Aortic arch baroreceptor implant for treating hypertension

Abstract

Implanted devices and associated methods of treatment for treating hypertension are provided herein. Such an implant device is configured to be placed in a target region of an aortic arch of a patient to sufficiently stretch an arterial wall in the target region to cause a pressure reflex. Typically, the implant is designed to stretch a target region within the aortic arch by at least 20%, and still allows the arterial wall to be exposed to pulsating flow and allows lateral blood flow into the secondary branch artery. The implant may include two or more expandable structures interconnected in series by an axially expandable flexible connection to accommodate the curvature and complex geometry of the aortic arch to anchor the implant in the aortic arch while appropriately stretching the target region. The target region includes a cylindrical section of the aortic arch between the left common carotid artery and the left subclavian artery.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 336,818, filed on April 29, 2022, and U.S. Provisional Application No. 63 / 443,656, filed on February 6, 2023, the disclosures of which are incorporated herein by reference in their entireties. Technical Field

[0002] In one aspect, the present invention is directed to implantable devices for treating hypertension, and associated components, systems, and methods. Background Art

[0003] One in two adults in the United States has high blood pressure. However, only 24% of patients have their blood pressure adequately controlled. High blood pressure is the leading preventable cause of heart attack, stroke, and death. However, a 10 mmHg (millimeters of mercury) drop in blood pressure reduces this cardiovascular risk by 20%.

[0004] For decades, drug therapy has been the mainstay of hypertension treatment, despite documented poor patient compliance with antihypertensive drug regimens. In 2004, a landmark trial of catheter-based medical devices (i.e., Symplicity 1) first demonstrated the blood pressure-lowering effect of renal denervation via a radiofrequency ablation catheter. Findings from additional clinical trials of renal denervation using radiofrequency and ultrasound energy (i.e., the SPYRAL and RADIANCE trials) have confirmed these findings, although the blood pressure-lowering effects were more modest, with decreases of approximately 5–10 mmHg in dynamically recorded systolic blood pressure.

[0005] Vascular Dynamics develops intravascular implants for the treatment of hypertension that rely on a stent-like device inserted into the carotid artery that lowers blood pressure by stretching the arterial wall from the inside and enhancing the carotid baroreflex. In a 2017 study, this carotid baroreflex modulation device significantly reduced dynamically recorded systolic blood pressure by more than twice that reported in a renal denervation trial. While clinical results initially looked promising, with several patients reporting dramatic reductions in blood pressure that lasted two to three years, clinical results were mixed as some patients suffered transient ischemic attacks (TIAs), which hampered further trials and subsequent development.

[0006] Another challenge is deploying the device in the carotid sinus, which is the primary target of the device. Since the carotid sinus carries blood to the brain, any difficulties encountered in this area, such as trauma to the arterial tissue during deployment, subsequent displacement of the device, and / or plaque accumulation in this area due to the device or trauma, may result in a transient ischemic attack (TIA) or stroke, leading to adverse or fatal patient outcomes. For clinicians who lack experience with this sensitive area, such as placement of carotid artery stents, performing procedures in this area may present unnecessary risks to the patient.

[0007] Therefore, there remains a need for hypertension treatment devices and methods that can provide the clinical benefits seen in baroreflex responses while avoiding the significant drawbacks associated with the conventional methods described above. There is also a need for devices that can improve the ease and consistency of implantation, thereby avoiding known adverse effects, allowing a variety of clinicians to perform implantation, and more reliably provide patients with a positive therapeutic effect to reduce hypertension over the long term. Summary of the invention

[0008] The present invention relates to an implantable hypertension treatment device for deployment within the aortic arch and associated treatment methods.

[0009] In one aspect, the present invention relates to a method for treating hypertension in a patient. Such a method may include the following steps: deploying an implant in the patient's aortic arch, wherein the implant includes a plurality of expandable structures, wherein each of the plurality of expandable structures has an expanded structure and a collapsed structure. In the collapsed structure, the implant can advance through the vascular system, and in the expanded structure, the implant engages the arterial wall of the aortic arch. The method also includes stretching at least a portion of the arterial wall along a target area (particularly along the inner curvature) of a cylindrical section surrounding the aortic arch by engaging one of the expandable structures, thereby triggering a pressure reflex response of pressure receptors in the target area, and exposing most of the arterial wall along the target area to pulsating blood flow through one or more main openings of the implant, thereby maintaining the pressure reflex response caused by the implant for a long time. In some embodiments, the portion of the arterial wall is preferably stretched by at least 20%. In some embodiments, the target area is the entire cylindrical strip of the aorta between the left common carotid artery and the left subclavian artery. Preferably, the implant extends beyond the target area in two directions to ensure optimal engagement with the target area.

[0010] On the other hand, the present invention relates to an implant device for treating hypertension in a patient. Such implants may include two or more expandable structures interconnected in series by a flexible connector, and the expandable structure has a collapsed structure for advancing through the patient's vascular system and an expanded structure for engaging the arterial wall in the patient's aorta. In some embodiments, each expandable structure is formed by one or more wires formed with an expandable design (e.g., one or more nitinol wires formed with a winding, sinusoidal or zigzag design to form a circumferential ring or band). In some embodiments, each expandable structure is defined by a single continuous wire. In some embodiments, each expandable structure is a laser cutting design in a single tube. In some embodiments, the entire implant with multiple expandable structures and flexible connectors can be defined by the laser cutting design of a single tube. In this wire or laser cutting embodiment, the expandable structure can have a substantially circular cross section. In some embodiments, each of the expandable structures includes a plurality of elongated frames, each frame having a pair of struts, the pair of struts defining opposite lateral sides and spaced apart to define a main opening therebetween, wherein the frames are interconnected along adjacent lateral sides to form a regular polygonal cross section.

[0011] In some embodiments, the implant includes three expandable structures, wherein the middle expandable structure is arranged at the target location to activate the baroreceptor nerve, and the proximal expandable structure and the distal expandable structure act as anchors to fix the middle structure at the target location. In such embodiments, the expandable structures may have the same or different sizes. In some embodiments, the implant includes three expandable structures, wherein the lateral dimension of the middle structure is greater than the lateral dimension of the proximal expandable structure and the distal expandable structure (e.g., 1.3-1.5 times). This method allows even more stretching (e.g., 30% or more) along the target area, because the proximal structure and the distal structure help transition the arterial wall and inhibit tearing or dissection of the stretched blood vessel. The size of at least one expandable structure is designed so that when expanded in the target area of ​​the aortic arch, a pair of struts of the corresponding frame stretch the arterial tissue in the target area to a sufficient pressure reflex response of the baroreceptors in the target area, such as stretching 20% ​​or more, and the main opening between the struts exposes the arterial wall of the target area to the pulsating blood flow to maintain the pressure reflex response for a long time. It will be understood that the expandable structure can be any structure described herein (e.g., a linking frame, a continuous wire, a laser cutting portion). BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1A An exemplary implant device is shown deployed along a target area in a patient's aortic arch in accordance with some embodiments.

[0013] Figure 1BAnother exemplary implant device is shown deployed along a target area in a patient's aortic arch in accordance with some embodiments.

[0014] Figure 2 A general view of the vascular and baroreceptor anatomy is shown, along with an illustration of the location of the carotid baroreceptors targeted by a conventional device.

[0015] Figure 3A Details of an exemplary type of baroreceptor called PEIZO1 are shown.

[0016] Figure 3B The response of the central nervous system to baroreflex stimulation in regulating blood pressure is shown.

[0017] Figure 4 The anatomy of the vasculature of the aortic arch is shown.

[0018] Figure 5 The embryonic anatomy that later develops into the aortic arch is shown.

[0019] Figure 6 The anatomy of the aortic arch is shown showing additional detail regarding the target region in accordance with aspects of the present invention.

[0020] Figure 7 The histology of arterial tissue within the target region is shown.

[0021] Fig. 8A Fluorescent staining images from animal studies are shown, illustrating the distribution of baroreceptors in the target area.

