Aortic arch baroreceptor implant for the treatment of hypertension

Abstract

Implantable devices and treatments for hypertension are provided. The implantable device is configured to be placed in a target region of the aortic arch in a patient, thereby adequately engaging the arterial wall in the target region to stretch and / or tension the arterial wall, thereby eliciting a baroreflex response. Such an implant may include one or more expandable structures configured to engage an elongated target region in the aortic arch. The target region may extend along most of the aortic arch, including a cylindrical segment of the aortic arch between the left common carotid artery and the left subclavian artery. The elongated target region may also extend at least between the origin of the brachiocephalic artery and the origin of the left subclavian artery. Such embodiments may utilize one or more expandable structures having a non-circular cross-section that stretch and reshape the arterial wall to induce tension within the arterial wall, thereby producing a robust baroreflex response.

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 594,903, filed October 31, 2023, and U.S. Provisional Application No. 63 / 657,565, filed June 7, 2024, the disclosures of which are incorporated herein by reference in their entirety for all purposes.

[0002] This application is generally related to the following applications: PCT patent application No. PCT / US2023 / 020608, filed May 1, 2023, entitled "Delivery Catheter and Methods of Delivery for Aortic Arch Baroreceptor Hypertension Implants"; U.S. Nonprovisional Application No. 18 / 929,165, filed concurrently with this application (October 28, 2024), entitled "Delivery Catheter and Methods of Delivery for Aortic Arch Baroreceptor Hypertension Implants"; and U.S. Baroreflex Gauge and Mapping Device and Methods of PCT application number PCT / US2024 / 016200, entitled "Use of a pressure reflection metering and mapping device and method of use", is incorporated herein by reference in its entirety for all purposes. Technical Field

[0003] In one aspect, the present invention relates to implantable devices for treating hypertension, as well as associated components, systems and methods. Background Technology

[0004] In the United States, one in two adults has high blood pressure. However, only 24% of these individuals have their blood pressure adequately controlled. High blood pressure is a leading preventable cause of heart attack, stroke, and death. However, a 10 mmHg reduction in blood pressure can decrease this cardiovascular risk by 20%.

[0005] For decades, despite documented poor patient adherence to antihypertensive medication regimens, drug therapy has remained the primary means of treating hypertension. In 2004, a landmark trial of catheter-based medical devices (Symplicity 1) first demonstrated the blood pressure-lowering effect of renal denervation via radiofrequency ablation catheters. Findings from additional clinical trials utilizing radiofrequency and ultrasound energy for renal denervation (the SPYRAL and RADIANCE trials, respectively) corroborated these findings, although with a more moderate blood pressure-lowering effect, reducing dynamically recorded systolic blood pressure by approximately 5 mm Hg to 10 mm Hg.

[0006] Vascular Dynamics has developed an endovascular implant for hypertension that relies on an expandable device inserted into the carotid artery. This device lowers blood pressure by stretching the artery wall from within and enhancing the carotid baroreflex. In a 2017 study, this carotid baroreflex modulator significantly reduced dynamically recorded systolic blood pressure by more than twice that reported in a renal denervation trial. While initial clinical results appeared promising, with several patients reporting significant blood pressure reductions that lasted two to three years, outcomes have been mixed, as some patients have experienced transient ischemic attacks (TIAs), hindering further trials and subsequent development.

[0007] Another challenge arises in deploying the device in the carotid sinus, its primary target area. Since the carotid sinus carries blood to the brain, any difficulties encountered in this region—such as trauma to the arterial tissue during deployment, subsequent device displacement, and / or plaque buildup in the area due to the device or trauma—can lead to TIA or stroke, resulting in adverse or fatal patient outcomes. Performing procedures in this area may pose unnecessary risks to the patient for clinicians lacking experience with this sensitive region, such as those with experience placing carotid stents.

[0008] Additional devices have been developed specifically for stretching the arterial walls at discrete target locations—including specific locations in the carotid artery and aorta; however, clinical studies to date have shown that this approach remains ineffective or produces inconsistent results and fails to significantly reduce blood pressure (e.g., by more than 10 mm Hg, preferably about 20 mm Hg).

[0009] Therefore, there remains a need for hypertension treatment devices and methods that utilize baroreflex responses to provide a reliable and robust therapeutic response while avoiding the considerable drawbacks associated with conventional methods described above. There is also a need for devices that allow for improved ease and consistency of implantation, thereby avoiding known adverse effects, allowing for implantation by a wide range of clinicians, and providing more reliable and positive therapeutic effects for patients to lower hypertension in the long term. Summary of the Invention

[0010] This invention relates to an implantable hypertension treatment device and associated treatment methods for deployment in the aortic arch.

[0011] In one aspect, the present invention relates to a method for treating hypertension in a patient. These methods may include the steps of: deploying an implant within the patient's aortic arch, wherein the implant comprises a plurality of expandable structures interconnected by angularly or helically oriented bridging members, each of the plurality of expandable structures having an expanding configuration and a collapsing configuration. In the collapsing configuration, the implant can advance through the vascular system, and in the expanding configuration, the implant engages the arterial wall of the aortic arch. The method further requires stretching and preferably reshaping the shape of at least a portion of the arterial wall along a target region. In some embodiments, the target region includes a cylindrical segment that surrounds the aortic arch (particularly along the inner curvature) by engaging one of the expandable structures, thereby triggering a baroreflex response of pressure receptors within the target region and exposing a large portion of the arterial wall along the target region to pulsating blood flow through one or more major openings of the implant to sustain the implant-induced baroreflex response over a long period. In some embodiments, this portion of the arterial wall is preferably stretched by at least 10%, typically at least 20%, and preferably reshaped. In some embodiments, this portion of the arterial wall is reshaped into a rectangular or elliptical shape. In some implementations, the target region comprises 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 region in both directions to ensure optimal engagement with the entire target region.

[0012] In another aspect, the present invention relates to an implantable device for treating hypertension in a patient. Such an implant may include one or more expandable structures interconnected in series by bridging members, the expandable structures having a collapsed configuration for advancement through the patient's vascular system and an expanded configuration for engagement with the arterial wall within the patient's aorta. In some embodiments, each of the expandable structures is formed from one or more filaments formed in an expandable design (e.g., one or more nitinol filaments formed in a meandering, sinusoidal, or zigzag design to form a circumferential loop or band). In some embodiments, each expandable structure is defined by a single continuous filament. In some embodiments, each expandable structure is a laser-cut design in a single tube or multiple filaments (e.g., 12, 24, 35, 48, etc.). In some embodiments, the bridging members between adjacent expandable structures are angled or helically oriented to allow the implant to better conform to the curvature of the aortic arch. In some embodiments, each expandable structure includes an expandable loop (e.g., a sinusoidal or zigzag pattern with peaks and valleys). In some embodiments, the entire implant having multiple expandable structures and flexible connectors can be defined by a laser-cut design of a single tube. In such wire-cut or laser-cut embodiments, the expandable structure can have a substantially circular cross-section. In some embodiments, each of the expandable structures includes multiple elongated frames, each frame having a pair of struts defining opposing 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. As used herein, “frame” can refer to “unit” or any similar structure.

[0013] In some embodiments, the implant includes two expandable structures interconnected by a flexible bridging member to accommodate the curvature of the arch. In some embodiments, the implant includes three expandable structures, wherein an intermediate expandable structure is positioned at a target location to activate baroreceptor nerves, and proximal and distal expandable structures act as anchors to secure the intermediate structure at the target location. In such embodiments, the expandable structures may have the same or different dimensions. In some embodiments, the implant includes three expandable structures, wherein the lateral dimension of the intermediate structure is larger than the lateral dimensions of the proximal and distal expandable structures (e.g., 1.3 to 1.5 times). This approach allows for even greater stretching along the target region (e.g., 10%, 20%, 30% or more) because the proximal and distal structures facilitate arterial wall transition and inhibit tearing or dissection of the stretched vascular system. It is also desirable to reshape arteries with the implant, which will be discussed in further detail below. In some embodiments, the implant or one or more expandable structures of the implant have a variable diameter or flared shape. In some embodiments, the implant includes one or more barbs to facilitate long-term anchoring. At least one of the expandable structures is sized such that, upon expansion within a target region of the aortic arch, the paired struts of the respective frame stretch the arterial tissue in the target region sufficiently to elicit a baroreflex response from pressure receptors in the target region, such as stretching by 10% or more, typically 20% or more, and / or reshaping the arterial wall to apply wall tension, while the main opening between the struts exposes the arterial wall of the target region to pulsating blood flow to maintain the baroreflex response long-term. It should be understood that the expandable structure can be any structure described herein (e.g., connecting frames, continuous filaments, laser-cut sections).

[0014] In some embodiments, the implant includes one or more proximal tethers through which the implant can be retracted by a tool or delivery sheath for removal or repositioning. The tethers may include proximal connectors thereon that are releasably attached to a retaining ring of the delivery tool or catheter. In such embodiments, the implant can be used to measure a baroreflex response, and the implant's position can be adjusted based on the response.

[0015] In one aspect, the present invention relates to an implant for treating hypertension in a patient. The implant has a collapsed configuration for advancement through the patient's vascular system and an expanded configuration for engagement with the arterial wall within the patient's aortic arch. The implant may include one or more expandable structures. In some embodiments, the implant has a total length of at least 60 mm, such that when deployed in the aortic arch, the implant extends along a target area at least between the origin of the brachiocephalic artery and the origin of the left subclavian artery. In some embodiments, the implant has a non-circular cross-section along its entire length when expanded to induce wall tension along the entire area of ​​the aortic arch, thereby eliciting a baroreflex response from baroreceptors in the target area. The implant has sufficient flexibility to accommodate the curvature of the aortic arch along an elongated region. In some embodiments, any lateral opening in the implant is large enough to allow lateral blood flow through said lateral opening to reach any lateral branch of the aortic arch and expose the arterial wall to pulsating blood flow to maintain a long-term responsiveness.

[0016] In some embodiments, the implant has an elliptical, oval, or pill-shaped cross-section. In some embodiments, the non-circular cross-section is a regular polygonal shape. In some embodiments, the non-circular cross-section is constant along the entire length of the implant. In some embodiments, the non-circular cross-section is variable (e.g., increasing / decreasing or tapering) along the length of the implant. In some embodiments, the maximum lateral dimension of the implant is greater than 25 mm. In some embodiments, the maximum lateral dimension of the implant is between 40 mm and 60 mm. In some embodiments, the total length of the implant is about 60 mm or longer, typically between 70 mm and 90 mm. In some embodiments, the implant is self-expanding. In some embodiments, the implant is made of one or more woven or braided wires. Typically, the implant is formed of nitinol. In some embodiments, the implant is formed by laser-cut tubes. In some embodiments, the implant is designed such that when expanded, the gap opening has a sufficient area, such as at least 9 mm². 2 Typically at 9 mm 2 Up to 30 mm 2 Within a certain range, to allow blood flow through it and expose the arterial wall to pulsating blood flow.

[0017] In another aspect, the present invention relates to a method for treating hypertension in a patient. Such a method may include the steps of: deploying an implant within the patient's aortic arch, said implant having a collapsed configuration for advancement through the patient's vascular system and an expanded configuration for engaging the arterial wall within the patient's aortic arch; engaging the arterial wall with the implant in the expanded configuration along a target area extending at least between the origin of the brachiocephalic artery and the origin of the left subclavian artery, wherein the implant has a non-circular cross-section when expanded, thereby inducing wall tension along the target area within the aortic arch; and exposing a significant portion of the arterial wall along the target area to a pulsatile blood flow side opening of the implant to sustain a pressure reflex response induced by the implant over a long period. Attached Figure Description

[0018] Figure 1A An exemplary implantable device, deployed along a target region in a patient's aortic arch according to some embodiments, is shown.

[0019] Figure 1B Another exemplary implantable device is shown, deployed along a target region in a patient's aortic arch according to some embodiments.

[0020] Figure 1C Another exemplary implantable device is shown, deployed along a target region in a patient's aortic arch according to some embodiments.

[0021] Figure 1D An exemplary implantable device is shown, deployed along an elongated target region of a patient's aortic arch according to some embodiments.

