Methods and devices for treating targeted vasculature

Abstract

A method of treating a hemorrhage with a treatment fluid includes delivering the treatment fluid to targeted vasculature including the hemorrhage to modulate blood flow to the targeted vasculature. The treatment fluid includes a viscosifying polymer, a hemostatic agent, a vasoconstrictor, or a combination thereof. A flow guide device including a cylindrical structure with a low porosity wall, wherein the flow guide device is configured to be deployed in a parent artery including ostia of targeted vasculature. The flow guide device can facility the delivery of a treatment fluid to targeted vasculature.

Description

METHODS AND DEVICES FOR TREATING TARGETED VASCULATURECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 554,999 filed Feb. 17, 2024, U.S. Provisional Patent Application Serial No. 63 / 557,754 filed Feb. 26, 2024, U.S. Provisional Patent Application Serial No. 63 / 557,777 filed Feb. 26, 2024, U.S. Provisional Patent Application Serial No. 63 / 557,786 filed Feb. 26, 2024, U.S. Provisional Patent Application Serial No. 63 / 673,992 filed Jul. 22, 2024, and U.S. Provisional Patent Application Serial No. 63 / 682,640 filed Aug. 13, 2024, the disclosures of which are incorporated herein in its entirety by reference.BACKGROUND

[0002] Vascular and tissue disorders, including hemorrhage, ischemia, tumors, arteriovenous malformations, and atherosclerosis, are significant health challenges. Therapeutic agents and medical devices are employed to treat these conditions, with endovascular localized delivery offering advantages in efficacy and safety. This approach enhances the concentration of therapeutic agents at the target site, as demonstrated in treatments for brain tumors, acute ischemic stroke, and arteriovenous malformations. Technological advancements in selective delivery hold promise for more precise targeting and reduced complications.

[0003] Intracerebral hemorrhage (ICH) is a particularly challenging vascular disorder, accounting for over 10% of the estimated 17 million strokes worldwide each year. ICH has a high mortality rate of 40%, and only 20% of survivors achieve functional independence at six months. Despite decades of research, no FDA-approved drug or device has been proven in randomized human trials to improve ICH outcomes. Clinical trials have explored various treatments, including blood pressure management, coagulopathy reversal, and surgical evacuation of hematomas, but these have not shown significant improvements in outcomes.

[0004] ICH commonly occurs in the basal ganglia, thalamus, cerebral lobes, brain stem, and cerebellum. The bleeding typically originates from small penetrating arteries, leading to hematoma formation. These lesions are characterized by the rupture of small artery branches, which are 50-700 micrometers in diameter, and exhibit breakage of elastic lamina, atrophy, fragmentation of smooth muscle, dissections, and cellular degeneration. Hematoma volume andgrowth are powerful predictors of death and disability, with substantial expansion occurring in approximately one-third of patients within the first few hours after ICH onset. This growth is potentially modifiable, making it an appealing therapeutic target.

[0005] The need for effective treatment of intracerebral hemorrhages is underscored by the poor outcomes associated with current interventions. The focus remains on developing strategies that can effectively limit hematoma growth and improve patient prognosis.SUMMARY OF THE INVENTION

[0006] Various aspects of the present disclosure provide a method of treating a hemorrhage with a treatment fluid. The method includes delivering the treatment fluid to targeted vasculature including the hemorrhage to modulate blood flow to the targeted vasculature. The treatment fluid includes a viscosifying polymer, a hemostatic agent, a vasoconstrictor, or a combination thereof.

[0007] Various aspects of the present disclosure provide a method of treating a cerebral hemorrhage with a treatment fluid. The method includes delivering the treatment fluid to targeted vasculature including the hemorrhage to modulate blood flow to the targeted vasculature. The treatment fluid includes a viscosifying polymer, a hemostatic agent, a vasoconstrictor, or a combination thereof. The viscosifying polymer is chosen from albumin, alginate, chitosan, collagen, hyaluronic acid / salt, gelatin, dextran, fibrinogen, hydroxyethyl starch, polysaccharides, stroma-free hemoglobin, carrageenan, agrose, gellan, gum, fucoidan, xanthan gum, cellulose, starch, chitin, pectin, xylan, glycogen, lignin, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, polyhydroxyalkanoates, polyhydroxybutyrate, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, poly(2-ethyl-2- oxazoline), a polysorbates, poly(acrylic acid), poly(N-vinylcaprolactam), and a combination thereof. The hemostatic agent is chosen from aprotinin, nafamostat, tranexamic acid, epsilon- aminocaproic acid, desmopressin acetate, estrogen, fresh frozen plasma, prothrombin complex concentrate, recombinant Factor Vila, chitosan, collagen, fibrinogen, gelatin, thrombin, desmopressin, vitamin K, and a combination thereof. The vasoconstrictor is chosen from norepinephrine, epinephrine (adrenaline), angiotensin II, vasopressin (antidiuretic hormone, ADH), phenylephrine, pseudoephedrine, dopamine, midodrine, methoxamine, pitressin,terlipressin, desmopressin, angiotensin TI, giapreza, ergotamine, methylergonovine, methergine, naphazoline, oxymetazoline, xylometazoline, Bay K 8644, and a combination thereof.

[0008] Various aspects of the present disclosure provide a method delivering of a treatment fluid endovascularly. The delivering of the fluid can be performed using a microcatheter, using a needle, using a conduit, or a combination thereof. In various aspects, a syringe fluidly connected to the microcatheter, needle, or conduit, can be used to inject the treatment fluid to the targeted vasculature, or to the parent arteries that supply blood to the targeted vasculature. The treatment fluid includes a viscosifying polymer, a hemostatic agent, a vasoconstrictor, or a combination thereof. The viscosifying polymer is chosen from albumin, alginate, chitosan, collagen, hyaluronic acid / salt, gelatin, dextran, fibrinogen, hydroxyethyl starch, polysaccharides, stroma-free hemoglobin, carrageenan, agrose, gellan, gum, fucoidan, xanthan gum, cellulose, starch, chitin, pectin, xylan, glycogen, lignin, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, polyhydroxyalkanoates, polyhydroxybutyrate, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, poly(2-ethyl-2- oxazoline), a polysorbates, poly(acrylic acid), poly(N-vinylcaprolactam), and a combination thereof. The hemostatic agent is chosen from aprotinin, nafamostat, tranexamic acid, epsilon- aminocaproic acid, desmopressin acetate, estrogen, fresh frozen plasma, prothrombin complex concentrate, recombinant Factor Vila, chitosan, collagen, fibrinogen, gelatin, thrombin, desmopressin, vitamin K, and a combination thereof. The vasoconstrictor is chosen from norepinephrine, epinephrine (adrenaline), angiotensin II, vasopressin (antidiuretic hormone, ADH), phenylephrine, pseudoephedrine, dopamine, midodrine, methoxamine, pitressin, terlipressin, desmopressin, angiotensin II, giapreza, ergotamine, methyl ergonovine, methergine, naphazoline, oxymetazoline, xylometazoline, Bay K 8644, and a combination thereof.

[0009] Various aspects of the present disclosure provide a flow guide device. The flow guide device can be used to deliver a treatment fluid endovascularly to targeted vasculature, such as targeted vasculature that supplies blood to hemorrhages, diseased tissues, or tumors. The flow guide device includes a cylindrical structure with a low porosity wall. The flow guide device is configured to be deployed in a parent artery including ostia of the targeted vasculature. The cylindrical structure includes a proximal portion and a distal portion with an expanded or inflated diameter that ensures full opposition of the proximal portion and the distal portion to a vessel wall of the parent artery. The cylindrical structure also includes a central portion with anexpanded or inflated diameter that is less than the expanded or inflated diameter of the proximal portion and the distal portion to provide a gap between the ostia of the targeted vasculature and the wall of the central portion.

[0010] Various aspects of the present disclosure provide a flow guide device. The flow guide device includes a cylindrical structure with a low porosity wall. The flow guide device is configured to be deployed in a parent artery including ostia of targeted vasculature. The cylindrical structure includes a proximal portion and a distal portion with an expanded diameter that ensures full opposition of the proximal portion and the distal portion to a vessel wall of the parent artery. The cylindrical structure also includes a central portion with an expanded diameter that is 1 mm to 7 mm and that is 0.001 mm to 2 mm less than the expanded diameter of the proximal portion and the distal portion to provide a gap between the ostia of the targeted vasculature and the wall of the central portion. The cylindrical structure includes a selfexpanding stent including metallic wire woven brains or a laser-cut metallic tube. The flow guide has a length of 10 mm to 70 mm and the proximal and distal portions of the flow guide have a length of at least 3 millimeters.

[0011] Various aspects of the present disclosure provide a flow guide device. The flow guide device includes a cylindrical structure with a low porosity wall. The flow guide device is configured to be deployed in a parent artery including ostia of targeted vasculature. The cylindrical structure includes a proximal portion and a distal portion with an inflated diameter that ensures full opposition of the proximal portion and the distal portion to a vessel wall of the parent artery. The cylindrical structure also includes a central portion with an inflated diameter that is 1 mm to 7 mm and that is 0.001 mm to 2 mm less than the inflated diameter of the proximal portion and the distal portion to provide a gap between the ostia of the targeted vasculature and the wall of the central portion. The cylindrical structure includes an inflatable balloon including a double layer and an open lumen that extends through the balloon through the proximal, central, and distal portions of the cylindrical structure. The flow guide has a length of 10 mm to 70 mm and the proximal and distal portions of the flow guide have a length of at least 3 millimeters.

[0012] Various aspects of the present disclosure provide a medical device system for targeted endovascular delivery of a fluid. The medical device system includes a flow guide device. The flow guide device includes a cylindrical structure with a low porosity wall. Theflow guide device is configured to be deployed in a parent artery including ostia of targeted vasculature. The cylindrical structure includes a proximal portion and a distal portion with an expanded or inflated diameter that ensures full opposition of the proximal portion and the distal portion to a vessel wall of the parent artery. The cylindrical structure also includes a central portion with an expanded or inflated diameter that is less than the expanded or inflated diameter of the proximal portion and the distal portion to provide a gap between the ostia of the targeted vasculature and the wall of the central portion. The medical device system includes a microcatheter for delivering the flow guide device to a parent artery including ostia of intended- to-treat branch arteries. The medical device system also includes a delivery wire connected to the proximal end of the flow guide device for deployment and retraction thereof, or tubing attached to a balloon of the flow guide device for delivery, inflation, deflation, and retraction of the balloon. Optionally, the system can include a second microcatheter for delivering a fluid to the space between the flow guide device wall and the ostia of intended-to-treat branch arteries, or the flow guide device can include a conduit for delivering the fluid to the space between the flow guide device wall and the ostia of intended-to-treat branch arteries, or the system can include a needle or a conduit for delivering the fluid to the space between the flow guide device wall and the ostia of intended-to-treat branch arteries, or a combination thereof.

[0013] Various aspects of the present disclosure provide a method of using a flow guide device. The flow guide device can be part of a medical device system for targeted endovascular delivery of a fluid. The flow guide device includes a cylindrical structure with a low porosity wall. The flow guide device is configured to be deployed in a parent artery including ostia of targeted vasculature. The cylindrical structure includes a proximal portion and a distal portion with an expanded or inflated diameter that ensures full opposition of the proximal portion and the distal portion to a vessel wall of the parent artery. The cylindrical structure also includes a central portion with an expanded or inflated diameter that is less than the expanded or inflated diameter of the proximal portion and the distal portion to provide a gap between the ostia of the targeted vasculature and the wall of the central portion. The method includes delivering the flow guide device to the parent artery including ostia of targeted vasculature. The method includes modulating blood flow to the ostia of the targeted vasculature with the flow guide device and / or endovascularly delivering a fluid to the gap between the ostia of the targeted vasculature and thewall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature. The method also includes retracting the flow guide device from the parent artery.

[0014] Various aspects of the present disclosure provide a method of treating a hemorrhage with a flow guide device. The flow guide device includes a cylindrical structure with a low porosity wall. The flow guide device is configured to be deployed endovascularly in a parent artery including ostia of targeted vasculature. The cylindrical structure includes a proximal portion and a distal portion with an expanded or inflated diameter that ensures full opposition of the proximal portion and the distal portion to a vessel wall of the parent artery. The cylindrical structure also includes a central portion with an expanded or inflated diameter that is less than the expanded or inflated diameter of the proximal portion and the distal portion to provide a gap between the ostia of the targeted vasculature and the wall of the central portion. The method includes delivering the flow guide device in the parent artery including ostia of targeted vasculature including the hemorrhage. The method includes modulating blood flow to the ostia of the targeted vasculature with the flow guide device and / or delivering a fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature. The method also includes retracting the flow guide device from the parent artery.

[0015] Various aspects of the present disclosure provide a method of treating an intracerebral hemorrhage with a flow guide device. The flow guide device includes a cylindrical structure with a low porosity wall. The flow guide device is configured to be deployed endovascularly in a parent artery including ostia of targeted vasculature. The cylindrical structure includes a proximal portion and a distal portion with an expanded or inflated diameter that ensures full opposition of the proximal portion and the distal portion to a vessel wall of the parent artery. The cylindrical structure also includes a central portion with an expanded or inflated diameter that is less than the expanded or inflated diameter of the proximal portion and the distal portion to provide a gap between the ostia of the targeted vasculature and the wall of the central portion. The method includes delivering the flow guide device in the parent artery including ostia of targeted vasculature including the intracerebral hemorrhage. The method includes modulating blood flow to the ostia of the targeted vasculature with the flow guide device and delivering a fluid endovascularly to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to thetargeted vasculature. The fluid includes a viscosifying polymer chosen from albumin, alginate, chitosan, collagen, hyaluronic acid / salt, gelatin, dextran, fibrinogen, hydroxyethyl starch, polysaccharides, stroma-free hemoglobin, carrageenan, agrose, gellan, gum, fucoidan, xanthan gum, cellulose, starch, chitin, pectin, xylan, glycogen, lignin, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, polyhydroxyalkanoates, polyhydroxybutyrate, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, poly(2-ethyl-2- oxazoline), a polysorbates, poly(acrylic acid), poly(N-vinylcaprolactam), and a combination thereof; a hemostatic agent chosen from aprotinin, nafamostat, tranexamic acid, epsilon- aminocaproic acid, desmopressin acetate, estrogen, fresh frozen plasma, prothrombin complex concentrate, recombinant Factor Vila, chitosan, collagen, fibrinogen, gelatin, thrombin, desmopressin, vitamin K, and a combination thereof; a vasoconstrictor chosen from norepinephrine, epinephrine (adrenaline), angiotensin II, vasopressin (antidiuretic hormone, ADH), phenylephrine, pseudoephedrine, dopamine, midodrine, methoxamine, pitressin, terlipressin, desmopressin, angiotensin II, giapreza, ergotamine, methyl ergonovine, methergine, naphazoline, oxymetazoline, xylometazoline, Bay K 8644, and a combination thereof; or a combination thereof. The method also includes retracting the flow guide device from the parent artery.

[0016] Various aspects of the flow guide device, medical system, and method of the present disclosure provide advantages of increased efficacy and / or precision in treatment compared to other medical devices and methods of using the same. For example, various aspects of the endovascular treatment of the present disclosure can allow for more localized delivery of therapeutic agents directly to the targeted vasculature, tissues, or tumors, enhancing treatment efficacy. Various aspects of the endovascular treatment of the present disclosure can provide modulation of blood flow to the hemorrhagic site, thereby suppressing bleeding and promoting hemostasis and effectively managing hemorrhages. Various aspects of the flow guide device or method of the present disclosure can provide increased concentrations of therapeutic agents at the target site, improving outcomes for conditions like brain tumors and arteriovenous malformations. Various aspects of the flow guide device of the present disclosure can provide modulation of blood flow to the hemorrhagic site, thereby suppressing bleeding and promoting hemostasis and effectively managing hemorrhages. Various aspects of the flow guide device of the present disclosure can allow for more precise delivery of therapeutic agents directly to thetargeted vasculature, tissues, or tumors, enhancing treatment efficacy. By providing endovascular localized delivery, various aspects of the flow guide device or method of the present disclosure can provide increased concentrations of therapeutic agents at the target site, improving outcomes for conditions like brain tumors and arteriovenous malformations.

[0017] Various aspects of the flow guide device, medical system, and method of the present disclosure provide advantages of increased safety and / or reduced complications compared to other medical devices and methods of using the same. For example, various aspects of the flow guide device of the present disclosure can isolate the delivered fluid from the blood flow of the parent artery, reducing the risk of complications from unintended delivery to nontargeted areas. Various aspects of the flow guide device or method of the present disclosure can ensure that blood flow to downstream arteries is maintained, thereby preventing ischemic injury during treatment.

[0018] Various aspects of the flow guide device, medical system, and method of the present disclosure provide advantages of increased versatility and / or adaptability compared to other medical devices and methods of using the same. For example, various aspects of the flow guide device or method of the present disclosure can be used to deliver a wide variety of therapeutic agents, including high viscosity fluids, hemostatic agents, vasoconstrictors, and thrombolytics, thereby allowing for tailored treatment strategies. Various aspects of the flow guide device of the present disclosure can be adjusted in terms of surface coverage and porosity to control the flow rate and optimize treatment for specific anatomical characteristics.

[0019] Various aspects of the flow guide device, medical system, and method of the present disclosure provide advantages of more temporary intervention and / or more easily reversible intervention compared to other medical devices and methods of using the same. For example, various aspects of the method of the present disclosure or the method of using the flow guide device of the present disclosure can include the use of viscous fluids and other agents to allow for temporary modulation of blood flow, which can be reversed once the desired therapeutic effect is achieved. Various aspects of the method of the present disclosure or the method of using the flow guide device of the present disclosure can include the use of treatment agents like high viscosity fluids and hemostatic agents which are designed to be gradually metabolized and cleared, allowing for restoration of normal blood flow post-treatment.

[0020] Various aspects of the flow guide device, medical system, and method of the present disclosure provide advantages of enhanced therapeutic outcomes compared to other medical devices and methods of using the same. For example, in aspects of the method of the present disclosure of the method of using the flow guide device of the present disclosure including delivery of multiple therapeutic agents, the combination of different therapeutic agents can provide synergistic effects, enhancing the overall efficacy of the treatment. In various aspects of the method of the present disclosure or the method of using the flow guide device of the present disclosure, the delivered therapeutic agents are formulated for sustained release, providing prolonged therapeutic activity at the site of the hemorrhage.

[0021] Various aspects of the flow guide device, medical system, and method of the present disclosure provide advantages of a localized intervention to ensure effective treatment for bleeding disorders such as hemorrhages, which can provide more effective results than wholebody treatment via medication. Various aspects of the flow guide device, medical system, and method of the present disclosure provide advantages of a temporary and non-occlusive or only temporarily-occlusive intervention of hemorrhages that is more effective and safer than existing agents for hemorrhage treatment such as embolic agents. In comparison, current endovascular agents for hemorrhage treatment such as embolic agents all result in occlusion or non-temporary occlusion which is prone to serious ischemic complications.BRIEF DESCRIPTION OF THE FIGURES

[0022] The drawings illustrate generally, by way of example, but not by way of limitation, various aspects of the present invention.

[0023] FIG. 1 is an illustration of an intracerebral hemorrhage at the basal ganglia, in accordance with various aspects of the present disclosure.

[0024] FIG. 2 is an illustration of a flow guide device deployed to ostia bleeding vasculature, in accordance with various aspects of the present disclosure.

[0025] FIG. 3 is an illustration delivery of a treatment fluid to the space between a device wall and the ostia to treat vasculature via a delivery conduit, in accordance with various aspects of the present disclosure.

[0026] FIG. 4 is an illustration of post-intervention with the hemorrhage disorder treated and with all devices removed from the vasculature, in accordance with various aspects of the present disclosure.

[0027] FIG. 5 is an illustration of a flow guide device, in accordance with various aspects of the present disclosure.

[0028] FIG. 6 is an illustration of flow guide device, in accordance with various aspects of the present disclosure.

[0029] FIG. 7 is an illustration of a flow guide device, in accordance with various aspects of the present disclosure.

[0030] FIG. 8 is an illustration of a coronal view of the human cerebral artery system and common anatomical sites of intracerebral hemorrhage, in accordance with various aspects of the present disclosure.

[0031] FIG. 9 is an illustration of an intracerebral hemorrhage at the basal ganglia, in accordance with various aspects of the present disclosure.

[0032] FIG. 10 is an illustration of method of treating an intracerebral hemorrhage including delivering a viscous fluid to the vasculature, in accordance with various aspects of the present disclosure.

[0033] FIG. 11 is an illustration of an injected viscous fluid being gradually cleared with blood circulation, in accordance with various aspects of the present disclosure.

[0034] FIG. 12 is an illustration of a reverse agent administrated arterially with the viscosifying polymers of an injected viscous fluid being broken down by a reverse agent to facilitate clearance of the injected viscous fluid with blood circulation, in accordance with various aspects of the present disclosure.

[0035] FIG. 13 is an illustration of an intracerebral hemorrhage at the basal ganglia, in accordance with various aspects of the present disclosure.

[0036] FIG. 14 is an illustration navigating a catheter to a parent artery of hemorrhaging tissue via an endovascular approaches with assistance of a guidewire, in accordance with various aspects of the present disclosure.

[0037] FIG. 15 is an illustration of a method of treating intracerebral hemorrhage including delivering a flow modulation stent to a targeted artery via a catheter with expansion ofthe stent after unsheathing from the catheter, in accordance with various aspects of the present disclosure.

[0038] FIG. 16 is an illustration a flow modulation device, in accordance with various aspects of the present disclosure.

[0039] FIG. 17 is an illustration of flow modulation device, in accordance with various aspects of the present disclosure.

[0040] FIG. 18 is an illustration of a method of treating an intracerebral hemorrhage including delivering a hemostatic agent into the vasculature via a device, in accordance with various aspects of the present disclosure.

[0041] FIG. 19 is an illustration of an injected hemostatic agent 8 being gradually metabolized and eliminated from the vasculature, in accordance with various aspects of the present disclosure.

[0042] FIG. 20 is an illustration of a thrombolytic agent administrated arterially with intravascular clots being broken down to facilitate restoration of blood flow, in accordance with various aspects of the present disclosure.

[0043] FIG. 21 is an illustration of a method for treating intracerebral hemorrhage including a device for delivery of vasoconstrictor agents into the vasculature, in accordance with various aspects of the present disclosure.

[0044] FIG. 22 is an illustration of injected vasoconstrictor agents 8 being gradually metabolized and eliminated from the vasculature, in accordance with various aspects of the present disclosure.

[0045] FIG. 23 is an illustration of vasodilator agents 9 administrated arterially and to counteract the effect of vasoconstrictor agents 10 to facilitate restoration of blood flow, in accordance with various aspects of the present disclosure.

[0046] FIG. 24 illustrates a representative picture of a flow modulation device, in accordance with various aspects of the present disclosure.

[0047] FIG. 25A illustrates a flow modulation device, microcatheter, and flow guide device, in accordance with various aspects of the present disclosure.

[0048] FIG. 25B illustrates treatment of an intracerebral hemorrhage with a flow modulation device, microcatheter, and flow guide device, in accordance with various aspects of the present disclosure.

[0049] FIG. 26A illustrates a bench flow model, in accordance with various aspects of the present disclosure.

[0050] FIG. 26B illustrates blood flow rate versus time during bench flow model testing of a flow modulation device using the bench flow model of FIG. 26A, in accordance with various aspects of the present disclosure.

[0051] FIG. 27 illustrates a bench flow model with a flow guide device, with the inset showing a close-up of the flow guide device, in accordance with various aspects of the present disclosure.

[0052] FIG. 28 A illustrates anatomy of canine cerebral arteries, in accordance with various aspects of the present disclosure.

