Implantable stent device, system, and method of use thereof

Abstract

A vascular implant comprising a frame having a first surface and an opposing second surface and a valve seeding element positioned on the first surface. The valve seeding element protrudes from the first surface of the frame.

Description

[0001] Attorney Docket No.206589-0002-00 WO

[0002] TITLE OF THE INVENTION

[0003] Implantable Stent Device, System, and Method of Use Thereof

[0004] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 788,456 filed on April 14, 2025.

[0005] BACKGROUND OF THE INVENTION

[0006] Post Thrombotic Syndrome (PTS) is a common complication of deep vein thrombosis (DVT) where individuals develop a spectrum of symptoms that arise from chronic venous reflux, obstruction, and hypertension (Kahn, S. R. Hematology Am Soc Hematol Educ Program 2016, 413-418 (2016), Rabinovich, A. & Kahn, S. R. Blood 131, 2215-2222 (2018)). PTS symptoms develop in 33-50% of patients diagnosed with lower extremity DVT, impacting hundreds of thousands of patients annually in the US alone (Chaitidis, N. et al. Curr Pharm Des 28, 550-559 (2022), Farrell, J. J. et al. Cardiovasc Diagn Ther 6, 623-631 (2016), Baldwin, M. J. et al. J Thromb Haemost 11, 795-805 (2013)). Symptoms include pain, swelling, skin changes, and recurrent ulcers in the affected limb. Studies have found that 5-10% of DVT patients will develop venous ulcers because of PTS progression (Kahn, S. R. Hematology Am Soc Hematol Educ Program 2016, 413-418 (2016), Chaitidis, N. et al. Curr Pharm Des 28, 550-559 (2022), Kahn, S. R. et al. Circulation 130, 1636-1661 (2014)). Patients with PTS have significantly lower quality of life, reduced work force participation, and significantly higher medical costs than those who had a DVT but did not develop PTS (Baldwin, M. J. et al. J Thromb Haemost 11, 795-805 (2013), Kahn, S. R. et al. J Thromb Haemost 2, 2146-2151 (2004), Kahn, S. R. et al. J Thromb Haemost 6, 1105-1112 (2008), Silva, J. C. et al. Ann Vase Surg 85, 253-261 (2022)). Economic analysis of DVT patients found that patients who develop PTS symptoms have 50% higher medical treatment costs than those with DVT alone, costing the US healthcare system approximately S200M annually (Ashrani, A. A. & Heit, J. A. J Thromb Thrombolysis 28, 465-476 (2009), Fernandez, M. M., et al.

[0007] Clinicoecon Outcomes Res 7, 451-462 (2015), Reynolds, S. K. D. B. B. K. B. J. L. J. R. S. D. J. R. M. W. American Journal of Health-System Pharmacy 69, 567-572 (2012),Attorney Docket No.206589-0002-00 WO

[0008] MacDougall, D. A., et al. American Journal of Health-System Pharmacy 63, S5-S15 (2006)). PTS lacks consistently effective therapies, particularly in patients with damaged and incompetent venous valves.

[0009] Proper management of DVT, including extended anticoagulation and thrombectomy, reduces the risk of remaining clot and clot recurrence, which also reduces PTS incidence and severity (Saedon, M. & Stansby, G. Phlebology 25 Suppl 1, 14-19 (2010), Cucuruz, B. et al. J Vase Surg Venous Lymphat Disord 8, 390-395 (2020), Abramowitz, S. et al., J Vase Surg Venous Lymphat Disord, 101825 (2024)). However, PTS remains a common complication following DVT resolution. Patients with PTS are initially treated with conservative therapies of compression and weight loss and exercise plans (Rabinovich, A. & Kahn, S. R. Blood 131, 2215-2222 (2018), Chaitidis, N. et al. Curr Pharm Des 28, 550-559 (2022)). Compression garments are the most used therapy for PTS symptoms and can help reduce symptom burden but do not reverse or prevent PTS onset (Krizanova, O. et al. Int Wound J 21 (2023), Cosmi, B. et al. Front Cardiovasc Med 9, 762443 (2022), Machin, M. et al. Expert Rev Cardiovasc Ther 19, 191-200 (2021), Kahn, S. R. et al. Lancet 383, 880-888 (2014), Kahn, S. R. et al. BMC Cardiovasc Disord 7, 21 (2007)). Active compression is typically reserved for patients with severe PTS symptoms, and clinical studies have shown that a fraction of patients will resolve their ulcers from active compression therapy (Rabinovich, A. & Kahn, S. R. Blood 131, 2215-2222 (2018), Cohen, J. M„ et al. Chest 1, 308-320 (2012), O’Donnell, M. J. et al. Thrombosis and haemostasis 99, 623-629 (2008)). There are also subsets of patients who respond to pharmaceutical treatments, including certain venoactive drugs and statins (Cucuruz, B. et al. J Vase Surg Venous Lymphat Disord 8, 390-395 (2020), Makedonov, I. et al. J Clin Med 9 (2020), Caiano, L. M. et al. J Thromb Haemost 21, 944-952 (2023), Scalia, R. & Stalker, T. J. Microcirculation 9, 431-442 (2002)).

[0010] However, these effects are modest and unpredictable in who will be a responder to the treatments, which limits the clinical impact of the treatments (Rabinovich, A. & Kahn, S. R. Blood 131, 2215-2222 (2018), Chaitidis, N. et al. Curr Pharm Des 28, 550-559 (2022), Makedonov, I. et al. J Clin Med 9 (2020), Caiano, L. M. et al. J Thromb Haemost 21, 944-952 (2023)). Surgical treatments, such as venous angioplasty and stenting are highly effective at opening venous obstruction and relieving related PTS symptoms (Chaitidis,Attorney Docket No.206589-0002-00 WO

[0011] N. et al. Curr Pharm Des 28, 550-559 (2022), Machin, M. et al. Expert Rev Cardiovasc Ther 19, 191-200 (2021), Goel, R. R., et al. Cochrane Database SystRev 9, Cd001097 (2021), Ma, X. et al. J Endovasc Ther, 15266028241245325 (2024), Comerota, A. J. et al. J Vase Interv Radiol 35, 834-845 (2024), Badesha, A. S. et al. J Vase Surg Venous Lymphat Disord 12, 101722 (2024)). Surgical approaches to treat venous reflux include bypasses, to reroute flow around compromised valves, and surgical repairs or formation of new valves from vessel wall (Goel, R. R., et al. Cochrane Database Syst Rev 9, Cd001097 (2021), Vasudevan, T. et al. Journal of Vascular Surgery: Venous and Lymphatic Disorders 9, 1200-1208 (2021), Zong, Q. et al. Medicine in Novel Technology and Devices 21, 100288 (2024)). However, these procedures are more invasive and lack evidence of clinical efficacy, which limits their use (Schleimer, K. et al. Journal of Vascular Surgery: Venous and Lymphatic Disorders 7, 592-600 (2019), Krizanova, O. et al. Int Wound J 21 (2023), Goel, R. R., et al. Cochrane Database Syst Rev 9, Cd001097 (2021), Garg, N. et al. Journal of vascular surgery 53, 383-393 (2011)). Thus, patients with chronic reflux continue to have limited treatment options and persistent symptoms.

[0012] Prosthetic venous valves have failed to treat PTS and venous reflux. The degree of venous reflux following a DVT is predictive of PTS symptom development and severity (Myers, K. A. et al. J Vase Surg 21, 605-612 (1995), Yamaki, T. et al. J Thromb Haemost 5, 305-312 (2007), Vedantham, S. Thromb Res 123 Suppl 4, S62-65 (2009)). As a result, the concept of using prosthetic valves in patients with venous reflux and PTS was initially proposed over 30 years ago, and in the proceeding decades many designs have been developed and tested (Zong, Q. et al. Medicine in Novel Technology and Devices 21, 100288 (2024), Dotter, C. T. et al. Seminars in Roentgenology 16, 7-12 (1981). The various iterations have included bicuspid and mono-leaflet designs made from autologous tissues, fixed animal tissue, advanced synthetic materials, and creating valves from existing vein wall (Vasudevan, T. et al. Journal of Vascular Surgery: Venous and Lymphatic Disorders 9, 1200-1208 (2021), Zong, Q. et al. Medicine in Novel Technology and Devices 21, 100288 (2024), Taheri, S. A. et al. The American Journal of Surgery 156, 111-114 (1988), Ofenloch, J. C. et al. Annals of Vascular Surgery 11, 62-67 (1997), Pavcnik, D. et al. Journal of Vascular Surgery 40, 1223-1227 (2004), Pavcnik, D. et al. Journal of Vascular and Interventional Radiology 16, 1511-1516 (2005), Pavcnik,Attorney Docket No.206589-0002-00 WO

[0013] D. et al. Journal of Vascular Surgery 46, 338-345 (2007), PE, T. in Proceedings of the Twelfth Annual Meeting of the American Venous Forum, Phoenix, AZ, February 3-6, 2000, Pavcnik, D. et al. Journal of Vascular Surgery 35, 598-602 (2002)). Despite the long development history of prosthetic valves, none have been successfully developed into a product available for patients. The key challenges for prosthetic valves are thrombosis at the valve, successfully reducing reflux, and successful placement and stability of the stents (Vasudevan, T. et al. Journal of Vascular Surgery: Venous and Lymphatic Disorders 9, 1200-1208 (2021), Zong, Q. et al. Medicine in Novel Technology and Devices 21, 100288 (2024), Pavcnik, D. et al. Journal of Vascular Surgery 40, 1223-1227 (2004), Pavcnik, D. et al. Journal of Vascular and Interventional Radiology 16, 1511-1516 (2005), Pavcnik, D. et al. Journal of Vascular Surgery 46, 338-345 (2007), Pavcnik, D. et al. Journal of Vascular Surgery 35, 598-602 (2002)). Thrombosis is a common risk for vascular implants due to the foreign material stimulating inflammation and activating the coagulation cascade. This risk is further enhanced in a prosthetic valve, where the patients typically have reduced venous blood return, and the valve leaflets inherently create a region of stasis in the downstream sinus of the valve. Prosthetic valves also often struggle to effectively reduce reflux due to the materials used for the leaflets, leaflet design, and flexibility (Vasudevan, T. et al. Journal of Vascular Surgery: Venous and Lymphatic Disorders 9, 1200-1208 (2021), Zong, Q. et al. Medicine in Novel Technology and Devices 21, 100288 (2024)). Finally, some prosthetic valves have had issues with stability when placed as they come under significant pressure when closing against refluxing flow, which reduces their efficacy and poses a safety risk (Zong, Q. et al. Medicine in Novel Technology and Devices 21, 100288 (2024)).

[0014] An additional condition related to vascular valve failure includes central lymphatic incompetence. Patients with various cardiac complications, such as heart failure, frequently develop systemic lymphedema, causing swelling in various tissues, causing additional symptoms, and complicating their clinical care. The lymphatic system collects fluid from tissue beds throughout the body and returns the fluid into venous circulation at the lympho-venous junction (LVJ). The lymphatic system is a low pressure vascular system that is not connected to the heart and relies on internal vascular contraction to propel flow, thus, there is a lympho-venous valve that regulates flow fromAttorney Docket No.206589-0002-00 WO

[0015] the lymphatic system into the venous system. Heart failure often causes increased venous pressures, resulting from decreased efficiency of right-sided heart filling. The increased venous pressures can block lympho-venous valve opening and congest the entire lymphatic system, leading to fluid buildup, lymphatic vessel complications, and symptom onset. There is no current treatment to restore proper valve function to the lympho-venous junction to restore fluid balance.

[0016] There remains a need in the art to provide new treatment options for PTS and systemic lymphedema.

[0017] SUMMARY OF THE INVENTION

[0018] In some aspects, the invention relates to a vascular implant.

[0019] In some embodiments, the vascular implant comprises a tubular frame having an inlet, an outlet, and a lumen therethrough, the lumen forming an inner surface of the frame. In some embodiments, a valve seeding element is positioned on the inner surface of the frame.

[0020] In some embodiments, the valve seeding element of the invention comprises a sloped surface that extends into the lumen.

[0021] In some embodiments, the vascular implant comprises a frame having a first surface and an opposing second surface, and a valve seeding element positioned on the first surface.

[0022] In some embodiments, the valve seeding element of the invention protrudes from the first surface of the frame of the vascular implant.

[0023] In some embodiments, the vascular implant comprises a second valve seeding element positioned on the inner surface of the frame.

[0024] In some embodiments, the second valve seeding element comprises a sloped surface that extends into the lumen.

[0025] In some embodiments, the first and second valve seeding elements are positioned across from each other with the lumen therebetween.

[0026] In some embodiments, the sloped surface of the valve seeding element extends into the lumen by at least 5%, at least 12.5%, or at least 33% of the lumen height at the tallest point of the sloped surface.Attorney Docket No.206589-0002-00 WO

[0027] In some embodiments, the valve seeding element comprises a vertical surface, wherein the vertical surface extends from the apex of the sloped surface away from the lumen.

[0028] In some embodiments, the vertical surface of the valve seeding element is straight, concave, or convex.

