Compositions and methods for vascular stabilization

Abstract

Compositions and methods stabilize existing or imparted vascular states of blood vessels. In an example, a composition for vascular stabilization can include a crosslink breaker, a protein denaturant, a crosslinking agent, or some combination thereof provided the composition includes at least the crosslink breaker or the protein denaturant if the composition includes the crosslinking agent. The crosslink breaker breaks existing protein crosslinks in a luminal wall of a blood vessel. The protein denaturant denatures proteins in the luminal wall of the blood vessel. The crosslinking agent establishes new protein crosslinks in the luminal wall of the blood vessel. The composition can be formulated into a formulation for direct administration to the luminal wall of the blood vessel by an intravascular medical device to stabilize an existing vascular state of the blood vessel or an imparted vascular state of the blood vessel.

Description

COMPOSITIONS AND METHODS FOR VASCULAR STABILIZATIONPRIORITY

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 606,515, filed December 5, 2023, which is incorporated by reference in its entirety into this application.BACKGROUND

[0002] Peripheral vascular procedures such as balloon angioplasty and stent placement have proven to be successful medical interventions for the treatment of various conditions of the peripheral vasculature. Indeed, these procedures have offered patients improved bloodvessel patency, increased blood flow, symptomatic relief, and enhanced quality of life. However, such peripheral vascular procedures can have potential drawbacks and complications that clinicians and patients must consider. In an example, balloon angioplasty can result in acute recoil (e.g., vessel constriction) and decreased blood flow following balloon deflation, thereby requiring further medical intervention such as stent placement to improve blood-vessel patency. In another example, stents, while useful to maintain such patency, permanently remain in patients’ bodies. Their continued presence there can lead to stent thrombosis (e.g., clot formation in or around stents), in-stent restenosis, or stent fracture, which can necessitate even further medical intervention. What is needed are peripheral vascular treatments and procedures that obviate at least the foregoing potential drawbacks and complications.

[0003] Disclosed herein are compositions and methods that address at least the foregoing.SUMMARY

[0004] Disclosed herein is a composition for vascular stabilization including, in some embodiments, a crosslink breaker, a protein denaturant, a crosslinking agent, or some combination thereof. The crosslink breaker breaks existing protein crosslinks in a luminal wall of a blood vessel. The protein denaturant denatures proteins in the luminal wall of the blood vessel. The crosslinking agent establishes new protein crosslinks in the luminal wall of the blood vessel. The composition is formulated into a formulation for direct administration to theluminal wall of the blood vessel by an intravascular medical device to stabilize an existing vascular state of the blood vessel or an imparted vascular state of the blood vessel.

[0005] In some embodiments, the composition includes at least the crosslink breaker or the protein denaturant if the composition includes the crosslinking agent.

[0006] In some embodiments, the existing vascular state of the blood vessel is an aneurysmal state of the blood vessel. The formulation is for direct administration to the luminal wall of the blood vessel about an aneurysm to stabilize the aneurysm as it exists in the aneurysmal state of the blood vessel and, thereby, reduce a risk of aneurysmal progression to a more severe condition including aneurysmal rupture.

[0007] In some embodiments, the crosslinking agent establishes the new protein crosslinks in the luminal wall of the blood vessel about the aneurysm, which limits further bulging of the luminal wall of the blood vessel. This stabilizes the aneurysm as it exists in the aneurysmal state of the blood vessel and reduces the risk of aneurysmal progression to a more severe condition including aneurysmal rupture.

[0008] In some embodiments, the imparted vascular state of the blood vessel is a dilated state of the blood vessel. The formulation is for direct administration to the luminal wall of a dilated portion of the blood vessel to stabilize the blood vessel as it exists in the dilated state of the blood vessel and, thereby, substantially maintain patency of the blood vessel upon removal of the intravascular medical device.

[0009] In some embodiments, the crosslink breaker breaks the existing protein crosslinks in the luminal wall of the blood vessel about the dilated portion of the blood vessel, which limits the dilated portion of the blood vessel from returning to a pre-dilated state of the blood vessel. This stabilizes the blood vessel as it exists in the dilated state of the blood vessel and substantially maintains patency of the blood vessel upon removal of the intravascular medical device.

[0010] In some embodiments, the protein denaturant denatures proteins in the luminal wall of the blood vessel about the dilated portion of the blood vessel, which allows denatured proteins in the dilated portion of the blood vessel to refold and reorganize in a thermodynamically favorable configuration different than a pre-dilated state of the blood vessel. This stabilizes the blood vessel as it exists in the dilated state of the blood vessel andsubstantially maintains patency of the blood vessel upon removal of the intravascular medical device.

[0011] In some embodiments, the crosslinking agent establishes the new protein crosslinks in the luminal wall of the blood vessel about the dilated portion of the blood vessel, which limits the dilated portion of the blood vessel from returning to a pre-dilated state of the blood vessel. This stabilizes the blood vessel as it exists in the dilated state of the blood vessel and substantially maintains patency of the blood vessel upon removal of the intravascular medical device.

[0012] In some embodiments, the crosslinking agent is one or more small-molecule organic compounds or salts thereof, one or more enzymes, one or more biopolymers, or some combination of the foregoing crosslinking agents.

[0013] In some embodiments, the one-or-more small-molecule organic compounds or salts thereof are selected from genipin; ferulic acid; a plurality of proanthocyanidins; a plurality of theaflavins including theaflavin; a plurality of catechin stereoisomers; epigallocatechin gallate (“EGCG”); ascorbic acid, optionally, in combination with copper; 1, 2, 3,4,6- pentagalloyl glucose (“PGG”); a plurality of non-azo 1,8-naphthalimides; a plurality of diazirines; l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (“EDC”); a plurality of N- hydroxysuccinimides including N-hydroxy succinimide (“NHS”), ethylene glycol bis(succinimidyl succinate) (“EGS”), and 3-mercaptopropanyl-N-hydroxysuccinimide ester (“MPNHS”); glutathione; glutaraldehyde; diglycoaldehyde; galactose dialdehyde; a plurality of polyaldehydes via periodate-oxidized monosaccharides, disaccharides, and oligosaccharides; a plurality of polyaldehydes via periodate-oxidized polyols; and a plurality of light-activated crosslinkers including 4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein and riboflavin.

