WO2014041428A2

WO2014041428A2 - Bioabsorbable embolic coil

Info

Publication number: WO2014041428A2
Application number: PCT/IB2013/002386
Authority: WO
Inventors: Christopher G.M. Ken
Original assignee: Ken Christopher G M
Priority date: 2012-08-18
Filing date: 2013-08-18
Publication date: 2014-03-20
Also published as: WO2014041428A3

Abstract

The invention is a bioabsorbable embolic coil for insertion into a vascular defect. The coil comprises a bioabsorbable material such as a bioabsorbable metal, alloy or polymer, or a combination of any of these. The metal can be Mg, or other bioabsorbable metal. The metal can be electropositive relative to human vasculature such as Mg or Fe. The electropositive metals may recruit endothelial cells to the site of a vascular defect. The recruited endothelial cells can form an endothelial layer of cells that wall off the defect from blood flow in about the same amount of time that the bioabsorbable metal is absorbed into the body. Bioabsorbtion of the embolic material may eliminate the mass effect, and forming an endothelial layer walling off the defect may reduce the risk of recanalization.

Description

BIOABSORBABLE EMBOLIC COIL

CONTINUITY DATA

The application claims priority from an earlier filed provisional application of the same title, filed with the US Patent Office 8-18-12 and having the serial number 61684736.

TECHNICAL FIELD

The technical field of the invention is embolic coils for treating vascular defects such as aneurysms. Materials science applies in the selection of materials to form embolic implants.

BACKGROUND

Much attention has been given to the challenge of developing materials suitable for use in making medical device implants. One commonly implanted medical device is an embolic coil. Embolic coils are typically made of platinum, a relatively inert metal, and are placed in vascular defects such as aneurysms to reduce the risk of the aneurysm rupturing and causing a hemorrhagic stroke. The coil acts to fill the space occupied also by the blood of the aneurysm, and to promote clotting of the blood in the aneurysm. Classically, implants including embolic coils, have been permanent, meant to remain in the body for the life of the patient. Metals and alloys that are relatively inert have been used to make embolic coils.

Implanting embolic coils, although a good solution to an acute risk of aneurysm rupture, can make the aneurysm grow if the abnormal blood flow resumes. Sometimes, as a result, the aneurysm requires more coils to be implanted at a later date, or the aneurysm may require further treatment. There exists an estimated 30% incidence of recoiling for aneurysms treated with embolic coils. Also, even if the aneurysm is successfully walled off, existing permanent coils can create problems by the volume they occupy in the vasculature, called "mass effect". See the article at http://stroke.ahaiournals.org/content/33/10/2536.full for a complete detail of both the history and methods of coiling to treat vascular defects. The article is included in this application in appendix 1 , and is herein incorporated by reference. It would be desirable to develop an embolic coil that reduces the recanalization rate of coiling and that reduces the mass effect experienced when aneurysms are filled with coils.

SUMMARY

The invention is the use of bioabsorbable metals to make embolic coils. The optimal metal for such a coil comprises magnesium (Mg), a metal known to bioabsorb safely in the body. Iron (Fe) may also be used. In addition, other metal alloys comprising bioabsorbable metals can be used for making the embolic coils. Optimally, the metals in the alloy material are bioabsorbable. Preferably all the metals of the alloy are bioabsorbable. The metals that make up the alloy that forms the coil do not need to bioabsorb at the same rate. The coil, however, is designed to bioabsorb.

In addition to using a bioabsorbable metal alloy to make an embolic coil, at least one of the metals may also be chosen for an electropositive character, to beneficial effect in the coil device. Highly electropositive metals tend to attract endothelial cells in the body and recruit them to the region where the device is implanted. Recruitment of endothelial cells to the aneurysm where the coil is implanted can be a benefit to healing the aneurysm. It is beneficial to promote development and growth of a layer of endothelial cells at the aneurysm, such as at the mouth or neck of an aneurysm to wall it off.

The invention therefore provides a coil device having two useful qualities: a material that attracts endothelial cells to promote forming an endothelial layer of cells in the vasculature, and a material that is bioabsorbed in the body. The bioabsorption feature is important because when the vascular defect is filled with metal a phenomenon called the "mass effect" occurs. The mass effect is the effect of a metallic bulk or mass that interferes with other functioning in the brain.