[0053] FIG. 28B illustrates treatment of water-based viscous fluid to a basilar artery in a canine in-vivo model via a microcatheter using a flow modulation device, in accordance with various aspects of the present disclosure.

[0054] FIG. 28C illustrates pre-treatment baseline blood flow in a canine in-vivo model visualized by contrast injection, in accordance with various aspects of the present disclosure.

[0055] FIG. 28D illustrates reduced blood flow during treatment in a canine in-vivo model visualized by contrast injection, in accordance with various aspects of the present disclosure.

[0056] FIG. 28E illustrates restored blood flow after treatment in a canine in-vivo model visualized by contrast injection, in accordance with various aspects of the present disclosure.

[0057] FIG. 28F illustrates diffusion weighted MRIs of a canine in-vivo model posttreatment, in accordance with various aspects of the present disclosure.

[0058] FIG. 28G illustrates baseline diffusion weighted MRIs of a canine in-vivo model, in accordance with various aspects of the present disclosure.

[0059] FIG. 29A illustrates the creation of intracerebral hemorrhage in a rat brain used for treatment evaluation, in accordance with various aspects of the present disclosure.

[0060] FIG. 29B illustrates blood flow rate versus volume injected during endovascular treatment of a rat model compared to a bench flow model, in accordance with various aspects of the present disclosure.

[0061] FIGS. 30A-B illustrate slices of treated and untreated rat brains, in accordance with various aspects of the present disclosure.

[0062] FIG. 31 illustrates treatment of a cerebral hemorrhage using a microcatheter to deliver treatment fluid to the parent artery including ostia of targeted vasculature that includes the cerebral hemorrhage, in accordance with various aspects of the present disclosure.

[0063] FIG. 32 illustrates the treated cerebral hemorrhage after removal of the treatment fluid administered in FIG. 31, in accordance with various aspects of the present disclosureDETAILED DESCRIPTION OF THE INVENTION

[0064] Reference will now be made in detail to certain aspects of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[0065] Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

[0066] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” or “at least one of A or B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section.

[0067] In the methods described herein, the acts can be carried out in a specific order as recited herein. Alternatively, in any aspect(s) disclosed herein, specific acts may be carried outin any order without departing from the principles of the invention, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately or the plain meaning of the claims would require it. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0068] The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range.

[0069] The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially free of’ as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that about 0 wt% to about 5 wt% of the composition is the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.

[0070] As used herein, the term “polymer” refers to a molecule having at least one repeating unit and can include copolymers.Method of treating a hemorrhage.

[0071] Various aspects of the present disclosure provide a method of treating a hemorrhage with a treatment fluid. The method can include delivering the treatment fluid to targeted vasculature including the hemorrhage to modulate blood flow to the targeted vasculature, wherein the treatment fluid includes a viscosifying polymer, a hemostatic agent, a vasoconstrictor, or a combination thereof. The treatment fluid described herein is an aqueous treatment fluid having the components thereof dissolved in water or saline. The method can optionally include repeating the delivering of the treatment fluid.

[0072] The method can include performing the delivering of the treatment fluid endovascularly. The delivering the fluid can be performed using a microcatheter, using a needle, using a conduit, or a combination thereof. The delivering the fluid can be performed using theflow guide device described herein to locally administer to the fluid to the ostia of the targeted vasculature within the parent artery, of the delivering of the fluid can be performed without the flow guide device such as without any flow guide device by injecting the fluid directly into the parent artery or injecting the fluid directly into the targeted vasculature. In various aspects, a syringe fluidly connected to the microcatheter, needle, or conduit, can be used to inject the treatment fluid to the parent artery or to the targeted vasculature.

[0073] The hemorrhage can be a hemorrhage in any part of the body. The hemorrhage can be a cerebral hemorrhage. The hemorrhage can be located within the brain, chest cavity (e.g., hemothorax), abdominal cavity, peritoneal cavity, retroperitoneum, gastrointestinal tract, thorax, spleen, liver, pelvis, uterus, a muscle, a joint, or can be a hemorrhage from long bone fractures. The hemorrhage can be an intracerebral hemorrhage, epidural hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, thoracic hemorrhage, gastrointestinal (GI) hemorrhage, abdominal hemorrhage, retroperitoneal hemorrhage, musculoskeletal hemorrhage, subconjunctival hemorrhage, postpartum hemorrhage, or ectopic pregnancy rupture.

[0074] The treatment fluid can be injected endovascularly. The treatment fluid can be injected into a parent artery that supplies blood to the targeted vasculature. The treatment fluid can be injected into a parent artery comprising ostia of the targeted vasculature. The treatment fluid can be injected into the targeted vasculature. The treatment fluid can be injected into a proximal section of the parent artery that supplies blood to the targeted vasculature. The treatment fluid can be injected into the parent artery within 0 mm to 1 m of ostia of the targeted vasculature, or 0 to 200 mm, or 0 mm to 50 mm, or less than or equal to 1 m and greater than or equal to 0 mm and less than, equal to, or greater than 1 mm, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, or 950 mm.

[0075] The hemorrhage can be an intracerebral hemorrhage. The treatment fluid can be injected endovascularly within the brain. The treatment fluid can be injected into a parent artery in the brain that supplies blood to the targeted vasculature. The treatment fluid can be injected into a parent artery in the brain comprising ostia of the targeted vasculature. The treatment fluid can be injected into the targeted vasculature in the brain. The treatment fluid can be injected into a proximal section of the parent artery in the brain that supplies blood to the targeted vasculature.The treatment fluid can be injected into the parent artery within 200 mm of the ostia of the targeted vasculature, or within 50 mm of the ostia of the targeted vasculature, or 0 mm to 200 mm, or 0 mm to 50 mm, or less than or equal to 200 mm and greater than or equal to 0 mm and less than, equal to, or greater than 1 mm, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 195 mm.

[0076] The delivery of the treatment fluid can suppress bleeding of the hemorrhage, slow or prevent growth of the hemorrhage, or a combination thereof. The modulating of blood flow to the ostia of the targeted vasculature can suppress bleeding by reducing the pressure and flow rate at a site of the hemorrhage. The modulating of blood flow to the targeted vasculature can slow or prevent the growth of the hemorrhage by limiting the influx of blood to a site of the hemorrhage. The modulating of blood flow to the targeted vasculature can facilitate the natural hemostatic process by creating conditions that promote clot formation at a site of the hemorrhage. The modulating of blood flow to the targeted vasculature reduces the risk of rebleeding by stabilizing the hemodynamic environment around a site of the hemorrhage. The modulating of blood flow to the targeted vasculature can enhance the efficacy of concurrently administered therapeutic agents by maintaining them at a site of the hemorrhage for a longer duration. The modulating of blood flow to the targeted vasculature can reduce or minimize ischemic injury to surrounding tissues by ensuring adequate perfusion while controlling the hemorrhage. The modulating of blood flow to the targeted vasculature can aid in the resolution of the hemorrhage by facilitating the clearance of blood products from a site of the hemorrhage.

[0077] The method can include dynamically adjusting the modulating of blood flow to the targeted vasculature in response to real-time imaging feedback to optimize treatment outcomes for the hemorrhage. The modulating of blood flow to the targeted vasculature can be tailored to the specific location and severity of the hemorrhage to maximize therapeutic effectiveness. The modulating of blood flow to the targeted vasculature can be part of a comprehensive treatment strategy that includes monitoring and adjusting other physiological parameters to support hemorrhage resolution.

[0078] The modulation of the blood flow to the targeted vasculature can have a duration of 30 minutes to 6 hours, or less than or equal to 6 hours and greater than or equal to 30 minutes and less than, equal to, or greater than 40 minutes, 50 minutes, 1 hour, 1.5, 2, 2.5, 3, 3.5, 4, 4.5,5, or 5.5 hours. The modulation of the blood flow to the ostia of the targeted vasculature can include reducing the blood flow to the targeted vasculature by any suitable amount. For example, the modulation of the blood flow to the ostia can result in a blood flow rate to the targeted vasculature that is 0% to 99% of original (pre-treatment) blood flow rates to the targeted vasculature, or 0% to 90%, or 20% to 70%, or less than or equal to 99% and greater than or equal to 0% and less than, equal to, or greater than 1%, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 82, 84, 86, 88, 90, 91, 92, 93, 94, 95, 96, 97, or 98%. The modulation of the blood flow to the ostia can result in a blood pressure in the targeted vasculature that is 0% to 99% of original (pre-treatment) blood pressure in the targeted vasculature, or 0% to 90%, or less than or equal to 99% and greater than or equal to 0% and less than, equal to, or greater than 1%, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 82, 84, 86, 88, 90, 91, 92, 93, 94, 95, 96, 97, or 98%.

[0079] Any suitable volume of the treatment fluid can be delivered to the targeted vasculature, such as 0.5 mL to 5,000 mL, or 0.5 mL to 20 mL, or less than or equal to 5,000 mL and greater than or equal to 0.5 mL and less than, equal to, or greater than 1 mL, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,500, 2,000, 2,500, 3,000, 3,500, 4,000, or 4,500 mL.

[0080] In addition to the viscosifying polymer, hemostatic agent, vasoconstrictor, or combination thereof, the treatment fluid can further include an embolization agent, a thrombolysis agent, a chemotherapy agent, a reverse agent for the polymer, hemostatic agent, or vasoconstrictor, or a combination thereof.

[0081] The fluid can include a viscosifying polymer. The viscosifying polymer can be any suitable viscosifying polymer. The viscosifying polymer can be chosen from albumin, alginate, chitosan, collagen, hyaluronic acid / salt, gelatin, dextran, fibrinogen, hydroxyethyl starch, polysaccharides, stroma-free hemoglobin, carrageenan, agrose, gellan, gum, fucoidan, xanthan gum, cellulose, starch, chitin, pectin, xylan, glycogen, lignin, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, polyhydroxyalkanoates, polyhydroxybutyrate, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, poly(2-ethyl-2- oxazoline), a polysorbates, poly(acrylic acid), poly(N-vinylcaprolactam), and a combination thereof. The viscosifying polymer can include alginate, hyaluronic acid / salt, dextran,hydroxyethyl starch, polysaccharides, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, or a combination thereof. The one or more viscosifiers can form any suitable proportion of the fluid. For example, the viscosifier (e.g., the viscosifying polymer) can be 1 mg / mL to 300 mg / mL of the fluid, or 5 mg / mL to 100 mg / mL, or less than or equal to 300 mg / mL and greater than or equal to 1 mg / mL and less than, equal to, or greater than 2 mg / mL, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, or 290 mg / mL of the fluid. The viscosifying polymer can have a molecular weight in a range of 10,000 to 2,000,000 Dalton or g / mol, such as less than or equal to 2,000,000 Dalton and greater than or equal to 10,000 Dalton and less than, equal to, or greater than 20,000 Dalton, 30,000, 40,000, 50,000, 75,000, 100,000, 150,000, 200,000, 300,000, 400,000, 500,000, 600,000, 700,000, 800,000, 900,000, 1,000,000, 1,100,000, 1,200,000, 1,300,000, 1,400,000, 1,500,000, 1,600,000, 1,700,000, 1,800,000, or 1,900,000 Dalton. In various aspects, the fluid further includes a cross-linking agent that forms hydrogels at the site of treatment. Suitable hydrogels can have a storage modulus of 0.1 Pa to 300 Pa. Examples of suitable hydrogels are, not limited to, albumin with aldehydes, alginate with calcium ion, hyaluronic acid / salt with divinyl sulfone, collagen with aldehydes, gelatin with aldehydes, chitosan with aldehydes, chitosan with genipin, or combinations thereof. The fluid including the viscosifying polymer can have a viscosity of 10 centipoise to 500,000 centipoise, or 10 centipoise to 150,000 centipoise, or 1,000 centipoise to 150,000 centipoise, or less than or equal to 150,000 centipoise and greater than or equal to 10 centipoise and less than, equal to, or greater than 12 centipoise, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,250, 1,500, 1,750, 2,000, 2,500, 3,000, 4,000, 5,000, 7,500, 10,000, 15,000, 20,000, 25,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000, 100,000, 110,000, 120,000, 130,000, 140,000, 150,000, 200,000, 250,000, 300,000, 350,000, 400,000, or 450,000 centipoise.

[0082] For treatment fluids including a viscosifying polymer, the treatment fluid can be formulated to increase the resistance to blood flow at the site of the hemorrhage, thereby reducing bleeding and promoting hemostasis. The treatment fluid can be designed to penetrate the downstream arterioles and capillaries, increasing local blood viscosity and reducing flow to the hemorrhagic site. The treatment fluid can be delivered in a volume sufficient to achieve a targeted reduction in blood flow rate to a site of the hemorrhage site, thereby suppressingbleeding. The viscosifying polymer can be combined with a cross-linking agent to form a hydrogel that provides sustained modulation of blood flow and supports clot formation at a site of the hemorrhage. The viscosifying polymer can be tailored to the specific characteristics of the hemorrhage, such as size and location, to optimize therapeutic outcomes. The treatment fluid can be delivered in a controlled manner to ensure even distribution and effective treatment of the hemorrhage. The treatment fluid including the viscosifying polymer can be designed to be gradually cleared from a site of the hemorrhage, allowing for restoration of normal blood flow once the hemorrhage is resolved. The treatment fluid including the viscosifying polymer can enhance the retention of therapeutic agents at a site of the hemorrhage, thereby improving the efficacy of the treatment. The method can further include administering a reverse agent to the targeted vasculature. The reverse agent can de-viscosify the treatment fluid including the viscosifying agent. The reverse agent can be part of the fluid that includes the highly viscous fluid, or the reverse agent can be administered after the administration of the highly viscous fluid. The reverse agent can include alginate lyse, chitinase, chitosanase, lysozyme, collagenase, hyaluronidase, P-D-glucuronidase, P-N-acetyl-hexosaminidase, gelatinase, dextranase, glycoside hydrolases, streptokinase, alteplase, Reteplase, tenecteplase, urokinase, prourokinase, anistreplase, or a combination thereof.

[0083] The treatment fluid can include a hemostatic agent. The hemostatic agent can be any suitable one or more hemostatic agents. The fluid can include a hemostatic agent chosen from aprotinin, nafamostat, tranexamic acid, epsilon-aminocaproic acid, desmopressin acetate, estrogen, fresh frozen plasma, prothrombin complex concentrate, recombinant Factor Vila, chitosan, collagen, fibrinogen, gelatin, thrombin, desmopressin, vitamin K, and a combination thereof. The fluid can include a hemostatic agent that is tranexamic acid, epsilon-aminocaproic acid, prothrombin complex concentrate, recombinant Factor Vila, or a combination thereof. The one or more hemostatic agents can form any suitable proportion of the fluid. For example, the hemostatic agent can be 0.001 wt% to 100 wt% of the non-aqueous components of the fluid, or 0.001 wt% to 50 wt%, or less than or equal to 100 wt% and greater than or equal to 0.001 wt% and less than, equal to, or greater than 0.005, 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 wt%. The hemostatic can be present in the fluid in sufficient concentration such that 10 mg to 5,000 mg or 10 IU (international units) to 5,000 IU are delivered during the treatment, or 50 mg to 2,000 mgor 50 IU to 2,000 IU, or less than or equal to 5,000 mg or IU and greater than or equal to 10 mg or IU, and less than, equal to, or greater than 20 mg or IU, 40, 60, 80, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1,000, 1,200, 1,400, 1,600, 1,800, 2,000, 2,200, 2,400, 2,600, 2,800, 3,000, 3,200, 3,400, 3,600, 3,800, 4,000, 4,200, 4,400, 4,600, or 4,800 mg or IU.

[0084] The hemostatic agent can be formulated to promote platelet aggregation and fibrin clot formation at a site of the hemorrhage, thereby reducing bleeding. The hemostatic agent can be delivered in a concentration sufficient to achieve rapid hemostasis and stabilize a site of the hemorrhage. The hemostatic agent can be designed to enhance the natural coagulation cascade, facilitating the formation of a stable clot at a site of the hemorrhage. The hemostatic agent can be delivered in a controlled manner to ensure even distribution and effective treatment of the hemorrhage. The hemostatic agent can be tailored to the specific characteristics of the hemorrhage, such as size and location, to optimize therapeutic outcomes. The hemostatic agent can be designed to be gradually metabolized and cleared from the site, allowing for restoration of normal blood flow once the hemorrhage is resolved. The hemostatic agent can enhance the retention of therapeutic agents at the hemorrhagic site, thereby improving the efficacy of the treatment. The hemostatic agent can be combined with other therapeutic agents to provide a synergistic effect in treating the hemorrhage. The hemostatic agent can be delivered in a form that allows for sustained release, providing prolonged hemostatic activity at a site of the hemorrhage. The method can further include administration of a thrombolytic agent to the targeted vasculature. The thrombolytic agent can reverse the effects of the hemostatic agent. The thrombolytic agent can be administered in the fluid that includes the hemostatic agent, or the thrombolytic agent can be administered after the administration of the fluid that includes the hemostatic agent. The thrombolytic agent can include any suitable thrombolytic agent, such as streptokinase, alteplase, reteplase, tenecteplase, urokinase, prourokinase, and anistreplase, chitinase, chitosanase, collagenase, gelatinase, or a combination thereof.

[0085] The fluid can include a vasoconstrictor. The vasoconstrictor can be any suitable vasoconstrictor. For example, the vasoconstrictor can be chosen from norepinephrine, epinephrine (adrenaline), angiotensin II, vasopressin (antidiuretic hormone, ADH), phenylephrine, pseudoephedrine, dopamine, midodrine, methoxamine, pitressin, terlipressin, desmopressin, angiotensin II, giapreza, ergotamine, methylergonovine, methergine, naphazoline, oxymetazoline, xylometazoline, Bay K 8644, and a combination thereof. The fluid can include avasoconstrictor that is norepinephrine, epinephrine (adrenaline), angiotensin II, vasopressin (antidiuretic hormone, ADH), phenylephrine, pseudoephedrine, dopamine, midodrine, or a combination thereof. The one or more vasoconstrictor agents can form any suitable proportion of the fluid. For example, the vasoconstrictor can be 0.001 wt% to 100 wt% of non-aqueous components of the fluid, or 0.001 wt% to 50 wt%, or less than or equal to 100 wt% and greater than or equal to 0.001 wt% and less than, equal to, or greater than 0.005 wt%, 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 wt%. The vasoconstrictor can be present in the fluid in sufficient concentration such that during administration of the fluid about 1 microgram to 200 micrograms or 1 IU to 200 IU of the vasoconstrictor are administered per 1 minute, or 2 micrograms to 100 micrograms or 2 IU to 100 IU per 1 minute, or less than or equal to 200 micrograms or IU and greater than or equal to 1 microgram or IU or less than, equal to, or greater than 2 micrograms or IU, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, or 190 micrograms or IU per 1 minute.

[0086] The vasoconstrictor can be formulated to induce contraction of the vessel walls at the site of the hemorrhage, thereby reducing blood flow and minimizing bleeding. The vasoconstrictor can be delivered in a concentration sufficient to achieve rapid vasoconstriction and stabilize the hemorrhagic site. The vasoconstrictor can be designed to enhance the natural hemostatic process by reducing vessel diameter and promoting clot formation at the site of the hemorrhage. The vasoconstrictor can be delivered in a controlled manner to ensure even distribution and effective treatment of the hemorrhage. The vasoconstrictor can be tailored to the specific characteristics of the hemorrhage, such as size and location, to optimize therapeutic outcomes. The vasoconstrictor can be designed to be gradually metabolized and cleared from the site, allowing for restoration of normal blood flow once the hemorrhage is resolved. The vasoconstrictor can enhance the retention of therapeutic agents at the hemorrhagic site, thereby improving the efficacy of the treatment. The vasoconstrictor can be combined with other therapeutic agents to provide a synergistic effect in treating the hemorrhage. The vasoconstrictor can be delivered in a form that allows for sustained release, providing prolonged vasoconstrictive activity at the site of the hemorrhage. The method can further include administering a vasodilator agent to the targeted vasculature. The vasodilator agent can reverse the effects of the vasoconstrictor. The vasodilator agent can be administered in the fluid that includes thevasoconstrictor, or after administration of the fluid that includes the vasoconstrictor. The vasodilator agent can be any suitable vasodilator agent. The vasodilator agent can include nitroglycerin, sodium nitroprusside, hydralazine, calcium channel blockers, phentolamine, prazosin, doxazosin, labetalol, or a combination thereof.

[0087] The treatment fluid can include a thrombolytic or fibrinolytic agent. The thrombolytic or fibrinolytic agent can be any suitable thrombolytic or fibrinolytic agent. The thrombolytic or fibrinolytic agent can include streptokinase, alteplase, reteplase, tenecteplase, urokinase, prourokinase, anistreplase, or a combination thereof. The thrombolytic or fibrinolytic agent can be any suitable proportion of the fluid. For example, the thrombolytic or fibrinolytic agent can be 0.001 wt% to 100 wt% of non-aqueous components of the fluid, or 0.001 wt% to 50 wt% of non-aqueous components of the fluid, or less than or equal to 100 wt% and greater than or equal to 0.001 wt% and less than, equal to, or greater than 0.005 wt%, 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 wt%. The thrombolytic or fibrinolytic agent can be present in the fluid in sufficient quantity such that during administration of the fluid about 5 mg to 100 mg of the thrombolytic or fibrinolytic agent is delivered per hour, or 10 mg to 50 mg, or less than or equal to 100 mg and greater than or equal to 5 mg and less than, equal to, or greater than 10 mg, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 mg of the thrombolytic or fibrinolytic agent is delivered per hour.Flow guide device.

[0088] Various aspects of the present invention provide a flow guide device. The flow guide device can include a cylindrical structure having a low porosity wall. The flow guide device can be configured to be deployed in a parent artery including ostia of targeted vasculature. The cylindrical structure can include a proximal portion and a distal portion with an expanded or inflated diameter that ensures full opposition of the proximal portion and the distal portion to a vessel wall of the parent artery. The cylindrical structure can also include a central portion with an expanded or inflated diameter that is less than the expanded or inflated diameter of the proximal portion and the distal portion to provide a gap between the ostia of the targeted vasculature and the wall of the central portion. The gap can be any suitable size, such as 0.001 mm to 2 mm when the device is deployed in the parent artery, or 0.5 mm to 1 mm, or less than orequal to 2 mm and greater than or equal to 0.001 mm and less than, equal to, or greater than 0.005 mm, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9 mm. The flow guide device can include an opening (e.g., a lumen) through the device that is parallel to a longitudinal direction of the device, allowing the device to maintain blood flow through the parent artery while the flow guide device is deployed in the parent artery. The flow guide device can be configured to be delivered and retracted using endovascular approaches. The flow guide device can be configured to be visible using imaging techniques, such as under fluoroscopy, during deployment and retraction.

[0089] The flow guide device can be used to direct fluid (e.g., a treatment fluid) to the targeted vasculature by directing fluid to the ostia of the targeted vasculature in the parent artery. The flow guide can be used to modulate blood flow to the targeted vasculature by modulating blood flow to the ostia of the targeted vasculature in the parent artery. The flow guide device can be used for a combination of directing fluid to the targeted vasculature and modulating blood flow to the targeted vasculature. The flow guide device can maintain blood flow to downstream arteries while directing the fluid to the targeted vasculature and / or while modulating blood flow to the targeted vasculature. The flow guide device can isolate the delivered fluid from the blood flow of the parent artery and direct it to the targeted vasculature. The fluid can be an aqueous fluid. The fluid can include any suitable therapeutic agent. For example, the fluid can include a high viscosity fluid (e.g., an aqueous fluid including a viscosifying polymer such as a biopolymer or other water-soluble polymer), hemostatic agents, vasoconstrictor agents, embolization agents, thrombolysis agents, chemotherapy agents, or a combination thereof. The flow guide device can be used for targeted endovascular delivery of a fluid, such as for treatment of a hemorrhage. For example, the flow guide device can be used for targeted endovascular delivery of a fluid to treat an intracerebral hemorrhage. The flow guide device can be used for targeted endovascular delivery of a fluid to treat an intracerebral hemorrhage, epidural hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, thoracic hemorrhage, gastrointestinal (GI) hemorrhage, abdominal hemorrhage, retroperitoneal hemorrhage, musculoskeletal hemorrhage, subconjunctival hemorrhage, postpartum hemorrhage, or ectopic pregnancy rupture.