[0022] Figure 2 A conventional view of the anatomical structure of the vascular system and baroreceptors is shown, along with an illustration of the location of the carotid artery baroreceptors as targeted by a conventional device.

[0023] Figure 3A Details of an exemplary type of pressure sensor, known as PEIZO1, are shown.

[0024] Figure 3B This demonstrates the central nervous system's response to baroreflex stimuli in regulating blood pressure.

[0025] Figure 3C Details of an exemplary type of pressure sensor, known as PEIZO1, are shown.

[0026] Figure 4 The anatomical structure of the aortic arch vascular system is shown.

[0027] Figure 5 This shows the embryonic anatomy that later developed into the aortic arch.

[0028] Figure 6 The anatomical structure of the aortic arch according to various aspects of the invention is shown, with additional details regarding the target region illustrated.

[0029] Figure 7 The histology of arterial tissue within the target area is shown.

[0030] Figure 8A The image shown is a fluorescently stained image from an animal study, illustrating the distribution of pressure receptors in the target region.

[0031] Figure 8B A fluorescently stained image is shown, illustrating the location of pressure receptors within the arterial wall of the aortic lumen.

[0032] Figures 9A to 9B The figure shows the results of an animal study, which demonstrates that baroreceptors in the aorta are more sensitive than those in the carotid artery.

[0033] Figures 10A to 10D An exemplary implant with two expandable structures interconnected by flexible connectors, according to some embodiments, is shown. The structures are defined by four frames and have a square cross-section. Figure 10E An exemplary implant with three expandable structures according to some embodiments is shown.

[0034] Figures 11A to 11B An alternative implementation of the implant is shown, wherein the expandable structure is defined by three frames and has a triangular cross-section.

[0035] Figures 12A to 12B An alternative implementation of the implant is shown, wherein the expandable structure is defined by five frames and has a hexagonal cross-section.

[0036] Figures 13A to 13D An alternative embodiment of an implant with three expandable structures is shown, according to some embodiments, wherein the middle structure has an increased lateral dimension.

[0037] Figures 14A to 14C Various sizes and characteristics of the aorta are shown, which were examined in patient studies to determine the appropriate size for implant structures to be deployed in the aorta.

[0038] Figures 15A to 15D The mechanism of action according to an embodiment of the invention is illustrated, by which a suitably sized structure engages and stretches the substantially circular (e.g., 25 mm diameter) aortic wall to achieve sufficient stretching and remodeling to induce a pressure reflection.

[0039] Figure 16The figure illustrates a portion of the target region of the aorta according to some embodiments, the portion being the entire aortic segment between the LCCA and LSA.

[0040] Figure 17 The figure illustrates a delivery catheter configured to deliver and deploy an implant in the aortic arch according to some embodiments.

[0041] Figures 18A to 18D The figure illustrates the delivery of an exemplary implant along a target region to the aortic arch using a delivery catheter, according to some embodiments.

[0042] Figures 19 to 20 The figure illustrates a method of treating hypertension with an implant according to some embodiments.

[0043] Figures 21A-1 to 21C-3 The figure illustrates an alternative design for an expandable structure for an aortic arch baroreceptor implant, according to some embodiments.

[0044] Figure 22 The figure illustrates the relationship between the compliance of simulated aortic arch vessels before and after implantation, according to some implementation methods.

[0045] Figures 23A to 23B The figure illustrates an exemplary implant utilizing multiple expandable structures interconnected by flexible connectors and deployed in the aortic arch, according to some embodiments. These expandable structures are similar to... Figures 21A-1 to 21C-3 Those in it.

[0046] Figures 24A to 24F The figure illustrates an alternative flexible connector design between adjacent expandable structures for an aortic arch baroreceptor implant, according to some embodiments.

[0047] Figure 25 The figure illustrates another exemplary implant for treating hypertension according to some embodiments, which is configured to stretch the arterial wall circumferentially and axially.

[0048] Figure 26 The diagram illustrates deployment in the aortic arch according to some implementation methods. Figure 25 The steps involved in implanting the device.

[0049] Figure 27 Another exemplary implant in a deployment configuration for use in the treatment of hypertension, according to some embodiments, is depicted.

[0050] Figure 28 Depicting a constrained configuration according to some embodiments Figure 27 Exemplary implants.

[0051] Figure 29The constrained unfolding configuration is described according to some embodiments. Figure 27 Exemplary implants.

[0052] Figure 30A The deployment configuration is described according to some implementation methods. Figure 27 implants, and Figure 30B The relevant cross-sectional view is shown.

[0053] Figure 31A The deployment configuration is described according to some implementation methods. Figure 27 implants, and Figure 31B The relevant cross-sectional view is shown.

[0054] Figure 32 Exemplary implants for delivery in a constrained configuration according to some embodiments are depicted, and Figure 33 The figure shows the implant in its deployment configuration.

[0055] Figure 34 The text describes a pillar structure with equal lengths, according to some embodiments.

[0056] Figure 35 A pillar structure with variable length is depicted according to some embodiments.

[0057] Figures 36A to 36B An exemplary implant structure according to some embodiments is shown, which is formed of braided wire and has a non-circular cross-sectional shape to tension the artery in which the implant structure is deployed by reshaping the artery.

[0058] Figure 36C An exemplary implant structure according to some embodiments is shown, which is laser-cut and has a non-circular cross-sectional shape to tension the artery in which the implant structure is deployed by reshaping.

[0059] Figure 37 and Figure 38A Images and blood pressure recordings of animals undergoing clamping maneuvers at different locations in the aorta to assess baroreflex responses are shown, as well as... Figures 38B to 38C The curvature of the corresponding position from the ultrasound is shown.

[0060] Figures 39 to 40 The distribution of aortic arch baroreceptors at different locations in the aorta, as determined by human histological studies, is shown.

[0061] Figures 41A to 41B Ultrasound images of the aortic arch before and after manual clamping of the lateral artery are shown in an animal study.

[0062] Figures 42A to 42BThe figures show a cross-sectional view and a side view of a braided implant with an elliptical cross-sectional shape according to some embodiments.

[0063] Figures 43A to 43B The figure illustrates alternative implant designs according to some implementation methods.

[0064] Figures 44A to 44B The distribution of baroreceptors in the aorta is shown.

[0065] Figure 45 The figure illustrates the mechanism of action of baroreceptor responses in the aorta.

[0066] Figure 46 The baroreceptor ion channels in the aortic arch wall were depicted.

[0067] Figure 47 The theory behind arterial wall stretching to activate baroreflex response in conventional methods is described.

[0068] Figure 48A The figure shows the natural aorta and the aorta with a pressure stent implant, demonstrating that wall tension leads to greater activation of pressure receptors, and Figures 48B to 48C The diagram shows the arterial wall before and after tensioning with the implanted element.

[0069] Figure 49 The figure illustrates a delivery catheter configured to deliver and deploy an implant in the aortic arch according to some embodiments.

[0070] Figure 50 A method for delivering an implant for treating hypertension, according to some embodiments, is described. Detailed Implementation

[0071] In one aspect, the present invention relates to an implantable device for treating hypertension, the implantable device being configured to be implanted in a target area within the aortic arch to elicit a baroreflex response, thereby lowering blood pressure.

[0072] I. Physiological baroreflex response To understand the physiological response of the baroreflex, it is helpful to understand the interactions between the nervous system within the patient's anatomy. This includes aspects such as the location of baroreceptors and their relationship to the vascular system, baroreceptor cells, and the interactions between baroreceptors and the central nervous system. Figures 2 to 3B As shown.

[0073] Blood pressure sensation occurs at several hotspots within the vascular system. The afferent neurons of the vagus nerve (cranial nerve 10) and glossopharyngeal nerve (cranial nerve 9) target the aortic arch and carotid sinus, respectively. Vagus sensory neurons enter the aorta via fine nerve branches called the aortic depressor nerve, while glossopharyngeal neurons enter the carotid sinus via the carotid sinus nerve (see...). Figure 2 The aortic depressor nerve and carotid sinus nerve are composed of bundles of fibers, including mechanosensory and chemosensory afferent nerves. Mechanosensory nerve fibers mediate the baroreflex. These mechanosensory nerve fibers terminate in specialized nerve endings called baroreceptors, which penetrate the arterial wall. Baroreceptors are stretch receptors; they do not directly measure pressure but sense the stretching of the artery. Each heartbeat's blood pressure pulsation radially stretches the arterial wall, and this arterial dilation activates mechanosensory neurons. Baroreceptor neurons are long sensory neurons that run from the aorta to the brain, transmitting input directly to the brainstem. Activation of these baroreceptor neurons reduces sympathetic output from the brainstem and increases parasympathetic output, ultimately lowering blood pressure and heart rate (a condition known as the baroreflex).

[0074] At the molecular level, baroreceptors are actually complex protein structures that form ion channels at the sensory terminals of baroreceptor nerve fibers (see...). Figures 3A to 3C (See Figures 61 to 63). Stimulation of ion channels leads to cation inflow into neurons and depolarization, during which signals are transmitted along the nerve cell. Baroreceptor nerve endings are located in the outer wall of the artery between the media and adventitia (see Figures 61 to 63). Figure 8B (and Figure 62).

[0075] Baroreceptor neurons are long sensory neurons that run from arteries to the brain, directly transmitting input to the brainstem. The aortic arch baroreceptor nerve signal originates from the arterial wall, travels through the aortic depressor nerve, then via the superior laryngeal nerve to the vagus nerve, and from the vagus nerve to the brainstem (see...). Figure 2 and Figure 3B The brainstem reflexively modulates this signal, thereby reducing sympathetic nerve output to the circulation and increasing parasympathetic nerve output to the circulation. Blood pressure and heart rate decrease. This series of events is known as the baroreflex.

[0076] Early animal studies indicated that this response was associated with stretching of the arterial walls, which occurs naturally in cases of hypertension. Later animal studies showed that the baroreflex response can be transient or persistent, depending on whether the stimulation of the arterial receptor site is static or pulsatile. Static stimulation leads to a drop in systemic blood pressure, but returns to normal after a few minutes, while non-static, pulsatile stimulation (e.g., similar to naturally pulsatile blood flow) shows that the drop in systemic blood pressure is persistent.

[0077] Since the 1960s, modulating the baroreflex, particularly the carotid baroreflex, has been a primary target for device-based treatments of refractory hypertension. The first attempts involved pacemaker-type devices: electrodes placed around the carotid sinus nerve were connected via wires to an implantable stimulator. Stimulating this nerve that innervates the carotid baroreceptors bypassed intra-arterial stimulation and lowered 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. Nevertheless, pacemaker-type implants are unlikely to be a device-based solution for refractory hypertension due to significant drawbacks—first, patients do not wish to have the generator surgically inserted into their chest. To overcome this limitation, Vascular Dynamics has developed a stent-like intravascular implant that stretches the carotid artery wall from within to amplify the carotid baroreflex signal. The device employs a non-articulated, monomorphic design configured for a straight segment proximal to the internal carotid artery. In early clinical trials, the device successfully lowered blood pressure in patients with refractory hypertension, but there was a risk of transient ischemic attack (TIA) in a small number of patients. Various drawbacks associated with this approach exist, which may contribute to an increased risk of stroke and TIA.

[0078] This invention seeks to avoid the aforementioned drawbacks associated with conventional methods by providing an endovascular implant for inducing an improved baroreflex response within the aortic arch. In an exemplary embodiment, the invention relates to an implant having one or more expandable structures configured to engage and reshape the arterial wall along a target region of the aorta, particularly the aortic arch, to generate tension within the arterial wall to induce a baroreflex response. In some embodiments, the invention is configured to engage a target region of the aortic arch opposite the left subclavian artery, including an internal curvature. This target region may be defined as a cylindrical segment of the aortic arch between the LCCA and LSA. Theoretically, this portion of the aortic arch is particularly rich in baroreflex receptors, and these receptors have increased sensitivity compared to baroreflex receptors in various other regions, such as the carotid sinus. Because this region of the aortic arch is believed to provide an enhanced response, the implant can achieve a more consistent and reliable reduction in blood pressure. Furthermore, implantation in this region avoids the drawbacks associated with delivery and implantation in sensitive areas of the carotid sinus, which may increase the risk of TIA and stroke. Therefore, the implant described herein provides a stronger baroreflex response to lower blood pressure, improves ease of delivery and implantation, and is believed to reduce the risk of adverse events.