[0029] In some embodiments, the horizontal length of the valve seeding element is in the range of about 5 mm to about 50 mm.

[0030] In some embodiments, the sloped surface of the valve seeding element comprises a micropattem.

[0031] In some embodiments, the sloped surface of the valve seeding element comprises a first micropattem and the vertical surface of the valve seeding element comprises a second micropattern.

[0032] In some embodiments, the first micropattern and the second micropattem of the valve seeding element are different micropatterns.

[0033] In some embodiments, the vascular implant comprises a resorbable material. In some embodiments, the tubular frame of the vascular implant comprises a mesh.

[0034] In some embodiments, the tubular frame of the vascular implant comprises a middle length and two end openings, wherein the two end openings have a greater perimeter than the middle length.

[0035] In some embodiments, the tubular frame comprises a spacing between the valve seeding element and the outlet.

[0036] In some aspects, the invention relates to a method of generating a recirculation zone in the lumen of a vessel of a subject having a flow of fluid therethrough.

[0037] In some embodiments, the method of generating a recirculation zone comprises the steps of implanting a flow diverting element in a vessel of the subject, partially occluding fluid flow in the vessel adjacent to the flow diverting element by diverting fluid flow towards a central region of the vessel lumen, and generating a recirculation zone downstream of the partial occlusion and adjacent to the flow diverting element.

[0038] In some embodiments, the method comprises the step of applying external pneumatic compression to the subject.Attorney Docket No.206589-0002-00 WO

[0039] In some embodiments, the flow diverting element of the method comprises any vascular implant of the invention.

[0040] In some embodiments, the subject of the method is diagnosed with post thrombotic syndrome, deep vein thrombosis, chronic venous reflux, and systemic lymphedema.

[0041] In some embodiments, the vessel of the method is a deep vein.

[0042] In some embodiments, the method comprises the step of providing a compression device for application of external pneumatic compression.

[0043] In some embodiments, the compression device of the method comprises a compression garment, a cuff, a sequential compression device, or a rapid cycling compression device.

[0044] In some embodiments, the external pneumatic compression of the method is applied as a pulse with a pulse duration of at most 20 seconds, at most 10 seconds, at most 5 seconds, at most 1 second, at most 0.5 seconds, at most 0.35 seconds, at most 0.25 seconds, at most 0.15 seconds, or at most 0.1 seconds.

[0045] In some embodiments, the external pneumatic compression of the method is applied as a pulse with a frequency of at least 1 / min, at least 5 / min, at least 6 / min, at least 10 / min, or at least 12 / min.

[0046] In some embodiments, the flow diverting element of the method is implanted in a vein upstream of a lymphovenous junction.

[0047] In some aspects, the invention relates to a method of generating a leaflet valve in the vein of a subject.

[0048] In some embodiments, the method of generating a leaflet valve in the vein of a subject comprises the steps of positioning a vascular implant of the invention in a vein of a subject, generating a recirculation zone downstream and adjacent to the valve seeding element of a valve seeding element of the vascular implant, and growing a layer of endothelial cells over the exposed surfaces of the valve seeding element.

[0049] In some embodiments, the valve seeding element of the method degrades after growth of the layer of endothelial cells.Attorney Docket No.206589-0002-00 WO

[0050] BRIEF DESCRIPTION OF THE DRAWINGS

[0051] The following detailed description of embodiments of the invention will be better understood when read in conjunction with the appended drawings. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[0052] Figure 1 depicts a schematic of the pathology of post thrombotic syndrome (PTS) Figures 2A and 2B depict the hemodynamic regulation of valve formation. Figure 2A depicts a schematic showing endothelial cell signaling during valve development and maintenance. Figure 2B depicts representative images of FOXC2 (red) and PROXI (green) expression at mouse venous valves.

[0053] Figures 3A and 3B depict an exemplary vascular implant device. Figure 3A depicts an oblique view of an exemplary stent device. Figure 3B depicts a view of the lumen of an exemplary stent device.

[0054] Figure 4 depicts an exemplary embodiment of a stent device including a valve seeding element.

[0055] Figure 5 depicts a side view of an exemplary embodiment of a valve seeding element in a stent device.

[0056] Figure 6 depicts is a vertical cross-sectional view of the valve seeding element in a stent device.

[0057] Figures 7A through 7D depict computational fluid dynamics simulations (CFDs) of various valve seeding element embodiments under different simulated flow rates. Figure 7A depicts CFDs of valve seeding element embodiments with concave, straight, and convex geometries having 33% maximum vessel occlusion and 5 mm length. Figure 7B depicts CFDs of valve seeding element embodiments having a concave shape, 5 mm length, and either 10%, 25%, and 33% maximum vessel occlusion. Figure 7C depicts a comparison of CFDs of valve seeding element embodiments of 5 mm length or 10 mm length. Figure 7D depicts CFDs of valve seeding element embodiments having 5 mm length, concave shape, and 25% maximum stenosis at different inlet velocities.

[0058] Figure 8A through 8D depict valve seeding (VS) stent and rapid cycling compression device (RCCD) therapy. Figure 8A depicts a rendering of the valve-seedingAttorney Docket No.206589-0002-00 WO

[0059] stent design. Figure 8B depicts a schematic showing the comparison of the traditional prosthetic stent compared to the valve-seeding design. Figure 8C depicts a model of endothelial coverage and hemodynamic stimulation, leading to a regenerated valve.

[0060] Figures 9A and 9B depict an exemplary valve seeding (VS) stent design and computation fluid dynamic (CFD) simulations. Figure 9A depicts a model of the effects of recirculatory flow on valve endothelial phenotypes. Figure 9B depicts representative images of CFD data showing the size and velocity of the recirculation zone (blue dashed line) downstream of each valve-seeding leaflet.

[0061] Figure 10 depicts an exemplary method of treating chronic venous reflux, post thrombotic syndrome, or deep vein thrombosis.

[0062] Figures 11 A and 1 IB depict a schematic of a method for treating systemic lymphedema. Figure 11 A depicts a schematic of a blocked lympho-venous junction caused systemic lymphedema. Figure 1 IB depicts the application of an exemplary stent device including a single valve seeding element stent for the treatment of a lympho-venous junction blockage.

[0063] Figure 12 depicts a side view of an exemplary embodiment of a stent device including a single valve seeding element applied upstream of a lympho-venous junction in a vein.

[0064] Figure 13 depicts a schematic of the various design features of an exemplary valve seeding stent design.

[0065] Figure 14 depicts an exemplary embodiment of a stent device including a valve seeding element.

[0066] Figure 15 depicts an exemplary embodiment of a stent device including a valve seeding element.

[0067] DETAILED DESCRIPTION

[0068] The following discussion omits or only briefly describes conventional features of implantable stent devices, systems, and methods of use thereof that are apparent to those skilled in the art. Those of ordinary skill may thus recognize that other elements may beAttorney Docket No.206589-0002-00 WO

[0069] desirable and / or necessary to implement the devices, systems, and methods described herein. It is noted that various examples are described in detail with reference to the drawings. Reference to these various examples does not limit the scope of the claims attached hereto. Additionally, any examples set forth in this specification are intended to be non-limiting and merely set forth some of the many possible implementations for the appended claims. Further, particular features described herein can be used in combination with other described features in each of the various possible combinations and permutations. As such, it is understood that the detailed description is exemplary and explanatory only and is not restrictive of the broad inventive concepts upon which the examples disclosed herein are based.

[0070] Unless otherwise specifically defined herein, all terms are to be given their broadest reasonable interpretation. This includes meanings implied from the specification as well as meanings understood by those skilled in the art and / or as defined in dictionaries, treatises, etc.

[0071] It is noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless otherwise specified. The terms “includes” and / or “including,” when used in this specification, specify the presence of stated features, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof.

[0072] Relative terms such as “horizontal,” “vertical,” “up,” “down,” “top,” and “bottom” as well as derivatives thereof (e.g., “horizontally,” “downwardly,” “upwardly,” etc.) should be construed to refer to the orientation as then-described or as shown in the drawing figure under discussion. These relative terms are for convenience of description and normally are not intended to require a particular orientation in actuality. Terms including “inwardly” versus “outwardly,” “longitudinal” versus “lateral” and the like are to be interpreted relative to one another or relative to an axis of elongation, or an axis or center of rotation, as appropriate. Terms concerning attachments, coupling and the like, such as “connected” and “interconnected,” refer to a relationship wherein structures are secured or attached to one another either directly or indirectly through intervening structures, as well as both movable or rigid attachments or relationships, unless expresslyAttorney Docket No.206589-0002-00 WO

[0073] described otherwise. The phrases “operatively” or “operably connected” indicates such an attachment, coupling or connection that allows the pertinent structures to operate as intended by virtue of that relationship.

[0074] Reference throughout the specification to “exemplary”, “one example”, “an example” or “some examples” means that a particular feature, structure, or characteristic described in connection with at least one example of the subject matter disclosed. Thus, the appearance of the phrases “in one example”, “in an example” or “in some examples” in various places throughout the specification is not necessarily referring to the same example. Further, the particular features, structures or characteristics of “one example”, “an example” or “some examples” may be combined in any suitable manner with each other to form additional examples of such combinations. It is intended that examples of the disclosed subject matter cover modifications and variations thereof. Terms such as “first,” “second,” “third,” etc., merely identify one of a number of portions, components, steps, operations, functions, and / or points of reference as disclosed herein, and likewise do not necessarily limit embodiments of the present disclosure to any particular configuration or orientation.

[0075] Moreover, throughout this disclosure, various aspects can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, 6, and any whole and partial increments there between. This applies regardless of the breadth of the range. As used herein, the term “about” in reference to a measurable value, such as an amount, a temporal duration, and the like, is meant to encompass variations of plus or minus 20%, plus or minus 10%, plus or minus 5%, plus or minus 1%, and plus or minus 0.1% of the specified value, as such variations are appropriate.Attorney Docket No.206589-0002-00 WO

[0076] The terms “proximal,” “distal,” “anterior,” “posterior,” “medial,” “lateral,” “superior,” and “inferior” are defined by their standard usage indicating a directional term of reference. For example, “proximal” refers to a position that is situated nearer to the center of a body or point of attachment or interest, while “distal” refers to a position that is situated away from the center of the body or point of attachment or interest. In another example, “anterior” refers to the front of a body or structure, while “posterior” refers to the rear of a body or structure, in relation to a relative viewpoint. In another example, “medial” refers to the direction towards the midline of a body or structure, and “lateral” refers to the direction away from the midline of a body or structure. In some examples, “lateral” or “laterally” may refer to any sideways direction. In another example, “superior” refers to the top of a body or structure, while “inferior” refers to the bottom of a body or structure. It should be understood, however, that the directional term of reference may be interpreted within the context of a specific body or structure, such that a directional term referring to a location in the context of the reference body or structure may remain consistent as the orientation of the body or structure changes.

[0077] The present invention discloses vascular implant devices, systems, and methods of use thereof. Although such features are disclosed, it should be appreciated that aspects of the devices, systems, and methods disclosed herein may be operated in conjunction with other systems or devices, including any therapies for chronic venous reflux, any therapies for post thrombotic syndrome, any therapies for deep vein thrombosis, any additional venous stents, any venous stents that open up a congestion point, any venous stents that open up a congestion point but do not resolve venous reflux, any surgery or procedure, the administration of any bioactive molecules to a subject, the administration of venoactive drugs to a subject, the administration of statins to a subject, any exercise plan, any weight loss plan, or any compression device. The devices disclosed herein may be coated with any drug. The drug coating a device may be a drug that reduces inflammation and / or promotes endothelial growth. The drug coating a device may be a growth factor and / or an anticoagulant.

[0078] Veins return blood to the heart from all the organs of the body. Many veins, particularly those in the arms and legs including deep veins, have one-way valves also called venous valves. Each valve consists of two flaps (cusps or leaflets) with edges thatAttorney Docket No.206589-0002-00 WO

[0079] meet. Blood flowing toward the heart pushes the flaps open. If gravity or muscle contractions try to pull the blood backward or if blood begins to back up in a vein, the flaps are pushed closed, so the blood does not flow backward. Thus, valves help the return of blood to the heart and prevent backward flow by opening when the blood flows toward the heart and closing when blood might flow backward (Douketis, J.D. (2023, December). (Douketis, J. D. (2023, December). Overview of the venous system -overview of the venous system. Merck Manual Consumer Version.).

[0080] Venous valves may be injured or may become incompetent after blood clot formation in the deep veins, in response to deep vein thrombosis (DVT), or due to vascular remodeling and valve stiffening due to age or other vascular conditions (Figure 1, top). Injuries to a venous valve may lead to chronic venous reflux in blood flow further leading to any number of adverse effects in a subject. In some examples, chronic venous hypertension and / or venous obstruction can be caused by valve damage (Figure 1, middle). Chronic venous hypertension and / or venous obstruction may also ultimately lead to post thrombotic syndrome (PTS) symptoms in a subject (Figure 1, bottom). PTS symptoms may include pain, swelling, skin changes, tissue damage, vessel leak and swelling, and recurrent ulcers.