When the invention is practiced, the embolic coil is constructed from an alloy of bioabsorbable metals, at least one of which is magnesium. Additionally, the alloy can comprise another highly electropositive metal. Possibly all the metals in the alloy can be both bioabsorbable and electropositive relative to blood and vascular potentials. Upon implantation in an aneurysm in a human, the embolic coil having at least one electropositive metal in the alloy that forms the coil recruits endothelial cells (by its electropositive character) to the mouth of the aneurysm. The recruited endothelial cells serve to wall off the aneurysm as they form an endothelial layer or layers at the mouth of the aneurysm. As the aneurysm is walling off, the alloy is being absorbed into the body, reducing any burden of foreign material remaining in the aneurysm. When walled off from blood flow by the newly formed endothelial layer, the aneurysm shrinks. The coil implant made of an alloy formed from

bioabsorbing electropositive metals can be optimized to bioabsorb at a favorable rate as it recruits endothelial cells to the site where the device is implanted.

It is important that the body is not burdened with too much of any one metal during the process of bioabsorption. Testing bioabsorbable materials can be done in test mammals or using in vitro corrosion simulations that attempt to mimic in vivo conditions (e.g. such as eagle's minimum essential medium (EMEM). Research into the corrosion and biocompatibility of dental alloys conducted by Manaranche et al. European Cells and Materials Vol. 9. Suppl. 1 , 2005 (pages 35-36), discusses factors that can be used in making decisions about amounts of various metals in the alloy. The article is hereby incorporated by reference in its entirety.

Electric potential across blood vessels has been measured and is generally negative. Devices made of an alloy having at least one electropositive metal and a device structure having sufficient surface area can recruit endothelial cells to the site. The electropositivity of the metal encourages endothelialization in the presence of the electronegative charges of the blood and body tissues. The electropositive character of the material on the surface of the device in relation to the charge of blood and tissue (which is electronegative in comparison) provides an environment that promotes endothelialization to heal the vascular defect.

Upon healing with endothelialization, the pressure is evenly distributed along the parent vessel in a manner that precludes recanalization at the defect post treatment. After the endothelialization process is complete, new blood no longer has access to the walled-off defect.

According, the invention is a coil device for inserting in human vasculature comprising a bioabsorbable material. The bioabsorbable material can be a metal. The bioabsorbable material can be an alloy having at least one bioabsorbable metal. The bioabsorbable material can be a bioabsorable polymer. The material can be a combination or composite of a metal or metals and a polymer or polymers. The metal can be magnesium, or the metal alloy can comprise magnesium metal. The metal can be electropositive relative to human vasculature. At least one metal in the metal alloy can be electropositive relative to human vasculature. The bioabsorbable material can be substantially absorbed in the human body in about 30 days. A portion of the bioabsorbable material can be substantially absorbed in the human body in about 30 days. A remainder of the bioabsorbable material can be

substantially absorbed in the human body within about 45, about 60, about 90, about 120, about 150, or about 180 days. The device material can comprise an alloy of two or more bioabsorbable electropositive metals. The metals of the bioabsorbable material of the device are selected from Mg, Zn, Ca, Fe, Cu, Li, Na, K, Sc, Rb, Sr, Y, Cs, Ba, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, La, Th, Pa, U, Ti, V, Cr, Co, Ni, Ga, Ge, Cd, In, Sn, and Sb. The selected metal should be biocompatible. The bioabsorbable material can be more than one element, metal, polymer or alloy. The bioabsorbable material can be a combination material or a composite material. The combination can comprise a metal, a metal alloy, a polymer, a polymer composite, or a metal-polymer or alloy-polymer composite material. The

bioabsorbable material can be a combined material, such as for example a combination of a metal and a metal alloy, a combination of a metal and a polymer, a combination of an alloy and a polymer, a combination of more than one polymer, and a combination of a composite material and a metal, metal alloy or polymer.

Combined materials can be combined as a weave, fabric, braid, or cable. For example, fibers or wires of metal, alloy, or polymer can be wrapped, braided, or cabled to form a spring coil or other embolic device capable of being delivered to a vascular defect in a patient's body.

