Patent Application
20120029638
The present invention relates generally to the field of medical implants, and more particularly relates to medical implants that include a vertebral body replacement device that alone, or in combination with other components, are configured to deliver a therapeutic substance.
The use of therapeutic substances in combination with medical implants has beneficial characteristics in many treatments. Therapeutic substances may be useful in promoting healing, fighting infection and disease by killing various pathogens such as bacteria, viruses, and microorganisms, promoting favorable cellular activity, killing cancer cells, or any of a wide variety of beneficial results. It may be advantageous to associate a therapeutic substance with a medical implant where the medical implant is implanted in a particularly advantageous location for effective application of the therapeutic substance.
It is a continuing challenge in the art to provide medical implants that may be conveniently and securely placed to deliver effective amounts of therapeutic substances in effective locations. A procedure for which delivery of therapeutic substances may be useful is a vertebral body replacement procedure. It is sometimes necessary to remove one or more vertebrae, or a portion of the vertebrae, from the human spine in response to various pathologies. For example, one or more of the vertebrae may become damaged as a result of tumor growth, or may become damaged by a traumatic or other event. Removal, or excision, of a vertebra may be referred to as a vertebrectomy. Excision of a generally anterior portion, or vertebral body, of the vertebra may be referred to as a corpectomy. An implant is usually placed between the remaining vertebrae to provide structural support for the spine as a part of a corpectomy or vertebrectomy.
Improved devices may be configured to provide delivery of one or more therapeutic substances from vertebral body replacement devices or from a component associated with vertebral body replacement devices. It may be advantageous to provide medical implants capable of delivering a therapeutic substance that may be placed in a sequence that is complementary to existing surgical procedures.
An embodiment of the invention is a medical implant configured to deliver a therapeutic substance. The medical implant embodiment may include a vertebral body replacement device having a first end and a substantially opposite second end, and a sheath coupled to the vertebral body replacement device. The sheath may cover substantially all of the vertebral body replacement device from the first end to the second end. The sheath may also include a therapeutic substance deliverable from the sheath to one or more anatomic structures positionable adjacent to the medical implant.
Another embodiment of the invention is a medical implant configured to deliver a therapeutic substance. The medical implant embodiment may include at least one therapeutic substance reservoir, two or more nozzles in fluid communication with the at least one therapeutic substance reservoir, and a vertebral body replacement device. The vertebral body replacement device may have a first end, a substantially opposite second end, and one or more sides extending from the first end to the second end, wherein the one or more sides at least in part define an interior of the vertebral body replacement device. The two or more nozzles may be coupled to the vertebral body replacement device to direct therapeutic substance from the interior of the vertebral body replacement device.
Yet another embodiment of the invention is a medical implant configured to deliver a therapeutic substance. The medical implant embodiment may include a vertebral body replacement device having a first end, a substantially opposite second end, and one or more sides extending from the first end to the second end, wherein the one or more sides at least in part define an interior of the vertebral body replacement device. The medical implant embodiment may also include an insert captured within the interior of the vertebral body replacement device. The insert may include one or more therapeutic substances deliverable from the insert and a release mechanism for permitting the one or more therapeutic substances to be delivered from the insert.
An embodiment of a medical implant configured to deliver a therapeutic substance is shown in
In the illustrated embodiment, the first end 111 and the second end 112 incorporate SCEPTOR™ Universal Endcleats. In some embodiments, the vertebral body replacement device may include other devices or structures at one or both of its ends or may be a unitary device that has no other separate structures or devices associated with its ends. The illustrated vertebral body replacement device 110 has a substantially circular cross-sectional shape. In other embodiments, a vertebral body replacement device may have a lateral periphery of one or more walls having a cross-sectional shape that is substantially oval, kidney shape, triangle, rectangle, square, any polygonal or curved shape, or any combination of shapes.
A sheath 120 is shown coupled to the vertebral body replacement device 110 and covering substantially all of the vertebral body replacement device 110 from the first end 111 to the second end 112. The illustrated sheath 120 terminates outside of each of the SCEPTOR™ Universal Endcleats. In other embodiments, a sheath may be captured within endcleats or other end pieces or may extend around a periphery of an end piece of any functional type.