[0014] In some embodiments, the one-or-more enzymes are selected from transglutaminase and amine oxidase.

[0015] In some embodiments, the one-or-more biopolymers are selected from glucan; dextran; and a plurality of polyaldehydes via periodate-oxidized polysaccharides including glucan and dextran.

[0016] In some embodiments, the crosslink breaker is one or more inorganic compounds or salts, one or more small-molecule organic compounds or salts thereof, one or more enzymes, or some combination of the foregoing crosslink breakers.

[0017] In some embodiments, the one-or-more inorganic compounds or salts include calcium chloride.

[0018] In some embodiments, the one-or-more small-molecule organic compounds or salts thereof are selected from 3-phenacyl-4,5-dimethylthiazolium chloride and urea.

[0019] In some embodiments, the one-or-more enzymes are selected from a plurality of proteases.

[0020] In some embodiments, the protein denaturant is one or more inorganic compounds or salts, one or more small-molecule organic compounds or salts thereof, one or more ionic liquids, or some combination of the foregoing protein denaturants.

[0021] In some embodiments, the one-or-more inorganic compounds or salts include sodium sulfite.

[0022] In some embodiments, the one-or-more small-molecule organic compounds or salts thereof are selected from a plurality of Ci-Cs alcohols including ethanol; urea; guanidinium chloride; guanidinium thiocyanate; sodium dodecyl sulfate (“SDS”); acetone; and acetonitrile.

[0023] Also disclosed is a method for vascular stabilization including, in some embodiments, an advancing operation and an administering operation. The advancing operation includes advancing an intravascular medical device to a diseased portion of a blood vessel. The administering operation includes directly administering a formulation to a luminal wall of the blood vessel in the diseased portion of the blood vessel to stabilize an existing vascular state of the blood vessel or an imparted vascular state of the blood vessel. The formulation includes a crosslink breaker, a protein denaturant, a crosslinking agent, or some combination thereof. The crosslink breaker breaks existing protein crosslinks in the luminal wall of the blood vessel. The protein denaturant denatures proteins in the luminal wall of the blood vessel. The crosslinking agent establishes new protein crosslinks in the luminal wall of the blood vessel.

[0024] In some embodiments, the composition includes at least the crosslink breaker or the protein denaturant if the composition includes the crosslinking agent

[0025] In some embodiments, the existing vascular state of the blood vessel is an aneurysmal state of the blood vessel. The administering of the formulation to the luminal wall of the blood vessel about an aneurysm stabilizes the aneurysm as it exists in the aneurysmal state of the blood vessel and, thereby, reduces a risk of aneurysmal progression to a more severe condition including aneurysmal rupture.

[0026] In some embodiments, the method further includes a dilating operation. The dilating operation includes dilating the blood vessel such that the imparted vascular state of the blood vessel is a dilated state of the blood vessel. The administering of the formulation to the luminal wall of a dilated portion of the blood vessel stabilizes the blood vessel as it exists in the dilated state of the blood vessel and, thereby, substantially maintains patency of the blood vessel upon removal of the intravascular medical device.

[0027] These and other features of the concepts provided herein will become more apparent to those of skill in the art in view of the accompanying drawings and following description, which describe particular embodiments of such concepts in greater detail.BRIEF DESCRIPTION OF DRAWINGS

[0028] FIG. 1 illustrates direct administration of a formulation for vascular stabilization to a luminal wall of a blood vessel by an intravascular medical device in accordance with some embodiments.

[0029] FIG. 2 provides a chart showing immediate changes in arterial circumference after treatment of shorter segments of porcine artery with various components of the formulation for vascular stabilization in accordance with some embodiments.

[0030] FIG. 3 provides a chart showing immediate changes in arterial circumference after treatment of longer segments of porcine artery with various components of the formulation for vascular stabilization in accordance with some embodiments.

[0031] FIG. 4 provides a chart showing long-term changes in arterial circumference after treatment of segments of porcine artery with various components of the formulation for vascular stabilization in accordance with some embodiments.DESCRIPTION

[0032] Before some particular embodiments are disclosed in greater detail, it should be understood that the particular embodiments disclosed herein do not limit the scope of the concepts provided herein. It should also be understood that a particular embodiment disclosed herein can have features that can be readily separated from the particular embodiment and optionally combined with or substituted for features of any of a number of other embodiments disclosed herein.

[0033] Regarding terms used herein, it should also be understood the terms are for the purpose of describing some particular embodiments, and the terms do not limit the scope of the concepts provided herein. Ordinal numbers (e.g., first, second, third, etc.) are generally used to distinguish or identify different features or steps in a group of features or steps, and do not supply a serial or numerical limitation. For example, “first,” “second,” and “third” features or steps need not necessarily appear in that order, and the particular embodiments including such features or steps need not necessarily be limited to the three features or steps. In addition, any of the foregoing features or steps can, in turn, further include one or more features or steps unless indicated otherwise. Labels such as “left,” “right,” “top,” “bottom,” “front,” “back,” and the like are used for convenience and are not intended to imply, for example, any particular fixed location, orientation, or direction. Instead, such labels are used to reflect, for example, relative location, orientation, or directions. Singular forms of “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise.

[0034] “Proximal” is used to indicate a portion, section, piece, element, or the like of a medical device intended to be near or relatively nearer to a clinician when the medical device is used on a patient. For example, a “proximal portion” or “proximal section” of the medical device includes a portion or section of the medical device intended to be near the clinician when the medical device is used on the patient. Likewise, a “proximal length” of the medical device includes a length of the medical device intended to be near the clinician when the medical device is used on the patient. A “proximal end” of the medical device is an end of the medical device intended to be near the clinician when the medical device is used on the patient. The proximal portion, the proximal section, or the proximal length of the medical device need not include the proximal end of the medical device. Indeed, the proximal portion, the proximal section, or the proximal length of the medical device can be short of the proximal end of the medical device. However, the proximal portion, the proximal section, or the proximal lengthof the medical device can include the proximal end of the medical device. Should context not suggest the proximal portion, the proximal section, or the proximal length of the medical device includes the proximal end of the medical device, or if it is deemed expedient in the following description, “proximal portion,” “proximal section,” or “proximal length” can be modified to indicate such a portion, section, or length includes an end portion, an end section, or an end length of the medical device for a “proximal end portion,” a “proximal end section,” or a “proximal end length” of the medical device, respectively.