[0079] Early animal studies of different baroreceptor responses have identified anatomical "hotspots" of baroreceptors at various locations in the vascular system, including the left common carotid artery and the left subclavian artery. Figure 4 A narrow cylindrical band extending circumferentially around the aortic arch between the origin of the fourth pharyngeal arch artery (in the aortic arch). This area is shown... Figure 8A In the fluorescently stained image, the image shows baroreceptors stained red. This baroreceptor-rich region can define a cylindrical segment of the aortic arch between the LCCA and LSA. Figure 4 The target is shown as T.

[0080] These pressure receptor "hot spots" originate from the pharyngeal arch artery in the embryo, such as Figure 5 As shown. The third pharyngeal arch artery develops into a symmetrical structure, namely the left and right carotid arteries. In contrast, the right fourth pharyngeal arch artery (R4PA) becomes the proximal right subclavian artery, while the left fourth pharyngeal arch artery (L4PA) develops into... Figure 6 The image shows a relatively narrow cylindrical band B in the aortic arch. This band has distinct characteristics compared to other areas of the aortic arch.

[0081] This band in the aortic arch is histologically different from other areas because it has fewer smooth muscle cells and an increased elastic layer. Figure 7 The left column shows the tissue segment passing through segment B of the aortic arch, compared to the right column. Figure 6 Compared to aortic segment C, this region shows fewer smooth muscle cells and an increased elastic layer. More common aortic arch baroreceptors are located in region B (e.g., Figure 2 (As shown). However, various animal and human studies have shown that baroreceptors in this region actually exhibit a unique local distribution, extending along band B surrounding the aortic arch, such as... Figure 8A As shown. Furthermore, the pressure receptors in the aortic lumen are located on the outer layer of the inner aortic wall, such as... Figure 8B The fluorescent image shown illustrates pressure receptor nerve fibers stained pink.

[0082] There are few reports on the localization of aortic arch baroreceptors in humans. An early study suggested that baroreceptor nerves encircle the aorta at the origin of the left subclavian artery, and the same author later indicated that they may extend from the brachiocephalic artery around the aorta to the ligamentum arteriosus. Several earlier studies have shown that baroreceptors were found along this region of the aortic arch, extending up to 40% of its circumference. Partly due to the aforementioned histology of this region, baroreceptors are thought to behave differently from baroreceptors in other regions, including the carotid artery. At least one animal study has shown that aortic baroreceptors have a lower pressure threshold for the action potential compared to carotid baroreceptors, see [see...]. Figure 9A Animal studies further showed that 20% uniaxial stretching caused a significant increase in cytosol calcium fluorescence in aortic arch baroreceptor neurons, but did not cause an increase in cytosol calcium fluorescence in carotid artery baroreceptor neurons. Figure 9B As shown. Therefore, it is believed that aortic baroreceptors in the human aorta are more sensitive than those in the carotid arteries. Therefore, using implants specifically constructed for deployment within the aortic region to engage and tension the arterial wall in this target region allows for a more consistent and pronounced baroreflex response than conventional carotid implants. Furthermore, to elicit robust and consistent responses across different patient populations, it is believed advantageous to engage and tension the target region along a large portion of the aorta, so as to tension multiple locations along an elongated region to account for potential differences in baroreceptor distribution or activation responses between different patients.

[0083] It is noteworthy that the literature describes the presence of baroreceptors in various locations throughout the body, including the carotid artery and aorta. Some publications describing passive baroreceptor implants briefly mention a list of various possible implantation sites, broadly including the aorta; however, no literature teaches any specific target area for the aortic arch. Furthermore, no literature addresses the unique challenges of implantation in the aortic arch region, which leads conventional approaches to focus primarily on the carotid artery, often accessed to perform additional procedures such as placing a carotid stent to address stenosis in that area.

[0084] Therefore, the present invention seeks not only to provide an improved baroreflex response by implantation in a specific target region within the aortic arch, but also to allow for implantation at this unique site while improving ease of implantation. Importantly, this claimed implant and method avoids the disadvantages associated with intracarotid procedures and implantations, which can lead to increased adverse events due to complications during deployment in this region. Furthermore, some embodiments seek to tension the arterial wall along an elongated region within the aortic arch, thereby providing a more consistent and robust baroreflex response.

[0085] While delivering an implant in the aortic arch offers significant advantages, namely the ability to target aortic arch baroreceptors in a target region including a narrow band surrounding the aorta, certain challenges associated with deployment in this region also exist. Because the aortic arch is much larger in diameter than the carotid artery, the diameter of the implant must correspond to the diameter within the aortic arch to adequately engage the tissue and achieve stretching of the arterial wall (e.g., 20% or more, 20% to 50%, or even 20% to 100%). In one aspect, this stretching can include tension in the arterial wall. In other embodiments, this tension can be provided through controlled remodeling of the arterial wall. Furthermore, to prevent implant flipping or rotation, the length of the implant should preferably be significantly greater than its maximum lateral dimension (e.g., diameter), for example, about 25 mm, 30 mm, 40 mm, or greater, typically between 30 mm and 40 mm. In some embodiments, the implant has a length such as 60 mm or longer to engage elongated target regions, thereby providing a more consistent and robust baroreflex response. In some implementations, the length of the entire implant is 70 mm or greater (e.g., about 70 mm to 90 mm, 70 mm to 80 mm, or about 85 mm).

[0086] Another challenge is that the aorta is the body's main artery, thus carrying a large volume of blood through the aortic arch and into secondary arteries branching from the aorta (e.g., BA, LCC, LSA). Therefore, to provide consistent engagement and tension in the target area over the long term, the implant must be constructed to withstand the forces of pulsating blood flow through the aortic arch and the lateral forces from blood flow into the secondary arteries without displacement. Furthermore, the implant should be constructed to expose a significant portion of the arterial wall in the target area to the pulsating blood flow to provide the aforementioned sustained reduction in blood pressure, rather than a transient response when the arterial wall is isolated from the blood flow. In some implementations, the implant provides sufficient tension to elicit a baroreflex response, resulting in a blood pressure reduction of at least 10 mm Hg, 20 mm Hg, 30 mm Hg, 40 mm Hg, 50 mm Hg, or 60 mm Hg or greater in hypertensive patients. Another challenge is that the implant must allow blood to flow freely laterally into the secondary branch arteries. Therefore, the implant itself is constructed with a primary opening in the expandable structure that allows both exposure of the arterial wall and lateral blood flow to any adjacent secondary arteries.

[0087] II. Exemplary Implantable Device Figure 1AAn exemplary implantable device 100 for treating drug-resistant hypertension is shown, which is implanted within the aortic arch (AA). The implant is an expandable device inserted into the aortic arch and lowers blood pressure by internally stretching the aortic arch walls and enhancing the aortic arch baroreflex. Secondary branch vessels branching from the top of the AA include the brachiocephalic artery (BA), the left common carotid artery (LCCA), and the left subclavian artery (LSA).

[0088] As shown in the figure, the implant 100 includes two expandable structures 10, 20 interconnected in series by an axially expandable connector 30. The expandable structures are arranged longitudinally along the aorta, which facilitates anchoring and stable placement of the implant within the tortuous aortic arch. Given the relatively large size, high blood flow rate, and tortuous morphology of the aorta, anchoring a single expandable structure in this region can be challenging. By utilizing two or more structures positioned along different sections of the aorta, the implant adapts to the curvature and complex geometry of the aorta to help anchor the implant at the target location. Furthermore, 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 trauma to the arterial wall, which can reduce inflammation and thrombus formation, which can lead to the formation of atherosclerotic plaques. Although a deployment of the first expandable structure 10 off-center is shown, it should be understood that the structure can be centrally located on the target region T. The implant may also include a proximal tether 50 to facilitate retraction of the partially deployed implant, thereby removing or repositioning the implant. As shown, the expandable structure has a non-circular (i.e., square) shape when expanded, reshaping the arterial wall to tension the arterial wall along a target region of the aorta. In some embodiments, the implant is sized such that the flat portion of the expandable structure does not contact the arterial wall, thereby promoting a long-term pressure-reflex response.

[0089] Figure 1BAnother exemplary implantable device 110 for treating drug-resistant hypertension is shown, which is implanted within the aortic arch AA. This embodiment includes three expandable structures 10, 20, and 40, interconnected in series by a plurality of flexible connectors 30. The implant is configured such that the intermediate expandable structure 40 is deployed at the target region T to activate pressure receptors in the region, while the proximal structure 10 and the distal structure 20 act as anchors, providing additional stability and facilitating the transition of the arterial wall to the intermediate expandable structure. As shown, the lateral dimension of the intermediate expandable structure 40 is larger than that of the proximal and distal expandable structures. Typically, the lateral dimension of the intermediate structure is 1.2 to 2 times larger than that of the proximal and distal structures, preferably about 1.3 to 1.5 times larger. This configuration allows for further stretching and reshaping of the arterial wall in the target region, as the proximal and distal structures stretch the arterial wall to a lesser extent, thereby facilitating the transition of the arterial wall to the increased stretching in the target region. Because the proximal and distal structures disperse some of the tensile forces at the central region, this reduces the risk of dissection along the target region due to increased tension. Furthermore, this configuration provides greater stability to the intermediate structure at the target region. The implant may also include a tether 50 extending proximally to facilitate retraction of the partially deployed implant, thereby removing or repositioning it. Various other aspects of the implant can be combined with… Figure 1A Those that are similar or identical to those described in the text.

[0090] like Figures 1A to 1B As shown, the expandable structure can be formed from multiple open wire frames, which are formed by spaced-out struts defining each lateral side. The lateral sides of adjacent frames are interconnected along the lateral struts, such that the frames form a regular polygonal shape that is axially symmetrical about the longitudinal axis of the expandable structure. It should be understood that various other expandable structures or connecting bridging elements can be used, such as... Figure 32 A and Figure 33 Those shown in Figure A. The expandable structure has a collapsed configuration (e.g., within a delivery catheter) for advancement through the vascular system and an expanded configuration (as shown), in which the transverse struts engage with the arterial wall of the aorta, thereby sufficiently stretching the arterial wall between each pair of struts in the frame to elicit a pressure-reflex response. The flexible connector 30 is axially expandable (e.g., a zigzag connector) to allow the two expandable structures to extend along different longitudinal axes, thereby accommodating varying degrees of curvature and complex three-dimensional geometry of the aortic arch. With this configuration, torsion 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. (See reference...) Figures 10A to 12BAdditional details regarding the expandable structure are understandable. While these embodiments depict implants defined by interconnecting frames, it should be understood that these aspects are applicable to a variety of other types of expandable structures, such as expandable structures formed by one or more wires or laser-cut designs formed by tubes.

[0091] Figure 1C Another exemplary embodiment of the implant 140 is shown, which has an asymmetrical structure that better conforms to the curvature of the aortic arch and promotes more uniform engagement and tension of the arterial wall along the elongated target region. As used herein, "asymmetrical" refers to an expandable structure that is asymmetrical when viewed from the lateral side, for example, as... Figure 1C As shown, the shape is a trapezoid with one side longer than the other. As illustrated, the aortic arch has a large curvature, with the radius r1 of the inner curvature being much smaller than the radius r2 of the outer curvature. In the aforementioned embodiments, this curvature results in variable gaps between the expandable structures, requiring more flexible connectors to accommodate these variations. In this embodiment, the implant 140 includes three asymmetric expandable structures 10', 20', and 40', which have a larger length on one side along the outer curvature of the aortic arch and a shorter length on the side positioned along the inner curvature of the aortic arch. These asymmetric expandable structures allow for smaller, more uniform gaps between the structures, enabling a more uniform length for the connector 30', which allows for a more robust connector design than in existing embodiments.