The illustrated sheath 120 includes a therapeutic substance deliverable from the sheath 120 to one or more anatomic structures positionable adjacent to the medical implant 100. The delivery of therapeutic substance may be in any direction from a medical implant. The amount and timing of delivery of therapeutic substance may be controlled by one or more of placement of the sheath, inclusion of type and amount of therapeutic substance in various parts of the sheath, and release characteristics of the therapeutic substance or the sheath.
Another embodiment of a medical implant configured to deliver a therapeutic substance is shown in
The medical implant 200 may also include additional pieces such as cleats or other connection mechanisms to extend the length of the device or provide connection to adjacent vertebrae at one or both of the first and second ends 211, 212. Similar to the vertebral body replacement device 110, the vertebral body replacement device 210 may include any functional shape or configuration.
A sheath 220 is shown coupled to the vertebral body replacement device 210 and covering substantially all of the vertebral body replacement device 210 from the first end 211 to the second end 212. The sheath 220 is shown coupled to the vertebral body replacement device 210 by a sheath fastener 225 at a first location near the first end 211. The sheath 220 is also shown coupled to the vertebral body replacement device 210 by a band 230 at a second location near the second end 212. The illustrated sheath fastener 225 is a bolt or screw and washer. In other embodiments, any other screw, pin, clip, or other effective mechanism may be used. A separate washer may be used, a washer may not be used, or fasteners of some embodiments may incorporate a washer or force spreading portion in a unitary device. The illustrated band 230 for fastening a sheath wraps around the second end 212 and is shortened or tightened to capture the sheath 220 between the band 230 and the second end 212. In some embodiments, the band 230 may be a hose clap of any variety or any device effective to wrap around or otherwise capture the sheath 220 relative to a vertebral body replacement device.
Another embodiment of a medical implant configured to deliver a therapeutic substance is shown in
Any of the sheaths disclosed specifically herein (120, 220, 320) or otherwise represented by this disclosure may include a therapeutic substance deliverable from the sheath to one or more anatomic structures positionable adjacent to the medical implant of which a sheath is a part or to which a sheath may be added. The delivery of therapeutic substance may be in any direction from a medical implant. The amount and timing of delivery of therapeutic substances may be controlled by one or more of placement of the sheath, inclusion of type and amount of therapeutic substance in various parts of the sheath, and release characteristics of the sheath and the therapeutic substances. In some embodiments, the sheath may be made at least in part from a relatively rigid material. In other embodiments, the sheath may be made at least in part from a relatively elastic material or include relatively elastic regions. A sheath that includes elastic material or regions may be capable of stretching over a component to be affixed to the component, or may, for example, stretch to remain in place over an expandable vertebral body to move from a collapsed state to an expanded state. A sheath may include one or more specific stretching portions or may be formed to include folds or bellows that expand when a force is applied.
In the embodiments shown in
All or a part of a sheath may include a polymeric body configured to elute the therapeutic substance. The polymeric body may further elute the therapeutic substance at a predetermined rate. Alternatively or in addition, a sheath may at least in part be porous, and the therapeutic substance may be at least in part disposed in the pores of a sheath.
The sheath in whole or in part may comprise a polymeric material into or onto which a therapeutic substance is incorporated. Any polymeric material may be used. The polymeric material may be biocompatible and capable of presenting or eluting the therapeutic substance in an effective amount. Biocompatible polymers may be obtained from natural or synthetic sources, and may be bioresorbable. Examples of natural materials of which the polymer may be composed include collagen, elastin, silk, and demineralized bone matrix. Other examples of suitable polymeric materials include organic polymers such as silicones, polyamines, polystyrene, polyurethane, acrylates, polysilanes, polysulfone, methoxysilanes, and the like. Other polymers that may be utilized include polyolefins, polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymers and copolymers, ethylene-covinylacetate, polybutylmethacrylate; vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers with each other and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, resins, and ethylene-vinyl acetate copolymers; polyamides, such as Nylon 66 and polycaprolactam; polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins; polyurethanes; rayon; rayon-triacetate; cellulose; cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; carboxymethyl cellulose; polyphenyleneoxide; polytetrafluoroethylene (PTFE); polyethylene, low density polyethylene; polymethylmethacrylate (PMMA); polyetheretherketone (PEEK); and polyetherketoneketone (PEKK). The polymer may also be a polymeric hydroxyethylmethacrylate (PHEMA). Suitable bioresorbable synthetic polymers include poly(L-lactide), poly(D,L-lactide), poly(L-co-D,L-lactide), polyglycolide, poly(lactide-co-glycolide), poly(hydroxylbutyrate), poly(hydroxyvalerate), tyrosine-derived polycarbonate, polyanhydride, polyorthoester, polyphosphazene, poly(dioxanone), and polyglyconate. Other similar polymers known to the art may be used and various mixtures of polymers may be combined to adjust the properties of the composition as desired.
