WO2014036809A1

WO2014036809A1 - Endoluminal drug delivery devices with applications in blood vessels

Info

Publication number: WO2014036809A1
Application number: PCT/CN2013/001051
Authority: WO
Inventors: David Chuen Chun LAM; Alexander Ka Ngai LAM; John Ching Kwong KWOK; Matthew Ming Fai Yuen; Ka Kit LEUNG; Wai Lun KO; Chi Hang CHON
Original assignee: The Hong Kong University Of Science And Technology
Priority date: 2012-09-06
Filing date: 2013-09-06
Publication date: 2014-03-13

Abstract

Endoluminal coil devices comprising coil -shaped bodies are provided for delivering beneficial agents or combinations of beneficial agents topically inside aberrant cavities to initiate topical medicinal effects. Also provided are uses of the medical delivery devices for providing aneurysm treatment and vessel wall stabilization. The coil-shaped bodies are made of biodegradable material.

Description

ENDOLUMINAL DRUG DELIVERY DEVICES WITH APPLICATIONS IN BLOOD

VESSELS

DESCRIPTION

CROSS-REFERENCE TO RELATED APPLICATION The present application claims the benefit of U.S. Provisional Application Serial No. 61/697,328, filed September 6, 2012, which is hereby incorporated by reference herein in its entirety, including any figures, tables, or drawings.

TECHNICAL FIELD

This disclosure pertains generally to endoluminal delivery devices for the treatments of vascular and endoluminal diseases and more specifically for the treatment of intracranial vascular diseases.

BACKGROUND OF THE INVENTION

According to the U.S. National Institute of Neurological Disorders and Stroke, there are 10 cases of intracranial aneurysm ruptures in every 100,000 people each year. An aneurysm is an abnormal change in the shape or diameter of a blood vessel. The vessel from which the aneurysm protrudes is the parent vessel. Saccular aneurysms look like a sac protruding out from the parent vessel. Saccular aneurysms have a neck and can be prone to rupture. Fusiform aneurysms are a form of aneurysm in which a blood vessel is expanded circumferentially in all directions. As an aneurysm grows larger, its walls generally become thinner and weaker. This decrease in wall integrity, particularly for saccular aneurysms, increases the risk of the aneurysm rupturing and hemorrhaging blood into the surrounding tissue, with serious and potentially fatal health outcomes.

Aneurysms have been known to form in a plurality of locations through the body, including, for example, the brain, the abdomen, and throughout the circulatory system. Several surgical techniques for treating aneurysms have been developed. Initially, an aneurysmectomy was required to repair the dysfunctional tissue. The aneurysmectomy procedure requires the surgeon to gain access to the aneurysm, excise the aneurysm, and replace the void with a prosthetic graft. An alternate method of treating cerebral aneurysms called "microsurgical clipping" also requires the skull of the patient to be opened in order to place a metallic clip across the neck of the aneurysm, thereby excluding the aneurysm from the blood flow. The risks of both methods are relatively high, especially for elderly or medically complicated patients.

Endovascular coiling procedure is a less invasive method involving placement of one or more coils, delivered through a catheter, into the aneurysm until the sac of the aneurysm is completely packed with coils. It helps to trigger a thrombus inside the aneurysm. Although endovascular coiling is deemed to be safer than surgical clipping, it has its own limitations. First, after the aneurysm is filled with the coils, it will remain its original size. As a result, the pressure on the surrounding tissue exerted by the aneurysm will not be removed. Second, this procedure is effective for the aneurysm that involves a well-formed sac with a small neck. When used to treat the wide-neck aneurysm, the coil is likely to protrude into the parent vessel. A solution to prevent coil protrusion is to use a stent in combination with coiling embolization. In the stent-assisted coiling procedure, a stent is first placed across the aneurysm neck, serving as a scaffold inside the lumen. Then, the coils are delivered into the sac of the aneurysm through the interstices of the stent. Typical vasa-occlusive devices and materials include platinum micro-coils, hog hair, microfibrillar collagen, various polymeric agents, material suspensions, and other space filling materials.

A disadvantage of filling an aneurysm with devices is that the vasa-occlusive mass may impinge on nerves or other biological structures, thereby resulting in adverse biological symptoms. Another problem associated with vasa-occlusive devices is maintaining the device within the aneurysm. Blood flow through an otherwise functional blood vessel may be compromised should the device migrate from the aneurysm during or following implantation, thereby possibly resulting in a vascular embolism. Furthermore, with coils filling the sac of the aneurysm, the aneurysm size remains the same after the treatment. In addition, the method is not applicable to pseudo-aneurysm where no fully formed aneurysm sac can be identified.