[0035] “Distal” is used to indicate a portion, section, piece, element, or the like of a medical device intended to be near, relatively nearer, or even in a patient when the medical device is used on the patient. For example, a “distal portion” or “distal section” of the medical device includes a portion or section of the medical device intended to be near, relatively nearer, or even in the patient when the medical device is used on the patient. Likewise, a “distal length” of the medical device includes a length of the medical device intended to be near, relatively nearer, or even in the patient when the medical device is used on the patient. A “distal end” of the medical device is an end of the medical device intended to be near, relatively nearer, or even in the patient when the medical device is used on the patient. The distal portion, the distal section, or the distal length of the medical device need not include the distal end of the medical device. Indeed, the distal portion, the distal section, or the distal length of the medical device can be short of the distal end of the medical device. However, the distal portion, the distal section, or the distal length of the medical device can include the distal end of the medical device. Should context not suggest the distal portion, the distal section, or the distal length of the medical device includes the distal end of the medical device, or if it is deemed expedient in the following description, “distal portion,” “distal section,” or “distal length” can be modified to indicate such a portion, section, or length includes an end portion, an end section, or an end length of the medical device for a “distal end portion,” a “distal end section,” or a “distal end length” of the medical device, respectively.

[0036] “About,” as in about a particular amount, concentration, or the like of a component in the composition or formulation for vascular stabilization, is intended to reflect the particular amount or concentration of the component in the composition or formulation is within rounding or measurement uncertainty as it is defined in metrology. For example, a single dose of the formulation described herein for mitigating head trauma can be “about 31.8 g,” which can include 31.79 g to 31.81 g of the formulation due to at least rounding.

[0037] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art.

[0038] As set forth above, peripheral vascular procedures such as balloon angioplasty and stent placement have proven to be successful medical interventions for the treatment of various conditions of the peripheral vasculature. Indeed, these procedures have offered patients improved blood-vessel patency, increased blood flow, symptomatic relief, and enhanced quality of life. However, such peripheral vascular procedures can have potential drawbacks and complications that clinicians and patients must consider. In an example, balloon angioplasty can result in acute recoil (e.g., vessel constriction) and decreased blood flow following balloon deflation, thereby requiring further medical intervention such as stent placement to improve blood-vessel patency. In another example, stents, while useful to maintain such patency, permanently remain in patients’ bodies. Their continued presence there can lead to stent thrombosis (e.g., clot formation in or around stents), in-stent restenosis, or stent fracture, which can necessitate even further medical intervention. What is needed are peripheral vascular treatments and procedures that obviate at least the foregoing potential drawbacks and complications.

[0039] Disclosed herein are compositions and methods that address at least the foregoing. Indeed, it should be understood that the compositions and methods disclosed herein can be extended to peripheral artery disease (“PAD”) below the knee (“BTK”) where a stable increased diameter resistant to recoil is beneficial; arteriovenous fistula (“AVF”) where a stable increased diameter and blood flow on the venous side aids with fistula maturation and its utility for hemodialysis; and abdominal aortic aneurysm (“AAA”) where aneurysmal sac growth typically progresses to become unpredictable and life-threatening.Compositions

[0040] A composition for vascular stabilization can include one or more crosslink breakers, one or more protein denaturants, one or more crosslinking agents, or some combination thereof. As such, the composition can include a single crosslink breaker up to a plurality of crosslink breakers, a single protein denaturant up to a plurality of protein denaturants, a single crosslinking agent up to a plurality of crosslinking agents, or some combination thereof, wherein the plurality of crosslink breakers can be two, three, four, five, or more crosslink breakers, the plurality of protein denaturants can be two, three, four, five, or more protein denaturants, and the plurality of crosslinking agents can be two, three, four, five,or more crosslinking agents. Notwithstanding the foregoing, references to such components of the composition herein are often provided as singular references (e.g., the crosslink breaker, the protein denaturant, and the crosslinking agent) for expository expediency.Crosslink Breakers

[0041] The crosslink breaker breaks existing protein crosslinks in the luminal wall of a blood vessel. Such a crosslink breaker can be one or more inorganic compounds or salts, one or more small-molecule organic compounds or salts thereof, one or more enzymes, or some combination of the foregoing crosslink breakers.

[0042] In an example, the one-or-more inorganic compounds or salts can include calcium chloride.

[0043] In another example, the one-or-more small-molecule organic compounds or salts thereof can be selected from 3-phenacyl-4,5-dimethylthiazolium chloride and urea; however, the one-or-more small-molecule organic compounds or salts thereof can include various weak acids and bases including that of urea. The one-or-more enzymes can be selected from a plurality of proteases.Protein Denaturants

[0044] The protein denaturant denatures proteins in the luminal wall of a blood vessel but leaves at least primary protein structure intact. As such, the protein denaturant can denature the proteins in the luminal wall of a blood vessel at a level of quaternary protein structure, tertiary protein structure, secondary protein structure, or some combination thereof. Such a protein denaturant can be one or more inorganic compounds or salts, one or more smallmolecule organic compounds or salts thereof, one or more ionic liquids, or some combination of the foregoing protein denaturants.

[0045] In an example, the one-or-more inorganic compounds or salts can include sodium sulfite.

