WO2005014071A1 - Methods and devices for the treatment of intervertebral discs - Google Patents
Methods and devices for the treatment of intervertebral discs Download PDFInfo
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- WO2005014071A1 WO2005014071A1 PCT/US2004/025389 US2004025389W WO2005014071A1 WO 2005014071 A1 WO2005014071 A1 WO 2005014071A1 US 2004025389 W US2004025389 W US 2004025389W WO 2005014071 A1 WO2005014071 A1 WO 2005014071A1
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- active agent
- intervertebral disc
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- solid body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
- A61F2002/30316—The prosthesis having different structural features at different locations within the same prosthesis; Connections between prosthetic parts; Special structural features of bone or joint prostheses not otherwise provided for
- A61F2002/30535—Special structural features of bone or joint prostheses not otherwise provided for
- A61F2002/30581—Special structural features of bone or joint prostheses not otherwise provided for having a pocket filled with fluid, e.g. liquid
- A61F2002/30586—Special structural features of bone or joint prostheses not otherwise provided for having a pocket filled with fluid, e.g. liquid having two or more inflatable pockets or chambers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
- A61F2002/30667—Features concerning an interaction with the environment or a particular use of the prosthesis
- A61F2002/30677—Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2/44—Joints for the spine, e.g. vertebrae, spinal discs
- A61F2/442—Intervertebral or spinal discs, e.g. resilient
- A61F2002/444—Intervertebral or spinal discs, e.g. resilient for replacing the nucleus pulposus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
- A61L2300/254—Enzymes, proenzymes
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
- A61L2300/414—Growth factors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
- A61L2300/622—Microcapsules
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/38—Materials or treatment for tissue regeneration for reconstruction of the spine, vertebrae or intervertebral discs
Definitions
- the present application relates generally to methods and devices for the treatment of intervertebral discs and, in particular, to controlled release devices comprising a chemonucleolysis agent or multiple active agents and to methods of treatment comprising implanting the devices into an intervertebral disc.
- intervertebral discs are cartilaginous plates surrounded by a fibrous ring that lie between the vertebral bodies and serve to cushion them.
- fibrous tissue annulus f ⁇ brosus
- the soft disc material nocleus pulposus
- This squeezing or protrusion of the disc has been called herniated disc, ruptured disc, herniated nucleus pulposus, or prolapsed disc.
- the extruded nucleus pulposus may press on a spinal nerve which may result in nerve damage, pain, numbness, muscle weakness and even paralysis.
- intervertebral discs Common methods of providing relief for damaged intervertebral discs include surgical removal of all or a portion of the intervbertebral disc followed by fusion of the adjacent vertebrae. Although fusion can eliminate certain of the aforementioned symptoms, the restricted motion of the fused segment increases the range of motion required of the adjoining intervertebral discs and can therefore enhance their degeneration. As an alternative to fusion, the disc can be replaced with a spacer designed to simulate healthy intervertebral disc motion. The materials from which these disc spacers are made
- an intervertebral disc implant comprising a chemonucleolysis agent in solid form
- the chemonucleolysis agent is capable of the proteolytic degradation of the nucleus pulposus of an intervertebral disc.
- the implant can be a solid body comprising the chemonucleolysis agent.
- the solid body can be an elongate solid body or a microsphere.
- the solid body can further comprise a binder.
- the binder can be a bioresorbable polymer.
- the implant can comprise a plurality of unconsolidated particles at least some of which comprise the chemonucleolysis agent.
- chemonucleolysis agents include chymopapain or chondroitinase ABC.
- an intervertebral disc implant comprising a first active agent and a second active agent different than the first active agent is provided wherein both the first active agent and the second active agent are in solid form.
- the implant can be a solid body comprising the first and second active agents.
- the solid body can be an elongate solid body or a microsphere.
- the microsphere can include a core comprising the first active agent and a shell comprising the second active agent.
- the elongate solid body can include a core comprising the first active agent and a sheath comprising the second active agent.
- the implant can comprise a plurality of unconsolidated particles at least some of which comprise the first active agent and at least some of which comprise the second active agent.
- the first active agent can be a chemonucleolysis agent and the second active agent can be a growth factor.
- the growth factor can be a transforming growth factor- ⁇ protein, a bone morphogenetic protein, a fibroblast growth factor, a platelet-derived growth factor, or an insulin-like growth factor.
- a method of treatment comprising: placing an implant as set forth above in an intervertebral space of a mammal.
- the implant can comprise either a chemonucleolysis agent in solid form or a first active agent and a second active agent different than the first active agent wherein the first active agent and the second active agent are both in solid form.
- Implanting can comprise: inserting a needle/trocar assembly into the intervertebral space such that the inserted end of the trocar is inside the nucleus pulposus of an intervertebral disc; removing the needle; placing the implant(s) (e.g., one or more solid bodies or the particulate material) into the trocar; pushing the implant(s) into the nucleus pulposus of the intervertebral disc; and removing the trocar.
- Implanting can further comprise: forming an aperture into the intervertebral space of the mammal; and pushing a solid body implant(s) through the aperture and into the intervertebral disc space.
- the implant(s) can comprise a chemonucleolysis agent and a second active agent different than the chemonucleolysis agent.
- the solid body can be an elongate solid body including a core comprising the second active agent, and a sheath comprising the chemonucleolysis agent such that, after implantation, the chemonucleolysis agent is released in a first phase of release and the second active agent is released in a second phase of release.
- the second active agent can be a growth factor and the method can further comprise injecting cells into the disc space during the second phase of release.
- FIG. 1 illustrates two alternative methods, as shown in Fig. la and Fig. lb, of preparing an intervertebral disc implant.