Yet another method uses a stent alone to treat an aneurysm. By positioning lower porosity regions over the neck of the aneurysm, a reduction in blood flow to the aneurysm sac is achieved. The reduced flow results in hemostasis and increases the possibility of the formation of a clot in the cavity. However, the formation of a blood clot within the aneurysm cavity will not contribute to any structural changes in the aneurysm wall and methods of strengthening of the aneurysm wall are needed to alleviate the risk of wall rupture in the event that residual blood flow into the cavity occurs upon thrombus remodeling. Furthermore, methods to expedite the shrinking process of the aneurysm sac once blood flow has been aborted are critical in order to provide safe, long-term treatment solutions.

While stents may be covered with various coatings designed to limit blood flow to the aneurysm, typically including biologically compatible polymers, films, and fabrics, the application of these coatings to the stents increases the cross-sectional diameter of the device, thereby resulting in a high profile stent graft. The treatment of cerebral aneurysms, due to the small size of cerebral blood vessels, requires the device to be deliverable to the aneurysm through a micro-catheter. Therefore, high profile stent grafts are typically not used in the treatment of cerebral aneurysms.

Drugs may potentially be delivered into aberrant cavities by needle injection via open surgery or endovascular injection with aid of guide wires and catheters. However, for needle injection into an intracranial aneurysm, the skull has to be opened before injection and there could be a risk of aneurysm rupture during the insertion of the needle through the wall of the aneurysm. For endovascular injection, as drugs will be transferred into the cavity in form of solutions, quick diffusion of drugs into the main flow stream of blood can occur.

For the foregoing reasons, there is a need to develop a device that allows topical drug delivery to the site of the aberrant cavity.

BRIEF SUMMARY

The present invention is directed to a device for delivering beneficial agents topically to aberrant cavities of blood vessels in the cranium of humans or other endoluminal areas. A delivery device having features of the present invention comprises a structure for delivering drugs to the aberrant cavity, the structure being attached to a micro catheter. The structure can be made of a coil comprised of biocompatible materials including, but not limited to, metals or polymers. The coil can be made with a porous material where the pores contain beneficial agents, or can be coated with beneficial agent-loaded coating, and also, or alternatively, can be coated with a porous material where the pores contain beneficial agents. The device can topically release a drug or combination of drugs from a coating or porous material into the aberrant cavities. Moreover, the device can deliver combinations of drugs that can transform liquid into solid, where the solid can form a seal at the cavity mouth to reduce fluid pressure inside the cavity. The device can be fabricated with, but not limited to, biodegradable or bio- soluble materials, which can completely dissolve and further allow the cavity to shrink. The combinations of drugs delivered by the device can strengthen the walls surrounding the cavities.

Embodiments of the present invention provide delivery devices to treat aberrant cavities, including but not limited to aberrant cavities inside the cranium. An embodiment provides endoluminal delivery devices which can, but are not limited to, release drugs or combinations of drugs into the lumen of the aberrant cavities. A further embodiment of the invention provides delivery devices which can, but are not limited to, release drugs or combinations of drugs over a prolonged period of time. Another embodiment of the present invention provides devices which can, but are not limited to, form bonds with surrounding walls to prevent dislodgement. Yet another objective provides delivery devices which can, but are not limited to, strengthen the walls surrounding the aberrant cavities. A still further embodiment provides devices which can be fabricated with, but are not limited to, biodegradable materials, which can completely dissolve and allow the shrinkage of aberrant cavities after beneficial agent treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows a schematic diagram of an in vitro experimental setup for a pressure profile study in a silicone aneurysm model.

Figure 2 shows a schematic diagram of an aneurysm model section with controlled dimensions (unit: mm).

Figure 3 shows the positions in an aneurysm model section to be measured to obtain a pressure profile.

Figure 4 shows pressure profiles in the parent vessel (a) and inside the aneurysm (b). The local cavity of the aneurysm has been injected with calcium-based drugs at a normal concentration insufficient to initiate coagulation. Figure 5 shows pressure profiles in the parent vessel (a) and inside the aneurysm (b). The local cavity of the aneurysm has been injected with calcium-based drugs at 10 x the normal concentration sufficient to initiate coagulation.

Figure 6 shows the peak pressure of anti-coagulated human blood in pulsatile flow with time in the parent vessel (a) and inside the aneurysm (b) when calcium-based drugs at a normal concentration insufficient to initiate coagulation are injected into the local cavity of the aneurysm.

Figure 7 shows the peak pressure of anti-coagulated human blood in pulsatile flow with time in the parent vessel (a) and inside the aneurysm (b) when calcium-based drugs at 10 x normal concentration sufficient to initiate coagulation are injected into the local cavity of the aneurysm.