[0022] Figure 8B A fluorescent stained image is shown, illustrating the location of baroreceptors within the arterial wall of the aortic lumen.

[0023] Figures 9A-9B Results from previous animal studies are presented, showing that baroreceptors in the aorta are more sensitive than those in the carotid arteries.

[0024] Figures 10A-10D An exemplary implant having two expandable structures interconnected by a flexible connector, the two structures being defined by four frames and having a square cross-section, according to some embodiments, is shown, and Fig. 10E An exemplary implant having three expandable structures is shown in accordance with some embodiments.

[0025] Figures 11A-11B An alternative embodiment of an implant is shown in which the expandable structure is defined by three frames and has a triangular cross-section.

[0026] Figures 12A-12BAn alternative embodiment of an implant is shown in which the expandable structure is defined by five frames and has a hexagonal cross-section.

[0027] Figures 13A-13D An alternative embodiment of an implant having three expandable structures is shown, wherein the intermediate structure has an increased transverse dimension, according to some embodiments.

[0028] Figures 14A-14C Shown are various dimensions (A, B, C, D, E) and features of the aorta that were examined in patient studies to determine the appropriate size of an implant structure deployed in the aorta.

[0029] Figures 15A-15D The mechanism of action according to an embodiment of the present invention is shown by which an appropriately sized structure engages and stretches the substantially circular (eg, 25 mm diameter) aortic wall to achieve sufficient stretch to induce a baroreflex.

[0030] Fig.16 A target region of the aorta is shown according to some embodiments, which is the entire aorta segment between the LCCA and the LSA.

[0031] Fig.17 A delivery catheter configured to deliver and deploy an implant in an aortic arch is shown in accordance with some embodiments.

[0032] Figures 18A-18D An exemplary implant is shown being delivered along a target area to the aortic arch using a delivery catheter, according to some embodiments.

[0033] Figure 19-20 Methods of treating hypertension using an implant according to some embodiments are shown.

[0034] Figures 21A-1 to 21C-3 Alternative designs for expandable structures of aortic arch baroreceptor implants according to some embodiments are shown.

[0035] Fig. 22 The relationship between the compliance of a simulated aortic arch vessel before and after placement of an implant is shown in accordance with some embodiments.

[0036] Figures 23A-23B An exemplary implant utilizing multiple expandable structures interconnected by flexible connectors and deployed in the aortic arch is shown, similar to Figures 21A-1 to 21C-3 The structure in .

[0037] Figures 24A-24F Alternative flexible connector designs between adjacent expandable structures for an aortic arch baroreceptor implant are shown in accordance with some embodiments.

[0038] Fig.25 Another exemplary implant for treating hypertension configured to stretch an arterial wall circumferentially and axially is shown in accordance with some embodiments.

[0039] Fig.26 Deployment in the aortic arch according to some embodiments is shown Fig.25 The steps of implantation. DETAILED DESCRIPTION

[0040] In one aspect, the present invention is directed to an implantable device for treating hypertension configured to be implanted at a target area within the aortic arch to induce a baroreflex response, thereby reducing blood pressure. I. Physiological baroreflex response

[0041] In order to understand the physiological responses of the baroreflex response, it is helpful to understand the interactions between the nervous system within the patient's anatomy. Various aspects of the baroreceptor location with the vasculature, baroreceptor cells, and the interaction of the baroreceptors with the central nervous system, such as Figure 2-3B shown.

[0042] Blood pressure sensation occurs at several hot spots within the vascular system. Afferent nerves from the vagus nerve (i.e., cranial nerve 10) and the glossopharyngeal nerve (i.e., cranial nerve 9) target the aortic arch and the carotid sinus, respectively. Vagal sensory neurons enter the aorta via a thin nerve branch called the depressor aortic nerve, while glossopharyngeal neurons enter the carotid sinus via the carotid sinus nerve (see Figure 2 ). The aortic depressor nerve and the carotid sinus nerve are composed of common bundles of fibers, including mechanosensory and chemosensory afferents. Mechanosensory nerve fibers mediate the baroreflex. The ends of these mechanosensory nerve fibers have specialized nerve endings called baroreceptors, which penetrate the arterial wall. Baroreceptors are stretch receptors that do not measure pressure directly, but rather sense the stretching of the artery. The pulsation of blood pressure with each heartbeat stretches the arterial wall radially, and this arterial stretch in turn activates mechanosensitive neurons. Baroreceptor neurons are long sensory neurons from the aorta to the brain that transmit input directly to the brainstem. Activation of these baroreceptor neurons decreases sympathetic output from the brainstem and increases parasympathetic output, ultimately decreasing blood pressure and heart rate (called the baroreflex).

[0043] At the molecular level, baroreceptors are actually complex protein structures that form ion channels at the sensory endings of baroreceptor nerve fibers (see Figure 3A ). Stimulation of ion channels results in an influx of cations into the neuron and depolarization, whereby a signal is transmitted along the nerve cell. Baroreceptor nerve endings are located in the outer wall of the artery, between the tunica media and the adventitia (see Figure 8B ).

[0044] Baroreceptor neurons are long sensory neurons in the arteries to the brain that transmit input directly to the brainstem. Aortic arch baroreceptor nerve signals originate from the arterial wall, travel through the aortic depressor nerve, then via the superior laryngeal nerve to the vagus nerve, and from there to the brainstem (see Figure 2 and 3B ). The brainstem reflexively regulates this signal, decreasing sympathetic and increasing parasympathetic output to the circulatory system. Blood pressure and heart rate decrease. This series of events is called the baroreflex.

[0045] Early animal studies showed that this response was associated with arterial wall stretching, which occurs naturally in high blood pressure. Later animal studies showed that the baroreflex response could be either transient or sustained, depending on whether the stimulation at the arterial receptor site was static or pulsatile, respectively. Static stimulation caused a decrease in systemic blood pressure that returned to normal after a few minutes, whereas non-static pulsatile stimulation (e.g., similar to natural pulsatile blood flow) showed a sustained decrease in systemic blood pressure.

[0046] Modulation of the baroreflex, and in particular the carotid baroreflex, has been a major target of device-based therapy for difficult-to-control hypertension since the 1960s. The first attempts involved a pacemaker-type device: electrodes placed around the carotid sinus nerve were connected to an implantable stimulator via wires. Stimulation of this nerve innervating the carotid baroreceptors bypasses stimulation within the artery and can lower blood pressure via the carotid baroreflex arc. This technology continues to be used in human clinical trials. A similar type of device for the aortic arch baroreceptors, or more precisely the aortic depressor nerve, has been successfully used to lower blood pressure in a goat experimental model. Despite this, pacemaker-type implants are unlikely to become a device-based solution for refractory hypertension because they have significant disadvantages, such as the reluctance of patients to have a generator surgically inserted into their chest. To overcome this limitation, Vascular Dynamics has developed a stent-like intravascular implant that stretches the carotid wall from the inside and amplifies the carotid baroreflex signal. The device uses a non-articulated, single-form design that is configured for use in a straight segment of the proximal internal carotid artery. In early clinical trials, the device successfully lowered blood pressure in people with resistant hypertension, but there was a small risk of transient ischemic attacks (TIAs) in the brain. There are various disadvantages associated with this approach that can lead to an increased risk of stroke and TIAs.

[0047] The present invention seeks to avoid the above-mentioned disadvantages associated with conventional methods by providing an intravascular implant that causes an improved baroreflex response in the aortic arch. In an exemplary embodiment, the present invention relates to an implant having one or more expandable structures, the expandable structure being configured to stretch the arterial wall along a target area of ​​the aorta, specifically along the aortic arch. In some embodiments, the present invention is configured to engage a target area of ​​the aortic arch opposite the left subclavian artery, the aortic arch including an inner curvature. The target area can be defined as a cylindrical section of the aortic arch between the LCCA and the LSA. In theory, this part of the aortic arch is particularly rich in baroreflex receptors, and these receptors have a higher sensitivity than baroreceptors in various other areas such as the carotid sinus. Since this area of ​​the aortic arch is believed to provide an enhanced response, the implant can achieve a more consistent and reliable reduction in blood pressure. Further, implantation in this area avoids the disadvantages associated with delivery and implantation at a sensitive area of ​​the carotid sinus, which may increase the risk of TIA and stroke. Therefore, the implant described herein provides a more powerful baroreflex response to reduce blood pressure, improves the ease of delivery and implantation, and is believed to reduce the risk of adverse events.