[0081] Shear stress patterns caused by fluid flow in a vein, or deep vein, may influence venous valve formation and venous valve maintenance. Now referring to Figure 2A, oscillatory shear stress (OSS) caused by blood flow in a vein may promote venous valve formation or venous valve maintenance. Therefore, manipulating the blood flow patterns, and in turn shear stress patterns, within a vein may promote valve formation or valve maintenance. Endothelial cells may upregulate any molecular programs that lead to valve formation in response to sensed shear stress patterns. For example, endothelial cells may upregulate the expression of transcription factors PROXI and FOXC2 which may lead valve formation. Now referring to Figure 2B, PROXI and FOXC2 expression in venous valve endothelial cells is stimulated by periodic recirculatory flow.

[0082] In some examples, the invention comprises a vascular implant, such as a patch or stent-like device, that may support venous valve formation or regeneration. The device may be placed in any vessel including a deep vein. The device may influence blood flow patterns, also known as hemodynamics, or shear stress patterns in a vein to promoteAttorney Docket No.206589-0002-00 WO

[0083] venous valve formation or regeneration. The device may also provide a surface that influences endothelial cell growth, proliferation, differentiation, and / or maintenance to promote venous valve formation or regeneration. In some examples, a cellular valve, or venous valve, is formed in a blood vessel from a subject’s own tissue or cells at the location that the device is applied. In some examples, the device includes one or more surfaces that protrude from the device into the lumen of the vessel in which it is placed, such that the subject’s cells form a new intravascular architecture in the approximate shape of the protruding surfaces. The new intravascular architecture may create local hemodynamics that promote or stimulate new venous valve formation from the subject’s own cells. In some examples, the device degrades after cellular formation of the venous valve.

[0084] Referring now to Figures 3 and 4, disclosed herein is a vascular implant in the form of a stent-like device 100 that may support venous valve formation or regeneration. In some examples, the stent device 100 includes a generally tubular or cylindrical frame 108 having a first opening or upstream opening 120, a second opening or downstream opening 122 and forming a lumen 124 through which a fluid may flow along pathway 126. Included on an interior surface 128 of frame 108 within lumen 124 is one or more valve seeding elements 300, such as seeding elements 300a and 300b. In other embodiments, frame 108 is not tubular or cylindrical, and instead may be a generally planar, sheet-like shape that is flexible, such that the planar sheet can conform to any portion of a subject’s vessel wall. For example, frame 108 may be a patch that engages the interior vessel wall surface. In some examples, the patch can be sized to overlap within the vein, such that it effectively forms a tube or cylindrical shape after being deployed and positioned within the vein and wrapping circumferentially about the inner vessel wall surface.

[0085] Again, in some embodiments, the frame 108 is generally tubular or cylindrical. The horizontal cross section of upstream opening 120, downstream opening 122, and lumen 124 may be any size or shape along the length of frame 108. In some examples, the horizontal cross section of upstream opening 120, downstream opening 122, and lumen 124 may match the dimensions of the vessel in which the device 100 is designed to be applied. In other words, the shape of frame 108 may be contoured to any portion of theAttorney Docket No.206589-0002-00 WO

[0086] interior vessel wall. The frame 108 may be any length, L, along the vessel in which it is applied. The frame 108 may be any thickness. The frame 108 may be flexible such that it may be manipulated (folded, compacted, stretched, expanded, or any other suitable manipulation) to fit in a desired vessel. As contemplated herein, one or more portions of the frame 108 may be rigid, flexible, and / or elastic.

[0087] In some embodiments, the frame 108 is a mesh with an exterior surface configured to engage or attach to the interior vessel wall. The frame 108 may function to maintain the device 100 in the location at which the device 100 is applied. For example, the attachment mesh may have an outer surface that may adhere or latch to a vessel wall. In some embodiments, the frame 108 has any roughness or has any coefficient of friction such that it maintains the location of the device 100 in a vessel. In some embodiments, one or more portions of the frame 108 exerts a radial force on the vessel wall that secures the device 100 in the applied location. In some examples, the amount of radial force on the vessel wall exerted by the frame 108 is enough force that the device 100 maintains its location, but not enough force as to substantially influence vessel shape or vessel lumen size. The frame 108 may include hooks, microhooks, needles, microneedles, pins, or any protrusion that may promote the adherence of the frame 108 to the vessel wall.

[0088] In some examples, the frame 108 does not promote the opening of a vessel. For example, the frame 108 may impart minimal or no outward force on the vessel or the frame 108 may be sufficiently flexible such that it does not influence vessel shape. In other examples, the frame 108 does promote the opening of a vessel. In some embodiments, the frame 108 is designed such that it exerts a radial force against the interior of the vessel wall such that the vessel becomes less occluded or such that the diameter of the vessel is increased.

[0089] In some embodiments, the frame 108 may have frame ends 110. The frame ends 110 may comprise the upstream opening 120 and the downstream opening 122 of the frame 108. In some embodiments, the frame ends 110 are designed to adhere to the vessel wall. In some embodiments, the frame ends 110 engage with or adhere to the vessel wall and the remaining length of the frame 108 between frame ends 110 is adjacent to and optionally in contact with the vessel wall, but does not attach or affix thereto. In someAttorney Docket No.206589-0002-00 WO

[0090] embodiments, the frame ends 110 adhere to the vessel wall more fully or have a greater adherence to the vessel wall than the rest of the frame 108. In some examples, the frame ends 110 may exert a greater radial force on the vessel wall than other portions of the frame 108. In some examples, the frame ends 110 may be constructed of a material with a rougher surface or greater coefficient of friction than the other portions of the frame 108. In some examples, the frame ends 110 may include hooks, microhooks, needles, microneedles, pins, or any protrusion that may promote adherence more so than other portions of the remaining length of the frame 108 between frame ends 110. In some examples, as depicted in Figure 14, frame ends 110 comprise a ring-like strut configured to engage and / or anchor stent-like device 100 against a vessel wall.

[0091] Referring back to Figures 3 and 4, in some examples, the frame ends 110 may be flared outward to promote adherence to or engagement with the vessel. The frame ends 110 may flare outward at any angle and for any length. The attachment frame ends 110 may flare outward with any curvature. The increase in diameter of the upstream opening 120 and downstream opening 122 due to the outward flaring of the frame ends 110 may be related to an increase in radial force exerted on the vessel wall by the frame ends 110 compared to the rest of the frame 108. In some examples, the ends may be composed of a shape memory material and thus expand or flare outwards into the vessel walls when deployed from a catheter. In some embodiments, the frame 108 is configured such that it may be applied with a laparoscopic tool. For example, the frame 108 may be compressible such that it may be included in a laparoscopic device. In some examples, the frame 108 may be expanded to desired dimensions at the location of implantation using a balloon or other inflatable component or expandable component of a laparoscopic device.

[0092] The frame 108 can be constructed of any material known in the art suitable for vascular implantation, including any biocompatible materials approved for implantation or combinations thereof. The frame 108 may have any desired structure, such as a mesh, a set or network of struts, a sheet-like material forming a solid surface, or any combination thereof. For example, the frame 108 may be composed of a metal, aAttorney Docket No.206589-0002-00 WO

[0093] polymer, or any composite material. In some embodiments, the frame 108 is a mesh that has struts and spacings of any dimensions and geometry.

[0094] Now referring to Figures 14 and 15, depicted is an exemplary embodiment of stent-like device 100. As depicted in Figures 14 and 1 , in some embodiments, frame 108 comprises one or more ring-like struts 190. Struts 190 may be circular, elliptical, or an irregular shape. Struts 190 may be configured to fit against the interior circumference of a vessel. A strut 190 may comprise a wave-like geometry having any number of waves extending in any direction with respect to the circumference of the ring of strut 190. A wave-like geometry may aid in engaging a vessel wall and / or securing stent-like device 100 against a vessel wall. In some embodiments, struts 190 are positioned with any spacing, including a regular spacing or a variable spacing. In some embodiments, frame 108 comprises a mesh in addition struts 190. In some embodiments, struts 190 may be connected by one or more connector portions 192 as depicted in Figure 15. Connector portions 192 may be constructed of the same or a different material as struts 190.

[0095] In some examples, the frame 108 may be constructed of the same material or a different material as one or more included valve seeding elements 300. In some examples, the frame 108 is resorbable or degradable after implantation. For example, the frame 108 may be a resorbable metal including magnesium. In some examples, the frame 108 is an antithrombotic material or includes an antithrombotic coating.

[0096] In some examples, the frame 108 is incorporated with, coated with, or otherwise includes a bioactive molecule. In some examples, the bioactive molecule promotes valve regeneration or any other cell outcome. In some examples, the bioactive molecule is a drug, a small molecule, a peptide, a protein, a growth factor, or a nucleic acid. In some embodiments, the bioactive molecule is incorporated into the frame material, or is included in a coating of the frame material, such that it has a time-dependent release from the frame 108.

[0097] In some embodiments, frame 108 comprises one, two, or more structural rods 170. Structural rods 170 may connect any components of stent-like device 100 including any portion of frame 108, any struts 190, frame ends 110, and / or any valve seeding elements 300. For example, structural rods 170 may be positioned along the entire lengthAttorney Docket No.206589-0002-00 WO

[0098] or any portion of the length of device 100. In some embodiments, a structural rod 170 connects any valve seeding elements 300 to any frame 108 portion including any struts 190 of frame 108.

[0099] Referring again to Figures 3 and 4, one or more valve seeding elements 300 (such as 300a and / or 300b) may be positioned at any location within lumen 124 on the interior surface 128 of the frame 108. As contemplated herein, the valve seeding elements 300 may serve as a scaffold to promote the formation of a venous valve leaflet from native tissue. As contemplated herein, the valve seeding elements 300 may serve as a flow diverting element. A flow diverting element may function to influence flow patterns in a vessel. For example, a flow diverting element may generate a flow recirculation zone 106 with any properties. The valve seeding elements 300 may be a solid structure, a porous structure, an open framed structure, or a hollow structure.

[0100] Now referring to Figure 5, shown is a side view of an exemplary valve seeding element 300 against the interior surface 128 of a frame 108. The valve seeding element 300 may be designed with any features to promote the formation of a downstream flow recirculation zone 106 within the device 100 and vessel with any desired properties.

[0101] In some embodiments, frame 108 comprises a spacing downstream of a valve seeding element 300. For example, the spacing may allow a portion of a vessel wall access to the vessel interior. A spacing may be beneficial for valve regeneration. For example, it may be beneficial for shear or other forces to be more directly imparted on a vessel wall downstream of a valve seeding element 300 and / or in proximity to recirculation zone 106. In some embodiments, a structural element having low surface area is positioned across the spacing and may connect valve seeding element to downstream portions of frame 108 thereby allowing for a spacing between a valve seeding element 300 and further downstream portions of frame 108.For example, a rodlike structure or a mesh portion may be positioned across the spacing and may connect a valve seeding element 300 to downstream portions of frame 108 thereby allowing for a spacing between a valve seeding element 300 and further downstream portions of frame 108. In some examples, as depicted in Figures 14 and 15, a structural rod 170 may connect valve seeding element to downstream portions of frame 108 across a spacing. ForAttorney Docket No.206589-0002-00 WO

[0102] example, a spacing may comprise the spacing between a valve seeding element 300 and nearest downstream strut 190 to a valve seeding element 300. For example, a spacing may span a distance of length, v. In some embodiments, length, v, is the distance between the downstream edge of a valve seeding element 300 and nearest downstream strut 190.

[0103] Figure 14 depicts a view of an exemplary stent device 100 including valve seeding elements 300a and 300b. As shown in Figure 14, one, two, or more structural rods 170 may connect any portions of stent device 100. One, two, or more structural rods 170 may connect a valve seeding element 300 with any portions of stent device 100. A set of one, two, or more structural rods 170 may be positioned at any point along the circumference of frame 108. For example, a set of one, two, or more structural rods may be positioned along the circumference of frame 108 with any spacing including a regular spacing or a variable spacing. In some embodiments, a structural rod 170 is positioned along the circumference such that it is positioned in between valve seeding element 300a and valve seeding element 300b. For example, valve seeding element 300a may be positioned across from valve seeding element 300b and two structural rods 170 may be positioned between either ends of the valve seeding elements 300a and 300b. For example, valve seeding elements 300a and 300b may in total span the circumference of device 100 and / or a vessel and a structural rod 170 may be positioned at both meeting points of valve seeding elements 300a and 300b. In some embodiments, a first structural rods 170 is positioned across from a second structural rod 170 along the circumference. In some embodiments, structural rods 170 are positioned at a position along the circumference of stent-like device 100 where the protrusion of valve seeding elements 300 into the lumen is at a minimum, is negligible, or is zero.

[0104] Figure 15 depicts a view of an exemplary stent device 100 including at least one valve seeding element 300. Figure 15 depicts a view looking directly at the lumen facing surface (luminal surface 304) of a valve seeding element 300. As depicted in Figure 15, stent-like device 100 may comprise a structural rod 170 on either side of a valve seeding element 300. For example, as described above, a stent-like device 100 may comprise two valve seeding elements 300 positioned across from each other and a structural rod 170Attorney Docket No.206589-0002-00 WO

[0105] may be positioned between opposing valve seeding elements 300 along the circumference of device 100 on either side of each opposing valve seeding element 300.