[0092] Figure 1D An exemplary implantable device 150 for treating drug-resistant hypertension is shown, which is implanted within the aortic arch (AA). In this embodiment, the implant is an expandable device inserted into the aortic arch, and the implant enhances the aortic arch baroreflex by lowering blood pressure from within by tensioning the aortic arch wall in a non-circular (e.g., elliptical, oval) cross-sectional shape. Secondary branch vessels, the brachiocephalic artery (BCA), the left common carotid artery (LCCA), and the left subclavian artery (LSA) branch from the top of the AA. As shown, the implant 150 is sized to fully engage with the aortic wall to reshape the wall's curvature and has a suitable length to extend along most of the aortic arch, at least along the target area from proximal to distal to the origin of the brachiocephalic artery. In one aspect, the implant is formed from braided or stranded wire to create a larger interstitial space than a conventional stent, thereby avoiding obstruction of blood flow to the lateral arteries and exposing the arterial wall to pulsating blood flow to maintain long-term responsiveness. In some embodiments, the implant can be laser-cut from a tube. In some implementations, the implant is sized such that the flatter portion of the implant does not contact the arterial wall for at least a portion of the cardiac cycle, thereby promoting a long-term baroreflex response.

[0093] Figures 10A to 10D An exemplary implantation device 100 is shown, which has two laterally expandable structures 10, 20 interconnected in series by a plurality of flexible connectors 30. Figure 10A A cross-sectional view is shown, while Figure 10B A side view is shown. Figures 10C to 10D The same view is shown, but the device is rotated 45 degrees along the longitudinal axis. The implantation device may also include one or more visual markers 31, such as coatings or gold or platinum dots on the flexible connectors 30, to aid in positioning during implantation. In this embodiment, the flexible connectors are axially expandable (e.g., zigzag connectors), and a total of four connectors extend between the apexes of adjacent coronal portions of the first and second expandable structures. Figure 10E An exemplary implantation device 100''' is shown, having three laterally expandable structures 10, 20, 40 interconnected by flexible connectors 30. It should be understood that some embodiments may also include additional such structures (e.g., 4, 5, 6, etc.) connected in the same or different ways.

[0094] In this embodiment, each expandable structure 10, 20 includes four elongated frames (10a / 10b / 10c / 10d) connected along adjacent lateral sides to form a square cross-section, such as... Figure 10AAs shown. Each frame includes at least two linear strut segments 11, 12 defining opposite lateral sides and curved, trauma-resistant coronals 13, 14 connecting the proximal and distal ends, respectively. Therefore, the overall shape of the frame is rectangular or pill-shaped. As shown, the trauma-resistant coronals 13, 14 are slightly curved to form a semicircle or smaller arc, allowing the proximal or distal end to abut against tissue without trauma to the arterial wall. The struts and coronals define the entire frame, leaving a primary opening 15 through which the arterial wall is exposed to pulsating blood flow and allows lateral blood flow into secondary branch arteries. In some embodiments, the struts of adjacent frames are defined as single struts, such that the square cross-section implant has only four struts in total, one at each corner. It should also be noted that the entire frame can be formed as a single continuous filament, such that the coronal and struts are different portions of the same filament. In some implementations, the frame is designed to avoid any sharp corners or angular features less than 100 degrees. This ensures that the proximal and distal ends of the frame remain untraumatized and helps prevent the formation of thrombi or plaques within the frame along the main openings that maintain lateral blood flow through it. This design is advantageous because the square cross-section provides sufficient engagement of the arterial walls between the opposing side struts of each frame to stretch or reshape the arterial walls without overstretching any portion of the arterial walls, while still maintaining normal aortic function and blood flow. While this implementation includes two expandable structures interconnected by four flexible connectors, the implant may include additional expandable structures connected in series in the same manner and may include more or fewer flexible connectors.

[0095] It should be understood that these concepts can be used for a variety of other shapes / designs, such as triangles or any regular polygonal cross-section, such as Figures 11A to 13D Those shown. Figures 11A to 11B An implant 100' is shown having a first expandable structure 10' and a second expandable structure 20', each expandable structure having a... Figure 10A Similar to those frames, the difference is that each component is formed by three frames, resulting in a triangular cross-section (e.g., an equilateral triangle). In this embodiment, the maximum lateral dimension of the component will be the length of each side of the triangle, which stretches the three parts of the arterial wall. Figures 12A to 12B Another implant 100'' is shown, which has a first expandable structure 10'' and a second expandable structure 20'', each expandable structure being composed of... Figure 10A The frames in this example are similar in structure, but differ in that each component is formed by five frames to create a hexagon that stretches the five sections of the arterial wall. In this embodiment, the maximum lateral dimension will be the distance between the vertex and the midpoint of the opposite side. Figures 13A to 13D An implant 110 with three expandable structures 10, 20, and 40 is shown (see Figure 1B The lateral dimension d2 of the intermediate expandable structure 40 is larger than the lateral 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 about 1.3 to 1.5 times larger. In this embodiment, dimension d2 is 1.3 times larger than d1. As discussed above, this configuration further improves the stability of the implanted device in the aortic arch and advantageously allows for further stretching or remodeling of the arterial wall in the target region, which would otherwise be unsafe to perform. This is feasible by utilizing the proximal and distal expandable structures to transition the arterial wall and reduce the risk of dissection or tearing outside the target region.

[0096] In another aspect, the implant is sized specifically to fit the human aortic arch to engage the arterial wall with the transverse struts of the expandable structure, thereby anchoring the implant within the aortic arch and adequately stretching or reshaping the arterial wall in the target region. In the embodiment shown in Figure 1, the implant is positioned such that the first expandable structure 10 is positioned relative to the LSA along the target region of the cylindrical band surrounding the aorta, as previously described. Therefore, the engagement of the paired transverse struts in this region stretches the arterial wall and stimulates highly sensitive pressure receptors in the region. In some embodiments, the implant is sized to achieve a 2:1 implant-to-aortic diameter ratio in the pressure receptor target region.

[0097] III. Size design of implants for the aortic arch A baroreceptor amplification device is an intravascular implant designed to amplify a baroreflex response by stimulating a highly sensitive baroreceptor at a precise location within the aorta. This is achieved by appropriately sizing the implant, as described herein, to achieve adequate stretching of the arterial wall within the target area (e.g., at least 15%, typically 20% or more). The implant size is designed based on the unique morphology of the human aortic arch. In some embodiments, suitable sizes for such implants have been determined through computed tomography angiography (CTA) studies of the human aorta. Measurements of the aortic arch were obtained from 50 patients, including men and women aged 53 to 88 years. The measurements were tabulated, and the mean and range were determined according to Tables 1 and 2 below.

[0098] Table 1 shows the average values ​​of various aortic arch measurements, including the aortic arch diameter along regions A, B, C, and D (see Table 1). Figure 14B ) and the length E extending between segment A and segment D (see Figure 14A ).

[0099] Table 1. Mean measurements of the aortic arch

[0100] Table 2 shows the range of various aortic arch measurements, including the diameter and length E of the aortic arch along regions A, B, C, and D.

[0101] Table 2. Measurement range of aortic arch

[0102] In one respect, the diameter and length dimensions can be considered to exhibit relatively small variations, as indicated by small standard deviations and narrow ranges. Figure 14C As shown, the aortic arch region has multiple distinct areas, where portions of the implantable device may be implanted or anchored by one or more portions of the implantable device. Therefore, the design of the implantable device should not only accommodate the target region (e.g., typically region E) but may also include proximal and distal expandable structures configured to engage the inner diameter along a more proximal region (e.g., region F or G) and a more distal region (e.g., region AD). Thus, it is believed that implants of appropriately designed sizes can be fabricated to fit most patients within the aforementioned range. It is noteworthy that the arterial wall can be safely stretched up to 50%, and possibly up to 100% in healthy patients, such that variations in stretch due to aortic size differences are acceptable, provided the target region is sufficiently stretched (e.g., at least 20%). Alternatively, the average and range of these sizes are believed to guarantee implants of different sizes. In some embodiments, a set of implants of different sizes (e.g., 3 to 10 different sizes) may be provided, and the size can be easily selected based on specific measurements of the aortic arch for a given patient (see Table 3 below). In another alternative, the implant can be custom-made based on the patient's unique measurements. These latter two options may be ideal for patients with highly variable morphology or particularly complex aortic arch geometry.

[0103] Based on the average values ​​and ranges of the human aorta described above, the dimensions of two or more expandable structures can be appropriately determined for placement within the aorta. In exemplary embodiments, each expandable structure has a length between 30 mm and 60 mm, typically about 40 mm, and a maximum lateral dimension (e.g., diameter) greater than 25 mm, such as between 30 mm and 55 mm, typically between 30 mm and 46 mm. These dimensions accommodate most aortas of the average adult while providing the remodeling required to elicit a pressure-reflex response along the target area. The expandable structures may have the same or different lengths and may have the same or different diameters.

[0104] Table 3 below shows a set of different implant sizes and associated diameters, based on a list of aortic arch sizes from over 50 patients in a CTA study. Component A refers to expandable structures positioned more distally to the target region (20 in Figure 1), and component B refers to expandable structures positioned more proximally (…). Figure 1A (10) As described above, the size of the implant can be selected based on the patient's unique morphology according to a CT scan of the aortic arch. It should be understood that a set of sizes may include any of the sizes described or any combination thereof, as well as various additional combinations not listed.

[0105] Table 3. Dimensions (diameter) of implant configurations

[0106] In another aspect, two or more expandable structures are connected in series by a plurality of flexible connectors. Preferably, the connectors are axially expandable (e.g., zigzag design) to optimize consistency with the external and internal curvatures of the aortic arch. In some embodiments, the connectors are axially expandable from 5 mm to 20 mm, typically about 5 mm to 10 mm. In some embodiments, the connectors are expanded between an unexpanded 5 mm and up to about 10 mm or more fully, so that the connectors on the external curvature of the aortic arch can expand while the connectors on the internal curvature of the aortic arch can remain unexpanded, such as... Figures 1A to 1B As shown.

[0107] In another aspect, the length of each expandable structure is typically between 30 mm and 50 mm, preferably about 40 mm, such that the total length of the entire implant, including the flexible connector, is between 65 mm and 110 mm, typically between 70 mm and 90 mm, depending on the axial extension of the connector. These lengths allow the implant to extend at least 10 mm beyond the transverse aspect of the brachiocephalic artery and the transverse aspect of the left subclavian artery to ensure a safe and stable loading zone for the device. According to CTA studies, the implant is approximately 85 mm long when the connector is not expanded, and approximately 10 mm or more (e.g., 10 mm to 20 mm) when the connector is fully expanded.

[0108] Based on previous animal studies, it is believed that the baroreceptors in the human aortic arch require stretching of at least approximately 20% to achieve a significant increase in baroreceptor neural signals. Arterial wall stretching is generally associated with remodeling, which is thought to introduce tension within the arterial wall, thereby evoking a baroreflex response. It should be understood that in some implementations, tension can be induced through sufficient remodeling even with stretching less than 20%. It is noteworthy that, considering the tension gradient through the aortic wall thickness associated with local shape changes or tortuosity, tension of 20% or greater can be achieved through sufficient remodeling. For example, see the following reference... Figures 48B to 48C Further discussion is needed. Therefore, the implant is sized to have a maximum lateral dimension or diameter that is at least 20% larger than the natural diameter at the target region (e.g., measurement C from a CT angiography study) and is constructed in a remodeled wall manner to apply sufficient tension in the arterial wall to elicit a pressure-reflex response. In some embodiments, the maximum lateral dimension is about 25 mm or greater, since the smallest human aortic diameter is about 25 mm. In some embodiments, the larger lateral dimension is in the range of about 30 mm to 60 mm. In some embodiments, the lateral dimension is constant along the length of the implant. In some embodiments, the lateral dimension is variable (e.g., larger along the middle portion to improve transition, or tapered to match variations in the aortic diameter along the arch). The implant diameter should be sufficient to ensure adequate aortic arch wall fit at the terminal landing area (e.g., locations A and D in Figure 13) just beyond the lateral origin of the brachiocephalic artery and the left subclavian artery, to ensure adequate tension of the arterial wall. For sizing design, the implant diameter is measured as the maximum lateral dimension (e.g., for a square cross-section, such as...). Figure 10A (Diagonal shown). According to CTA studies, implant sizes can be designed with various diameters, such as 30 mm, 34 mm, 38 mm, 42 mm, 46 mm, and 50 mm. Implants can be constructed to include components A and B with different diameters, as shown in Table 4.