[0048] Early animal studies of differential baroreceptor responses have identified anatomical “hot spots” of baroreceptors at different locations in the blood vessels, including narrow cylindrical bands between the left common carotid artery and the left subclavian artery ( Figure 4 The region extends circumferentially around the aortic arch between the origin of the fourth pharyngeal artery in the Fig. 8A The fluorescent staining image of FIG. 1 shows the baroreceptors stained red. The baroreceptor-rich region can be defined as a cylindrical segment of the aortic arch between the LCCA and the LSA. Figure 4 The target T is shown in FIG.

[0049] These “hot spots” of baroreceptors originate from the embryonic pharyngeal arch arteries, e.g. Figure 5 The third pharyngeal artery develops into symmetrical structures, namely the right and left carotid arteries. In contrast, the right fourth pharyngeal artery (R4PA) becomes the proximal right subclavian artery, while the left fourth pharyngeal artery (L4PA) develops into the Figure 6 A relatively narrow cylindrical band of the aortic arch is shown in B. This band has different characteristics compared to other areas in the aortic arch.

[0050] This band of the aortic arch differs histologically from other regions in that it has fewer smooth muscle cells and an increased elastic lamina. Figure 7 The histological sections of aortic arch segment B are shown in the left column, and the Figure 6Compared to the aortic section in C, it shows fewer smooth muscle cells and an increased elastic layer. The more well-known aortic arch baroreceptors are located in region B (e.g. Figure 2 However, various animal and human studies have shown that baroreceptors in this region actually have a distinct local distribution that extends along the band B that wraps around the aortic arch, as shown in Figure 2. Fig. 8A In addition, the pressure receptors in the aorta lumen are located on the outer layer of the aortic wall, such as Figure 8B A fluorescent image showing baroreceptor nerve fibers stained pink is shown.

[0051] There are few human reports of the localization of baroreceptors in the aortic arch. One early study noted that baroreceptor nerves wrap around the aorta at the origin of the left subclavian artery, and the same authors later noted that they may extend from the brachiocephalic artery around the aorta to the ligamentum arteriosum. Some early studies have shown that baroreceptors are found along this region of the aortic arch extending up to 40% of the circumference. Partly due to the histology of this region described above, it is thought that the baroreceptors behave differently from baroreceptors in other regions including the carotid arteries. At least one animal study suggests that aortic baroreceptors have a lower pressure threshold for stimulating action potentials than carotid baroreceptors, see Fig.9A Animal studies have further shown that 20% uniaxial stretch induces a significant increase in cytosolic calcium fluorescence in aortic arch baroreceptor neurons, but not in carotid artery baroreceptor neurons. Fig. 9B As shown. Therefore, it is believed that the aortic baroreceptors in the human aorta are more sensitive than the baroreceptors in the carotid arteries. Therefore, using an implant specifically configured for deployment in the aortic region to stretch the arterial wall in this target area may achieve a more consistent and pronounced baroreflex response than with a conventional carotid artery implant.

[0052] Notably, the literature describes the presence of baroreceptors at various locations in the body, including the carotid arteries and aorta, and some publications describing passive baroreflex implants mention in passing a list of various possible implant locations, which generally include the aorta; however, none of the literature teaches any specific target area of ​​the aortic arch. Furthermore, none of the literature addresses the unique challenges of implantation in the aortic arch region, which have led to traditional approaches focusing primarily on the carotid arteries, which are typically accessed for the purpose of performing some other procedure, such as placing a carotid stent to address stenosis in that region.

[0053] Thus, the present invention seeks not only to provide an improved baroreflex response by implantation in a specific target region in the aortic arch, but also to allow implantation at this unique location while improving the ease of implantation. Importantly, the claimed implants and methods avoid the disadvantages associated with surgery and implantation within the carotid artery, which can lead to an increase in adverse events due to complications of deployment in this region.

[0054] While delivering the implant to the aortic arch has significant advantages, namely the ability to target aortic arch baroreceptors in the narrow band that wraps the aorta, there are also certain challenges associated with deployment in this area. Since the diameter of the aortic arch is much larger than that of the carotid artery, the implant diameter must correspond to the diameter of the aortic arch in order to fully engage the tissue to achieve the necessary stretching of the arterial wall (e.g., stretching 20% ​​or more, 20-50% or even 20-100%). Further, in order to prevent the implant from flipping or rotating, the length of the implant should preferably be significantly greater than its maximum transverse dimension (e.g., diameter), such as about 40 mm or greater. In some embodiments, the length of the entire implant is 70 mm or greater (e.g., about 85 cm).

[0055] Another challenge is that the aorta is the main artery in the body, so a large amount of blood flow is transported through the aortic arch and into the secondary arteries (e.g., BA, LCC, LSA) that branch out of the aorta. Therefore, in order to provide consistent engagement and stretching at the target area for a long time, the implant must be constructed to withstand the force of the pulsating blood flow through the aortic arch and the lateral force from the blood flow directed into the secondary arteries without displacement. Further, the implant should be constructed to expose most of the arterial wall in the target area to the pulsating blood flow to provide the above-mentioned continuous blood pressure drop, rather than the transient reaction when the arterial wall is isolated from the blood flow. Another challenge is that the implant must allow blood to flow freely in the lateral direction into the secondary branch artery. Therefore, the implant itself is constructed with a main opening in the expandable structure, which allows both exposure of the arterial wall and lateral blood flow to feed any adjacent secondary artery. II. Exemplary Implant Devices

[0056] Figure 1A An exemplary implant device 100 for treating drug-resistant hypertension is shown, which is implanted in the aortic arch AA. The implant is an expandable device inserted into the aortic arch and reduces blood pressure by stretching the aortic arch arterial wall from the inside and enhancing the aortic arch baroreflex. Secondary branch vessels, the brachiocephalic artery (BA), the left common carotid artery (LCCA), and the left subclavian artery (LSA) branch from the top of the AA.

[0057] As shown, implant 100 comprises two expandable structures 10, 20, which are interconnected in series by an axial expandable connector 30. The expandable structures are arranged longitudinally along the aorta, which helps the anchoring and stable placement of the implant in the curved aortic arch. In view of the relatively large size, high blood flow rate and curved morphology of the aorta, anchoring a single expandable structure in this area may prove challenging. By utilizing two or more structures arranged along different parts of the aorta, the implant adapts to the curvature and complex geometry of the aorta to help anchor the implant at the target location. In addition, by relying on the engagement of two or more structures along the aorta, the anchoring force of the implant is distributed over a larger area, thereby minimizing the trauma to the arterial wall, which can reduce inflammation and thrombosis, and thrombosis may cause the formation of atherosclerotic plaques. Although the first expandable structure 10 shown is deployed off-center, it will be understood that the structure can be centrally located on the target area T.

[0058] Figure 1B Another exemplary implant device 110 for treating drug-resistant hypertension is shown, which is implanted in the aortic arch AA. This embodiment includes three expandable structures 10, 20, 40, which are interconnected in series by multiple flexible connectors 30. The implant is configured so that the intermediate expandable structure 40 is deployed at the target area T to activate the pressure receptors in the area, while the proximal structure 10 and the distal structure 20 act as anchors, providing additional stability and also helping to transition the arterial wall to the intermediate expandable structure. As shown, the transverse dimension of the intermediate expandable structure 40 can be greater than the transverse dimension of the proximal expandable structure and the distal expandable structure. Typically, the transverse dimension of the intermediate structure is 1.2-2 times larger than the transverse dimension of the proximal structure and the distal structure, preferably about 1.3-1.5 times. This configuration allows further stretching of the arterial wall at the target area, because the proximal structure and the distal structure stretch the arterial wall to a lesser extent, thereby helping to transition the arterial wall to the increased stretch in the target area. This reduces the risk of dissection along the target area due to increased stretching because the proximal and distal structures distribute some of the forces from stretching at the central area. Further, this configuration provides greater stability to the intermediate structures at the target area. Other aspects of the implant can be similar to Figure 1A The aspects described in are similar or identical.