[0106] Referring back to Figure 5, in some embodiments, a spacing begins immediately downstream of a valve seeding element 300. In some embodiments, a spacing may begin immediately at downstream edge 305 of a valve seeding element 300. In alternative embodiments, a spacing begins at some distance downstream of a valve seeding element 300. In some embodiments, the spacing has a length v. The length, v, may be sufficient to allow for valve regeneration. The length, v, may have a length such that the spacing at least spans a recirculation zone 106. In some embodiments, length, v, is in the range of 0.5 cm to 2.5 cm. In some embodiments, length, v, is or is about 0.5 cm, 0.75 cm, 1.0 cm, 1.25 cm, 1.5 cm, 1.75 cm, 2.0 cm, 2.25 cm, or 2.5 cm. In some embodiments, length, v, is at least 0.5 cm, 0.75 cm, 1.0 cm, 1.25 cm, 1.5 cm, 1.75 cm, 2.0 cm, 2.25 cm, or 2.5 cm.

[0107] In some embodiments, valve seeding element 300 may have a frame engagement surface 302 and a luminal surface 304. The frame engagement surface 302 may rest against the interior surface 128 of the frame 108 and be affixed thereto. The frame engagement surface 302 may have an upstream or beginning edge 301 and a downstream edge 305. The luminal surface 304 may also begin at the beginning edge 301, gradually protrude into the lumen 124 and reach an end at apex edge 303. The luminal surface 304 may protrude into the lumen 124 at an angle of incline 307. Lastly, valve seeding element 300 includes a downstream support surface or recirculation surface 306 formed between edge 305 and apex edge 303. The height, z, of the valve seeding element 300 may be defined as the distance the apex edge 303 protrudes into the lumen 124 from the inner surface 128. The beginning edge 301 may be upstream of the apex edge 303 such that the valve seeding element 300 occludes a greater percentage of the vessel at the apex edge 303 than at the beginning edge 301. The length, y, of the valve seeding element 300 may be the distance from the beginning edge 301 to the most downstream point of edge 305, apex edge 303, or a portion of recirculation surface 306. The height, z, and therefore the degree of blood vessel occlusion at the apex edge 303 may depend on the angle or curvature of incline 307 and the length, y. A valve seeding element 300 may be configured such that downstream of the support surface 306 the blood vessel is notAttorney Docket No.206589-0002-00 WO

[0108] occluded or is less occluded than at the lengthwise location of the apex edge 303. The luminal surface 304 and the support surface 306 may be of any slope or curvilinear shape as desired.

[0109] Now referring to Figure 6, depicted is a vertical cross-sectional view of the valve seeding element 300. The valve seeding element 300 may have any width, x (i.e. the span of beginning edge 301 as it wraps circumferentially about frame 108 and tracking the interior vessel wall). The width, x, may be any length. In some embodiments, the width, x, is 50% or about 50% of the circumference of the vessel in which the valve seeding element 300 is applied. The valve seeding element 300 may be applied to veins of any size. In some embodiments, the valve seeding element 300 is applied to veins ranging from 0.3 cm to 2 cm in diameter, and therefore the veins range from about 1 cm to about 6 cm in circumference. Therefore, the width, x in some embodiments may range from 0.5 cm to 3 cm or about 0.5 cm to about 3 cm such that the width, x is approximately 50% of the vessel circumference. The valve seeding element 300 may have any curvature such that it fits in the interior of the frame 108 and such that the frame engagement surface 302 may match the curvature of the frame 108 or the curvature of the interior vessel wall. The curvature of the valve seeding element 300 may be designed with dimensions, including a circumference or perimeter, that match the blood vessel in which it is designed to be positioned.

[0110] In some embodiments, the height, z, of a valve seeding element varies along its width, x or remains the same along its width, x. In some embodiments, the height, z, of a valve seeding element varies across its width, x, and is described by any mathematical function, for example a linear function, a parabolic function, an exponential function, or a logarithmic function. In some embodiments, the height, z of a valve seeding element 300 is greatest at the midpoint of the width, x of the valve seeding element 300. In some embodiments, the height, z, decreases steadily at a linear rate from the midpoint of the width, x to either endpoint of the width, x. In some embodiments, the height, z, is approximately zero at either endpoint of the width, x. Two identical valve seeding elements 300 may be placed across from each other in a vessel, each valve seeding element 300 having a width that is 50% or about 50% of the vessel circumference suchAttorney Docket No.206589-0002-00 WO

[0111] that the two valve seeding elements 300 may meet at the endpoints of the width, x. In this embodiment, the total vessel occlusion at each width, x endpoint may be approximately zero or otherwise may be negligible. In some examples, as depicted in Figures 14 and 15, a structural rod 170 may be positioned along the length of frame 108 where two valve seeding elements 300 meet in a vessel. For example, structural rods 170 may be positioned at each width, x, endpoint where vessel occlusion is minimal, negligible, or zero.

[0112] Now referring back to Figure 3B, in some examples there are two valve seeding elements 300a and 300b. The valve seeding elements 300a and 300b may be positioned at the same lengthwise location of the frame 108 directly across from each other with the lumen 124 therebetween. Therefore, two corresponding venous valve leaflets may be formed and may be aligned at the same lengthwise location of frame 108 and corresponding vessel in which device 100 is implanted. The valve seeding elements 300a and 300b may be identical, or they may be different in size and shape. In some examples, each valve seeding element may span a width, x, that is half or about half of the circumference of the frame 108 or the vessel.

[0113] As mentioned previously, the partial occlusion of the vessel created by the seeding elements 300 protruding into the lumen 124 of device 100 may be expressed as a percent occlusion of the vessel or of lumen 124 of device 100. For example, in some embodiments the partial occlusion of the vessel created by a single valve seeding element 300 (e.g. height z) is 12.5% or about 12.5%. In some embodiments, the partial occlusion of the vessel created by a single valve seeding element 300 is in the range of 5% to 25% or about 5% to about 25%. In some examples where two identical valve seeding elements 300 are positioned on opposing sides of interior surface 128, such as seeding elements 300a and 300b in Figure 3B, the occlusion of the vessel in total is 25% or about 25%. In some examples where two identical valve seeding elements 300 are positioned on opposing sides of interior surface 128, such as seeding elements 300a and 300b in Figure 3B, the total occlusion of the vessel is in the range of 10% to 50% or about 10% to about 50%. In some examples, the percent occlusion created by one or more valve seeding elements 300 positioned on an interior surface 128 is equal to or less than about 1%, 2%,Attorney Docket No.206589-0002-00 WO

[0114] 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, or 50%. In some examples, the percent occlusion created by one or more valve seeding elements 300 positioned on an interior surface 128 is equal to or less than about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 30%, about 35%, about 40%, or about 50%. In some examples, the percent occlusion created by one or more valve seeding elements 300 is any value between 1% and 50%.

[0115] In some examples, height, z, maximum height, z, or average height, z, along the width, x, of a valve seeding element 300 is any suitable height. In some examples, the maximum height, z, of a valve seeding element 300 is in the range of 0.015 cm to 1 cm or about 0.015 cm to about 1 cm. In some embodiments, the maximum height, z, is an appropriate height such that 5% to 25% or about 5% to about 25% occlusion of the vessel is achieved by a single valve seeding element 300. As stated earlier, in some embodiments, the valve seeding element 300 is applied to veins ranging from 0.3 cm to 2 cm in diameter.

[0116] In some examples, the length, y, of a valve seeding element 300 is any length. In some examples, the length, y, of a valve seeding element 300 is the same as the length, L, of the frame 108. In some examples, the length, y, is or is about 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm, 30 mm, 31 mm, 32 mm, 33 mm, 34 mm, 35 mm, 36 mm, 37 mm, 38 mm, 39 mm, 40 mm, 41 mm, 42 mm, 43 mm, 44 mm, 45 mm, 46 mm, 47 mm, 48 mm, 49 mm, or 50 mm. In some embodiments, the length, y is in the range of 5 mm to 10 mm or about 5 mm to about 50 mm. In some examples, the length, y, is or is about 5 mm or 10 mm.

[0117] In some examples, the luminal surface 304 protrudes into the lumen at any rate along the length, y, of the valve seeding element 300. In some examples, the luminal surface 304 protrudes into the lumen at a linear rate along the length, y, of the valveAttorney Docket No.206589-0002-00 WO

[0118] seeding element 300. For example, the incline angle 307 of a valve seeding element 300 may be any angle. In some examples, the incline angle 307 may be or be about 1°, 1.5°, 2°, 2.5°, 3°, 3.5°, 4°, 4.5°, 5°, 5.5°, 6°, 6.5°, 7°, 7.5°, 8°, 9°, 9.5°, 10°, 10.5°, 11°, 11.5°, 12°, 12.5°, 13°, 13.5°, 14°, 14.5°, 15°, 15.5°, 16°, 16.5°, 17°, 17.5°, 18°, 18.5°, 19°, 19.5°, 20°, 20.5°, 21°, 21.5°, 22°, 22.5°, 23°, 23.5 °, 24 °, 24.5 °, 25 °, 25.5. °, 26.5 °, 27 °, 27.5 °, 28 °, 28.5 °, 29 °, 29.5 °, 30 °, 30.5 °, 31°, 31.5°, 32°, 32.5°, 33°, 33.5°, 34°, 34.5°, 35°, 35.5°, 36° 36.5°, 37°, 37.5°, 38°, 38.5°, 39°, 39.5°, 40°, 40.5°, 41°, 41.5°, 42°, 42.5°, 43°, 43.5°, 44°, 44.5°, 45°, 45.5°, 46°, 46.5°, 47°, 47.5°, 48°, 48.5°, 49°, 49.5°, or 50° In some examples, the incline angle 307 is an angle in the range of 1° to 50°. The incline angle 307 may be chosen to reach a desired vessel occlusion at a maximum height, z.

[0119] In some embodiments, the rate of increase in the protrusion into the lumen of the valve seeding element 300 along the length, y, is not constant. In some embodiments, the rate of increase in protrusion of a valve seeding element 300 may increase or decrease over its length, y. In some examples, the protrusion into the lumen of a valve seeding element 300 over its length, y, may be defined by any mathematical function, for example a linear function, a parabolic function, an exponential function, or a logarithmic function. For example, the luminal surface 304 of a valve seeding element 300 may be linear, concave, or convex.

[0120] As shown in Figures 7A-7D, the support surface 306 may have any desired profile. In some examples, the support surface 306 is flat. In some examples, the support surface 306 is concave. In some examples, the support surface 306 is convex. In some examples, the support surface profile is a combination of flat regions, concave regions, and / or convex regions. In some examples, edge 305 and apex 303 align such that a surface 306 that is perpendicular to the vessel length may connect edge 305 and apex 303. In other words, in some examples edge 305 and apex 303 are positioned such that edge 305 and apex 303 are the same lengthwise position along a vessel. In some examples, edge 305 and apex 303 are positioned such that apex 303 is further downstream than is edge 305. In some examples, edge 305 and apex 303 are positioned such that apex 303 is further upstream than is edge 305. In some embodiments, the supporting surface 306 has a constant curvature or a variable curvature along height z.Attorney Docket No.206589-0002-00 WO

[0121] The valve seeding element 300 may be a single unit structure or it may be formed by separate component part segments. The valve seeding element 300 may be constructed of any material. In some embodiments, the valve seeding element 300 is sufficiently rigid such that it can maintain its shape after implantation in a vessel and / or in the presence of fluid flow through the lumen 124 of the frame 108. In some embodiments, the valve seeding element 300 is sufficiently rigid such that it can maintain a desired vessel occlusion after implantation in a vessel. In some embodiments, the valve seeding element 300 is flexible and / or elastic such that it may be compressed to aid its use with laparoscopic instruments. In some embodiments, the rigidity of the valve seeding element 300 is such that it is rigid enough to maintain a desired shape after implantation but flexible enough such that it may be compressed for use with a laparoscopic instrument. In some embodiments, the surfaces of the valve seeding element 300, including the luminal surface 304 and downstream support surface 306, is smooth such that it may promote laminar flow along the lumen 124 of the frame 108. In some embodiments, the surfaces of valve seeding element 300 are rough or have any coefficient of friction. In some embodiments, the material of the valve seeding element 300 is chosen to increase or decrease the sheer stress imparted on the fluid of the vessel. In some embodiments, the valve seeding element 300 is composed of any material that is antithrombotic or antimicrobial. In some embodiments, the valve seeding element 300 is composed of a metal, a ceramic, a polymer, a biological polymer, or any composite material. In some embodiments, the luminal surface 304 and support surface 306 are composed of a different material than the rest of the valve seeding element 300. In some embodiments, the frame engagement surface 302 is constructed such that it may adhere to a frame 108.