- FIG. 2 illustrates the steps of a method for implanting an intervertebral disc implant as prepared by the methods described in Fig. la and Fig. lb..
- FIG. 3 illustrates the performance of an intervertebral disc implant after implantation into an intervertebral disc space.
- FIG. 4 shows an intervertebral disc implant for the delivery of at least two active agents.
- FIG. 5 illustrates the performance of an intervertebral disc implant placed as shown in FIG. 2 after implantation into an intervertebral disc space.
- FIG. 1 illustrates two alternative methods, as shown in Fig. la and Fig. lb, of preparing an intervertebral disc implant.
- FIG. 2 illustrates the steps of a method for implanting an intervertebral disc implant as prepared by the methods described in Fig. la and Fig. lb.
- FIG. 6 illustrates a method of treating an intervertebral disc using an intervertebral disc implant, placed as in FIG. 2, wherein cells are injected into the disc space after chemonucleolysis is complete.
- FIG. 7 illustrates an intervertebral disc implant for the delivery of at least three active agents.
- FIG. 8 is a cross-sectional view of a microsphere comprising a chemonucleolysis agent.
- FIG. 9 illustrates a method of treating an intervertebral disc wherein microspheres comprising a chemonucleolysis agent are mixed in liquid solution and injected into an intervertebral disc space.
- FIG. 10 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of at least two active agents.
- FIG. 11 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of at least three active agents.
- FIG. 12 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of at least three active agents having a sheath/core configuration wherein two of the active agents are in different portions of the sheath and the third active agent is in the core.
- FIG. 13 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of at least three active agents having a sheath/core configuration wherein one of the active agents is in the sheath and the second and third active agents are in different portions of the core.
- FIG. 14 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of at least two active agents having a rod configuration wherein alternating portions of the rod contain each of the two active agents.
- FIG. 15 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of multiple active agents having a rod configuration wherein segments of the rod contain different active agents.
- FIG. 16 illustrates various profile shapes (FIGS. A-O) for intervertebral disc implants.
- FIG. 17 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of at least two active agents having a rod configuration, a pointed insertion end and a hydrogel coating to provide lubricity.
- FIG. 18 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of at least two active agents having a rod configuration, a pointed insertion end, a hydrogel coating to provide lubricity and x-ray marker beads.
- FIG. 19 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of at least two active agents having a rod configuration, a pointed insertion end, a hydrogel coating to provide lubricity and an x-ray marker thread.
- FIG. 20 illustrates a method of implanting an intervertebral disc implant according to the steps shown in FIG. 20a and FIG. 20b.
- FIG. 21 provides photographs of porcine (pig) discs.
- FIG. 21 A shows an untreated (control) disc.
- FIG. 21B shows a disc treated with chymopapain in saline solution.
- FIG. 21C shows a disc treated with an implant, comprising chymopapain and collagen powder, according to one embodiment of the invention.
- the disclosed methods of treatment do not require the surgical removal of disc tissues.
- the disclosed methods and devices can be used to treat various conditions of the intervertebral disc including, but not limited to, protrusion, hemiation, discogenic pain, dehydration and degeneration.
- the implants incorporate one or more active agents. By using the implants, detrimental side effects typically associated with direct injection of an active agent in liquid form (including leakage and overdose) can be reduced or eliminated.
- Methods of incorporating one or more active agents into a compact implantable device are also provided.
- the devices can be delivered into the nucleus pulposus through a small opening or aperture in the annulus fibrosus.
- the device can provide a controlled and/or sustained release of one or more active agents from the implanted device to the surrounding disc tissues.
- the device can comprise an active agent and a inert binder or matrix material.
- the binder is preferably an inert material.
- the binder can be chosen to provide an implant with desired release characteristics.
- the device can be of any size and shape suitable for implantation into the inetrvertebral disc space of a mammal.
- the device is compact in cross-section for delivery to the disc space though a small opening or aperture.
- the device is an elongate solid body.
- the elongate solid body can, for example, be a rod having a rounded or tapered insertion end.
- FIG. 1 illustrates two alternative methods of preparing an intervertebral disc implant.
- an active agent 10 e.g., a chemonucleolysis agent such as chymopapain
- a binder 12 in an appropriate ratio.
- the active agent 10 is chymopapain
- the chymopapain in powder form can be mixed with the binder.
- the binder 12 can be a hygroscopic bioresorbable polymer.
- the active agent/binder mixture can then be consolidated under pressure and/or heat 16 into elongated rods 18.
- the elongated rods can have a circular cross-section with a diameter of approximately 1 mm. Rods having a larger or smaller diameter can also be used.
- a second method of making an implant which is illustrated in FIG. IB, a mixture of an active agent and a binder 22 is combined with a solvent 24. The resulting solution is then mixed 26, and poured into a casting mold 28. The solvent 24 is then allowed to evaporate 30. The resulting casting can then be removed from the mold. As shown in FIG. IB, multiple devices 32 can be obtained from the mold.
- the concentration or quantity of chymopapain per unit length of the rods can be determined from the manufacturing process.
- the amount of active agent (e.g., chymopapain) in an implant can be determined from the ratio of active agent/binder in the mixture and from the volume or weight of the implant.
- the appropriate length of rod can then be chosen to achieve the desired dosage.
- the implant as described above can be used for the treatment of patients with a protruded disc and sciatica that meet the criteria for treatment using chemonucleolysis. Before implementing the method of treatment, the patient can be worked up as if he or she would receive an injection of chymopapain in solution.
- FIG. 2 A method of implanting a device as set forth above comprising a chemonucleolysis agent such as chymopapain is illustrated in FIG. 2 (A-H).