[0059] like Figure 1A-1BAs shown, the expandable structure can be formed by a plurality of open wire frames formed by spaced apart struts that define each lateral side. The lateral sides of adjacent frames are interconnected along the lateral struts so that the frames form a regular polygonal shape that is symmetrical along the longitudinal axis of the expandable structure. The expandable structure has a collapsed structure (e.g., in a delivery catheter) and an expanded structure (as shown in the figure) for advancing through the vascular system, in which the lateral struts engage the arterial wall of the aorta, thereby fully stretching the arterial wall between each pair of struts in the frame to induce a pressure reflex response. The flexible connector 30 can be axially expandable (e.g., a zigzag connector) to allow the two expandable structures to extend along different longitudinal axes, thereby accommodating different degrees of curvature and complex three-dimensional geometries of the aortic arch. With this construction, twisting of the aorta or adjacent large vessels is minimized, and compressive damage to surrounding anatomical structures such as the left recurrent laryngeal nerve is avoided. It can be seen by reference to Figures 10A-12B Although these embodiments depict implants defined by interconnected frameworks, it will be appreciated that these aspects are applicable to various other types of expandable structures, such as expandable structures formed from one or more wires or laser cut designs formed from tubes.

[0060] Figures 10A-10D An exemplary implant device 100 is shown having two laterally expandable structures 10 , 20 interconnected in series by a plurality of flexible connectors 30 . Fig. 10A A cross-sectional view is shown, and Fig. 10B A lateral side view is shown. Figures 10C-10D The same view is shown, but the device is rotated 45 degrees along the longitudinal axis. The implant device can also include one or more visual markers 31 thereon, such as a coating or gold or platinum point on the flexible connector 30, to assist in positioning during implantation. In this embodiment, the flexible connector is axially expandable (e.g., a zigzag connector), and a total of four connectors extend between the apex of the adjacent crowns of the first expandable structure and the second expandable structure. Fig. 10E An exemplary implant device 100'' is shown having three laterally expandable structures 10, 20, 40 interconnected by a flexible connector 30. It will be understood that some embodiments may also include additional such structures (e.g., 4, 5, 6, etc.) connected in the same or different manner.

[0061] In this embodiment, each expandable structure 10, 20 comprises four elongated frames (10a / 10b / 10c / 10d) connected along adjacent lateral sides to form a square cross-section, such as Fig. 10AAs shown. Each frame includes at least two linear strut sections 11, 12 defining opposite lateral sides, and curved anti-traumatic crowns 13, 14, which connect the proximal end and the distal end, respectively. Therefore, the overall shape of the frame is rectangular or pill-shaped. As shown, the anti-traumatic crowns 13, 14 are gently bent to form a semicircle or a smaller arc so that the engagement of the proximal or distal end against the tissue does not cause trauma to the arterial wall. The struts and crowns define the entire frame, which leaves a main opening 15 through which the arterial wall is exposed to pulsating blood flow and allows lateral blood flow to enter the secondary branch arteries. In some embodiments, the struts of adjacent frames are defined as single struts, so that a square cross-section implant will have only four struts in total, with one strut on each corner. It is also worth noting that the entire frame can be formed as a single continuous wire so that the crown and the struts are different parts of the same wire. In some embodiments, the frame is designed to avoid any sharp corners or angled features less than 100 degrees, which ensures that the proximal and distal ends of the frame remain atraumatic and helps avoid thrombus or plaque formation within the frame along the main openings through which lateral blood flow is maintained. This design is advantageous because the square cross-section provides sufficient stretching of the arterial wall between the struts on opposite sides of each frame without overstretching any one portion of the arterial wall, but still maintaining normal function and blood flow of the aorta. Although this embodiment includes two expandable structures interconnected by four flexible connectors, the implant can include additional expandable structures connected in series in the same manner and can include more or fewer flexible connectors.

[0062] It will be appreciated that these concepts can be used with a variety of other shapes / designs, such as triangles or any regular polygonal cross-section, such as Figures 11A-13D Those shown in . Figures 11A-11B An implant 100' is shown having a first expandable structure 10' and a second expandable structure 20', each structure having a Fig. 10A A similar frame as in, except that each component is formed by three frames so that the cross section is triangular (e.g., an equilateral triangle). In this embodiment, the maximum transverse dimension of the component will be the length of each side of the triangle, which stretches three parts of the arterial wall. Figures 12A-12B Still another implant 100" is shown having a first expandable structure 10" and a second expandable structure 20", each structure being composed of Fig. 10A A similar frame formation is shown in FIG. 1, except that each component is formed of five frames to form a hexagon that stretches five portions of the arterial wall. In this embodiment, the maximum transverse dimension will be the distance between the vertex and the midpoint of the opposite side. Figures 13A-13D An implant 110 having three expandable structures 10, 20, 40 is shown (see Figure 1B), wherein the intermediate expandable structure 40 has a transverse dimension d2 that is greater than the transverse dimension d1 of the proximal expandable structure 10 and the distal expandable structure 20. Dimension d2 can be 1.2 to 2 times larger than d1, preferably approximately 1.3-1.5 times. In this embodiment, dimension d2 is 1.3 times larger than d1. As previously described, this configuration further improves the stability of the implant device in the aortic arch and advantageously allows further stretching of the target area rather than safely performing stretching in other circumstances. This is made possible by utilizing the proximal expandable structure and the distal expandable structure to transition the arterial wall and reduce the risk of dissection or tearing outside the target area.

[0063] On the other hand, the size of the implant is specifically designed for the size of the human aortic arch so that the arterial wall engages with the lateral struts of the expandable structure, thereby anchoring the implant within the aortic arch and fully stretching the arterial wall in the target area. In the embodiment shown in Figure 1, the implant is positioned so that the first expandable structure 10 is positioned relative to the LSA along the target area of ​​the cylindrical band wrapped around the aorta, as previously described. Therefore, the engagement of a pair of lateral struts in this area stretches the arterial wall and stimulates the highly sensitive pressure receptors in this area. In some embodiments, the size of the implant is designed to achieve a 2:1 implant to aorta diameter ratio at the pressure receptor target area. III. Dimensioning of aortic arch implants

[0064] The baroreceptor amplification device is an intravascular implant designed to amplify the baroreflex response by stimulating highly sensitive baroreceptors in precise locations within the aorta. This is achieved by appropriately designing the size of the implant described herein to achieve sufficient stretching of the arterial wall in the target area (e.g., at least 15%, typically 20% or more). The implant is sized based on the unique morphology of the human aortic arch. In some embodiments, the applicable size for such an implant has been determined by a computed tomography angiography (CTA) study of the human aorta. Measurements of the aortic arch CTA were obtained from 50 patients, including men and women between the ages of 53 and 88 years old. The measurements were tabulated and the average and range were determined according to Tables 1 and 2 below.