[0122] In some examples, one or more surfaces or surface portions of valve seeding element 300 can be functionalized with a molecule or moiety. This may include functionalization with cellular binding factors, cellular growth factors, hydrophobic particles, hydrophilic particles, and the like. In some embodiments, the valve seeding element 300 is a biocompatible material. In some embodiments, the material of the valve seeding element 300 or the surface of the material of the valve seeding element 300 may promote cell attachment, cell growth, cell differentiation, cell sternness, and / or venous valve formation. In some embodiments, the luminal surface 304 and / or the supportAttorney Docket No.206589-0002-00 WO

[0123] surface 306 may promote cell attachment, cell growth, cell differentiation, cell sternness, or venous valve formation. In some embodiments, portions of the valve seeding element 300 may have different surfaces depending on the desired amount of cell attachment or desired attached cell types. For example, the valve seeding element 300 may include a micropattern, any biological polymer, and / or any molecules that promote cell attachment including RGD peptide sequences on its surface. The valve seeding element may have a surface that promotes any cell outcome on only its luminal surface 304, on only its support surface 306, or on only the luminal surface 304 and support surface 306. The valve seeding element may have different surfaces on the luminal surface 304 and support surface 306. The surface of luminal surface 304 and the surface of support surface 306 may support the same cell outcome or different cell outcomes.

[0124] A micropattem of a valve seeding element 300 may comprise any suitable micropattern. The characteristics of a micropattern including spacing between raised portions of the micropattern, size of the raised portions of the micropattem, shape of the raised portions of the micropattern, and orientation of the raised portions of the micropattern may influence the amount of cells and cell types attached to the valve seeding element 300 and the shape of the cells (i.e., cell morphology) of the cells attached to the valve seeding element 300. The characteristics of a micropattern including spacing between raised portions of the micropattern, size of the raised portions of the micropattern, shape of the raised portions of the micropattem, and orientation of the raised portions of the micropattern may be designed for desired cell attachment or desired cell outcomes.

[0125] In some embodiments, a molecule or any combination of molecules that promotes any desired cell differentiation, desired cell sternness, desired gene expression profde, desired cell morphology, prevents scarring, prevents fibrosis, promotes valve formation, or any other desired biological outcome or cell phenotype is included in, incorporated with, or coated onto the valve seeding element 300 or any portion of the valve seeding element 300. In some embodiments, the method of inclusion, incorporation, or coating of a molecule promotes its controlled or gradual release over any timescale. Different molecules or molecule combinations may be coated on different portions of the valveAttorney Docket No.206589-0002-00 WO

[0126] seeding element 300. In some examples, the molecule may be a protein, a peptide, a growth factor, a hormone, a drug, a small molecule, a nucleic acid, or combinations thereof. In some embodiments, the molecule effects signaling of any cellular pathway. In some embodiments, the molecule effects mTOR, mTORCl, NF AT, NFATcl, AKT signaling, AMPK signaling, KFL2, KLF4, Connexin37 / 43, GATA2, PROXI, FOXC2, PIEZO1, and / or NF AT signaling.

[0127] It should be appreciated that portions of the valve seeding element 300 may have different surfaces including different molecule or moiety functionalization, different coating, different micropattems, different biological polymers. For example, luminal surface 304 and support surface 306 may each have the same surface or may each have different surfaces. For example, luminal surface 304 and / or support surface 306 may include different surfaces on different respective surface portions. The surfaces for luminal surface 304, support surface 306, and / or respective portions thereof, may be chosen depending on desired cell outcomes for cells that interact with luminal surface 304, support surface 306, and / or respective portions thereof. For example, surfaces may be chosen for a desired amount of cell attachment and / or desired attached cell types. For example, surfaces may be chosen for a desired cell differentiation outcome, a desired cell sternness, a desired cell gene expression profile, a desired cell morphology, a desired actuation or inhibition of any cell signaling pathway, and / or any desired cell phenotype of cells thereon.

[0128] In some embodiments, the valve seeding element 300 is molded or 3D printed. In some embodiments, the valve seeding element 300 is resorbable. In some embodiments, the valve seeding element 300 is designed such that it may be resorbed or degraded after the formation of a venous valve from native cells or tissue in the location of the valve seeding element 300. For example, the valve seeding element 300 may be or include a resorbable or degradable biological polymer including collagen or gelatin. In some examples, the valve seeding element 300 is a resorbable metal including magnesium or includes a resorbable metal including magnesium. In some examples, the valve seeding element 300 may include a biological molecule that is recognized by cells or specific enzymes to promote degradation or cleavage. For example, the valve seeding elementAttorney Docket No.206589-0002-00 WO

[0129] 300 may include molecules recognized by matrix metalloproteinases for degradation or cleavage.

[0130] In some embodiments, as in Figure 8, one or more valve seeding elements 300 may be positioned in a vessel and such that a valve leaflet may be generated on each valve seeding element 300. Two valve seeding elements 300 may be positioned across from each other at the same lengthwise location of the vessel such that two valve leaflets may be formed and may together make up a venous valve. For example, as in Figure 8B, after implantation of the stent 100, endothelial cells may cover the surface area of a luminal surface 304 and support surface 306 of a valve seeding element 300. In some examples, as in Figure 8C, the endothelial cells may form a valve leaflet in between the flow valve seeding element 300 and the luminal space of the stent 100 and / or vessel. In some examples, the valve leaflet matures, grows, and / or extends farther into the lumen over time. In some examples, valve seeding elements 300 are positioned across from each other in the vessel with the lumen of the vessel therebetween. In this example, a valve leaflet may be formed on both valve seeding elements 300 and may mature, grow, and extend, until a mature and / or functional two leaflet valve is formed. Mature and / or functional valve leaflets may meet physically to preclude refluxing flow. The maturity of a developing valve leaflet may be defined by different stages of growth. Initially, endothelial cells may cover the valve seeding elements 300. Then, endothelial cells may proliferate away from the structure to form a leaflet structure. Finally, the leaflet structure may become large enough and mature enough such that forming leaflet structures on the opposite sides of a vessel interior wall physically meet and preclude refluxing flow. In some embodiments, the cells of the generating or maturing valve leaflet may express PROXI and FOXC2. In some embodiments, lower shear stress regions promote endothelial cell proliferation and coverage while higher shear stress regions induce cells to deposit matrix for valve generation.

[0131] The stent device 100 may be optionally used in combination with any other device, treatment, or instructions to a subject. For example, or movements of a subject may be designed to promote the formation of any flow pattern in the vessel and therefore create the desired shear stress patterns. For example, a subject may be instructed toAttorney Docket No.206589-0002-00 WO

[0132] perform a movement protocol that is designed to promote the formation of any flow pattern in the vessel and therefore create any desired shear stress patterns. Again, in some embodiments a valve seeding element 300 may serve as a flow diverting element. A flow pattern may be defined by flow directions and velocities. An exemplary local flow pattern generated by the stent device 100 may include any number of recirculation zones 106. In an exemplary embodiment, two recirculation zones 106 are generated by the device. For example, a stent device 100 may comprise two valve seeding elements 300 that each generate a corresponding flow recirculation zone 106.

[0133] A flow recirculation zone 106 may have substantially recirculatory flow. In some embodiments, the flow patterns including any flow recirculation zones 106 that are generated in the vessel after the stent 100 is applied are beneficial for venous valve generation or regeneration. In some embodiments, the magnitude and geometry of the occluded region of the vessel caused by the shape of a valve seeding element 300 is designed to promote the formation of one or more flow recirculation zones 106 downstream of the valve seeding element 300. In some embodiments, a flow recirculation zone 106 is formed as a result of the geometry of a valve seeding element 300. In some embodiments, a flow recirculation zone 106 is formed downstream of a support surface 306 of a valve seeding element 300. In some embodiments, a flow recirculation zone 106 is formed downstream of and adjacent to a support surface 306 of a valve seeding element 300. In some embodiments, any number of valve seeding elements 300 of a stent device 100 may generate flow recirculation zones 106 downstream of the corresponding valve seeding element 300. In some embodiments, a valve seeding element 300 in combination with the corresponding downstream flow recirculation zone 106 promotes the generation of a venous valve leaflet from native tissue. For example, the formation of two recirculation zones 106 by two valve seeding elements 300 may promote the formation of a venous valve from native tissue that has two valve leaflets. In some embodiments, the valve seeding element 300 serves as a flow diverting element and the corresponding flow recirculation zone 106 alone promotes the generation of a venous valve leaflet. In some embodiments, a flow recirculation zone 106 is positioned proximal to a spacing of a device 100. A spacing proximal to a flow recirculation zone 106 mayAttorney Docket No.206589-0002-00 WO

[0134] allow for the recirculation zone 106 to be more proximal to a vessel wall and / or allow for a desired force or shear to be more directly imparted on a vessel wall.

[0135] A flow recirculation zone 106 may be defined by any flow pattern. A flow recirculation zone 106 may have any shape. A flow recirculation zone 106 may mimic or recapitulate any flow patterns found near a native venous valve, for example as depicted in Figure 9A. A flow recirculation zone 106 may have any length along the vessel length, any height that extends into vessel lumen, and may be otherwise bounded by the vessel wall. A flow recirculation zone 106 may be defined as having a lesser flow velocity than other nearby locations in the vessel. A flow recirculation zone 106 may be defined as having substantially recirculatory flow. A flow recirculation zone 106 may be defined as having flow that is generally opposite of the native blood flow direction of the vessel. A flow recirculation zone 106 may be defined as having a turbulent flow. A flow recirculation zone 106 may have more turbulent flow than other nearby locations of the blood vessel. A flow recirculation zone 106 may have any Reynolds number, for example a recirculation zone 106 may have a lesser Reynold’s number than other nearby locations of the blood vessel. A flow recirculation zone 106 may be defined by the local shear stress imparted on the vessel wall. For example, a flow recirculation zone 106 may be the location of a greater shear stress than nearby vessel areas. A flow recirculation zone 106 may be defined by the location of an opposite direction shear stress than nearby vessel areas. An exemplary flow recirculation zone 106 is represented in Figure 9B.

[0136] In some embodiments, a flow recirculation zone 106 is defined by any imparted shear stress or flow patterns known in the art to promote valve regeneration or de novo valve formation. In some embodiments, any flow pattern depicted in Figure 7A through Figure 7D may define a flow recirculation zone 106. In some embodiments, a flow recirculation zone 106 is defined as a region of greater oscillatory shear stress than nearby regions. In some embodiments, a flow recirculation zone 106 may contain within it a portion with relatively high shear stress and a portion with relatively low shear stress. A high shear stress portion of a flow recirculation zone 106 may be upstream of a low shear stress portion of a flow recirculation zone 106. High shear and low shear portions of a flow recirculation zone 106 may promote different cell phenotypes. Endothelial cellAttorney Docket No.206589-0002-00 WO

[0137] signaling driven by high shear, for example KLF2 and / or KLF4 signaling, may be important for the generation of the front side of a valve. In contrast, endothelial cell signaling driven by lower shear may be important for the generation of the back side of a valve. A combination of high shear induced cell phenotypes and low shear induced cell phenotypes may be beneficial for local valve generation. Periodic oscillations of flow in which flow recirculates or reverses direction may be important for valve regeneration. Periodic oscillations of flow in a flow recirculation zone may occur during periods of high centerline flow in the vein. High centerline flow may be of velocities greater than 5 cm / s.

[0138] Any property of the valve seeding element 300 may relate to any property of a downstream flow recirculation zone 106.

[0139] In some embodiments, the maximum occlusion of a vessel caused by a valve seeding element 300 is designed to form a downstream flow recirculation zone 106 with any desired properties. For example, a greater occlusion by a valve seeding element 300 may result in more turbulent flow or a larger flow recirculation zone 106. In some examples, the maximum occlusion caused by the valve seeding element 300 is chosen or engineered such that a desired flow recirculation zone 106 is generated downstream, but the blood vessel is still sufficiently open to allow blood flow.

[0140] In some embodiments, the length, y, width, x, and height, z, or average height, z, along the width of any valve seeding element 300 is designed to form a recirculation zone 106 with any desired properties.

[0141] In some embodiments, the rate of increase in protrusion of luminal surface 304 of a valve seeding element 300 is chosen such that a desired flow recirculation zone 106 is formed downstream. In some embodiments, the incline angle 307 of a valve seeding element 300 is chosen such that a desired flow recirculation zone 106 is formed downstream.

[0142] In some embodiments, the properties of a support surface 306 of a valve seeding element 300, including curvature, concavity, or convexity, are designed to promote aAttorney Docket No.206589-0002-00 WO

[0143] flow recirculation zone 106 of certain desired properties. For example, a concave support surface 306 may promote the formation of a larger flow recirculation zone 106.