[0046] In another example, the one-or-more small-molecule organic compounds or salts thereof can be selected from a plurality of Ci-Cs alcohols including ethanol; urea; guanidinium chloride; guanidinium thiocyanate; sodium dodecyl sulfate (“SDS”); acetone; and acetonitrile.Crosslinking Agents

[0047] The crosslinking agent establishes new protein crosslinks in the luminal wall of a blood vessel. Such a crosslinking agent can be one or more small-molecule organic compounds or salts thereof, one or more enzymes, one or more biopolymers, or some combination of the foregoing crosslinking agents.

[0048] In an example, the one-or-more small-molecule organic compounds or salts thereof can be selected from genipin; ferulic acid; a plurality of proanthocyanidins; a plurality of theaflavins including theaflavin; a plurality of catechin stereoisomers; epigallocatechin gallate (“EGCG”); ascorbic acid, optionally, in combination with copper; 1, 2, 3,4,6- pentagalloyl glucose (“PGG”); a plurality of non-azo 1,8-naphthalimides; a plurality of diazirines; l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (“EDC”); a plurality of N- hydroxysuccinimides including N-hydroxy succinimide (“NHS”), ethylene glycol bis(succinimidyl succinate) (“EGS”), and 3-mercaptopropanyl-N-hydroxysuccinimide ester (“MPNHS”); glutathione; glutaraldehyde; diglycoaldehyde; galactose dialdehyde; a plurality of polyaldehydes via periodate-oxidized monosaccharides, disaccharides (e.g., lactose, sucrose, etc.), and oligosaccharides; a plurality of polyaldehydes via periodate-oxidized polyols; and a plurality of light-activated crosslinkers including 4,5,6,7-tetrachloro-2’,4’,5’,7’- tetraiodofluorescein (i.e., rose Bengal) and riboflavin.

[0049] In another example, the one-or-more enzymes can be selected from transglutaminase (e.g., microbial transglutaminase [“mTG”]) and amine oxidase.

[0050] In another example, the one-or-more biopolymers can be selected from glucan; dextran; and a plurality of polyaldehydes via periodate-oxidized polysaccharides including glucan and dextran.

[0051] Notably, the composition can advantageously include the crosslinking agent and at least the crosslink breaker or the protein denaturant together with the crosslinking agent. In an example, the composition can include theaflavin as the crosslinking agent and ethanol as the protein denaturant, optionally, as an ethanolic solution of theaflavin. However, it should be understood that the crosslink breaker, the protein denaturant, or both can be in a separate composition from that including the crosslinking agent for sequential administration of the formulations derived therefrom. Whether in a same composition or different compositions, pairing the crosslinking agent with the crosslink breaker, the protein denaturant, or both, allowsfor destabilization of an existing vascular state of a blood vessel such as a stenosed state of the blood vessel by breaking the existing protein crosslinks in the luminal wall of the blood vessel, denaturing the proteins in the luminal wall of the blood vessel, or both followed by stabilization of an imparted vascular state of the blood vessel such as a dilated state of the blood vessel by establishing the new protein crosslinks in the luminal wall of the blood vessel.

[0052] While the composition or the formulation set forth below is generally described as targeting a luminal wall of a blood vessel, it should be understood that the composition or formulation is not limited thereto. Indeed, the composition or formulation can target any one or more structures of a blood vessel selected from at least a tunica intima, an internal elastic lamina, a basement membrane, a tunica media, an external elastic lamina, and a tunica adventitia, wherein the foregoing structures are generally ordered from a luminal surface to an abluminal surface of such a blood vessel. Further, the composition or formulation can target any one or more substructures of the foregoing one-or-more structures of a blood vessel. For example, the composition or formulation can target endothelial cells of the tunica intima; smooth muscle cells, collagen, elastin, or proteoglycans of the tunica media; fibroblasts, collagen, or elastin of the tunica adventitia; or some combination thereof. As such, the crosslink breaker can break existing protein crosslinks in any structure or substructure of a blood vessel; the protein denaturant can denature proteins in any structure or substructure of a same or different blood vessel; and the crosslinking agent can establish new protein crosslinks in any structure or substructure of the same or different blood vessel.Formulations

[0053] The composition for vascular stabilization can be formulated into any administrable formulation for at least direct administration to the luminal wall of a blood vessel by the intravascular medical device 100 set forth below to stabilize an existing vascular state of the blood vessel or an imparted vascular state of the blood vessel. In addition to the foregoing components of the composition (i.e., the crosslink breaker, the protein denaturant, and the crosslinking agent), the formulation can include any pharmaceutically acceptable excipients (e.g., carriers, vehicles, adjuvants, etc.) or other additives (e.g., entrainers) needed for a multidose or single-dose dosage form suitable for the administration to the luminal wall of the blood vessel. The multi dose dosage form can be a bulk powder, plurality of particles of any shape or size, paste, disintegrating thin film, suspension, emulsion, or solution including the composition. The single-dose dosage form can be a pre-measured amount of the powder; a pre-measured amount of the particles; a pre-measured amount of the paste; a pre-cut, disintegrating thin film; or a pre-measured amount of the suspension, emulsion, or solution. In an example, the composition can be formulated into a solution for administration by the intravascular medical device 100. The solution can be in a multidose dosage form administered through a distal end portion 104 of the intravascular medical device 100 by way of a medication lumen 106 of the intravascular medical device 100. Alternatively, the solution can be in a single-dose dosage form administered through the distal end portion 104 of the intravascular medical device 100 by way of diffusion from the distal end portion 104 of the intravascular medical device 100 in which the solution in impregnated. In another example, the composition can be formulated into, for example, a powder, plurality of particles, or paste for administration by the intravascular medical device 100, wherein the powder, particles, or paste is a single-dose dosage form administered from the distal end portion 104 of the intravascular medical device 100 by way of diffusion from the distal end portion 104 of the intravascular medical device 100 on which the powder, particles, or paste is coated or adsorbed.