[0090] The flow guide can be used to deliver a treatment fluid with one or more active treatment ingredients to the targeted vasculature with precision that increases efficacy and / orreduces complications. The targeted vasculature can be a vasculature that is intended to be treated with the treatment fluid. The targeted vasculature can be a vasculature that is ruptured and bleeding, or a vasculature that supplies blood to a diseased tissue region, or a vasculature that supplies blood to a tumor. The targeted vasculature can be a vasculature that includes a tumor.

[0091] The flow guide can include an expanding stent, such as a self-expending stent, that includes metallic wire woven braids of a laser-cut metallic tube. The flow guide can expand to an expanded diameter upon removal from a delivery catheter (e.g., a microcatheter). The metallic wire can be chosen from any suitable metallic wire, such as nickel -titanium alloy, platinum alloy, cobalt-chromium-nickel alloy, or a combination thereof. In various aspects the stent is free of a cover layer to modify porosity of the stent. In other aspects, the stent includes a cover layer to reduce porosity of the wall of the stent, wherein the cover layer is positioned outside or inside a frame of the stent. The cover layer can be made of any suitable material. For example, the stent can include braided metal mesh, polymeric fabric, elastic membrane, porous membrane, or a combination thereof.

[0092] In aspects of the flow guide device with or without a cover layer, the flow guide device can have a surface coverage (e.g., a percentage of the outer surface free of pores) that is about 20% to 100%, or 20% to 70%, or 20% to 50%, or less than or equal to 100% and greater than or equal to 20% and less than, equal to, or greater than 25%, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 82, 84, 86, 88, 90, 92, 94, 95, 96, 97, 98, or 99%. In aspects of the flow guide device with or without a cover layer, the flow guide device can have a porosity of 0% to 80%, or 30% to 80%, or 50% to 80%, or less than or equal to 80% and greater than or equal to 0% and less than, equal to, or greater than 1%, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75%. In aspects of the flow guide device with or without a cover layer, the flow guide device can have a pore density of 0 pores / mm2to 45 pores / mm2, or 10 pores / mm2to 45 pores / mm2, or less than or equal to 45 pores / mm2and greater than or equal to 0 pores / mm2and less than, equal to, or greater than 2 pores / mm2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, or 44 pores / mm2.

[0093] The flow guide device can include a proximal end structure with stent struts or braiding wires that come together to one point. The proximal end structure can be held together by a process including crimping, laser welding, soldering, adhesive bonding, or a combinationthereof. The point can be configured to connect with a delivery wire for deployment and retraction of the flow guide device.

[0094] The flow guide device includes an inflatable balloon including an open lumen. The open lumen can be in the center of the inflatable balloon and can be parallel to a longitudinal direction of the balloon. The inflatable balloon can include a double layer and with an open lumen that extends through the balloon through the proximal, central, and distal portions of the cylindrical structure running parallel to a longitudinal direction of the balloon. The balloon can be configured to be inflated and / or deflated after deployment of the flow guide device to the desired location in the parent artery. The inflatable balloon can include tubing attached to the balloon for delivery, inflation, and deflation of the balloon.

[0095] The proximal and distal portions can have any suitable length. For example, the proximal and distal portions can have a length of 3 mm to 7 mm, or a length of at least 3 millimeters, or a length of less than 7 mm and greater than 3 mm and less than, equal to, or greater than 3.5 mm, 4, 4.5, 5, 5.5, 6, or 6.5 mm.

[0096] The proximal and distal portions can have any suitable expanded or inflated diameter such that the proximal and distal portions completely contact the inside of the parent vessel. The expanded or inflated diameter of the proximal portion and distal portion can be 1 mm to 7 mm, or less than or equal to 7 mm and greater than or equal to 1 mm and less than, equal to, or greater than 1.5 mm, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, or 6.5 mm.

[0097] The central portion can have any suitable length, such as a length of 2 mm to 30 mm, or 5 mm to 15 mm, or less than or equal to 30 mm and greater than or equal to 2 mm and less than, equal to, or greater than 3 mm, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 mm. The central portion can have any suitable diameter such that a gap is formed between the central portion and the inner wall of the parent artery, such as a diameter of 1 mm to 7 mm, or less than or equal to 7 mm and greater than or equal to 1 mm and less than, equal to, or greater than 1.5 mm, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, or 6.5 mm. The central portion has an expanded or inflated diameter that is less than the expanded or inflated diameter of the proximal portion and the distal portion, such as an expanded or inflated diameter that is 0.001 mm to 2 mm less than the expanded or inflated diameter of the proximal portion and the distal portion, or 0.5 mm to 1 mm less, or less than or equal to 2 mm and greater than or equal to 0.001 mm and less than, equal to, or greater than 0.005 mm, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5,0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9 mm less than the expanded or inflated diameter of the proximal portion and the distal portion.

[0098] The flow guide device can have any suitable diameter prior to expansion in the parent artery. For example, the flow guide device can have an unexpanded or uninflated diameter of less than or equal to 1 mm, or 0.01 mm to 1 mm, or less than or equal to 1 mm and greater than or equal to 0.01 mm and less than, equal to, or greater than 0.05 mm, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, or 0.95 mm.

[0099] The flow guide device can have any suitable length. For example, the flow guide device can have a length of 5 mm to 70 mm, or 10 mm to 25 mm, or less than or equal to 70 mm and greater than or equal to 5 mm and less than, equal to, or greater than 6 mm, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 55, 60, or 65 mm.Medical device system.

[0100] Various aspects of the present disclosure provide a medical device system for targeted endovascular delivery of a fluid. The medical device system can include the flow guide device of the present disclosure. The medical device system can include a microcatheter for delivering the flow guide device to a parent artery of a bleeding disorder (e.g., hemorrhage) to be treated. The medical device system can also include a delivery wire connected to the proximal end of the flow guide device for deployment and retraction of the flow guide device. The flow guide device can include a proximal end structure with stent struts or braiding wires that come together to one point and connect with the delivery wire. Optionally, the system can include a second microcatheter for delivering a fluid to the space between the flow guide device wall and the ostia of intended-to-treat branch arteries, or the flow guide device can include a conduit for delivering the fluid to the space between the flow guide device wall and the ostia of intended-to- treat branch arteries, or the system can include a needle or a conduit for delivering the fluid to the space between the flow guide device wall and the ostia of intended-to-treat branch arteries, or a combination thereof.

[0101] Various aspects of the present disclosure provide a medical device system for targeted endovascular delivery of a fluid. The medical device system can include the flow guide device of the present disclosure including an inflatable balloon. The medical device system can include a microcatheter for delivering the flow guide device to a parent artery of a bleedingdisorder (e.g., hemorrhage) to be treated. The medical device system can also include tubing attached to the balloon for delivery, inflation, deflation, and retraction of the balloon.Optionally, the system can include a second microcatheter for delivering a fluid to the space between the flow guide device wall and the ostia of intended-to-treat branch arteries, or the flow guide device can include a conduit for delivering the fluid to the space between the flow guide device wall and the ostia of intended-to-treat branch arteries, or the system can include a needle or a conduit for delivering the fluid to the space between the flow guide device wall and the ostia of intended-to-treat branch arteries, or a combination thereof.

[0102] Various aspects of the present disclosure provide a medical device system for modulation of blood flow without delivery of a fluid. The medical device system includes the fluid guide device of the present disclosure. The medical device system also includes a delivery wire connected to the proximal end of the flow guide device for deployment and retraction of the flow guide device. The flow guide device can include a proximal end structure with stent struts or braiding wires that come together to one point and connect with the delivery wire.Method of using the flow guide device.

[0103] Various aspects of the present disclosure provide a method of using the flow guide device of the present disclosure. The method can include delivering the flow guide device to the parent artery including ostia of targeted vasculature. The flow guide device can be delivered to the parent artery in any suitable way, such as by using a delivery catheter, such as a microcatheter for delivery of the flow guide device. In various aspects, the flow guide device can expand when removed from the delivery catheter. The method can include modulating blood flow to the ostia of the targeted vasculature with the flow guide device and / or delivering a fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature. The method can also include retracting the flow guide device from the parent artery. The method can include modulating blood flow to the ostia of the targeted vasculature with the flow guide device. The method can include delivering the fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature. The method can include modulating blood flow to the ostia of the targeted vasculature with the flow guide device and delivering the fluid to the gap between the ostia ofthe targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature. The method can be a method of treating hemorrhage, ischemia, tumors, arteriovenous malformation, atherosclerosis, or a combination thereof.

[0104] Various aspects of the method of using the flow guide device can be used for treatment of a vasculature or tissue disorder such as hemorrhage, ischemia, tumors, arteriovenous malformation, atherosclerosis, or to treat bleeding disorders within the brain, chest cavity (e.g., hemothorax), abdominal cavity, peritoneal cavity, retroperitoneum, gastrointestinal tract, thorax, spleen, liver, pelvis, uterus, a muscle, a joint, or can be a hemorrhage from long bone fractures. The method can achieve a targeted intra-arterial delivery of a fluid including one or more treatment agents, such as intra-arterial embolization, intra-arterial thrombolysis, and intra-arterial chemotherapy. During use of the flow guide device, the space around the ostia of targeted vasculature in the parent artery is isolated from flow in the parent artery by a flow barrier provided by the flow guide device. The fluid can be delivered via a second microcatheter to the space between the device wall and the ostia of the targeted vasculature in the parent artery, the fluid can be delivered to the space via a needle or conduit, the fluid can be delivered to the space via a conduit in the flow guide device, or a combination thereof. The flow guide can be used to deliver the treatment fluid with one or more active treatment ingredients to the targeted vasculature with precision that increases efficacy and / or reduces complications. The targeted vasculature can be a vasculature that is intended to be treated with the treatment fluid. The targeted vasculature can be a vasculature that is ruptured and bleeding, or a vasculature that supplies blood to a diseased tissue region, or a vasculature that supplies blood to a tumor. The targeted vasculature can be a vasculature that includes a tumor.

[0105] FIG. 1 is an illustration of an intracerebral hemorrhage that occurred at the basal ganglia, in which 1 is the parent artery which supplies blood to the hemorrhagic tissue; 2 is the bleeding arterial vasculature, i.e., the targeted sites of treatment; and 3 is the hematoma of the hemorrhage. Various aspects of the method of the present disclosure can be used to treat other vascular and tissue disorders, where 2 and 3 can be, not limited to, ischemia tissue, tumors, arteriovenous malformation, and atherosclerosis.

[0106] FIG. 2 illustrates an example of medical device system of the present disclosure and a method of use of the same. The method can include delivering and deploying a flow guide device via a catheter 4 into the parent artery with a goal of treating the hemorrhagic tissue with afluid. The flow guide device can be deployed in the parent artery to the location of ostia of the bleeding penetrating arteries (e.g., ostia of the targeted vasculature). The flow guide device can achieve isolation of the space around ostia of the bleeding vasculature by a flow barrier provided by the flow guide device. The isolation is ensured by a cylindrical structure with a high surface coverage (low porosity) wall, a distal portion, 6, and a proximal portion, 7, which fully oppose to the vessel wall. The opposition to the vessel wall can provide an anchor to prevent migration of the flow guide device during treatment, and can provide a seal to the vessel wall to prevent leakage of blood flow from the parent artery to the ostia of the targeted vasculature and to prevent leakage of the treatment fluid from the gap into the parent artery. The central portion of the invented flow guide device, 5, can have a slightly smaller diameter to create a space (e.g., a gap) between device wall and the parent artery where ostia of the bleeding vasculature origin. The flow guide device can have a proximal end design, 8, which connected with a delivery wire. The delivery wire and proximal stent structure can ensure the delivery and retraction of the flow guide device.

[0107] An example of fluid guidance by the invented flow guide device system is illustrated in FIG. 3. A fluid, 9, of high viscosity, and / or hemostatic agents or embolization agents, can be delivered via a second microcatheter, 10, to the space between device wall and the ostia of the target vasculature. The delivered fluid can be isolated from the blood flow of the parent artery and directed to the targeted vasculature by the flow guide device. The flow guide device can be used to treat other vascular and tissue disorders, such as ischemia tissue, tumors, arteriovenous malformation, or atherosclerosis, wherein the delivered fluid, 9, can include a thrombolysis agent, a chemotherapy agent, an embolization agent / device.

[0108] FIG. 4 is an illustration of post-intervention with the flow guide device, illustrating that the hemorrhage disorder is treated and all devices are removed from the vasculature. When the desired treatment is achieved by the delivered agents in the fluid, the deployed flow guide device (and the one or more catheters) can be retracted and removed and the blood flow can be restored to its normal conditions.

[0109] The flow guide device can include a structure at its proximal end to ensure the device can be retracted or resheathed to a microcatheter after deployment. The proximal structure may include stent struts or braiding wires that come together to one point wherein the point further connects with a delivery wire. The struts and wires a proximal end can be heldtogether with the delivery wire by a crimping process using a mark band, a laser welding process, a soldering process, or an adhesive. The struts and wires at the proximal end can be designed and arranged to minimize flow disruption. The struts and wires at proximal end of the stent can have a surface coverage less than 30% to ensure blood flow to portions of the parent artery downstream of the treatment location therethrough.

[0110] FIG. 5 is an illustration of an example of the medical device system. The illustrated device system, 11, includes a wire woven stent with low porosity wall, 12, a proximal portion, a distal portion, 13, a proximal end structure, 14, and a joint, 15, with a delivery wire, 16. The stent has a proximal portion and a distal portion with a diameter to ensure a full opposition to the vessel wall. The stent has a proximal end design where the struts or wires come together and bind with a delivery wire. The delivery wire and proximal stent structure allow the delivery and retraction of the stent with a catheter.[0U1] The flow guide device can include a self-expanding stent made of a braided mesh cylinder constructed of interwoven stands of alloy wire. This design can result in a selfexpandable and a high surface coverage structure. Suitable alloy wires can include nickeltitanium alloy, platinum alloy, cobalt-chromium-nickel alloy, or a combination thereof. Suitable alloy wires can include drawn filled tubing (DFT) wires, with a core of gold, platinum, silver, tantalum, or nitinol, and a sheath of nickel -titanium alloy, nitinol, platinum alloy or cobalt- chromium-nickel alloy. The number of woven strands of the braids can be in the range of 36 to 144. The size (e g., diameter) of alloy wires can be in the range of 15 micrometer to 50 micrometer. The invented flow guide stents can include a cover layer outside or inside the metal wire braids to increase surface coverage. The additional layer may cover a portion or full length of the stent frame.

[0112] In various aspects, the higher the surface coverage of the stent wall is, the more separation of delivered fluid from the flow in parent artery occurs. Surface coverage can be defined as the closed covered area divided by the total stent wall area. Surface coverage is related to the porosity which is defined as the proportion of the open material-free area to the total stent wall area. Pore-density of the stent wall is another parameter affected its flow modulation. Pore density is the number of pores per area (pores / mm2), which can be an independent parameter to the porosity defined above. The flow guidance effect of the flow guide device is also a function of the gap size between the stent wall and ostia of the targetedvasculature branches. The targeted flow guidance effect can be achieved by the combination of surface coverage (or porosity), pore density, and the distance between stent wall and ostia of penetrating arteries. The suitable combination of surface coverage, pore density, and stent profile can be determined by bench flow model experiments and in-vivo animal model testing.

[0113] FIG. 6 illustrates flow guide device including a stent frame and a cover layer with low porosity. The illustrated device system, 17, includes a stent frame, 20, a cover layer with low porosity, 18, a proximal portion and distal portion, 19, a stent proximal end structure, and a joint with a delivery wire. The stent has a proximal portion and a distal portion with a diameter to ensure a full opposition to the vessel wall. The stent has a proximal end design where the struts or wires come together and bind with a delivery wire. The delivery wire and proximal stent structure allow the delivery and retraction of the stent with a catheter. The invented flow guide stent frame can be laser cut from an alloy tube. Suitable tube alloys can include nitinol, nickel -titanium alloy, cobalt-chromium-nickel alloy, or platinum alloy. The strut size of the stent can have a size of 40 micrometer to 200 micrometer.

[0114] The flow guide device can include an additional cover layer with porosity of 30% to 80% to increase surface coverage of the flow guide device. The high surface coverage layer may cover a portion or full length of the stent frame. The high surface coverage layer can be placed outside or inside a metallic stent, or a sandwiched design between two stent frames. The high surface coverage (or low porosity) layer of the stent can be made of a braided metal mesh, or a polymeric fabric, or an elastic membrane, or a porous membrane, or combination thereof. The braided metal mesh used as a cover layer can be similar to the wire braided stent. The polymeric fabric materials can include one or combination of polyester, polyethylene terephthalate (PET), polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), ultra-high molecular weight polyethylene (UHMWPE), or resorbable polymers. The elastic membrane material can include one or combination of polyurethane, pebax, nylon elastomers, or other thermoplastic elastomers. The porous membrane material can include one or combination of expanded polytetrafluoroethylene (ePTFE) or polyethylene terephthalate.

[0115] In various aspects the flow guide device is or includes an inflatable balloon. FIG. 7 is an illustration of an example of the flow guide device. The illustrated device system can include a double layer balloon, 21, with a middle portion, 22, a proximal portion and distal portion, 23, an end structure, 24, joint with a delivery and inflation shaft, and an open lumen, 25.The balloon has a proximal portion and a distal portion with larger diameter to ensure a full opposition to the vessel wall. The balloon has a double layer and an open design at both proximal and distal ends to provide an open lumen. The open lumen ensures blood flow to downstream arteries.

[0116] The flow guide device including a balloon can have a cylindrical structure with a lumen therethrough. The wall of the cylindrical balloon can be inflated or deflated after deployed to desired location. The lumen of the cylindrical balloon is open when the balloon is inflated, maintaining blood flow to the downstream arteries and preventing ischemia injury. When deployed at ostia of the bleeding arteries, the balloon can ensure an isolation of the space around ostia of the bleeding vasculature. A treatment fluid can be delivered via a microcatheter to the space between balloon wall and the ostia of intended to treat branch arteries, or a needle or conduit can be used to deliver the treatment fluid to the space, or a conduit in the flow guide device can be used to deliver the treatment fluid to the space, or a combination thereof. The delivered fluid can be isolated from the blood flow of the parent artery and directed to the targeted vasculature by the flow guide device.

[0117] Various aspects of the present disclosure provide a method of using the flow guide device of the present disclosure for treating a hemorrhage. The method can include delivering the flow guide device in the parent artery including ostia of targeted vasculature including the hemorrhage. The method can include modulating blood flow to the ostia of the targeted vasculature with the flow guide device and / or delivering a fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature. The method can also include retracting the flow guide device from the parent artery. The method can include modulating blood flow to the ostia of the targeted vasculature with the flow guide device. The method can include delivering a fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature. The method can include modulating blood flow to the ostia of the targeted vasculature with the flow guide device and delivering a fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature.

[0118] The hemorrhage can be any suitable hemorrhage that can be treated by the flow guide device. For example, the hemorrhage can be an intracerebral hemorrhage. Thehemorrhage can be an intracerebral hemorrhage, epidural hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, thoracic hemorrhage, gastrointestinal (GI) hemorrhage, abdominal hemorrhage, retroperitoneal hemorrhage, musculoskeletal hemorrhage, subconjunctival hemorrhage, postpartum hemorrhage, or ectopic pregnancy rupture. The method can include performing the delivering of the flow guide device and retracting the flow guide device using endovascular approaches. The method can include selecting a suitable size and configuration of the flow guide device based on anatomical characteristics of the parent artery and / or the targeted vasculature. The method can include performing the delivering of the flow guide device and retracting the flow guide device using a delivery wire connected to a proximal end of the flow guide device. The method can include observing the flow guide device using an imaging technique during the delivery and / or retraction of the flow guide device, such as using fluoroscopy to image the flow guide device. In various aspects, the delivering, the modulating blood flow and / or delivery of the fluid, and the retracting are performing once and not more than once. In various aspects, the delivering, the modulating blood flow and / or delivery of the fluid, and the retracting are performed more than once (e.g., two, three, or four or more times).

[0119] The open structure of the flow guide device, including an opening through the device that is parallel to a longitudinal direction of the device, can allow the flow guide device to maintain blood flow through the parent artery while the device is deployed in the parent artery and while the device is used for modulation of blood flow to the targeted vasculature and / or delivery of the fluid to the targeted vasculature. The method can include maintaining blood flow to downstream arteries of the parent artery while modulating blood flow to the targeted vasculature and / or delivering the fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device.

[0120] The method can include modulating blood flow to the ostia of the targeted vasculature with the flow guide device. The modulation of the blood flow can be a result of the physical structure of the flow guide device alone, a result of the delivery of the fluid to the ostia of the targeted vasculature alone, or a combination of the physical structure of the flow guide device and the delivery of the fluid to the ostia of the targeted vasculature. The modulation of the blood flow to the targeted vasculature can have a duration of 30 minutes to 6 hours, or less than or equal to 6 hours and greater than or equal to 30 minutes and less than, equal to, or greater than 40 minutes, 50 minutes, 1 hour, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, or 5.5 hours. The modulation ofthe blood flow to the ostia of the targeted vasculature can include reducing the blood flow to the targeted vasculature by any suitable amount. For example, the modulation of the blood flow to the ostia can result in a blood flow rate to the targeted vasculature that is 0% to 99% of original (pre-treatment) blood flow rates to the targeted vasculature, or 0% to 90%, or 20% to 70%, or less than or equal to 99% and greater than or equal to 0% and less than, equal to, or greater than 1%, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 82, 84, 86, 88, 90, 91, 92, 93, 94, 95, 96, 97, or 98%. In aspects of the method including delivery of a fluid to the gap between the ostia of the targeted vasculature and the central portion of the flow guide device, blood flow rates greater than 0% of the original blood flow can allow blood flow to transport at least a portion of the delivered fluid to the targeted vasculature. The modulation of the blood flow to the ostia can result in a blood pressure in the targeted vasculature that is 0% to 99% of original (pre-treatment) blood pressure in the targeted vasculature, or 0% to 90%, or less than or equal to 99% and greater than or equal to 0% and less than, equal to, or greater than 1%, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 82, 84, 86, 88, 90, 91, 92, 93, 94, 95, 96, 97, or 98%.

[0121] The modulating of blood flow to the ostia of the targeted vasculature can suppress bleeding, slows or prevents growth of the hemorrhage, or a combination thereof. The modulating of blood flow to the ostia of the targeted vasculature can suppress bleeding by reducing the pressure and flow rate at a site of the hemorrhage. The modulating of blood flow to the ostia of the targeted vasculature can slow or prevent the growth of the hematoma by limiting the influx of blood to a site of the hemorrhage. The modulating of blood flow to the ostia of the targeted vasculature can facilitates the natural hemostatic process by creating conditions that promote clot formation at a site of the hemorrhage. The modulating of blood flow to the ostia of the targeted vasculature can reduce the risk of rebleeding by stabilizing the hemodynamic environment around a site of the hemorrhage. The modulating of blood flow to the ostia of the targeted vasculature can enhance the efficacy of concurrently administered therapeutic agents by maintaining them at a site of the hemorrhage for a longer duration than would be possible without the modulation of blood flow. The modulating of blood flow to the ostia of the targeted vasculature can reduce or minimize ischemic injury to surrounding tissues by ensuring adequate perfusion while controlling the hemorrhage. The modulating of blood flow to the ostia of the targeted vasculature can aid in the resolution of the hemorrhage by facilitating the clearance ofblood products from a site of the hemorrhage. The method can include dynamically adjusting the modulating of blood flow to the ostia of the targeted vasculature in response to real-time imaging feedback to optimize treatment outcomes for the hemorrhage. The modulating of blood flow to the ostia of the targeted vasculature can be tailored to the specific location and severity of the hemorrhage to increase or maximize therapeutic effectiveness. The modulating of blood flow to the ostia of the targeted vasculature can be part of a broader or comprehensive treatment strategy that includes monitoring and adjusting other physiological parameters to support hemorrhage resolution.