- a hypodermic needle or needle/trocar assembly shown
- appropriate size 42 e.g., having an inner diameter slightly larger than 1 mm
- the needle/trocar assembly can be inserted into the disc space between adjacent vertebrae 34, 36 until the needle tip passes through the outer and inner annulus fibrosis 38 to the center (i.e., the nucleus pulposus) of the intervertebral disc. Needle tip location can be verified using fluoroscopy.
- the needle 44 can then be removed leaving the hollow trocar 48 in position as shown in FIG. 2C.
- an appropriate length or lengths of implant 52 can then be inserted into the trocar and a stylet 50 can be used to push the length or lengths of rod 52 forward until it is deposited near the center of the nuclear disc space.
- a stylet is shown, a blunt needle or other pushing device can be employed.
- the trocar 48 and stylet 50 can then be removed and the implant(s) left behind within the nucleus pulposus as shown in FIG. 2H.
- three implants 52 are shown being implanted. However, more or fewer implants can be used to achieve the desired effect.
- the performance of a device comprising a chemonucleolysis agent such as chymopapain after implantation in a disc is illustrated in FIG. 3 (A-E). As shown in FIG.
- disc implants 52 (three shown) have been implanted into the nucleus pulposus 40 of an intervertebral disc.
- the hygroscopic polymer in the device can absorb water rapidly in the hydrated nucleus pulposus.
- the implant can swell up and release the chemonucleolysis agent 54, 56 58 to the surrounding disc tissues as shown in FIGS. 3B, 3C and 3D.
- the chymopapain released from the implant exerts a proteolytic action on the surrounding disc tissues.
- the implanted devices 52 are gradually eroded as shown in FIG. 3E and eventually disappear upon resorption.
- the techniques and devices described herein provide a safe and effective means for various types of disc treatment including, but not limited to, chemonucleolysis, pain- management, repair, and regeneration. These techniques and devices also allow for the controlled and/or sustained release of desirable active agents within the disc. Further, the techniques and devices described herein can deliver an active agent to a localized area of the disc. For example, an implant comprising a chemonucleolysis agent such as chymopapain can be used to achieve localized degradation of the nucleus of an intervertebral disc without the destruction of other disc tissues including the annulus fibrosus. In this manner, reductions in the intradiscal pressure can be achieved using an implant comprising a chemonucleolysis agent.
- chemonucleolysis agent such as chymopapain
- the devices can incorporate substances for chemonucleolysis such as chymopapain.
- the devices can also comprise pharmaceutical agents for therapeutic treatment. Exemplary pharmaceutical agents include, but are not limited to, steroids and pain medications.
- the device can also include growth factors and/or cells for disc repair or regeneration. Since many of these materials are currently in use, the risks of using a device comprising these active agents are reduced.
- the implants described herein also provide for minimally invasive delivery or implantation.
- the implants can be used to deliver an active agent to an essentially intact intervertebral discs.
- the surgical removal of disc tissues is not required.
- the disclosed methods and devices can be used to treat various conditions of the disc (e.g. protrusion, herniation, discogenic pain, dehydration, degeneration, etc.) using appropriate active agents while minimizing the potential detrimental side effects typically associated with direct injection of active agents such as leakage or overdose.
- Various means of incorporating active agents into a compact implantable device are provided. Methods for the delivery of the device into the nucleus of an intervertebral disc through a small annular opening are also provided.
- the devices allow for the controlled and/or sustained release of active agents the disc tissues surrounding the device.
- the device comprises at least two (2) materials:
- an active agent e.g., a therapeutic agent
- a binder or matrix material e.g., a binder or matrix material.
- the binder is preferably an inert material.
- the device can be of any size and shape.
- the device is preferably compact in cross-section for delivery into the disc space though a small annular opening in the disc annulus.
- the proposed methods and devices offer various advantages and can be used for various treatments of the ivt disc including, but not limited to, chemonucleolysis, pain- management, disc repair, and disc regeneration. Set forth below are descriptions of various embodiments of devices comprising a single active agent and methods of using these devices to treat an intervertebral disc.
- Embodiment 1 According to this embodiment, chymopapain in powder form is mixed with a hygroscopic bioresorbable polymer in appropriate ratio. The mixture is consolidated under pressure and/or heat into elongated rods with a diameter of approximately 1 mm.
- This device can be used for the treatment of patients with a protruded disc and/or sciatica that meet the criteria for chemonucleolysis. The patient can be worked up as if he or she would receive an injection of chymopapain solution.
- a hypodermic needle of an appropriate size e.g., having an inner diameter slightly larger than the device outer diameter
- an appropriate length of implant is then inserted into the needle and a stylet is used to push the rod forward until it is deposited near the center of the nuclear disc space.
- the needle is then removed and the implant is left behind within the nucleus pulposus.
- the hygroscopic polymer absorbs water rapidly in a hydrated nucleus pulposus, the rod swells up and releases chymopapain to surrounding disc tissues for proteolytic action.
- Embodiment 2 pain medication in powder form is mixed with a bioresorbable polymer in an appropriate ratio. The mixture is consolidated under pressure and/or heat into elongated rods with a diameter of approximately 1 mm.
- This device is proposed for treatment of patients with discogentic pain.
- the patient can be worked up as if he or she would receive an injection of pain medication in liquid form.
- a hypodermic needle with appropriate size e-g., an inner diameter slightly larger than the outer diameter of the implant
- Needle tip location can be verified using fluoroscopy.
- An appropriate length or lengths of implant is then inserted into the needle and a stylet or other pushing device is used to push the implant forward until it is deposited near the center of the nuclear disc space.
