Patent Application
20070041950
This invention relates to an apparatus and methods for performing repairs on defect sites that span more than one kind of tissue.
It is well known in the art that implants can be inserted into damaged bone or cartilage layers to treat injuries to those tissue layers. One type of implant procedure involves inserting plugs of healthy bone or cartilage that are harvested from a healthy area of the patient's body and transplanted into the defect, as disclosed in U.S. Pat. No. 5,152,763 (Johnson et al.), U.S. Pat. No. 5,919,196 (Bobic et al.), and U.S. Pat. No. 6,358,253 (Torrie et al.). In the alternative, an implant can consist of synthetic material, such as porous biocompatible foams or polymers, for example as disclosed in U.S. Pat. No. 4,186,448 (Brekke et al.), U.S. Pat. No. 5,607,474 (Athanasiou et al.), and U.S. Pat. No. 5,716,413 (Walter et al). patent application Ser. No. 10/785,388, filed Feb. 23, 2004, entitled “Bone and cartilage implant delivery device”, and U.S. Ser. No. 11/290,142 filed Nov. 30, 2005, entitled “Implants and delivery system for treating defects in articulating surfaces”, hereby incorporated by reference, disclose a delivery method and device for implanting material into a tissue defect.
Tissue defects can be repaired using tissue engineering scaffolds. For optimal repair and healing, such scaffolds generally require the addition of bioactive agents (e.g. cultured cells, growth factors, proteins, peptides, autologous agents, xenogenic agents, and/or allogenic agents). Particular tissue engineering difficulties can occur where a tissue defect spans different types of tissues or tissue regions. U.S. Pat. No. 5,981,825. In such cases, the biological conditions associated with each tissue region can be significantly different. Simultaneous repair of adjacent tissues can require delivery of different bioactive agents by different regions of the implant. This presents specific engineering problems for implants spanning multiple tissue regions. To maximize the implant's effectiveness at repairing the defect, the implant should have different phases, wherein each phase is tailored to the particular tissue that surrounds that phase. For instance, the mechanical properties (e.g. the stiffness) of the implant can be tailored to match those of the surrounding tissue. Also, the growth conditions may be different in each tissue region so that different types and/or amounts of growth factors should be specifically confined within each implant region. For some cases, different bioactive agents are required in the two regions. In addition, it may sometimes be necessary that a bioactive agent in the first implant region be excluded from the second implant region. The physical properties of each tissue region may be different, necessitating that the material used to construct each phase be different.
For example, implants for osteochondral repair must treat both a bone and cartilage region. For such repair regions, it may be desirable to selectively add a bone morphogenic protein (BMP), or other bioactive agents including, but not limited to, a cocktail of growth factors to the region of the implant to be inserted into the bone region and to add expanded cultured chondrocytes to the region of the implant to be inserted into the cartilage region. It can be advantageous to exclude the BMP from the chondrocytes to avoid chondrocyte transformation into hypertrophic chondrocytes or osteoblasts, thus forming bone in the cartilage region. In addition, for optimum cartilage formation the expanded cultured chondrocytes should be maintained at a high concentration within a limited volume. Thus, implants that span a bone and cartilage region should optimally be constructed as two phases, wherein there is no communication between the two phases for a defined period of time. The devices and methods of the present invention address the need in the art to construct multi-phase implants, tailored for the multi-tissue region defect site to be repaired.
The present invention provides a multi-phase implant assembly device and methods for preparing multi-phase implants to correct tissue defect sites in patients that can span more than one type of tissue. The multi-phase implants can be used for a variety of applications, including osteochondral repair, bone-ligament reattachment, muscle-ligament attachment, muscle-bone attachment and other non-orthopedic applications. The different types of tissues to be repaired include, but are not limited to, bone, tendon, cartilage, muscle, ligament, nerve and skin.
