BIOACTIVE ANEURYSM CLIP

FIELD OF THE INVENTION

The present invention relates to cerebral aneurysm clips.

BACKGROUND OF THE INVENTION

Subarachnoid hemorrhage is caused by a ruptured brain aneurysm which is a ballooning of a weakened region of a brain artery occurring in approximately 2% of the population. A commonly used procedure is the surgical closure of the neck of the aneurysm by a metal clip to prevent rupture or re-rupture of the aneurysm. However, metallic aneurysm clips as those described in the prior art, such as in US 4,360,023 to Sugita et al., have serious drawbacks. For example, metals and metal alloys interfere with imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI), thereby causing significant artefacts on post-operative CT and MRI scans making it impossible for physicians to make diagnoses in the regions of the aneurysm treated with this generation of clips. Due to the magnetic properties, there is also a risk of clip movement during MRI, associated with death or permanent disability. Additionally, due to their non-resorbable nature, all metallic clips hitherto known carry the risk of permanent tissue compression in regions especially sensitive to foreign materials, such as the optic nerve, potentially impairing the patient's quality of life. In addition, their present design has not allowed for the delivery of bioactive substances to the intracranial environment.

Cerebral aneurysm clips made of non-metallic materials have been described in US 4,943,298 to Fujita et al., in order to overcome the problems of CT and MRI interference. The clips are composed of blades made of ceramic and a spring made of rubber or fiber- reinforced polymer resins. However, as shown in '298, most of the ceramic materials tested still cause CT artefacts except for silicon carbide which has poor electric insulating properties excluding it from the list of the preferred materials. Rubber-like materials as those proposed for the spring part generally lack the mechanical strength required for aneurysmal clipping. Moreover, ceramic, rubber, and polymer resins as those described in '298 are non-resorbable, thus carrying the risk of long-term complications including permanent tissue compression.

It has generally been accepted that medical implants should remain in the patient's body only for a period of time necessary to achieve the desired results, in order to avoid long- term foreign-body reactions, allow for surgical re-approaching of the implant site, and avoid replacement operations due to growth in the pediatric population. A biodegradable clip which disappears after aneurysmal closure leaving behind a permanently sealed aneurysmal neck would be useful in the surgical treatment of cerebral aneurysms. Such a biodegradable clip would, after its disappearance, avoid any interference with CT or MRI, movement in the magnetic field, as well as tissue compression.

Cerebral aneurysm clips made of biodegradable shape-memory polymers consisting of lactide and glycolide homo- and copolymers have been described in US 4,950,258 to Kawai et al. The shape-memory effect allows for opening of erroneously placed clips by heating which causes a force to a memorized opened shape. A major disadvantage of the materials described in '258 is that the shape-memory effect occurs at relatively low temperatures and even in the range of body temperature, associated with the risk of

shape recovery and gradual opening of the implanted clip. Additionally, due to the polymer degradation profile, these polymeric clips would rapidly lose their mechanical strength post surgery, leading to a high risk of aneurysmal re-opening. Moreover, the aneurysmal re-opening of clips as described in '258 would further be facilitated due to the lack of any locking mechanism.

Another disadvantage of known aneurysm clips is the lack of any bioactive coating or agent to promote rapid aneurysm closure.

SUMMARY OF THE INVENTION

By considering the aforementioned limitations of clips in the prior art it would be advantageous to manufacture cerebral aneurysm clips which are biodegradable and bioactive, and which have the option of being lockable. It is evident that a biodegradable clip is only advantageous in the presence of a bioactive component which is able to promote aneurysmal closure. A biodegradable clip would disappear as soon as the aneurysm is occluded, thereby avoiding unwanted compression of brain tissue or being a source of artefacts on future imaging studies. The bioactivity of the clip would ensure the rapid formation of a permanent sealing of the aneurysmal neck, which would otherwise be prone to re-opening due to decreasing mechanical strength of the clip as a result of its degradation. A locking mechanism would be of additional advantage to prevent any premature aneurysmal re-opening post surgery. To facilitate surgical handling, it would be advantageous to provide a clip design that allows to unlock and reopen a previously locked clip in order to correct its placement during surgery. Such a locking and unlocking of the clip should be possible as often as necessary to place the clip in an optimal position. The clip may be made of a material which is non- ferromagnetic (or preferably diamagnetic) and therefore less prone to incur CT or MRI

inference. Due to degradation of the clip, any biodegradable material of metallic or non- metallic nature could be used since there would be no CT or MRI inference in the region of the closed aneurysm after complete resorption of the clip. Alternatively, certain nonbiodegradable materials that do not significantly impede CT or MRI viewing may also be used, and may be preferred for a variety of structural, manufacturing, therapeutic and other reasons. Furthermore, the ability to implant materials, substances or medications within or on the clip placed within the intracranial environment in close proximity to brain arteries would also allow for the treatment of cerebral arterial vasospasm or hydrocephalus.