Figure 8 shows pressure profiles in the parent vessel (a) and inside the aneurysm (b) where coils coated with biodegradable polymer loaded with normal local coagulation factor amounts were deployed into the local cavity of the aneurysm.

Figure 9 shows pressure profiles in the parent vessel (a) and inside the aneurysm (b) where coils coated with biodegradable polymer loaded with 18 x normal coagulation factor amounts were deployed into the local cavity of the aneurysm.

Figure 10 shows the peak pressure of anti-coagulated human blood in pulsatile flow with time in the parent vessel (a) and inside the aneurysm (b) when coils coated with biodegradable polymer loaded with normal local coagulation factor amounts were deployed into the local cavity of the aneurysm.

Figure 11 shows the peak pressure of anti-coagulated human blood in pulsatile flow with time in the parent vessel (a) and inside the aneurysm (b) when coils coated with biodegradable polymer loaded with 18x normal local coagulation factor amounts were deployed into the local cavity of the aneurysm.

DETAILED DISCLOSURE OF THE INVENTION

The subject invention relates to systems and methods for providing aneurysm treatment, and vessel wall stabilization. This description is not to be taken in a limiting sense, but is merely for the purpose of illustrating the general principles of the invention. Those of skill in the art will recognize that the following description is merely illustrative of the principles of the invention, which may be applied in various ways to provide many different alternative embodiments.

Implantable medical devices include physical structures for delivering drugs or reagents to desired sites within the vascular system of a human body. These devices may take up diversified shapes and configurations depending upon specific applications. Common implantable medical devices include stents, vena cava filters, grafts, and aneurysm coils.

Although exemplary devices implantable in blood vessels are described, they are applicable to other cavities or endoluminal ducts inside an animal body including, but not limited to, the cerebral circulation system, tracheobronchial system, the biliary hepatic system, the esophageal bowel system, and the urinary tract system. Embodiments of the invention, some of which are described herein are readily adaptable for use in the repair of a variety of vessels, including, but not limited to, treatment or repair of aneurysms.

Stents are expandable prostheses employed to maintain vascular and endoluminal ducts or tracts of the human body open and unoccluded. For example, stents are now frequently used to maintain the patency of a coronary artery after dilation by a balloon angioplasty procedure. A stent is a typically a tubular meshwork structure having an exterior surface defined by a plurality of interconnected struts and spaces between the struts. The tubular structure is generally expandable from a first position, wherein the stent is sized for intravascular insertion, to a second position, wherein at least a portion of the exterior surface of the stent contacts and engages the vessel wall where the stent has been placed.

The expanding of the stent is accommodated by flexing and bending of the interconnected struts throughout the structure. The force for expansion can be applied externally as from an inflated balloon onto which the stent is loaded prior to placement, or the stent may be self-expanding. A myriad of strut patterns are known for achieving various design goals such as enhancing strength, maximizing the expansion ratio or coverage area, enhancing longitudinal flexibility or longitudinal stability upon expansion, etc. One pattern may be selected over another in an effort to optimize those parameters that are of particular importance for a particular application. While a stent may be deployed by radial expansion under outwardly directed radial pressure exerted, for example, by active inflation of a balloon of a balloon catheter on which the stent is mounted, the stent may be self-expandable. In some instances, passive spring characteristics of a preformed elastic (i.e., self-opening) stent serve the purpose, while in others shape memory materials are used, such that upon activation by the appropriate energy source, the stent deforms into a pre-determined memorized shape. Regardless of design, in all cases the stent is expanded to engage the inner lining or inwardly facing surface of the vessel wall with sufficient resilience to allow some contraction, but also with sufficient stiffness to largely resist the natural recoil of the vessel wall following deployment.

A guide wire lumen is used for introducing a guide wire in a balloon catheter, and the balloon inflating lumen for inflating the balloon after the stent has been placed at a desired location. A connector is used for separating the guide wire lumen and the balloon inflating lumen. The balloon catheter shaft carries the guide wire lumen and the balloon inflating lumen separately. Ring markers on the catheter shaft are used so that the start of balloon tapers and the edges of the stent can be visualized by X-ray.

Conveniently, the delivery catheter can be a conventional balloon dilation catheter used for angioplasty procedures. The balloon can be formed of suitable materials such as irradiated polyethylene, polyethylene terephthalate, polyvinylchloride, nylon, and copolymer nylons such as PEBAX™. Other polymers may also be used. In order for the stent to remain in place on the balloon during delivery to the desired site within an artery, the stent is typically crimped onto the balloon. However, the precise design choices in delivery systems are not limiting to the scope of the disclosure.