The multi-phase implant device or “implant assembly” can be used to construct a two-phase implant, wherein each phase is separated by a membrane. The implant assembly is also used to construct a three-or-more-phase implant, wherein adjacent phases are separated by a membrane. In an embodiment, the implant assembly comprises a base and a cover. The base comprises a bottom portion, a top portion and a lower implant compartment having a cross-sectional shape that extends through the top and bottom portions. The cover is secured to the base and the cover comprises an upper portion having an upper implant compartment, wherein the upper implant compartment has a cross-section equivalent to the cross section of the base lower implant compartment. The cover further comprises a lower portion having a lower receiving compartment shaped to receive the top portion of the base thereby securing the cover to the base. “Equivalent” is used herein to specify that the implant phase contained in the upper implant compartment and the implant phase contained in the lower implant compartment substantially align with respect to each other such that the assembled implant can be removed from the implant assembly by applying a force to one end of the implant. If the cross-section is not equivalent, the phases are said to be unaligned such that applying a force to one end of the implant to remove the implant from the assembly results in significant deformation, tearing and/or damage to the implant. The cross-section of the receiving compartment encompasses the cross-section of the lower and upper implant compartments.
An embodiment of the implant assembly further comprises a well located at the top surface of the base lower implant compartment (e.g. the face that opposes the bottom surface of the cover when the cover is secured to the base). This well is designed to receive a membrane that separates each of the adjacent implant phases. In an embodiment, an o-ring is positioned on the surface of the top portion of the base for contacting a membrane positioned between the cover and the base. Another embodiment is an o-ring on a surface of the lower portion of the cover for contacting a membrane positioned between the cover and the base. In an embodiment both o-rings are used such that one o-ring is between the membrane bottom surface and base top surface and another o-ring is between the membrane upper surface and the cover bottom surface. In an embodiment, one or more of the o-rings are used in combination with the well for contacting a membrane positioned between the cover and the base. In an embodiment, no o-rings and no well is used, so that the membrane is positioned and held between the implant compartments by securing the cover to the base, thereby holding the membrane in place. The well depth can be less than the membrane thickness to facilitate sealingly connecting the base to the cover.
In an embodiment the cover is secured to the base by one or more welds, adhesives, and fastening means on the base removably engaged with fastening means on the cover. Fastening means that are removably engagable include, but are not limited to, snap beads and threaded connections.
In an embodiment, the fastening means comprises a snap bead, wherein the snap bead comprises a circumferential undercut located between the base bottom portion and base top portion; compartment overhang located at the bottom of the cover lower portion. The compartment overhang can snap into the base circumferential undercut, thereby engaging the cover lower portion to the circumferential undercut. A plurality of slots positioned along the cover lower portion facilitates sealingly connecting the cover lower portion to the circumferential undercut. These slots facilitate radial deformation, and radial recovery, of the cover lower portion as the lower portion passes over the base top portion and snaps into place upon the compartment overhang reaching the circumferential undercut.
In an embodiment, the implant compartment's cross-sectional shape can have any user-defined shape. To facilitate removal of a multi-phase implant contained within the assembly device by applying a force to one end of the multi-phase implant, in an embodiment an implant compartment's cross-sectional area and shape is constant over the implant height and equivalent to the cross-sectional area and shape of an adjacent implant compartment. The cross-section of the implant compartment can be, for example, square, hexagonal, triangular, rectangular, oblong, or any shape best suited to repair a tissue defect site. In an embodiment, the cross-section of the implant compartment is circular. In an embodiment, the implant cross-section can vary with implant height (e.g. instead of a cylinder, the implant can be “cone” shaped).
Any of the implant assemblies disclosed herein can contain a membrane having two surfaces, an upper surface facing the upper implant compartment and a lower surface facing the lower implant compartment. In the two-phase embodiment the membrane is located between the base opposing faces of the base and the cover. In an embodiment the membrane is positioned and secured using any one or more of a well and one or two o-rings. The membrane can be impermeable, selectively or partially permeable or permeable. In an embodiment the membrane is impermeable. In an embodiment the membrane is permeable or selectively permeable. In an embodiment the membrane is selectively permeable. In an embodiment the membrane is permeable.
Any of the implant assemblies disclosed herein further comprise a first phase of an implant located within the lower compartment and attached to the lower surface of the membrane, and/or a second phase of an implant located within the upper compartment and attached to the upper surface of the membrane. In an embodiment the first and second phases comprise materials having the same composition. In an embodiment the first and second phases each comprise different materials. The phases can be three-dimensional matrices such as scaffolds to facilitate cell growth or controlled release of growth factors or pharmaceutical drugs. In an embodiment the first phase is adapted for bone implantation and the second phase is adapted for cartilage implantation. As used herein, “adapted” refers to varying the characteristics of the phase to match the characteristics of the tissue in which the phase is to be implanted. In one embodiment, the characteristics that are matched are mechanical characteristics as disclosed in U.S. Pat. No. 5,607,474, and can be one or more of porosity, stiffness and compressibility properties.