DETAILED DESCRIPTION

The invention facilitates a process of healing a vascular defect such as an aneurysm using an approach embodying intervention without dramatic disruption to the vessel. To achieve this, the coil implant is either a single bioabsorbable metal or an alloy of two or more bioabsorbable metals. Eventually, some time after implantation of the coil, the coil will be absorbed into the body fluids and tissue.

Further, at least one of the metals selected for the alloy used to make the coil, in addition to being bioabsorbable, is highly electropositive. Preferrably all the metals of the alloy are in addition to being bioabsorbable, also electropositive relative to the electric potential of human blood and vascular tissue. In the presence of the bioabsorbing coil, the blood in the aneurysm will begin to clot, and the electropositive character of the material will draw endothelial cells to the site around the coil, including the neck of the aneurysm. As endothelial tissue begins to form in and around the aneurysm, the metal of the alloy absorbs into the body. Eventually, the aneurysm is walled off from blood flow with a layer of endothelial cells, the coil has absorbed into the body, and normal blood flow is restored to the vessel where there once was a vascular defect.

As to the structural design of the coil, traditional designs can be used. In addition, the coil can have a stretch resistant polymer member inside a

bioabsorbable alloy coating, shell, or tube. The stretch resistant polymer member can also be a bioabsorable polymer material such as, for example PGLA, PGA, or EGA. Also, a fiber can be wound in a coil-like structure. The fiber can be cabled from bioabsorbable alloy wire, bioabsorbable metal wire, and bioabsorable polymer strands, each alone or in any combination, such as, for example, either with one type of wire such as the alloy alone, metal wire each wire from a different metal, a combination of metal, or metal alloy wires, and a combination of metal or metal alloy and polymer. The material or materials used to make the embolic coil can be woven, braided, cabled or otherwise integrated together to form a length that can then be used to form a primary spring coil. Composite materials can be used to form the strands, fibers or wires that form the spring coil. Other designs of embolic devices may also be used along the same principles: i.e. that the device will eventually bioabsorb in the vascular defect in the patient's body.

Bioabsorbable metals include Mg, Zn, Ca, Ga, Cu, Zn, In, Ni, Cr, and Fe. Presently, most of the interest and work in creating bioabsorbable metal alloys includes Mg as a primary component. All of these bioabsorbable metals are also either very electropositive, or electropositive. Elements that are already known to play physiological roles in the human body are generally biocompatible in their metallic forms and therefore are suitable materials for constructing bioabsorbable implants. Presently, in the medical device industry, the two primary material candidates for bioabsorbable stents are magnesium, iron, and their alloys.

Alternative solutions have included the development of magnesium- rare earth (Mg- RE) alloys which benefit from the low cytotoxicity of RE elements. Testing

bioabsorbable materials can be done in test mammals or using in vitro corrosion simulations that attempt to mimic in vivo conditions (e.g. such as eagle's minimum essential medium (EMEM). Work done to develop bioabsorbable stents is instructive for the purpose of using magnesium as a primary constituent in an implantable coil. Magnesium, while degrading without toxic effects on humans, has been shown to degrade in the human body in about 30 days. The target retention of a stent is optimally (or at least) about 3 to 6 months, making Magnesium a less favorable material for stents.

However, for the purposes of a coil made of magnesium, it is important to note that endothelialization in vascular tissue may occur within 30 days of stimulus.

Magnesium, in addition to be a bioabsorbable material is also a highly electropositive element. Therefore, coils having magnesium as either the only component, or as one of two or more components may both recruit endothelial cells to the aneurysm, and thereby promote endothelialization at the aneurysm, and bioabsorb at approximately the same rate that the new endothelium is growing. Optimally, by the time the aneurysm is walled-off with an endothelial layer, the magnesium in the stent has been absorbed by the body.

Basic embolic coils made of platinum and non-absorbing materials are described in USPN 4,794,069. General coil delivery is described in USPN 5,624,449, USPN 5,423,829, USPN 5,234,437, USPN 5,540,680, USPN 5,534,295, and USPN 5,122,136, and can be facilitated by any number of coil delivery methods. These patent references are hereby incorporated in their entirety.