According to a first aspect of the invention, a bioactive clip is provided for closure of an aneurysm. The clip has a clip body that is made of a resilient material. A pair of blades extend forward from a central pivot point and lie substantially parallel with each other in a closed orientation. A reinforcing element extends back from the central pivot opposite the blades, and has opposing sides that may be pinched together to open the blades. Thus, the blades can be thereby operated to clamp a neck portion of an aneurysm to which the clip is applied to close the aneurysm.

The clip body comprises at least one contact surface which has a bioactive element selected to promote closure of the aneurysm. The resilient material may itself be a bioactive material.

In one possible embodiment, the resilient material may be a bioresorbable or biodegradable material. Preferably, the bioresorbable or biodegrable material is selected from the group consisting of polyesters, polyorthoesters, polycarbonates, polyanhydrides, polyurethanes, polyphosphazenes, polyphosphoesters, polysaccharides, polypeptides, polyolefines, polyglycols, and derivatives, copolymers,

and blends thereof; calcium phosphates, glass ceramics; metals or metal alloys, the main constituent of which is iron, lithium, magnesium, zinc or aluminum.

Alternatively, or in combination, the resilient material may be a shape memory material. To avoid artefacts or distortion in imaging, preferably the resilient material is a non- ferromagnetic material.

Many designs of clip bodies are possible. In one embodiment, the clip body comprises a single strip of resilient material which is simply looped upon itself and joined at the pivot to provide the pair of blades extending forward, and the reinforcing element extending back. In this embodiment, the reinforcing element is a looped portion of the strip of resilient material.

The bioactive element may be a bioactive functionality on the contact surface. Preferably, the bioactive functionality is selected from the group consisting of amine, epoxide, hydrazide, isocyanate, isothiocyanate, carboxyl, aldehyde, anhydride, imine, hydroxyl groups.

Alternatively, or in combination, the clip may have a bioactive agent attached to or embedded on or with the contact surface. Preferably, the bioactive agent is selected from the group consisting of proteins, peptides, polysaccharides, oligosaccharides, and drugs, such as calcium channel blockers and hydroxyl radical scavengers.

In one possible embodiment, the bioactive agent may be embedded within a polymeric layer on the contact surface. Preferably, the polymeric layer is selected from the group consisting of polyesters, polyorthoesters, polycarbonates, polyanhydrides, polyurethanes, polyphosphazenes, polyphosphoesters, polysaccharides, polypeptides, polyolefines, polyglycols, as well as derivatives, copolymers, and blends thereof.

Preferably, one or both of the resilient material or the bioactive element is a material selected for treatment of cerebral vasospasm or hydrocephalus.

The clip may include a locking mechanism to retain the blades in closed orientation. This may be particularly advantageous to ensure continuous and consistent exposure of the bioactive element to a neck portion of the aneurysm.

Various designs of locking mechanisms are possible. In one possible embodiment, the locking mechanism employs a hook at a distal end of one of the blades which is operable to hook over the distal end of the other blade when the blades are in the closed orientation, to thereby securely but releasably retain the blades together.

In another possible embodiment, a resilient connection element is disposed so as to span between the opposing sides of the reinforcing element. The resilient connection element has a relieved portion which acts as a flexible hinge, so that the connection element can be switched between a forward position wherein the flexible hinge is pointed toward the central pivot of the clip and a backward position wherein the flexible hinge is pointed away from the central pivot of the clip. This resilient connection element operates to block the opposing sides from being pinched together when the connection element is in the forward position, thereby preventing the blades from being actuated away from their closed orientation.

The connection element may have a first side and a second side, which generally correspond to sides on the clip body. Each of the sides of the connection element has a pair of leading elements extending forward from the connection element to engage a groove defined in the side of the clip body. These leading elements in their respective grooves thus act as a guide for forward and backward movement of the connection element into and out of locking engagement.

Each pair of leading elements on each side of the clip body may be further secured by being joined together by a bridging element to retain the leading elements in their respective grooves.

The locking mechanism may be integral with the clip body or it may be a separate piece from the clip body.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 A is a side view of a cerebral aneurysm clip of the present invention.

Figure 1 B is a second side view of a cerebral aneurysm clip of the present invention.

Figure 2A is an enlarged side view to show one possible plasma-treated region of the blades of the biodegradable clip.

Figure 2B is an enlarged side view to show one possible polymer-coated region of the blades of the clip, which additionally contains a bioactive agent.

Figure 3A is a side view to show a suitable clip locking mechanism.

Figure 3B is a side view to show another suitable clip locking mechanism.