[0065] Table 1 shows the mean values ​​of various aortic arch measurements, including the aortic arch diameters along regions A, B, C, and D (see Fig. 14B ) and the length E extending between section A and section D (see Fig.14A ). Table 1. Average measurements of the aortic arch

[0066] Table 2 shows the ranges of various aortic arch measurements, including aortic arch diameter along regions A, B, C, D and length E as described above. Table 2. Aortic arch measurement range

[0067] In one aspect, diameter and length dimensions can be considered to exhibit relatively little variation, as demonstrated by small standard deviations and narrow ranges. Fig. 14C As shown, the aortic arch region has a plurality of different regions, wherein the various parts of the implant device may be implanted or anchored by one or more parts of the implantable device. Therefore, the implant device design should not only adapt to the target region (e.g., typically region E), but also include a proximal expandable structure and a distal expandable structure, which are configured to engage the inner diameter along the more proximal region (e.g., region F or G) and the more distal region (e.g., region AD). Therefore, it can be considered to manufacture an implant of appropriate size to fit most patients within the above range. It is worth noting that the arterial wall can be safely stretched up to 50%, and may be up to 100% in healthy patients, so that as long as the target region is fully stretched (e.g., at least 20%), the stretching variation caused by the difference in aortic size is acceptable. Alternatively, it can be considered that the average and range of these sizes guarantee implants of different sizes. In some embodiments, a set of implants of different sizes (e.g., 3-10 different sizes) can be provided, and the size can be easily selected according to the specific measurements of the aortic arch of a given patient (see Table 3 below). In another alternative, the implant can be customized according to the unique measurements of the patient. The latter two options may be well suited for patients with highly variable aortic arch morphology or particularly complex geometry.

[0068] Based on the above-mentioned average values ​​and ranges for the human aorta, two or more expandable structures can be appropriately sized to be placed in the aorta. In an exemplary embodiment, the length of each expandable structure is between 30 mm and 60 mm, typically about 40 mm in length, and the maximum transverse dimension (e.g., diameter) is between 30 mm and 55 mm, typically between 30 mm and 46 mm. These dimensions accommodate most aortas of ordinary adults while providing the stretch required to induce a pressure reflex response along the target area. The lengths of the expandable structures can be the same or different, and the diameters can be the same or different.

[0069] Table 3 below shows a set of implants of different sizes and associated diameters, which are based on a list of relevant sizes of aortic arches in more than 50 patients in a CTA study. Component A refers to the more distal expandable structure (20 in FIG. 1 ) disposed at the target area, and component B refers to the more proximal expandable structure (10 in FIG. 1 ) disposed at the target area. As described above, the implant size suitable for the patient's unique morphology can be selected based on a CT scan of the patient's aortic arch. It will be understood that a set of sizes can include any of the sizes or any combination thereof, as well as various other combinations not listed. Table 3. Implant configuration dimensions (diameter) size Part A Part B 1 30 mm 30mm 2 30mm 34mm 3 30mm 38mm 4 34mm 34mm 5 34mm 38mm 6 34mm 42mm 7 38mm 38mm 8 38mm 42mm 9 38mm 46mm 10 42mm 42mm 11 42mm 46mm 12 42mm 50mm

[0070] In another aspect, two or more expandable structures are connected in series by a plurality of flexible connectors. Preferably, the connector is axially expandable (e.g., a zigzag design) to optimize conformity with the outer and inner curvatures of the aortic arch. In some embodiments, the connector is axially expandable by 5-20 mm, typically about 5-10 mm. In some embodiments, the connector is between an unexpanded 5 mm and up to about 10 mm or more fully expanded, such that the connector on the outer curvature of the aortic arch can be expanded while the connector on the inner curvature of the aortic arch can remain unexpanded, such as Figure 1A-1B shown.

[0071] On the other hand, the length of each expandable structure is typically between 30mm and 50mm, preferably about 40mm, so that the total length of the entire implant including the flexible connector is between 65mm and 110mm, typically between 70-90mm, depending on the axial extension of the connector. These lengths allow the implant to extend at least 10mm beyond the lateral aspect of the brachiocephalic artery and the lateral aspect of the left subclavian artery to ensure a safe and stable load zone for the device. Based on CTA studies, the implant is approximately 85mm when the connector is not expanded and approximately 10mm or greater (e.g., 10-20mm) when the connector is fully expanded.

[0072] Based on previous animal studies, it is believed that human aortic arch baroreceptors require stretching of at least approximately 20% to achieve a significant increase in baroreceptor nerve signaling. Therefore, the implant is sized to have a maximum transverse dimension, or diameter, that is at least 20% larger than the natural diameter at the target area (e.g., measurement C in CT angiography studies). The diameter of the implant should be sufficient to ensure adequate conformation to the aortic arch wall at the terminal landing zone beyond the lateral outlets of the brachiocephalic and left subclavian arteries (e.g., locations A and D in Figure 13). For sizing purposes, the diameter of the implant is measured as the largest transverse dimension (e.g., for a square cross-section, Fig. 10ABased on CTA studies, the implant can be sized to a variety of different diameters, such as 30 mm, 34 mm, 38 mm, 42 mm, 46 mm, and 50 mm. The implant can be constructed from components A and B of different diameters, such as those shown in Table 3. IV. Mechanism of Action

[0073] To further understand the sizing of the implant, the mechanism by which the implant lowers blood pressure should be understood. It is helpful to think of the aortic arch as a circular cross section and the arterial wall as discrete arc lengths, e.g. Fig.15A The arc length formula is shown in the figure. In the case of an implant with a square cross section (such as Fig. 10A As shown in Figure 1, the diameter of the aorta is considered to be a circle divided into equal parts (e.g., four equal parts). If the diameter of the aortic arch is 25 mm, the radius will be 12.5 mm and the length of each arc will be 19.6 mm, as shown in Figure 1. Fig. 15B After insertion of the same example 30 mm diameter implant, the aortic arch radius will be 15 mm and each arc length will be 23.6 mm, provided that the aortic arch remains circular, as shown in FIG. Fig. 15C shown.

[0074] Therefore, due to the 20% increase in radius, from the baseline ( Fig. 15B ) to after implantation( Fig.15D ) will increase by 20% while the other variables remain constant. In other words, each arc of the aorta will stretch by 20%. However, the aortic arch does not remain circular after insertion of the implant. The radius of curvature of each arc increases while the central angle corresponding to that arc decreases (see Figure 23C). The changes in these two variables in opposite directions confound accurate estimates of the resulting arc length and the degree of aortic arch stretch, but this approach provides a sufficiently reasonable estimate of the stretch obtained to appropriately size the implant to achieve at least a 20% stretch. It is worth noting that the above analysis assumes that Fig. 10A The implant in the figure has a square cross section, but this analysis can be modified to take into account Fig.11A An implant that will divide the cross section into three equal parts or Fig. 12A The implant will divide the cross section into five equal parts.

[0075] Thus, by the above methods, the implant can be sized to provide at least 20% stretching of the target artery wall. In some embodiments, the implant can be slightly oversized to ensure at least 20% stretching or to accommodate changes in aortic size while still ensuring at least 20% stretching in all cases. In some embodiments, the implant can be configured to provide additional stretching, for example, 20-30%, 50%, or even 100% stretching can be safely performed in many patients.

[0076] As previously described, this design allows the device to be deployed and stabilized at a primary anatomical target within the vasculature. Preferably, the target location is within the aortic arch to stretch the aortic arch baroreceptors, which are positioned along a cylindrical segment of the aortic arch that wraps the aorta between the origins of the left common carotid artery and the left subclavian artery (including along the inner curvature) based on human aortic arch CT angiographic studies. The aortic arch baroreceptors extend along the inner curvature of the aortic arch and extend circumferentially around the aortic arch to the outer curvature or saddle region of the aortic arch, but the greatest concentration of these baroreceptors is located on the segment of the aortic arch adjacent to the left subclavian artery that wraps the aorta along diameter C, as shown in FIG. Fig.16 The target T is shown in FIG. The implant constructs described herein are specifically configured to target this location but also to stretch the adjacent baroreceptors as much as is safe and possible. V. Delivery and Placement at Target Areas

[0077] In another aspect, the implant device is particularly well suited for intravascular delivery and deployment because the implant has a collapsed configuration for advancement through the vasculature and an expanded configuration for engaging the arterial wall, as shown in Figure 1. In the collapsed configuration, the implant is disposed in a delivery catheter to facilitate intravascular delivery to a target location at the aortic arch and subsequent deployment.