[0109] IV. Mechanism of Action To further understand the size of the implant, it's necessary to understand the mechanism by which the implant lowers blood pressure. Imagine the aortic arch as a circular cross-section and the arterial wall as discrete arc lengths, such as... Figure 15A The diagram shown and the arc length formula are helpful. This is especially relevant in cases where the implant has a square cross-section (such as...). Figure 10A As shown), the aortic diameter is considered to be a circle divided into equal parts (e.g., four equal parts). If the aortic arch diameter is 25 mm, then the radius is 12.5 mm, and each arc length is 19.6 mm, as... Figure 15B As shown. In the same example, after inserting an implant with a diameter of 30 mm, as... Figure 15C As shown, the aortic arch has a radius of 15 mm and each arc is 23.6 mm long, provided that the aortic arch remains circular.

[0110] Therefore, because the radius increased by 20%, from the baseline ( Figure 15B ) to after implantation ( Figure 15DThe arc length of the aortic arch will increase by 20%, while other variables remain constant. In other words, each arc of the aorta will be stretched by 20%. However, after implantation, the aortic arch no longer remains circular. It is believed that stretching and reshaping the arterial wall in this way will impart sufficient tension within the arterial wall to elicit a robust pressure-reflex response. The radius of curvature of each arc increases, while the central angle corresponding to that arc decreases (see Figure 23C). The changes of these two variables in opposite directions confound accurate estimates of the resulting arc length and the degree of aortic arch stretch; however, this method provides a reasonably reasonable estimate of the stretch obtained to appropriately determine the implant size to achieve at least 20% stretch. It is worth noting that the above analysis assumes... Figure 10A The implant in the image has a square cross-section, but this analysis can be modified to take into account... Figure 11A An implant that divides the cross-section into three equal parts or Figure 12A An implant whose cross-section is divided into five equal parts.

[0111] Therefore, using the methods described above, the implant size can be designed to provide at least 20% stretching and / or remodeling of the target arterial 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 and / or remodeling in all cases. In some embodiments, the implant can be configured to provide additional stretching, for example, 20% to 30%, 50%, or even 100% stretching and / or remodeling can be safely achieved in many patients.

[0112] As previously described, this design allows for the deployment and stabilization of the device at key anatomical targets within the vascular system. Preferably, this target location is within the aortic arch to stretch and / or reshape aortic arch baroreceptors positioned along an elongated target region comprising a cylindrical segment of the aortic arch that, according to human aortic arch CT angiography studies, encircles the aorta between the origins of the left common carotid artery and the left subclavian artery (including along the internal curvature). Aortic arch baroreceptors extend along the internal curvature of the aortic arch and circumferentially around the arch to its external curvature or sellar region, but the highest concentration of these baroreceptors is located on a segment of the aortic arch adjacent to the left subclavian artery, which encircles the aorta along diameter C, such as... Figure 16 The target T is shown in the diagram. The implant configuration described herein is specifically configured for this location while stretching or tensioning adjacent pressure receptors as safely as possible.

[0113] V. Delivery and placement at the target area In another respect, implantable devices are particularly well-suited for intravascular delivery and deployment because the implants have a collapsible configuration for advancement through the vascular system and an expanding configuration for engagement with the arterial wall, such as... Figures 1A to 1D As shown. In the collapsed configuration, the implant is positioned within a delivery catheter to facilitate intravascular delivery to the target site at the aortic arch and subsequent deployment.

[0114] In an exemplary embodiment, the implant is a self-expanding structure preloaded into a sheathed delivery catheter, such as... Figure 17 As shown in the figure, the intravascular delivery catheter is designed to deliver an implant in a collapsed configuration and to position and deploy the implant at the target location, such as... Figure 16 As shown. The delivery catheter includes an internal guidewire lumen, allowing it to advance along the guidewire GW located in the aortic arch. In the illustrated embodiment, the delivery catheter 200 includes a catheter stem 201 on which the implant 100 collapses, and a retractable sheath 202 is disposed on the catheter stem, the retractable sheath 202 constraining the implant in a collapsed configuration until the implant is positioned at the desired target location, for example by visualization using markers (e.g., radiopaque markers or ultrasound markers). It should be understood that the catheter may include any other implants described herein, such as implants 110, 120, 130, 140. Markers may be coatings or markers attached to one or both of the connectors and / or expandable structures. In some embodiments, the connectors may be made of a different material than the frame, making the connectors themselves clearly visible through visualization techniques. Markers may also help identify and control the rotational direction of the implant during delivery and deployment. The delivery catheter may also include a distal tip 203 for guiding advancement on the GW and a flushing port 211 for flushing before, during, or after delivery. The delivery catheter includes a handle 210 through which the clinician can retract the sheath to deploy a self-expanding implant. Typically, the total length of the delivery catheter ( l The length of the catheter should be between 100 cm and 150 cm (e.g., approximately 135 cm) to facilitate easy access to the aortic arch by inserting the catheter through the femoral artery. The rod 201 can be rotated to aid in the orientation of the implant, such as by utilizing asymmetric expandable structures. Figure 1C Implants.

[0115] In some embodiments, the delivery catheter may be configured to deliver the entire implant as the sheath retracts, rapidly and sequentially deploying both the first and second expandable structures. The length of the expandable structures is sufficient to allow expandable structure 10 to be deployed at the target location even with any minor axial movement during deployment. Although structure 20 is deployed first, the goal of positioning and deployment is to deploy structure 10 at the target location. In other embodiments, the delivery catheter may be configured to allow the sheath to retract incrementally by a specified distance to sequentially deliver expandable structures, first placing the more distal second structure, then precisely positioning the first expandable structure at the target location, with an axially expandable connector providing some leeway for positioning the last deployed expandable structure. In still other embodiments, the implant may be sac-like and disposed in a collapsed configuration on the sac of the delivery catheter, the sac size being suitably designed to expand within the aorta to expand and deploy the implant in the target region.

[0116] During deployment, the implant utilizes the struts of the frame to form a lattice of openings. These struts are designed to stretch and / or reshape the aortic arch and stimulate aortic arch baroreceptors, thereby lowering blood pressure. Simultaneously, the arterial walls are exposed to each aortic pulsation through the frame's main openings. Figures 10A to 12B The example implementation is shown in the example implementation.

[0117] Figures 18A to 18D The sequential steps of an exemplary method for treating hypertension by deploying the implantable device described herein are shown. Figure 18A As shown, the guidewire GW is advanced through the entry point (e.g., the femoral artery) and then through the vascular system into the aortic arch. Visualization techniques, such as fluoroscopy, can verify the placement of the GW in the target area. Figure 18B As shown, the delivery catheter 200 advances along the GW, and the catheter has an implant 100 which is disposed in a collapsed configuration on the catheter stem 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 retracts, thereby allowing the self-expanding implant 100 to be resiliently deployed into its expanded configuration, wherein two expandable structures 10, 20 engage with the arterial wall, as shown. Figure 18C As shown. The guidewire GW and delivery catheter 201 are then withdrawn, anchoring the implant at a target location in the aortic arch, wherein at least one expandable structure 100 engages with and stretches the arterial wall at the target region to lower blood pressure over a long period, as shown. Figure 18D As shown.

[0118] Figure 19An exemplary method for treating hypertension with an implantable device is illustrated. The method includes the steps of: deploying an implant comprising one or more expandable structures along a target region in the aortic arch, the target region being defined as a narrow band encircling the aorta between the LCCA and LSA; stretching the arterial wall along the target region by at least 20% using struts of the implant, thereby eliciting a baroreflex response; and exposing a significant portion of the stretched target region to pulsating blood flow through a major opening between the struts of the implant, thereby providing a long-term reduction in blood pressure. In some embodiments, the implant is configured to reshape the arterial wall, thereby inducing tension within the arterial wall to elicit a baroreflex response.

[0119] Figure 20 Another exemplary method for treating hypertension by deploying an implant into the aortic arch is illustrated. The method includes the steps of: deploying an implant comprising two or more expandable structures along a target region in the aortic arch, wherein at least one expandable structure engages with the target region; stretching the arterial wall along the aortic arch by at least 15%, typically about 20%, using struts of the implant to induce a baroreflex response to lower blood pressure; exposing a significant portion of the stretched target region to pulsating blood flow through a major opening between the struts of the implant to provide a long-term reduction in blood pressure; and permanently anchoring the implant in the target region with two or more expandable structures, wherein the expandable structures are interconnected in series via axially expandable connectors to accommodate the curvature and complex geometry of the aortic arch, thereby providing long-term fixation. In some embodiments, the implant is configured to reshape the arterial wall, thereby inducing tension within the arterial wall to induce a baroreflex response.

[0120] Figures 21A-1 to 21C-3 Alternative designs for expandable structures are shown, each defined by one or more wires. (Similar to...) Figures 10A to 13DUnlike the predefined frame connected along the lateral sides as depicted in the description, each expandable structure can be defined by one or more filaments, designed to fit the desired size and characteristics of the implant. In some embodiments, the expandable structure can be formed from a single continuous filament extending in a meandering, sinusoidal, or zigzag pattern to form a circumferential loop or band of the desired size across the target area and apply sufficient external force upon expansion to stretch the arterial wall by the required amount (e.g., about 20% or more). In some embodiments, the expandable structure is formed from two or more filaments defined in a pattern to form a circumferential loop or band of the desired size and apply the required force. Typically, the filaments are nitinol and are set to a forming diameter sufficiently large than the arterial diameter to stretch the artery to the target diameter, ensuring adequate stretching of the pressure receptor. The filament specifications can be selected to ensure force requirements are met and to ensure implant lifespan. It is worth noting that in many such implementations, the cross-sectional shape of these expandable structures is substantially circular, which allows the expandable structure to uniformly increase the radius of the vessel wall, while the design still adequately exposes the arterial wall to pulsating forces after deployment.

[0121] Figures 21A-1 to 21C-3 The image shows three different designs of expandable structures formed from wire (e.g., nitinol wire). Figure 10A , Figure 10B and Figure 10C ). Figures 21A-1 to 21C-1 The structure at the forming diameter is shown. Figures 21A-2 to 21C-2 The structure at the diameter of the blood vessel is shown. Figures 21A-3 to 21C-3A structure in a constrained configuration for delivery to a target location in the aorta is shown. In the illustrated embodiment, the construction and dimensions are designed to be deployable within the aortic arch. In some embodiments, when the aortic vessel diameter is in the range of 20 mm to 25 mm, the expandable structure can be configured to form a diameter between 35 mm and 40 mm, typically about 38 mm. Studies have shown that this applies sufficient force to simulated vessels of these diameters 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 in the range of 10 mm to 30 mm, typically 10 mm to 25 mm. In some embodiments, 10A has a length of about 23 mm at the vessel diameter, 10B has a length of about 17 mm, and 10C has a length of about 14 mm. In the constrained configuration, the lengths are slightly longer (e.g., 24 mm, 18 mm, and 15 mm, respectively) due to a shortening effect. In some embodiments, the wire diameter is between 0.2 mm and 1.5 mm, typically between 0.5 mm and 1 mm, and more typically about 0.6 mm. In some embodiments, the expandable structure is designed to have a non-circular cross-section to facilitate arterial wall remodeling, thereby inducing tension in the arterial wall to elicit a pressure-reflex response.

[0122] Use and Figures 21A-1 to 21C-3 Similar wire-structure implementations were investigated to demonstrate the feasibility of the implant in providing adequate stretching by increasing arterial diameter and / or reshaping the artery, while still allowing sufficient compliance to maintain long-term effects. These studies were conducted in resin tubing with a compliance of 0.45 mm, which mimics the compliance and structure of the aortic arch wall. The results were presented in... Figure 22 As shown in the figure, the compliance of the 0.45 mm resin tube was measured and recorded. An 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 datasets fit well by linear regression with a second-order polynomial.

[0123] Figure 22This indicates that the implanted ring continuously stretches the resin tube while maintaining compliance. For example, at a pressure of 50 mmHg, the diameter of the implanted ring increases from 20 mm to approximately 23 mm, or a 15% stretch. Similarly, at a pressure of 200 mmHg, the diameter of the implanted ring increases from 25 mm to approximately 29 mm, or a 16% stretch. The effect of the implanted 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 vessel) is approximately 21 mm. Inserting the implanted ring into this tube increases the diameter to approximately 24 mm, which is equivalent to a pressure of 180 mmHg in the empty tube. In this case, the external force of the implanted ring is equivalent to a static pressure of +80 mmHg. In this example, the baroreceptor is stimulated by a 15% stretch, or an equivalent pressure increase of +80 mmHg. Therefore, it is hypothesized that the implanted ring will trigger a baroreceptor response consistent with this pressure increase, thereby reducing systemic pressure.

