WO2012009665A1

WO2012009665A1 - Temporary bone filler

Info

Publication number: WO2012009665A1
Application number: PCT/US2011/044235
Authority: WO
Inventors: David Skaggs
Original assignee: Childrens Hospital Los Angeles
Priority date: 2010-07-16
Filing date: 2011-07-15
Publication date: 2012-01-19

Abstract

The present invention provides a device, kits, and methods for temporarily filling a hole in a bone without promoting bone growth. The device is comprised of a non-porous material, such as poly(etheretherketone), poly(methyl methacrylate), silicone, ceramic, or polyethylene. In an embodiment, the device is coated with a compound to help eliminate or prevent infection. The methods of the invention generally comprise introducing the device into the bone and allowing the device to be maintained in the bone temporarily.

Description

TEMPORARY BONE FILLER

CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application relies on and claims the benefit of the filing date of U.S. provisional patent application number 61/364,947, filed 16 July 2010, the entire disclosure of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Field of the Invention

[002] The present invention relates to the field of bone surgery. More specifically, the present invention provides a non-porous temporary filler for a hole in a bone. The temporary filler does not substantially promote bone growth.

Description of Related Art

[003] Bone surgery, such as spinal fusion surgery, craniai-facial reconstruction/trauma and dentistry, can require that holes be made in the bone. For example, patients that have undergone surgery involving the placement a screw into a bone will have a hole in the bone when the screw is removed. In situations where removal of the screw is permanent, regrowth of bone into the hole closes the hole over time. However, there are situations where temporary removal of a screw is necessary, such as when an infection develops at the site of implantation of the screw. Frequently, after treatment and clearance of the infection, a new screw is implanted at the same site as the original screw. During the infection clearing period, which generally lasts a minimum of six weeks but often up to six months or even longer, new bone typically forms and fills the space left by the removed screw. The newly formed bone is harder and denser than the original bone, making it much more difficult for the surgeon to drill into the new bone in order to put in a new screw. This difficulty also results in increased risks associated with the surgery, particularly damage to surrounding tissue if a drill or other tool or implant is diverted to a different location. It is uncommon to fill the hole left by the original screw at this time, particularly in cases of infection, as foreign bodies serve as a nidus for infection and thus make clearing the infection less likely.

[004] Bone hole fillers currently in use are generally designed as long term implants, typically to reduce bone stress and promote bone growth by using coating molecules such as bone-morphogenetic protein (BMP) or other growth factors. In some cases, the implant is bioresorbable, elastic, or porous to promote new tissue formation.

[005] Although some temporary bone fillers have been described, they are generally comprised of a soft material, such as putty or a powdery composition, and are designed to be used to promote new bone formation. For example, U.S. Patent No. 4,407,793 to Akima et al. provides a composition for a temporary substitution for bone tissue defects consisting of a cyanacrylic acid ester and a powder-like filler, which is designed to be decomposed over time in situ.

SUMMARY OF THE INVENTION

[006] The inventors have recognized that there is a need in the art for a bone filler that temporarily fills a hole in a bone and prevents new bone from forming so that additional surgery at the site of the hole is less difficult and less risky than if no bone filler is used or if a bone filler known in the art is used. The present invention addresses the need in the art by providing a new bone hole filler that 1) prohibits new bone growth as a result of being structurally biologically inert, and 2) promotes or assists in clearance of an infection as a result of the presence of an anti- infectious agent on or in the filler. The filler is composed of one or more materials and can be used to temporarily fill a hole in a bone. In contrast to temporary bone fillers known in the art, the present bone filler is not degraded in situ. Rather, the bone hole filler is biologically inert and thus not degraded, but instead removed from the hole once a suitable amount of time has passed (e.g., the time required for treatment of an infection). The presence of the bone hole filler in the bone hole decreases or abolishes bone growth into the hole, and maintains the hole in the bone, which facilitates implantation of a new connector or fastener (e.g., screw, pin) into the original hole. To the inventors' knowledge, there are no known temporary bone fillers that are designed to temporarily prohibit new bone growth.