[0144] In some embodiments, the stent device 100 is applied to any vein in which flow is refluxing and / or any vein which would benefit from improved valve function. In some embodiments, the stent device 100 is applied at a location in which the generation of a venous valve is desired. The stent device 100 may be applied in a deep vein. The stent device 100 may be applied in the deep veins in the leg, arm, any limb, groin, or any other location. The stent device 100 may be applied at a location of damaged venous valves, a location of an incompetent venous valve, or a location of inflammation in a vein of a subject. The stent device 100 may be implanted at a location of chronic venous reflux or reduced venous flow. The stent device 100 may be implanted at a location of or near venous tissue damage, venous ulceration, venous vessel leak, venous vessel wall fibrosis, vein narrowing, venous vessel lesions and / or venous vessel swelling. For example, the stent device 100 may be applied at a location in which a blood clot was located in a subject’s vein. For example, the stent device 100 may be applied in subjects that have had or are currently diagnosed with deep vein thrombosis (DVT) or post thrombotic syndrome (PTS). The blood clot may have been removed at some point in time before the stent device 100 is applied. The blood clot may have embolized at some point in time before the stent device 100 is applied. In some embodiments, the stent device 100 may be applied after a venous angioplasty procedure, in the location of a venous angioplasty procedure, or near the location of a venous angioplasty procedure. In some embodiments, the stent device 100 is applied at the site of a lymphovenous junction. In some embodiments, the stent device 100 is applied at the site of a lymphovenous junction in which reduced pressure in the valve sinus of the lymphovenous junction would improve flow from a lower pressure vessel into a higher pressure vessel.

[0145] In some embodiments, a surgery or laparoscopic procedure is performed to remove a blood clot in a subject and subsequently implant the stent device 100 in the location at which the blood clot was removed. In some embodiments, the stent device 100 may be implanted at a location upstream or downstream of the removed blood clot. In some embodiments, any number of stent devices 100 are implanted in a subject.Attorney Docket No.206589-0002-00 WO

[0146] In some examples, as appreciated by one skilled in the art, the implantation of a stent device 100 can be combined with any other treatments or treatment strategies for DVT, PTS, or other diseases associated with chronic venous reflux. Additional treatments may be administered or prescribed before implantation of the stent 100, concurrently with the implantation of a stent 100, and / or after the implantation of a stent 100. For example, the implantation of a stent device 100 in a subject may be combined with the administration of blood thinner treatments, anticoagulants, antithrombotics, venoactive drugs, statins, or any other drugs known for treating PTS, DVT, or chronic reflux. In some examples, the implantation of a stent device 100 in a subject may be combined with a suggested weight loss plan, a suggested exercise plan, barometric surgery, or administration of drugs that aid in weight loss. In some examples, the implantation of a stent device 100 in a patient may be combined with the compression of the subject’s limbs, compression of the affected limb, or any active compression therapy. In some examples, the implantation of a stent device 100 in a subject may be combined with the application of a compression garment. Suitable compression garments include a compression sleeve. In some examples, the implantation of a stent device 100 in a subject may be combined with a venous angioplasty procedure. In some examples, the implantation of a stent device 100 is combined with any other surgical procedure.

[0147] In some examples, the implantation of a stent device 100 in a subject is combined with methods to manipulate flow in the vessel at the location of the implanted stent 100. For example, methods used to increase flow, increase flow speed, or increase flow frequency in the vessel at the location of the implanted stent 100 may be used. Flow in the vessel may be manipulated such that any desired flow patterns or hemodynamics are achieved at the location of or nearby the location of the implanted stent 100. For example, flow may be manipulated such that any desired number of flow recirculation zones 106 with any desired flow properties or desired dimensions are generated at locations near the stent device 100. In some examples, flow may be manipulated such that a desired flow recirculation zone 106 with any desired flow properties or desired dimensions is generated downstream of a valve seeding element 300. For example, flow may be manipulated such that a desired pulsatile flow frequency or desired flow speed is attained at the location of the implanted stent 100. The desired flow pattern may promoteAttorney Docket No.206589-0002-00 WO

[0148] valve generation or valve regeneration. For example, any exercise, muscle tension exercises, any massage, any massage therapy, or any compression therapy may be applied to a limb or any location downstream or upstream of an implanted stent 100.

[0149] In some embodiments, the application of a secondary device to manipulate flow in the vessel at the location of the implanted stent device 100 is applied. For example, the stent device 100 may be implanted in a vein in a limb of a subject and the secondary flow manipulating device may be applied to the same limb. Exemplary flow manipulating devices include but are not limited to compression garments, compression sleeves, cuffs, or an RCCD. In some embodiments, a flow manipulating device is applied to a subject in a location upstream of the vein in which the implantable stent device 100 is applied. For example, the stent device 100 may be implanted in a vein in an upper limb of a subject and the secondary flow manipulating device may be applied to a lower area of the same limb. In some aspects, now referring to Figure 10, the invention relates to a method 200 of promoting venous valve generation or treating chronic venous reflux, PVT, or DVT, comprising the steps of 210 implanting a stent device that partially occludes blood flow in a blood vessel of a subject that partially occludes blood flow, and 220 applying hemodynamic therapy to the subject.

[0150] In some embodiments of step 210, the stent is an embodiment of the stent device 100. In some embodiments of step 210, the subject has chronic venous reflux. In some embodiments of step 220, the hemodynamic therapy comprises external pneumatic compression applied with the aid of a pneumatic compression system. In some embodiments of step 220, the hemodynamic therapy comprises instructing the subject to perform an exercise program. Any compression system or device may be used including sequential compression devices. In some embodiments, the pneumatic compression system is a cuff, a pump, a sleeve, or a garment. In some embodiments, the pneumatic compression system is a Kendall SCD compression system, a Hemo-Force pump, or FlowTron compression garment. In some embodiments, the pneumatic compression system is a rapid cycling compression device (RCCD). Exemplary pneumatic compression systems, device, and methods are described in International Patent Application No. PCT / US2021 / 054927 incorporated by reference herein in its entirety.Attorney Docket No.206589-0002-00 WO

[0151] In some embodiments, the pneumatic compression system is designed such that a desired volume and frequency of recirculating blood at the location of an implanted stent is achieved. In some embodiments, the pneumatic compression system applies a pulse of any magnitude of pressure for any duration. Any combination of compression device, compression pressure, compression time, or compression frequency may be used. For example, the applied pressure during a pulse may be or be about 40 mmHg, about 45 mmHg, about 50 mmHg, about 55 mmHg, about 60 mmHg, about 65 mmHg, about 70 mmHg, about 75 mmHg, or about 80 mmHg. In some embodiments, the applied pressure during a pulse may be in the range of 40 mmHg to 80 mmHg or about 40 mmHg to about 80 mmHg. The duration of an applied pulse of pressure may be any length of time, for example 0.15 s. In some embodiments, the duration of an applied pressure may be in the range of 0.15 s to 0.35 s or about 0.15 s to about 0.35 s. In some examples, the duration of a pulse of pressure is or is about 0.1 s, 0.15 s, 0.2 s, 0.25 s, 0.3 s, 0.35 s, 0.4 s, 0.45 s, 0.5 s, 0.55 s, 0.6 s, 0.65 s, 0.7 s, 0.75 s, 0.8 s, 0.85 s, 0.9 s, 0.95 s, 1 s, 2 s, 3 s, 4 s, 5 s, 6 s, 7 s, 8 s, 9 s, or 10 s. In some examples a pulse of pressure is applied at any frequency. For example, the frequency may be or be about 1-2 pulses per minute, 1 pulse per minute, 2 pulses per minute, 3 pulses per minute, 4 pulses per minute, 5 pulses per minute, 6 pulses per minute, 7 pulses per minute, 8 pulses per minute, 9 pulses per minute, 10 pulses per minute, 11 pulses per minute, 12 pulses per minute, 13 pulses per minute, 14 pulses per minute, 15 pulses per minute, 16 pulses per minute, 17 pulses per minute, 18 pulses per minute, 19 pulses per minute, or 20 pulses per minute. In some embodiments, the frequency of applied pressure pulses is in the range of 6 pulses per minute to 12 pulses per minute or about 6 pulses per minute to about 12 pulses per minute. In some examples, the external compression is applied to a subject during a session for any session length. In some examples, external compression sessions are applied at any frequency, for example, daily or weekly.

[0152] In some examples, a subject’s symptoms are tracked and pneumatic compression methods are modified based on a subject’s symptoms. Any symptoms of chronic venous reflux, PTS, or DVT, may be tracked. In some examples, the progression of valve regeneration in the location of the applied stent device 100 is tracked. In some examples, progress may be tracked by ultrasound based methods. For example, venous reflux mayAttorney Docket No.206589-0002-00 WO

[0153] be quantified by measuring the velocity and duration of reversing flow using ultrasound based methods while the subject is challenged. The challenge may include the subject standing up, a Valsalva maneuver, or a proximal compression. In another example, ultrasound based methods may be used to visualize a regenerating valve including the valve’s length or any other aspects of the valve geometry.

[0154] In some examples, pneumatic compression methods are modified based on characteristics of a subject including the subject’s blood pressure, weight, Body Mass Index, age, or exercise or activity level. In some embodiments, the generation of a valve at the location of the implanted stent may be tracked, for example through the use of any imaging techniques. In this embodiment, the pneumatic compression methods may be modified based on the maturity level, growth, or formation of a venous valve at the location of the implanted stent.

[0155] The lymphatic system collects fluid from tissue beds throughout the body and returns the fluid into venous circulation. The fluid enters the venous circulation at a lympho-venous junction (LVJ). In some instances, for example in the case of a disease or disorder, fluid may be blocked from entering venous circulation from the lymphatic system at an LVJ (Figure 11 A). In some instances, fluid may not be able to enter venous circulation from the lymphatic system due to high venous pressures compared to lower lymphatic vessel pressures. This can cause any number of poor outcomes in a subject.

[0156] Referring now to Figures 1 IB and 12, the stent device 100 may be configured such that a low pressure flow recirculation zone 106 is formed at or near a lympho-venous junction (LVJ). For example, the flow recirculation zone 106 may be formed on the vein side of an LVJ therefore forming a gradient in which there is higher pressure in the lymphatic vessel than the vein at an LVJ. Positioning a low pressure area or any flow recirculation zone 106 on the vein side of an LVJ may allow for fluid in a lymph vessel to readily enter a vein and therefore enter venous circulation.

[0157] As contemplated herein, valve seeding elements 300 may function as flow diverting elements. For example, a flow diverting element may function to influence flow patterns in a vessel. A flow diverting element may or may not support cell growth orAttorney Docket No.206589-0002-00 WO

[0158] valve formation. A flow diverting element may promote a flow recirculation zone 106 with any properties described herein.

[0159] In some embodiments, the stent device 100 includes a single valve seeding element 300. The single valve seeding element 300 may be positioned such that the downstream edge 305 of the valve seeding element 300 is at or near the downstream opening 122 of the frame 108 of the stent device 100. In this embodiment, a flow recirculation zone 106 may be formed downstream of the support surface 306 of the valve seeding element 300 and therefore downstream of the frame 108. For example, the stent device 100 may be placed near an LVJ in a subject such that the downstream edge 305 of the valve seeding element 300 and the downstream opening 120 of the frame 108 are upstream of the LVJ in a vein. The valve seeding element 300 may be placed such that it is adjacent to a portion of a vein wall that contains an LVJ. A greater degree of vessel stenosis or vessel occlusion induced by the valve seeding element 300 may result in a larger low-pressure zone within the sinus.

[0160] The stent device 100 may be placed such that a valve seeding element 300 is any distance upstream of an LVJ in a vein. In some embodiments, the stent device 100 is placed such that a valve seeding element 300 is less than or equal to 1 cm upstream of an LVJ or less than or equal to about 1 cm upstream of an LVJ.

[0161] In some embodiments, the single valve seeding element 300 promotes the formation of a single venous valve leaflet in vein just upstream of an LVJ. The formation of a single venous valve leaflet upstream of an LVJ may decrease fluid pressure on the vein side of an LVJ and therefore allow lymphatic fluid to readily enter the vein. As mentioned previously, a valve seeding element 300 and / or the frame 108 of a stent device 100 may be bioresorbable such that it may be degraded over time. For example, a single venous valve leaflet may form from native tissue while the valve seeding element 300 degrades leaving only native tissue in the vessel.

[0162] In some aspects, the invention relates to a method of treating systemic lymphedema in a subject. In some aspects, the invention relates to relieving a blockage at an LVJ in a subject. In some embodiments, the method includes applying a vascular implant that at least partially occludes a vessel in a subject. In some embodiments, theAttorney Docket No.206589-0002-00 WO

[0163] vascular implant is applied upstream of an LVJ in a subject. In some embodiments, the method includes, occluding a portion of a vessel adjacent to and upstream of an LVJ. In some embodiments, the method includes applying a vascular implant such that a low pressure area in a vein at or near an LVJ is generated. In some embodiments of the method, the vascular implant is any embodiment of the stent device 100. In some embodiments, the vascular implant is any embodiment of the stent device 100 that includes a single valve seeding element 300. In some embodiments, a single venous valve leaflet is formed from native tissue upstream of an LVJ after implantation of a stent device 100.

[0164] Embodiments

[0165] Embodiment 1. A vascular implant comprising a tubular frame having an inlet, an outlet and a lumen therethrough, the lumen forming an inner surface of the frame, and a valve seeding element positioned on the inner surface of the frame, wherein the valve seeding element comprises a sloped surface that extends into the lumen.