[0124] Although it has been shown that acute stimulation of the baroreceptor reflex leads to an immediate drop in systemic blood pressure, it has also been shown that a sustained response requires maintaining a pulsatile pattern. Figure 22 It was also shown that, with the implanted ring in place (the vascular analogue treated with the implanted ring), the pulsatility of the empty tube (the natural vascular analogue) was maintained. This is evident because the slopes of the compliance curves for the empty tube and the implanted ring tube are essentially parallel. For example, between 100 mmHg and 200 mmHg, the pulsatility of the empty tube was between 21 mm and 25 mm (19%), while the pulsatility of the same tube with the implanted ring was between 24 mm and 29 mm (21%).

[0125] Figures 23A to 23B The figure illustrates another embodiment 120, which utilizes multiple expandable structures 10, 20, 40, each having a wiring design as shown in Figures 21A to 21C, and interconnected by flexible connectors 30. In this embodiment, D V Indicates the nominal diameter of the blood vessel. (D) A It is the diameter of the active segment, which is greater than D. V This is to allow the required tension to be applied while maintaining the pulsatility of the expandable structural design. D and D P D represents the expansion diameter of the distal and proximal expandable structures, respectively. D Maximum diameter and D P Each of the terms can be greater than or equal to D. ATo fully engage the vascular system and prevent migration. In some embodiments, the proximal and distal expandable structures may have a flared design to provide resistance to migration. In some embodiments, the expandable structures may include barbs or gripping coatings to resist migration. In some embodiments, the implant may be configured to adhere after deployment (e.g., via adhesive or coating) to allow for repositioning during deployment. Flexible connectors or bridging elements connect the three expandable structures, each capable of axially elongating or compressing, allowing for flexible bending to match the shape of the bow. For example, flexible connectors allow for more stretching / elongation at the outer radius and less stretching or even compression along the inner radius of the bow, such as... Figure 23B As shown.

[0126] It should be understood that these wire-designed expandable structures can also be used as expandable structures for the implants shown in Figures 10 to 13, and can have similar dimensions. For example, the central structure can be designed to be larger in diameter than the proximal and distal structures, for example, 1.2 to 1.5 times larger in diameter or maximum lateral dimension than the proximal and distal structures. It is also understood that a variety of flexible connector designs can be used. Figures 24A to 24F Various flexible connector designs are described, including one or more sine curves (such as...). Figure 24A As shown), V-shaped part ( Figures 24B to 24D ), zigzag area ( Figure 24E ) or coiled structure (such as Figure 24F (As shown), to allow axial expansion between adjacent rings or structures. While a specific flexible connector or bridging element is described herein, it is understood that any suitable flexible connector can be used, and the bridging element design shown can be further expanded to provide increased axial elongation for better adaptation to the aortic arch.

[0127] VI. Design and Deployment of Alternative Implants As described in the foregoing embodiments, it is assumed that the implanted device utilizes circumferential stretching stimulation to activate the aortic baroreceptor nerves. However, it should be understood that axial stretching may also be relevant and can be used to provide additional activation of the baroreceptors. In some embodiments, the implant may be configured to stretch the arterial wall axially, in addition to stretching in the lateral direction or alternatively stretching in the lateral direction.

[0128] Figures 25 to 26 An implantable device is described that is configured to stretch the arterial wall circumferentially / laterally and axially, thereby providing additional activation of baroreceptors to further enhance the baroreflex response.

[0129] like Figure 25As shown, implant 121 may include expandable structures with different configurations, wherein an intermediate expandable structure 40 provides circumferential (e.g., lateral) stretching as described throughout the application, and a connector 30 between the proximal expandable structure 10 and the distal expandable structure 20 is configured to provide axial stretching along the arterial wall. Similar to some of the foregoing embodiments, this design may be a three-structure design with a proximal anchoring structure, a distal anchoring structure, and an intermediate active structure deployed at the target region. In this design, the flexible connector (i.e., bridging member) 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 axial force upon deployment.

[0130] Figure 26 Deployment is shown Figure 25 The implantation procedure involves the following steps: In the first step, the distal structure 20 is deployed at a location distal to the target region. In the second step, the intermediate active structure 40 is deployed at the target region. 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 applies an axial load to the flexible connector, thereby providing axial tension to the arterial wall between the distal and intermediate structures 40. In the third step, when the proximal structure 10 is deployed, the connector 30 between the intermediate and proximal structures 10 is compressed again during deployment by pushing the delivery catheter, such that the compressed bridging connector provides additional axial directional tension from the intermediate structure 40 to the proximal structure 10. Therefore, this method not only provides circumferential tension in the target region through the deployed intermediate active structure, but also provides axial tension from the target region in both the proximal and distal directions, thereby providing enhanced baroreceptor activation or potentially equivalent baroreceptor activation with a reduced implant diameter. While specific designs are described here, it is understood that various other designs of connectors and / or proximal and distal expandable structures can provide axially oriented tensile forces to provide enhanced pressure receptor activation.

[0131] Therefore, the implantable device and related methods described herein address an unmet clinical need for treating patients with severe hypertension who are unresponsive to multiple pharmacological agents. Existing conventional treatments and therapies (e.g., renal denervation, carotid artery devices) have minimal or limited impact on this population due to their limited antihypertensive effects or risk of adverse events. The implant described herein aims to meet this unmet clinical need based on historical and animal studies and the identification of the unique anatomy and physiology of aortic arch baroreceptors, as well as the aforementioned CT angiography studies. The implant described herein allows for sufficient stretching of a specific target area of ​​the aortic arch, which triggers highly sensitive baroreceptors, thereby reliably and continuously lowering the patient's blood pressure while avoiding the adverse risks and drawbacks associated with conventional methods targeting other vascular systems, such as the carotid artery.

[0132] On another front, implants can be constructed to better adapt to the curvature of the aortic arch by using asymmetric, expandable structures. For example... Figure 1C As shown, the radius r1 of the bow's inner curvature is much smaller than the radius r2 of its outer curvature, which may pose inconsistent engagement and anchoring challenges to conventional support structures. In the aforementioned embodiments, such as Figure 1A In these implementations, the implant utilizes a variety of structures to address these challenges. In these implementations, the segments defining the length of each expandable structure are uniform in the circumferential direction of the implant, such that, to accommodate the curvature of the aortic arch, the gap between adjacent expandable structures is larger along the outer curvature than along the inner curvature (see...). Figures 1A to 1B Therefore, these configurations utilize sufficiently flexible and expandable connectors to accommodate this variable clearance. In other embodiments, such as Figure 1C In some embodiments, the implant may include one or more asymmetric segments or expandable structures, i.e., having a larger length along the outer radius of the aortic arch and a shorter length along the inner radius of the aortic arch, such as... Figure 1C The implant 140 is shown in the diagram. This provides a more consistent gap between the structures, simplifying the requirements for connectors between expandable structures. For example, connectors do not need to bend or stretch along the outer curvature over a longer gap and can have a uniform length between expandable structures. This can be advantageous because a smaller gap means that the aortic arch has more consistent and reliable contact essentially along the entire length of the implant, thus providing a better pressure reflex response. It should be understood that these aspects can be incorporated into any implant described herein.

[0133] Figures 27 to 33Additional details of these subsequent embodiments with asymmetric expandable structures are shown. In this exemplary implant, each expandable structure has a trapezoidal shape having a longer side along the outer curvature of the aortic arch and a shorter side along the inner curvature of the aortic arch for placement. As in the foregoing embodiments, the implant may include one or more expandable structures interconnected by flexible connectors.

[0134] exist Figure 27 In the illustrated embodiment, the implant 140 includes a first expandable structure 10', a second expandable structure 20', and a third expandable structure 40', which are interconnected in a more uniform gap by flexible connectors 30' having substantially the same length. As shown, each expandable structure is trapezoidal in shape (viewed from the side) and has a short side L1 opposite to the long side L2. Figure 28 A side view of the implant in a constrained configuration is shown. Figure 29 An implant 140 in a constrained configuration but fully deployed is shown. With this configuration, the expanded shape of the implant 140 more closely conforms to the natural shape of the aortic arch. In some embodiments, the ratio of the long side to the short side is in the range of 2:1 to 3:1. In some embodiments, these expandable structures are formed by struts of varying lengths between L1 and L2. The L1 strut is intended to be positioned at the inner radius r1 of the arch (denoted as the 0-degree position), and the longer L2 strut is intended to be positioned along the outer radius r2 of the arch (denoted as the 180-degree position). Therefore, this embodiment matches the expanded shape of the implant to the natural anatomical shape of the arch, thereby minimizing unintended forces or displacements on the anatomical structures. In this embodiment, the gaps between the expandable structures are more uniform, reducing the amplitude and variation of the stretching or compression required in the connectors. This reduces the resulting average strain and cyclic strain, and improves the durability and lifespan of the implant. In some embodiments, markers may be included on the implant to aid in the orientation of the implant during delivery and placement in the aortic arch.

[0135] On another front, these implants can be defined in various cross-sectional shapes. Figure 30A In one embodiment, the implant 140' has three asymmetric expandable structures 10', 20', and 40', with cross-sections P1, P0, and P1', where P0 is located at the apex of the foot arch, and P1 and P1' are located proximally and distally to the apex, respectively. Figure 30B As shown, the cross-sections are all nominally circular. It should be understood that the cross-sections can all have the same diameter, or they can have different diameters (e.g., a larger diameter at P0, or the diameter can be increased or decreased to accommodate the taper of the aortic arch). Figure 31AIn one embodiment, the implant 140'' has three asymmetric expandable structures 10'', 20'', and 40'', with cross-sections P1, P0, and P1', where P0 is located at the apex of the foot arch, and P1 and P1' are located proximally and distally to the apex. Figure 31B As shown, the cross-sections are all non-circular, particularly oval or elliptical in shape. In such embodiments, the orientation of the major axis of the oval / elliptical shape can be cranial / caudate, as shown in Option 1, or medial / lateral, as shown in Option 2. The ratio of the major axis to the minor axis can be uniform over the entire length, or it can increase at the apex, or decrease at the proximal or distal segments. It should be understood that the cross-sections can all be of the same size / or orientation, or they can have different diameters and / or orientations (e.g., a larger diameter at P0, or the diameter can be increased or decreased to accommodate the taper of the bow).

[0136] Figure 32 Another example of an implant 140 with three asymmetric expandable structures is shown, which is in a constrained configuration and has connectors 30 extending between the expandable structures. As can be seen, the struts are longer along the top side of the implant than along the bottom side. Figure 33 An implant 140 in a deployment configuration is shown, in which three asymmetric expandable structures 10, 20, and 40 are expanded, and, although the connectors 30 are of the same or similar length, the curvature of the entire implant to accommodate the bow is evident. It should be understood that these depictions are illustrations of the concept of asymmetric expandable structures and do not necessarily reflect actual relative dimensions or geometry.

[0137] Figure 34 Depicting for implants (such as Figure 1A An example of a strut configuration 100a of an expandable structure for an implant 100 is shown, wherein the strut has a uniform length and width in the circumferential direction of each expanded chamber segment. This approach provides consistent unit size and mechanical properties, but as mentioned above, variable gaps may occur between the expandable structures when deployed in the aortic arch.

[0138] Figure 35 Depicting for implants (such as Figure 1CAn example of a strut configuration 140a of an expandable structure of implant 140 is shown, wherein the length of the strut is variable, such that each expandable structure is asymmetrical when viewed from the side. As shown, the expandable structure 10 includes a shorter strut L1 and a longer strut L2, thereby defining an asymmetrical expandable structure that better adapts to the curvature of the aortic arch. By using struts of variable length, an asymmetrical compliant arch shape is produced upon expansion. It should be understood that, in the field of stent design, considering a beam with one end fixed and the other end free but guided, the strut can be approximated as a simple beam, and the deflection can be related to the standard force and strain equations (the strut parameters are width (w), length (L), and thickness (t), which are constant) and the exemplary strut dimensions in the table below, along with strain and force.