An aneurysm generally is defined as a wall expansion of a blood vessel. Along the spectrum of possible occurrences, on the one end of the spectrum the aneurysm comprises a separate lumen from the original vessel, in which case the aneurysm sac is connected to the original lumen by a neck, whereas at the other end of the spectrum the aneurysm comprises an enlargement of the original lumen. Clinical manifestations of aneurysms generally fall into a category between these two scenarios.

In some embodiments, the instant invention is delivered by means of a stent as known in the art. The stent is first mounted onto an inflatable balloon on the distal extremity of the delivery catheter, and the stent is mechanically crimped onto the exterior of the folded balloon. The catheter/stent assembly is then introduced into the vasculature through a guiding catheter. A guide wire is disposed across the diseased arterial section and then the catheter/stent assembly is advanced over the guide wire that has been placed in the vessel until the stent is substantially located at the site of the diseased or damaged portion of the vessel. At this point, the balloon of the catheter is inflated, expanding the stent against the artery. The expanded stent engages the vessel wall, which serves to hold open the artery after the catheter is withdrawn.

Alternatively, a resilient or self-expanding stent can be deployed without dilation balloons. Self-expanding stents can be pre-selected according to the diameter of the blood vessel or other intended fixation site. Self-expanding stents can be fashioned from resilient materials such as stainless steel, and the like, wherein the stent is loaded onto the delivery device in a compressed state, and upon placement at the desired location is allow to naturally elastically expand. Expandable stents can also be fashioned from shape memory materials such as nickel-titanium alloys and the like, wherein the stent is expanded from a first shape to a second shape by activation with an energy source such as heat, magnetic fields, or an RF pulse, for example.

Due to the characteristics of intracranial blood vessels, the intracranial device is designed to be very flexible, have a low profile when crimped onto the delivery catheter and have a thin wall. As the device is used in small vessels, it does not necessarily possess, or need, the highest possible radial strength.

In one embodiment of the instant invention, the stent is a fenestrated stent as is known in the art, and comprises a first end, a second end, and a stent wall which defines a stent lumen. The stent wall comprises plurality of fenestrations, or cells, allowing flexibility of the stent, and allowing blood flow through the stent wall, as well as delivery of material into the aneurysm sac. The stent may comprise any of the fenestration configurations known in the art which allow the deposit of coils in an aberrant cavity.

In one embodiment, the present invention provides a medical delivery device for topical delivery of therapeutic agents to the lumen or surrounding tissues of a cavity inside the body of a subject, comprising: a body having a coil shape, wherein the coil-shaped body is made of biocompatible material, wherein the coil-shaped body comprises a porous structure for loading and releasing therapeutic agents,

the coil-shaped body is coated with a biodegradable coating capable of loading and releasing therapeutic agents, or

the coil-shaped body, upon which therapeutic agents can be loaded and released, is made of biodegradable material.

In one embodiment, at least part of the coil-shape body is coated with a coating made of biodegradable material, wherein a porous structure is part of the biodegradable coating.

In one embodiment, the medical delivery device for topical delivery of therapeutic agents to the lumen or surrounding tissues of a cavity of a subject comprises: a body having a coil shape, wherein the body is made of biocompatible material; wherein at least part of the body is coated with a coating made of biodegradable material, wherein at least part of the biodegradable coating has porous structure for loading and releasing one or more therapeutic agents.

In other embodiments the biodegradable coating is not porous, but is loaded with beneficial agent throughout, the beneficial agent being released as the coating degrades. In another embodiment, the coil-shaped body is not porous, but is loaded with beneficial agent throughout, the beneficial agent being released as the coating degrades.

In one embodiment, the cavity is an aneurysm, such as an intracranial or abdominal aneurysm.

A variety of biocompatible polymers can be utilized according to the present invention.

The biocompatible polymers can be synthetic polymers, natural polymers, or combinations thereof. As used herein the term "synthetic polymer" refers to polymers that are not found in nature, even if the polymers are made from naturally occurring biomaterials. The term "natural polymer" refers to polymers that are naturally occurring. In embodiments where the coil includes at least one synthetic polymer, suitable biocompatible synthetic polymers can include, but are not limited to, polyvinyl alcohol (PVA), aliphatic polyesters, poly(amino acids), copoly(ether-esters), polyalkylenes, oxalates, polyamides, tyrosine derived polycarbonates, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters, polyoxaesters containing amine groups, poly(anhydrides), polyphosphazenes, and blends thereof. Suitable synthetic polymers for use in the present invention can also include biosynthetic polymers based on sequences found in polyvinyl alcohol (PVA), collagen, elastin, thrombin, fibronectin, starches, poly(amino acid), poly(propylene fumarate), gelatin, alginate, pectin, fibrin, oxidized cellulose, chitin, chitosan, tropoelastin, hyaluronic acid, ribonucleic acids, deoxyribonucleic acids, polypeptides, proteins, polysaccharides, polynucleotides and combinations thereof.