[0054] When the composition is formulated into the foregoing powder, particles, paste, disintegrating thin film, suspension, emulsion, or solution for administration by the intravascular medical device 100, the formulation can independently range in percent concentration such as weight percent (w / w), weight / volume percent (w / v), or volume percent (v / v) for each component of the crosslink breaker, the protein denaturant, and the crosslinking agent present in the formulation. As to weight percent concentrations, the concentration of the crosslink breaker, the protein denaturant, or the crosslinking agent in the formulation can independently be at least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% (w / w). Further as to weight percent concentrations, the concentration of the crosslink breaker, the protein denaturant, or the crosslinking agent in the formulation can independently be no more than about 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or 1% (w / w). As to weight / volume percent concentrations, the concentration of the crosslink breaker, the protein denaturant, or the crosslinking agent in the formulation can independently be at least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% (w / v). Further as to weight / volume percent concentrations, the concentration of the crosslink breaker, the protein denaturant, or the crosslinking agent in the formulation can independently be no more than about 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or 1% (w / v). As to volume percent concentrations, the concentration of the crosslink breaker, theprotein denaturant, or the crosslinking agent in the formulation can independently be at least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% (v / v). Further as to volume percent concentrations, the concentration of the crosslink breaker, the protein denaturant, or the crosslinking agent in the formulation can independently be no more than about 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or 1% (v / v).

[0055] Alternatively, when the composition is formulated into the foregoing solution for administration by the intravascular medical device 100, the formulation can independently range from a micromolar concentration to a molar concentration for each component of the crosslink breaker, the protein denaturant, and the crosslinking agent present in the formulation. As to micromolar concentrations, the concentration of the crosslink breaker, the protein denaturant, or the crosslinking agent in the formulation can independently be at least about 1 pM, 10 pM, 50 pM, 100 pM, 250 pM, 500 pM, 750 pM, or 1000 pM. Further as to micromolar concentrations, the concentration of the crosslink breaker, the protein denaturant, or the crosslinking agent in the formulation can independently be no more than about 1000 pM, 750 pM, 500 pM, 250 pM, 100 pM, 50 pM, 10 pM, or 1 pM. As to millimolar concentrations, the concentration of the crosslink breaker, the protein denaturant, or the crosslinking agent in the formulation can independently be at least about 1 mM, 10 mM, 50 mM, 100 mM, 250 mM, 500 mM, 750 mM, or 1000 mM. Further as to millimolar concentrations, the concentration of the crosslink breaker, the protein denaturant, or the crosslinking agent in the formulation can independently be no more than about 1000 mM, 750 mM, 500 mM, 250 mM, 100 mM, 50 mM, 10 mM, or 1 mM. As to molar concentrations, the concentration of the crosslink breaker, the protein denaturant, or the crosslinking agent in the formulation can independently be at least about 1 M, 2 M, 3 M, 4 M, 5 M, 6 M, 7 M, 8 M, 9M or 10 M. Further as to molar concentrations, the concentration of the crosslink breaker, the protein denaturant, or the crosslinking agent in the formulation can independently be no more than about 10 M, 9 M, 8 M, 7 M, 6 M, 5 M, 4 M, 3 M, 2 M, or 1 M.

[0056] Whether the composition is formulated into the foregoing powder, particles, paste, disintegrating thin film, suspension, emulsion, or solution, the formulation can be configured for direct administration to the luminal wall of a blood vessel by the intravascular medical device 100 set forth below to stabilize an existing vascular state of the blood vessel or an imparted vascular state of the blood vessel.

[0057] In an example, the existing vascular state of the blood vessel can be an aneurysmal state of the blood vessel. The formulation can be configured for direct administration to the luminal wall of the blood vessel about an aneurysm to stabilize the aneurysm as it exists in the aneurysmal state of the blood vessel and, thereby, reduce a risk of aneurysmal progression to a more severe condition including aneurysmal rupture. Indeed, the crosslinking agent establishes the new protein crosslinks in the luminal wall of the blood vessel about the aneurysm, which limits further bulging of the luminal wall of the blood vessel. This stabilizes the aneurysm as it exists in the aneurysmal state of the blood vessel and reduces the risk of aneurysmal progression to a more severe condition including aneurysmal rupture.

[0058] In another example, the imparted vascular state of the blood vessel can be a dilated state of the blood vessel. The formulation can be for direct administration to the luminal wall of a dilated portion of the blood vessel to stabilize the blood vessel as it exists in the dilated state of the blood vessel and, thereby, substantially maintain patency of the blood vessel upon removal of the intravascular medical device 100. Indeed, the crosslink breaker breaks the existing protein crosslinks in the luminal wall of the blood vessel about the dilated portion of the blood vessel, which limits the dilated portion of the blood vessel from returning to a predilated state of the blood vessel. Further, the protein denaturant denatures the proteins in the luminal wall of the blood vessel about the dilated portion of the blood vessel, which allows denatured proteins in the dilated portion of the blood vessel to refold and reorganize in a thermodynamically favorable configuration different than the pre-dilated state of the blood vessel, thereby limiting the dilated portion of the blood vessel from returning to the pre-dilated state of the blood vessel. Even further, the crosslinking agent establishes the new protein crosslinks in the luminal wall of the blood vessel about the dilated portion of the blood vessel, which limits the dilated portion of the blood vessel from returning to the pre-dilated state of the blood vessel. Each component of the crosslink breaker, the protein denaturant, and the crosslinking agent thusly stabilizes the blood vessel as it exists in the dilated state of the blood vessel and substantially maintains patency of the blood vessel upon removal of the intravascular medical device 100.Intravascular Medical Device

[0059] FIG. 1 illustrates direct administration of the formulation to a luminal wall of a blood vessel by an intravascular medical device 100 in accordance with some embodiments.

[0060] As shown, the intravascular medical device 100 can include an elongate member 102 having a distal end portion 104 configured to directly administer the formulation to the luminal wall of the blood vessel. Indeed, the distal end portion 104 of the elongate member 102 can be configured as a diffuser for administering a solution of the formulation from a medication lumen 106 of the intravascular medical device 100. Alternatively, the distal end portion 104 of the elongate member 102 can be impregnated with the solution of the formulation for diffusion from the distal end portion 104 of the intravascular medical device 100; however, a powder, plurality of particles, or paste of the formulation can be alternatively coated or adsorbed onto the distal end portion 104 of the intravascular medical device 100 for diffusion from the distal end portion 104.