- the needle is then removed and the implant is left behind within the nucleus pulposus.
- the rod gradually releases pain medication to surrounding disc tissues for pain relief.
- the polymer gradually degrades and eventually disappears upon resorption, which occurs after the medication is depleted.
- Embodiment 3 According to this embodiment, growth factors in powder form are mixed with a natural bioresorbable polymer in an appropriate ratio. The mixture is then consolidated under pressure into elongated rods with a diameter of approximately 1 mm. Other techniques for incorporating active agents such as growth factors in powder form into an inert binder are well known in the drug delivery industry and can be used to manufacture the implants. The concentration or quantity of growth factors per unit length of the rods can be determined from the active agent binder ratio used in manufacturing the implant and from the dimensions of the implant. This embodiment of the device is proposed for treatment of patients with a mild to moderately degenerated disc (i.e., a black disc).
- a black disc i.e., a black disc
- a hypodermic needle with appropriate size e.g., an inner diameter slightly larger than the outer diameter of the implant
- a hypodermic needle with appropriate size e.g., an inner diameter slightly larger than the outer diameter of the implant
- Needle tip location can be verified using fluoroscopy.
- An appropriate length of implant is then inserted into the needle and a stylet or other pushing device (e.g., a blunt needle) is used to push the implant forward until it is deposited near the center of the nuclear disc space.
- the needle is then removed and the implant is left behind within the nucleus pulposus.
- the rod swells up, begins erosion and gradually releases growth factors to surrounding disc tissues for disc repair or regeneration.
- Embodiment 4 involves the use of microspheres comprising an active agent.
- chymopapain is incorporated into microspheres comprising a binder (e.g., a hygroscopic bioresorbable polymer) at a desired ratio using methods known in the drug delivery industry.
- the concentration or quantity of chymopapain per unit weight of microsphere can be determined from the ratio of active agent to binder.
- This device is proposed for the treatment of patients with a herniated disc and sciatica that meet the criteria for treatment with chemonucleolysis. A method of using the above described device is illustrated in FIG. (A-D).
- the patient can be worked up as if he or she would receive an injection of chymopapain in solution.
- the microspheres 86 can be mixed with a solvent 88 such as saline (FIG. 9A) and placed in a delivery device 90 (FIG. 9B).
- a syringe connected to a hypodermic needle of appropriate diameter is shown.
- the needle of the delivery device 90 can then be inserted into the disc space until the needle tip is located near the center of the nucleus pulposus 40 (FIG. 9C). Needle tip location can be verified using fluoroscopy.
- An appropriate quantity of microspheres 86 dispersed in solvent 88 can then be injected into the center of the disc (FIG. 9D).
- Embodiment 5 This embodiment is similar to Embodiment 2 except that the microspheres described in Embodiment 4 are used as an implant.
- Embodiment 6 This embodiment is similar to Embodiment 3 except that the microspheres described in Embodiment 4 are used as an implant.
- Embodiments 7-9 These embodiments are similar to Embodiments 1-3 except that implants comprising non-resorbable hydrogel polymer binders instead of resorbable polymer binders are used.
- Embodiments 10-12 These embodiments are similar to Embodiments 1-3 except that implants comprising non-resorbable non-hydrogel polymer binders instead of resorbable polymer binders are used.
- methods and devices for the treatment multiple conditions of the disc e.g. protrusion, herniation, discogenic pain, dehydration, degeneration, etc.
- These devices and methods can also be used to minimize the potential side effects typically associated with the direct injection of active agents in solution form to the intervertebral disc such as leakage, overdose, or drug interactions.
- active agents e.g., a chemonucleolysis agent, a pain medication, and/or a growth factor
- a compact implantable device e.g., a chemonucleolysis agent, a pain medication, and/or a growth factor
- methods for the delivery of the device into the nucleus disc space through a small annular opening e.g., a chemonucleolysis agent, a pain medication, and/or a growth factor
- the device Once implanted, the device can exhibit controlled and/or sustained release of multiple active agents at different rates and/or time points from the device to the surrounding disc tissues.
- the devices can comprise at least two different active agents (e.g., therapeutic substances) and one or more different binders or matrix materials.
- the device can be of any size and shape, but is preferably compact in cross-section for delivery to the disc space though a small annular opening.
- the proposed methods and devices offer several advantages and can be applied for multiple treatments of the disc either simultaneously or sequentially (e.g. chemonucleolysis, pain-management, repair, regeneration, etc.)
- the devices and methods described herein provide a safe and effective means for multiple types of disc treatment (e.g.
- the devices and methods can also provide for the controlled and/or sustained release of multiple active agents within the disc with a single implantation.
- potential detrimental side effects associated with the injection of an active agent in solution can be avoided. These side effects include leakage, overdose and/or drug interactions.
- the devices and techniques described herein also allow for multiple therapeutic effects to be achieved either simultaneously or sequentially with one implantation while minimizing adverse/side effects.
- the devices can incorporate any combination of two or more active agents.
- the device can incorporate a combination of a chemonucleolysis agent (e.g., chymopapain or chondroitinase ABC), a pharmaceutical agent for therapeutic treatment
- the devices and methods provide for minimally invasive delivery or implantation which can reduce discomfort to the patient during implantation and speed recovery.
- Devices for the delivery of multiple active agents to an essentially intact intervertebral disc and methods of treatment using these devices are described herein. These methods of treatment do not require the surgical removal of disc tissue.
- the devices can be used to treat multiple conditions of the disc simultaneously or sequentially. Exemplary conditions which can be treated include, but are not limited to, protrusion, herniation, discogenic pain, dehydration, and degeneration.