[0078] In an exemplary embodiment, the implant is a self-expanding structure preloaded into a sheathed delivery catheter, such as Fig.17 As shown, the intravascular delivery catheter is designed to deliver the implant in a collapsed configuration and to position and deploy the implant at a target location, such as Fig.16As shown. The delivery catheter includes an internal guide wire lumen so that it can advance along the guide wire GW positioned in the aortic arch. In the illustrated embodiment, the delivery catheter 200 includes a catheter shaft 201, on which the implant 100 collapses, and on which a retractable sheath 202 is arranged, which constrains the implant in a collapsed configuration until the implant is positioned at the desired target position, such as by visualization of a marker (e.g., a radiopaque marker or an ultrasound marker). The marker can be a coating or marker attached to a connector and / or any one or both expandable structures. In some embodiments, the connector can be made of a material different from the frame so that the connector itself is clearly visible through visualization techniques. The delivery catheter can also include a distal end 203 to guide advancement on the GW, and a flushing port 211 for flushing before, during, or after delivery. The delivery catheter includes a handle 210, by which the clinician can retract the sheath to deploy the self-expanding implant. Typically, the total length (l) of the delivery catheter is between 100-150 cm (eg, about 135 cm) to allow easy access to the aortic arch by inserting the catheter through the femoral artery.

[0079] In some embodiments, the delivery catheter can be configured to deliver the entire implant when the sheath is retracted, thereby quickly and continuously deploying the first expandable structure and the second expandable structure. The length of the expandable structure is sufficient to make the expandable structure 10 still deployed at the target location despite any slight axial movement during deployment. Although the structure 20 is deployed first, the goal of positioning and deployment is to deploy the structure 10 at the target location. In other embodiments, the delivery catheter can be configured to allow the sheath to be incrementally retracted to a specified distance to sequentially deliver the expandable structure, first placing the farther second structure, and then accurately positioning the first expandable structure at the target location, and the axially expandable connector provides some room for the positioning of the expandable structure deployed last. In other embodiments, the implant can be sac expandable and arranged on the sac of the delivery catheter in a collapsed structure, and the sac is suitably sized to expand in the aorta to expand and deploy the implant in the target area.

[0080] When deployed, the implant uses the struts of the framework to form a lattice of openings designed to stretch the aortic arch and stimulate aortic arch baroreceptors, thereby reducing blood pressure while the arterial wall is exposed through the main openings of the framework to each aortic pulse, such as Figures 10A-12B As shown in the example embodiments.

[0081] Figures 18A-18D 1 shows sequential steps of an exemplary method for treating hypertension by deploying an implant device as described herein. Fig.18AAs shown, the guide wire GW is advanced through an entry point (e.g., the femoral artery) and through the vasculature into the aortic arch. Visualization techniques such as fluoroscopy can verify the position of the GW in the target area. Fig.18B As shown, a delivery catheter 200 is advanced along the GW, the catheter having an implant 100 disposed in a collapsed configuration on a catheter shaft 201 and constrained within a retractable outer sheath 202. Once the implant is positioned at the desired target location within the aortic arch, the outer sheath 202 is retracted, allowing the self-expanding implant 100 to be elastically deployed into its expanded configuration, wherein the two expandable structures 10, 20 engage the arterial wall, as shown in FIG. Fig.18C The guide wire GW and the delivery catheter 201 are then withdrawn, leaving the implant anchored at the target location within the aortic arch, and at least one expandable structure 100 engages and stretches the arterial wall against the target area to reduce blood pressure over a long period of time, as shown. Fig.18D shown.

[0082] Fig.19 An exemplary method of treating hypertension using an implant device is shown. The method includes the steps of: deploying an implant including one or more expandable structures along a target region in the aortic arch, the target region being defined as a narrow band enveloping the aorta between the LCCA and the LSA; stretching the arterial wall along the target region by at least 20% using struts of the implant, thereby inducing a baroreflex response; and exposing a majority of the stretched target region to pulsatile blood flow through major openings between struts of the implant, thereby providing long-term blood pressure reduction.

[0083] Fig. 20 Another exemplary method of treating hypertension by deploying an implant to an aortic arch is shown. The method includes the steps of deploying an implant including two or more expandable structures along a target area in the aortic arch, wherein at least one expandable structure engages the target area; using struts of the implant to stretch the arterial wall along the aortic arch by at least 15%, typically about 20%, thereby inducing a baroreflex response to reduce blood pressure; exposing a majority of the stretched target area to pulsatile blood flow through the main openings between the struts of the implant, thereby providing long-term blood pressure reduction; and anchoring the implant in the target area for a long time using two or more expandable structures, wherein the expandable structures are interconnected in series by axial expandable connectors to accommodate the curvature and complex geometry of the aortic arch, thereby providing long-term fixation.

[0084] Figures 21A-1 to 21C-3 Alternative designs of expandable structures are shown, each of which is defined by one or more wires. Figures 10A-13DUnlike the predefined frameworks shown connected along the lateral sides, each expandable structure can be defined by one or more wires, which define the design according to the desired size and characteristics of the implant. In some embodiments, the expandable structure can be formed by a single continuous wire that extends in a meandering, sinusoidal or zigzag pattern to form a circumferential ring or band of the desired size, thereby spanning the target area and applying sufficient outward force when expanding to stretch the arterial wall to the desired amount (e.g., about 20% or more). In some embodiments, the expandable structure is formed by two or more wires, which are defined in the following pattern to form a circumferential ring or band of the desired size and apply the required force. Typically, the wire is nitinol and is set with a forming diameter much larger than the arterial diameter to stretch the artery to the target diameter, thereby ensuring that the pressure receptor is fully stretched. The specifications of the wire can be selected to ensure that the force requirements are met and the service life of the implant is ensured. It is worth noting that in many such embodiments, the cross-sectional shape of these expandable structures is substantially circular, so that the expandable structure uniformly increases the radius of the vessel wall, while the design still fully exposes the arterial wall to the pulsating force after deployment.

[0085] Figures 21A-1 to 21C-3 Three different designs (10A, 10B, and 10C) of expandable structures formed from wire (eg, Nitinol wire) are shown. Figures 21A-1 to 21C-1 The structure is shown at the formed diameter. Figures 21A-2 to 21C-2 The structure is shown at the diameter of the vessel. Figures 21A-3 to 21C-3 The structure under the constraint structure is shown for delivery to the target position in the aorta. In the embodiment shown, the design structure and size are designed for deployment in the aortic arch. In some embodiments, when the aorta has a vessel diameter in the range of 20-25mm, the expandable structure can be configured so that the diameter formed is between 35-40mm, typically about 38mm, and studies have shown that this simulated blood vessels of these diameters apply enough force to achieve appropriate stretching of the arterial wall (e.g., typically 20% or more). In these embodiments, the length l2 at the vessel diameter can be between 10-30mm, typically 10-25mm. In some embodiments, under the vessel diameter, 10A has a length of about 23mm, 10B has a length of about 17mm, and 10C has a length of about 14mm. In the constraint structure, due to the shortening effect, the length is slightly longer (e.g., 24mm, 18mm and 15mm, respectively). In some embodiments, the wire diameter is between 0.2mm and 1.5mm, typically between 0.5mm and 1mm, and more typically about 0.6mm.

[0086] Use something like Figures 21A-1 to 21C-3The wire structure embodiments in the aortic arch were studied to demonstrate the feasibility of the implant to provide appropriate stretch by increasing the diameter of the artery while still allowing sufficient compliance to maintain long-term effects. These studies were conducted in compliant 0.45 mm resin tubing that was created to simulate the compliance and structure of the arterial wall in the aortic arch. The results of the study are presented in Fig. 22 . The compliance of the 0.45 mm resin tube was measured and recorded. The exemplary expandable structure was placed in the same 0.45 mm resin tube, and the resulting compliance (dashed line) was plotted together with the compliance of the empty tube (solid line). Both data sets were well fitted by linear regression of a second order polynomial.