[007] In one aspect, the present invention provides a composition of matter for temporarily filling a hole in a bone without substantially promoting bone growth into the hole. As the composition has applicability in the medical/veterinary fields, the composition of matter can be considered as a device for filling a hole in a bone. For example, the composition of matter can be used to fill a hole that has been left behind after a screw is removed from the bone of a patient. Broadly speaking, the composition/device comprises a non-porous material that retards or blocks growth of bone into the hole left behind by removal of a surgical fastener. The device can be coated or embedded with a compound, such as an antibiotic, prior to placement into the bone hole to aid in eliminating or preventing infection at the site.

[008] In another aspect, the device is provided as a component of a kit. In general, a kit according to the invention comprises at least one device of the invention and packaging material for the device(s). Of course, the kit can contain any number of devices, which can be provided all in a single container or each in a separate container. Providing devices in individual containers is preferred in order to maintain the sterility of the devices. In one embodiment, the kit contains different sizes of the device so the appropriate size device can be used during surgery.

[009] In yet another aspect, the present invention provides methods for temporarily filling a hole in a bone using the device of the present invention. The methods generally comprise implanting the bone filler device into a hole in a bone and allowing the device to be temporarily situated and retained in the bone. As the method is for temporarily filling a bone hole, the method preferably comprises removing the device at some point in time after implantation.

DETAILED DESCRIPTION OF VARIOUS

EMBODIMENTS OF THE INVENTION

[010] Reference will now be made in detail to various exemplary embodiments of the invention. The following description is provided to assist the reader in understanding various embodiments and features of embodiments of the invention, and should not be considered as a limitation on the invention as disclosed herein and claimed below.

[Oil] Before embodiments of the present invention are described in detail, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Further, where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither, or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[012] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the term belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The present disclosure is controlling to the extent it conflicts with any incorporated publication.

[013] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an antibiotic" includes a plurality of antibiotics and reference to "a fastener" includes reference to one or more fasteners, of any type and combination of types, and equivalents thereof known to those skilled in the art, and so forth. Furthermore, the use of terms that can be described using equivalent terms include the use of those equivalent terms. Thus, for example, the use of the term "subject" is to be understood to include the terms "patient", "animal", "human", and other terms used in the art to indicate one who is subject to a medical treatment.

[014] Broadly speaking, the present invention provides a non-porous composition of matter that is formed in a manner that allows it to be used as a device for temporarily filling a hole in a bone. The hole may have been made by any kind of surgery that encompasses drilling or forming a cavity in the natural bone structure, such as spinal fusion surgery, cranial-facial reconstruction, long bone trauma reconstruction, joint replacement, and dental surgery.

[015] In general, the device is made of one or more materials that are non-porous or substantially non-porous and are biologically inert. Preferably, the device comprises at least one material that has one or more of the following characteristics: biocompatible (e.g., does not evoke an inflammatory or toxic response when place inside the subject's body), acceptable shelf- life (e.g., does not noticeably degrade when maintained in the dark at room temperature for one year), acceptable in vivo life (e.g., does not noticeably degrade in vivo for at least six months), strong mechanical properties (e.g., similar to or exceeding the mechanical stiffness of bone), and impermeable to soft and hard tissue in-growth. Preferably, the physical structure of the device is not brittle. That is, the substance(s) used to make the device should have sufficiently high tensile strength as to allow for removal of the entire device when desired, without any breakage.

Further, it is preferred that the physical structure of the device be radioopaque, allowing for facile determination of the location of the device after implantation.

[016] In preferred embodiments, the device is coated, impregnated, or both coated and impregnated, with an antibacterial agent (used interchangeably herein with "antibiotic"), which partially or, most preferably, completely inhibits bacterial growth (e.g., biofilm growth) on and/or around the device in situ or kills bacteria on and/or around the device in situ. That is, the anti-bacterial agent should be bacteriostatic or bacteriocidal. In highly preferred embodiments, the anti-bacterial agent is released from the device over a pre-determined period of time to provide long-term dosing of anti-bacterial agent at the site of implantation of the device. Those of skill in the medical and veterinary arts are well aware of the numerous antibacterial agents suitable for use with the device of the invention without the need to recite such agents herein. Non-limiting examples of antibiotics useful according to the invention are gentamycin, tobramycin, rifampin, and minocycline. The skilled artisan is also fully capable of determining the amount of antibiotic to be used without undue or excessive experimentation. It is to be understood that, according to the invention, a device is considered to be "biologically inert" even in embodiments where the device comprises an antibiotic (which is a biologically active agent) or other compound that is impregnated or coated, or both, on or in the device. As such, it is to be understood that the biological "inertness" refers to the materials that make up the physical structure of the device, and does not necessarily refer to other substances in or on the device.