In another embodiment, any of the implant assemblies having implant phases therein can contain one or more bioactive agent. “Bioactive agent,” as used herein, is used very broadly to refer to any substance that has a biological effect. The bioactive agent can include those that promote or inhibit cellular growth, migration, extracellular matrix deposition or cellular expression of RNA or protein. The bioactive agent can be naturally occurring or can be a pharmaceutical drug. The bioactive agent can include any cell type, including but not limited to, osteoblasts, chondrocytes, fibroblasts, muscle cells (smooth, cardiac and/or skeletal), nerve cells, epithelial cells, endothelial cells, and any combination or subcombination thereof. A bioactive agent also encompasses components of extracellular matrix, such as demineralized bone, processed tissue, elastin, collagen or cartilage matrix. In one embodiment the bioactive agent is a growth factor, pharmaceutical drug or suspension of cells. The bioactive agent may be autologous, allogenic or xenogenic agent. In an embodiment, the bioactive agent is selected from the group consisting of growth factors, extracellular matrix, pharmaceutical drugs, and suspensions of cells.
In another embodiment, the implant assembly device is for constructing an implant with three or more phases. This assembly is similar to the two-phase implant assembly in that it can include a base and cover, as discussed for the two-phase implant. An added component for a three-phase implant is one or more intermediate units positioned between the cover and the base. In an embodiment, the intermediate has a lower portion similar to the lower portion of the cover, and an upper portion similar to the top portion of the base. An intermediate implant compartment spans the upper portion of the intermediate part. An intermediate receiving compartment spans the lower portion of the intermediate part and in an embodiment, has a cross-sectional shape and area equivalent to the implant compartments contained in the base, cover and any other intermediate units. In an embodiment, the intermediate upper portion is secured to the cover. The intermediate upper portion comprising an intermediate implant compartment having a cross-sectional shape equivalent to the cross-sectional shape of the lower implant compartment, an upper intermediate portion sized to engage the lower receiving compartment of the cover, and a port running from outside the intermediate unit to the intermediate implant compartment for the addition or introduction of one or more bioactive agents to the intermediate implant compartment. The intermediate lower portion is secured to the base, the intermediate lower portion having an intermediate receiving compartment sized to receive the base top portion. In an embodiment, the implant assembly comprises two or more identical intermediate units.
The three-or-more phase implants, in an embodiment, further comprise a membrane positioned between each of the adjacent implant compartments. The membrane can be received by a well located at the top of the intermediate implant compartment. In an embodiment, any of the implant assemblies further comprise an o-ring on a top surface of the intermediate upper portion for contacting a membrane positioned between the intermediate portion and the cover and an o-ring on the bottom surface of the intermediate lower portion for contacting a membrane positioned between the intermediate portion and the base.
In an embodiment, the intermediate unit is secured to the base and the cover by one or more of welds, adhesives, and fastening means on the base removably engaged with fastening means on the cover, as discussed previously for the two-phase implant.
Any number of intermediate parts can be stacked between the base and cover to assemble an any-number-phase implant. An intermediate implant phase can be received by the intermediate implant compartment prior to assembling the intermediate part with the cover and the base. A needle port can be located through the outside wall of the intermediate part to communicate with the intermediate implant compartment. This port can facilitate the addition of one or more bioactive compounds suspended in a fluid to the intermediate phase. The port can be a hole or a septum for injecting fluid into the intermediate implant phase. A second port can be located through the outside wall of the intermediate part to provide an escape path for air contained within the intermediate implant void volume that is displaced by the inserted fluid. Alternatively, the intermediate implant can be loaded with a bioactive compound prior to assembly with the cover and the base, including by centrifugal introduction. For assistance in identifying the phase to which a bioactive compound should be added, each of the intermediate parts contained within the implant assembly device can be color-coded. Any one or more of the cover, base and intermediate parts can have a means for visually ensuring the implant is appropriately situated. Such means includes a transparent window, a slot, or at least a portion of the holder comprising a transparent material.
