the circuit is configured to write the result of the comparator circuit to a flip-flop on the falling edge of the solenoid trigger signal. 107. A balloon catheter assembly as described in any one of the appendices 93 to 106, wherein the detected system condition is one or more of the following: abnormal pressure, system leak, or balloon burst.

[0197] 108. A kit comprising a balloon catheter assembly as described in any one of the appendices 63 to 107. 109. The kit described in Appendix 108, further comprising a pulse generator described in any one of Appendix 1 to 52.

[0198] 110. A pulsatile balloon catheter system comprising: (a) a pulse generator; (b) a balloon catheter assembly operably connected to the pulse generator and configured to be remotely operated. A pulsatile balloon catheter system configured to be remotely operated. 111. The pulsatile balloon catheter system according to appended claim 110, configured to provide treatment-based feedback information to a user. 112. The pulsatile balloon catheter system according to appended claim 111, wherein the treatment-based feedback information includes one or more of balloon pressure, volume change, treatment success, and balloon frequency. 113. The pulsatile balloon catheter system according to appended claim 111 or 112, configured to provide treatment-based feedback information to a user via one or more of audio, visual, and tactile (e.g., vibration). 114. The pulsatile balloon catheter system according to any one of appended claims 110 to 113, comprising a station for an operator to perform a treatment using the system. 115. The pulsatile balloon catheter system according to appended claim 114, wherein the station is shielded.

[0199] 116. The pulsatile balloon catheter system according to any one of appended claims 110 to 115, wherein the balloon catheter assembly comprises a catheter component and a distal balloon pre-filled with a liquid. 117. The pulsatile balloon catheter system according to appended claim 116, wherein the liquid comprises saline or contrast agent liquid. 118. The pulsatile balloon catheter system according to any one of appended claims 110 to 117, wherein the balloon catheter assembly comprises a distal balloon configured to automatically contract upon release of pressure. 119. The pulsatile balloon catheter system according to appended claim 118, wherein the distal balloon comprises a composite balloon.

[0200] In at least some of the embodiments described above, one or more elements used in one embodiment may be interchangeably used in another embodiment unless such substitution is technically feasible. It will be understood by those skilled in the art that various other omissions, additions, and modifications may be made to the methods and structures described above without departing from the scope of the claimed subject matter. All such modifications and changes are intended to be within the scope of the subject matter defined by the appended claims.

[0201] In general, it will be understood by those skilled in the art that the terms used herein, and in particular in the appended claims (e.g., the text of the appended claims), are generally intended to be “open” terms (for example, “including” should be interpreted as “including but not limited to,” “having” as “at least having,” and “includes” as “including but not limited to,” etc.). It will further be understood by those skilled in the art that where a certain number of introduced claim enumerations are intended, such intent will be explicitly enumerated in the claims, and where such enumerations are not present, such intent does not exist. For example, for the sake of understanding, the following appended claims may include the use of the introductory phrases “at least one” and “one or more” to introduce claim enumerations. However, even if the same patent claim includes an introductory phrase such as "one or more" or "at least one," and an indefinite article such as "a" or "an," the use of such phrases should not be interpreted as meaning that the introduction of a claim enumeration by the indefinite article "a" or "an" limits any particular patent claim containing such introduced claim enumeration to embodiments containing only one such enumeration (for example, "a" and / or "an" should be interpreted as meaning "at least one" or "one or more"), and the same applies to the use of definite articles used to introduce claim enumerations. Furthermore, even if a specific number of introduced claim enumerations are explicitly listed, a person skilled in the art will recognize that such enumerations should be interpreted as meaning at least the number listed (for example, a bare enumeration of "two enumerations" without other modifiers means at least two enumerations, or two or more enumerations).Furthermore, when conventions similar to "at least one of A, B, and C, etc." are used, such constructions are generally intended to be understood by those skilled in the art (for example, "a system having at least one of A, B, and C" includes, but is not limited to, systems having A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). When conventions similar to "at least one of A, B, or C, etc." are used, such constructions are generally intended to be understood by those skilled in the art (for example, "a system having at least one of A, B, or C" includes, but is not limited to, systems having A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those skilled in the art that substantially any disjunctive word and / or disjunctive phrase presenting two or more alternative terms, whether in the specification, claims, or drawings, should be understood as intended to include the possibility of including one of the terms, either of the terms, or both of the terms. For example, the phrase "A or B" should be understood to include the possibility of "A" or "B" or "A and B".

[0202] Furthermore, if any feature or aspect of this disclosure is described from the perspective of the Marsch Group, a person skilled in the art will recognize that the disclosure is also described from the perspective of an individual member of the Marsch Group or any subgroup of a member of the Marsch Group.

[0203] For any and all purposes, including providing written explanations so as will be understood by those skilled in the art, all scopes disclosed herein also encompass any and all possible sub-scopes, and combinations thereof. Any listed scope can be readily recognized as sufficiently indicating and enabling that the same scope can be broken down into at least equal 1 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 10, etc. As a non-limiting example, each scope considered herein can readily be broken down into the lower third, the middle third, the upper third, etc. So as will be understood by those skilled in the art, all terms such as “maximum,” “at least,” “greater than,” and “less than” include the numbers listed and refer to scopes that can be subsequently broken down into sub-scopes as considered above. Finally, as will be understood by those skilled in the art, a scope includes each individual member. Thus, for example, a group having 1 to 3 articles refers to a group having 1, 2, or 3 articles. Similarly, a group having 1 to 5 items refers to a group having 1, 2, 3, 4, or 5 items, etc.