Aliphatic polyesters include, but are not limited to, homopolymers and copolymers of lactide (which includes lactic acid, D-,L- and meso lactide); glycolide (including glycolic acid); trimethylene carbonate (l,3-dioxan-2-one); alkyl derivatives of trimethylene carbonate; .delta.- valerolactone; hydroxy butyrate; hydroxyvalerate; l,4-dioxepan-2-one (including its dimer 1,5,8,12-tetraoxacyclotetradecane-7, 14-dione); 1 ,5-dioxepan-2-one; 6,6-dimethyl-l ,4-dioxan-2- one; 2,5-diketomorpholine; ethylene carbonate; ethylene oxalate; 3-methyl-l,4-dioxane-2,5- dione; 3,3-diethyl-l,4-dioxan-2,5-dione; 6,6-dimethyl-dioxepan-2-one; 6,8-dioxabicycloctane-7- one and polymer blends thereof. Aliphatic polyesters used in the present invention can be homopolymers or copolymers (random, block, segmented, tapered blocks, graft, triblock, etc.) having a linear, branched or star structure.

As used herein, the term "glycolide" is understood to include polyglycolic acid. Further, the term "lactide" is understood to include L-lactide, D-lactide, blends thereof, and lactic acid polymers and copolymers.

The biocompatible material of the present invention can, optionally, be formed from a bioresorbable or bioabsorbable material that has the ability to resorb in a timely fashion in the body environment.

The term "bioresorbable" or "biodegradable" refers to the ability of materials to be broken down and/or absorbed by normal chemical, biochemical and/or physical processes such as erosion, dissolution, corrosion, degradation, hydrolysis, abrasion, fatigue, etc, and their combinations.

In one embodiment, the medical device of the present invention is for implantation into a subject. "Implant" as a noun is used herein in a broad sense, to include any material placed inside the body by any method other than ingestion or inhalation, or placed on the surface of a body, wherein the material is placed inside the body for a period of longer than 30 minutes, including, but not limited to, longer than 1 hour, longer than 1 day, longer than 3 days, longer than 10 days, longer than 15 days, longer than 1 month, and longer than 3 months. "Implant" as a verb refers herein to the process of putting the material inside the body by any method other than ingestion or inhalation, wherein the material is placed inside the body for a period of longer than 30 minutes, including, but not limited to, longer than 1 hour, longer than 1 day, longer than 3 days, longer than 10 days, longer than 15 days, longer than 1 month, and longer than 3 months.

In certain embodiments, biocompatible metals include, but are not limited to, titanium, a titaniuam alloy, magnesium, magnesium alloy, tungsten, tungsten alloy, zinc, zinc alloy, aluminum, aluminum alloy, iron, iron alloy, steel, manganese, manganese alloy, calcium, calcium alloy, zirconium, and zirconium alloy.

The non-metallic solid in the metal, semi-metal, or alloy part of the metals can be in the form of powder, fiber, crystal, nanocrystal, nanoparticle or nano-fiber, or a combination thereof. More than one chemical composition of non-metallic solid can be present.

In one embodiment, the instant invention comprises a coil which is implanted into the aneurysm sac. A coil introduction instrument comprising a microcatheter carrying the coil may be advanced through the stent lumen, through the fenestration of the stent wall, and the coil deposited from the microcatheter into the aneurysm sac. Alternatively, the microcatheter may be advanced alongside the stent and through the aneurysm neck, and the coil deposited into the aneurysm sac. The coil introduction instrument may further comprise a shield located proximal to the microcatheter tip, the shield positionable to bridge the aneurysm neck as the coil is introduced into the aneurysm, preventing migration of the coil out of the aneurysm sac.

In one embodiment, the coil comprises several layers. The first layer of the coil comprises a first biocompatible material that can include, but is not limited to, metal and polymers. The second layer of the invention comprises a second biocompatible material. In one embodiment, the second layer comprises a porous biocompatible material that can include, but is not limited to, a hydrogel comprising chitosan, as taught by Lerouge et al. (US 201 1/0286925 Al), which is incorporated by reference in its entirety to the extent it is not inconsistent with the teachings herein. The second layer is superposed and laminated to the first layer of the coil.