[0061] The distal end portion 104 of the intravascular medical device 100 can be configured to be inflatable by way of an inflation lumen 108 for inflating the distal end portion 104 into a diseased portion of the blood vessel such as a stenosis for imparting an imparted vascular state of the blood vessel such as a dilated state of the blood vessel. In embodiments in which the distal end portion 104 of the elongate member 102 includes the solution of the formulation impregnated therein or the powder, particles, or paste of the formulation coated or adsorbed thereon, the distal end portion 104 of the intravascular medical device 100 can be configured to simultaneously administer the formulation to the luminal wall of the blood vessel and, thereby, stabilize the imparted vascular state of the blood vessel. In embodiments in which the distal end portion 104 of the elongate member 102 is configured as the diffuser for administering the solution of the formulation from the medication lumen 106, the distal end portion 104 of the intravascular medical device 100 can be configured to subsequently administer the formulation to the luminal wall of the blood vessel and, thereby, stabilize the imparted vascular state of the blood vessel. Notably, the inflation lumen 108 and the medication lumen 106 can be the same lumen, as shown, wherein the solution of the formulation doubles as an inflatant.

[0062] Additionally or alternatively, the distal end portion 104 of the intravascular medical device 100 can be configured to be steerable by way of one or more steering wires 110 for steering the distal end portion 104 into or toward a diseased portion of the blood vessel such as an aneurysm for administering the formulation to the luminal wall of the blood vessel and, thereby, stabilizing an existing vascular state of the blood vessel.

[0063] While not shown, the distal end portion 104 of the intravascular medical device 100 can additionally or alternatively be configured with one or more heating elements (e.g., circumferential wires) for heating the distal end portion 104 of the intravascular medical device 100 and contacting a diseased portion of the blood vessel such as a stenosis for breaking the crosslinks in the luminal wall of the blood vessel, denaturing the proteins in the luminal wall of the blood vessel, or both, thereby respectively obviating the crosslink breaker, the protein denaturant, or both in the formulation.

[0064] It should be understood that the configuration of the intravascular medical device 100 can vary in view of the foregoing description as needed for different modes of administration. In an example, a solution, powder, plurality of particles, or paste of the formulation including the crosslink breaker, the protein denaturant, the crosslinking agent, or some combination thereof can be administered all at once by way of diffusion from the distal end portion 104 of the intravascular medical device 100, as set forth above. In another example, different formulations such as a powder, plurality of particles, or paste of a first formulation including the crosslink breaker, the protein denaturant, or some combination thereof coated or adsorbed onto the distal end portion 104 of the intravascular medical device 100 and a solution of a second formulation including the crosslinking agent in the medication lumen 106 can be administered sequentially. Indeed, the first formulation coated or adsorbed onto the distal end portion 104 of the intravascular medical device 100 can be administered first to destabilize the luminal wall of a diseased (e.g., stenosed) portion of a blood vessel before, during, or after inflation of the distal end portion 104 of the intravascular medical device 100, and the second formulation in the medication lumen 106 can be administered second by way of diffusion through the distal end portion 104 of the intravascular medical device 100 to stabilize an imparted (e.g., dilated) state of the blood vessel. In another example, heat by the one-or-more heating elements to break the crosslinks in the luminal wall of a blood vessel, denaturing the proteins in the luminal wall of the blood vessel, or both, can be administered sequentially with the foregoing second formulation including the crosslinking agent in the medication lumen 106. Indeed, the heat can be administered first to destabilize the luminal wall of a diseased (e.g., stenosed) portion of a blood vessel before, during, or after inflation of the distal end portion 104 of the intravascular medical device 100, and the second formulation in the medication lumen 106 can be administered second by way of diffusion through the distal end portion 104 of the intravascular medical device 100 to stabilize an imparted (e.g., dilated) state of the blood vessel.

[0065] It should be understood that the administration of the formulation is not limited to administration by the intravascular medical device 100. Indeed, an iontophoresis device and one or more associated iontophoresis patches can be used alone or in combination with the intravascular medical device 100 to administer the formulation. In an example, the formulation including at least the crosslinking agent can be incorporated into the one-or-more iontophoresis patches for electromotive drug administration (“EMDA”) to the luminal wall of a blood vessel about an aneurysm to stabilize the aneurysm as it exists in an aneurysmal state of the blood vessel. In another example, a first formulation including the crosslink breaker, the protein denaturant, or both can be incorporated into the one-or-more iontophoresis patches for EMDA to destabilize the luminal wall of a diseased (e.g., stenosed) portion of a blood vessel before, during, or after inflation of the distal end portion 104 of the intravascular medical device 100. A second formulation including the crosslinking agent can be subsequently administered by diffusion from or through the distal end portion 104 of the intravascular medical device 100 to stabilize an imparted (e.g., dilated) state of the blood vessel. As set forth above, the second formulation can be a powder, plurality of particles, or paste coated or adsorbed onto the distal end portion 104 of the intravascular medical device 100 for diffusion therefrom; the second formulation can be a solution absorbed into the distal end distal end portion 104 of the intravascular medical device 100 for diffusion therefrom; or the second formulation can be the solution in the medication lumen 106 of the intravascular medical device 100 for diffusion through the distal end portion 104 thereof.Methods

[0066] Methods include methods for preparing the compositions and formulation set forth above as well as methods for vascular stabilization with the foregoing compositions and formulations.

[0067] A method for vascular stabilization can include one or more operations selected form an advancing operation, a dilation operation, and an administering operation.

[0068] The advancing operation can include advancing the intravascular medical device 100 to a diseased portion of a blood vessel.

[0069] The administering operation can include directly administering the formulation to the luminal wall of the blood vessel in the diseased portion of the blood vessel to stabilize an existing vascular state of the blood vessel, which can be an aneurysmal state of the bloodvessel, as set forth above. Further, the formulation can include the crosslink breaker to break the existing protein crosslinks in the luminal wall of the blood vessel, the protein denaturant to denature the proteins in the luminal wall of the blood vessel, the crosslinking agent to establish the new protein crosslinks in the luminal wall of the blood vessel, or some combination of the crosslink breaker, the protein denaturant, and the crosslinking agent. The administering of such a formulation to the luminal wall of the blood vessel about an aneurysm stabilizes the aneurysm as it exists in the aneurysmal state of the blood vessel and, thereby, reduces a risk of aneurysmal progression to a more severe condition including aneurysmal rupture.