- the use of the devices for treatment can minimize the potential side effects typically associated with the direct injection of active agents in solution form such as leakage, overdose, or adverse drug interactions.
- Various means of incorporating more than one active agent into a compact implantable device are provided.
- methods for the delivery of the device into the nucleus pulposus through a small annular opening are also provided.
- the device can exhibit controlled and/or sustained release of active agents at different rates and/or time points from the device to surrounding disc tissues.
- the device can comprise at least two different active agents (e.g., therapeutic substances) and one or more inert binders (matrix materials).
- each of the active agents can be combined with a different binder to achieve a desired release profile for each active agent.
- the device can be of any size and shape which can be implanted into an intervertebral disc.
- the device is compact in cross- section for delivery to the disc space though a small annular opening in the annulus f ⁇ brosus of the disc.
- the proposed methods and devices offer several advantages.
- the devices can be used to achieve multiple treatments of the disc simultaneously or sequentially (e.g. chemonucleolysis, pain-management, repair, regeneration, etc.).
- Set forth below are various embodiments of devices comprising multiple active agents and methods of using these devices to treat an intervertebral disc.
- Embodiment 13 This device, which is depicted in FIG. 4, has an elongate solid body with a circular cross section.
- the device 60 includes a core 62 and a sheath 61.
- the core 62 comprises one or more growth factor and the sheath 61 comprises a chemonucleolysis agent (e.g., chymopapain).
- the shell can also comprise a binder.
- the binder can be a highly resorbable polymer which releases chymopapain quickly after implantation in the disc nucleus and therefore disappears within a short time (e.g. a few weeks) to expose the core 62 of the device. This phase of release is denoted release phase 1.
- release phase 1 chemonucleolysis is accomplished with the quick release of the chemonucleolysis agent.
- the core can comprise a more slowly resorbable polymer. Once the core is exposed, the growth factors in the core can be released to stimulate disc cells to repair and/or regenerate the disc. This phase of release is denoted release phase 2. During release phase 2, various cells may be optionally injected into the disc space to accelerate the repair or regeneration process.
- This device can be made using the following procedure. One or more growth factors are mixed with a first binder (e.g., a first bioresorbable polvmer) and consolidated into a small diameter rod under pressure and/or heat. The resulting rod is subsequently coated with a mixture of a chemonucleolysis agent (e.g., chvmopapain) and a second bioresorbable polvmer.
- a first binder e.g., a first bioresorbable polvmer
- a chemonucleolysis agent e.g., chvmopapain
- This device can be used for treatment of patients with a protruded disc and sciatica that meet the criteria for chemonucleolysis. Implantation can be performed similarly to the method described above and illustrated in FIG. 2A-2H. For example, the patient can be worked up as if he or she would receive an injection of chymopapain in solution.
- a hypodermic needle or a trocar/needle assembly with appropriate size e.g., an inner diameter slightly larger than 1 mm
- Needle tip location can be verified using fluoroscopy.
- FIG. 5A-5E The performance of a device as set forth above after implantation into an intervertebral disc is illustrated in FIG. 5A-5E.
- FIG. 5 A a cross-sectional representation of two adjacent vertabrae 34, 36 and an intervertebral disc comprising an annulus fibrosus 38 and a nucleus pulposus 40 is shown.
- FIG. 5B a device 60 is shown implanted in the nucleus pulposus 40.
- the device 60 is an elongate solid body comprising an inner core surrounded by a sheath.
- the core comprises growth factors and a first bioresorbable polymer and the sheath comprises chymopapain and a second bioresorbable polymer wherein the first polymer is absorbed at a slower rate than the second polymer. Since the faster resorbable polymer in the sheath absorbs water rapidly in the hydrated nucleus pulposus, the sheath swells up and releases chvmopapain to the surrounding disc tissues for proteolysis and rapidly erodes away (release phase 1 of 2). Release phase 1 of the device is illustrated in FIG. 5B and 5C. As shown in FIG.
- the release 63 of the chemonucleolysis agent results in controlled degradation of the disc nucleus 64.
- the chemonucleolysis which occurs during release phase 1 can result in the reduction of intradiscal pressure and disc dehydration which can alleviate pain and sciatica.
- the core As the sheath of the device is degraded, the core is exposed. The core of the device subsequently degrades and releases one or more growth factors 66, 68 to begin the disc repair/regeneration process (release phase 2 of 2). Release phase 2 is illustrated in FIG. 5D and 5E. As shown in FIG.
- the release of the growth factors 66, 68 into the nucleus during phase 2 can stimulate disc cells to repair or regenerate the disc 65 by synthesis of proteoglycan. This can help prevent, reduce or slow disc degeneration that may result from nucleolysis after treatment with a chemonucleolysis agent such as chymopapain.
- the core of the device is gradually eroded as shown in FIG. 5E and the device eventually disappears upon resorption.
- Embodiment 14 In this embodiment, the device described above in Embodiment
- cells 72 loaded in a syringe 70 can be injected into the nucleus during the release of the one or more growth factors 66.
- the cells can be injected after the completion of chymonucleolysis and/or during the release of the growth factor 66 for disc repair/regeneration. Depending on the device, this may up to a few weeks to a few months after implantation.
- Embodiment 15 This embodiment is similar to Embodiment 14 except fibrochondrocyte (instead of notochordal) cells are injected into the disc space during release phase 2.
- Embodiment 16 This embodiment is similar to Embodiment 15 except mesenchymal stem cells (instead of notochordal cells) are injected into the disc space during release phase 2.
- Embodiment 17 This embodiment is similar to Embodiment 13 except pain medication is used as an active agent in the core of the device instead of growth factors. Implantation of this embodiment of the device allows for pain management following chemonucleolysis of the nucleus.