In one embodiment, the second coating layer of the coil is loaded with and releases one beneficial agent at a predictable rate. In another embodiment, the second coating layer of the coil is loaded with and releases more than one beneficial agent at a predictable rate. In one embodiment, the second coating layer comprises porous material containing one beneficial agent within the pores and the beneficial agent is released from the pores at a predictable rate. In another embodiment, the second coating layer comprises porous material containing more than one beneficial agent within the pores and the beneficial agents are released from the pores at a predictable rate.

In one embodiment, the second coating layer of the coil releases at a predictable rate a topical blood coagulation-inducing agent. After implantation of the coil, blood is allowed to flow into the aneurysm sac through the stent fenestrations, and the blood coagulation-inducing agent on the coil is activated to induce local blood coagulation.

In another embodiment, the second coating layer of the coils releases at a predictable rate a vessel wall-strengthening beneficial agent.

In yet another embodiment, the second coating layer releases at a predicable rate both a topical blood coagulation-inducing beneficial agent and a vessel wall-strengthening beneficial agent.

In one embodiment the first layer of the device comprises a biodegradable material which will be absorbed partially or completely at a predictable rate. In another embodiment, the second coating layer of the device comprises a biodegradable material which will be absorbed partially or completely at a predictable rate. When the device is made wholly from biodegradable materials, the device can be partially or completely absorbed by the body to enable the cavity to heal and shrink without impediment. This new ability enables topical drug treatment, reduces wall rupture risk, and enables healing without coil interference.

In another embodiment, the present invention provides a method for topically delivering an effective amount of one or more therapeutic agents to the lumen or surrounding tissues of a cavity inside the body of a subject, wherein the method comprises:

loading an effective amount of therapeutic agent into a medical delivery device of the present invention;

introducing the medical device into the cavity and positioning the medical delivery device inside the cavity.

In one embodiment, the targeted cavity is inside an aneurysm. In one embodiment, the delivery device is introduced into the targeted cavity inside the body via the endovascular system. In one embodiment, the therapeutic agent is loaded into at least one pore of a porous structure of the coiled body member of the medical device.

In other embodiments, the therapeutic agent is loaded onto the coil-shaped body or into a biodegradable coating of the medical delivery device.

The delivery device of the present invention can be introduced to the target cavity via a catheter, and utilizing devices such as a stent, a filter, a dilation balloon, a thrombectomy device, an atherectomy device, and/or an embolic protection device.

In one embodiment, the steps of introducing the medical delivery device of the present invention to a cavity inside the body comprises: inserting a fenestrated stent loaded on a balloon system into the lumen of an intracranial parent vessel using endovascular catheterization;

positioning the stent/balloon in the lumen of the parent vessel such that a microcatheter loaded with the coil-shaped medical device can be inserted into the aberrant cavity through the fenestrations of the stent or, alternatively, before the stent is placed.

Therapeutic agents that can be delivered using the delivery device of the invention include, but are not limited to, embolizing factors, anti-embolizing factors, anti-restenotic compounds, agents for promoting endothelial cellular adhesion, and growth factors.

In one embodiment, the present invention provides a method of treating an aneurysm, comprising loading an effective amount of a therapeutic agent into the medical delivery device of the present invention; and

introducing the medical delivery device into the aneurysm and positioning the medical device delivery inside the aneurysm.

The term "treatment" or any grammatical variation thereof (e.g., treat, treating, and treatment etc.), as used herein, includes but is not limited to, ameliorating or alleviating a symptom of a disease or condition, reducing, suppressing, inhibiting, lessening, or affecting the progression, severity, and/or scope of a condition.

The term "subject," as used herein, describes an organism, including mammals such as primates, to which treatment with the compositions according to the present invention can be provided. Mammalian species that can benefit from the disclosed methods of treatment include, but are not limited to, apes, chimpanzees, orangutans, humans, monkeys; and domesticated animals such as dogs, cats, horses, cattle, pigs, sheep, goats, chickens, mice, rats, guinea pigs, and hamsters. In a preferred embodiment, the subject is a human.

The term "effective amount," as used herein, refers to an amount that is capable of preventing, ameliorating, or treating a disease or disorder.

In certain embodiments, the present invention provides endoluminal coil devices to deliver beneficial agents or combinations of beneficial agents topically inside aberrant cavities to initiate topical medicinal effects via the release of beneficial agents or combinations of beneficial agents from biodegradable coatings and/or porous structures of the devices into the cavities. The devices can be made of materials including, but not limited to, biodegradable materials that can dissolve partly or completely to allow shrinkage of the cavity size after deployment. The medical delivery device of the present invention can form bonds with surrounding walls to prevent dislodgement from the cavities.