A therapeutic substance may be incorporated into or coated on a polymeric material of a sheath using any known or later developed technique. For example, the therapeutic substance may be adhered to a surface of any part of a sheath, adsorbed into a sheath, or compounded into the polymeric material that forms a sheath. Accordingly, the therapeutic substance may be embedded, coated, mixed or dispersed on or in the material of a sheath. A coating method may be determined by the material of a sheath and the therapeutic substance utilized. Such methods include but are not limited to, dipping, spraying, rolling, plating and embedding the coating into a surface by any means. For example, a polymeric sheath may be coated by dipping or spray coating polymeric resin and crosslinker with the therapeutic substance as substituent or dissolved within the polymer. Curing may be achieved chemically, photochemically or thermally. Other common methods include dip or spray coating water insoluble resin containing a therapeutic substance followed by drying or grafting directly onto the substrate chemically or photochemically.
Additional examples of ways to form at least a portion of a sheath include blending a therapeutic substance with a polymer and then forming the polymer into the sheath, or portion of the sheath. Alternatively, the therapeutic substance may be in a solution with the polymer to form a coating. The therapeutic substance may be attached to a polymeric material by a chemical modification of the surface such as surface grafting by hydrolyzable linkage of the therapeutic substance to the surface or by photolinking the therapeutic substance to the surface. Surface polymerization, derivatization or absorption may also be used. Other examples of obtaining a surface bound therapeutic substance include any existing means, such as ion implantation, chemical modification of the surface, photochemical or chemical grafting or formation of a crosslinked surface immobilized network. Silver ions, where used, may be deposited on a surface of a sheath by vacuum deposition, ion sputtering or surface deposition, among others. A surface of a sheath may be pretreated according to known methods such as plasma treatment prior to exposure to the coating material. Where solvents are present in a therapeutic substance, such solvents may be biocompatible if residue remains after the therapeutic substance is applied.
A therapeutic substance may comprise one or more of the following: antibiotics, antiseptics, analgesics, bone growth promoting substances, anti-inflammatants, anti-coagulants, antifungal agents, steroids, enzymes, immunosuppressants, antithrombogenic compositions, vaccines, hormones, growth inhibitors, growth stimulators, chemotherapy drugs, and the like. A therapeutic substance may be any drug or bioactive agent which can serve a useful therapeutic or even diagnostic function when released into a patient. More than one therapeutic substance may be present in or on a sheath for a particular treatment within the scope of the invention.
A therapeutic substance may include pharmaceuticals that target particular cells, such as but not limited to, cancer cells. A therapeutic substance may be any radiopharmaceutical or radionuclide, for example. A therapeutic substance may be a pure bone-seeking radioisotopes, such as strontium-89 and phosphorus-32 or a radioisotope that has been combined with other bone-seeking agents, such as samarium-153, rhenium-186, and iodine-131.
A therapeutic substance may include a DNA-damaging agent, such as chlorambucil, cyclophosphamide or melphalan, collectively referred to as alkylating agents. These DNA-damaging agents damage the DNA so severely that the cancer cell is killed. Other DNA-damaging agents, such as carboplatinum, attach to the DNA and prevent the cancer cell from growing.