[017] The device can be coated or impregnated with any number of substances instead of or in addition to an antibiotic. For example, the device of the invention can be coated, impregnated, or both coated and impregnated with one or more other bioactive agents that can be

advantageously used in treatment of the subject. For example, the device can comprise one or more antifungal agents, one or more antiviral agents, or a combination of these. In some embodiments, the device is coated with, impregnated with, or both coated and impregnated with one or more anti-inflammatory agents, one or more an anti-scarring agents, or both. Those of skill in the art are aware of other bioactive agents that can be advantageously used, without the need to provide an exhaustive list here. The invention contemplates all combinations of antibiotics, antifungals, antivirals, and other bioactive agents as internal and/or surface agents for the biologically inert structural component of the device.

[018] In exemplary embodiments, the device comprises one or more non-porous plastics, silicones, or ceramics, or combinations of two or all three of these. Suitable plastics include thermoplastic polymers and thermosetting polymers. Non-limiting examples of plastics include, but are not limited to, poly(methyl methacrylate) (PMMA), fluoroplastics (e.g.,

polytetrafluoroethylene (PTFE), polyfluoroacetate), polysulfone, polyacrylates, polyamides (e.g., nylon), polyamide-imide, polycarbonate, polyetheretherketone (PEEK), polyethylene (e.g., ultrahigh molecular weight polyethylene; UHMWPE), acrylonitrile butadiene styrene (ABS), polyoxymethylene (e.g., Delrin®, DuPont, Wilmington, DE), polyvinylchloride (PVC), polypropylene, and phenolic, or combinations of two or more of these. These materials, and others encompassed by the invention but not specifically recited herein, do not promote the growth of bone around the opening of the cavity and aid in maintaining the integrity of the hole. They are also highly, essentially, or completely biologically inert, reducing the likelihood of initiating a biological reaction (e.g., immune reaction) while present in the subject's body.

[019] In an exemplary preferred embodiment, the device comprises polyetheretherketone (PEEK). PEEK has several properties that are advantageous as a non-porous, biologically inert material, including: high biocompatibility (e.g., little or no immunogenicity, toxicity; high stability in vivo); strength (e.g., it provides superior strength to graft fixation without the concern of graft failure or breakage during insertion); ideal modulus (PEEK is a superior match to bone modulus, which minimizes stress shielding); easy to machine/extrude/form (e.g., it is relatively easy to make the device in the various shapes needed to address the various different sizes and shapes of holes in bones due to surgical intervention); and it is approved by the U.S. Food and Drug Administration (FDA) for in vivo use for spinal surgery.

[020] Although the device can comprise one or more metals as the structural component of the device, metals are not highly preferred due to their tendency to migrate over time into and through bone, as well as their susceptibility to act as a nidus for infections. Further, it is preferable to use a substance with a similar modulus to bone to reduce migration of the device. In general, metals do not have a similar modulus to bone, and are thus less preferred as substance for the physical structure of the device.

[021] The device may comprise the non-porous material as the sole component of the device, or the device may include other substances. For ease of manufacture, it is preferred that the device be substantially or completely formed of the same non-porous material or materials. However, embodiments of the invention contemplate a device having 1) a core material of one substance, which can, but is not necessarily non-porous and/or biologically inert, surrounded by 2) a shell of non-porous and biologically inert material. Such a multi-layer device can be preferable where the non-porous, biologically inert material is relatively expensive, and reduction in the volume required to form a device is reduced by using a relatively thin coating of the non-porous material over the less expensive core material.

[022] The device preferably is a surgical screw comprising a threaded body with a relatively large head. The relatively large head prevents the device from migrating over time deeper into, and possibly out the other side of, the bone into which it is placed. The

diameter/width of the head is at least 120% of the diameter/width of the body, such as, for example, 130%, 140%, 150%, or 200%. In some embodiments, the threads of the device are provided with barbs or other backwardly angled protrusions that reduce or abolish the backward movement of the device out of the bone into which it is placed until or unless the device is intentionally removed.