[0204] Although the aforementioned inventions are described in some detail as examples and illustrations for the purpose of clarifying understanding, it will be readily apparent to those skilled in the art, in light of the teachings of the present invention, that certain changes and modifications can be made to them without departing from the spirit or scope of the appended claims.

[0205] Therefore, the foregoing is merely illustrative of the principles of the present invention. Those skilled in the art will understand that various configurations embodying the principles of the present invention and falling within its spirit and scope can be devised, although these are not explicitly described or illustrated herein. Furthermore, all examples and conditional statements listed herein are intended primarily to assist the reader in understanding the principles of the present invention and the concepts to which the inventors have contributed to the advancement of the art, and should be interpreted not as limitations to such specifically listed examples and conditions. In addition, all descriptions herein listing the principles, aspects, and embodiments of the present invention, as well as specific examples thereof, are intended to encompass both their structural and functional equivalents. Moreover, such equivalents are intended to include both currently known equivalents and those to be developed in the future, i.e., any development element that performs the same function regardless of its structure. Furthermore, nothing disclosed herein, whether or not such disclosure is explicitly listed in the claims, is intended to be made available to the public.

[0206] Accordingly, the scope of the present invention is not intended to be limited to the exemplary embodiments illustrated and described herein. Rather, the scope and spirit of the present invention are embodied in the appended claims. In the claims, § 112(f) or § 112(6) of the U.S. Patent Act is expressly defined as being invoked to limit such claims only if the exact phrase “means for” or the exact phrase “steps for” that begin the limitation to the claims is enumerated, and if such exact phrase is not used in the limitation to the claims, § 112(f) or § 112(6) of the U.S. Patent Act is not invoked.

[0207] Cross-reference of related applications In accordance with Section 119(e) of the United States Patent Act, this application claims priority to the filing dates of U.S. Provisional Patent Application No. 63 / 274,832 filed on 2 November 2021, U.S. Provisional Patent Application No. 63 / 241,295 filed on 7 September 2021, and U.S. Provisional Patent Application No. 63 / 145,641 filed on 4 February 2021, the disclosures of which are incorporated herein by reference in their entirety.

Claims

1. A pulsating balloon catheter system, (a) A pulse generator and (b) A balloon catheter assembly operably connected to the pulse generator and It is equipped with, The balloon catheter assembly, (i) A proximal connector configured to operably connect the balloon catheter assembly to the pulse generator and to convert the first pulse energy generated by the pulse generator into a second pulse energy, (ii) Distal balloon and (iii) A catheter component comprising a fluid passage operably positioned between the proximal connector and the distal balloon, configured to propagate the second pulse energy along the fluid passage from the proximal connector to the distal balloon, and A pulsating balloon catheter system equipped with this system.

2. The pulsating balloon catheter system according to claim 1, wherein the proximal connector comprises a proximal chamber and a distal chamber separated by a membrane.

3. The pulsating balloon catheter system according to claim 2, wherein the proximal chamber contains a gas and the distal chamber contains a liquid.

4. The pulsating balloon catheter system according to claim 2 or 3, wherein the proximal connector further comprises a pressure sensor operably coupled to the distal chamber.

5. The pulsating balloon catheter system according to any one of claims 2 to 4, wherein the proximal connector comprises a membrane position sensor configured to detect changes in the membrane position of the membrane.

6. The pulsating balloon catheter system according to any one of claims 1 to 5, wherein the proximal connector further comprises an electrical assembly.

7. The catheter component is Proximal flexible tube and Distal catheter shaft and A connector that connects the distal end of the proximal flexible tube to the proximal end of the distal catheter shaft. A pulsating balloon catheter system according to any one of claims 1 to 6, comprising:

8. The pulsating balloon catheter system according to any one of claims 1 to 7, wherein the distal balloon comprises a composite balloon.

9. The pulsating balloon catheter system according to claim 8, wherein the composite balloon comprises an extensible component and a non-extensible component.

10. The pulsating balloon catheter system according to any one of claims 1 to 9, wherein the balloon catheter assembly comprises a sealed assembly filled with a predetermined volume of liquid.

11. The pulsating balloon catheter system according to any one of claims 1 to 10, wherein the pulse generator is configured to generate pneumatic pulse energy.

12. A pulsating balloon catheter system according to any one of claims 1 to 11, configured to generate pressure pulses having an amplitude selected based on therapeutic efficacy.

13. A pulsating balloon catheter system according to any one of claims 1 to 12, further configured to detect the system state.

14. A balloon catheter assembly, (a) A proximal connector configured to operably connect the balloon catheter assembly to a pulse generator and to convert the first pulse energy generated by the pulse generator into a second pulse energy, (b) Distal balloon and (c) A catheter component comprising a fluid passage operably positioned between the proximal connector and the distal balloon, configured to propagate the second pulse energy along the fluid passage from the proximal connector to the distal balloon, and A balloon catheter assembly equipped with the following features.

15. A pulsating balloon catheter system, (a) A pulse generator and (b) A balloon catheter assembly operably connected to the pulse generator and It is equipped with, A pulsating balloon catheter system configured for remote operation.

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