A therapeutic substance may include antitumor antibiotics, such as daunorubicin, doxorubicin, idarubicin, and mitoxantrone, which insert themselves into the DNA of a cancer cell, prevent the DNA from functioning normally, and often kill the cancer cell.
A therapeutic substance may include antimetabolites, such as methotrexate, fludarabine, and cytarabine. These drugs mimic substances that the cancer cell needs to build DNA and RNA. When a cancer cell uses the antimetabolite instead of the natural substances, it cannot produce normal DNA or RNA, and the cell dies.
A therapeutic substance may include DNA-repair enzyme inhibitors, such as etoposide or topotecan. These inhibitors attack the cancer cell proteins that normally repair any damage to the cell DNA. Repair of DNA damage is a normal and vital process in the cell, without which the cancer cell is much more susceptible to damage and is prevented from growing.
A therapeutic substance may include vincristine or vinblastine. These agents damage cancer cells by blocking mitosis. This prevents the cancer cells from dividing and multiplying.
A therapeutic substance may include antibodies that are made specifically to attach to cancer cells. Once these antibodies attach to the cancer cells, the antibodies interfere with the cells' functions and kill the cells. Some antibodies may also be linked to a toxin or radioactive substance. When these antibodies attach to cancer cells, one or more of the antibodies, the toxin, and the radioactive substance work to kill cancer cells.
A therapeutic substance may include radiation sources that remain physically within a sheath, but that emit radiation in a desired direction from the sheath. By way of non-limiting example, a radiation source may be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic energy or substances. A radioactive therapeutic substance may also be a fluid made from any solution of radionuclide(s), e.g., a solution of I-125 or I-131, or a radioactive mixture may be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90. Radionuclides may also be provided in a gel. One radioactive material useful in some embodiments is Iotrex®, a nontoxic, water soluble, nonpyrogenic solution containing sodium 3-(125I)iodo-4-hydroxybenzenesulfonate (125I-HBS), available from Proxima Therapeutics, Inc. of Alpharetta, Ga. Radioactive micro spheres of the type available from the 3M Company of St. Paul, Minn., may also be incorporated into or introduced into a sheath. A radioactive source may be preloaded into a medical implant at the time of manufacture or loaded after the medical implant has been implanted.
A therapeutic substance may include any antibiotic suitable for use in a human. As used herein, “antibiotic” means an antibacterial agent. The antibacterial agent may have bateriostatic and/or bacteriocidal activities. Nonlimiting examples of classes of antibiotics that may be used include tetracyclines (e.g. minocycline), rifamycins (e.g. rifampin), macrolides (e.g. erythromycin), penicillins (e.g. nafcillin), cephalosporins (e.g. cefazolin), other beta-lactam antibiotics (e.g. imipenem, aztreonam), aminoglycosides (e.g. gentamicin), chloramphenicol, sufonamides (e.g. sulfamethoxazole), glycopeptides (e.g. vancomycin), quinolones (e.g. ciprofloxacin), fusidic acid, trimethoprim, metronidazole, clindamycin, mupirocin, polyenes (e.g. amphotericin B), azoles (e.g. fluconazole) and beta-lactam inhibitors (e.g. sulbactam). Nonlimiting examples of specific antibiotics that may be used include minocycline, rifampin, erythromycin, nafcillin, cefazolin, imipenem, aztreonam, gentamicin, sulfamethoxazole, vancomycin, ciprofloxacin, trimethoprim, metronidazole, clindamycin, teicoplanin, mupirocin, azithromycin, clarithromycin, ofloxacin, lomefloxacin, norfloxacin, nalidixic acid, sparfloxacin, pefloxacin, amifloxacin, enoxacin, fleroxacin, temafloxacin, tosufloxacin, clinafloxacin, sulbactam, clavulanic acid, amphotericin B, fluconazole, itraconazole, ketoconazole, and nystatin. Other antibiotics may also be used.
To enhance the likelihood that bacteria will be killed or inhibited, it may be desirable to combine one or more antibiotics. It may also be desirable to combine one or more antibiotics with one or more antiseptics. Agents having different mechanisms of action and/or different spectrums of action may be most effective in achieving such an effect.