The medical device of the present invention can deliver beneficial agents or combinations of beneficial agents including, but not limited to, agents for activating the transformation of a liquid into a solid to seal the inside of the cavities (such agents can provide intra-luminal pressure reduction). The medical device of the present invention can deliver beneficial agents or combinations of beneficial agents including, but not limited to, agents strengthening the walls surrounding the cavities to reduce the risk of rupture. Treatment or recovery of aberrant cavities can be achieved by the claimed functions of our devices.

Although the present invention has been described in considerable detail with reference to certain preferred versions thereof, other versions are possible. For example, the device can be fabricated of a coil with multiple coil members and can display alternative shapes, the second layer can be coated with beneficial agents or loaded in its entirety with beneficial agents, the beneficial agents can be selected from a group of agents affecting blood coagulation and vessel wall strength including, but not limited to, beneficial agents affecting the intima, media, and adventitial layer of the aberrant cavity wall. Therefore, the spirit and scope of the appended claims should not be limited to the description of the preferred versions contained herein. EXAMPLES

Following are examples that illustrate procedures for practicing the invention. These examples should not be construed as limiting. EXAMPLE 1— Endo-luminal pressure reduction with topically injected agents

To demonstrate the practice of embodiments of the invention, experiments were carried out to study the effect of topically delivered calcium and coagulation factors on the intra-aneurysmal pressure by either injecting reversal agents or coating the coil with biodegradable coating loaded with reversal agents to counter the anti-coagulants in the blood circulating in an artificial silicone vessel. One objective of this study was to access the effectiveness of the method in the enhancement of intra-aneurysmal thrombosis under pulsatile flow of anti-coagulated human blood by measuring the flow pressure profile in an in vitro silicone artery model with an aneurysm. Another objective was examining the behavior of the pressure profile under different situations (i.e., mesh porosity, input pressure profile, anticoagulant amount, amount of reversal agents deployed in coated embolization coil) under pulsatile flow of human blood with anticoagulants such as sodium citrate and heparin.

A closed-loop flow circulation system was designed and set up to monitor the pressure profile under pulsatile flow, which consisted of a programmable pulsating pump and programmable external electronic valves that were driven by a step motor, and stiff medical fluid transfusion pipes. The diameters of the channels of the flow circulation system were in the range of intracranial artery diameters. The set-up was placed on the same horizontal plane to minimize hydrostatic pressure effect. The aneurysm model section was made of medical grade silicone (NuSil) employing a wax forming method. The internal shape with desired parent vessel inner diameter, aneurysm diameter, curvature and size of the aneurysm neck was first molded by wax. The mold was then coated with 3 layers of silicone and finally the wax inside the model was eliminated by melting in an oven. In the aneurysm model section, pressures at 2 different positions as shown in Figure 3 (inside the aneurysm and before the stent) were measured by a fiber optic pressure sensor (OPP-M Fiber optic miniature physiological pressure sensor, opSens, Canada) through SoftSens data acquisition software. Pressures at these positions were inserted and measured separately in order to minimize the downstream flow disturbance caused by the pressure sensor which can lead to pressure perturbation.

Pulsatile flow experiments were carried out with this system and the flow parameters used are shown in Table 1. The viscosity of the human blood is 3.5 cP. The whole setting was covered with an acrylic box and was maintained at 38 °C with a thermostat.

Table 1. Flow parameters used in the pulsatile flow experiments.

The pressure profiles measured by the pressure sensor at different time intervals were compared to observe the changing pressure trend. The peak pressures in different settings were extracted from the measured pressure profiles and plotted according to the weight of coating of the added coils, concentration of the loaded reversal drugs, porosities of the deployed mesh and range of blood pressure, to investigate any correlations between the peak pressure reduction efficiency and these parameters.

Figures 4 and 5 illustrate the pressure profiles measured in the parent vessel and in the aneurysm by optical pressure sensors when different amounts of calcium-based agents are injected into the aneurysm part of the silicone aneurysm model.

Figures 6 and 7 illustrate the comparisons of the peak flow pressure extracted from the pressure profiles measured in the parent vessel and in the aneurysm with different amounts of coagulation factors directly injected into the local cavity of the aneurysm after deployment of a low porosity mesh. When the amount of calcium ions injected into aneurysmal lumen was insufficient to affect coagulation, there was no pressure reduction trend observed within 1 hour of pulsatile flow of anti-coagulated blood. When the amount of calcium-based drugs was increased sufficient to affect blood coagulation (10 times the normal amount), pressure reduction was observed starting 50 minutes after calcium injection. Therefore, local delivery of reversal agents inside the aneurysm is feasible to induce blood coagulation in the aneurysm.