[0122] The method can include delivering the fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature. The delivering of the fluid to the gap can include delivering the fluid to the gap using a microcatheter, using a needle, using a conduit, using a conduit in the flow guide device, or a combination thereof. The fluid can be an aqueous fluid. The fluid can include any suitable therapeutic agent. For example, the fluid can include a high viscosity fluid (e.g., an aqueous fluid including a viscosifying polymer, such as a biopolymer or other water-soluble polymer), hemostatic agents, vasoconstrictor agents, embolization agents, thrombolysis agents, chemotherapy agents, or a combination thereof. The volume of fluid injected can be in the range of 0.5 mL to 5,000 mL, or 0.5 mL to 20 mb, or less than or equal to 5,000 mL and greater than or equal to 0.5 mL and less than, equal to, or greater than 1 mL, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,500, 2,000, 2,500, 3,000, 3,500, 4,000, or 4,500 mL. The fluid delivered to the gap can be transported to the targeted vasculature via blood flow (e.g., blood flow from the parent artery through the flow guide device and to the gap), via injection pressure of the fluid, or a combination thereof.

[0123] The fluid can include a thrombolytic or fibrinolytic agent. The thrombolytic or fibrinolytic agent can be any suitable thrombolytic or fibrinolytic agent. The thrombolytic or fibrinolytic agent can include streptokinase, alteplase, reteplase, tenecteplase, urokinase, prourokinase, anistreplase, or a combination thereof. The thrombolytic or fibrinolytic agent can be any suitable proportion of the fluid. For example, the thrombolytic or fibrinolytic agent can be 0.001 wt% to 100 wt% of non-aqueous components of the fluid, or 0.001 wt% to 50 wt% of non-aqueous components of the fluid, or less than or equal to 100 wt% and greater than or equalto 0.001 wt% and less than, equal to, or greater than 0.005 wt%, 0.01, 0.05, 0.1, 0.5, 1 , 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 wt%. The thrombolytic or fibrinolytic agent can be present in the fluid in sufficient quantity such that during administration of the fluid about 5 mg to 100 mg of the thrombolytic or fibrinolytic agent is delivered per hour, or 10 mg to 50 mg, or less than or equal to 100 mg and greater than or equal to 5 mg and less than, equal to, or greater than 10 mg, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 mg of the thrombolytic or fibrinolytic agent is delivered per hour.

[0124] Various aspects of the flow guide device can be used for treatment of intracerebral hemorrhages (also known as intraparenchymal hemorrhages). Most bleeding in intracerebral hemorrhage occurs at small penetrating arteries. The blood flow modulation caused by the flow guide device can reduce blood flow to the bleeding small arteries to suppress bleeding and hematoma growth. The invented flow guide device and method of using the same can achieve a balance of reducing blood flow to the hemorrhage while preventing ischemia, which is critical for treatment of brain vascular disorders. When adequate resolution of the intended to treat hemorrhage is achieved, the deployed flow guide device can be retracted and removed and the blood flow is restored to its normal conditions. The flow guide device can be delivered and retracted by using a microcatheter with endovascular approaches.

[0125] As a result of deployment of the flow guide device, there is a low porosity barrier between the incoming blood flow of the parent artery and ostia of penetrating arteries (e.g., of targeted vasculature). The presence of such low porosity barrier substantially reduces blood flow from the parent artery to the affected penetrating arteries. The flow reduction leads to suppression, if not stopping, the bleeding from the hemorrhagic arterioles and capillaries. The flow reduction can facilitate the progression of hemostasis and it can ultimately seal the bleeding vessels. While the blood flow to the hemorrhagic tissue is reduced, the porosity of the flow guide device can ensures a level of blood supply to the affected penetrating arteries to prevent ischemia during the treatment. The lumen of the deployed device can be open to maintain blood flow to the downstream arteries. When adequate resolution of the hemorrhage is achieved, the deployed flow guide device can be retracted and removed and the blood flow can be restored to its normal conditions. It is critical to prevent ischemia in brain tissue when treating intracerebral hemorrhage. For example, a permeant occlusion or chronic hypoperfusion may stop or suppressthe bleeding in hemorrhagic tissue; such interventions, however, can cause brain tissue ischemia, (i.e., ischemic stroke) in the affected and downstream tissue. The flow guide device and method of using the same can achieve a balance of reducing blood flow while preventing ischemia.

[0126] FIG. 8 illustrates a coronal mid-plane view of the human cerebral artery system and common anatomical sites of intracerebral hemorrhage. Intracerebral hemorrhages most commonly involve cerebral lobes, originating from penetrating cortical branches of the anterior, middle, or posterior cerebral arteries (A); basal ganglia, originating from ascending lenticulostriate branches of the middle cerebral artery (B); the thalamus, originating from ascending thalmogeniculate branches of the posterior cerebral artery (C); the pons, originating from paramedian branches of the basilar artery (D); and the cerebellum, originating from penetrating branches of the posterior inferior, anterior inferior, or superior cerebellar arteries (E).

[0127] FIG. 13 is an illustration of an intracerebral hemorrhage that occurred at the basal ganglia, in which 1 is middle cerebral artery; 2 is the branches and perorating arterial vasculature; 3 is the sites of bleeding in the vasculature; and 4 is the resulting hematoma of the hemorrhage.

[0128] FIG. 14 is an illustration of an example of a catheter, 6, navigating to the parent artery of the hemorrhaging tissue via endovascular approaches, with assistant of a guidewire, 5. The catheter can be used to deliver the treatment fluid described herein endovascularly, either alone or with the assistance of a device such as the flow guide device.

[0129] FIG. 15 is an illustration of an example of a flow guide device being used to treat intracerebral hemorrhage, in which the flow guide device is delivered to the targeted artery via a catheter and the flow guide device has expanded and opened after unsheathing from the catheter. The flow guide device wall, 7, has a low porosity (high surface coverage) to provide a flow barrier to branches and penetrating arterial vasculature. The flow guide device has a proximal portion, 8, and a distal portion that opposes fully to the vessel wall to prevent migration. The flow guide device has a proximal end design, 9, where the struts or wires come together and bind with a delivery wire, 10. The delivery wire and proximal end structure ensure the delivery and retraction of the flow guide device with the catheter. The low porosity stent wall reduces blood flow to penetrating arterial vasculature and suppresses the hemorrhage.

[0130] In various aspects, a catheter is navigated to the responsible parent artery of the hemorrhagic disorder, such as the middle cerebral artery. When the microcatheter tip isnavigated to desired location, the flow guide device can be delivered and self-expanded in the targeted location after unsheathing from the catheter. The flow guide device has a high surface coverage, i.e., a low porosity. As a result, there is a low porosity wall of the flow guide device between the incoming blood flow and ostia of penetrating arteries. The presence of such low porosity barrier can substantially reduce blood flow from the parent artery to the affected penetrating arteries. The targeted value of the blood flow rate to the penetrating arteries after the flow guide device deployment can be 20% to 70% that of the original or normal physiological blood flow. The duration of the flow restriction in the targeted vasculature by the flow guide device can be in a range of 30 mins to 6 hours. The treatment can be repeated in the acute stage of the hemorrhage until adequate resolution of the hemorrhage is achieved. The flow reduction can lead to suppression, if not stopping, of the bleeding from the hemorrhagic arterioles and capillaries. The flow reduction can facilitate the progression of hemostasis and it can ultimately seal the bleeding vessels. While the blood flow to the hemorrhagic tissue is reduced, the porous wall of the flow guide device can ensure a level of blood supply to the affected penetrating arteries to prevent ischemia of the target vasculature during the treatment. In the meantime, the lumen of the expanded flow guide device is open to maintain blood flow to the downstream arteries. When adequate resolution of the hemorrhage is achieved, the deployed flow guide device can be retracted and removed and the blood flow can be restored to its normal conditions. The flow guide device and methods of using the same can achieve a balance of reducing blood flow while preventing ischemia.

[0131] FIG. 4 is an illustration of post-intervention illustrating that the bleeding has stopped and hematoma growth has been suppressed and all devices have been removed from the vasculature.

[0132] FIG. 16 is an illustration of an example of a medical device system including the flow guide device. The system, 11, includes a flow guide device with a low porosity wall, 12, a flow guide device proximal portion, 13, a flow guide device proximal end structure, and a joint, 15, with a delivery wire, 16. FIG. 16 illustrates a flow guide device that is self-expanding and includes a braided mesh cylinder constructed of interwoven stands of alloy wire. This design results in a self-expandable and a high surface coverage structure.

[0133] FIG. 17 is an illustration of an example of a medical device system including the flow guide device. The system, 17, includes a flow guide device frame, 19, a cover layer withlow porosity, 18, a flow guide device proximal portion, a flow guide device proximal end structure, and a joint with a delivery wire. FIG. 17 illustrates one of the aspects includes a stent and a cover layer of low porosity.Method of using the flow guide device with a high viscosity fluid.

[0134] The method of using the flow guide device can include delivering a fluid that is a high viscosity fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature. The fluid can have any suitable viscosity. For example, the fluid at the time of delivery to the gap can have a viscosity of 10 centipoise to 500,000 centipoise, or 10 centipoise to 150,000 centipoise, or 1,000 centipoise to 150,000 centipoise, or less than or equal to 150,000 centipoise and greater than or equal to 10 centipoise and less than, equal to, or greater than 12 centipoise, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,250, 1,500, 1,750, 2,000, 2,500, 3,000, 4,000, 5,000, 7,500, 10,000, 15,000, 20,000, 25,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000, 100,000, 110,000, 120,000, 130,000, 140,000, 150,000, 200,000, 250,000, 300,000, 350,000, 400,000, or 450,000 centipoise. The viscosity of the fluid can be achieved via the addition of one of more viscosifiers to the fluid. The one of more viscosifiers can be any suitable viscosifiers. For example, the fluid can include a viscosifying polymer such as a biopolymer or other water- soluble polymer. The viscosifying polymer can include a hydrogel or a hydrogel starting material that can be crosslinked to form a hydrogel. The viscosifying polymer can be chosen from albumin, alginate, chitosan, collagen, hyaluronic acid / salt, gelatin, dextran, fibrinogen, hydroxyethyl starch, polysaccharides, stroma-free hemoglobin, carrageenan, agrose, gellan, gum, fucoidan, xanthan gum, cellulose, starch, chitin, pectin, xylan, glycogen, lignin, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, polyhydroxyalkanoates, polyhydroxybutyrate, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, poly(2-ethyl-2-oxazoline), a polysorbates, poly(acrylic acid), poly(N- vinylcaprolactam), and a combination thereof. The viscosifying polymer can include alginate, hyaluronic acid / salt, dextran, hydroxy ethyl starch, polysaccharides, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, or a combination thereof. The one or more viscosifiers can form any suitable proportion of the fluid. For example, the viscosifier(e g., the viscosifying polymer) can be 1 mg / mL to 300 mg / mL of the fluid, or 5 mg / mL to 100 mg / mL, or less than or equal to 300 mg / mL and greater than or equal to 1 mg / mL and less than, equal to, or greater than 2 mg / mL, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, or 290 mg / mL of the fluid. The viscosifying polymer can have a molecular weight in a range of 10,000 to 2,000,000 Dalton or g / mol, such as less than or equal to 2,000,000 Dalton and greater than or equal to 10,000 Dalton and less than, equal to, or greater than 20,000 Dalton, 30,000, 40,000, 50,000, 75,000, 100,000, 150,000, 200,000, 300,000, 400,000, 500,000, 600,000, 700,000, 800,000, 900,000, 1,000,000, 1,100,000, 1,200,000, 1,300,000, 1,400,000, 1,500,000, 1,600,000, 1,700,000, 1,800,000, or 1,900,000 Dalton. In various aspects, the fluid further includes a cross-linking agent that forms hydrogels at the site of treatment. Suitable hydrogels can have a storage modulus of 0.1 Pa to 300 Pa. Examples of suitable hydrogels are, not limited to, albumin with aldehydes, alginate with calcium ion, hyaluronic acid / salt with divinyl sulfone, collagen with aldehydes, gelatin with aldehydes, chitosan with aldehydes, chitosan with genipin, or combinations thereof.

[0135] The high viscosity fluid can increase the resistance to blood flow at the site of the hemorrhage, thereby reducing bleeding and promoting hemostasis. The high viscosity fluid can penetrate the downstream arterioles and capillaries, increasing local blood viscosity and reducing flow to the hemorrhagic site. The high viscosity fluid can be delivered in a volume sufficient to achieve a targeted reduction in blood flow rate to a site of the hemorrhage site, thereby suppressing bleeding. The high viscosity fluid can include cross-linking agents to form a hydrogel (i.e., having a higher viscosity than the fluid at the time of delivery to the gap) that provides sustained modulation of blood flow and supports clot formation at a site of the hemorrhage. The high viscosity fluid can be tailored to the specific characteristics of the hemorrhage, such as size and location, to optimize therapeutic outcomes. The high viscosity fluid can be delivered in a controlled manner to ensure even distribution and effective treatment of the hemorrhage. The high viscosity fluid can be gradually cleared from a site of the hemorrhage, allowing for restoration of normal blood flow once the hemorrhage is resolved. The high viscosity fluid can enhance the retention of therapeutic agents at a site of the hemorrhage, thereby improving the efficacy of the treatment.

[0136] The highly viscous fluid can achieve blood flow modulation in the bleeding arterial vasculature via endovascular approaches. When adequate resolution of the hemorrhage is achieved, the blood flow can be restored to its normal range by the clearance of the viscous fluid or hydrogel via blood circulation. The method can also include a reversal procedure to assist blood flow restoration by administration of a reverse agent via arterial or venous approaches. The reverse agent can have a property of breaking down the viscous fluid or hydrogel materials and blood clots under physiological conditions. The temporary and reversible nature of the modulation of the blood flow can enable treatment of the hemorrhagic disorders without causing ischemic injury, a critical requirement for treatments of a brain tissue disorders. For example, a permeant occlusion or chronic hypoperfusion may stop or suppress the bleeding in hemorrhagic tissue, but such interventions would cause brain tissue ischemia, i.e., ischemic stroke.

[0137] Various aspects of the method include the administration of reverse agents into the gap between the central portion of the flow guide device and the ostia of the targeted vasculature in the wall of the parent artery. The purpose of reverse agents is to restore the blood flow when adequate resolution of the hemorrhage is achieved. The selected reverse agents can be administrated separately or injected together with the viscous fluid. The selected reverse agents can be administrated to the arterial locations via endovascular approaches, or to the venous circulation. The reverse agents can include, but are not limited to, one or a combination of alginate lyse, chitinase, chitosanase, lysozyme, collagenase, hyaluronidase, -D- glucuronidase, P-N-acetyl-hexosaminidase, gelatinase, dextranase, glycoside hydrolases, streptokinase, alteplase, reteplase, tenecteplase, urokinase, prourokinase, and anistreplase. The viscous fluid and / or reverse agent can be in a form of a solution, a hydrogel, or dispersed particles. The dispersed particles are with a diameter of from 100 nanometers to 500 micrometers. The highly viscous fluid and reverse agents can be packaged in in a form of solution, hydrolyzed, or in a lyophilized form which is ready to be recombined with saline prior to clinical use.

[0138] The highly viscous fluid and reverse agents can be administered together as mixture. For example, the viscosifying polymer and its reverse agent can be mixed together in a lyophilized form. In another example, the viscosifying polymer and its reverse agent can be mixed together in a form of micro-particles.

[0139] FIG. 8 illustrates a coronal mid-plane view of the human cerebral artery system and common anatomical sites of intracerebral hemorrhage. Intracerebral hemorrhages most commonly involve cerebral lobes, originating from penetrating cortical branches of the anterior, middle, or posterior cerebral arteries (A); basal ganglia, originating from ascending lenticulostriate branches of the middle cerebral artery (B); the thalamus, originating from ascending thalmogeniculate branches of the posterior cerebral artery (C); the pons, originating from paramedian branches of the basilar artery (D); and the cerebellum, originating from penetrating branches of the posterior inferior, anterior inferior, or superior cerebellar arteries (E).

[0140] FIG. 9 is an illustration of an intracerebral hemorrhage that has occurred at the basal ganglia, in which 1 is middle cerebral artery; 2 is the branches and perorating arterial vasculature; 3 is the sites of bleeding in the vasculature; and 4 is the resulting hematoma of the hemorrhage.

[0141] FIG. 10 illustrates an exemplary treatment with flow guide device, in which 5 is an injector for delivering the invented viscous fluid or hydrogel; 6 is a delivery conduit such as a microcatheter; 7 is a device to assist the delivery of the treatment fluid; 8 is the viscous fluid delivered into the vasculature. In more detail of the exemplary treatment, a microcatheter, 6, is navigated to the responsible parent artery of the hemorrhagic disorder, which is the middle cerebral artery in this case. When the microcatheter tip is navigated to desired location, a viscous fluid or hydrogel, 8, is injected to the conduit of the microcatheter by using an injector, 5. The injected viscous fluid or hydrogel can then penetrate to the branches and perforating arteries where the hemorrhage occurs, which is the basal ganglia in this case. An assistant device, 7, can be deployed in the targeted artery prior to the injection (e.g., via another microcatheter) to guide the injected fluid to flow to the target territory.

[0142] As illustrated in FIG. 10, the injected viscous fluid, 8, can penetrate further to the downstream arterioles and tissue capillaries along with the blood flow and lead to an increase of viscosity and flow resistance which results in reduction of blood flow to the targeted vasculature. Such reduction of blood flow can suppress the bleeding of the hemorrhagic arterioles and capillaries in hemorrhagic tissue, while the flow reduction can facilitate the progression of hemostasis and ultimately seal the bleeding vessels. The targeted value of the blood flow rate after injection of viscous fluid can be from 20% to 70% that of the original or normal physiological blood flow. The fluid can include a viscosifying polymer such as a hydrogelincluding biopolymers, water, and electrolytes. The injection of the viscous fluid may be repeated in the acute stage of the hemorrhage until adequate resolution of the hemorrhage is achieved. The duration of the flow restriction in the targeted vasculature by the injected fluid can be in a range of 30 mins to 6 hours.

[0143] FIG. 11 is an illustration of the injected viscous fluid, 8, gradually cleared with blood circulation, after the bleeding sites is sealed and the hemorrhage is resolved. The viscous fluid travels with the blood flow to exit the arterial vasculature and enters venous circulation, enabling treatment of the hemorrhagic disorders without causing ischemic injury, a critical requirement for treatments of intracerebral hemorrhage.

[0144] FIG. 12 is an illustration of a reverse agent administrated arterially and the viscosifying polymers of the viscous fluid having been broken down, 10, by a reverse agent, 9, which can facilitate clearance of the injected viscous fluid with blood circulation. When adequate resolution of the hemorrhage is achieved, the blood flow may be restored to its normal range by the clearance of the viscous fluid by blood circulation. The method can include a reversal procedure to assist the blood flow restoration by administration of a reverse agent. The reverse agent injected to the vasculature can have a property of breaking down the viscous fluid, hydrogel material, blood clots, or a combination thereof under physiological conditions. The selected reverse agents can be administrated to the arterial locations via endovascular approaches, or to the venous circulation. The selected reverse agents can be mixed with the viscous fluid before the injection and injected together with the viscous fluid, or the reverse agents can be injected after the viscous fluid is injected. The reverse agents can include, but are not limited to, one or combination of alginate lyse, chitinase, chitosanase, lysozyme, collagenase, hyaluronidase, P-D-glucuronidase, P-N-acetyl-hexosaminidase, gelatinase, dextranase, glycoside hydrolases, streptokinase, alteplase, reteplase, tenecteplase, urokinase, prourokinase, and anistreplase.

[0145] FIG. 4 is an illustration of post-intervention showing that the bleeding has stopped and hematoma growth has been suppressed and all devices have been removed from the vasculature. It also illustrates the clearance of the injected fluid from the targeted vasculature.Method of using the flow guide device with a hemostatic agent.

[0146] The method of using the flow guide device can include delivering a fluid that includes a hemostatic agent to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature.The hemostatic agent can be any suitable one or more hemostatic agents. The fluid can include a hemostatic agent chosen from aprotinin, nafamostat, tranexamic acid, epsilon-aminocaproic acid, desmopressin acetate, estrogen, fresh frozen plasma, prothrombin complex concentrate, recombinant Factor Vila, chitosan, collagen, fibrinogen, gelatin, thrombin, desmopressin, vitamin K, and a combination thereof. The fluid can include a hemostatic agent that is tranexamic acid, epsilon-aminocaproic acid, prothrombin complex concentrate, recombinant Factor Vila, or a combination thereof. The one or more hemostatic agents can form any suitable proportion of the fluid. For example, the hemostatic agent can be 0.001 wt% to 100 wt% of the non-aqueous components of the fluid, or 0.001 wt% to 50 wt%, or less than or equal to 100 wt% and greater than or equal to 0.001 wt% and less than, equal to, or greater than 0.005, 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 wt%. The hemostatic can be present in the fluid in sufficient concentration such that 10 mg to 5,000 mg or 10 IU to 5,000 IU are delivered during the treatment, or 50 mg to 2,000 mg or 50 IU to 2,000 IU, or less than or equal to 5,000 mg or IU and greater than or equal to 10 mg or IU, and less than, equal to, or greater than 20 mg or IU, 40, 60, 80, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1,000, 1,200, 1,400, 1,600, 1,800, 2,000, 2,200, 2,400, 2,600, 2,800, 3,000, 3,200, 3,400, 3,600, 3,800, 4,000, 4,200, 4,400, 4,600, or 4,800 mg or IU.

[0147] The hemostatic agent can promote platelet aggregation and fibrin clot formation at a site of the hemorrhage, thereby reducing bleeding. The hemostatic agent can be delivered in a concentration sufficient to achieve rapid hemostasis and stabilize a site of the hemorrhage. The hemostatic agent can enhance the natural coagulation cascade, facilitating the formation of a stable clot at a site of the hemorrhage. The hemostatic agent can be delivered in a controlled manner to ensure even distribution and effective treatment of the hemorrhage. The hemostatic agent can be tailored to the specific characteristics of the hemorrhage, such as size and location, to optimize therapeutic outcomes. The hemostatic agent can be gradually metabolized and cleared from the site, allowing for restoration of normal blood flow once the hemorrhage is resolved. The hemostatic agent can enhance the retention of therapeutic agents at the hemorrhagic site, thereby improving the efficacy of the treatment. The hemostatic agent can becombined with one or more other therapeutic agents to provide a combined or synergistic effect in treating the hemorrhage. The hemostatic agent can be delivered in a form that allows for sustained release, providing prolonged hemostatic activity at a site of the hemorrhage.

[0148] When adequate resolution of the hemorrhage is achieved, the blood flow can be restored to its normal range by metabolism of the administrated hemostatic agent. In various aspects, the method includes a reversal procedure including administration of a thrombolytic agent. The thrombolytic agent can facilitates breakdown of intravascular clots under physiological conditions. The method can include localized and controlled-reversible nature in the administration of a hemostatic agent, which enables treatments of the hemorrhagic disorders without causing ischemic injury, a critical requirement for treatment of brain tissue disorders.