[0070] The dilating operation can include dilating the diseased portion of the blood vessel before the administering operation to impart an imparted vascular state of the blood vessel. In accordance with the dilating operation, such an imparted vascular state of the blood vessel can be a dilated state of the blood vessel, as set forth above. Notably, a dilated portion of the blood vessel can be smaller than, commensurate with, or greater than the diseased portion of the blood vessel.

[0071] In an alternative of the foregoing administering operation, the administering operation following the dilating operation can include directly administering the formulation to the luminal wall of the blood vessel in the diseased portion of the blood vessel to stabilize the imparted vascular state of the blood vessel, which can be the dilated state of the blood vessel. Further, the formulation can include the crosslink breaker to break the existing protein crosslinks in the luminal wall of the blood vessel, the protein denaturant to denature the proteins in the luminal wall of the blood vessel, the crosslinking agent to establish the new protein crosslinks in the luminal wall of the blood vessel, or some combination of the crosslink breaker, the protein denaturant, and the crosslinking agent. The administering of such a formulation to the luminal wall of the blood vessel about the dilated portion of the blood vessel stabilizes the blood vessel as it exists in the dilated state of the blood vessel and, thereby, substantially maintains patency of the blood vessel upon removal of the intravascular medical device 100.Examples

[0072] Excised porcine carotid artery segments were treated with one or more of the components of the composition or formulation sequentially or in combination to obtain the results shown in FIGS. 1-3. Both the shorter, 2 mm-long artery segments and the longer, >10 mm-long artery segments were either inverted or not, placed on a balloon, expanded via balloon inflation, and exposed to the one-or-more components of the composition or formulation. (SeeFIGS. 1 and 2.) Notably, the results obtained for the protein denaturants were unexpected in both the magnitude and duration of their effects (FIG. 3).

[0073] FIG. 2 provides a chart showing immediate changes in arterial circumference after treatment of the shorter, 2 mm-long segments of porcine artery with the one-or-more components of the composition of formulation for vascular stabilization in accordance with some embodiments. Indeed, FIG. 2 shows example increases in arterial circumference after concomitant inflation of the distal end portion 104 of the intravascular medical device 100 and exposure of dilated segments of porcine artery to the one-or-more of the components of the composition or formulation. Abbreviations: 10' (10 minutes); CaCh (calcium chloride); M (molar); Tx (treatment); PGG (pentagalloyl glucose); mTG (microbial transglutaminase); U (units); Gen (genipin); EtOH (ethanol); and Glut (glutaraldehyde).

[0074] FIG. 3 provides a chart showing immediate changes in arterial circumference after treatment of the longer, >10 mm-long segments of porcine artery with the one-or-more components of the composition of formulation for vascular stabilization in accordance with some embodiments. Indeed, FIG. 3 shows example increases in arterial circumference after concomitant inflation of the distal end portion 104 of the intravascular medical device 100 and exposure of dilated segments of porcine artery to the one-or-more of the components of the composition or formulation. Abbreviations: 10' (10 minutes); Tx (treatment); EtOH (ethanol); Gen (genipin); CaCh (calcium chloride); M (molar); Guan Chi (guanidinium chloride); MPNHS (3 -mercaptopropionic acid N-hydroxysuccinimide ester); Asc / Cu (ascorbic acid and copper at respective concentrations shown); and PAC (proanthocyanidins).

[0075] FIG. 4 provides a chart showing long-term changes in the arterial circumference after the treatment of at least some of the shorter segments of porcine artery with the one-or- more components of the composition of formulation for vascular stabilization in accordance with some embodiments. Notably, FIG. 3 shows an unexpected magnitude and duration of vascular stabilization for the 2 mm-long segments of porcine artery, particularly with respect to the protein denaturants. Abbreviations: 10' (10 minutes); Tx (treatment); EtOH (ethanol); M (molar); Guan Chi (guanidinium chloride).

[0076] While some particular embodiments have been disclosed herein, and while the particular embodiments have been disclosed in some detail, it is not the intention for the particular embodiments to limit the scope of the concepts provided herein. Additionaladaptations or modifications can appear to those of ordinary skill in the art, and, in broader aspects, these adaptations or modifications are encompassed as well. Accordingly, departures may be made from the particular embodiments disclosed herein without departing from the scope of the concepts provided herein.

Claims

CLAIMSWhat is claimed is:

1. A composition for vascular stabilization, comprising: a crosslink breaker for breaking existing protein crosslinks in a luminal wall of a blood vessel; a protein denaturant for denaturing proteins in the luminal wall of the blood vessel; a crosslinking agent for establishing new protein crosslinks in the luminal wall of the blood vessel; or some combination thereof, the composition formulated into a formulation for direct administration to the luminal wall of the blood vessel by an intravascular medical device to stabilize an existing vascular state of the blood vessel or an imparted vascular state of the blood vessel.

2. The composition of claim 1, wherein the composition includes at least the crosslink breaker or the protein denaturant if the composition includes the crosslinking agent.

3. The composition of either claim 1 or 2, wherein the existing vascular state of the blood vessel is an aneurysmal state of the blood vessel, the formulation for direct administration to the luminal wall of the blood vessel about an aneurysm to stabilize the aneurysm as it exists in the aneurysmal state of the blood vessel and, thereby, reduce a risk of aneurysmal progression to a more severe condition including aneurysmal rupture.

4. The composition of claim 3, wherein the crosslinking agent establishes the new protein crosslinks in the luminal wall of the blood vessel about the aneurysm, which limits further bulging of the luminal wall of the blood vessel, thereby stabilizing the aneurysm as it exists in the aneurysmal state of the blood vessel and reducing the risk of aneurysmal progression to a more severe condition including aneurysmal rupture.