The multi-phase implant and associated holder can be placed into a suitable holder that mates the multi-phase implant to a delivery device. Such a holder is a convenient means for inserting the multi-phase implant into an appropriate delivery device. Alternatively, the implant can be removed from the holder and then loaded into the delivery device without using a holder. In an embodiment, the multi-phase implant is disposed within a delivery device. Such delivery devices are known in the art, and include U.S. patent application Ser. Nos. 10/785,388 and 11/290,142, hereby incorporated by reference. Briefly, the delivery device comprises a tubular outer shaft and an inner shaft. The tubular outer shaft having a proximal and distal end, a longitudinal axis, and an internal bore along the longitudinal axis of the outer shaft. The inner shaft having a distal end and a proximal end suitable for insertion into a defect, said inner shaft adapted to fit within said internal bore of the outer shaft so that the inner shaft and the outer shaft are slidably engaged. The implant is then ready for insertion, by the delivery device, into a patient tissue defect.
In an embodiment, the implant assembly for constructing a multi-phase implant comprises a base and a cover. The base comprises a bottom portion, a top portion and a lower implant compartment having a cross-sectional shape that extends the length of the base. The cover comprises an upper portion having an upper implant compartment, wherein the upper implant compartment cross-sectional shape is equivalent to the cross-sectional shape of the lower implant compartment, and a lower portion having a lower receiving compartment sized to receive the top portion of the base. The assembly also comprises means for positioning a membrane between the base and cover portions located on a top surface of the base and means for sealingly engaging the base with the cover.
The means for positioning the membrane includes a well, having a depth less than the thickness of the membrane, on one or more of the base and cover. Such a well allows the membrane to be positioned, and assists in keeping the membrane in place while the base and the cover are engaged. Another means for positioning utilizes one or more o-rings, wherein the o-rings are located between the membrane top surface and cover and/or the membrane bottom surface and the base. These o-rings facilitate appropriate positioning of the membrane by minimizing stress and associated deformation and compression when the base and cover are engaged. Another means for positioning utilizes both a well and one or more o-rings. Means for positioning also includes no well or no o-rings and refers to an appropriately-sized and composition membrane that is held between opposing parallel faces from the top of the base and bottom of the cover, wherein the membrane does not does not excessively deform when the base and cover engage.
The means for sealingly engaging the base with the cover includes a snap bead, threaded connection, thermoplastic sealed by ultrasonic welding and adhesives. Any of these means are suitable for sealingly engaging the base and cover such that the presence of the membrane along with the engagement of the base and cover prevents fluid from transiting from one compartment to another compartment or leaking out of the assembly between the cover and the base.
In an embodiment, the implant assembly further comprises one or more intermediate units placed between the base and cover. The intermediate unit comprises an intermediate upper portion and an intermediate lower portion. The intermediate upper portion comprises an intermediate implant compartment having a cross-sectional shape equivalent to the cross-sectional shape of the lower implant compartment, an upper intermediate portion sized to fit into the lower receiving compartment of the cover, means for positioning a membrane between said intermediate implant compartment and an adjacent compartment located on the top surface of the upper intermediate portion, and means for the intermediate upper portion to sealingly engage the cover lower portion. The intermediate lower portion comprises an intermediate receiving compartment sized to receive the base top portion, and means for the intermediate lower portion to sealingly engage with the base. Optionally, the intermediate unit further comprises a needle port through the intermediate upper portion for adding and introducing a bioactive agent to the intermediate implant compartment.
Means for positioning a membrane between said intermediate implant compartment and an adjacent compartment are as described for the two-phase (base and cover) implant, and includes a well, an o-ring, combination of a well and an o-ring, and a pair of opposing parallel faces, that when engaged, position the membrane.
Means for the intermediate upper portion to sealingly engage the cover lower portion and means for the intermediate lower portion to sealingly engage with the base are as described for the two-phase (base and cover) implant, and includes a snap bead, threaded connection, thermoplastic sealed by ultrasonic welding and adhesives.
An embodiment of the present invention is a multi-phase implant made by any of the implant assemblies disclosed herein, wherein adjacent phases are separated by a membrane. The implant is a two-phase implant having one membrane. The implant is a three-phase implant having two membranes. The implant is a more than three phase implant having more than two membranes. Each phase can contain one or more bioactive agents. In an embodiment, each phase is adapted for insertion into a particular tissue. In an embodiment, the membrane separating the adjacent phases has a thickness between 125 μm and 250 μm.
A further embodiment is an implant adapted for insertion into a tissue defect, said implant comprising a membrane having a top surface and a bottom surface, with a first implant phase attached to the membrane top surface and a second implant phase attached to said membrane bottom surface.
