Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-09-14
2003-07-29
Naff, David M. (Department: 1651)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S093700, C435S176000, C435S177000, C435S395000
Reexamination Certificate
active
06599516
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to implant materials having access channels for enhanced cell-mediated resorption of the implant into living tissue. This invention also relates to materials for the cell-mediated remodeling of an implant.
Damage to body tissue often requires the use of an implant material to replace, support or repair the damaged tissue. For example, implants may be used in the repair of bone fractures or periodontal defects, replacement of damaged cartilage and soft tissues such as muscle tissue and collagen.
In the case of fracture, disease or other injury to bone, proper healing and bone remodeling depends on the successful stabilization of the bone site and the ability to induce bone regeneration and repair. In the instances where damage to the bone is large, a bone graft material (implant) may be introduced into the bone site to bridge the gap left by the damaged bone in order to fill open spaces and prevent fibrous ingrowth into the defect, as well as to aid in the stabilization of the fracture. Often times a resorbable bone graft material is selected to serve this function. Both biologically derived materials such as autographs and allografts, as well as synthetic glasses, calcium phosphates and calcium sulfates, are examples of resorbable bone graft materials.
A variety of synthetic bone implants have been shown to be resorbed or partially resorbed by host cells. Cells which are recognized as important in the resorption process include osteoclasts, osteoblasts, macrophages and vascularizing elements. Since these cells necessarily gain access to the implant by way of the surface, specific surface characteristics may significantly affect remodeling and resorption rates. For example, the ratio of implant surface area to implant volume is expected to have significant ramifications on implant resorption and remodeling rates by cells.
A variety of materials have been proposed for use as bone implant materials, including porous metals, biodegradable organic polymers, and ceramic materials. The use of calcium phosphate materials as implants in bone sites is known. Calcium phosphate cements represent biocompatible materials which provide the components necessary for the formation of bone, namely, calcium and phosphate ions, and which may act as a substrate for bone growth, i.e., they are osteoconductive.
Materials for use as implants range from substantially non-resorbable materials, i.e., porous metals, bioglass and corraline, to highly resorbable materials, i.e., selected organic polymers, calcium phosphates, and composites thereof. In most applications, it is desirable to have materials which are highly resorbable, and which can be replaced by living tissue in a short time period. Furthermore, the implant material ideally is capable of being formed into complex shapes that fit the contours of the repair site. An accurately contoured implant will enhance the integration of natural tissue at the site.
Calcium phosphate cements are known, which set rapidly at room and/or body temperature. See, U.S. Pat. Nos. 5,522,893, 5,525,148, RE 33,161 and RE 33,221 to Chow et al, U.S. Pat. No. 5,605,713 to Boltong et al. and U.S. Pat. No. 5,336,264 to Constantz et al. Such cements provide the ability to form complex shapes with intimate host bone contact, however, the osteoconductivity and the remodeling capability of the resulting material may often be less than desired.
Lee et al. in U.S. Pat. Nos. 5,683,461 and 5,783,217 describe a bioresorbable calcium phosphate cement which is an excellent osteoconductive substrate. The calcium phosphate implant is resorbed in as little as 3-12 weeks in small animal models, and bone tissue substantially similar to naturally occurring bone is formed in its place. Even in these calcium phosphate cements, the remodeling capability sometimes is less than ideal, particularly when they are used to produce large volume implants.
Porosigens have been used to increase porosity in materials. Porosigens include additives, usually particulate in nature, which are leached out or dissolved to form pores or voids which increase the porosity of the implant. While porosigens have been associated with increased resorbability, known porosigens do not provide adequate access to the interior of the implant on a scale sufficient to permit cell-mediated resorption or remodeling of the implant.
Chow et al in U.S. Pat. No. 5,525,148 report the use of pore-forming agents to create pores sufficiently large to cause vascularization of tissue which infiltrates the cement once placed in the body. Chow reports the addition of particulate additives such as sugars, sodium bicarbonate or phosphate salts, which are removed by resorption into the body tissue, dissolution in physiological fluids, or heating after the cement has hardened (presumably before implantation). Due to the nature of the particulate additive, the pores are on the micron or submicron scale, i.e., “non-macro” scale, and the internal porosity remaining after the porosigen is removed is random and often non-continuous.
Solid ceramic implants have been prepared in a variety of sizes and shapes.
Johnson et al. in WO 99/16479, entitled “Bone Substitute Materials”, describe a hard, open ceramic framework as a bone implant material. The porous structure is obtained by coating an open-celled organic material with a ceramic oxide and then sintering to burn out the open-celled material.
Boyan et al. in U.S. Pat. No. 5,492,687, entitled “Biodegradable Implant for Fracture Nonunions,” describe a substitute bone graft material having interconnected pores and canals having the size, shape and spacing corresponding to Haversian canals, i.e., naturally occurring canals of cortical bone which allow vascularization. The implant is formed by casting a polymeric gel into the desired shape, including channels, and drying to form a solid implant.
In the above examples, the implant is a solid structure in which the porous substructure is introduced into the material prior to implant. Such implant structures are not moldable or able to form complex shapes with intimate host bone contact.
There remains a need to provide an implant material and methodology, in which access into the interior of the implant material is provided, while retaining the host-conforming ability of a paste or putty.
Furthermore, there remains a need to increase the rate and level of cellular ingress into the implant so that the remodeling rate and efficiency of implant material is enhanced.
There remains a need for providing greater access to cells of living tissue to the interior of an implant material to increase implant resorption and tissue remodeling.
SUMMARY OF THE INVENTION
The present invention provides means for cellular access into the interior of a malleable implant to optimize cell contact with the implant material. The access means is a macrostructure that provides access to the interior of a soft, conformable implant material, which upon hardening provides a structural access channel for cells to the interior of the implant.
In one aspect, the inventive implant includes a malleable implant material, and a non-particulate access means for providing macroscopic access into the interior of the implant to cells of the living tissue.
In preferred embodiments, the implant has at least one cross-sectional dimension of greater than 3 mm, and preferably at least one cross-sectional dimension of greater than 1 cm.
In other preferred embodiments, the malleable implant material is comprised of a bioresorbable material and a physiologically acceptable fluid. The malleable material is selected from the group consisting of calcium phosphates, collagens, and fibrins. In one embodiment, the malleable implant material is hardenable, or the malleable implant material is an osteoconductive material.
In one embodiment, the calcium phosphate is selected from the group consisting of amorphous calcium phosphate, tricalcium phosphate, hydroxyapatite, calcium deficient hydroxyapatite, poorly crystalline hydroxyapatite (PCHA), calcium deficient
Etex Corporation
Hale and Dorr LLP
Naff David M.
LandOfFree
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