- Embodiment 18 This embodiment is similar to Embodiment 13 except that both a pain medication and chymopapain are incorporated into the sheath of the device for simultaneous pain relief and chemonucleolysis during the first phase of release.
- One or more growth factors are incorporated into the core of the device.
- Embodiment 19 This embodiment is similar to Embodiment 13 except that the device comprises three regions instead of two: a core, an inner sheath, and an outer sheath.
- pain medication can be incorporated into the outer sheath and a chemonucleolysis agent (e.g., chymopapain) can be incorporated into the inner sheath of the device.
- Growth factors can be incorporated into the core of the device.
- the device 74 comprises a core 80, an inner sheath 78 and an outer sheath 76.
- This device has three release phases.
- the active agent e.g., a pain medication
- a chemonucleolysis agent e.g., chymopapain
- phase 3 one or more growth factors are released from the core for disc repair and regeneration.
- Embodiment 20 This embodiment is similar to Embodiment 14 except the implanted devices are microspheres instead of elongate solid bodies.
- the microspheres can be suspended in solution (e.g., saline) and injected into the intervertebral disc space using a hypodermic needle.
- a microsphere comprising first and second active agents is shown in FIG. 8.
- the microsphere 81 includes a core 82 comprising a first active agent and a shell 84 comprising a second active agent.
- the first active agent can be a growth factor
- the second active agent can be a chemonucleolysis agent such as chymopapain.
- Embodiment 21 This embodiment is similar to Embodiment 13 except that the sheath of the device comprises chymopapain and a temperature-sensitive bioresorbable hydrogel.
- Embodiment 22 This embodiment is similar to Embodiment 14 except that the core of the device that contains one or more growth factors comprises a pH-sensitive resorbable polymer binder. After chemonucleolysis, the polymer binder in the sheath degrades significantly and lowers the local pH. This change in pH triggers the core to release the one or more growth factors for disc repair and/or regeneration.
- Embodiment 23 This embodiment is similar to Embodiment 14 except chondroitinase ABC is used instead of chymopapain as a chemonucleolysis agent.
- Embodiment 24 This embodiment relates to the treatment of a "black” disc. In the case of a degenerated, dehydrated or “black” disc, chemonucleolysis is not necessary.
- a device suitable for the treatment of such a disc is provided which is similar to Embodiment 14 except that pain medication is used as an active agent in the sheath instead of chymopapain. Growth factors are included in the core for repair or regeneration of the disc.
- microspheres comprising pain medication in the shell and growth factors in the core can also be used. The microspheres can be implanted into an intervertebral disc using the technique illustrated in FIG. 9.
- FIG. 10-15 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of multiple (i.e., two) active agents. As shown in FIG.
- the device 98 is an elongate solid body comprising a first region 100 and a second region 102 adjacent to the first region 100.
- the first region 100 can comprise a first active agent and the second region 102 can comprise a second active agent.
- Each of the regions 100, 102 can also comprise a binder.
- the binder in each of the regions can be the same or different.
- the binder in each region can be chosen to achieve the desired release characteristics for each active agent.
- FIG. 1 1 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of multiple (i.e., three) active agents. As shown in FIG.
- 1 lJhe device 104 is an elongate solid body comprising a first region 106, a second region 108 adjacent to the first region 106, and a third region 110 adjacent to the second region 108.
- the first region 106 can comprise a first active agent
- the second region 108 can comprise a second active agent different than the first active agent
- the third region 110 can comprise a third active agent different than the first and second active agents.
- Each of the regions 106, 108, 1 10 can also comprise a binder.
- the binder in each of the regions 106, 108, 1 10 can be the same or different.
- the binder in each region 106, 108, 1 10 can be chosen to achieve the desired release characteristics for the active agent contained in that region.
- the device 1 12 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of multiple (i.e., three) active agents.
- the device 1 12 has a sheath/core configuration.
- the sheath comprises a first region 114 and a second region 116 each of which can comprise a different active agent.
- a third active agent is included in the core 118.
- Each of the regions 114, 116, 118 can also comprise a binder.
- the binder in each of the regions 114, 116, 118 can be the same or different.
- the binder in each region 114, 116, 118 can be chosen to achieve the desired release characteristics for each active agent.
- the device 120 has a sheath/core configuration.
- the sheath 126 can comprise a first active agent.
- the core comprises a first region 122 and a second region 124 each of which can comprise a different active agent (e.g., second and third active agents, respectively).
- Each of the regions 122, 124, 126 can also comprise a binder.
- the binder in each of the regions 122, 124, 126 can be the same or different.
- the binder in each region 122, 124, 126 can be chosen to achieve the desired release characteristics for each active agent.
- FIG. 14 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of multiple (i.e., two) active agents having an elongate configuration.
- the device 128 comprises regions of a first active agent 130 alternating with regions of a second active agent 132.
- Each of the regions can also comprise a binder.
- the binder in each of regions 130 and regions 132 can be the same or different.
- the binder in each of regions 130 and regions 132 can be chosen to achieve the desired release characteristics for each active agent.
- FIG. 15 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of multiple active agents having an elongate configuration. As shown in FIG.
- the device 134 comprises adjacent regions 136, 138, 140, 142, 144, 146, 148 each comprising a different active agent. Although seven regions are shown, devices having more or fewer regions can also be used.
- Each of the regions 136, 138, 140, 142, 144, 146, 148 can also comprise a binder.
- the binder in each of the regions 136, 138, 140, 142, 144, 146, 148 can be the same or different.