In an embodiment, the first implant phase has a composition that is different than the second implant phase composition. In a further embodiment, the first implant phase and/or second implant phase of the implant contains one or more bioactive agent.
Each of the implant phases are adapted for implantation into a specific tissue. In one embodiment the first implant phase is adapted for bone implantation and the second implant phase is adapted for cartilage implantation. In one embodiment, the adaptation is matching mechanical properties of the implant phase to the mechanical properties of the tissue in which each phase is implanted. The mechanical properties include, but are not limited to, porosity, compressibility and stiffness. In addition, the bioactive agents are selectively loaded into a phase so as to maximize repair of the particular tissue surrounding that phase.
The invention is also a method for constructing two-phase implants and three-or-more-phase implants, wherein each phase is separated from an adjacent phase by a membrane. In an embodiment, the method is for constructing a two-phase implant with the two phases separated by a membrane, comprising providing a first holder for a first implant phase, also comprising a holder for a membrane at a first end of the first holder, providing a second holder for a second implant phase, inserting a first implant phase into said first holder, inserting a membrane into said first end of the first holder and attaching the membrane to said first phase; and inserting a second implant phase into said second holder and attaching it to said membrane to construct a two-phase implant with the two phases separated by a membrane.
In an embodiment, the method is constructing a two-phase implant, with a first (e.g. a base) and a second (e.g. a cover) holder containing a first and a second implant phase. The first implant phase optionally contains a well at one end for receiving a membrane. A membrane is inserted into the well of the first holder and attached to the first implant phase. The second implant phase, contained in a second holder is attached to the membrane. The first and second holders are sealingly engaged. In this manner, the implant comprises a first and second phase, with the two phases separated by a membrane.
A three-or-more-phase implant is similarly constructed by using one or more intermediate parts, in addition to a cover and a base. An intermediate (e.g. third) phase is inserted into the one or more intermediate implant compartments and attached to the lower face of the intermediate membrane. The intermediate part with the intermediate (third) implant phase and membrane is then sealingly engaged to the base so that the intermediate implant phase attaches to the top surface of the membrane disposed in the base's well. The cover is then sealingly engaged to the top portion of the intermediate part. A first implant phase is inserted into the lower compartment and attached to the bottom surface of the membrane separating the intermediate (third) phase and the first phase. A second implant phase is inserted into the upper compartment and attached to the upper surface of the membrane separating the second phase and the intermediate (third) phase. By inserting additional intermediate parts, containing additional intermediate (e.g. 4th, 5th, etc.) phases between the cover and base, any-number-phase implants are constructed.
In an embodiment, the method further comprises sealingly engaging the first and second holders. In an embodiment, the method further comprises inserting a membrane that is impermeable or selectively permeable.
In an embodiment, the method further comprises inserting one or more bioactive agents into the first implant phase and inserting one or more bioactive agents into the second implant phase. In an embodiment the bioactive agent is applied to the phase before the phase is inserted into the device. In an embodiment the bioactive agent is applied to the phase after the phase is inserted into the device. In an embodiment, the one or more bioactive agents in the first phase promote a first tissue repair by selectively delivering the bioactive agent in the first implant phase to the first tissue and the one or more bioactive agents in the second implant phase promote a second tissue repair by selectively delivering the bioactive agent in the second implant phase to the second tissue. In an embodiment, the first tissue is cartilage and the second tissue is bone. In an embodiment, the one or more bioactive agents in the phase to promote cartilage repair comprises a suspension of chondrocytes.
The method further comprises inserting an implant into a delivery device. In an embodiment, the method further comprises inserting the implant from the delivery device into a defect in a patient. In an embodiment, the defect in a patient spans bone tissue and cartilage tissue.
The invention may be further understood by the following non-limiting examples. Although the description herein contains many specificities, these should not be construed as limiting the scope of the invention but as merely providing illustrations of some of the presently preferred embodiments of the invention. For example, thus the scope of the invention should be determined by the appended claims and their equivalents, rather than by the examples given.
A “snap bead” is one means for sealingly connecting the base and cover. As used herein, snap bead refers to the radius of the receiving compartment 7 being sufficiently expanded during the assembly process so that the base top portion 2 passes cover compartment overhang 10. Once the base top portion 2 passes cover compartment overhang 10, the radius of receiving compartment 7 returns back to normal as compartment overhang 10 snaps into circumferential undercut 5, thereby fitting the base's top portion 2 into the cover's receiving compartment 7. Optional slots 11 in the cover facilitate in sealingly connecting the base and cover by allowing a reversible radius increase as compartment overhang 10 passes over base top portion 2, and a corresponding radius decrease as compartment overhang 10 snaps into circumferential undercut 5. A snap bead mechanism is one means whereby the cover and base can sealingly engage each other.