[0166] Embodiment 2. The vascular implant of embodiment 1, further comprising a second valve seeding element positioned on the inner surface of the frame, wherein the second valve seeding element comprises a sloped surface that extends into the lumen, and wherein the first and second valve seeding elements are positioned across from each other with the lumen therebetween.

[0167] Embodiment 3. The vascular implant of any of the previous embodiments, wherein the sloped surface of the valve seeding element extends into the lumen by at least 5%, at least 12.5%, or at least 33% of the lumen height at the tallest point of the sloped surface.

[0168] Embodiment 4. The vascular implant of any of the previous embodiments, wherein the valve seeding element further comprises a vertical surface, wherein the vertical surface extends from the apex of the sloped surface away from the lumen.

[0169] Embodiment 5. The vascular implant of embodiment 4, wherein the vertical surface is straight, concave, or convex.Attorney Docket No.206589-0002-00 WO

[0170] Embodiment 6. The vascular implant of any of the previous embodiments, wherein the horizontal length of the valve seeding element is in the range of 5 mm to 50 mm.

[0171] Embodiment 7. The vascular implant of any of the previous embodiments, wherein the sloped surface comprises a micropattern.

[0172] Embodiment 8. The vascular implant of any one of embodiments 4-7, wherein the sloped surface comprises a first micropattern and the second surface comprises a second micropattern.

[0173] Embodiment 9. The vascular implant of embodiment 8, wherein the first micropattern and the second micropattem are different micropatterns.

[0174] Embodiment 10. The vascular implant of any of the previous embodiments, wherein the vascular implant further comprises a resorbable material.

[0175] Embodiment 11. The vascular implant of any of the previous embodiments, wherein the tubular frame comprises a mesh.

[0176] Embodiment 12. The vascular implant of any of the previous embodiments, wherein the tubular frame further comprises a middle length and two end openings, wherein the two end openings have a greater perimeter than the middle length.

[0177] Embodiment 13. The vascular implant of any of the previous embodiments, wherein the tubular frame comprises a spacing between the valve seeding element and the outlet. Embodiment 14. A vascular implant comprising a frame having a first surface and an opposing second surface, and a valve seeding element positioned on the first surface, and wherein the valve seeding element protrudes from the first surface of the frame.

[0178] Embodiment 15. A method of generating a recirculation zone in the lumen of a vessel of a subject having a flow of fluid therethrough, comprising the steps of implanting a flow diverting element in a vessel of the subject, partially occluding fluid flow in the vessel adjacent to the flow diverting element by diverting fluid flow towards a central region of the vessel lumen, and generating a recirculation zone downstream of the partial occlusion and adjacent to the flow diverting element.Attorney Docket No.206589-0002-00 WO

[0179] Embodiment 16. The method of embodiment 15, further comprising the step of applying external pneumatic compression to the subject.

[0180] Embodiment 17. The method of embodiment 15 or 16, wherein the flow diverting element comprises the vascular implant of any of the previous embodiments.

[0181] Embodiment 18. The method of any of embodiments 15-17, wherein the subject is diagnosed with one of the group consisting of: post thrombotic syndrome, deep vein thrombosis, chronic venous reflux, and systemic lymphedema.

[0182] Embodiment 19. The method of any of embodiments 15-18, wherein the vessel is a deep vein.

[0183] Embodiment 20. The method of any one of embodiments 16-19, further comprising the step of providing a compression device, and wherein the external pneumatic compression is applied using the compression device.

[0184] Embodiment 21. The method of embodiment 20, wherein the compression device is one or more of the group selected from: a compression garment, a cuff, a sequential compression device, and a rapid cycling compression device.

[0185] Embodiment 22. The method of any one of embodiments 16-21, wherein the external pneumatic compression is applied as a pulse with a pulse duration of at most 20 seconds, at most 10 seconds, at most 5 seconds, at most 1 second, at most 0.5 seconds, at most 0.35 seconds, at most 0.25 seconds, at most 0.15 seconds, or at most 0.1 seconds.

[0186] Embodiment 23. The method of any one of embodiments 16-22, wherein the external pneumatic compression is applied as a pulse with a frequency of at least 1 / min, at least 5 / min, at least 6 / min, at least 10 / min, or at least 12 / min.

[0187] Embodiment 24. The method of any one of embodiments 15-23, wherein the vessel is a vein, and the flow diverting element is implanted upstream of a lympho-venous junction. Embodiment 25. A method of generating a leaflet valve in the vein of a subject, comprising the steps of positioning the vascular implant of any of the previous embodiments in a vein of a subject, generating a recirculation zone downstream andAttorney Docket No.206589-0002-00 WO

[0188] adjacent to the valve seeding element of the vascular implant, and growing a layer of endothelial cells over the exposed surfaces of the seeding element.

[0189] Embodiment 26. The method of embodiment 25, wherein the valve seeding element degrades after growth of the layer of endothelial cells.

[0190] EXPERIMENTAL EXAMPLES

[0191] The invention is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only and the invention should in no way be construed as being limited to these Examples, but rather should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0192] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples therefore specifically point out exemplary embodiments of the present invention and are not to be construed as limiting in any way the remainder of the disclosure.

[0193] Example 1 : Stimulation of venous valve formation to treat PTS

[0194] Venous valve defects are a primary aspect of PTS pathology.

[0195] The pathology of PTS is driven by chronic venous hypertension resulting from vascular damage following DVT. During acute DVT a blood clot typically forms in the downstream sinus of a venous valve in the deep veins, typically in the leg or groin (Fig 1, top) (Kakkar, V. V. Ann R Coll Surg Engl 45, 257-276 (1969), Mackman, N. The Journal of Clinical Investigation 122, 2331-2336 (2012), Lensing, A. W. A. et al. The Lancet 353, 479-485 (1999)). The clot can grow to obstruct flow causing acute symptoms in the affected leg, and pieces of the clot may embolize causing cardiopulmonary symptoms (Mackman, N. The Journal of Clinical Investigation 122, 2331-2336 (2012), Lensing, A.Attorney Docket No.206589-0002-00 WO

[0196] W. A. et al. The Lancet 353, 479-485 (1999)). DVT clots cause significant local inflammation damaging venous valves resulting in incompetent valves and chronic reflux (Fig 1, middle-left) (Myers, K. A. et al. J Vase Surg 21, 605-612 (1995), Labropoulos, N. et al. J Vase Surg 26, 736-742 (1997), Yamaki, T. et al. J Thromb Haemost 5, 305-312 (2007)). Post-DVT patients often have reduced venous flow, remaining clot, and inflammation which can lead to fibrotic vessel walls and lesion development that narrow the veins and restrict outflow (Fig 1, middle-right) (Schleimer, K. et al. Journal of Vascular Surgery: Venous and Lymphatic Disorders 7, 592-600 (2019), Vedantham, S. Thromb Res 123 Suppl 4, S62-65 (2009)). Chronic reflux, obstruction, or a combination of both lead to venous hypertension. Chronic venous hypertension drives fluid extravasation causing edema, chronic inflammation, and tissue breakdown resulting in the characteristic symptoms of PTS (Fig 1, bottom) (Bittar, L. F. et al. PLoS One 15, e0227150 (2020), Rabinovich, A. et al. Thromb Res 136, 289-297 (2015), Roumen-Klappe, E. M. et al. J Thromb Haemost 7, 582-587 (2009), Shbaklo, H. et al. Thromb Haemost 101, 505-512 (2009)).

[0197] Devices, systems, and methods for stimulating venous valve formation are described in this example. Venous valve formation stimulation by altering intravascular architecture and providing hemodynamic therapy to stimulate endothelial signaling that drives natural valve formation is described.

[0198] Venous valves form in response to endothelial flow sensing.

[0199] Vascular valve development is initiated and regulated by hemodynamic signaling to the local endothelium through a highly conserved molecular pathway (Bazigou, E. et al. The Journal of Clinical Investigation 121, 2984-2992 (2011), Munger, S. J. et al. Dev Biol 412, 173-190 (2016)). Studies have shown that endothelial cells sensing of oscillatory shear stress (OSS) upregulates the expression of transcription factors PROX I and FOXC2, which activate a downstream pathway that leads to matrix deposition, endothelial cell proliferation, and valve formation (Fig 2A) (Munger, S. J. et al. Dev Biol 412, 173-190 (2016), Sabine, A. et al. Dev Cell 22, 430-445 (2012), Geng, X. et al. Dis Model Meeh 10, 1273-1287 (2017), Sweet, D. T. et al. J Clin Invest 125, 2995-3007 (2015)). Venous valve endothelial expression of PROXI and FOXC2 is maintained throughout life, stimulated by periodic recirculatory flow in the valve sinus stimulated byAttorney Docket No.206589-0002-00 WO

[0200] physical movement (Fig 2A - 2B) (Sabine, A. et al. The Journal of Clinical Investigation 125, 3861-3877 (2015), Lyons, O. et al. Journal of Experimental Medicine 214, 2437-2452 (2017), RajeevaPandian, N. K. et al. Small 16, e2003401 (2020), Saygili Demir, C. et al. J Cell Biol 222 (2023)). Mouse genetic models have shown that the loss of PROXI or FOXC2 expression prevents valve formation, and post-natal deletion leads to valve regression (Bazigou, E. et al. The Journal of Clinical Investigation 121, 2984-2992 (2011), Munger, S. J. et al. Dev Biol 412, 173-190 (2016), Sabine, A. et al. Dev Cell 22, 430-445 (2012), Sweet, D. T. et al. J Clin Invest 125, 2995-3007 (2015)). Additionally, FOXC2 mutations have been linked to human venous valve disease and disorders (Lyons, O. et al. Journal of Experimental Medicine 214, 2437-2452 (2017), Shadrina, A. S. et al. Phlebology 31, 640-648 (2016), Mellor, R. H. et al. Circulation 115, 1912-1920 (2007)). A therapeutic approach to specifically recapitulate valve formation hemodynamics at a designated site to stimulate local endothelial signaling and valve formation to treat chronic venous reflux and relieve PTS symptoms is described.

[0201] Stimulation of venous valve formation to treat PTS.

[0202] In this example, PTS is treated by addressing the underlying defect, loss of valve function, through the creation of new venous valves. The described technology includes two components, 1) a valve-seeding stent (VS stent) for intravascular deployment, and 2) an external rapid cycling compression device (RCCD) to stimulate endothelial cell formation of valves through hemodynamic therapy. The VS stent contains two 3-dimensional valve-seeding elements that when covered with endothelial cells creates a vascular architecture that enhances natural hemodynamic stimulation of valve-formation signaling (Fig 8A - 8B). The VS stent is designed to be resorbable and includes novel micropatterned element surface to increase endothelial cell coverage. The valve-seeding element design minimizes zones of stasis, to reduce the risk of thrombosis, and stent displacement compared to traditional prosthetic valve designs (Fig. 8B). The efficacy of the VS stent is enhanced by the combined treatment with a previously developed RCCD system. The RCCD provides pneumatic compression of the calf to stimulate rapid pulses of venous flow that specifically create endothelial stimulating hemodynamics to activation valve program transcription factors (Fig. 8C). The RCCD also stimulates anticlotting and anti-inflammatory effects on venous endothelium further supporting veinAttorney Docket No.206589-0002-00 WO

[0203] health and recovery. Together, the technology aims to reduce reflux and provide a novel treatment for chronic venous reflux in PTS and other venous insufficiency patients to improve outcomes and reduce the cost of lifelong care (Fig 8C).

[0204] The application of the understanding of endothelial signaling during valve development to drive new venous valve formation in PTS patients is described. By understanding the hemodynamic and cellular mechanisms behind both valve formation and valve associated thrombosis, a novel combination therapy was designed.

[0205] Some aspects of the example technology to stimulate venous valve formation include the following aspects. The VS stent uses a valve-inspired geometry to create a structure that mimics early valve development and enhances hemodynamic signaling to the local endothelium to express the valve-formation genetic pathway. The external compression system generates pulses of compression that are 20 - 100 times shorter but 12 times more frequent than currently used compression therapy systems to specifically increase endothelial expression of the valve-forming genetic pathway. A biomimetic vascular in vitro system is used to assess the function of VS stent prototype devices under physiological geometries and flow conditions. A material patterning technique is used to enhance endothelialization of VS stent designs.

[0206] Valve-seeding element design.

[0207] Valve formation requires endothelial proliferation, matrix deposition, and cell organization into valve leaflets. Recent studies have demonstrated that vascular valve endothelium respond the presence and degree of recirculatory flow, which alters the endothelial proliferation and protein deposition (Rajeeva Pandian, N. K. et al. Small 16, e2003401 (2020), Saygili Demir, C. et al. J Cell Biol 222 (2023), Welsh, J. D. et al. J Clin Invest 129, 5489-5500 (2019), Hoofnagle, M. et al. The journal of trauma and acute care surgery Publish Ahead of Print (2023), Sabine, A. et al. Developmental Cell 22, 430-445 (2012)). It has been found that valve endothelium exposed to high recirculatory shears, like those on valve leaflets, increased matrix deposition, and those exposed to lower recirculatory shear, on the wall in the valve sinus, were stimulated to proliferate (Fig 9A) (Saygili Demir, C. et al. J Cell Biol 222 (2023)). This model was shown in lymphatic valve biology, which is highly conserved in venous valves. Computational Fluid Dynamic (CFD) simulations of various architectures were performed and the downstreamAttorney Docket No.206589-0002-00 WO

[0208] recirculatory hemodynamics were evaluated to determine the effect of various architectures for stimulating valve formation hemodynamics.