[0139] strain

[0140] force

[0141] Table 4: Example support column dimensions (length L and width W)

[0142] As previously mentioned, in some embodiments, the shape conforming to the vertex is most preferably composed of struts of variable length, with the longest strut (at the vertex of the bow) typically being about two to three times the length of the shortest strut. The first three rows of Table 4 estimate the maximum strain for struts of lengths of 10 mm, 20 mm, and 30 mm, all struts having equal width. l =1mm. When the length is doubled, the strain changes by a factor of 4, and when the strut width is tripled, the strain changes by a factor of 9. The coefficient of force variation is 8 to 27. The bottom three rows of Table 4 estimate the preferred variable strut widths required to compensate for a 2 to 3-fold change in strut length. Preferably, in some embodiments, the asymmetric expandable structure is defined by struts of variable length, with the longest strut preferably being 2 to 3 times the length of the shortest strut, and intermediate struts having an intermediate length. It should be understood that these dimensions are exemplary and various other dimensions / ratios can be utilized.

[0143] Figures 36A to 36C Another exemplary implant is depicted, a single implant spanning most of the aortic arch, such as Figure 1D The implant 150 is shown. This implant is designed with a non-circular cross-sectional shape to alter the shape of the aortic arch during internal deployment. Figures 36A to 36B Implant design 150a is shown as a strut-like, braided, or braided expandable structure designed to have a non-circular cross-section upon expansion, although this structure typically includes fewer braids / staff and a larger opening, with staff reductions typically of 30%, 40%, 50%, 60%, 70%, or more. Figure 36A As shown, the braided structure has sufficient flexibility in the transverse direction to adapt to the curvature of the aortic arch. For example... Figure 36B As shown, the non-circular cross-section 151 is elliptical. The implant can be formed from one or more strands of wire twisted together to extend the wire in a spiral shape, which allows for greater lateral flexibility. Figure 36C Another implant design 150b, formed as a laser-cut tube, is shown, with the strut configured such that, upon deployment, the implant forms a non-circular cross-section 151, which is elliptical. In some embodiments, the implant may optionally include one or more engagement / release features 152 at one or both ends to facilitate delivery and deployment of the implant. These features may include loops, incision portions, or any features described herein.

[0144] In these embodiments, the implant 150 is at least 60 mm long, typically about 70 mm to 90 mm, allowing it to extend along most of the aortic arch in the target area, thereby activating multiple regions of the baroreceptors and providing a more consistent and robust response. Furthermore, by relying on the device to engage along most of the aorta, the implant's anchoring force is distributed over a larger area, avoiding the need for individual anchoring structures or features, thus minimizing trauma to the arterial wall. This can reduce inflammation and thrombus formation, which can lead to the formation of atherosclerotic plaques.

[0145] It should be understood that these concepts can be used for a variety of other shapes / designs, and non-circular cross sections can also be other non-circular shapes, including but not limited to: triangles, squares, rectangles or any regular polygonal shapes.

[0146] In another aspect, the implant is sized specifically to fit the human aortic arch in order to engage the arterial wall with the structure, thereby anchoring the implant within the aortic arch and adequately engaging the arterial wall within the target area. Preferably, the target area is large enough to include multiple target regions or locations rich in sensitive pressure receptors, including, as previously described, a cylindrical band that spans the LSA and surrounds the aorta adjacent to the LSA. Therefore, engagement with the non-circular cross-section of the braided implant tensions the arterial wall and stimulates highly sensitive pressure receptors in that region.

[0147] Figures 42A to 42B An exemplary implant 150 formed of braided or twisted wire is shown. Figure 42AAs shown, the device has an elliptical cross-section 151 when expanded and a maximum diameter D of suitable size to reshape the aorta. In some embodiments, D can be 30 mm or larger, typically 40 mm to 60 mm. The length (l) is a suitable length extending along most of the aorta to cover the entire target area. In some embodiments, the length... l It is 60 mm or larger, typically 70 mm to 90 mm. For example... Figure 42B As shown, the braided structure is designed to include a gap space 153, the area of ​​which is larger than that in a conventional support, such as 9 mm. 2 or larger (approximately 9 mm) 2 Up to 30 mm 2 The area A of the implant. The implant may also include one or more markers 152 at the proximal and / or distal ends to aid in placement along the target area.

[0148] Figures 43A to 43B Alternative implant designs are shown. Figure 43A In this implant 160, two or more ridges 164 extend along their length and are spaced apart by transverse struts, thereby creating a large open space 165 therebetween to expose the arterial wall to blood flow. The ridges engage with the arterial wall to reshape it into an asymmetrical, non-circular cross-sectional shape 161, thereby tensioning the wall along the target area to elicit a pressure-reflex response. The implant design may include various other aspects and dimensions mentioned above, including markers 162 at the proximal and / or distal ends. Figure 43B In this implant, 170 includes a single coiled filament, which is assumed to have a non-circular cross-sectional shape 171 upon expansion. The implant design may include various other aspects and dimensions mentioned above, including markers 172 at the proximal and / or distal ends. The advantage of both designs is the presence of much larger lateral openings or opening spaces to allow lateral blood flow and expose the arterial wall to pulsatile flow. It should be understood that the concepts described herein are not limited to these designs, and the implant can be any design that engages the arterial wall to reshape the aorta, giving it a non-circular cross-sectional shape, thereby tensioning the wall to elicit a pressure-reflex response.

[0149] VII. Size design for implants used in the aortic arch to reshape A baroreceptor amplification device is an intravascular implant designed to amplify a baroreflex response by stimulating a highly sensitive baroreceptor at a precise location within the aorta. This is achieved by appropriately sizing the implant, as described herein, to achieve adequate engagement of the arterial wall within the target region for remodeling (e.g., at least 5%, 10%, 15%, or more). The implant size is designed based on the unique morphology of the human aortic arch. In some embodiments, suitable sizes for such implants have been determined through computed tomography angiography (CTA) studies of the human aorta. Measurements of the aortic arch were obtained from 50 patients, including men and women aged 53 to 88 years. The measurements were tabulated, and the mean and range were determined according to Tables 1 and 2 previously shown.

[0150] In one respect, the diameter and length dimensions can be considered to exhibit relatively small variations, as indicated by small standard deviations and narrow ranges. Figure 39 As shown, the aortic arch region has multiple distinct areas, where portions of the implantable device may be implanted or anchored by one or more portions of the implantable device. Therefore, the design of the implantable device should accommodate the entire target region. Thus, it is believed that implants of appropriately designed sizes can be fabricated to fit most patients within the aforementioned range. Alternatively, the average and range of these sizes are believed to guarantee implants of different sizes. In some embodiments, a set of implants of different sizes (e.g., 3 to 10 different sizes) can be provided, and the size can be easily selected based on specific measurements of the aortic arch for a given patient. In another alternative, the implant can be customized based on the patient's unique measurements. The latter two options may be well-suited for patients with highly variable morphology or particularly complex aortic arch geometry.

[0151] VIII. Mechanism of action of wall tension To further understand the size of the implant, it is important to understand the mechanism by which the implant lowers blood pressure. It is helpful to consider the aortic arch as having a circular cross-section and the arterial wall as discrete arc lengths, as shown in the figure and the arc length formula.

[0152] As previously mentioned, the conventional approach of stimulating baroreceptors with intravascular implants assumes that stretching of the arterial wall activates the baroreceptors. Studies have shown that the narrow cylindrical region of the aorta contralateral to the LSA is rich in baroreceptors; therefore, stretching this region would necessarily activate the baroreceptors, resulting in a predictable and perceptible decrease in blood pressure.

[0153] However, animal studies (using dogs, which typically have the same arrangement of baroreceptors in the aorta as humans) showed different results. Experimental studies showed that all three canine subjects responded to aortic clamping along the aortic arch. The maximum drop in systolic blood pressure averaged 18 mm Hg. Surprisingly, the aortic arch triggering locations varied considerably among the three dogs. Aortic clamping was performed on each dog at locations A, B, and C on the aortic arch, as follows: Figure 37 As shown. Dog 1 only shows a response at position B. Dog 2 only shows a response at position C. Dog 3 shows a response at all positions A, B, and C. Figure 38A One of the typical blood pressure records is shown at the top, and the blood pressure record during the clamping action is shown at the bottom, illustrating the drop in blood pressure between the arterial clamping point and the release point (indicated by arrows). Figures 38B to 38C The curvature change caused by the gripping action of dog 3 at position B is shown. Figure 38B The ultrasound subplot in the image represents the baseline curvature. Figure 38C The subplots in the image represent the curvature during the clamping action. Each subplot represents a frame (time sample) in the ultrasound recording. Within each frame, these points represent the circumferential curvature around the vessel, with circumferential position expressed in degrees and curvature in units of 1 / mm. Note that under baseline conditions, the mean curvature is approximately 0.1 (1 / mm), and the maximum curvature is approximately 0.2 (1 / mm); these values ​​correspond to a mean radius of 10 mm (or a mean diameter of 20 mm) and a minimum local radius of approximately 5 mm (or an equivalent minimum local diameter of approximately 10 mm). Compare this to... Figure 38C Compared to the subplot in the figure, it shows that for an equivalent diameter of 5 mm, the average curvature is about 0.2 (1 / mm) and the maximum curvature is about 0.4 (1 / mm), which corresponds to a minimum local radius of 2.5 mm (equivalent to a minimum local diameter of 5 mm). These experimental observations suggest that shape changes that double the local curvature (or halve the effective local curvature radius) are sufficient to elicit the desired pressure receptor response.

[0154] Figures 39 to 40 The distribution of aortic arch baroreceptors is shown in a human histological study. Figure 39 In the image, the shaded area represents the target region along most of the aortic arch and appears to encompass all potential areas where baroreceptors are activated. The target region extends from the proximal LCC to the distal LSA. Figure 40 The nerve counts in each region are shown, with higher concentrations observed in regions extending along D, E, and F.

[0155] Figures 41A to 41B An ultrasound image of the aorta is shown during an aortic clamping procedure. Figure 41A The baseline shape of the aortic arch is shown, which is typically a circle with a radius of R. Figure 41BThe image shows the shape of the clamped aortic arch with a radius R' greater than the radius R. As shown, the clamping action significantly alters the geometry of the aortic arch baroreceptor region and increases the radius of curvature, thereby increasing the wall tension within the aortic arch.

[0156] Figures 44A to 44B The distribution of baroreceptors is shown in a location rich in baroreceptors in the aortic arch. Figure 44A The aortic arch with baroreceptor tissue is depicted (shown in red). Figure 44B This is a cross-section (black) showing the distribution of baroreceptors circumferentially around the aortic arch. The baroreceptor nerve fibers are shown at the top.

[0157] Figure 45 This illustrates the role of ion channels in baroreceptor activation. Baroreceptor sensors are mechanosensitive ion channels (called Piezo channels) located at the ends of nerve fibers connecting the aorta and the brainstem. When these ion channels open or are triggered, the nerve depolarizes, sending signals to the brainstem to lower blood pressure.

[0158] Figure 46 The baroreceptor ion channels (ic) in the aortic wall, particularly in the adventitia (a) layer, are shown.

[0159] Figure 47 The conventional theory behind arterial wall stretching to activate the baroreflex response is described. It is generally believed that stretching of the arterial wall separates or opens ion channels, so an implant that stretches the arterial wall opens most of the ion channels and results in a robust baroreflex response.