Any antiseptic suitable for use in a human may be used as or as part of a therapeutic substance. As used herein, “antiseptic” means an agent capable of killing or inhibiting the growth of one or more of bacteria, fungi, or viruses. Antiseptic includes disinfectants. Nonlimiting examples of antiseptics include hexachlorophene, cationic bisiguanides (i.e. chlorhexidine, cyclohexidine) iodine and iodophores (i.e. povidone-iodine), para-chloro-meta-xylenol, triclosan, furan medical preparations (i.e. nitrofurantoin, nitrofurazone), methenamine, aldehydes (glutaraldehyde, formaldehyde), silver sulfadiazine and alcohols. It may be desirable that the one or more antiseptics selected kill or inhibit the growth of one or more microbes that are associated with infection following surgical implantation of a medical device. Such bacteria may include Stapholcoccus aureus, Staphlococcus epidermis, Pseudomonus auruginosa, and Candidia. To enhance the likelihood that microbes will be killed or inhibited, it may be desirable to combine one or more antiseptics. It may also be desirable to combine one or more antiseptics with one or more antibiotics. Antimicrobial agents having different mechanisms of action and/or different spectrums of action may be most effective in achieving such an effect.
A therapeutic substance may be present in the sheath at any concentration effective, either alone or in combination with another therapeutic substance. Generally, a therapeutic substance may be present in a sheath at a range of between about 0.5% and about 20% by weight. For example, a therapeutic substance may be present in a sheath at a range of between about 0.5% and about 15% by weight or between about 0.5% and about 10% by weight.
A therapeutic substance may comprise an antimicrobial material including metals known to have antimicrobial properties, such as silver, gold, platinum, palladium, iridium, tin, copper, antimony, bismuth, selenium and zinc. Compounds of these metals, alloys containing one or more of these metals, or salts of these metals may be coated onto the surface of a sheath or added to the material from which a sheath is made during the manufacture of the sheath or compounded into the base material. One therapeutic substance will contain silver ions and may be obtained through the use of silver salts, such as silver acetate, silver benzoate, silver carbonate, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, silver protein, or silver sulfadiazine, among others. In an embodiment where selenium is used, the selenium may be bonded to the surface of a sheath, providing an antimicrobial coating.
A therapeutic substance may also comprise an osteoconductive, osteogenic, or osteoinductive material. For example and without limitation, a therapeutic substance may include various bioceramic materials, calcium phosphate and other members of the calcium phosphate family, fluorapatite, bioactive glass, and collagen-based materials. Members of the calcium phosphate family include materials such as hydroxyapatite, α-tricalcium phosphate, β-tricalcium phosphate, tetracalcium phosphate, dicalcium phosphate dihydrate, ocatacalcium phosphate, and the like. A therapeutic substance may include an osteoinductive or osteogenic materials such as osteoblast cells, platelet-derived growth factors (PDGFs), bone morphogenetic proteins (BMPs), insulin-like growth factors (IGFs), basic fibroblast growth factor (bFGF), cartilage derived morphogenetic protein (CDMP), growth and differentiation factors (GDFs), LIM mineralization proteins, transforming growth factor beta family (TGF-β), and other bone proteins, such as CD-RAP. These proteins can be recombinantly produced or obtained and purified from an animal that makes the proteins without the use of recombinant DNA technology. Recombinant human BMP is referred to as “rhBMP”; recombinant human GDF is referred to as “rhGDF”. Any bone morphogenetic protein is contemplated, including bone morphogenetic proteins designated as BMP-1 through BMP-18. Mimetics of growth factors can also be used in the devices of the present invention for inducing the growth of bone.
Each BMP may be homodimeric, or may be heterodimeric with other BMPs (e.g., a heterodimer composed of one monomer each of BMP-2 and BMP-6) or with other members of the TGF-β superfamily, such as activins, inhibins and TGF-β 1 (e.g., a heterodimer composed of one monomer each of a BMP and a related member of the TGF-β superfamily). Any of these substances may be used individually or in mixtures of two or more. One or more statins may also be included in a therapeutic substance. Non-limiting examples of statins that may be included in the devices of the present invention include atorvastatin, cerivastatin, fluvastatin, lovastatin, mavastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. The therapeutic substance may include various other organic species known to induce bone formation, and combinations thereof.