[023] As discussed above, the device of the invention can include an antibiotic or other bioactive agent as an internal and/or external component. As the devices are non-porous, impregnation is not a highly preferred way to provide the antibiotic or other bioactive agent. However, impregnation can be advantageous in some situations. For example, if the structural integrity of the device is somehow intentionally or unintentionally compromised, antibiotic or other bioactive agent located in the interior of the device can be released. Various techniques are known in the art for impregnating medical fasteners with bioactive agents, and any such technique can be used. For example, techniques for inserting layers of silver into PEEK structures are known in the art. Likewise, coating can be achieved by any number of techniques known in the art. For example, direct coating can be used via physical methods {e.g., dipping, spraying), chemical methods (e.g., use of chemical conjugates), or plasma methods (e.g., plasma deposition). Furthermore, coating by way of indirect methods can be used. For example, the device can be coated using a carrier molecule that is capable of binding to the device surface and an antibiotic, thus linking the two. The carrier molecule can be a biodegradable molecule, such as polylactic acid (PLA) or copolylactic acid / glycolic acid (PLGA). Use of a biodegradable carrier molecule allows for release of the antibiotic from the surface of the device as the carrier is degraded in situ. Alternatively, antibiotics and silver can be used to prepare the antibiotic coatings. Non-limiting suitable techniques for coating are disclosed, for example, in Damm et al. (Surface & Coatings Technology, Vol. 202, pp. 5122-5126, 2008).

[024] In general, the size of the device will vary depending on the size of the hole in the bone left as a result of removal of the fastener or connector (these terms being used

interchangeably herein) originally occupying the hole. The size of the hole will, in general, be dictated by the size of the fastener or connector removed. As such, in general, the size of the devices of the invention will be similar or identical to the size of the fastener or connector removed. Fasteners and connectors for medical and veterinary bone surgery are known to the skilled artisans in these arts. As such, the skilled artisan is apprised of the various sizes that are encompassed by the present invention without the need for each of the available fasteners and connectors to be listed herein. Non-limiting sizes include diameters of from about 2.0 mm to about 1.0 cm, such as 2.5 mm, 3.0 mm, 3.5 mm, 5.0 mm, 5.5 mm, 7.5 mm, or 8.5 mm. Non- limiting lengths include about 3 mm to about 10 cm, such as 5 mm, 8 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm, 60 mm, 65 mm, 70 mm, 75 mm, 80 mm, 85 mm, 90 mm, 95 mm, 100 mm, 125 mm, 150 mm, 175 mm, 200 mm, 300 mm, 400 mm, 500 mm, 1 cm, or 2 cm. Of course, as noted above, one of skill in the art will immediately recognize that the ranges specifically recited herein inherently include each and every value encompassed by the ranges, without the need for this document to specifically list each and every value.

[025] In essence, the device can have any diameter/width and any length that is relevant to surgical connectors and fasteners, and the holes created by them. For example, a device according to the invention for use in a child can have a diameter of 5 mm and a length of 30 mm. Likewise, for use in an adult, the device can have a diameter of 7.5 mm and a length of 30 mm.

[026] As has been discussed previously, the size of the device does not have to exactly match the size of the hole. Indeed, in applications relating to removal of surgical

fasteners/connectors due to bacterial infection, it is preferred that the device be slightly smaller than the hole that it fills. A slight gap between the device and the hole wall (i.e., the bone) is preferred in these situations to promote influx of the subject's immune cells, including B cells, T cells, and macrophages, which promotes clearance of the bacterial infection. In general, the gap between the device and the bone will range from about 40 micrometers to about 1 millimeter. Exemplary non-limiting examples of gap sizes include 40 micrometers, 50 micrometers, 75 micrometers, 100 micrometers 125 micrometers, 150 micrometers, 200 micrometers, 250 micrometers, 300 micrometers, 400 micrometers, 500 micrometers, 750 micrometers, 1000 micrometers, and all of the other micrometer values falling within the range of 40 to 1000 micrometers. In some embodiments, the gap is up to 2 millimeters, including all of the micrometer values falling within 1 millimeter and 2 millimeter, inclusive. It is to be understood that the gap values discussed here relate to the distance between a particular point on the device and the corresponding point on the bone. For instance, a gap of 100 micrometers means a gap measured from the edge of thread of the device to the corresponding trough in the bone.