- the binder in each of the regions 136, 138, 140, 142, 144, 146, 148 can be chosen to achieve the desired release characteristics for each active agent.
- the devices can have be of any shape and size suitable for implantation into the intervertebral space of a mammal.
- the device can be an elongate solid body.
- the cross section of the elongate solid body can have a maximum dimension of five (5) mm or less.
- the cross section of the elongate solid body can have a maximum dimension of three (3) mm or less, two (2) mm or less, or one (1) mm or less.
- maximum dimension refers to the longest straight line that can be drawn on a given area.
- the maximum dimension of a circle is its diameter.
- the cross-section of the device can be of any shape.
- the cross section can be circular or polygonal (e.g., octagonal).
- the shape and size of the implant can be chosen to achieve the desired release characteristics from the device.
- FIGS 16A-160 illustrate various profile shapes for elongate solid body intervertebral disc implants.
- the insertion end of the device can be square (not shown).
- the elongate solid body of the device 156, 164 can have a rounded insertion end 158, 166.
- FIG. 16B and 16D the elongate solid body of the device 156, 164 can have a rounded insertion end 158, 166.
- the elongate solid body of the device 152, 160, 168, 174, 180, 186, 192, 198, 204, 210, 216, 222, 226 can have a tapered or pointed insertion end 154, 162, 170, 176, 182, 188, 194, 200, 206, 212, 218, 223, 227
- the shape of the leading end can be chosen to facilitate implantation. For example, a tapered or rounded leading end can require less force to insert through a small aperture than a square leading end.
- the end opposite the insertion end (i.e., the trailing end) of the elongate solid body of the device 152, 156, 160, 164 may be square.
- the trailing end of the elongate solid body may be rounded 172 or tapered 174 as shown in FIG. 16E and 16F, respectively, or concave 184, 190, 196, 202, 208 as shown in FIG. 16G-16K.
- FIG. 16L-160 are profile shapes of alternative elongate solid body implants. As shown in FIG. 16L, the implant 210 can have a tapered end 212 and a series of serrations
- FIG. 16M illustrates an alternative embodiment of an intervertebral disc implant 230 for the delivery of multiple (i.e., two) active agents. As shown in FIG.
- the device 230 has an elongate configuration comprising two regions 232, 234 each of which contain a different active agent and a tapered insertion end 231.
- the device also has a coating 236 to provide lubricity.
- the coating 236 may be a hydrogel coating.
- FIG. 18 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of multiple (i.e., two) active agents.
- the device 238 has an elongate configuration, a pointed insertion end 239, and a coating 236 to provide lubricity.
- the device also comprises x-ray markers 240 (two shown). As shown in FIG. 18, the x-ray markers 240 are beads. As also shown in FIG.
- each of the regions of the device 232, 234 comprises a marker 240.
- the x-ray markers 240 can comprise a material detectable by x-ray. Exemplary materials for the x-ray markers 240 include, but are not limited to, barium sulfate, platinum and tantalum.
- FIG. 19 illustrates an alternative embodiment of an intervertebral disc implant for the delivery of multiple (i.e., two) active agents. As shown in FIG. 19, the device 242 has an elongate configuration, a pointed insertion end 243, and a coating 236 to provide lubricity.
- the device also has an x-ray marker 244 in the form of a thread.
- the x-ray marker 244 can comprise a material detectable by x-ray.
- FIG. 20A and 20B illustrate a method of implanting an intervertebral disc implant of the type shown in FIG. 16A-160.
- an aperture 248 is made through the annulus 38 and into the nucleus 40 of an intervertebral disc.
- a hollow tube 250 e.g., a trocar
- a hollow tube 250 having an internal diameter slightly larger than the outer diameter of the device 246 being implanted is then placed into contact with the annulus 38 such that the end of the tube 250 is over the aperture 248.
- the implant 246 is placed in the tube and pushed through the aperture and into the nucleus 40 as shown in FIG.
- Insertion of the device 246 can be accomplished using a pushing device 252 such as a blunted needle or a stylet or a puch rod.
- the implant shown in FIG. 20A and 20B has a concave trailing end 253.
- the concave trailing end 253 helps to keep the pushing device engaged in the implant 246 as the implant 246 is being inserted into the nucleus 40.
- the tissues surrounding the aperture 248 collapse behind the inserted device 246 thereby partially closing the dilated aperture 248.
- the pushing device 252 is removed (not shown) thereby leaving behind an aperture in the annulus that is significantly smaller than the diameter of the device inserted. Insertion of a device larger than the aperture is possible due to the viscoelastic nature of the annular tissue and the very short times involved in the dilation/ insertion step.
- Exemplary active agents which can be incorporated into the devices include, but are not limited to: chemonucleolysis agents such as chymopapain, collagenase, chondroitinase-ABC and human proteolytic enzymes; pain medications such as codeine, propoxyphene, hydrocodone, and oxycodone; and growth factors such as transforming growth factor ⁇ proteins, bone morphogenetic proteins, fibroblast growth factors, platelet-derived growth factors, and insulin-like growth factors. Any of the aforementioned active agents or combinations thereof can be incorporated into the device.
- chemonucleolysis agents such as chymopapain, collagenase, chondroitinase-ABC and human proteolytic enzymes
- pain medications such as codeine, propoxyphene, hydrocodone, and oxycodone
- growth factors such as transforming growth factor ⁇ proteins, bone morphogenetic proteins, fibroblast growth factors, platelet-derived growth factors, and insulin-like growth factors. Any of
- binders or matrix materials include, but are not limited to: non-resorbable polymers such as poly(urethanes), poly(siloxanes ⁇ , poly(methyl methacrylate), poly(ethylene), poly(vinyl alcohol, poly(vinyl pyrrolidon), poly(2-hydroxy ethyl methacrylate), poly(acrylic acid), poly(ethylene-co-vinyl acetate, poly(ethylene glycol), poly(methacrylic acid), and polyacrylamide; bioresorbable polymers such as polylactides (PLA), polyglycolides (PGA), poly(lactide-co-glycolides) (PLGA), polyanhydrides, and polyorthoesters; and natural polymers such as: polysaccharides, collagens, silk, elastin, keratin, albumin, and fibrin.