[0149] As the injected hemostatic agent travels to the downstream arterioles and tissue capillaries of the targeted vasculature, it leads to a hemostasis and reduction of blood flow to the targeted vasculature. The reduction of blood flow can suppress the bleeding of the hemorrhagic arterioles and capillaries in hemorrhagic tissue, and hemostasis by the hemostatic agent can ultimately seal the bleeding vessels. Such local hemostasis can have a nature of temporary intervention and it can be eliminated by metabolism of the administrated hemostatic agent. The injection of the hemostatic agent may be repeated in the acute stage of the hemorrhage until adequate resolution of the hemorrhage is achieved. Various aspects of the method also include a procedure to restore the blood flow by administration of a thrombolytic agent when an adequate resolution of the hemorrhage is achieved. The thrombolytic agent can dissolve clots in the affected vasculature under physiological conditions. The thrombolytic agent can be administrated to the arterial locations via endovascular approaches, or to the venous circulation. The thrombolytic agents include, but not limited to, one or a combination of Streptokinase, Alteplase, Reteplase, Tenecteplase, Urokinase, Prourokinase, and Anistreplase, Chitinase, chitosanase, collagenase, and gelatinase.

[0150] The injected hemostatic agent can decrease of the blood flow rate to the hemorrhagic region. The targeted value of the blood flow rate after injection of hemostatic agents can be from 20% to 70% that of the original or normal physiological blood flow. The injection of the hemostatic agents may be repeated in the acute stage of the hemorrhage until adequate resolution of the hemorrhage is achieved. The duration of flow restriction in the vasculature by the injected fluid can be in a range of 30 minutes to 6 hours.

[0151] The hemostatic agents and thrombolytic agents can be in a solution, dispersed particles, or in a lyophilized form which is ready to be recombined with saline prior to clinical use. The hemostatic agents and / or thrombolytic agents can be in embedded in a polymer matrix or micro-particles.

[0152] FIG. 8 illustrates a coronal mid-plane view of the human cerebral artery system and common anatomical sites of intracerebral hemorrhage. Intracerebral hemorrhages most commonly involve cerebral lobes, originating from penetrating cortical branches of the anterior, middle, or posterior cerebral arteries (A); basal ganglia, originating from ascending lenticulostriate branches of the middle cerebral artery (B); the thalamus, originating from ascending thalmogeniculate branches of the posterior cerebral artery (C); the pons, originating from paramedian branches of the basilar artery (D); and the cerebellum, originating from penetrating branches of the posterior inferior, anterior inferior, or superior cerebellar arteries (E).

[0153] FIG. 9 is an illustration of an intracerebral hemorrhage that occurred at the basal ganglia, in which 1 is middle cerebral artery; 2 is the branches and perorating arterial vasculature; 3 is the sites of bleeding in the vasculature; and 4 is the resulting hematoma of the hemorrhage.

[0154] FIG. 18 is an illustration of medical device system including a flow guide device for treating intracerebral hemorrhage, in which 5 is an injector for delivering hemostatic agent; 6 is a delivery conduit for hemostatic agent such as a catheter; 7 is a flow guide device to assist the delivery of the hemostatic agent; 8 is hemostatic agent delivered into the vasculature. In more detail of the exemplary treatment, a microcatheter, 6, can be navigated to the responsible parent artery of the hemorrhagic disorder, which is the middle cerebral artery in this case. When the microcatheter tip is navigated to desired location, a hemostatic agent, 8, can be injected to the conduit of the microcatheter by using an injector, 5. The injected hemostatic agent can then penetrate to the branches and perforating arteries where the hemorrhage occurs, which is the basal ganglia in this case. An assistant device, 7, can be deployed in the targeted artery prior to the injection to guide the injected hemostatic agent to flow to the target territory.

[0155] As illustrated in FIG. 18, the injected hemostatic agent, 8, can penetrate to the downstream arterioles and tissue capillaries of the targeted vasculature, and it can lead to a hemostasis and reduction of blood flow to the targeted vasculature. The reduction of blood flow can suppress the bleeding of the hemorrhagic arterioles and capillaries in hemorrhagic tissue, andhemostasis by the hemostatic agent ultimately seal the bleeding vessels. The targeted value of the blood flow rate after injection of hemostatic agent can be from 20% to 70% that of the original or normal physiological blood flow.

[0156] FIG. 19 is an illustration showing that the injected hemostatic agent, 8, can be gradually metabolized and eliminated from the vasculature, after the bleeding sites is sealed and the hemorrhage is resolved. Such metabolism and elimination enables treatments of the hemorrhagic disorders without causing ischemic injury, a critical requirement for treatment of brain tissue disorders such as intracerebral hemorrhages.

[0157] FIG. 20 is an illustration of a thrombolytic agent administrated arterially and with break down of intravascular clots 10 by a thrombolytic agent, 9, which can facilitate restoration of blood flow. When adequate resolution of the hemorrhage is achieved, the blood flow may be restored to its normal range. Various aspects of the method include a reversal procedure to assist the blood flow restoration by administration of a thrombolytic agent to dissolve intravascular clots when adequate resolution of the hemorrhage is achieved. The thrombolytic agents can be administrated to the arterial locations via endovascular approaches, or to the venous circulation.

[0158] FIG. 4 is an illustration of post intervention that the bleeding is stopped and hematoma growth has been suppressed and all devices are removed from the vasculature. It also illustrates the clearance of the injected fluid from the targeted vasculature.Method of using the flow guide device with a vasoconstrictor.

[0159] The method of using the flow guide device can include delivering a fluid that includes a vasoconstrictor to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature. The vasoconstrictor can be any one or more vasoconstrictor agents. The fluid can include a vasoconstrictor chosen from norepinephrine, epinephrine (adrenaline), angiotensin II, vasopressin (antidiuretic hormone, ADH), phenylephrine, pseudoephedrine, dopamine, midodrine, methoxamine, pitressin, terlipressin, desmopressin, angiotensin II, giapreza, ergotamine, methylergonovine, methergine, naphazoline, oxymetazoline, xylometazoline, Bay K 8644, and a combination thereof. The fluid can include a vasoconstrictor that is norepinephrine, epinephrine (adrenaline), angiotensin II, vasopressin (antidiuretic hormone, ADH), phenylephrine, pseudoephedrine, dopamine, midodrine, or a combination thereof. The one ormore vasoconstrictor agents can form any suitable proportion of the fluid. For example, the vasoconstrictor can be 0.001 wt% to 100 wt% of non-aqueous components of the fluid, or 0.001 wt% to 50 wt%, or less than or equal to 100 wt% and greater than or equal to 0.001 wt% and less than, equal to, or greater than 0.005 wt%, 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 wt%. The vasoconstrictor can be present in the fluid in sufficient concentration such that during administration of the fluid about 1 microgram to 200 micrograms or 1 IU to 200 IU of the vasoconstrictor are administered per 1 minute, or 2 micrograms to 100 micrograms or 2 IU to 100 IU per 1 minute, or less than or equal to 200 micrograms or IU and greater than or equal to 1 microgram or IU or less than, equal to, or greater than 2 micrograms or IU, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, or 190 micrograms or IU per 1 minute.

[0160] The vasoconstrictor can induce contraction of the vessel walls at the site of the hemorrhage, thereby reducing blood flow and minimizing bleeding. The vasoconstrictor can be delivered in a concentration sufficient to achieve rapid vasoconstriction and stabilize the hemorrhagic site. The vasoconstrictor can enhance the natural hemostatic process by reducing vessel diameter and promoting clot formation at the site of the hemorrhage. The vasoconstrictor can be delivered in a controlled manner to ensure even distribution and effective treatment of the hemorrhage. The type and concentration of the vasoconstrictor used can be tailored to the specific characteristics of the hemorrhage, such as size and location, to optimize therapeutic outcomes. The vasoconstrictor can be gradually metabolized and cleared from the site of the hemorrhage, allowing for restoration of normal blood flow once the hemorrhage is resolved. The vasoconstrictor can enhance the retention of one or more other therapeutic agents at the hemorrhagic site, thereby improving the efficacy of the treatment. The vasoconstrictor can be combined with other therapeutic agents to provide a combined or synergistic effect in treating the hemorrhage. The vasoconstrictor can be delivered in a form that allows for sustained release, providing prolonged vasoconstrictive activity at the site of the hemorrhage.

[0161] Local administration of vasoconstrictor agents can stop bleeding in hemorrhagic tissue and prevent hematoma growth. The injected vasoconstrictor agents can decrease the blood flow rate to the targeted vasculature (e.g., the hemorrhagic region). The targeted value of the blood flow rate after injection of vasoconstrictor agents can be from 20% to 70% that of theoriginal or normal physiological blood flow. When adequate resolution of the hemorrhage is achieved, the blood flow is restored to its normal range by metabolism of the administrated vasoconstrictor agent. Various aspects of the method include a reversal procedure including administration of a vasodilator agents. The vasodilator agents can increase diameter of the affected vessels and can restore blood flow to its normal range. The vasodilator agents can include, but not limited to, one or a combination of Nitroglycerin, Sodium Nitroprusside, Hydralazine, Calcium Channel Blockers, Phentolamine, Prazosin, Doxazosin and Labetalol. The localized administration and controlled-reversible nature of the vasoconstrictor agent can enable treatment of the hemorrhagic disorders without causing ischemic injury, a critical requirement for treatments of a brain tissue disorders. The injection of the vasoconstrictor agents may be repeated in the acute stage of the hemorrhage until adequate resolution of the hemorrhage is achieved. The duration of flow restriction in the vasculature by the injected fluid can be in a range of 30 minutes to 6 hours.

[0162] The vasoconstrictor agents and vasodilator agents can be in a solution, dispersed particles, or a lyophilized form which is ready to be recombined with saline prior to clinical use. The vasoconstrictor agents and vasodilator agents can be in embedded in a polymer matrix or micro-particles.

[0163] FIG. 8 illustrates a coronal mid-plane view of the human cerebral artery system and common anatomical sites of intracerebral hemorrhage. Intracerebral hemorrhages most commonly involve cerebral lobes, originating from penetrating cortical branches of the anterior, middle, or posterior cerebral arteries (A); basal ganglia, originating from ascending lenticulostriate branches of the middle cerebral artery (B); the thalamus, originating from ascending thalmogeniculate branches of the posterior cerebral artery (C); the pons, originating from paramedian branches of the basilar artery (D); and the cerebellum, originating from penetrating branches of the posterior inferior, anterior inferior, or superior cerebellar arteries (E).

[0164] FIG. 9 is an illustration of an intracerebral hemorrhage occurred at basal ganglia, in which 1 is middle cerebral artery; 2 is the branches and perorating arterial vasculature; 3 is the sites of bleeding in the vasculature; and 4 is the resulting hematoma of the hemorrhage.

[0165] FIG. 21 is an illustration of a medical device system including a flow guide device for treating intracerebral hemorrhage, in which 5 is an injector for delivering vasoconstrictor agents; 6 is a delivery conduit for vasoconstrictor agents such as a catheter; 7 is aflow guide device to assist the delivery of the vasoconstrictor agents; 8 is vasoconstrictor agents delivered into the vasculature. In more detail of the exemplary treatment, a microcatheter, 6, is navigated to the responsible parent artery of the hemorrhagic disorder, which is the middle cerebral artery in this case. When the microcatheter tip is navigated to desired location, a vasoconstrictor agent, 8, can be injected to the conduit of the microcatheter by using a proper injector, 5. The injected vasoconstrictor agents can then penetrate to the branches and perforating arteries where the hemorrhage occurs, which is the basal ganglia in this case. A flow guide device, 7, can be deployed in the targeted artery prior to the injection to guide the injected vasoconstrictor agents to flow to the target territory.

[0166] As illustrated in FIG. 21, the injected vasoconstrictor agent, 8, can penetrate to the downstream arterioles and tissue capillaries of the targeted vasculature, and it can lead to a vessel wall constraint and reduction of blood flow to the targeted vasculature. The reduction of blood flow can suppress the bleeding of the hemorrhagic arterioles and capillaries in hemorrhagic tissue, and the hemostasis can ultimately seal the bleeding vessels.

[0167] To achieve targeted flow reduction, dosage of the vasoconstrictor agents can be determined by bench flow model experiments, in-vivo animal model testing, or in-situ diagnosis tools such as fluoroscopy imaging analysis during the treatment.

[0168] FIG. 22 is an illustration showing the injected vasoconstrictor agent, 8, being gradually metabolized and eliminated from the vasculature after the bleeding sites is sealed and the hemorrhage is resolved.

[0169] FIG. 23 is an illustration of a vasodilator agent, 9, administrated arterially and to counter the residual vasoconstrictors, 10, which would facilitate restoration blood flow. When adequate resolution of the hemorrhage is achieved, the blood flow can be restored to its normal range.

[0170] FIG. 4 is an illustration of post-intervention showing that the bleeding is stopped and hematoma growth has been suppressed and all devices have been removed from the vasculature. It also illustrates the clearance of the injected fluid from the targeted vasculature.Examples

[0171] Various aspects of the present invention can be better understood by reference to the following Examples which are offered by way of illustration. The present invention is not limited to the Examples given herein.

[0172] Background of intracerebral hemorrhage. Intracerebral hemorrhage (ICH), mostly caused by the rupture of small arterioles, is the 2ndmost common type of stroke with around 80,000 cases annually in the US. There are few effective treatments, reflected by up to 50% mortality at 1 year and most survivors left with permanent disability. Global intracerebral haemorrhage factsheet 2025 by World Stroke Organisation (WSO) reported that ICH accounted for 28.8% if all incidents of strokes, 45.6% of all stroke deaths, and 49.5% of DALYs (disability- adjusted life years) due to stroke in 2021. Hematoma volume is the primary predictor of morbidity and mortality and hematoma growth is therefore the key treatment target. Acutely lowering blood pressure is the only intervention currently available to reduce hematoma growth, but has very low efficacy. Surgery to evacuate the hematoma is only operated for large hemorrhages (> 30 mL), which is to prevent secondary injury and it cannot reverse the primary injury. Hematoma growth (defined as >33% or >6 mL) is reported in 20-30% of the patients results in progressively neurological deterioration. The Flow Modulation Device is to stop bleeding during the acute phase. There is a therapeutic time window and 20-30% of the patients (-20,000 annually in the US) could benefit from the treatment.

[0173] Device and treatment description. The device, Flow Modulation Device, is a device to treat intracerebral hemorrhage. The Flow Modulation Device includes a water-based viscous fluid packed in a syringe injector. The water-based fluid contains sodium hyaluronate and water. The syringe injector is a plastic syringe. A representative picture of the device is shown in FIG. 24. The images provided are for illustration purposes and they may not be the exact appearance of the devices in its final form.

[0174] The Flow Modulation Device is for treating intracerebral hemorrhage via an endovascular procedure. The treatment suppresses and stops bleeding at acute phase by reducing blood flow to the hemorrhagic region. The blood flow reduction is achieved by increasing of blood viscosity with injection of the water-based viscous fluid from the Flow Modulation Device.

[0175] The treatment is based on the principle of hemodynamics as described in Hagen- Poiseuille equation, Q = (K * P * r4) / (8*r]*l). The blood flow rate, Q, is determined by vesseldiameter (r), blood viscosity (r|), pressure gradient (P), and vessel length (1). The water-based viscous fluid has the properties of a rheological thickening agent which increases the blood viscosity, r], and therefore reduce the blood flow rate to the ruptured vasculature. The treatment is delivered via conventional endovascular approaches. A syringe injector, a microcatheter and a flow guide device are used to deliver the contents of the Flow Modulation Device to the targeted vasculature. FIG. 25A illustrates a flow modulation device, microcatheter, and flow guide device. FIG. 25B illustrates treatment of an intracerebral hemorrhage with a flow modulation device, microcatheter, and flow guide device. The anatomical sites of intracerebral hemorrhage includes cortical branches (A), basal ganglia (B), the thalamus (C), the pons (D), and the cerebellum (E). FIG. 25B illustrates an intended treatment at the basal ganglia (B), the most common site, in which 1 is middle cerebral artery, one of the major arteries in the brain; 2 is the perorating side-branches arising from the middle cerebral artery which supply blood to the basal ganglia; 3 is the bleeding sites of ruptured vasculature at basal ganglia; and 4 is the hematoma from the hemorrhage. The viscous fluid, 8, is delivered to the targeted bleeding vasculature, 2, by endovascular approaches, in which 5 is the Flow Modulation Device, 6 is the microcatheter; and 7 is the flow guide device.

[0176] The treatment is conducted by trained neuro-interventionists in an angio-suite. A microcatheter is navigated to the targeted parent artery (1 in FIG. 25B) responsible for the hemorrhage. The microcatheter tip is placed to the location proximal to the origins of sidebranch arteries. The targeted side-branches (2 in FIG. 25B) supply blood to the ruptured and bleeding vasculature (3 in FIG. 25B). The contents of the Flow Modulation Device is injected via the microcatheter to the parent artery (1 in FIG. 25B), and the injected fluid is then directed to the hemorrhagic vasculature (3 in FIG. 25B) following blood flow. The injected contents of the Flow Modulation Device is visible in angiography during the treatment. Additionally a flow guide device (7 in FIG. 25B) can be deployed prior to the injection to further direct the injected fluid to the targeted ruptured vasculature. The flow guide device is a braided stent made of nitinol and platinum wires. The flow guide device acts as a flow directing device that ensures the injected fluid flow to the targeted side-branch arteries while reducing the amount of injected fluid flow to the other downstream arteries.

[0177] Percentages of components are weight percentages unless otherwise indicated.Example 1 . Bench flow model.

[0178] A bench flow model was set up as shown in FIG. 26A. The bench flow model included a flow loop, a pulsatile pump, a porous fabric block, a flow meter and a pressure meter. The bench flow model included an intend-to-treat and by-pass branches with a pulsatile flow circulation. The water-based viscous fluid was delivered from the Flow Modulation Device via a microcatheter. The bench flow model simulated the pulsatile flow, microvasculature flow resistance, and parallel branches of cerebral circulation. Pure water was used as circulation media of the pulsatile flow. The intended-to-treat branch and the by-pass branch had similar microvasculature resistance and therefore similar water flow rate prior to treatment. The treatment was conducted by injecting 0.25 mL with the Flow Modulation Device every 3 minutes to the treated branch via a microcatheter. The water flow rate in the treated branch decreased right after the injection and the reduced flow was sustained during the treatment. The flow returned to its original rate within 5 minutes after the injection stopped. The results of flow rate in treated branch are shown in FIG. 26B. It should be noted that the measured flow rate was the average value of every 10 mL of flow which resulted in apparent non-continuous change of flow rate with time.

[0179] A bench flow model with the flow guide device was set up as shown in FIG. 27. The flow model included the parent artery, targeted vessel (side branches) and downstream arteries with a pulsatile flow circulation, to simulate middle cerebral artery and its side branches. The targeted vessels to treat were the side branches that supply blood to the basal ganglia, because intracerebral hemorrhages at basal ganglia are caused by rupture of the side branches of the middle cerebral artery. The flow guide device (magnified in the inset of FIG. 27) was deployed in the parent vessel with the microcatheter tip jailed between the device and vessel wall. The water-based viscous fluid (with blue dye) was injected from the microcatheter. The results showed that the injected fluid (blue) was directed into the targeted side branches by the flow guide device, avoiding the downstream arteries.

[0180] The testing in bench flow model with pure water media showed that the Flow Modulation Device achieved its intended purposes in the bench flow model, i.e., to modulate flow rate of the targeted vasculature (FIG. 26B); and that the flow guide device provided assistance to direct the injected fluid to the targeted vessels (FIG. 27).Description of the bench flow modulation testing (FIGS. 26A-B).

[0181] Test group: Fluid containing hyaluronic acid (HA).

[0182] Methodology of testing: A bench flow model for flow modulation testing was setup as shown in FIG. 26A. It included a flow loop, a pulsatile pump, porous fabric blocks (to simulate flow resistance of vasculature), a flow meter and a pressure meter, and by-pass flow loop. The flow modulation device was delivered to the target branch via a microcatheter. The average flow rate of the targeted branch was measured prior to, during and after the delivery of the Flow Modulation Device. The average flow rate was measured for every 10 mL of flow.

[0183] Conditions of testing: Pure water was used as circulation media of the pulsatile flow. The flow rate was 8.7 ml / min and under a systolic pressure of 112-123 mmHg and diastolic pressure of 108-110 mmHg generated by a pulsatile pump. The treatment shown in FIGS. 26A-B was conducted by injecting 0.25 mL of contents from the Flow Modulation Device within 30 seconds for every 3 minutes to the targeted branch via a microcatheter.

[0184] Results: As shown in FIG. 26B, the water flow rate in the treated branch decreased right after the injection of the Flow Modulation Device, and the reduced flow was sustained during the treatment. The flow returned to its original rate within 5 minutes after the injection stopped.

[0185] Conclusions: The Flow Modulation Device achieved its intended purposes in the bench flow model, i.e., to modulate flow rate of the targeted vasculature.Description for the bench model of targeted delivery testing (FIG. 27),

[0186] Test group: Fluid containing hyaluronic acid.

[0187] Methodology of testing: A bench flow model with a flow guide device deployed was setup as shown in FIG. 27. Flow model includes the parent artery, targeted vessel (side branches) and downstream arteries with a pulsatile flow circulation. The model was used to simulate middle cerebral artery (parent) and its side branches. The targeted vessel to treat was the side branches that supply blood to the basal ganglia. Intracerebral hemorrhages at the basal ganglia, a common location, are caused by rupture of the side branches of the middle cerebral artery. The flow guide device (magnified in top right of FIG. 27) was deployed in the parent vessel. A microcatheter was placed with its tip jailed between the device and vessel wall. The Flow Modulation Device (with blue dye) was injected from the microcatheter. The delivery anddistribution of the injected contents of the Flow Modulation Device can be visualized by the blue dye that mixed with the device. The average flow rate of the targeted branches was measured for every 10 mL of flow.

[0188] Conditions of testing: Pure water was used as circulation media of the pulsatile flow. The flow loop had a systolic pressure of around 120 mmHg and diastolic pressure of around 110 mmHg by a pulsatile pump. The water flow rate was 13 mL / min in the parent vessel, and 1.4 mL / min, 5 mL / min, 1.6 mL / min, and 5 mL / min in the four side branches, respectively. The treatment shown in FIG. 27 was conducted by injecting 1.0 mL from the Flow Modulation Device within 60 seconds via a microcatheter.

[0189] Results: As shown in FIG. 27, the injected fluid (with blue dye) was directed into the targeted side branches by the flow guide device, avoiding the downstream arteries. The water flow rate in the treated side branches had similar behavior as that shown in FIG. 26B, i.e., decreased flow after the injection from the Flow Modulation Device and a return to original flow rate gradually after the injection stopped.

[0190] Conclusions: The flow guide device provides assistance to direct the injected fluid to the targeted vessels.Example 2, In-vivo canine cerebral model.

[0191] A study was conducted in an in-vivo canine cerebral model using angiography. FIG. 28A illustrates anatomy of canine cerebral arteries. As shown in FIG. 28B, a microcatheter was navigated to the basilar artery (BA) by endovascular procedure in angio-suite, and the Flow Modulation Device was used to inject the water-based viscous fluid to the basilar artery via the microcatheter. 1 mL of the contents of the Flow Modulation Device were injected. The blood flow rate was evaluated by angiography pre-treatment (FIG. 28C), during treatment (FIG. 28D), and 10 minutes post-treatment (FIG. 28E). The blood flow rate reduction and restoration were evident by the angiography with contrast agents. It was evident from angiography that the blood flow rate in the treated arteries (BA and downstream) deceased with the injection from the Flow Modulation Device. The blood flow rate returned to original conditions within 10 minutes after the treatment. The injection from the Flow Modulation Device was repeated and the same effect on the blood flow was observed. Brain MRI was also conducted to evaluate the safety of thetreatment. MRI diffusion weight imaging (DWI) post-treatment showed no concern of ischemic injury as shown in FIG. 28F. Baseline MRI DWI is shown in FIG. 28G.