Preferably, where the device comprises a surface feature, such as a threaded body, the gap is sufficiently small that the device cannot be inserted into the hole without using a screwing motion. That is, the diameter of the screw threads should be greater than the diameter of the hole, as defined by the threads created in the bone by the original fastener.

[027] A purpose of the device is to reduce bone growth into the hole while the device is present in the hole. The object is to maintain at least some of the original hole so that there is enough space to insert at least a portion of a new fastener or connector, preferably the same type of fastener or connector that was originally implanted in the bone. In other words, an object is to maintain a hole that can act as a guide for replacement of the fastener, for example once an infection has been cleared. It can also be preferable to use a device that is slightly smaller than the hole to allow for limited growth of bone into the hole left by the original fastener or connector. In this way, when the device is removed and replaced with a new fastener or connector, the new fastener or connector has some new bone to which it can attach. However, not so much new bone will be present to cause difficulty in replacing the original fastener with a new one. This concept is particularly relevant to fasteners/connectors that are screws or other threaded fasteners/connectors. [028] The shape of the device can be spherical, circular, cylindrical, polygonal, or any shape that will allow a hole in a bone to be mostly, essentially completely, or completely filled with the device. Where the hole in the bone is of a certain geometrical shape (e.g., cylindrical), the device preferably has the same geometrical shape. For example, where the original fastener is a screw, the bone filler device of the invention is preferably in the shape of a screw having the same pitch and separation of threads as the original screw. Alternatively, where the original fastener is a screw with a generally cylindrical shape (e.g., except the tip), the bone filler can have the same generally cylindrical shape, but without threads. In this way, the general shape of the hole is retained, but bone is permitted to grow into the former thread regions. Further, an open area is provided between the hole and the device, allowing limited movement of blood cells into the hole. The two-dimensional shape and the three-dimensional shape of the head can be different than the body of the device. That is, a medical fastener with a cylindrical threaded body may have a head that has a circular two-dimensional profile. However, the head can alternatively have a hexagonal, square, etc. two-dimensional profile.

[029] The device of the invention is not limited in size or shape. However, it is envisioned that the various embodiments of the device will be similar in size and shape to bone fasteners and connectors used in the medical and veterinary arts. As such, embodiments of the device can be made in many different sizes and shapes in bulk fashion, based on the sizes and shapes of fasteners used in the art. Although there are numerous embodiments of the device, it is not necessary for the practitioner to fabricate an individual device based on the size and shape of a particular hole in a bone. Rather, the practitioner would merely need to know the size of the fastener to be removed, and select an appropriate bone filler device from among the various sizes available as a result of prior bulk production.

[030] The device of the invention is preferably sterile or has been sterilized. Numerous methods for sterilizing the substances that comprise the device of the invention are known, and any suitable method may be used. In exemplary embodiments, the devices are sterilized by autoclaving or irradiation. [031] The present device substantially or completely fills a hole in bone left by removal of a medical fastener or connector, thereby preventing new bone from forming into and covering the hole while the fastener or connector is absent. In contrast to bone fillers currently known in the art, the present device does not promote bone growth, but instead is designed to discourage or substantially discourage bone growth. One of the advantages of discouraging bone growth in the hole is that the hole is not replaced by new bone and therefore can easily be used as a site for further medical intervention, such as implantation of a new fastener or connector. However, as discussed above, in some instances, slight bone growth is preferred to provide some new tissue to which a permanent replacement fastener can attach.

[032] In an embodiment, the hole is formed by the removal of a screw. Upon removal of the screw, the device of the present invention is then used to substantially, but not completely, fill the cavity left by the screw. Placement of the temporary filler into the hole substantially prevents new bone from forming in the cavity. While there are many screw sizes, the screw-hole plug does not need to be an exact fit, but just large enough to provide a channel after it is removed to allow the new screw to be accurately placed. In other embodiments, different fasteners are envisioned, such as staples, anchors, hooks, and the like. In yet other embodiments, connectors, such as pins, rods, and the like are envisioned as the object that is originally present in the hole, and which is removed.