EXAMPLE 2— Endo-luminal pressure reduction with agents coated on the coil

Figures 8 and 9 illustrate the pressure profile measured in the parent vessel and in the aneurysm by optical pressure sensors when a coil was loaded with different amounts of calcium-based agents before being deployed inside the local cavity of the aneurysm. Other experimental parameters remained unchanged: temperature = 3$ , pressure range: 70 - 130 mmHg, vessel diameter = 5mm, aneurysm diameter = 15mm.

Figures 10 and 11 illustrate the comparisons of peak flow pressures extracted from the pressure profiles measured in the parent vessel and in the aneurysm with different amounts of coagulation factors loaded on the coil deployed into the local cavity of the aneurysm.

When the amount of calcium-based coagulation factors coated onto the coil was insufficient, no pressure reduction was observed within 1 hour of pulsatile flow of anti- coagulated blood. When the amount of calcium-based coagulation factors was increased to amounts sufficient to induce coagulation (18 times the normal amount), a peak pressure reduction could be observed starting 30 minutes after coil deployment. Therefore, local delivery of a coated coil loaded with a reversal agent or coagulation factor inside the aneurysm is feasible to induce coagulation within the aneurysm.

All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.

It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims. In addition, any elements or limitations of any invention or embodiment thereof disclosed herein can be combined with any and/or all other elements or limitations (individually or in any combination) or any other invention or embodiment thereof disclosed herein, and all such combinations are contemplated with the scope of the invention without limitation thereto.

Claims

We claim: 1. A medical delivery device for topical delivery of one or more therapeutic agents to the lumen or surrounding tissues of a cavity inside the body of a subject, comprising: a body having a coil shape, wherein the coil-shaped body is made of biocompatible material, wherein the coil-shaped body comprises a porous structure for loading and releasing therapeutic agents,

2. The medical delivery device of claim 1, wherein at least part of the coil-shaped body is coated with a coating made of biodegradable material, wherein a porous structure is part of the biodegradable coating.

3. The medical delivery device of claim 1, wherein the coiled-shaped body is made of biocompatible material selected from biocompatible metal, biocompatible polymer, or a combination of biocompatible metal and biocompatible polymer.

4. The medical delivery device of claim 1, wherein the coiled-shaped body is made of biodegradable material.

5. The medical delivery device of claim 1, which is loaded with an effective amount of a therapeutic agent.

6. The medical delivery device of claim 1, wherein the cavity is an aneurysm.

7. The medical delivery device of claim 6, wherein the therapeutic agent is selected from agents for activating transformation of a liquid into a solid to seal the inside of a cavity; agents that strengthen vascular walls surrounding the cavity; embolizing factors; anti-embolizing factors; anti-restenotic compounds; agents for promoting endothelial cellular adhesion; coagulation-inducing beneficial agents; and growth factors.

8. A method for topically delivering an effective amount of one or more therapeutic agents to the lumen or surrounding tissues of a cavity inside the body of a subject, wherein the method comprises:

loading an effective amount of a therapeutic agent into the medical delivery device of claim 1 ; and

introducing the medical device inside the cavity and positioning the medical device inside the cavity.

9. The method of claim 8, wherein the medical device is introduced into the cavity through the circulatory system of the subject.

10. The method of claim 8, wherein the medical device is introduced into the cavity via a catheter.

11. The method of claim 8, wherein at least part of the coil-shaped body is coated with a coating made of biodegradable material, wherein the porous structure is part of the biodegradable coating.

12. The method of claim 8, where the coiled-shaped body is made of biocompatible material selected from biocompatible metal, biocompatible polymer, or a combination of biocompatible metal and biocompatible polymer.

13. The method of claim 8, where the coiled-shaped body is made of degradable material.

14. The method of claim 8, wherein the medical delivery device is loaded with an effective amount of a therapeutic agent.

15. The method of claim 8, wherein the cavity is an aneurysm.

16. The method of claim 15, wherein the aneurysm is an intracranial or abdominal aneurysm.

17. The method of claim 8, wherein the subject is a human.

18. A method of treating an aneurysm, comprising loading an effective amount of a therapeutic agent into the medical delivery device of claim 1 ; and

introducing the medical device into the aneurysm and positioning the medical device inside the aneurysm.

19. The method of claim 18, wherein the medical delivery device is introduced into the cavity via a catheter.

20. The method of claim 18, where the coiled-shaped body is made of biocompatible material selected from biocompatible metal, biocompatible polymer, or a combination of biocompatible metal and biocompatible polymer.