[0160] Therefore, baroreceptor activation is often described as a response to "stretching" of the arterial wall; baroreceptors are commonly referred to as "stretch receptors." Thus, discrete regions rich in baroreceptors are stretched by expandable endovascular implants. Various conventional implants, such as those from Vasomotor, are sized and sized specifically to stretch discrete target portions of the endovascular implant. However, recent studies have shown that wall tension, rather than stretching, leads to baroreceptor activation. The strain formula is... ,in It is wall strain. Here, r is the pressure within the artery, r is the radius of the artery (i.e., the carotid bulb), and E is Young's modulus. The variable r is the only variable that the clinician or the implant can manipulate. This manipulation is explored through the aforementioned "clamping" technique, where the clinician manually clamps the exposed artery between two fingers, causing the round artery to become elliptical, where the radius of the apex of the ellipse increases, the lateral radius decreases, and the wall tension increases. Similarly, as... Figure 48AAs shown, deploying a pressure stent implant in the natural aorta causes the aorta to twist. Artery A twists from a circular shape to an elliptical shape, with region A of increased curvature and region B of decreased curvature (the pressure stent implant is not shown). Studies have shown that region B, with increased tension, leads to greater activation of baroreceptors (even without any apparent stretching). In this way, the pressure stent implant transforms the baroreceptor-triggered surgical approach into an endovascular technique for continuous baroreceptor amplification. In some embodiments, the implant may be a braided or twisted implant designed with more twisted threads along the major axis of the ellipse and fewer twisted threads along the minor axis, thereby reshaping the aorta and minimizing metal in the areas of the aorta where the most pulsatility is required. In some embodiments, the implant may be laser-cut from the tube to provide a desired non-circular cross-sectional shape. Figures 48B to 48C The aortic wall is shown before and after tensioning with the implanted element. Figure 48B A segment of the aortic wall is depicted, in which a tension gradient is known to exist along the wall thickness, and the wall stress (i.e. tension) is further affected by the hydrostatic pressure P. Figure 48C The same segment with a shape-changing twist, according to some embodiments, is depicted. This twist is caused by contact with an element of the implant (e.g., a strut, wire, or similar feature), thereby applying a radially outward force F. This local twist alters the stretching and tension differently on the inner and outer surfaces of the wall. Therefore, T1'>T1, T2'>T2, and (T2'-T1')≠(T2-T1). In some embodiments, the implant may be designed to apply force F, causing local twisting of the aorta to induce a T2' or T1' corresponding to a local stretch of greater than or equal to 20%.

[0161] It is well known that pressure sensing requires ion channels that mediate the neuronal perception of blood pressure, thereby generating a baroreceptor reflex response. Baroreceptors are triggered by ion channels (such as the PIEZO protein) located in the membrane wall at the ends of baroreceptor nerve cell fibers (see Zeng et al., Science 362, 464-467 (2018)). Although baroreceptors have long been referred to as “stretch receptors,” the role of stretching and tension in the activation of Piezo1 ion channels has been the subject of previous research, which has found that piezo ion channels are activated in response to cell membrane tension (see Lewis and Grandl. eLife 4:e12088, 2015). Therefore, baroreceptors have long been misdescribed as “stretch” receptors when they are in fact “tension” receptors. Studies have found that tension caused by changes in membrane curvature is the activating stimulus, and further, sustained modulation leads to inactivation, indicating that sustained activation requires sustained modulation of the membrane. Regarding membrane curvature, activation was found to occur at the flattest point of curvature. This suggests that the clinical response observed during the "clamping" action is the activation of baroreceptor ion channels along the flat portion of the elliptical vessel sidewall. The relationship between wall tension, pressure, and radius is explained by LaPlace's law, T = R x P, where T is wall tension, R is radius, and P is arterial pressure.

[0162] LaPlace's law applies to elastic blood vessels, and the elastin-rich segment of the aortic arch is innervated by baroreceptor nerve cell fibers (see Bergewerff 1999). Figure 7 The histological findings shown reveal the presence of these nerve cell fibers in the histology of regions B and C of the aortic arch. Eliminating elasticity reduces the wall tension of the baroreceptor artery wall; in short, baroreceptor ion channels do not depolarize without an increase in wall tension. Historically, this phenomenon has been demonstrated by: 1) applying a rigid cast around the baroreceptor artery; 2) equalizing the pressure inside and outside the baroreceptor artery wall; and 3) overstretching the artery wall with an intravascular frame. In each case, the baroreceptor signal terminates. Past research has shown that baroreceptor signals can be eliminated by applying a plaster cast around the carotid sinus (see Hauss 1948) and by equalizing the pressure inside and outside the artery (James, J. Physiol. 214:89-103 (1971)).

[0163] Therefore, given the obvious mechanism of action of the above-mentioned pressure reflex response, the pressure stent implant described herein seeks to achieve three objectives: i) to alter the cross-sectional geometry of the aortic arch to generate wall tension therein; ii) to maintain the elastic properties of the aortic arch tissue; and iii) to maintain the curvature of the aortic arch (i.e., to avoid elongation or straightening of the arch).

[0164] In another respect, implantable devices are particularly well-suited for intravascular delivery and deployment because the implants have a collapsible configuration for advancement through the vascular system and an expanding configuration for engagement with the arterial wall, such as... Figures 1A to 1D The implementation is illustrated. In the collapsed configuration, the implant is disposed in a delivery catheter to facilitate intravascular delivery to the target site at the aortic arch and subsequent deployment.

[0165] In an exemplary embodiment, the implant is a self-expanding structure preloaded into a sheathed delivery catheter, such as... Figure 49 As shown in the figure, the intravascular delivery catheter 400 is designed to deliver a collapsed implant 150 and to locate and deploy the implant along the target area within the aortic arch, as shown. Figures 1A to 1D and Figure 39 As shown. The delivery catheter includes an internal guidewire lumen, allowing it to advance along the guidewire GW located in the aortic arch. In the illustrated embodiment, the delivery catheter 200 includes a catheter stem 201 on which the implant 150 collapses, and a retractable sheath 202 is provided on the catheter stem, which restrains the implant in a collapsed configuration until the implant is positioned at the desired target area, positioning being, for example, through visualization using markers (e.g., radiopaque markers or ultrasound markers). In some embodiments, the connector may be made of a different material than the frame, making the connector itself clearly visible through visualization techniques. The delivery catheter may also include a distal tip 203 for guiding advancement on the GW and a flushing port 211 for flushing before, during, or after delivery. The delivery catheter includes a handle 210 through which the clinician can retract the sheath to deploy the self-expanding implant. Typically, the total length of the delivery catheter ( l The distance between 100 cm and 150 cm (e.g., about 135 cm) is so that the aortic arch can be easily accessed by inserting the catheter through the femoral artery.

[0166] In some embodiments, the delivery catheter may be configured to deliver the entire implant as the sheath retracts. The length of the expandable structure is sufficient to allow it to be deployed at the target area even with any minor axial movement during deployment. In some embodiments, the catheter may include incremental retraction to deliver the implant in a precisely controlled manner. In still other embodiments, the implant may be sac-like and disposed in a collapsed configuration on the sac of the delivery catheter, the sac being suitably sized to expand within the aorta to expand and deploy the implant in the target area.

[0167] In an exemplary delivery method, a guidewire GW is advanced through an entry point (e.g., the femoral artery) and through the vascular system into the aortic arch. Visualization techniques, such as fluoroscopy, can verify the placement of the GW in the target area. A delivery catheter 200, having an implant 100, is advanced along the GW. This implant is positioned in a collapsed configuration on a catheter stem 201 and restrained 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 resiliently deploy into its expanded configuration, thereby engaging with the arterial wall. The guidewire GW and delivery catheter 201 are withdrawn, anchoring the implant at the target area of ​​the aortic arch for long-term blood pressure reduction.

[0168] Figure 50 A method for treating hypertension is disclosed. The method includes the following steps: deploying an implant within a patient's aortic arch having a collapsed configuration for advancement through the patient's vascular system and an expanded configuration for engagement with the arterial wall within the patient's aortic arch; engaging the arterial wall with the implant in the expanded configuration along a target area extending at least between the origin of the brachiocephalic artery and the origin of the left subclavian artery, wherein the implant has a non-circular cross-section upon expansion, thereby inducing wall tension along the target area in the aortic arch by remodeling; and exposing a large portion of the arterial wall along the target area to a pulsatile blood flow side opening of the implant to maintain a long-term pressure-reflex response induced by the implant.

[0169] In the foregoing specification, the invention has been described with reference to specific embodiments thereof, but those skilled in the art will recognize that the invention is not limited thereto. Various features, embodiments, and aspects of the invention described above may be used alone or in combination. Furthermore, the invention can be used in any number of environments and applications beyond those described herein without departing from the broader spirit and scope of this specification. Therefore, the specification and drawings should be considered illustrative rather than restrictive. It should be understood that the terms “comprising,” “including,” and “having” as used herein are specifically intended to be understood as open-ended technical terms. It should be understood that various dimensions of embodiments are described herein or depicted in various drawings, and in some embodiments, corresponding dimensions may include variations, such as within + / - 25% or + / - 10% of the referenced values, and the inventive concept is not limited to these dimensions. Unless otherwise stated, the term “about” is considered to mean within + / - 10%. For all purposes, any references to publications, patents, or patent applications are incorporated herein by reference in their entirety.

Claims

1. An implant for treating hypertension in a patient, the implant comprising: An implant having a collapsed configuration for passage through the patient's vascular system and an expanded configuration for engagement with the arterial wall within the patient's aortic arch. The implant is sized such that when deployed in the aortic arch, the implant is at least 60 mm long, and the implant engages with the arterial wall of the aorta and extends along a target area, the target area including at least the region extending between the origin of the brachiocephalic artery and the origin of the left subclavian artery. The implant has a non-circular cross-section when it expands along the entire length of the implant to induce wall tension along the entire target area of ​​the aortic arch, thereby inducing a pressure reflex response of the pressure receptor in the target area; The implant has sufficient flexibility to adapt to the curvature of the aortic arch along the elongated region; and In this implant, any of the lateral openings is large enough to allow lateral blood flow through the lateral opening to reach any lateral branch and to expose the arterial wall to pulsating blood flow.

2. The implant device of claim 1, wherein, The non-circular cross-section is elliptical.

3. The implantation device according to claim 1, wherein, The non-circular cross-section is a regular polygon shape.

4. The implantation device according to claim 1, wherein, The non-circular cross-section is constant along the entire length of the implant.

5. The implantation device according to claim 1, wherein, The implant includes at least one expandable structure, the size of which is designed such that the maximum lateral dimension is between 30 mm and 80 mm.

6. The implantation device according to claim 5, wherein, The total length of the implant is between 60 mm and 90 mm.

7. The implantation device according to claim 1, wherein, The implant is self-expanding.

8. The implantation device according to claim 1, wherein, The implant is made of one or more threads woven or twisted together.

9. The implantation device according to any claim 8, wherein, The one or more wires are Nitinol.

10. The implantation device according to any claim 8, wherein, In the expanded configuration, the implant design has a plurality of interstitial openings, each interstitial opening having an area of 9 mm 2 or greater to allow blood flow through the interstitial openings and expose the arterial wall to pulsatile blood flow.

11. A method for treating hypertension in a patient, the method comprising: An implant is deployed within the patient's aortic arch, the implant having a collapsed configuration for advancing through the patient's vascular system and an expanded configuration for engaging the arterial wall within the patient's aortic arch, the implant having a length of at least 60 mm upon deployment; The arterial wall is joined to the expanded implant along a target region, the target region including at least the area extending between the origin of the brachiocephalic artery and the origin of the left subclavian artery, wherein the implant has a non-circular cross-section upon expansion, thereby inducing wall tension in the aortic arch along the target region; and The arterial wall along most of the target area is exposed to the pulsating blood flow side opening of the expandable structure to maintain the pressure reflex response induced by the implant over a long period.

12. The method according to claim 11, wherein, The non-circular cross-section is elliptical.

13. The method according to claim 11, wherein, The non-circular cross-section is a regular polygon shape.

14. The method according to claim 11, wherein, The non-circular cross-section is constant along the entire length of the implant.

15. The method according to claim 11, wherein, The length is between 60 mm and 100 mm.

16. The method according to claim 15, wherein, The implant is designed to have a maximum lateral dimension greater than 25 mm.

17. The method according to claim 11, wherein, The implant is self-expanding.

18. The method according to claim 11, wherein, The implant is made of one or more threads woven or twisted together.

19. The method according to claim 18, wherein, The one or more wires are Nitinol.

20. The method according to claim 18, wherein, In the expanded configuration, the implant design includes a plurality of interstitial openings, each interstitial opening having an area of 9 mm 2 or greater to allow blood flow through the interstitial openings to any side arteries in the aortic arch and to expose the arterial wall to pulsatile blood flow.

Images