[033] In another general aspect of the invention, the device is provided as part of a kit. A kit according to the invention is a container that contains one or more devices of the invention. For example, a kit may be a foil or plastic (or combination of the two) wrapper encasing one or more devices of the invention, preferably sealed to improve the ability to maintain sterility of the devices. It likewise may be a foil or plastic wrapper that encases two or more devices, either encasing a single device per encasement or encasing two or more devices per encasing.

Encasing one device per encasement allows a surgeon to use the number of devices needed to fill the holes in the bone, while allowing the remaining devices to stay sterile for later use.

[034] Kits may further comprise more elaborate or complex packaging material, such as a box that packages one or more containers. For example, a kit may comprise ten strips of five foil-encased devices that are encased individually. The exemplary kit may comprise ten strips of devices having all the same size, or it may comprise strips of devices having different sizes, either within one strip or among the ten strips. As such, a kit may contain two strips of devices for filling a 1 mm cylindrical hole, two strips of devices for filling a 2 mm cylindrical hole, two strips of devices for filling a 3 mm cylindrical hole, two strips of devices for filling a 4 mm cylindrical hole, and two strips of devices for filling a 5 mm cylindrical hole. Of course, any number of devices may be provided, in any combination of sizes, shapes, or compositions, per kit. In one embodiment, the kit is comprised of different sizes of the device so the appropriate size can be used in the surgery. The kit may further be comprised of surgical screws of different sizes.

[035] In a further general aspect, the present invention provides a method for temporarily filling a hole in a bone using the device of the present invention. The method comprises implanting, inserting, introducing, or otherwise placing the device into a hole left in a bone as a result of removal of a fastener or connector from the bone, and allowing the device to remain in the bone temporarily. The device can remain in the bone for several hours, weeks, or months. For example, the device can remain in the hole for three weeks to three months, four months, five months, six months, seven months, or more. Where the original fastener/connector is removed due to bacterial infection, the bone filler device of the present invention may remain in the hole for as long as is required to eliminate the infection. Where the infection is in the form of a biofilm, the device may remain in the hole for up to six months or longer. The practitioner may select the amount of time that the device is implanted based on any number of

considerations that are routinely taken into account for surgical interventions and general medical and veterinary applications.

[036] Placing the device into the hole in the bone can be any action that results in placement of the device into the hole. Typically, the act of placing comprises surgically placing the device into the hole. In embodiments where the device has no structural features that hold the device in place (e.g., the device has smooth sides) with no projections, the act of placing can simply be inserting the device into the hole. In embodiments where the device has structural features that hold the device in place, the act of placing will include additional actions that result in engaging the structural features with corresponding or complementary structural features of the bone. Typically, the structures of the bone are a result of structural features present on the medical fastener that is being temporarily replaced by the bone filler device of the present invention. For example, in situations where the original fastener/connector is a screw, and the device comprises threads on its body surface, the act of placing the device into the hole will include screwing the device into the hole.

[037] The method for temporarily filling a hole in a bone can be a method of inhibiting growth of bone into the hole. As discussed above, the structural component of the device of the invention is non-porous and biologically inert. Implantation of the device into a hole in a bone thus blocks growth of bone into the area of the hole occupied by the device. Accordingly, the device inhibits growth of bone during the period in which it is present in the bone. The level of inhibition is at least the extent to which the device occupies the volume of the hole left by removal of the original fastener.

[038] The method for temporarily filing a hole in a bone can also be a method of treating a subject suffering from an infection, a disease, or a disorder, such as a complication resulting from a prior surgical intervention. For example, the method can be a method of treating a bacterial infection, a fungal infection, a viral infection, a parasitic infection, or any combination of these. Likewise, it can be a method of treating an implant rejection or the necessity of implant removal due to untoward sequlae (e.g., spine implants that led to paralysis). Another non- limiting example is a method of treating poor soft-tissue healing over implants. In these embodiments, the device of the invention preferably comprises one or more antibiotics, one or more other bioactive agents, or combinations of the two types of substances, which are released over time during the period in which the device is present in the bone. Viewed in another light, the method of treating can be a method of treating a bacterial, fiingal, and/or viral infection at the site of implantation of the device. For example, the method can be a method of treating an infection by Staphylococcus aureus and/or Staphylococcus epidermidis. In exemplary embodiments, the infection is in the form of a biofilm. It is known in the art that biofilms are highly resistant to systemic antibiotic treatment. One advantage provided by the present invention is the ability to deliver high levels of antibiotics to the site of the biofilm by way of coating the device of the invention with relatively high amounts of one or more antibiotics. The device then, in essence, acts as a delivery vehicle for the antibiotics, which are then released in high concentrations directly at the site of infection. This delivery system provides a much more effective means for treating the biofilm infection than can be achieved by systemic treatment with the antibiotics.