Figure 4A is a perspective view and Figure 4B is a cross-sectional view to show yet another clip and clip locking mechanism.

DETAILED DESCRIPTION OF THE INVENTION

A bioactive aneurysm clip is provided. Various aspects of the clip according to various embodiments are shown in Figures 1-4B.

In accordance with one possible embodiment of present invention, the clip may include a biodegradable material for forming the blades 10 and/or reinforcing part 12 of a clip 8 as those exemplified in Figs. 1A and 1 B. The material, in addition to being biocompatible, may be selected from the group of bioresorbable polymers, bioresorbable ceramics, or bioresorbable metals. It should be understood that the terms "biodegradable", "biodissolvable" and "bioresorbable" are used interchangeably in the description of this invention. It should further be understood that the clip can also be a non-biodegradable clip (e.g. titanium or titanium alloy) which has been coated at least in part with a bioactive substance.

Suitable bioresorbable polymers in accordance with the present invention include those from the group of synthetic polyesters, such as homopolymers and copolymers based on glycolide, L-lactide, D,L-lactide, p-dioxanone, e-caprolactone; natural polyesters, such as those from the group of the polyhydroxyalkanoates, such as homopolymers and copolymers based on 3-hydroxybutyrate, 4-hydroxybutyrate, 3-hydroxyvalerate, 3- hydroxyhexanoate, 3-hydroxyoctanoate; polyorthoesters; polycarbonates, such as homopolymers and copolymers based on trimethylene carbonate, 2,2-dimethyl trimethylene carbonate; polyanhydrides, such as homopolymers and copolymers based on 1 ,3-bis(p-carboxyphenoxy)propane and sebacic acid; polyurethanes; polyphosphazenes; polyphosphoesters; polysaccharides, such as chitosan, hyaluronic acid, alginate, dextran, cellulose; polypeptides, such as collagen, gelatin, fibrin; as well as any derivatives, copolymers, and blends based on the abovementioned and any other group of bioresorbable polymers.

Furthermore, polymers which are biodissolvable (and thus bioresorbable) under physiological conditions may be used in accordance with the present invention, such as

homopolymers or copolymers based on vinyl alcohol, vinyl acetate, N-vinyl pyrrolidone, ethylene glycol, propylene glycol, as well as any other biodissolvable polymers as well as copolymers and blends based on biodegradable and biodissolvable polymers.

Suitable bioresorbable ceramics in accordance with the present invention include calcium phosphates, glass ceramics, as well as any other bioresorbable ceramic or mixture of bioresorbable ceramics.

Suitable bioresorbable metals in accordance with the present invention include iron which may contain carbon, or a metal alloy or sintered metal, the main constituent of which is selected from the group of alkaline metals, in particular lithium, alkaline earth metals, in particular magnesium, as well as iron, zinc or aluminum.

Furthermore, composite materials based on one or more polymers, ceramics, and metals, such as polymer/polymer, polymer/ceramic, ceramic/ceramic composites and other possible combinations, may be used in accordance with the present invention. Particularly preferred are fiber-reinforced or particle-reinforced composites. Suitable fibers include those made from polymers, aluminum and other metals, aluminum boron silicate, and carbon. Suitable particles include those made from tricalcium phosphate, hydroxyapatite, glass ceramics, polymer particles and metallic particles.

In accordance with the present invention, the material selected for forming the blades 10 of the clip may be different from that for forming the reinforcing part 12 of the clip. Additionally, different materials may be uniformly or non-uniformly mixed for forming the blades 10 and/or the reinforcing part 12 of the clip. Furthermore, one or more materials (biodegradable or not) may be used for forming coatings on parts of the clip or the entire clip. Thus for example, the blades 10 of the clip may be coated and/or further modified while the remaining parts of the clip may be unmodified. Alternatively, the remaining

parts of the clip could be modified to contain bioactive materials intended for delivery into the intracranial environment. The materials used for forming the clip and for coating the clip may be identical or different. For example, a polymer clip may be coated partly or entirely by one or more polymer coatings. Likewise, a metal clip may be coated partly or entirely by one or more polymer coatings. Additionally, the biodegradable clip may contain additives, such as plasticizers, reinforcing agents, fillers, dyes, and radio-opaque agents. Furthermore, therapeutic agents may be incorporated into the clip (either in the body of the clip or in the coated surface) which may be released in a controlled and sustained manner.

Methods for manufacturing clips made of polymers, ceramics, or metals in accordance with the present invention include technologies well-known in the art, such as melt- processing including injection-molding, die casting and sintering. Methods for manufacturing clip coatings in accordance with the present invention include those well- known in the art, such as processing from the melt or solutions.