5. The composition of either claim 1 or 2, wherein the imparted vascular state of the blood vessel is a dilated state of the blood vessel, the formulation for direct administration to the luminal wall of a dilated portion of the blood vessel to stabilize the blood vessel as it exists in the dilated state of the blood vessel and, thereby, substantially maintain patency of the blood vessel upon removal of the intravascular medical device.

6. The composition of claim 5, wherein the crosslink breaker breaks the existing protein crosslinks in the luminal wall of the blood vessel about the dilated portion of the blood vessel, which limits the dilated portion of the blood vessel from returning to a pre-dilated state of the blood vessel, thereby stabilizing the blood vessel as it exists in the dilated state of the blood vessel and substantially maintaining patency of the blood vessel upon removal of the intravascular medical device.

7. The composition of claim 5, wherein the protein denaturant denatures proteins in the luminal wall of the blood vessel about the dilated portion of the blood vessel, which allows denatured proteins in the dilated portion of the blood vessel to refold and reorganize in a thermodynamically favorable configuration different than a pre-dilated state of the blood vessel, thereby stabilizing the blood vessel as it exists in the dilated state of the blood vessel and substantially maintaining patency of the blood vessel upon removal of the intravascular medical device.

8. The composition of claim 5, wherein the crosslinking agent establishes the new protein crosslinks in the luminal wall of the blood vessel about the dilated portion of the blood vessel, which limits the dilated portion of the blood vessel from returning to a pre-dilated state of the blood vessel, thereby stabilizing the blood vessel as it exists in the dilated state of the blood vessel and substantially maintaining patency of the blood vessel upon removal of the intravascular medical device.

9. The composition of any claim of claims 1-8, wherein the crosslinking agent is one or more small-molecule organic compounds or salts thereof, one or more enzymes, one or more biopolymers, or some combination of the foregoing crosslinking agents.

10. The composition of claim 9, wherein the one-or-more small-molecule organic compounds or salts thereof are selected from genipin; ferulic acid; a plurality of proanthocyanidins; a plurality of theaflavins including theaflavin; a plurality of catechin stereoisomers; epigallocatechin gallate (“EGCG”); ascorbic acid, optionally, in combination with copper; 1,2,3,4,6-pentagalloyl glucose (“PGG”); a plurality of non-azo 1,8- naphthalimides; a plurality of diazirines; l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (“EDC”); a plurality of N-hydroxysuccinimides including N-hydroxysuccinimide (“NHS”), ethylene glycol bis(succinimidyl succinate) (“EGS”), and 3-mercaptopropanyl-N- hydroxysuccinimide ester (“MPNHS”); glutathione; glutaraldehyde; diglycoaldehyde;galactose dialdehyde; a plurality of polyaldehydes via periodate-oxidized monosaccharides, disaccharides, and oligosaccharides; a plurality of polyaldehydes via periodate-oxidized polyols; and a plurality of light-activated crosslinkers including 4,5,6,7-tetrachloro-2’,4’,5’,7’- tetraiodofluorescein and riboflavin.

11. The composition of claim 9, wherein the one-or-more enzymes are selected from transglutaminase and amine oxidase.

12. The composition of claim 9, wherein the one-or-more biopolymers are selected from glucan; dextran; and a plurality of polyaldehydes via periodate-oxidized polysaccharides including glucan and dextran.

13. The composition of any claim of claims 1-12, wherein the crosslink breaker is one or more inorganic compounds or salts, one or more small-molecule organic compounds or salts thereof, one or more enzymes, or some combination of the foregoing crosslink breakers.

14. The composition of claim 13, wherein the one-or-more inorganic compounds or salts include calcium chloride.

15. The composition of claim 13, wherein the one-or-more small-molecule organic compounds or salts thereof are selected from 3-phenacyl-4,5-dimethylthiazolium chloride and urea.

16. The composition of claim 13, wherein the one-or-more enzymes are selected from a plurality of proteases.

17. The composition of any claim of claims 1-16, wherein the protein denaturant is one or more inorganic compounds or salts, one or more small-molecule organic compounds or salts thereof, one or more ionic liquids, or some combination of the foregoing protein denaturants.

18. The composition of claim 17, wherein the one-or-more inorganic compounds or salts include sodium sulfite.

19. The composition of claim 17, wherein the one-or-more small-molecule organic compounds or salts thereof are selected from a plurality of Ci-Cs alcohols including ethanol;urea; guanidinium chloride; guanidinium thiocyanate; sodium dodecyl sulfate (“SDS”); acetone; and acetonitrile.

20. A method for vascular stabilization, comprising: advancing an intravascular medical device to a diseased portion of a blood vessel; directly administering a formulation to a luminal wall of the blood vessel in the diseased portion of the blood vessel to stabilize an existing vascular state of the blood vessel or an imparted vascular state of the blood vessel, the formulation including: a crosslink breaker for breaking existing protein crosslinks in the luminal wall of the blood vessel; a protein denaturant for denaturing proteins in the luminal wall of the blood vessel; a crosslinking agent for establishing new protein crosslinks in the luminal wall of the blood vessel; or some combination thereof.

21. The method of claim 20, wherein the formulation includes at least the crosslink breaker or the protein denaturant if the formulation includes the crosslinking agent22. The method of either claim 20 or 21, wherein the existing vascular state of the blood vessel is an aneurysmal state of the blood vessel, the administering of the formulation to the luminal wall of the blood vessel about an aneurysm to stabilize the aneurysm as it exists in the aneurysmal state of the blood vessel and, thereby, reduce a risk of aneurysmal progression to a more severe condition including aneurysmal rupture.

23. The method of either claim 20 or 21, further comprising dilating the blood vessel such that the imparted vascular state of the blood vessel is a dilated state of the blood vessel, the administering of the formulation to the luminal wall of a dilated portion of the blood vessel to stabilize the blood vessel as it exists in the dilated state of the blood vessel and, thereby, substantially maintain patency of the blood vessel upon removal of the intravascular medical device.

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