[039] The method of the invention preferably comprises removing the device at a point in time after implantation, such as after an infection has been cleared. Because the device does not promote bone growth, it can be removed without significant difficulty or trauma to the bone.

[040] As should be evident, the method can be practiced immediately upon removal of the original fastener from the bone. As such, in embodiments, the method further comprises removing a surgical fastener from a bone prior to placing the temporary bone filler of the invention into the hole resulting from removal of the original fastener. Yet further, the method can include cleaning the site of residence of the original fastener to remove or treat scarring, biofilm(s) or other bacterial growth, etc. Cleaning can be by way of physical removal or by way of treatment with one or more bioactive agents (e.g., antibiotics, antifungals, etc.)

[041] In an exemplary embodiment, the method of the invention comprises: removing a fastener or connector implanted in a bone of a patient; placing a bone filling device of the invention into the hole left by the fastener or connector upon its removal; and maintaining the device in the hole for an adequate amount of time to perform an ancillary action. The method can additional comprise, prior to removing the fastener or connector, accessing the site on the bone of the subject where the fastener or connector is implanted. Additionally or alternatively, the method can comprise removing the device from the hole after maintaining it in the hole. The step of accessing can be any surgical procedure in which the patient's bone is exposed such that the fastener or connector can be removed and the device implanted. Maintaining the device in the hole is performed by any suitable method, but typically will include passive maintenance by way of simple closure of the surgical access. [042] By "ancillary action", it is meant any action that is taken that relates to the removal of the fastener or connector. In exemplary embodiments, the ancillary action is treatment of the bone and, optionally, surrounding tissue for an infection. In other exemplary embodiments, the ancillary action is repositioning of one or more bones, or portions of bones, that are intended to be connected.

[043] The method of the invention can include additional steps. For example, where the method is practiced to fight a biofilm infection, one or more additional treatment steps known in the art can be included in the method. For example, the site of infection can be subject to one or more treatment rounds of ultrasound. Alternatively or additionally, the subject may be treated systemically with one or more bactericidal or bacteriostatic agent (e.g., an antibiotic) to supplement the antibiotic(s) delivered by way of the device, with an immune system promoting agent, or one or more other bioactive agents.

[044] In an embodiment, the method is a method for temporarily filling a hole in a bone resulting from removal of a surgical fastener from the bone, where the method comprises:

placing a bone filler device into the hole left in a bone as a result of removal of the fastener from the bone; and allowing the bone filler device to remain in the bone temporarily; wherein the bone filler device comprises a physical structure that is non-porous and biologically inert; and wherein the physical structure of the device has one or more antibiotics, antifungal agents, antiviral agents, or other bioactive agents, or any combination of these, coated on or impregnated in it. The method can further comprise removing the device from the hole in the bone. Alternatively or additionally, the method can comprise, prior to placing the device in the hole, removing the surgical fastener from the bone. According to embodiments of the method, the device is allowed to remain in the hole in the bone for adequate amount of time to perform an ancillary action, such as clearance of an infection at the site of placement of the device. The method can be practiced to temporarily fill the hole and substantially inhibit growth of new bone into the hole while the device remains in the hole. The size of the device can be smaller than the original size of the hole to create a space or gap between the device and the bone into which immune cells of a patient into which the device is placed can enter. [045] In view of the disclosure above, it should be evident that one aspect of the invention is the use of the device of the invention in medical and veterinary applications. Included among the various uses, mention can be made of the use for maintaining or substantially maintaining a hole in a bone for a fastener or connector. Typically, the hole is maintained temporarily by maintaining the device in the hole, then removing it. Additionally, mention can be made of the use of the device for inhibiting or substantially inhibiting growth of bone into a hole left as a result of removal of a surgical fastener or connector, such as a surgical screw. Due to its non- porous and biologically inert nature, the device of the invention can be used to block growth of bone into the space of a hole occupied by the device. Yet again, mention can be made of the use of the device for treating a bacterial infection. Typically in such a use, the device comprises one or more antibiotics, which are released upon implantation and maintenance of the device in a hole in a bone. In such uses, the methods of making the device can be considered methods of making a device for use in treatment of a subject suffering from a bacterial infection. Viewed another way, the methods of making the device can be considered methods of making a device for use in treatment of a bacterial infection, including methods of treatment of biofilms.