[0209] A simplified venous model with a 1 cm diameter tube and centerline flow velocity of ~20 cm / s, to approximate physiological vessel size and flow rate was used. Different size and shape valve-seeding element architectures were evaluated by their ability to generate local recirculatory flow (Fig 9B). These data can inform valve-seeding element design.

[0210] Computational Fluid Dynamic (CFD) simulations of various architectures were performed and the downstream recirculatory hemodynamics were evaluated Simscale software. A 2D simulation of a 20 cm long tube with a 1 cm diameter was used to approximate the physiology of a deep venous vessel that would be the site of clinically meaningful reflux. The applied flow velocities were varied between 5 cm / s (pathological), 22 cm / s (healthy), and 100 cm / s (peak flow). The kinetic viscosity of the simulated fluid was 9.34 m2 / s. Various valve-seeding element designs were integrated into the middle of the tube and evaluated the downstream flow effects for the degree of recirculation and disruption of laminar flow were simulated. The degree of stenosis of the element (10%, 25%, and 33%), and the length of the element (5mm vs 10mm) was varied. The downstream shape of the element (concave, straight, and convex) was also varied.

[0211] Figure 7A shows representative 2D CFD simulations of resulting hemodynamics from differently shaped embodiments of a valve seeding element 300. The represented valve seeding element 300 support surface 306 shapes are concave, straight, and convex. The inlet velocity in the simulations is 22 cm / s. The maximum velocity is 50 cm / s and is depicted in red. There is 33% stenosis at the most occluded point of the vessel. The valve seeding element 300 is 5 mm in length. The simulated flow velocity was calculated for each portion of a grid defined by 0.003 m by 0.003 m portions. The scaling factor of the depicted representations is 0.015.

[0212] Figure 7B shows representative 2D CFD simulations of resulting hemodynamics from embodiments of a valve seeding element 300. The represented embodiments of flow valve seeding elements 300 have different maximum stenosis of the vessel. The value of max stenosis that are represented are 10%, 25%, and 33%. The inlet velocity in theAttorney Docket No.206589-0002-00 WO

[0213] simulations is 22 cm / s. The maximum velocity is 50 cm / s and is depicted in red. The valve seeding elements 300 support surfaces 306 are a concave shape. The valve seeding elements 300 are 5 mm in length. The simulated flow velocity was calculated for each portion of a grid defined by 0.003 m by 0.003 m portions. The scaling factor of the depicted representations is 0.015.

[0214] Figure 7C shows representative 2D CFD simulations of resulting hemodynamics from embodiments of a valve seeding element 300. The represented embodiments of the valve seeding elements 300 have varying lengths, shapes, and maximum stenosis.

[0215] Figure 7D shows representative 2D CFD simulations of resulting hemodynamics from embodiments of a valve seeding element 300. The simulations have a range of inlet flow velocities including 5 cm / s, 22 cm / s, and 100 cm / s. The value of max stenosis that are represented are 10%, 25%, and 33%. The inlet velocity in the simulations is 22 cm / s. The valve seeding elements 300 support surfaces 306 are a concave shape. The valve seeding elements 300 are 5 mm in length.

[0216] Flow conditions with a 5 cm / s and 100 cm / s centerline flow rate were evaluated to simulate both pathologically reduced flow and peak flow during RCCD compression. Based on the CFD simulations, an initial valve-seeding element shape was generated that will create a 25% stenosis at its highest point and will have a shape with a concave backside shape to enhance both the size and velocity of the flow recirculation zone 106, creating the both low- and high-shear endothelial stimulation needed for valve formation (Fig 9B). Valve-seeding element designs can be evaluated to incorporate any other design requirements for supporting valve formation.

[0217] Development of a rapid cycling compression device (RCCD) to generate valvulogenic hemodynamics.

[0218] The critical element of the approach is the creation of recirculatory flow patterns at the site of the VS stent. Earlier studies found that physical activity was critical to creating frequent pulses of venous return that generate periods of recirculatory flow at the site of valve formation (Welsh, J. D. et al. J Clin Invest 129, 5489-5500 (2019)).

[0219] However, PTS patients often have inherently reduced venous flow and limited mobility due to their symptoms, which would both increase thrombotic risk and limit recirculatory flow generation. To generate the necessary hemostatic conditions in PTS patients, activeAttorney Docket No.206589-0002-00 WO

[0220] compression therapy during periods of immobility to augment venous return and increase the desired endothelial signaling and prevent stent clotting or inflammation is used. An external pneumatic compression system to provide rapid cycling compression to the calves of users to enhance recirculatory flow at venous valves was developed. The RCCD consists of an air control head unit and inflatable calf garments to provide compression and increased venous flow during use. Compared to existing pneumatic compression devices designed to increase venous return, the RCCD system uses similar compression pressures, but uses much shorter and more frequent compression cycles to alter flow. The short duration and high frequency of the compression pulses was optimized to maximize the volume and frequency of recirculating blood in the sinus of deep venous valves in the leg and groin. The recirculatory flow provides the shear-mediated signaling to the valve sinus endothelium and induces expression of PROXI and FOXC2 and downstream antithrombotic and anti-inflammatory endothelial gene expression (Welsh, J. D. et al. J Clin Invest 129, 5489-5500 (2019)). RCCD pulses are used on healthy human subjects found to test the effectiveness of RCCD pulses in creating valve sinus recirculation in the deep venous valves of immobilized subjects, and are compared to treatment with currently existing pneumatic compression devices (sequential compression devices or SCDs) which are designed for bulk blood movement but not optimized for valve sinus flow. Importantly, studies are performed in brain-dead organ donors who are entirely immobile and therefore unable to generate the muscular activity believed to generate OSS in the venous valve. Experiments are performed to measure PROXI and FOXC2 expression in venous valve endothelium in one leg that is treated with RCCD compared to an untreated and immobile leg. These experimental designs support the role of valve hemodynamics as critical for the expression of the endothelial valve-formation phenotype, and provide a mechanism for the identified risk factors of low physical activity and reduced venous flow in the progression of PTS.

[0221] VS stent design

[0222] Initial design requirements for each component of the stent are developed. The stent can include bioresorbable materials, micropatterning, and stent delivery systems.

[0223] Attachment mesh designAttorney Docket No.206589-0002-00 WO

[0224] Typical stents are designed to hold open a compressed or narrowed vessel. The described VS stent may not have a primarily structural function, therefore, the function of the attachment mesh portion of the VS stent is to anchor the stent in place and allow for endothelial coverage of the valve-seeding element and prevent stent migration or dislodgement. Various mesh designs and materials to optimize flexibility and resorption to reduce vessel irritation, without losing the stable anchoring function were envisioned (Fig 13). The design has aspects that are advantageous for clinical use.

[0225] Valve-seeding element design.

[0226] Some envisioned designs and materials for the valve-seeding elements are provided (Fig 13). CFD simulations have identified designs that create robust recirculation at the element with differences in the stenosis, shape, and length of the elements. Differences in these designs impact the design requirements for rapid endothelial coverage, timing of resorption, and impact on deployment can be evaluated. Micropatteming techniques can be incorporated into the manufacturing of the element design, to enhance endothelial coverage.

[0227] Example 2: Single Leaflet Valve Seeding (sl-VS) stent for treating systemic lymphedema Increased venous pressures caused by heart failure, any cardiac disease, or systemic lymphedema, can block lympho-venous valve opening at the lympho-venous junction (LVJ) and congest the entire lymphatic system, leading to fluid buildup, lymphatic vessel complications, and symptom onset (Figure 11 A).

[0228] Approximately 20% of healthy humans do not have a valve at their LVJ, and in these individuals the LVJ occurs directly behind a venous valve, suggesting that the venous valve sinus environment is sufficiently low pressure to allow for lymphatic flow freely into the venous system. In this example, a modified design of the VS stent is used to create a similar low-pressure microenvironment at the LVJ to increase lymphatic flow and restore fluid homeostasis. The VS stent can be altered to have a single leaflet design (sl-VS stent) with the single leaflet positioned at the terminus of the stent structure and positioned in the vein directly upstream from the LVJ to create a low-pressure zone and allow for lymphatic flow delivery (Figure 1 IB). This technology could be readily deployed using venous interventions which are far more technically feasible thanAttorney Docket No.206589-0002-00 WO

[0229] lymphatic interventions, and benefits from the other design elements of the VS stent, including not forming a full leaflet to reduce thrombotic risk and the potential to be bioresorbable.

[0230] The disclosures of each and every patent, patent application, and publication cited herein are hereby each incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

Attorney Docket No.206589-0002-00 WOCLAIMSWhat is claimed is:

1. A vascular implant comprising:a tubular frame having an inlet, an outlet and a lumen therethrough, the lumen forming an inner surface of the frame; anda valve seeding element positioned on the inner surface of the frame, wherein the valve seeding element comprises a sloped surface that extends into the lumen.

2. A vascular implant comprising:a frame having a first surface and an opposing second surface; and a valve seeding element positioned on the first surface; and wherein the valve seeding element protrudes from the first surface of the frame.

3. The vascular implant of claim 1, further comprising a second valve seeding element positioned on the inner surface of the frame,wherein the second valve seeding element comprises a sloped surface that extends into the lumen, andwherein the first and second valve seeding elements are positioned across from each other with the lumen therebetween.

4. The vascular implant of claim 1, wherein the sloped surface of the valve seeding element extends into the lumen by at least 5%, at least 12.5%, or at least 33% of the lumen height at the tallest point of the sloped surface.

5. The vascular implant of claim 1, wherein the valve seeding element further comprises a vertical surface, wherein the vertical surface extends from the apex of the sloped surface away from the lumen.Attorney Docket No.206589-0002-00 WO6. The vascular implant of claim 5, wherein the vertical surface is straight, concave, or convex.

7. The vascular implant of claim 1, wherein the horizontal length of the valve seeding element is in the range of 5 mm to 50 mm.

8. The vascular implant of claim 1, wherein the sloped surface comprises a micropattern.

9. The vascular implant of claim 5, wherein the sloped surface comprises a first micropattern and the vertical surface comprises a second micropattern.

10. The vascular implant of claim 9, wherein the first micropattem and the second micropattern are different micropatterns.

11. The vascular implant of claim 1, wherein the vascular implant further comprises a resorbable material.

12. The vascular implant of claim 1, wherein the tubular frame comprises a mesh.

13. The vascular implant of claim 1, wherein the tubular frame further comprises:a middle length; andtwo end openings, wherein the two end openings have a greater perimeter than the middle length.

14. The vascular implant of claim 1, wherein the tubular frame comprises a spacing between the valve seeding element and the outlet.

15. A method of generating a recirculation zone in the lumen of a vessel of a subject having a flow of fluid therethrough, comprising the steps of:Attorney Docket No.206589-0002-00 WOimplanting a flow diverting element in a vessel of the subject; partially occluding fluid flow in the vessel adjacent to the flow diverting element by diverting fluid flow towards a central region of the vessel lumen; and generating a recirculation zone downstream of the partial occlusion and adjacent to the flow diverting element.

16. The method of claim 15, further comprising the step of applying external pneumatic compression to the subject.

17. The method of claim 15, wherein the flow diverting element comprises the vascular implant of claim 1.

18. The method of claim 15, wherein the subject is diagnosed with one of the group consisting of: post thrombotic syndrome, deep vein thrombosis, chronic venous reflux, and systemic lymphedema.

19. The method of claim 15, wherein the vessel is a deep vein.

20. The method of claim 16, further comprising the step of providing a compression device, and wherein the external pneumatic compression is applied using the compression device.

21. The method of claim 20, wherein the compression device is one or more of the group selected from: a compression garment, a cuff, a sequential compression device, and a rapid cycling compression device.

22. The method of claim 16, wherein the external pneumatic compression is applied as a pulse with a pulse duration of at most 20 seconds, at most 10 seconds, at most 5 seconds, at most 1 second, at most 0.5 seconds, at most 0.35 seconds, at most 0.25 seconds, at most 0.15 seconds, or at most 0.1 seconds.

23. The method of claim 16, wherein the external pneumatic compression is applied as a pulse with a frequency of at least 1 / min, at least 5 / min, at least 6 / min, at least 10 / min, or at least 12 / min.Attorney Docket No.206589-0002-00 WO24. The method of claim 15, wherein the vessel is a vein, and the flow diverting element is implanted upstream of a lympho-venous junction.

25. A method of generating a leaflet valve in the vein of a subject, comprising the steps of:positioning the vascular implant of claim 1 or 2 in a vein of a subject; generating a recirculation zone downstream and adjacent to the valve seeding element of the vascular implant; andgrowing a layer of endothelial cells over the exposed surfaces of the seeding element.

26. The method of claim 25, wherein the valve seeding element degrades after growth of the layer of endothelial cells.

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