[0192] The canine study provided direct visual evidence that the Flow Modulation Device achieved its intended purposes in the in-vivo canine cerebral model, i.e., to modulate flow rate of the targeted vasculature. The safety of the treatment was demonstrated by MRI DWI pre- and post-treatment (FIGS. 28G and 28F, respectively).Test description for the canine study.

[0193] Test groups: Treatment fluid containing hyaluronic acid (HA).

[0194] Methodology of testing: A study was conducted in an in-vivo canine cerebral model under guidance of Fluoroscopy. As shown in FIG. 28B, a microcatheter was navigated to the basilar artery (BA) by an endovascular procedure under guidance of fluoroscopy. The contents of the Flow Modulation Device were injected to basilar artery via the microcatheter. The delivery and distribution of the injected contents of the Flow Modulation Device can be visualized by the contrast agent of Omnipaque 300 that was mixed with the device. The blood flow rate of the treated vasculature, basilar artery and its downstream vessels, were characterized qualitatively by DSA (digital subtracted angiography) with contrast injection, as shown in FIGS. 28C-E. The DSA run was conducted at prior to injection, and post injection at 1 minute, 2 minutes, 4 minutes and 10 minutes.

[0195] Conditions of testing: The testing was conducted in a Beagle of 24 months, weighted 14.6 kg. The conditions of the testing were similar to a typical endovascular procedure. The animal was under general anesthesia during the procedure and heartbeat, breathing rate, temperature, blood pressure, and activated blood clotting time were monitored. Antiplatelet therapy (oral acetylsalicylic acid and clopidogrel) was given 3 days prior to the operation and continuing daily until operation day. A heparinized saline drip was used for a constant flush of the catheters. The Flow Modulation Device was mixed with Omnipaque 300 at a volume ration of 1 to 1 prior to injection. 1 mL of the contents of the Flow modulation device including HA after mixing with Omnipaque was injected to the Bailor Artery. 1 ml from the device was injected via a microcatheter within 60 seconds. DSA runs were conducted to characterize blood flow rate qualitatively. After 20 minutes of the first injection, 1 mL of the contents of the Flow Modulation Device including HA after mixing with Omnipaque wasinjected around the same location of the basilar artery via the microcatheter. DSA runs were conducted to characterize blood flow rate qualitatively. The animal was terminated at the same day of the procedure after testing.

[0196] Results: The blood flow rate was evaluated by angiography prior to treatment, during treatment (1 mins after injection), and 10 minutes post-treatment. As shown in FIGS. 28C-E, it was evident from angiography that the blood flow rate in the treated arteries (BA and downstream) decreased with the injection of the Flow Modulation Device. The blood flow rate returned to original conditions within 10 minutes after the treatment. The data shown in FIGS. 28C-E was from the injection of 1 mL from the Flow Modulation Device including HA. Similar performance was observed with a repeated injection of 1 mL of the fluid from the Flow Modulation Device including HA.

[0197] Conclusions: The Flow Modulation Device achieved its intended purposes in the in-vivo canine cerebral model, i.e., to modulate flow rate of the targeted vasculature, and there were no safety concerns observed in MRI evaluation of the brain tissue post-treatmentExample 3 , In-vivo rat model.

[0198] Treatment using the Flow Modulation Device was conducted in a rat model. Blood flow rate reduction was measured quantitatively and compared with the results from the bench flow model. A disease model of intracerebral hemorrhage in rats was also create by surgical infusion of collagenase into the brain. The hemorrhage creation procedure is illustrated in FIG. 29A. The hemorrhage create procedure is described as follows. An incision was made in the neck and the common carotid artery (CCA), external carotid artery (ECA) and internal carotid artery (ICA) were surgically isolated around the bifurcation. A microcatheter (diameter of 0.5mm) was inserted from the ECA to the CCA to deliver the treatment, and a flow probe was placed around the ICA to monitor blood flow rate. The contents of the Flow Modulation Device was injected through the microcatheter into the CCA. The fluid was then directed by the blood flow to the ICA and the cerebral circulation. Blood flow rate in the targeted vessel, ICA, was measured by a Transonic perivascular flow probe. The testing showed that the blood flow rate in ICA decreased right after the injection of the Flow Modulation Device. The blood flow rate in the treated artery, ICA, was investigated with the injected volume of the Flow Modulation Device. The measured flow rate reduction in the rat model is shown in the chart of FIG. 29B.The results from the in-vivo rat model were compared with those from the bench water flow model using the same Flow Modulation Device, as shown in the chart of FIG. 29B. The injected volume from the Flow Modulation Device in the chart was standardized to compensate the difference of flow rate between the rat ICA and bench water flow model. The results in FIG.29B showed that the treatment with the Flow Modulation Device in the rat internal carotid artery had similar effect and behavior to those in bench water flow model.

[0199] A disease model of intracerebral hemorrhage in rats was also created by surgically infusion of collagenase into the brain. The procedure is illustrated in FIG. 29A. The rats with created intracerebral hemorrhage were treated by the Flow Modulation Devices with the procedure described above and it showed at least 30% reduction of hematoma in treated animals compared with untreated controls, as shown in FIGS. 30A-B.Bench Flow model testing.

[0200] Test group: Fluid containing HA.

[0201] Methodology and Conditions of testing: Bench flow model data in FIG. 29B was collected using same testing method as described for FIGS. 26A-B in Section 4.3.1. The injection volumes from the Flow Modulation Device of 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL and 0.6 mL were tested, respectively. The contents of the device were injected within 30-60 seconds via a microcatheter. Sufficient time was given between testing to allow the flow rate to return to its baseline value. The baseline flow rate was 8.7 mL / min. Fluid containing HA was used.Rat study.

[0202] Test group: Fluids containing HA.

[0203] Methodology of testing: Studies were conducted in an in-vivo rat cerebral model. The hemorrhage creation procedure is illustrated in FIG. 29A. The endovascular treatment is described as follows. An incision was made in the rat neck and the common carotid artery (CCA), external carotid artery (ECA) and internal carotid artery (ICA) were surgically isolated around the bifurcation. A micro-tube (diameter of 0.5mm) with a luer-lock hub was inserted from the ECA to the CCA to deliver the treatment, and a flow probe was placed around the ICA to monitor blood flow rate. The Flow Modulation Device was injected through the micro-tube into the CCA while the ECA was litigated. The fluid was then directed by the blood flow to theICA and the cerebral circulation. Blood flow rate in the targeted vessel, ICA, was measured by a transonic perivascular flow probe in real time. The minimum value of the flow rate in ICA during the device injection was recorded and taken as the measured flow with treatment.

[0204] Conditions of testing: The testing was conducted in female Sprague-Dawley rats, 200-300 g, 16 weeks old. The animals were under isoflurane sedation during the procedure. The contents of the Flow Modulation Device was injected to the internal carotid artery (ICA). 0.06 ml, 0.1 mL and 0.2 mL of the contents of the device was injected within 60 seconds. Sufficient time was given between testing to allow the blood flow rate of ICA to return to its baseline value. The baseline flow rate was 2.2 mL / min.

[0205] Results: It was evident from the transonic perivascular flow probes that the blood flow rate in the treated artery, left Internal Carotid Artery, deceased with the injection from the Flow Modulation Device. The blood flow rate returned to original conditions within 1 minutes after the treatment. The chart of FIG. 29B showed the measured flow rate reduction in the rat model with injection of the HA-containing fluid from the device. The results from in-vivo rat model were compared with those from the bench water flow model using the same Flow Modulation Device, as shown in the chart of FIG. 29B. The injected volume of the Flow Modulation Device used in FIG. 29A was standardized to compensate the difference of flow rate between the rat ICA and the bench water flow model. The X axis in FIG. 29B was the value of the injected volume (in mL) divided by the original flow rate of the treated vessel (in mL / min). The results in FIG. 29B showed that the treatment with the Flow Modulation Device in the rat internal carotid artery had similar effect and behavior to those in bench water flow model. The results in FIGS. 30A-B showed a significant reduction of hematoma (>35%) with the presently disclosed treatment compared with untreated.

[0206] Conclusions: The Flow Modulation Device achieved its intended purposes in the in-vivo rat internal carotid artery, i.e., to modulate flow rate of the targeted vasculature. The presently disclosed treatment resulted in a significant reduction of hematoma (>35%) as compared with untreated.Example 4, Potential device marketing, components, indications, instructions, and mode of action.Potential marketing.

[0207] The Flow Modulation Device can be physically packaged and marketed by itself. The compatible microcatheters and the flow guide devices can be physically packaged and marketed separately from the Flow Modulation Devices. The Flow Modulation Device can be labelled for use with compatible microcatheters and flow guide devices.

[0208] A flow guide device (FIG. 25A) can be deployed prior to the injection to further direct the injected fluid to the targeted ruptured vasculature. The flow guide device is a braided stent made of nitinol and platinum wires. As shown in FIG. 25A, the flow guide device is a cylindrical self-expanding stent. The flow guide device is braided from 48 strands of alloy wires, in which 36 of the wires are nitinol wires and 12 of the wires are platinum wires. The alloy wires have a round shape with diameter of 25 micrometer. The flow guide device is braided with pick per inch, i.e., number of wire cross per linear inch, of 275. The flow guide device has a range of diameter and length to select for anatomy of the targeted vessel. The diameter of the flow guide device has range from 1.5 mm to 5.0 mm with an increments of 0.25 mm. The length of the flow guide device has a range from 8 mm to 30 mm with an increments of 2 mm. The flow guide device acts as a flow directing device that ensures the injected fluid flow to the targeted sidebranch arteries while reducing the amount of injected fluid flow to the other downstream arteries. It should be noted that the purpose of the flow guide device is to enhance delivery efficiency of the contents of the Flow Modulation Device to targeted vasculature. The Flow Modulation Device may achieve its intended purpose without a flow guide device as shown in the canine and rat testing, in which the contents of the Flow Modulation Device follows the native blood flow to reach the targeted vasculature.Potential indications for use.

[0209] The Flow Modulation Device is intended to treat hemorrhage at an acute stage. The hemorrhage can be a cerebral hemorrhage, or a hemorrhage in any part of the body. For example, the hemorrhage can be located within the brain, chest cavity (e.g., hemothorax), abdominal cavity, peritoneal cavity, retroperitoneum, gastrointestinal tract, thorax, spleen, liver, pelvis, uterus, a muscle, a joint, or can be a hemorrhage from long bone fractures.Instructions for use.

[0210] The treatment is conducted by trained neuro-interventionists in an angio-suite. Major steps and instructions are described below.

[0211] In preparation, the contents of the Flow Modulation Device is mixed with a waterbased contrast agent, Omnipaque 300, by the clinicians prior to its use. The purpose of the contrast agents is to provide the operator a visual confirmation of the device location during the procedure under fluoroscopic guidance. The water-based contrast agent, Omnipaque 300, a regular supply in angio-suite for all endovascular diagnosis and operations, is not necessarily packaged with the Flow Modulation Device package. The compatible contrast agents and instruction for mixing can be supplied in the Flow Modulation Device package.

[0212] A microcatheter is navigated under fluoroscopic guidance to the targeted parent artery responsible for the hemorrhage, following conventional access procedures of neurovascular operations established for acute ischemic stroke and intracranial aneurysm treatment. The contents of the Flow Modulation Device can be injected via the microcatheter to the parent artery by the operators. The flow guide device can be deployed in a desired location prior to the injection to further direct the injected fluid to the targeted vasculature. The flow guide device can be visible under fluoroscopy. The instructions for the amount and injection speed of the Flow Modulation Device can be provided with the device in its package.Example 5, Use in human brain without flow guide device.

[0213] Treatment fluid is delivered to a parent artery including ostia of targeted vasculature that includes a cerebral hemorrhage to modulate blood flow to the targeted vasculature, as shown in FIG. 31. The treatment fluid is delivered using a syringe to inject the fluid into the parent artery via a microcatheter. The treatment fluid includes a viscosifying polymer, a hemostatic agent, a vasoconstrictor, or a combination thereof. After the blood flow to the hemorrhage has been modulated for a suitable amount of time, a reverse agent is injected into the parent artery using the syringe and microcatheter to remove the treatment fluid and reverse the effects of the treatment fluid, providing a treated hemorrhage as shown in FIG. 32. Because the treatment fluid does not provide full occlusion of blood flow and is only temporary, ischemic effects of the treatment are avoided.

[0214] The terms and expressions that have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms andexpressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the aspects of the present invention. Thus, it should be understood that although the present invention has been specifically disclosed by specific aspects and optional features, modification and variation of the concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of aspects of the present invention.Exemplary Aspects.

[0215] The following exemplary aspects are provided, the numbering of which is not to be construed as designating levels of importance:

[0216] Aspect 1 provides a flow guide device, the flow guide device comprising: a cylindrical structure with a low porosity wall, the flow guide device configured to be deployed in a parent artery comprising ostia of targeted vasculature, the cylindrical structure comprising a proximal portion and a distal portion with an expanded or inflated diameter that ensures full opposition of the proximal portion and the distal portion to a vessel wall of the parent artery, and a central portion with an expanded or inflated diameter that is less than the expanded or inflated diameter of the proximal portion and the distal portion to provide a gap between the ostia of the targeted vasculature and the wall of the central portion.

[0217] Aspect 2 provides the flow guide device of Aspect 1, wherein the flow guide device is for directing fluid to the targeted vasculature.

[0218] Aspect 3 provides the flow guide device of Aspect 2, wherein the flow guide device is configured to maintain blood flow to downstream arteries while directing the fluid to the targeted vasculature.

[0219] Aspect 4 provides the flow guide device of any one of Aspects 2-3, wherein the fluid delivered is chosen from high viscosity fluids, hemostatic agents, vasoconstrictor agents, embolization agents, thrombolysis agents, chemotherapy agents, and a combination thereof.

[0220] Aspect 5 provides the flow guide device of any one of Aspects 2-4, wherein the flow guide device is configured to at least partially isolate the delivered fluid from the blood flow of the parent artery and direct it to the targeted vasculature.

[0221] Aspect 6 provides the flow guide device of any one of Aspects 2-5, wherein the flow guide device is for targeted endovascular delivery of the fluid for treatment of an intracerebral hemorrhage, epidural hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, thoracic hemorrhage, gastrointestinal (GI) hemorrhage, abdominal hemorrhage, retroperitoneal hemorrhage, musculoskeletal hemorrhage, subconjunctival hemorrhage, postpartum hemorrhage, or ectopic pregnancy rupture.

[0222] Aspect 7 provides the flow guide device of any one of Aspects 1-6, wherein the flow guide device is for modulation of blood flow to the ostia of targeted vasculature at a treatment location.

[0223] Aspect 8 provides the flow guide device of Aspect 7, wherein the flow guide device is configured to maintain blood flow to downstream arteries while modulating blood flow to the targeted vasculature.

[0224] Aspect 9 provides the flow guide device of any one of Aspects 7-8, wherein the flow guide device is for modulation of blood flow to the targeted vasculature for treatment of an intracerebral hemorrhage, epidural hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, thoracic hemorrhage, gastrointestinal (GI) hemorrhage, abdominal hemorrhage, retroperitoneal hemorrhage, musculoskeletal hemorrhage, subconjunctival hemorrhage, postpartum hemorrhage, or ectopic pregnancy rupture.

[0225] Aspect 10 provides the flow guide device of any one of Aspects 1-9, wherein the flow guide device comprises a self-expanding stent comprising metallic wire woven braids or a laser-cut metallic tube.

[0226] Aspect 11 provides the flow guide device of Aspect 10, wherein the metallic wire is chosen from nickel -titanium alloy, platinum alloy, cobalt-chromium-nickel alloy, and combinations thereof.

[0227] Aspect 12 provides the flow guide device of any one of Aspects 10-11, wherein the stent comprises a cover layer to further reduce porosity of the wall, the cover layer being positioned outside or inside a frame of the stent.

[0228] Aspect 13 provides the flow guide device of Aspect 12, wherein the cover layer comprises a material chosen from braided metal mesh, polymeric fabric, elastic membrane, porous membrane, and combinations thereof.

[0229] Aspect 14 provides the flow guide device of any one of Aspects 1-13, wherein the proximal and distal portions have a length of 3 mm to 7 mm.

[0230] Aspect 15 provides the flow guide device of any one of Aspects 1-14, wherein the proximal and distal portions have a length of at least 3 millimeters.

[0231] Aspect 16 provides the flow guide device of any one of Aspects 1-15, wherein the expanded or inflated diameter of the proximal portion and distal portion is 1 mm to 7 mm.

[0232] Aspect 17 provides the flow guide device of any one of Aspects 1-16, wherein the expanded or inflated diameter of the proximal portion and distal portion is 1 mm to 5 mm.

[0233] Aspect 18 provides the flow guide device of any one of Aspects 1-17, wherein the central portion has a length of 2 mm to 30 mm.

[0234] Aspect 19 provides the flow guide device of any one of Aspects 1-18, wherein the central portion has a length of 5 mm to 15 mm.

[0235] Aspect 20 provides the flow guide device of any one of Aspects 1-19, wherein the central portion has an expanded or inflated diameter of 1 mm to 7 mm.

[0236] Aspect 21 provides the flow guide device of any one of Aspects 1-20, wherein the central portion has an expanded or inflated diameter of 1 mm to 5 mm.

[0237] Aspect 22 provides the flow guide device of any one of Aspects 1-21, wherein the central portion has an expanded or inflated diameter that is 0.001 mm to 2 mm less than the expanded or inflated diameter of the proximal portion and the distal portion.

[0238] Aspect 23 provides the flow guide device of any one of Aspects 1-22, wherein the central portion has an expanded or inflated diameter that is 0.5 mm to 1 mm less than the expanded or inflated diameter of the proximal portion and the distal portion.

[0239] Aspect 24 provides the flow guide device of any one of Aspects 1-23, wherein the flow guide device has an unexpanded or uninflated diameter of less than or equal to 1 mm.

[0240] Aspect 25 provides the flow guide device of any one of Aspects 1-24, wherein the flow guide device has an unexpanded or uninflated diameter of 0.01 mm to 1 mm.

[0241] Aspect 26 provides the flow guide device of any one of Aspects 1-25, wherein the flow guide device has a length of 5 mm to 70 mm.

[0242] Aspect 27 provides the flow guide device of any one of Aspects 1-26, wherein the flow guide device has a length of 10 mm to 25 mm.

[0243] Aspect 28 provides the flow guide device of any one of Aspects 1-27, wherein the flow guide device comprises a proximal end structure with stent struts or braiding wires that come together to one point.

[0244] Aspect 29 provides the flow guide device of Aspect 28, wherein the point is configured to connect with a delivery wire for deployment and retraction of the flow guide device.

[0245] Aspect 30 provides the flow guide device of any one of Aspects 28-29, wherein the proximal end structure is held together by a process chosen from crimping, laser welding, soldering, adhesive bonding, and a combination thereof.

[0246] Aspect 31 provides the flow guide device of any one of Aspects 1-30, wherein the flow guide device has a surface coverage of 20% to 100%.

[0247] Aspect 32 provides the flow guide device of any one of Aspects 1-31, wherein the flow guide device has a surface coverage of 20% to 70%.

[0248] Aspect 33 provides the flow guide device of any one of Aspects 1-32, wherein the flow guide device has a surface coverage of 20% to 50%.

[0249] Aspect 34 provides the flow guide device of any one of Aspects 1-33, wherein the flow guide device has a porosity of 0% to 80%.

[0250] Aspect 35 provides the flow guide device of any one of Aspects 1-34, wherein the flow guide device has a porosity of 30% to 80%.

[0251] Aspect 36 provides the flow guide device of any one of Aspects 1-35, wherein the flow guide device has a porosity of 50% to 80%.

[0252] Aspect 37 provides the flow guide device of any one of Aspects 1-36, wherein the flow guide device has a pore density of 0 pores / mm2to 45 pores / mm2

[0253] Aspect 38 provides the flow guide device of any one of Aspects 1-37, wherein the flow guide device has a pore density of 10 pores / mm2to 45 pores / mm2.

[0254] Aspect 39 provides the flow guide device of any one of Aspects 1-38, wherein the flow guide device has a pore density of 20 pores / mm2to 45 pores / mm2.

[0255] Aspect 40 provides the flow guide device of any one of Aspects 1-39, wherein the gap between a central portion of the wall and ostia of the targeted vasculature is 0.001 mm to 2 mm when deployed.

[0256] Aspect 41 provides the flow guide device of any one of Aspects 1-40, wherein the gap between a central portion of the wall and ostia of the targeted vasculature is in the range of 0.5 mm to 1 mm when deployed.

[0257] Aspect 42 provides the flow guide device of any one of Aspects 1-41, wherein the flow guide device is configured to be delivered and retracted using endovascular approaches.

[0258] Aspect 43 provides the flow guide device of any one of Aspects 1-42, wherein the flow guide device comprises an inflatable balloon comprising an open lumen.

[0259] Aspect 44 provides the flow guide device of Aspect 43, wherein the inflatable balloon comprises a double layer and an open lumen that extends through the balloon through the proximal, central, and distal portions of the cylindrical structure.

[0260] Aspect 45 provides the flow guide device of any one of Aspects 43-44, wherein the balloon is configured to be inflated or deflated after deployment of the flow guide device to the desired location.

[0261] Aspect 46 provides the flow guide device of any one of Aspects 1-45, wherein the flow guide device is configured to be visible under fluoroscopy during deployment and retraction.

[0262] Aspect 47 provides a flow guide device, the flow guide device comprising: a cylindrical structure with a low porosity wall, the flow guide device configured to be deployed in a parent artery comprising ostia of targeted vasculature, the cylindrical structure comprising a proximal portion and a distal portion with an expanded diameter that ensures full opposition of the proximal portion and the distal portion to a vessel wall of the parent artery, and a central portion with an expanded diameter that is 1 mm to 7 mm and that is 0.001 mm to 2 mm less than the expanded diameter of the proximal portion and the distal portion to provide a gap between the ostia of the targeted vasculature and the wall of the central portion, wherein the cylindrical structure comprises a self-expanding stent comprising metallic wire woven brains or a laser-cut metallic tube, wherein the flow guide has a length of 10 mm to 70 mm and wherein the proximal and distal portions of the flow guide have a length of at least 3 millimeters.

[0263] Aspect 48 provides a flow guide device, the flow guide device comprising: a cylindrical structure with a low porosity wall, the flow guide device configured to be deployed in a parent artery comprising ostia of targeted vasculature, the cylindrical structure comprising a proximal portion and a distal portion with an inflated diameter that ensures fullopposition of the proximal portion and the distal portion to a vessel wall of the parent artery, and a central portion with an inflated diameter that is 1 mm to 7 mm and that is 0.001 mm to 2 mm less than the inflated diameter of the proximal portion and the distal portion to provide a gap between the ostia of the targeted vasculature and the wall of the central portion, wherein the cylindrical structure comprises an inflatable balloon comprising a double layer and an open lumen that extends through the balloon through the proximal, central, and distal portions of the cylindrical structure, wherein the flow guide has a length of 10 mm to 70 mm and wherein the proximal and distal portions of the flow guide have a length of at least 3 millimeters.

[0264] Aspect 49 provides a medical device system for targeted endovascular delivery of a fluid, the medical device system comprising: the flow guide device of any one of Aspects 1-48; a microcatheter for delivering the flow guide device to a parent artery of a bleeding disorder to be treated; and a delivery wire connected to the proximal end of the flow guide device for deployment and retraction. Optionally, the system can include a second microcatheter for delivering a fluid to the space between the flow guide device wall and the ostia of intended-to-treat branch arteries, or the flow guide device can include a conduit for delivering the fluid to the space between the flow guide device wall and the ostia of intended-to-treat branch arteries, or the system can include a needle or a conduit for delivering the fluid to the space between the flow guide device wall and the ostia of intended-to-treat branch arteries, or a combination thereof.