In accordance with the present invention, the biodegradable clip is provided with bioactive functionalities to support the formation of a permanent sealing of the aneurysmal neck by stimulating and directing cellular adhesion, proliferation, differentiation and growth, and tissue regeneration after clipping and closure of the aneurysm. Bioactive functionalities may also activate coagulation or other cascades and may induce inflammatory or foreign-body reactions to stimulate tissue healing in a controlled manner. Bioactive materials could also be intended for the treatment or prevention of cerebral arterial vasospasm or hydrocephalus. Bioactivity may be imparted to parts of the clip or the entire clip. Thus for example, the blades 10 of the clip

may be bioactive while the remaining parts of the clip may be unmodified. Preferably, bioactivity is imparted by surface treatment of the blades of the clip.

Suitable methods for surface treatment include plasma modification, wet-chemical modification, and incorporation of bioactive agents by covalent or ionic binding to the surface of the clip and/or by incorporating in a polymeric coating on the surface of the clip.

Suitable reactants for plasma treatment may include argon, ammonia, hydrogen, nitrogen, oxygen, perfluorhexane, allylamine, allylalcohol, and water and any other reactants which allow for attachment or incorporation of functionalities to the surface 14 of the clip such as illustrated in Fig. 2A. Preferably, amine or oxygen groups may be incorporated into the surface of the clip.

Wet-chemical surface modification may include treatment with acids and bases, as well as with compounds containing one or more amine, epoxy, hydrazide, isocyanate, isothiocyanate, carboxyl, anhydride, imide groups or any other functional groups able to form covalent or ionic linkages with the surface of the clip. Those methods will be preferred which allow for incorporation of amine or oxygen functionalities, such as treatment with diamines, diisocyantes, dihydrazides, or dicarboxylic acids.

Plasma and wet-chemical methods may also be used to ionically or covalently bind bioactive agents to the surface of the clip. Such bioactive agents may include proteins, peptides, polysaccharides, oligosaccharides, and drugs, their derivatives, or any other compound or mixture of compounds which may allow for directed cell growth and tissue regeneration. Suitable bioactive agents may further include drugs preventing or treating vasospasm, such as Mg++; Fasudil; Nicaraven; Nicorandil; Felodipine; as well as, other calcium channel blockers and hydroxyl radical

scavengers and other antivasospastic drugs known to the art. Such bioactive agents may also be attached to the surface of the clip without pre-treatment by plasma or wet- chemical methods. Thus for example, bioactive compounds may form a layer on the surface of the clip which is stabilized by cross-linking or any other methods including changes in pH and temperature of solutions of the bioactive agent. Thus, for example, collagen layers may be formed by cross-linking of collagen solutions attached to the clip. As another example, chitosan layers may be formed by alkaline treating chitosan solutions attached to the clip.

Furthermore, one or more bioactive agents 16 may be incorporated in a polymeric layer 18 attaching the surface of the clip as illustrated in Fig. 2B. The polymeric layer may be made of a biodegradable or dissolvable material, such as those described above.

In accordance with the present invention, the biodegradable and bioactive clip may be provided with a locking mechanism, as exemplified in Figs. 3A, 3B, 4A and 4B. The lock may be designed as shown in Fig. 3A, by providing connection elements 20 between the reinforcing parts 12a and 12b of the clip. Elements 20 are connected by a hinge part 21 which can be moved towards the blades 10 for locking or in the reverse direction for unlocking the clip.

Alternatively, as shown in Fig. 3B, the distal part of one blade 10a of the clip may be provided with a hook 22 which can be latched over the other blade 10b of the clip. If necessary, hook 22 can be pushed towards and over the distal part of blade 10b, thereby unlocking the clip. Both designs, illustrated in Fig. 3A and 3B, may also be used in combination. Locking and unlocking of the clips can be performed by means of a suitable clip applier.

Locking can also be achieved by providing connection elements 24 between reinforcing parts 26a and 26b of the clip, as shown in Fig. 4A Elements 24 are connected by a hinge part 25 which can be moved towards the blades 28 for locking or in the reverse direction for unlocking the clip. Elements 24 are further connected to leading elements 30 anchored in grooves 32, as shown in Figs. 4A and 4B. Locking and unlocking can be performed by means of a suitable clip applier.

It will be understood that locking/unlocking clip designs which are modified to those illustrated in Figs. 3A, 3B, 4A and 4B may be provided, and that locking/unlocking clip designs may or may not be combined with bioactive surface modifications as those described above.

The foregoing description illustrates only certain preferred embodiments of the invention. The invention is not limited to the foregoing examples. That is, persons skilled in the art will appreciate and understand that modifications and variations are, or will be, possible to utilize and carry out the teachings of the invention described herein. Accordingly, all suitable modifications, variations and equivalents may be resorted to, and such modifications, variations and equivalents are intended to fall within the scope of the invention as described and within the scope of the claims.