[0087] Fig. 22 The implant ring is shown to continuously stretch the resin tube while maintaining compliance. For example, at a pressure of 50 mmHg, the implant ring increases the diameter from 20 mm to about 23 mm, or stretches 15%. Similarly, at a pressure of 200 mmHg, the implant ring increases the diameter from 25 mm to about 29 mm, or stretches 16%. The effect of the implant ring can also be explained from a pressure perspective. For example, at a pressure of 100 mmHg, the diameter of an empty tube (representing a natural hypertensive blood vessel) is about 21 mm. Placing the implant ring in the tube increases the diameter to about 24 mm, which corresponds to a pressure of 180 mmHg in the empty tube. In this case, the outward force of the implant ring is equivalent to a static pressure of +80 mmHg. In this example, the pressure receptors are stimulated by a 15% stretch or an equivalent pressure increase of +80 mmHg. Therefore, it is assumed that the implant ring will trigger a pressure receptor response consistent with the pressure increase, and will therefore reduce systemic pressure.

[0088] Although it has been demonstrated that acute stimulation of the baroreceptor reflex results in an immediate decrease in systemic blood pressure, it has also been demonstrated that a sustained response requires maintenance of pulsatile properties. Fig. 22 It was also shown that the pulsatility of the empty tube (natural vessel analog) was maintained with the implanted ring in place (implanted ring treated vessel analog). This was evident because the slopes of the compliance curves for the empty tube and the implanted ring tube were essentially parallel. For example, between 100 and 200 mmHg, the empty tube pulsated between 21 mm and 25 mm (19%), while the same tube with the implanted ring in place pulsated between 24 mm and 29 mm (21%).

[0089] Figures 23A-23B Another embodiment 120 is shown that utilizes multiple expandable structures 10, 20, 40, each having a wire design as shown in Figures 21A-21C, and interconnected by flexible connectors 30. In this embodiment, D V Indicates the nominal vessel diameter. A is the diameter of the active section, which is greater than D VTo apply the desired stretch, the expandable structure design maintains pulsatility. D and D P Denote the expanded diameters of the distal expandable structure and the proximal expandable structure, respectively. D Maximum diameter and D P Each of can be greater than or equal to D A to fully engage the vessel and prevent migration. In some embodiments, the proximal expandable structure and the distal expandable structure can have a flared design to provide resistance to migration. In some embodiments, the expandable structure can include barbs or a gripping coating for resisting migration. In some embodiments, the implant can be configured to be secured after deployment (e.g., such as by an adhesive or coating) to allow repositioning during deployment. A flexible connector or bridge connects the three expandable structures, each of which is capable of axially stretching or compressing, thereby allowing flexibility to match the shape of the arch. For example, the flexible connector allows more stretching / elongation at the outer radius and less stretching or even compression along the inner radius of the arch, such as Fig. 23B shown.

[0090] It will be appreciated that these wire design expandable structures can also be used as the expandable structures of the implant among Figure 10-13, and can have similar size.For example, the size of central structure can be greater than the diameter of proximal structure and distal structure, for example, diameter or maximum transverse dimension are 1.2-1.5 times larger than proximal structure and distal structure.It will also be appreciated that various flexible connector designs can be used. Figures 24A-24F Various flexible connector designs are depicted, including one or more sinusoidal curves (e.g. Fig.24A As shown), V-shaped portion (as Figures 24B-24D As shown), zigzag area (as shown Fig.24E as shown) or a coiled structure (as Fig.24F ), thereby allowing axial expansion between adjacent rings or structures. Although specific flexible connectors or bridges are depicted herein, it will be understood that any suitable flexible connector may be used and that the bridge design shown may be further extended to provide increased axial extension to better accommodate the aortic arch. VI. Alternative Implant Design and Deployment

[0091] As described in the previous embodiments, it is assumed that the implant device utilizes stimulation of circumferential stretch to activate the aortic baroreceptor nerves. However, it will be appreciated that axial stretch may also be relevant and may be used to provide additional activation of the baroreceptors. In some embodiments, the implant may be configured to stretch the arterial wall in an axial direction in addition to or in lieu of a transverse direction.

[0092] Figure 25-26Depicted is an implant device configured to stretch the arterial wall circumferentially / laterally and axially, thereby providing additional activation of baroreceptors to further enhance the baroreflex response.

[0093] like Fig.25 As shown, implant 121 can include expandable structures of different configurations, wherein the intermediate expandable structure 40 provides the circumferential (e.g., transverse) stretching described throughout the application, and the connector 30 to the proximal expandable structure 10 and the distal expandable structure 20 is configured to provide axial stretching along the arterial wall. As with some previous embodiments, the design can be a three-structure design with a proximal anchoring structure and a distal anchoring structure and an intermediate active structure deployed at the target area. In this design, the flexible connector (i.e., bridge) connecting the proximal structure 10 and the distal structure 20 to the intermediate active structure 40 is configured as an axial spring, which is compressible to provide an axial force when deployed.

[0094] Fig.26 Shows Fig.25 The deployment sequence steps of the implant are as follows. In the first step, the distal structure 20 is deployed at a position distal to the target area. In the second step, the intermediate active structure 40 is deployed at the target area. However, when the intermediate structure 40 is deployed, the delivery catheter 200 advances distally to compress the axial spring between the distal structure 20 and the intermediate structure 40, which axially loads the flexible connector, thereby providing an axial stretching force to the arterial wall between the distal structure and the intermediate structure 40. In the third step, when the proximal structure 10 is deployed, the connector 30 between the intermediate structure 40 and the proximal structure 10 is compressed by pushing the delivery catheter again during deployment, so that the compressed bridging connector provides additional axial stretching force from the intermediate structure 40 to the proximal structure 10. Therefore, this method can not only provide circumferential stretching at the target area by the deployed intermediate active structure, but also provide axial stretching from the target area in the proximal and distal directions, thereby providing enhanced pressure receptor activation or potentially equivalent pressure receptor activation at a reduced implant diameter. While specific designs are described herein, it will be appreciated that various other designs of the connector and / or the proximal and distal expandable structures may provide axial stretching forces to provide enhanced baroreceptor activation.

[0095] Therefore, the implant device and related methods described herein address the unmet clinical needs of treating patients with severe hypertension who are unresponsive to multiple drugs. Existing conventional treatments and therapies (e.g., renal neurectomy, carotid devices) have minimal or limited impact on such populations due to their limited antihypertensive effects or risk of adverse events. The implant currently described is intended to meet this unmet clinical need based on historical and animal studies and the unique anatomy and physiology of identifying aortic arch baroreceptors and the above-mentioned CT angiography studies. The implant described herein allows a specific target area of ​​the aortic arch to be fully stretched, which triggers highly sensitive baroreceptors, thereby continuously and reliably reducing the patient's blood pressure while avoiding the adverse risks and disadvantages associated with conventional methods for other blood vessels such as the carotid artery.

[0096] In the foregoing description, the present invention has been described with reference to specific embodiments of the present invention, but those skilled in the art will recognize that the present invention is not limited thereto. The various features, embodiments and aspects of the above invention may be used alone or in combination. In addition, without departing from the broader spirit and scope of the present specification, the present invention may be used in any number of environments and applications outside those described herein. Therefore, the present specification and the accompanying drawings should be regarded as illustrative rather than restrictive. It should be recognized that the terms "including", "comprising" and "having" used herein are particularly intended to be understood as open-ended terms. Unless otherwise stated, the term "about" is considered to mean within + / -10%. Any reference to a publication, patent or patent application is incorporated herein by reference in its entirety for all purposes.

Claims

1. A method for treating hypertension in a patient, the method comprising: deploying an implant within an aortic arch of a patient, the implant comprising a plurality of expandable structures interconnected by a flexible connector, wherein each of the plurality of expandable structures has an expanded configuration and a collapsed configuration, wherein in the collapsed configuration the implant is advanceable through vasculature, and wherein in the expanded configuration the implant engages an arterial wall of the aortic arch; stretching at least a portion of an arterial wall along a target region of the aortic arch by engaging a first expandable structure of the plurality of expandable structures, thereby triggering a baroreflex response of baroreceptors in the target region; and The target area is exposed to pulsatile blood flow along a substantial portion of the arterial wall through the plurality of major openings of the expandable structure to sustain the baroreflex response induced by the implant over a long period of time.

