Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-11-12
2001-12-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S423000, C424S422000, C424S428000, C424S484000, C424S486000, C424S489000, C623S011110
Reexamination Certificate
active
06328990
ABSTRACT:
BACKGROUND OF THE INVENTION
Since 1967 when van Wezel introduced and demonstrated the use of small globular particles as support for growth of anchorage-dependent cells in suspended cultures, a variety of composite materials and microspheres have been used in 3-dimensional (3D) cell cultures. They include dextran microspheres, polystyrene microspheres, polyacrylamide microspheres, and silica glass beads to name a few. Microcarriers made from degradable polymers have found applications in sustained delivery of drugs or other biologically active compounds (Uchida et al. 1997.
Chem. Pharm. Bull.
45:1539-1543; Wakiyama et al. 1982.
Chem. Pharm. Bull.
30:3719-3727; Mathiowitz et al. 1988.
J. Appl. Polym. Sci.
35:755-774; Mathiowitz et al. 1990.
Polymer
31:547-555; Albertson et al. 1996.
J. Appl. Polym. Sci.
62:695-705).
Calcium phosphate-based ceramics and glasses have the ability to bond with bone tissues and have been widely used in bone repair (Ducheyne, P. and J. Lemons. 1988.
Ann. NY Acad. Sci.
523). Based on a comparison of literature data it was suggested that 45S5 “bioactive” glass (45% SiO
2
, 24.5% Na
2
O, 24.5% CaO, and 6% P
2
O
5
) had the highest rate of bonding to bone (Hench, L.L. 1988.
Ann. NY Acad. Sci.
523:54-71), where “bioactive” means the material has the ability to interact or bind to living tissue. Recently, 45S5 bioactive glass has been considered for use as bioactive ceramic microspheres in 3D bone cell cultures in rotating bioreactors (Qiu et al. 1998.
Tissue Engineer.
4:19-34). The use of bone bioactive materials is of great interest in bone synthesis in vitro because of their ability to promote cell-material bonding and the potential to enhance bone formation.
It is believed that the presence and formation of calcium hydroxyapatite at the implant-bone interface is critical for bone bonding and is one of the key features necessary for successful bioactive bone implants. Calcium hydroxyapatite coatings on implants or calcium hydroxyapatite blocks have been used to produce implants with bone-binding abilities. Through use of an in vitro immersion method using a simulated physiological solution, a solution that mimics the ion concentration in body fluids, the formation of the calcium hydroxyapatite layers on bioactive glasses, bioactive glass-ceramics and polymers have been produced and this method of “in vitro immersion” used to predict bone-bonding potential of bone implant materials (Kokubo et al. 1990.
J. Biomed. Mater. Res.
24:721-734; Li et al. 1997.
J. Biomed. Mater. Res.
34:79-86).
Solid bioceramic microspheres typically have a density higher than 2 g/cm
3
. When they are used in bioreactors, the solid ceramic microspheres experience a high shear stress which causes cell detachment and damage (Qiu et al. 1998.
Tissue Engineer.
4:19-34). This problem has been solved by reducing the apparent density of the microspheres through a hollow structure approach (Qiu et al. 1999.
Biomaterials
20:989-1001). Cell culture studies have confirmed that the hollow bioceramic microspheres (SiO
2
/Al
2
O
3
/CaP) experience a low shear stress and can support 3D bone cell cultures in rotating bioreactors. However, because of their non-degradable component, Al
2
O
3
, hollow bioceramic microspheres cannot be completely replaced by bone tissues. New microcarriers that are bioactive, degradable and with a density low enough to produce a low shear stress, are desired.
A new bioactive and degradable composite material has been developed for use in 3-dimensional bone tissue engineering and bone implant materials.
SUMMARY OF THE INVENTION
An object of the present invention is a bioactive, degradable composite material where the composite is made from mixing a modified bioactive glass powder with a poly(lactic co-glycolic acid) polymer matrix. The composite may be used in tissue engineering for implantation or as a microcarrier for delivery of drugs.
Another object of the present invention is a solid-in-oil-in-water solvent removal method for production of bioactive, degradable composite materials, including microspheres.
Yet another object of the present invention is a method for inducing bone regeneration in an animal and a method for drug delivery in an animal.
Yet another object of the present invention is a method for producing bioactive and degradable scaffolds for 3-dimensional bone tissue engineering.
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Zhang R. and Ma, P.X. Porous poly (l-lactic acid)/apatite composites created by biomimetic process. 1998. Dept. of Biologic and Biomedical Engineering, 285-293.*
Alberton et al., “Preparation and Characterisation of Poly(adipic anhydride) Microspheres for Ocular Drug Delivery”,Jour. of Applied Polymer Science1996 62:695-705.
Baker et al., “The bone-bonding polymer Polyactive 80/20 induces hydroxycarbonate apatite formation in vitro”,Jour Biomedical Materaial Research1997 34:79-86.
Hench L., “Bioactive Ceramics”,Bioactive Ceramics,Part II, 54-71.
Kokubo et al., “Solutions able to reproduce in vivo surface-structure changes in bioactive glass-ceramic A-W3”, 1990 Journ Biomedical Materials Research, 24:721-734.
Mathiowitz et al., “Polyanhydride Microspheres as Drug Carriers. II. Microencapsulation by Solvent Removal”,Journal of App Polymer Science1988, 35: 755-774.
Mathiowitz et al., “Polyanhydride microspheres: 3. Morphology and characterization of systems made by solvent removal”,Polymer1990 31:547-554.
Qiu et al., “Formation and Differentiation of Three-Dimensional Rat Marrow Stromal Cell Culture on Microcarriers in a Rotating-Wall Vessel”,Tissue Engineering1998 4:19-26.
Qui et al., “Fabrication, characterization and evaluation of bioceramic hollow microspheres used as microcarriers for 3-D bone tissue formation in rotating bioreactors”,Biomaterials20, 1999 989-1001.
Radin et al., “The effect of calcium phosphate ceramic compositon and structure on in vitro behavior. II Precipitation”,Jour Biomedical Materials Research1993 27:35-45.
Uchida, et al., “Preparation and Characterization of Polylactic Acid Microspheres Containing Bovine insulin by a w/o/w Emulsion Solvent Evaporation Method”,Chem. Pharm. Bull.1997 45(9): 1539-1543.
Vert et al., “Bioresorable Plastic Materials for Bone Surgery”,Macromolecular Biomaterials,Chapter 6: 119-142.
Wakiyama et al., “Preparation and Evaluation in Vitro and in Vivo Polylactic Acid Microspheres containing Dibucaine”,Chem. Pharm Bull1982 3719-3727.
Zhang et al., “Porous poly (L-lactic acid)/apatite composites created biomimetic process”,Dept of Biologic and Materials Sciences and Biomedical Engineering,1998 285-293.
Ayyaswamy Portonovo S.
Ducheyne Paul
Qiu Qing-Qing
Di Nola-Baron Liliana
Licata & Tyrrell P.C.
Page Thurman K.
The Trustees of the University of Pennsylvania
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