- non-resorbable polymers such as poly(urethanes), poly(siloxanes ⁇ , poly(methyl methacrylate), poly(ethylene), poly(vinyl
- any combination of the above binders can be used in the device.
- various types of cells can be injected into the disc space during the growth factor releasing phase of the device in order to promote disc repair and regeneration.
- Exemplary cells that can be injected into the intervertebral disc during the growth-factor-releasing phase of the device include, but are not limited to, notochords, fibrochrondrocytes, and mesenchymal stem cells.
- the cells can be modified with a growth factor.
- the cells can be transfected with a nucleic acid (e.g., an expression vector) encoding a growth factor such as a bone morphogenetic protein or a LIM mineralization protein.
- the intervertebral disc implant can be formed by consolidating an admixture comprising a binder and one or more active agents into a solid body.
- the intervertebral disc implant can include a plurality of particles at least some of which comprise an active agent wherein the particles are unconsolidated (i.e., in loose admixture).
- the implant comprising particulate material can be implanted into an intervertebral disc using a hollow tube (e.g., a trocar) as a delivery device.
- the implant can further include particles comprising a binder.
- the particles comprising a binder can be mixed with the particles comprising the active agent to facilitate handling and delivery of the particulate material into the disc nucleus.
- At least some of the individual particles in the implant can comprise an active agent and a binder.
- Particles comprising an active agent and a binder can be made by mixing together particles of the active agent and the binder, forming a consolidated solid body from the admixture (e.g., using heat and/or pressure), and comminuting the solid body to form particles of the desired size.
- An implant comprising a plurality of particles wherein at least some of the particles comprise a first active agent and at least some of the particles comprise a second active agent is also provided.
- the implant according to this embodiment can further comprise a binder.
- the implant can be made by mixing particles of the first and second active agents with particles of the binder to form an implant.
- an admixture of first and second active agents and binder can be consolidated into a solid body and comminuted into particles to form the implant.
- individual particles in the implant comprise the first and second active agents as well as the binder.
- Implants comprising additional active agents can also be made using the techniques described above.
- the particles comprising active agent(s) in the implant can be sized to achieve a desired release profile. Smaller particles have a higher surface area and will therefore typically result in more rapid release of the active agent.
- the particles of active agent(s) in the implant can have an average diameter of 0.1 to 500 ⁇ m. According to further exemplary embodiments, the particles of active agent in the implant can have an average diameter of from 0.5 to 250 ⁇ m or from 1 to 100 ⁇ m.
- active agents having different particle sizes can be used in each region of the implant to achieve the desired release characteristics for that active agent. If a binder is used, the amount of binder in the implant can also be varied to achieve the desired release characteristics for the active agent(s) in the implant. In the case of particulate implants, the amount of binder can also be varied to achieve the desired handling characteristics for the particulate material.
- the implant can comprise from 10 to 100 % by volume of the active agent with the remainder (i.e., 0 to 90 % by volume) being binder.
- the implant can comprise from 25 to 75 % by volume of the active agent with the remainder (i.e., 25 to 75 % by volume) being binder.
- the implant is a solid body including multiple regions each comprising a different active agent, different amounts of binder can be used in each region of the implant to achieve the desired release characteristics for that active agent.
- FIG. 21 A is a picture of the control disc.
- FIG. 21B is a picture of the second disc.
- FIG. 21C is a picture of the third disc.
- chymopapain in solid form when delivered to the nucleus pulposus in the form of a controlled release device, can help prevent or minimize complications associated with the leakage of chymopapain resulting from direct injection of chymopapain in solution.
Abstract
Description
Claims
Priority Applications (4)
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AU2004263123A AU2004263123B2 (en) | 2003-08-06 | 2004-08-06 | Methods and devices for the treatment of intervertebral discs |
CA002534983A CA2534983A1 (en) | 2003-08-06 | 2004-08-06 | Methods and devices for the treatment of intervertebral discs |
JP2006522740A JP2007501075A (en) | 2003-08-06 | 2004-08-06 | Method and apparatus for intervertebral disc processing |
EP04780256A EP1658103A1 (en) | 2003-08-06 | 2004-08-06 | Methods and devices for the treatment of intervertebral discs |
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US10/634,798 US7169405B2 (en) | 2003-08-06 | 2003-08-06 | Methods and devices for the treatment of intervertebral discs |
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Also Published As
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CN100496621C (en) | 2009-06-10 |
US8920828B2 (en) | 2014-12-30 |
EP1658103A1 (en) | 2006-05-24 |
US20070128575A1 (en) | 2007-06-07 |
AU2004263123A1 (en) | 2005-02-17 |
US20070122446A1 (en) | 2007-05-31 |
US20050031666A1 (en) | 2005-02-10 |
US9061064B2 (en) | 2015-06-23 |
CA2534983A1 (en) | 2005-02-17 |
AU2004263123B2 (en) | 2010-03-25 |
US7169405B2 (en) | 2007-01-30 |
CN1852743A (en) | 2006-10-25 |
US20070003598A1 (en) | 2007-01-04 |
JP2007501075A (en) | 2007-01-25 |
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