Both terms electronegative and electropositive work to describe a chemical property of elements. Electronegativety describes the ability of an atom to attract electrons (or electron density) towards itself. Electropositivity is a measure of an element's ability to donate electrons. An atom's electronic identity is affected by both its atomic weight and the distance that its valence electrons reside from the charged nucleus. The higher the associated electronegativity number, the more an element or compound attracts electrons towards it. The most commonly used method of calculation of electronegativity is that originally proposed by Pauling. This gives a dimensionless quantity, commonly referred to as the Pauling scale, on a relative scale running from around 0.7 to 3.98 (hydrogen = 2.20). It is to be expected that the electronegativity of an element will vary with its chemical environment, and therefore the term electronegative or electropositive both imply a relative determination, that is an element is electropositive relative to something that is more electronegative (or less electropositive) than the first element. The electric charge and so electric character of the metals identified herein as suitable for the devices proposed is a value derived keeping in mind the context of a comparison to blood and tissue in the human body. The term electropositive metal or metal alloy is used because the charged values of the metals are cited with reference to something more

electronegative, like an element or metal having a higher electronegative charge, or in relation to electronegative charge of blood and tissue in the human body. In general, when looking at the periodic table of elements, electronegativity increases on passing from left to right along a period, and decreases on descending a group.

The electronegative value of human blood and tissue is attributed to the electronegative constituents of blood (white and red blood cells, platelets, and fibrinogen). Sawyer measured electric potentials in blood and plasma, noting negative streaming potentials in an active blood vessel and negative surface-charge density in the blood vessel walls, and that the streaming potential of the blood vascular interface in a healthy vessel is negative at the interface facing the blood. Sawyer also noted that the wall of a blood vessel tends to be negative at all points with reference to a pair of electrodes implanted across the blood vessel wall and residing in the flowing blood stream. In the face of normal blood pressure and blood flow the streaming potential will tend to remain negative. Sawyer's techniques indicated that the endothelial cells in intact endothelial surfaces look negative to the surrounding fluid and to the electrode tip as it approaches the endothelium from within the bloodstream. (Sawyer, et al. Bull. N. Y. Acad. Med. ROLE OF

ELECTROCHEMICAL SURFACE PROPERTIES Vol. 48, No. 2, February 1972) Sawyer's reference is hereby incorporated in its entirety.

Bioabsorbable metallic glass refers to a class of bulk metallic glass, which is based on magnesium. An alloy suitable as the material for the coil of this invention is called Mg-Zn-Ca metallic glass. Mg-Zn-Ca alloy has high strength, ductility, and plasticity (GU, et al. 2005 Mg-Ca-Zn "Bulk metallic glasses with high strength and significant ductility." Journal of Materials Research, 20, 1935-1938). Subsequent work increased the content of Mg and lowered the content of Zn to increase the plasticity of the material. (Li et al, 2008 "Microstructure and mechanical properties of bulk Mg-Zn-Ca amorphous alloys and amorphous matrix composites." Materials Science and Engineering: A, 487, 301 -308). More recently, silver-, calcium-, zinc-, copper- and magnesium- glass-forming alloys have been made with a range of novel properties including some alloys with good ductility. Some of these metallic glass alloy materials have superplastic formability and have shown properties suitable for their use as bioabsorbable medical devices. The cited references are incorporated in their entirety herein.

Research is underway to assess its feasibility for use as a biomaterial. The most well known publication, by a group of Swiss scientists led by Professor Jorg Loffler, tested a Mg-Zn-Ca metallic glass with a composition of Mg6oZn₃₅Ca₅. See also work at University of New South Wales, "BMGs for Electronic, Biomedical and Aerospace Applications". University of New South Wales. Apr 28, 2010. This reference is incorporated in its entirety herein.

The activity or electromotive series of metals is a listing of the metals in decreasing order of their reactivity with hydrogen-ion sources such as water and acids. In the reaction with a hydrogen-ion source, the metal is oxidized to a metal ion, and the hydrogen ion is reduced to H₂. The ordering of the activity series can be related to the standard reduction potential of a metal cation. The activity of a metal can be correlated with its Pauling electronegativity.