[0265] Aspect 50 provides the medical device system of Aspect 49, wherein the flow guide device comprises a proximal end structure with stent struts or braiding wires that come together to one point and connect with the delivery wire.

[0266] Aspect 51 provides a method of using the flow guide device of any one of Aspects 1-48, the method comprising: delivering the flow guide device to the parent artery comprising ostia of targeted vasculature; modulating blood flow to the ostia of the targeted vasculature with the flow guide device and / or delivering a fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature; and retracting the flow guide device from the parent artery.

[0267] Aspect 52 provides the method of Aspect 51 , comprising modulating blood flow to the ostia of the targeted vasculature with the flow guide device.

[0268] Aspect 53 provides the method of any one of Aspects 51-52, comprising delivering the fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature.

[0269] Aspect 54 provides a method of treating a hemorrhage with the flow guide device of any one of Aspects 1-48, the method comprising: delivering the flow guide device in the parent artery comprising ostia of targeted vasculature comprising the hemorrhage; modulating blood flow to the ostia of the targeted vasculature with the flow guide device and / or delivering a fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature; and retracting the flow guide device from the parent artery.

[0270] Aspect 55 provides the method of Aspect 54, wherein the hemorrhage is an intracerebral hemorrhage, epidural hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, thoracic hemorrhage, gastrointestinal (GI) hemorrhage, abdominal hemorrhage, retroperitoneal hemorrhage, musculoskeletal hemorrhage, subconjunctival hemorrhage, postpartum hemorrhage, or ectopic pregnancy rupture.

[0271] Aspect 56 provides the method of any one of Aspects 54-55, comprising maintaining blood flow to downstream arteries of the parent artery while modulating blood flow to the targeted vasculature and / or delivering the fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device.

[0272] Aspect 57 provides the method of any one of Aspects 54-56, comprising performing the delivering of the flow guide device and retracting the flow guide device using endovascular approaches.

[0273] Aspect 58 provides the method of any one of Aspects 54-57, comprising performing the delivering of the flow guide device and retracting the flow guide device using a delivery wire connected to a proximal end of the flow guide device.

[0274] Aspect 59 provides the method of any one of Aspects 54-58, comprising selecting a suitable size and configuration of the flow guide device based on anatomical characteristics of the parent artery and / or the targeted vasculature.

[0275] Aspect 60 provides the method of any one of Aspects 54-59, comprising observing the flow guide device using an imaging technique during the delivery and / or retraction.

[0276] Aspect 61 provides the method of any one of Aspects 54-60, comprising observing the flow guide device using fluoroscopy during the delivery and / or retraction.

[0277] Aspect 62 provides the method of any one of Aspects 54-61, comprising repeating the delivering, the modulating blood flow and / or delivery of the fluid, and the retracting.

[0278] Aspect 63 provides the method of any one of Aspects 54-62, comprising modulating blood flow to the ostia of the targeted vasculature with the flow guide device and delivering the fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature.

[0279] Aspect 64 provides the method of any one of Aspects 54-63, comprising modulating blood flow to the ostia of the targeted vasculature with the flow guide device.

[0280] Aspect 65 provides the method of Aspect 64, wherein the modulating of blood flow to the ostia of the targeted vasculature suppresses bleeding, slows or prevents growth of the hemorrhage, or a combination thereof.

[0281] Aspect 66 provides the method of any one of Aspects 64-65, wherein the modulating of blood flow to the ostia of the targeted vasculature suppresses bleeding by reducing the pressure and flow rate at a site of the hemorrhage.

[0282] Aspect 67 provides the method of any one of Aspects 64-66, wherein the modulating of blood flow to the ostia of the targeted vasculature slows or prevents the growth of the hematoma by limiting the influx of blood to a site of the hemorrhage.

[0283] Aspect 68 provides the method of any one of Aspects 64-67, wherein the modulating of blood flow to the ostia of the targeted vasculature facilitates the natural hemostatic process by creating conditions that promote clot formation at a site of the hemorrhage.

[0284] Aspect 69 provides the method of any one of Aspects 64-68, wherein the modulating of blood flow to the ostia of the targeted vasculature reduces the risk of rebleeding by stabilizing the hemodynamic environment around a site of the hemorrhage.

[0285] Aspect 70 provides the method of any one of Aspects 64-69, wherein the modulating of blood flow to the ostia of the targeted vasculature enhances the efficacy ofconcurrently administered therapeutic agents by maintaining them at a site of the hemorrhage for a longer duration.

[0286] Aspect 71 provides the method of any one of Aspects 64-70, wherein the modulating of blood flow to the ostia of the targeted vasculature minimizes ischemic injury to surrounding tissues by ensuring adequate perfusion while controlling the hemorrhage.

[0287] Aspect 72 provides the method of any one of Aspects 64-71, wherein the modulating of blood flow to the ostia of the targeted vasculature aids in the resolution of the hemorrhage by facilitating the clearance of blood products from a site of the hemorrhage.

[0288] Aspect 73 provides the method of any one of Aspects 64-72, wherein the modulating of blood flow to the ostia of the targeted vasculature is adjusted dynamically in response to real-time imaging feedback to optimize treatment outcomes for the hemorrhage.

[0289] Aspect 74 provides the method of any one of Aspects 64-73, wherein the modulating of blood flow to the ostia of the targeted vasculature is tailored to the specific location and severity of the hemorrhage to maximize therapeutic effectiveness.

[0290] Aspect 75 provides the method of any one of Aspects 64-74, wherein the modulating of blood flow to the ostia of the targeted vasculature is part of a comprehensive treatment strategy that includes monitoring and adjusting other physiological parameters to support hemorrhage resolution.

[0291] Aspect 76 provides the method of any one of Aspects 64-75, wherein a duration of flow restriction in the targeted vasculature is 30 minutes to 6 hours.

[0292] Aspect 77 provides the method of any one of Aspects 54-76, comprising delivering the fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature.

[0293] Aspect 78 provides the method of Aspect 77, wherein a volume of the fluid injected to the gap is 0.5 mb to 20 mL.

[0294] Aspect 79 provides the method of any one of Aspects 77-78, wherein the delivering the fluid to the gap comprises delivering the fluid to the gap using a microcatheter (e.g., a second microcatheter), using a needle, using a conduit, using a conduit in the flow guide device, or a combination thereof.

[0295] Aspect 80 provides the method of any one of Aspects 77-79, wherein the fluid is chosen from high viscosity fluids, hemostatic agents, embolization agents, thrombolysis agents, chemotherapy agents, and a combination thereof.

[0296] Aspect 81 provides the method of any one of Aspects 77-80, wherein a duration of flow restriction in the targeted vasculature by the fluid is 30 minutes to 6 hours.

[0297] Aspect 82 provides the method of any one of Aspects 77-81, wherein the fluid comprises a high viscosity fluid.

[0298] Aspect 83 provides the method of Aspect 82, wherein the high viscosity fluid comprises a viscosifying polymer chosen from albumin, alginate, chitosan, collagen, hyaluronic acid / salt, gelatin, dextran, fibrinogen, hydroxyethyl starch, polysaccharides, stroma-free hemoglobin, carrageenan, agrose, gellan, gum, fucoidan, xanthan gum, cellulose, starch, chitin, pectin, xylan, glycogen, lignin, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, polyhydroxyalkanoates, polyhydroxybutyrate, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, poly(2-ethyl-2-oxazoline), a polysorbates, poly(acrylic acid), poly(N-vinylcaprolactam), and a combination thereof.

[0299] Aspect 84 provides the method of any one of Aspects 82-83, wherein the high viscosity fluid comprises alginate, hyaluronic acid / salt, dextran, hydroxyethyl starch, polysaccharides, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, or a combination thereof.

[0300] Aspect 85 provides the method of any one of Aspects 82-84, wherein the high viscosity fluid comprises a hydrogel or a hydrogel starting material.

[0301] Aspect 86 provides the method of Aspect 85, wherein the hydrogel or hydrogel starting material comprises albumin with aldehydes, alginate with calcium ion, hyaluronic acid / salt with divinyl sulfone, collagen with aldehydes, gelatin with aldehydes, chitosan with aldehydes, chitosan with genipin, or a combination thereof

[0302] Aspect 87 provides the method of any one of Aspects 82-86, wherein a viscosifying polymer is 1 mg / mL to 300 mg / mL of the high viscosity fluid.

[0303] Aspect 88 provides the method of any one of Aspects 82-87, wherein a viscosifying polymer is 5 mg / mL to 100 mg / mL of the high viscosity fluid.

[0304] Aspect 89 provides the method of any one of Aspects 82-88, wherein the high viscosity fluid has a viscosity range of 10 centipoise to 500,000 centipoise to effectively modulate blood flow and treat the hemorrhage.

[0305] Aspect 90 provides the method of any one of Aspects 82-89, wherein the high viscosity fluid is formulated to increase the resistance to blood flow at the site of the hemorrhage, thereby reducing bleeding and promoting hemostasis.

[0306] Aspect 91 provides the method of any one of Aspects 82-90, wherein the high viscosity fluid is designed to penetrate the downstream arterioles and capillaries, increasing local blood viscosity and reducing flow to the hemorrhagic site.

[0307] Aspect 92 provides the method of any one of Aspects 82-91, wherein the high viscosity fluid is delivered in a volume sufficient to achieve a targeted reduction in blood flow rate to a site of the hemorrhage site, thereby suppressing bleeding.

[0308] Aspect 93 provides the method of any one of Aspects 82-92, wherein the high viscosity fluid is combined with a cross-linking agent to form a hydrogel that provides sustained modulation of blood flow and supports clot formation at a site of the hemorrhage.

[0309] Aspect 94 provides the method of any one of Aspects 82-93, wherein the high viscosity fluid is tailored to the specific characteristics of the hemorrhage, such as size and location, to optimize therapeutic outcomes.

[0310] Aspect 95 provides the method of any one of Aspects 82-94, wherein the high viscosity fluid is delivered in a controlled manner to ensure even distribution and effective treatment of the hemorrhage.

[0311] Aspect 96 provides the method of any one of Aspects 82-95, wherein the high viscosity fluid is designed to be gradually cleared from a site of the hemorrhage, allowing for restoration of normal blood flow once the hemorrhage is resolved.

[0312] Aspect 97 provides the method of any one of Aspects 82-96, wherein the high viscosity fluid enhances the retention of therapeutic agents at a site of the hemorrhage, thereby improving the efficacy of the treatment.

[0313] Aspect 98 provides the method of any one of Aspects 82-97, wherein the method further comprises administering a reverse agent into the gap between the ostia of the targeted vasculature and the central portion of the flow guide device.

[0314] Aspect 99 provides the method of Aspect 98, wherein the reverse agent is part of the fluid that includes the highly viscous fluid.

[0315] Aspect 100 provides the method of any one of Aspects 98-99, wherein the reverse agent is administered after the administration of the highly viscous fluid.

[0316] Aspect 101 provides the method of any one of Aspects 98-100, wherein the reverse agent comprises alginate lyse, chitinase, chitosanase, lysozyme, collagenase, hyaluronidase, P-D-glucuronidase, P-N-acetyl-hexosaminidase, gelatinase, dextranase, glycoside hydrolases, streptokinase, alteplase, Reteplase, tenecteplase, urokinase, prourokinase, anistreplase, or a combination thereof.

[0317] Aspect 102 provides the method of any one of Aspects 77-101, wherein the fluid comprises a hemostatic agent.

[0318] Aspect 103 provides the method of Aspect 102, wherein the fluid comprises a hemostatic agent chosen from aprotinin, nafamostat, tranexamic acid, epsilon-aminocaproic acid, desmopressin acetate, estrogen, fresh frozen plasma, prothrombin complex concentrate, recombinant Factor Vila, chitosan, collagen, fibrinogen, gelatin, thrombin, desmopressin, vitamin K, and a combination thereof.

[0319] Aspect 104 provides the method of any one of Aspects 102-103, wherein the hemostatic agent is tranexamic acid, epsilon-aminocaproic acid, prothrombin complex concentrate, recombinant Factor Vila, or a combination thereof.

[0320] Aspect 105 provides the method of any one of Aspects 102-104, wherein the hemostatic agent is 0.001 wt% to 100 wt% of non-aqueous components of the fluid.

[0321] Aspect 106 provides the method of any one of Aspects 102-105, wherein the hemostatic agent is 0.001 wt% to 50 wt% of non-aqueous components of the fluid.

[0322] Aspect 107 provides the method of any one of Aspects 102-106, wherein the hemostatic agent is formulated to promote platelet aggregation and fibrin clot formation at a site of the hemorrhage, thereby reducing bleeding.

[0323] Aspect 108 provides the method of any one of Aspects 102-107, wherein the hemostatic agent is delivered in a concentration sufficient to achieve rapid hemostasis and stabilize a site of the hemorrhage.

[0324] Aspect 109 provides the method of any one of Aspects 102-108, wherein the hemostatic agent is designed to enhance the natural coagulation cascade, facilitating the formation of a stable clot at a site of the hemorrhage.

[0325] Aspect 110 provides the method of any one of Aspects 102-109, wherein the hemostatic agent is delivered in a controlled manner to ensure even distribution and effective treatment of the hemorrhage.

[0326] Aspect 111 provides the method of any one of Aspects 102-110, wherein the hemostatic agent is tailored to the specific characteristics of the hemorrhage, such as size and location, to optimize therapeutic outcomes.

[0327] Aspect 112 provides the method of any one of Aspects 102-111, wherein the hemostatic agent is designed to be gradually metabolized and cleared from the site, allowing for restoration of normal blood flow once the hemorrhage is resolved.

[0328] Aspect 113 provides the method of any one of Aspects 102-112, wherein the hemostatic agent enhances the retention of therapeutic agents at the hemorrhagic site, thereby improving the efficacy of the treatment.

[0329] Aspect 114 provides the method of any one of Aspects 102-113, wherein the hemostatic agent is combined with other therapeutic agents to provide a synergistic effect in treating the hemorrhage.

[0330] Aspect 115 provides the method of any one of Aspects 102-114, wherein the hemostatic agent is delivered in a form that allows for sustained release, providing prolonged hemostatic activity at a site of the hemorrhage.

[0331] Aspect 116 provides the method of any one of Aspects 102-115, wherein the method further comprises administration of a thrombolytic agent to the gap between the ostia of the targeted vasculature and the central portion of the flow guide device.

[0332] Aspect 117 provides the method of Aspect 116, wherein the thrombolytic agent is administered in the fluid that comprises the hemostatic agent.

[0333] Aspect 118 provides the method of any one of Aspects 116-117, wherein the thrombolytic agent is administered after the administration of the fluid that comprises the hemostatic agent.

[0334] Aspect 119 provides the method of any one of Aspects 116-118, wherein the thrombolytic agent comprises streptokinase, alteplase, reteplase, tenecteplase, urokinase,prourokinase, and anistreplase, chitinase, chitosanase, collagenase, gelatinase, or a combination thereof.

[0335] Aspect 120 provides the method of any one of Aspects 77-119, wherein the fluid comprises a vasoconstrictor.

[0336] Aspect 121 provides the method of Aspect 120, wherein the fluid comprises a vasoconstrictor chosen from norepinephrine, epinephrine (adrenaline), angiotensin II, vasopressin (antidiuretic hormone, ADH), phenylephrine, pseudoephedrine, dopamine, midodrine, methoxamine, pitressin, terlipressin, desmopressin, angiotensin II, giapreza, ergotamine, methylergonovine, methergine, naphazoline, oxymetazoline, xylometazoline, Bay K 8644, and a combination thereof.

[0337] Aspect 122 provides the method of any one of Aspects 120-121, wherein the vasoconstrictor is norepinephrine, epinephrine (adrenaline), angiotensin II, vasopressin (antidiuretic hormone, ADH), phenylephrine, pseudoephedrine, dopamine, midodrine, or a combination thereof.

[0338] Aspect 123 provides the method of any one of Aspects 120-122, wherein the vasoconstrictor is 0.001 wt% to 100 wt% of non-aqueous components of the fluid.

[0339] Aspect 124 provides the method of any one of Aspects 120-123, wherein the vasoconstrictor is 0.001 wt% to 50 wt% of non-aqueous components of the fluid.

[0340] Aspect 125 provides the method of any one of Aspects 120-124, wherein the vasoconstrictor is formulated to induce contraction of the vessel walls at the site of the hemorrhage, thereby reducing blood flow and minimizing bleeding.

[0341] Aspect 126 provides the method of any one of Aspects 120-125, wherein the vasoconstrictor is delivered in a concentration sufficient to achieve rapid vasoconstriction and stabilize the hemorrhagic site.

[0342] Aspect 127 provides the method of any one of Aspects 120-126, wherein the vasoconstrictor is designed to enhance the natural hemostatic process by reducing vessel diameter and promoting clot formation at the site of the hemorrhage.

[0343] Aspect 128 provides the method of any one of Aspects 120-127, wherein the vasoconstrictor is delivered in a controlled manner to ensure even distribution and effective treatment of the hemorrhage.

[0344] Aspect 129 provides the method of any one of Aspects 120-128, wherein the vasoconstrictor is tailored to the specific characteristics of the hemorrhage, such as size and location, to optimize therapeutic outcomes.

[0345] Aspect 130 provides the method of any one of Aspects 120-129, wherein the vasoconstrictor is designed to be gradually metabolized and cleared from the site, allowing for restoration of normal blood flow once the hemorrhage is resolved.

[0346] Aspect 131 provides the method of any one of Aspects 120-130, wherein the vasoconstrictor enhances the retention of therapeutic agents at the hemorrhagic site, thereby improving the efficacy of the treatment.

[0347] Aspect 132 provides the method of any one of Aspects 120-131, wherein the vasoconstrictor is combined with other therapeutic agents to provide a synergistic effect in treating the hemorrhage.

[0348] Aspect 133 provides the method of any one of Aspects 120-132, wherein the vasoconstrictor is delivered in a form that allows for sustained release, providing prolonged vasoconstrictive activity at the site of the hemorrhage.

[0349] Aspect 134 provides the method of any one of Aspects 120-133, wherein the method further comprises administering a vasodilator agent to the gap between the ostia of the targeted vasculature and the central portion of the flow guide device.

[0350] Aspect 135 provides the method of Aspect 134, wherein the vasodilator agent is administered in the fluid that comprises the vasoconstrictor.

[0351] Aspect 136 provides the method of any one of Aspects 134-135, wherein the vasodilator agent is administered after administration of the fluid that comprises the vasoconstrictor.

[0352] Aspect 137 provides the method of any one of Aspects 134-136, wherein the vasodilator agent comprises nitroglycerin, sodium nitroprusside, hydralazine, calcium channel blockers, phentolamine, prazosin, doxazosin, labetalol, or a combination thereof.

[0353] Aspect 138 provides the method of any one of Aspects 77-137, wherein the fluid comprises a thrombolytic or fibrinolytic agent.

[0354] Aspect 139 provides the method of Aspect 138, wherein the thrombolytic or fibrinolytic agent comprises streptokinase, alteplase, reteplase, tenecteplase, urokinase, prourokinase, anistreplase, or a combination thereof.

[0355] Aspect 140 provides the method of any one of Aspects 138-139, wherein the thrombolytic or fibrinolytic agent is 0.001 wt% to 100 wt% of the fluid.

[0356] Aspect 141 provides the method of any one of Aspects 138-140, wherein the thrombolytic or fibrinolytic agent is 0.001 wt% to 50 wt% of the fluid.

[0357] Aspect 142 provides a method of treating an intracerebral hemorrhage with the flow guide device of any one of Aspects 1-48, the method comprising: delivering the flow guide device in the parent artery comprising ostia of targeted vasculature comprising the intracerebral hemorrhage; modulating blood flow to the ostia of the targeted vasculature with the flow guide device and delivering a fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature, wherein the fluid comprises a viscosifying polymer chosen from albumin, alginate, chitosan, collagen, hyaluronic acid / salt, gelatin, dextran, fibrinogen, hydroxyethyl starch, polysaccharides, stroma- free hemoglobin, carrageenan, agrose, gellan, gum, fucoidan, xanthan gum, cellulose, starch, chitin, pectin, xylan, glycogen, lignin, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, polyhydroxyalkanoates, polyhydroxybutyrate, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, poly(2-ethyl-2-oxazoline), a polysorbates, poly(acrylic acid), poly(N-vinylcaprolactam), and a combination thereof, a hemostatic agent chosen from aprotinin, nafamostat, tranexamic acid, epsilon- aminocaproic acid, desmopressin acetate, estrogen, fresh frozen plasma, prothrombin complex concentrate, recombinant Factor Vila, chitosan, collagen, fibrinogen, gelatin, thrombin, desmopressin, vitamin K, and a combination thereof, a vasoconstrictor chosen from norepinephrine, epinephrine (adrenaline), angiotensin II, vasopressin (antidiuretic hormone, ADH), phenylephrine, pseudoephedrine, dopamine, midodrine, methoxamine, pitressin, terlipressin, desmopressin, angiotensin II, giapreza, ergotamine, methylergonovine, methergine, naphazoline, oxymetazoline, xylometazoline, Bay K 8644, and a combination thereof, or a combination thereof; and retracting the flow guide device from the parent artery.

[0358] Aspect 143 provides a method of treating a hemorrhage with a treatment fluid, the method comprising: delivering the treatment fluid to targeted vasculature comprising the hemorrhage to modulate blood flow to the targeted vasculature, wherein the treatment fluid comprises a viscosifying polymer, a hemostatic agent, a vasoconstrictor, or a combination thereof.

[0359] Aspect 144 provides the method of Aspect 143, wherein the hemorrhage is an intracerebral hemorrhage, epidural hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, thoracic hemorrhage, gastrointestinal (GI) hemorrhage, abdominal hemorrhage, retroperitoneal hemorrhage, musculoskeletal hemorrhage, subconjunctival hemorrhage, postpartum hemorrhage, or ectopic pregnancy rupture.

[0360] Aspect 145 provides the method of any one of Aspects 143-144, wherein the treatment fluid is injected into a parent artery comprising ostia of the targeted vasculature, into a parent artery that supplies blood to the targeted vasculature, into the targeted vasculature, into an artery within the brain, or a combination thereof.

[0361] Aspect 146 provides the method of any one of Aspects 143-145, wherein the treatment fluid is injected into the parent artery within 200 mm of the ostia of the targeted vasculature.

[0362] Aspect 147 provides the method of any one of Aspects 143-146, wherein the treatment fluid is injected into the parent artery within 50 mm of the ostia of the targeted vasculature.

[0363] Aspects 148 provides the method of any one of Aspects 145-147, wherein the treatment fluid is injected to a proximal section of the parent artery.

[0364] Aspect 149 provides the method of any one of Aspects 144-148, wherein the delivery of the treatment fluid suppresses bleeding of the hemorrhage, slows or prevents growth of the hemorrhage, or a combination thereof.

[0365] Aspect 150 provides the method of any one of Aspects 144-149, comprising performing the delivering of the treatment fluid endovascularly.

[0366] Aspect 151 provides the method of any one of Aspects 144-150, comprising repeating the delivering of the fluid.

[0367] Aspect 152 provides the method of any one of Aspects 144-1 1, wherein the modulating of blood flow to the ostia of the targeted vasculature suppresses bleeding by reducing the pressure and flow rate at a site of the hemorrhage.

[0368] Aspect 153 provides the method of any one of Aspects 144-152, wherein the modulating of blood flow to the targeted vasculature slows or prevents the growth of the hemorrhage by limiting the influx of blood to a site of the hemorrhage.

[0369] Aspect 154 provides the method of any one of Aspects 144-153, wherein the modulating of blood flow to the targeted vasculature facilitates the natural hemostatic process by creating conditions that promote clot formation at a site of the hemorrhage.