[045] It will be apparent to those skilled in the art that various modifications and variations can be made in the practice of the present invention and in construction of the device without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention. It is intended that the specification be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

1. A method for temporarily filling a hole in a bone resulting from removal of a surgical fastener from the bone, said method comprising:

placing a bone filler device into the hole left in a bone as a result of removal of the fastener from the bone; and

allowing the bone filler device to remain in the bone temporarily;

wherein the bone filler device comprises a physical structure that is non-porous and biologically inert; and

wherein the physical structure of the device has one or more antibiotics, antifungal agents, antiviral agents, or other bioactive agents, or any combination of these, coated on or impregnated in it.

2. The method of claim 1 , further comprising removing the device from the hole in the bone.

3. The method of claim 1 or claim 2, further comprising, prior to placing the device in the hole, removing the surgical fastener from the bone.

4. The method of any one of claims 1 -3, wherein the device is allowed to remain in the hole in the bone for adequate amount of time to perform an ancillary action.

5. The method of claim 4, wherein the ancillary action is clearance of an infection at the site of placement of the device.

6. The method of any one of claims 1 -5, wherein the method temporarily fills the hole and substantially inhibits growth of new bone into the hole while the device remains in the hole.

7. The method of any one of claims 1 -6, wherein the amount of time the device remains in the hole is sufficient to clear an infection at the site of placement of the device.

8. The method of any one of claims 1 -7, wherein the size of the device is smaller than the original size of the hole to create a space between the device and the bone into which immune cells of a patient into which the device is placed can enter.

9. The method of any one of claims 1 -8, wherein the physical structure comprises one or more non-porous plastics, silicones, or ceramics, or combinations of two or all three of these.

10. The method of any one of claims 1-9, wherein the physical structure comprises one or more thermoplastic polymers, one or more thermosetting polymers, or combinations of one or more thermoplastic polymers with one or more thermosetting polymers.

1 1. The method of any one of claims 1-10, wherein the physical structure comprises: poly(methyl methacrylate) (PMMA); a fluoroplastic; polytetrafluoroethylene (PTFE);

polyfluoroacetate; polysulfone; a polyacrylate; a polyamide; nylon, a polyamide-imide; a polycarbonate; polyetheretherketone (PEEK), a polyethylene; acrylonitrile butadiene styrene (ABS); polyoxymethylene; polyvinylchloride (PVC); polypropylene; or phenolic; or a combination of two or more of these.

12. The method of any one of claims 1-11, wherein the device is a surgical screw, and placing the screw into the hole comprises screwing the device into the hole.

13. The method of any one of claims 1-12, which is a method of inhibiting growth of bone into the hole.

13. The method of any one of claims 1-12, which is a method of treating a subject suffering from an infection, a disease, or a disorder.

14. The method of any one of claims 1-13, which is a method of treating a bacterial, fungal, parasitic, and/or viral infection at the site of implantation of the device.

15. The method of any one of claims 1-14, which is a method of treating an implant rejection or the necessity of implant removal due to untoward sequlae, or a method of treating poor soft-tissue healing over implants.

16. Use of a bone filler device for substantially maintaining a hole in a bone for a surgical fastener, wherein the bone filler device comprises a physical structure that is non-porous and biologically inert, wherein the physical structure of the device has one or more antibiotics, antifungal agents, antiviral agents, or other bioactive agents, or any combination of these, coated on or impregnated in it, and wherein the size of the device is smaller than the original size of the hole to create a space between the device and the bone into which immune cells of a patient into which the device is placed can enter.

17. The use according to claim 16, wherein the size of the device and the biological inertness and non-porosity further inhibits growth of new bone into the hole at least in the volume of the hole occupied by the device.

18. The use according to either of claims 16 or 17, wherein the use is further a use of the device for treating a bacterial, fungal, parasitic, and/or viral infection.