The very electropositive metals include the following: Li, Na, Mg, K, Ca, Sc, Rb, Sr, Y, Cs, Ba, La, Fr, Ra, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, La, Th, Pa, and U. Most active metals have low electronegativities (EN < 1 .4). The cations generally have reduction potentials of -1 .6 V or below. They react with water to release hydrogen, are good reducing agents, and conversely are not very good oxidizing agents, and their ions can't be reduced to the metal in aqueous solution. Very electropositive metals readily ignite in air (burn) forming the oxides and their fires can't be extinguished with water but require sand which smothers the flames and does not react.

The electropositive metals include the following: Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, Ge, Cd, In, Sn, and Sb. These electropositive metals have

electronegativities between 1 .4 and 1 .9. Cations of these metals generally have standard reduction potentials between 0.0 and -1 .6 V. They do not react very readily with water to release hydrogen, but they react with H+. The electropositive metals do not burn in air as readily as the very electropositive metals. The surfaces of these metals will tarnish in the presence of oxygen forming a protective oxide coating. This coating protects the bulk of the metal against further oxidation (the metal is passivated). If the surface of the metal is in contact with both oxygen and water, corrosion can occur. In corrosion, the metal acts as an anode and is oxidized. (e.g. Fe (s) ^:^^{: z}— Fe²⁺ + 2e^")

Also, it is contemplated that any optional feature of the inventive variations described may be set forth and claimed independently, or in combination with any one or more of the features described herein.

Reference to a singular item, includes the possibility that there is a plurality of the same items present. More specifically, as used herein and in the appended claims, the singular forms "a" and "the" include plural referents unless specifically stated otherwise. In other words, use of the articles allow for at least one of the element in the description above as well as the claims below. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely", "only" and the like in connection with the recitation of claim elements, or use of a negative limitation.

Without the use of such exclusive terminology, the term comprising in the claims shall allow for the inclusion of any additional element irrespective of whether a given number of elements are enumerated in the claim, or the addition of a feature could be regarded as transforming the nature of an element set forth in the claims. Except as specifically defined herein, all technical and scientific terms used herein are to be given as broad a commonly understood meaning as possible while maintaining claim validity. The breadth of the present invention is not to be limited to the examples provided and/or the subject specification, but rather only by the scope of the claim language.

APPENDIX 1

http://stroke.ahajournals.org/content/33/10/2536.full

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All references cited are incorporated by reference in their entirety. Although the foregoing invention has been described in detail for purposes of clarity of understanding, it is contemplated that certain modifications may be practiced within the scope of the appended claims. The earlier filed provisional application USSN 61684736 to which this application claims priority is herein incorporated by reference in its entirety.

Claims

CLAIMS What is claimed is:

1 . A coil device for inserting in human vasculature comprising:

a bioabsorbable material.

2. The coil device of claim 1 , wherein the bioabsorbable material is a metal.

3. The coil device of claim 2, wherein the metal comprises a metal alloy having at least one bioabsorbable metal.

4. The coil device of claim 1 , wherein the bioabsorbable material comprises a polymer.

5. The coil device of claim 2, wherein the metal is magnesium.

6. The coil device of claim 3, wherein the metal alloy comprises magnesium.

7. The coil device of claim 2, wherein the metal is electropositive relative to human vasculature.

8. The coil device of claim 3, wherein the metal alloy comprises an electropositive metal, electropositive relative to human vasculature.

9. The coil device of claim 1 , wherein the bioabsorbable material is substantially absorbed in a human body in about 30 days.

10. The coil device of claim 2, wherein the metal is substantially absorbed in the human body in about 30 days.

1 1 . The coil device of claim 3, wherein at least one metal of the alloy is substantially absorbed in the human body in about 30 days.

12. A coil device for inserting in human vasculature comprising an alloy of two or more bioabsorbable electropositive metals.

13. The coil device of claim 12, wherein the metals are selected from Mg, Zn, Ca, Fe, Cu, Li, Na, K, Sc, Rb, Sr, Y, Cs, Ba, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, La, Th, Pa, U, Ti, V, Cr, Co, Ni, Ga, Ge, Cd, In, Sn, and Sb.

14. The coil device of claim 13, wherein the alloy is biocompatible.

15. The coil device of claim 12, further comprising a bioabsorbable polymer.