[0370] Aspect 155 provides the method of any one of Aspects 144-154, wherein the modulating of blood flow to the targeted vasculature reduces the risk of rebleeding by stabilizing the hemodynamic environment around a site of the hemorrhage.

[0371] Aspect 156 provides the method of any one of Aspects 144-155, wherein the modulating of blood flow to the targeted vasculature enhances the efficacy of concurrently administered therapeutic agents by maintaining them at a site of the hemorrhage for a longer duration.

[0372] Aspect 157 provides the method of any one of Aspects 144-156, wherein the modulating of blood flow to the targeted vasculature minimizes ischemic injury to surrounding tissues by ensuring adequate perfusion while controlling the hemorrhage.

[0373] Aspect 158 provides the method of any one of Aspects 144-157, wherein the modulating of blood flow to the targeted vasculature aids in the resolution of the hemorrhage by facilitating the clearance of blood products from a site of the hemorrhage.

[0374] Aspect 159 provides the method of any one of Aspects 144-158, wherein the modulating of blood flow to the targeted vasculature is adjusted dynamically in response to realtime imaging feedback to optimize treatment outcomes for the hemorrhage.

[0375] Aspect 160 provides the method of any one of Aspects 144-159, wherein the modulating of blood flow to the targeted vasculature is tailored to the specific location and severity of the hemorrhage to maximize therapeutic effectiveness.

[0376] Aspect 161 provides the method of any one of Aspects 144-160, wherein the modulating of blood flow to the targeted vasculature is part of a comprehensive treatmentstrategy that includes monitoring and adjusting other physiological parameters to support hemorrhage resolution.

[0377] Aspect 162 provides the method of any one of Aspects 144-161, wherein a duration of flow restriction in the targeted vasculature is 30 minutes to 6 hours.

[0378] Aspect 163 provides the method of any one of Aspects 144-162, wherein a volume of the treatment fluid delivered is 0.5 mL to 20 mL.

[0379] Aspect 164 provides the method of any one of Aspects 144-163, wherein the delivering the fluid comprises delivering the fluid using a microcatheter, using a needle, using a conduit, or a combination thereof.

[0380] Aspect 165 provides the method of any one of Aspects 144-164, wherein the fluid comprises a viscosifying polymer, a hemostatic agent, an embolization agent, a thrombolysis agent, a chemotherapy agent, or a combination thereof.

[0381] Aspect 166 provides the method of any one of Aspects 144-165, wherein a duration of flow restriction in the targeted vasculature by the fluid is 30 minutes to 6 hours.

[0382] Aspect 167 provides the method of any one of Aspects 144-166, wherein the fluid comprises a viscosifying polymer.

[0383] Aspect 168 provides the method of Aspect 167, wherein the viscosifying polymer is chosen from albumin, alginate, chitosan, collagen, hyaluronic acid / salt, gelatin, dextran, fibrinogen, hydroxyethyl starch, polysaccharides, stroma-free hemoglobin, carrageenan, agrose, gellan, gum, fucoidan, xanthan gum, cellulose, starch, chitin, pectin, xylan, glycogen, lignin, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, polyhydroxyalkanoates, polyhydroxybutyrate, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, poly(2-ethyl-2-oxazoline), a polysorbates, poly(acrylic acid), poly(N- vinylcaprolactam), and a combination thereof.

[0384] Aspect 169 provides the method of any one of Aspects 167-168, wherein the viscosifying polymer comprises alginate, hyaluronic acid / salt, dextran, hydroxyethyl starch, polysaccharides, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, or a combination thereof.

[0385] Aspect 170 provides the method of any one of Aspects 167-169, wherein the viscosifying polymer comprises a hydrogel or a hydrogel starting material.

[0386] Aspect 171 provides the method of Aspect 170, wherein the hydrogel or hydrogel starting material comprises albumin with aldehydes, alginate with calcium ion, hyaluronic acid / salt with divinyl sulfone, collagen with aldehydes, gelatin with aldehydes, chitosan with aldehydes, chitosan with genipin, or a combination thereof

[0387] Aspect 172 provides the method of any one of Aspects 167-171, wherein a viscosifying polymer is 1 mg / mL to 300 mg / mL of the treatment fluid.

[0388] Aspect 173 provides the method of any one of Aspects 167-172, wherein a viscosifying polymer is 5 mg / mL to 100 mg / mL of the treatment fluid.

[0389] Aspect 174 provides the method of any one of Aspects 167-173, wherein the treatment fluid has a viscosity range of 10 centipoise to 500,000 centipoise to effectively modulate blood flow and treat the hemorrhage.

[0390] Aspect 175 provides the method of any one of Aspects 167-174, wherein the treatment fluid is formulated to increase the resistance to blood flow at the site of the hemorrhage, thereby reducing bleeding and promoting hemostasis.

[0391] Aspect 176 provides the method of any one of Aspects 167-175, wherein the treatment fluid is designed to penetrate the downstream arterioles and capillaries, increasing local blood viscosity and reducing flow to the hemorrhagic site.

[0392] Aspect 177 provides the method of any one of Aspects 167-176, wherein the treatment fluid is delivered in a volume sufficient to achieve a targeted reduction in blood flow rate to a site of the hemorrhage site, thereby suppressing bleeding.

[0393] Aspect 178 provides the method of any one of Aspects 167-177, wherein viscosifying polymer is combined with a cross-linking agent to form a hydrogel that provides sustained modulation of blood flow and supports clot formation at a site of the hemorrhage.

[0394] Aspect 179 provides the method of any one of Aspects 167-178, wherein the viscosifying polymer is tailored to the specific characteristics of the hemorrhage, such as size and location, to optimize therapeutic outcomes.

[0395] Aspect 180 provides the method of any one of Aspects 167-179, wherein the treatment fluid is delivered in a controlled manner to ensure even distribution and effective treatment of the hemorrhage.

[0396] Aspect 181 provides the method of any one of Aspects 167-180, wherein the treatment fluid including the viscosifying polymer is designed to be gradually cleared from a siteof the hemorrhage, allowing for restoration of normal blood flow once the hemorrhage is resolved.

[0397] Aspect 182 provides the method of any one of Aspects 167-181, wherein the treatment fluid comprising the viscosifying polymer enhances the retention of therapeutic agents at a site of the hemorrhage, thereby improving the efficacy of the treatment.

[0398] Aspect 183 provides the method of any one of Aspects 167-182, wherein the method further comprises administering a reverse agent to the targeted vasculature.

[0399] Aspect 184 provides the method of Aspect 183, wherein the reverse agent is part of the fluid that includes the highly viscous fluid.

[0400] Aspect 185 provides the method of any one of Aspects 183-184, wherein the reverse agent is administered after the administration of the highly viscous fluid.

[0401] Aspect 186 provides the method of any one of Aspects 183-185, wherein the reverse agent comprises alginate lyse, chitinase, chitosanase, lysozyme, collagenase, hyaluronidase, P-D-glucuronidase, P-N-acetyl-hexosaminidase, gelatinase, dextranase, glycoside hydrolases, streptokinase, alteplase, Reteplase, tenecteplase, urokinase, prourokinase, anistreplase, or a combination thereof.

[0402] Aspect 187 provides the method of any one of Aspects 144-186, wherein the fluid comprises a hemostatic agent.

[0403] Aspect 188 provides the method of Aspect 187, wherein the fluid comprises a hemostatic agent chosen from aprotinin, nafamostat, tranexamic acid, epsilon-aminocaproic acid, desmopressin acetate, estrogen, fresh frozen plasma, prothrombin complex concentrate, recombinant Factor Vila, chitosan, collagen, fibrinogen, gelatin, thrombin, desmopressin, vitamin K, and a combination thereof.

[0404] Aspect 189 provides the method of any one of Aspects 187-188, wherein the hemostatic agent is tranexamic acid, epsilon-aminocaproic acid, prothrombin complex concentrate, recombinant Factor Vila, or a combination thereof.

[0405] Aspect 190 provides the method of any one of Aspects 187-189, wherein the hemostatic agent is 0.001 wt% to 100 wt% of non-aqueous components of the fluid.

[0406] Aspect 191 provides the method of any one of Aspects 187-190, wherein the hemostatic agent is 0.001 wt% to 50 wt% of non-aqueous components of the fluid.

[0407] Aspect 192 provides the method of any one of Aspects 187-191, wherein the hemostatic agent is formulated to promote platelet aggregation and fibrin clot formation at a site of the hemorrhage, thereby reducing bleeding.

[0408] Aspect 193 provides the method of any one of Aspects 187-192, wherein the hemostatic agent is delivered in a concentration sufficient to achieve rapid hemostasis and stabilize a site of the hemorrhage.

[0409] Aspect 194 provides the method of any one of Aspects 187-193, wherein the hemostatic agent is designed to enhance the natural coagulation cascade, facilitating the formation of a stable clot at a site of the hemorrhage.

[0410] Aspect 195 provides the method of any one of Aspects 187-194, wherein the hemostatic agent is delivered in a controlled manner to ensure even distribution and effective treatment of the hemorrhage.

[0411] Aspect 196 provides the method of any one of Aspects 187-195, wherein the hemostatic agent is tailored to the specific characteristics of the hemorrhage, such as size and location, to optimize therapeutic outcomes.

[0412] Aspect 197 provides the method of any one of Aspects 187-196, wherein the hemostatic agent is designed to be gradually metabolized and cleared from the site, allowing for restoration of normal blood flow once the hemorrhage is resolved.

[0413] Aspect 198 provides the method of any one of Aspects 187-197, wherein the hemostatic agent enhances the retention of therapeutic agents at the hemorrhagic site, thereby improving the efficacy of the treatment.

[0414] Aspect 199 provides the method of any one of Aspects 187-198, wherein the hemostatic agent is combined with other therapeutic agents to provide a synergistic effect in treating the hemorrhage.

[0415] Aspect 200 provides the method of any one of Aspects 187-199, wherein the hemostatic agent is delivered in a form that allows for sustained release, providing prolonged hemostatic activity at a site of the hemorrhage.

[0416] Aspect 201 provides the method of any one of Aspects 187-200, wherein the method further comprises administration of a thrombolytic agent to the targeted vasculature.

[0417] Aspect 202 provides the method of Aspect 201, wherein the thrombolytic agent is administered in the fluid that comprises the hemostatic agent.

[0418] Aspect 203 provides the method of any one of Aspects 201-202, wherein the thrombolytic agent is administered after the administration of the fluid that comprises the hemostatic agent.

[0419] Aspect 204 provides the method of any one of Aspects 201-203, wherein the thrombolytic agent comprises streptokinase, alteplase, reteplase, tenecteplase, urokinase, prourokinase, and anistreplase, chitinase, chitosanase, collagenase, gelatinase, or a combination thereof.

[0420] Aspect 205 provides the method of any one of Aspects 144-204, wherein the fluid comprises a vasoconstrictor.

[0421] Aspect 206 provides the method of Aspect 205, wherein the fluid comprises a vasoconstrictor chosen from norepinephrine, epinephrine (adrenaline), angiotensin II, vasopressin (antidiuretic hormone, ADH), phenylephrine, pseudoephedrine, dopamine, midodrine, methoxamine, pitressin, terlipressin, desmopressin, angiotensin II, giapreza, ergotamine, methylergonovine, methergine, naphazoline, oxymetazoline, xylometazoline, Bay K 8644, and a combination thereof.

[0422] Aspect 207 provides the method of any one of Aspects 205-206, wherein the vasoconstrictor is norepinephrine, epinephrine (adrenaline), angiotensin II, vasopressin (antidiuretic hormone, ADH), phenylephrine, pseudoephedrine, dopamine, midodrine, or a combination thereof.

[0423] Aspect 208 provides the method of any one of Aspects 205-207, wherein the vasoconstrictor is 0.001 wt% to 100 wt% of non-aqueous components of the fluid.

[0424] Aspect 209 provides the method of any one of Aspects 205-208, wherein the vasoconstrictor is 0.001 wt% to 50 wt% of non-aqueous components of the fluid.

[0425] Aspect 210 provides the method of any one of Aspects 205-209, wherein the vasoconstrictor is formulated to induce contraction of the vessel walls at the site of the hemorrhage, thereby reducing blood flow and minimizing bleeding.

[0426] Aspect 211 provides the method of any one of Aspects 205-210, wherein the vasoconstrictor is delivered in a concentration sufficient to achieve rapid vasoconstriction and stabilize the hemorrhagic site.

[0427] Aspect 212 provides the method of any one of Aspects 205-211, wherein the vasoconstrictor is designed to enhance the natural hemostatic process by reducing vessel diameter and promoting clot formation at the site of the hemorrhage.

[0428] Aspect 213 provides the method of any one of Aspects 205-212, wherein the vasoconstrictor is delivered in a controlled manner to ensure even distribution and effective treatment of the hemorrhage.

[0429] Aspect 214 provides the method of any one of Aspects 205-213, wherein the vasoconstrictor is tailored to the specific characteristics of the hemorrhage, such as size and location, to optimize therapeutic outcomes.

[0430] Aspect 215 provides the method of any one of Aspects 205-214, wherein the vasoconstrictor is designed to be gradually metabolized and cleared from the site, allowing for restoration of normal blood flow once the hemorrhage is resolved.

[0431] Aspect 216 provides the method of any one of Aspects 205-215, wherein the vasoconstrictor enhances the retention of therapeutic agents at the hemorrhagic site, thereby improving the efficacy of the treatment.

[0432] Aspect 217 provides the method of any one of Aspects 205-216, wherein the vasoconstrictor is combined with other therapeutic agents to provide a synergistic effect in treating the hemorrhage.

[0433] Aspect 218 provides the method of any one of Aspects 205-217, wherein the vasoconstrictor is delivered in a form that allows for sustained release, providing prolonged vasoconstrictive activity at the site of the hemorrhage.

[0434] Aspect 219 provides the method of any one of Aspects 205-218, wherein the method further comprises administering a vasodilator agent to the targeted vasculature.

[0435] Aspect 220 provides the method of Aspect 219, wherein the vasodilator agent is administered in the fluid that comprises the vasoconstrictor.

[0436] Aspect 221 provides the method of any one of Aspects 219-220, wherein the vasodilator agent is administered after administration of the fluid that comprises the vasoconstrictor.

[0437] Aspect 222 provides the method of any one of Aspects 219-221, wherein the vasodilator agent comprises nitroglycerin, sodium nitroprusside, hydralazine, calcium channel blockers, phentolamine, prazosin, doxazosin, labetalol, or a combination thereof.

[0438] Aspect 223 provides the method of any one of Aspects 144-222, wherein the fluid further comprises a thrombolytic or fibrinolytic agent.

[0439] Aspect 224 provides the method of Aspect 223, wherein the thrombolytic or fibrinolytic agent comprises streptokinase, alteplase, reteplase, tenecteplase, urokinase, prourokinase, anistreplase, or a combination thereof.

[0440] Aspect 225 provides the method of any one of Aspects 223-224, wherein the thrombolytic or fibrinolytic agent is 0.001 wt% to 100 wt% of the fluid.

[0441] Aspect 226 provides the method of any one of Aspects 223-225, wherein the thrombolytic or fibrinolytic agent is 0.001 wt% to 50 wt% of the fluid.

[0442] Aspect 227 provides a method of treating a cerebral hemorrhage with a treatment fluid, the method comprising: delivering the treatment fluid to targeted vasculature comprising the hemorrhage to modulate blood flow to the targeted vasculature, wherein the treatment fluid comprises a viscosifying polymer chosen from albumin, alginate, chitosan, collagen, hyaluronic acid / salt, gelatin, dextran, fibrinogen, hydroxyethyl starch, polysaccharides, stroma- free hemoglobin, carrageenan, agrose, gellan, gum, fucoidan, xanthan gum, cellulose, starch, chitin, pectin, xylan, glycogen, lignin, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, polyhydroxyalkanoates, polyhydroxybutyrate, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, poly(2-ethyl-2-oxazoline), a polysorbates, poly(acrylic acid), poly(N-vinylcaprolactam), and a combination thereof, a hemostatic agent chosen from aprotinin, nafamostat, tranexamic acid, epsilon- aminocaproic acid, desmopressin acetate, estrogen, fresh frozen plasma, prothrombin complex concentrate, recombinant Factor Vila, chitosan, collagen, fibrinogen, gelatin, thrombin, desmopressin, vitamin K, and a combination thereof, a vasoconstrictor chosen from norepinephrine, epinephrine (adrenaline), angiotensin II, vasopressin (antidiuretic hormone, ADH), phenylephrine, pseudoephedrine, dopamine, midodrine, methoxamine, pitressin, terlipressin, desmopressin, angiotensin II, giapreza, ergotamine, methyl ergonovine, methergine, naphazoline, oxymetazoline, xylometazoline, Bay K 8644, and a combination thereof, or a combination thereof.

[0443] Aspect 228 provides the flow guide device, medical device system, or method of any one or any combination of Aspects 1-227 optionally configured such that all elements or options recited are available to use or select from.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a hemorrhage with a treatment fluid, the method comprising: delivering the treatment fluid to targeted vasculature comprising the hemorrhage to modulate blood flow to the targeted vasculature, wherein the treatment fluid comprises a viscosifying polymer, a hemostatic agent, a vasoconstrictor, or a combination thereof.

2. The method of claim 1, wherein the treatment fluid is injected into a parent artery that supplies blood to the targeted vasculature or is injected into the targeted vasculature.

3. The method of claim 1, wherein the hemorrhage is an intracerebral hemorrhage.

4. The method of claim 1, wherein the hemorrhage is located within the brain, chest cavity, abdominal cavity, peritoneal cavity, retroperitoneum, gastrointestinal tract, thorax, spleen, liver, pelvis, uterus, a muscle, a joint, or can be a hemorrhage from long bone fractures.

5. The method of claim 1, wherein the delivering the fluid comprises delivering the fluid using a microcatheter, using a needle, using a conduit, or a combination thereof.

6. The method of claim 1, wherein the fluid comprises the viscosifying polymer, wherein the viscosifying polymer is chosen from a hydrogel, a hydrogel starting material, albumin, alginate, chitosan, collagen, hyaluronic acid / salt, gelatin, dextran, fibrinogen, hydroxyethyl starch, polysaccharides, stroma-free hemoglobin, carrageenan, agrose, gellan, gum, fucoidan, xanthan gum, cellulose, starch, chitin, pectin, xylan, glycogen, lignin, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, polyhydroxyalkanoates, polyhydroxybutyrate, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, poly(2-ethyl-2- oxazoline), a polysorbates, poly(acrylic acid), poly(N-vinylcaprolactam), and a combination thereof.

7. The method of claim 1, wherein the fluid comprises the hemostatic agent, wherein the hemostatic agent is chosen from aprotinin, nafamostat, tranexamic acid, epsilon-aminocaproic acid, desmopressin acetate, estrogen, fresh frozen plasma, prothrombin complex concentrate, recombinant Factor Vila, chitosan, collagen, fibrinogen, gelatin, thrombin, desmopressin, vitamin K, and a combination thereof.

8. The method of claim 1, wherein the fluid comprises the vasoconstrictor, wherein the vasoconstrictor is chosen from norepinephrine, epinephrine, angiotensin II, vasopressin, phenylephrine, pseudoephedrine, dopamine, midodrine, methoxamine, pitressin, terlipressin, desmopressin, angiotensin II, giapreza, ergotamine, methylergonovine, methergine, naphazoline, oxymetazoline, xylometazoline, Bay K 8644, and a combination thereof.

9. The method of claim 1, wherein the method further comprises delivering to the parent artery comprising ostia of targeted vasculature comprising the hemorrhage a reverse agent comprising: a reverse agent for the viscosifying polymer comprising alginate lyse, chitinase, chitosanase, lysozyme, collagenase, hyaluronidase, P-D-glucuronidase, 0-N-acetyl- hexosaminidase, gelatinase, dextranase, glycoside hydrolases, streptokinase, alteplase, Reteplase, tenecteplase, urokinase, prourokinase, anistreplase, or a combination thereof, or a reverse agent for the hemostatic comprising a thrombolytic agent comprising streptokinase, alteplase, reteplase, tenecteplase, urokinase, prourokinase, and anistreplase, chitinase, chitosanase, collagenase, gelatinase, or a combination thereof, or a reverse agent for the vasoconstrictor comprising a vasodilator comprising nitroglycerin, sodium nitroprusside, hydralazine, calcium channel blockers, phentolamine, prazosin, doxazosin, labetalol, or a combination thereof, or a combination thereof.

10. A flow guide device, the flow guide device comprising: a cylindrical structure with a low porosity wall, the flow guide device configured to be deployed in a parent artery comprising ostia of targeted vasculature, the cylindrical structure comprising a proximal portion and a distal portion with an expanded or inflated diameter thatensures full opposition of the proximal portion and the distal portion to a vessel wall of the parent artery, and a central portion with an expanded or inflated diameter that is less than the expanded or inflated diameter of the proximal portion and the distal portion to provide a gap between the ostia of the targeted vasculature and the wall of the central portion.

11. The flow guide device of claim 10, wherein the flow guide device modulates blood flow to the ostia of targeted vasculature at a treatment location while maintaining blood flow in the parent artery.

12. The flow guide device of claim 10, wherein the proximal and distal portions have a length of 3 mm to 7 mm, the expanded or inflated diameter of the proximal portion and distal portion is 1 mm to 7 mm, the central portion has an expanded or inflated diameter that is 0.001 mm to 2 mm less than the expanded or inflated diameter of the proximal portion and the distal portion, and the flow guide device has a length of 10 mm to 70 mm.

13. The flow guide device of claim 10, wherein the flow guide device comprises a selfexpanding stent comprising metallic wire woven braids or a laser-cut metallic tube, wherein the flow guide device comprises a proximal end structure with stent struts or braiding wires that come together to one point, wherein the point is configured to connect with a delivery wire for deployment and retraction of the flow guide device.

14. A medical device system for targeted endovascular delivery of a fluid, the medical device system comprising: the flow guide device of claim 10; a microcatheter for delivering the flow guide device to a parent artery comprising ostia of intended-to-treat branch arteries; and a delivery wire connected to the proximal end of the flow guide device for deployment and retraction.

15. A method of treating a hemorrhage with a flow guide device, the method comprising:delivering the flow guide device in the parent artery comprising ostia of targeted vasculature comprising the hemorrhage, the flow guide device comprising a cylindrical structure with a low porosity wall, the flow guide device configured to be deployed in a parent artery comprising ostia of targeted vasculature, the cylindrical structure comprising a proximal portion and a distal portion with an expanded or inflated diameter that ensures full opposition of the proximal portion and the distal portion to a vessel wall of the parent artery, and a central portion with an expanded or inflated diameter that is less than the expanded or inflated diameter of the proximal portion and the distal portion to provide a gap between the ostia of the targeted vasculature and the wall of the central portion; modulating blood flow to the ostia of the targeted vasculature with the flow guide device and / or delivering a fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature; and retracting the flow guide device from the parent artery.

16. The method of claim 15, wherein the hemorrhage is an intracerebral hemorrhage.

17. The method of claim 15, comprising maintaining blood flow in the parent artery while modulating blood flow to the targeted vasculature and / or while delivering the fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device.

18. The method of claim 15, comprising modulating blood flow to the ostia of the targeted vasculature with the flow guide device.

19. The method of claim 15, comprising delivering the fluid to the gap between the ostia of the targeted vasculature and the wall of the central portion of the flow guide device to deliver the fluid to the targeted vasculature, wherein the delivering the fluid to the gap comprises delivering the fluid to the gap using a microcatheter.

20. The method of claim 19, wherein the fluid comprises a viscosifying polymer, a hemostatic agent, a vasoconstrictor, an embolization agent, a thrombolysis agent, a chemotherapy agent, a reverse agent, a vasodilator agent, or a combination thereof.

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