The particular means utilized to sealingly engage the base and cover is not important, so long as fluid cannot travel between the lower and upper implant compartment by bypassing the membrane. “Sealingly engaged” or “engaging,” as used herein, refers to the cover and base mating at the face formed by the top portion 2 and lower portion 6, thereby compressing the membrane, and creating a seal whereby fluid cannot leak around the membrane between the upper implant and lower implant compartments. The membrane can be sealingly engaged by compressing the membrane thickness between two opposing parallel faces, or by disposing an o-ring within one or both mating faces of the device to compress the membrane. The membrane can optionally be located within a well 4.
The membrane can be prepared by pressing a polymer of 85/15 DL-PLG (IV=0.76), or other suitable polymeric material, between two sheets of release paper forming a desired permeable, selectively permeable or impermeable barrier. Alternatively, the membrane can be prepared by extrusion, solvent casting, or injection molding the material. The permeability (as well as the permeability selectivity) of the membrane can be controlled by means known in the art (e.g. by affecting membrane porosity and/or pore size, charge, etc.). The membrane can be constructed to selectively permit the passage of certain substances through the membrane, while excluding passage of other substances that could detrimentally affect the other implant phase. The final thickness is preferably between 125 and 250 μm. A sharp punch can be used to cut a disk from the membrane sheet to fit the well 4 contained within the base. The membrane 27 can then be placed within the well 4, and the base and cover mated, thereby forming two compartments separated by the membrane. The membrane thickness and compressibility govern the well depth. For example, the well depth is less than the membrane thickness.
An implant phase is comprised of a material, preferably a polymeric material, material composite or transplanted biological tissue, and can be fitted to the upper compartment and to the lower compartment. An example of material suitable for an implant phase of the present invention can be a composite of 85/15 DL-PLG, calcium sulfate, PGA fibers, and a surfactant. Other materials known to the art may also be used. This material can be punched or otherwise shaped to match the cross-sectional shape of the implant compartment. The punched material can be shaped like a plug and can be of any length. In one embodiment, the material is between 1 mm and 18 mm. Other examples of materials suitable for making phases in an implant are known in the art, including implant materials discussed in the Background section. The implant material can be bioerodible.
The implant materials are generally prepared and cut to the appropriate size outside the assembly device. A solvent solution can be used to wet the to-be-attached surface of the prepared implant phase, thereby partially dissolving the surface of the polymer to facilitate adhesion of the membrane. The wetted prepared implant phase can then be inserted into the appropriate implant compartment. This process can be repeated for the opposing membrane surface and other implant compartment. The materials within each phase can have different or similar properties. For example, each phase can have different mechanical properties (e.g. elasticity and/or porosity) that match the mechanical properties of the tissue in which each phase is to be implanted. The phases can also be prepared from different materials.
A first implant phase can be attached to the membrane by any means known in the art, including solvent adhesion, thermal adhesion, ultrasonic welding, chemical reaction, or the like. To maintain the structural integrity of the membrane, the process of attachment should not perforate the membrane. Similarly, a second implant phase can be attached to the other surface of the membrane, thereby creating a two-phase implant separated by a membrane that can be impermeable, permeable, or selectively-permeable. After assembly of the two-phase and membrane implant, the assembled implant can be cured at 72° C. under vacuum for 24 hours to remove residual solvent, if necessary. The assembly device containing the multi-phase implant can be packaged and sterilized by means known in the art (i.e. ethylene oxide, gamma irradiation, e-beam).
The implant phases, within the assembled device, can be loaded with the desired bioactive agent(s). In an embodiment, the bioactive agent(s) are loaded under sterile conditions, after the assembled device and implant have been sterilized. In one embodiment the bioactive agent(s) can be suspended in a fluid so that the suspension can be applied to, and absorbed and/or attached by, the implant phase. Depending on the particular bioactive agent, the phases can be loaded using a syringe-type delivery device. In another embodiment, bioactive agents are introduced to an implant phase by centrifugation. The agent is dispensed to the intended implant phase contained in the implant assembly and the implant assembly placed in a centrifuge tube. The tube containing the implant assembly is spun in a centrifuge at an appropriate speed to ensure infiltration of the agent into the void spaces of the implant phase. The process is readily accomplished under sterile conditions to ensure continued sterility using techniques known to the art.
