Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Solid support and method of culturing cells on said solid...
Reexamination Certificate
1998-11-13
2002-04-30
Naff, David M. (Department: 1651)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Solid support and method of culturing cells on said solid...
C424S078310, C424S423000, C435S180000, C435S396000, C435S402000
Reexamination Certificate
active
06379962
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of a biodegradable polymer scaffold for tissue engineering applications. More particularly, the present invention relates to a novel macroporous polymer scaffold having a high level of interconnectivity between macropores.
BACKGROUND OF THE INVENTION
Bone treatments for injuries, genetic malformations and diseases often require implantation of grafts. It is well known that autografts and allografts are the safest implants; however, due to the limited supply and the risks of disease transmission and rejection encountered with these grafts, synthetic biomaterials have also been widely used as implants. Complications in vivo were observed with some of these biomaterials, as mechanical mismatches (stress shielding) and appearance of wear debris lead to bone atrophy, osteoporosis or osteolysis around the implants (Woo et al., 1976; Terlesen et al., 1988).
A new approach, defined as Tissue Engineering (TE), has recently raised a lot of interest. Tissue engineering involves the development of a new generation of biomaterials capable of specific interactions with biological tissues to yield functional tissue equivalents. The underlying concept is that cells can be isolated from a patient, expanded in cell culture and seeded onto a scaffold prepared from a specific biomaterial to form a scaffold/biological composite called a “TE construct”. The construct can then be grafted into the same patient to function as a replacement tissue. Some such systems are useful for organ tissue replacement where there is a limited availability of donor organs or where, in some cases (e.g. young patients) inadequate natural replacements are available. The scaffold itself may act as a delivery vehicle for biologically active moieties from growth factors, genes and drugs. This revolutionary approach to surgery has extensive applications with benefits to both patient well-being and the advancement of health care systems.
The application of tissue engineering to the growth of bone tissue involves harvesting osteogenic stem cells, seeding them and allowing them to grow to produce a new tissue in vitro. The newly obtained tissue can then be used as an autograft. Biodegradable polyesters—in particular poly(lactide-co-glycolide)s—have been used as scaffolds for tissue engineering of several different cell populations, for example: chondrocytes (as described by Freed et al. in the J. of Biomed. Mater. Res. 27:11-13, 1993), hepatocytes (as described by Mooney et al. in the Journal of Biomedical Mat. Res. 29, 959-965, 1995) and most recently, bone marrow-derived cells (as described by lshaug et al in the J. Biomed. Mat. Res. 36: 17-28, 1997 and Holy et al., in Cells and Materials, 7, 223-234, 1997). Specifically, porous structures of these polyesters were prepared and seeded with cells; however, when bone marrow-derived cells were cultured on these porous structures, bone Ingrowth only occurred within the outer edge of 3-D polymeric scaffold (Ishaug et al, supra; Holy et al., supra). Thus, the polymeric scaffolds prepared in these instances were inadequate to allow for the cell growth required to render tissue suitable for implantation or for use as an autograft.
SUMMARY OF THE INVENTION
It has now been found that polymer scaffolds characterized by macropores in the millimeter size range with interconnections as seen in trabecular bone, are particularly useful for tissue engineering as they allow cell ingrowth which is crucial for the development of three-dimensional tissue. Such polymer scaffolds can be prepared using a novel process which combines the techniques of phase-inversion and particulate-leaching.
Accordingly, in one aspect of the present invention, there is provided a polymer scaffold comprising macropores, ranging in size between 0.5 mm to 3.5 mm, and having an interconnecting porosity similar to that found in human trabecular bone.
More particularly, the present invention provides a macroporous polymer scaffold with a trabecular morphology having a porosity of at least 50% and including polymer struts forming pore walls defining macropores which have a mean diameter in a range from about 0.5 to about 3.5 mm and are interconnected by macroporous passageways.
In one aspect of the invention there is provided a process for synthesizng a macroporous polymer scaffold with microporous polymer struts defining interconnected macropores, comprising the steps of:
mixing liquid polymer with particles to form a mixture of the liquid polymer and particles;
submerging the mixture in a non-solvent for the liquid polymer to precipitate said liquidpolymer producing a solidified mixture; and
submerging the solidified mixture into a solvent that dissolves the particles for a time sufficient to dissolve the particles to obtain said macroporous polymer scaffold with microporous polymer struts defining interconnected macropores.
In another aspect of the invention there is provided a macroporous polymer scaffold with microporous polymer struts defining interconnected macropores formed by mixing liquid polymer with particles to form a mixture of the liquid polymer and particles, submerging the mixture in a non-solvent for the liquid polymer to precipitate the liquid polymer to produce a solidified mixture, and submerging the solidified mixture into a solvent that dissolves, the particles for a time sufficient to dissolve the particles to obtain said macroporous polymer scaffold with microporous polymer struts defining interconnected macropores.
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K. Whang et al., “A Novel Method to Fabricate Bioabsorbable Scaffolds”,Polymer, Vol. 36, No. 4, pp. 837-842, 1995 Elsevier Science Ltd.
Mooney et al., “Novel Approach to Fabricate Porous Sponges of Poly (D,L-Lactic-co-glycolic acid) Without the Use of Organic Solvents”,Biomaterials, vol. 17, pp. 1417-1422, 1996 Elsevier Science Ltd.
Thomson et al., “Fabrication of Biodegradable Polymer Scaffolds to Engineer Trabecular Bone”,J. Biomater. Sci. Polymer Edn., Vol. 7, No. 1, pp. 23-38, 1995 VSP.
Mikos et al., “Laminated Three-Dimensional Biodegradable Foams for Use in Tissue Engineering”,Biomaterials, Vol. 14, No. 5, pp. 323-330, 1993 Butterworth-Heinemann Ltd.
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Ishaug-Riley et al., “Three-Dimensional Culture of Rat Calvarial Osteoblasts in Porous Biodegradable Polymers”,Biomaterials, Vol. 19, pp. 1405-1412, 1998 Elsevier Science Ltd.
Ishaug et al., “Bone Formation by Three-Dimensional Stromal Osteoblast Culture in Biodegradable Polymer Scaffolds”,Journal of Biomedical Materials Research, vol. 36, pp. 17-28, 1997 John Wiley & Sons, Inc.
Davies John E.
Holy Chantal E.
Shoichet Molly S.
Bonetec Corporation
Hill & Schumacher
Naff David M.
Schumacher Lynn C.
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