2. The method according to claim 1, characterized in that The portion of the arterial wall is stretched by at least 20%.

3. The method according to claim 1, characterized in that The target region is the cylindrical segment enveloping the aortic arch between the LCCA and LSA.

4. The method according to claim 1, characterized in that Each expandable structure includes one or more wires defining a design having a length greater than a transverse dimension thereof, wherein the implant is deployed such that the length of the expandable structure extends along the aorta in the direction of blood flow.

5. The method according to claim 4, characterized in that Each expandable structure comprises a single continuous nitinol wire.

6. The method according to claim 1, characterized in that Each expandable structure is defined by a laser cut design in a single tube.

7. The method according to claim 1, characterized in that Each expandable structure has a circular cross-section.

8. The method according to claim 4, characterized in that The implant includes three such expandable structures interconnected in series by a plurality of flexible connectors.

9. The method according to claim 1, characterized in that Each expandable structure includes a plurality of elongated frames having a length greater than a transverse dimension thereof, wherein the implant is deployed such that the length of the plurality of elongated frames extends along the aorta in the direction of blood flow.

10. The method according to claim 9, characterized in that Each frame includes a pair of struts defining opposing lateral sides of the frame and spaced a sufficient distance apart to stretch a portion of an arterial wall engaged by the pair of struts by at least 20% when the implant is deployed.

11. The method according to claim 10, characterized in that Each expandable structure includes three to five frames interconnected along adjacent lateral sides thereof to form a regular polygonal cross-section.

12. The method according to claim 11, characterized in that The struts are spaced apart a distance of between 20 mm and 40 mm to define a primary opening therebetween.

13. The method according to claim 12, characterized in that The linear struts may have a length of about 40 mm or greater.

14. The method according to claim 1, wherein: Also includes: Blood flow in one or more lateral arteries branching from the aortic arch is maintained by deploying one or more main openings of the plurality of first expandable structures and / or second expandable structures of the implant.

15. The method according to claim 1, wherein: Also includes: The position of the deployed implant along the target area is maintained over the long term by deploying a second expandable structure of the plurality of expandable structures in an adjacent area of ​​the aortic arch such that the first and second expandable structures are engaged together against the arterial wall to prevent the implant from falling out.

16. The method according to claim 15, characterized in that Maintaining position also includes: The curvature of the aortic arch is accommodated by expanding the flexible connector, wherein the flexible connector is axially extended a greater distance near the outer curvature of the aortic arch than one or more flexible connectors along the inner curvature of the aortic arch.

17. The method according to claim 15, characterized in that Maintaining position also includes: The implant is selected from a group of implants having different sizes of the first expandable structure and the second expandable structure based on measurements of the morphology of the patient's aortic arch obtained from computed tomography angiography.

18. The method of claim 1, wherein: Also includes: Trauma to the arterial wall during deployment and long-term implantation in the aortic arch is inhibited by a proximal anti-traumatic crown and a distal anti-traumatic crown of each frame, wherein the proximal anti-traumatic crown connects the proximal ends of the strut pairs of the corresponding frame, and the distal anti-traumatic crown connects the distal ends of the strut pairs of the corresponding frame, wherein the anti-traumatic crown includes a semicircular arc or a smaller arc.

19. An implant for treating hypertension in a patient, the implant comprising: a plurality of expandable structures interconnected in series by a flexible connector, wherein the plurality of expandable structures have a collapsed configuration for advancement through the vasculature of a patient and an expanded configuration for engaging an arterial wall within an aortic arch of the patient, wherein the flexible connector is axially extendable such that the plurality of expandable structures conform to the aortic arch when deployed in the aortic arch, and Wherein, at least one of the expandable structures is sized so that when expanded in a target area of ​​the aortic arch, the expandable structure increases the diameter of the blood vessel sufficiently to induce a pressure reflex response of the pressure receptors in the target area, and at the same time, the expandable structure fully exposes the arterial wall of the target area to the pulsating blood flow to maintain the pressure reflex response for a long time.

20. The implant device according to claim 19, characterized in that The at least one expandable structure is sized such that arterial tissue engaged by the pair of struts stretches the arterial wall between the struts by at least 20%.

21. The implant device according to claim 19, characterized in that The at least one expandable structure is dimensioned such that a maximum transverse dimension is between 25 mm and 60 mm.

22. The implant device according to claim 19, wherein: The at least one expandable structure is dimensioned such that a maximum transverse dimension is between 30 mm and 40 mm.

23. The implant device according to claim 19, characterized in that The at least one expandable structure is sized to have a length of approximately 40 mm or greater to ensure engagement of the target area.

24. The implant device according to claim 19, characterized in that Each expandable structure is dimensioned to have a length of approximately 40 mm or greater and to have a maximum transverse dimension of between 30 mm and 40 mm.

25. The implant device of claim 19, wherein: Each expandable structure has the same dimensions.

26. The implant device of claim 19, wherein: The plurality of expandable structures have different sizes.

27. The implant device of claim 19, wherein: The flexible connector is capable of axial expansion such that the implant conforms to the curvature of the aortic arch.

28. The implant device of claim 19, wherein: The implant is self-expandable.

29. The implant device according to claim 28, characterized in that The implant is formed at least in part from Nitinol.

30. The implant device of claim 19, wherein: The implant is balloon expandable.

31. The implant device of claim 19, wherein: Each expandable structure includes one or more wires defining a design having a length greater than a transverse dimension thereof, wherein the implant is deployed such that the length of the expandable structure extends along the aorta in the direction of blood flow.

32. The implant device of claim 31, wherein: Each expandable structure comprises a single continuous nitinol wire.

33. The implant device of claim 19, wherein: Each expandable structure is defined by a laser cut design in a single tube.

34. The implant device of claim 19, wherein: Each expandable structure has a circular cross-section.

35. The implant device of claim 19, wherein: The implant includes three such expandable structures interconnected in series by a plurality of flexible connectors.

36. The implant device of claim 19, wherein: Each of the plurality of expandable structures comprises: a plurality of elongated frames, each frame having a pair of struts defining opposing lateral sides and spaced apart to define a primary opening therebetween, wherein the frames are interconnected along adjacent lateral sides to form a regular polygonal cross-section of the implant, and 37. The implant device of claim 19, wherein: Each of the plurality of expandable structures includes four frames interconnected to form a square cross-section.

38. The implant device of claim 19, wherein: Each of the plurality of expandable structures includes three frames interconnected to form a triangular cross-section.

39. The implant device of claim 19, wherein: Each of the plurality of expandable structures includes five frames interconnected to form a hexagonal cross-section.

40. The implant device of claim 19, wherein: Each frame includes a proximal atraumatic end and a distal atraumatic end interconnected with the proximal and distal ends of the pair of struts, respectively, to avoid trauma to arterial tissue during delivery, deployment, and long-term implantation.

41. The implant device of claim 40, wherein: The proximal atraumatic end and the distal atraumatic end include a semicircular arc or a smaller arc.

42. The implant device of claim 19, wherein: The implant device also includes one or more markers visible by visualization techniques during delivery to aid in positioning the implant device at a target area within the aortic arch.

43. The implant device of claim 42, wherein: The one or more markers include radiopaque markers or ultrasound visible markers disposed on the plurality of flexible connectors.

44. The implant device of claim 19, wherein: The plurality of expandable structures includes three expandable structures, wherein a middle structure is configured for deployment at the target area, and a proximal expandable structure and a distal expandable structure are configured for providing anchoring of the middle structure at the target area.

45. The implant device of claim 44, wherein: The intermediate structure has a transverse dimension that is greater than a transverse dimension of each of the proximal expandable structure and the distal expandable structure.

46. ​​The implant device of claim 45, wherein: The intermediate expandable structure has a transverse dimension that is 1.3 to 15 times greater than the transverse dimensions of the proximal expandable structure and the distal expandable structure.

47. The implant device of claim 44, wherein: The flexible connector comprises an axially compressible spring, through which the implant provides axial stretching of the arterial wall when deployed.

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