Embodiments of the sheath may include two or more layers with differing therapeutic characteristics. By way of non-limiting example, a top layer may include an antibiotic to prevent postoperative infection; a second layer may include a chemotherapy agent to prevent recurrence of a tumor; a third layer may include a bioresorbable non-therapeutic to allow the effects of the chemotherapy agent to dissipate before introduction of the next therapeutic agent; and a fourth layer may include a bone growth promoting substance. Any other effective combination of layers may be used with one or more therapeutic substances and may or may not include inert layers, such as a bioresorbable non-therapeutic layer.
A medical implant 400 configured to deliver a therapeutic substance is illustrated in
The medical implant 400 shown includes a therapeutic substance reservoir 450 located within an interior of the vertebral body replacement device 410. In other embodiments, a therapeutic substance reservoir is located outside of the interior of a vertebral body replacement device. For example and without limitation, a therapeutic substance reservoir may be located outside of the interior of a vertebral body replacement device, but within a patient's body. In other embodiments, a therapeutic substance reservoir may be located outside of the interior of a vertebral body replacement device, and outside of a patient's body. As shown in
The medical implant 400 also includes nozzles 451, 452, 453 in fluid communication with the therapeutic substance reservoir 450. Any number of nozzles may be present with other embodiments. The nozzles 451, 452, 453 are coupled to the vertebral body replacement device 410 to direct therapeutic substance from the interior or the vertebral body replacement device 410. Nozzles may be located anywhere along a medical implant to direct therapeutic substance in a clinically advantageous way. The nozzles 451, 452 are shown in
The medical implant 400 may also include one or more valves to control flow of therapeutic substance from the nozzles 451, 452, 453. Valves may be located at a nozzle, along any of the respective tubes, at the therapeutic substance reservoir, outside of the medical implant, or at any other effective location. Valves may be controlled by any effective signal mechanism, including but not limited to, electrical, radio frequency, and pressure. Valves may be signaled directly or through one or more controller devices. By way of non-limiting example in
In some embodiments, no nozzles are directed from the interior of a vertebral body replacement device through certain, designated portions of the vertebral body replacement device. In these embodiments, the designated portions may be configured to be implanted adjacent to a spinal cord. This configuration may be useful to avoid directing therapeutic substances toward a spinal cord. Similarly, in some embodiments such a configuration may be used to avoid directing therapeutic substances toward vascular structures, such as, for example, the great vessels along an anterior portion of a spinal column. Any other anatomical part, including anatomical parts sensitive to a therapeutic, may be effectively avoided by selective direction of a therapeutic substance.
In some embodiments, two or more therapeutic substances may be directed through different nozzles of the medical implant. Two or more therapeutic substances may be directed through the same nozzle at different times or as a mixture. The medical implant 400 illustrated in
A medical implant 500 configured to deliver a therapeutic substance is illustrated in
Either of the inserts 600, 700 may be captured within the interior of the vertebral body replacement device 510, as indicated by the arrows in
The insert 600 is shown in cross-sectional view in
An insert 650, which may also be captured within the interior of the vertebral body replacement device 510, is shown in cross-sectional view in
The insert 700 that may also be captured within the interior of the vertebral body replacement device 510, as shown in
In another embodiment, an insert of the medical implant 500 may be a device that controls release of a therapeutic substance in any of the ways disclosed herein in association with the medical implant 400. In such an embodiment, the entire medical implant 400, or similar construct, may be placed within the vertebral body replacement device 510 to assemble a completed medical implant 500.
Terms such as around, near, opposite, top, side and the like have been used herein to note relative positions. However, such terms are not limited to specific coordinate orientations, but are used to describe relative positions referencing particular embodiments. Such terms are not generally limiting to the scope of the claims made herein.
While embodiments of the invention have been illustrated and described in detail in the disclosure, the disclosure is to be considered as illustrative and not restrictive in character. All changes and modifications that come within the spirit of the invention are to be considered within the scope of the disclosure.