As an example of loading bioactive components, a suspension of cultured chondrocytes can be prepared in a carrier gel and placed over the cartilage phase of a two-phase implant. The gel itself may be biologically active or inert, for example the chondrocytes may be suspended in an autogenous fibrin gel. The cell suspension is dispensed into the upper well of the implant and either allowed to soak into the pores of the implant or is gently centrifuged to encourage migration into the pores. Depending on the vehicle used for suspending the cells, additional treatment may be applied to activate gelation. For example, thrombin may be added to a fibrinogen solution to create a fibrin gel, or calcium ion may be added to activate an alginate gel. Other gel activation techniques as known in the art may also be applied.
Other cell types and suspension solutions may used. For example mesenchymal stem cells, adipose derived stem cells, muscle derived stem cells, stem cells from banked cord blood, or embryonic stem cells can be used, either in a differentiated or undifferentiated state. Gel carriers can be prepared from gelatin, hyaluronan, cellulose derivatives, polyethylene oxide (PEO), polysaccharides, polypeptides, and derivatives or combinations of these components. The gel may be cross linked, thixotropic, or temperature, pH, or ion responsive.
As for the two-phase implant assemblies, the means to sealingly engage the intermediate portion to one of another intermediate portion, cover, or base can be a snap bead, threaded connection, thermoplastic sealed by ultrasonic welding or adhesives. In one embodiment, snap beads are used as the sealingly engaging means. An intermediate compartment overhang 19 can be located at the bottom of the intermediate part 40 to snap into circumferential undercut 5 (or alternatively, an intermediate circumferential undercut 21 of another intermediate part), thereby sealingly engaging the intermediate part with the base (or another intermediate unit). An intermediate circumferential undercut 21 can be positioned along the intermediate upper portion 16 for sealingly engaging the cover 30 (or another intermediate lower portion 15). The intermediate part can have an intermediate well 22 for receiving an upper-intermediate separating membrane 23. As with the two-phase implant shown in
In this embodiment, any number of intermediate parts 40 can be connected to each other, with a base at one end and a cover on the opposite end, thereby forming an implant with any number of phases. Bioactive agent(s) can be selectively loaded onto the desired implant phase through a needle port 25, thereby tailoring the biological conditions of each implant phase to the tissue conditions that will surround each implant phase.
The base and cover components can be prepared from metal, alloys, plastics, composites, or the like. For economic and convenience reasons, the components are preferably plastic. The components can be either machined or molded to create the form.
When a Markush group or other grouping is used herein, all individual members of the group and all combinations and subcombinations possible of the group are intended to be individually included in the disclosure.
Every formulation or combination of components described or exemplified can be used to practice the invention, unless otherwise stated. Specific names of compounds are intended to be exemplary, as it is known that one of ordinary skill in the art can name the same compounds differently. One of ordinary skill in the art will appreciate that methods, device elements, starting materials, synthetic methods and structures, other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such methods, device elements, starting materials, synthetic methods, and structure are intended to be included in this invention. Whenever a range is given in the specification, for example, a temperature range, a time range, a size range, or a composition range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the disclosure.
As used herein, “comprising” is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, “consisting of” excludes any element, step, or ingredient not specified in the claim element. As used herein, “consisting essentially of” does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. Any recitation herein of the term “comprising”, particularly in a description of components of a composition or in a description of elements of a device, is understood to encompass those compositions and methods consisting essentially of and consisting of the recited components or elements. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.
All references throughout this application, for example patent documents including issued or granted patents or equivalents; patent application publications; and non-patent literature documents or other source material, are hereby incorporated by reference herein in their entireties, as though individually incorporated by reference, to the extent each reference is at least partially not inconsistent with the disclosure in this application (for example, a reference that is partially inconsistent is incorporated by reference except for the partially inconsistent portion of the reference).
This application claims the benefit of U.S. Provisional Application No. 60/649,418, filed Feb. 1, 2005, hereby incorporated by reference to the extent not inconsistent herewith.
| Number | Date | Country | |
|---|---|---|---|
| 60649418 | Feb 2005 | US |
