Surgery – Miscellaneous – Methods
Reexamination Certificate
2001-08-06
2003-12-16
McDermott, Corrine (Department: 3738)
Surgery
Miscellaneous
Methods
C623S023720
Reexamination Certificate
active
06662805
ABSTRACT:
FIELD OF THE INVENTION
The herein disclosed invention finds applicability in the field of preparation and implantation of tissue substitutes for tissue replacement and for prosthesis.
BACKGROUND OF THE INVENTION
The present inventors have previously described a microcarrier spinner culture system that facilitated maintenance of chondrocytic phenotype while enhancing proliferation. Articular chondrocytes were grown on dextran or crosslinked collagen microcarrier beads under controlled pH, oxygen levels, nutrient supply and mechanical agitation conditions. This represents a great advantage over the traditional static monolayer culture system, which facilitates proliferation but leads to a fibroblastic shift in phenotype. Likewise, it offers an alternative to the battery of three-dimensional gel or scaffold systems, which include agarose or collagen gels, calcium alginate gel, mixed fibrin-alginate gels, three-dimensional meshes of resorbable polymers such as polylactides or polyglycolides, and encapsulation in alginate beads. These latter culture techniques facilitate the maintenance of a chondrocytic phenotype, but are limited in maximizing proliferation.
A previously disclosed invention (referred to as PTO Ser. No. 09/825,632) can be described as a method of preparing cells for implantation comprising allowing cells (e.g., chondrocytes) to grow on microcarrier particles for an extended period of time and to secrete extracellular matrix components, thereby producing a cell-microcarrier aggregate useful for transplantation to a patient. The cell-microcarrier aggregates can be implanted directly or further cultured inside a mold that has been shaped to configure the geometry of the area of the body receiving the cells for transplantation. When further cultured in a mold, cell-microcarrier aggregates are consolidated into an implantable structure for repair or replacement of missing or diseased tissue. The microcarrier used to prepare the aggregate is a biocompatible, biodegradable material. This method also anticipates that cell-microcarrier aggregates, or consolidated implants prepared therefrom by further culturing in a mold, may be cryopreserved by standard methods in order to maintain cell viability and aggregate structure for future implantation or analysis.
In another embodiment of the PTO Ser. No. 09/825,632 invention, cell-microcarrier aggregates are cultured to provide a suspension of individual aggregates that may be implanted by injection by syringe or by other endoscopic or arthroscopic instruments suitable for their implantation into a diseased or damaged anatomic site. In this embodiment, cell-microcarrier aggregates may be implanted without any additional material to bind the aggregates together after implantation. Alternatively, a material capable of polymerizing or gelling after implantation may be mixed with the aggregate suspension prior to implantation in order to improve the fixation and localization of the aggregates after implantation, to stimulate more rapid consolidation of the aggregates in vivo, or to promote more rapid integration of the aggregates into the surrounding tissue.
Numerous studies of the implantation of solid tissue-engineered implants, especially soft-tissue analogs such as cartilage-like implants, have demonstrated that the fixation of these constructs to surrounding tissues is a significant problem in the long-term localization of the construct at the implantation site and to the subsequent integration of the implant with the surrounding tissue. Cartilage constructs such as those produced by culturing chondrocytes on biodegradable scaffolds, for example, have been reported by researchers at MIT and Advanced Tissue Sciences to “seal off” around their peripheral surfaces, resulting in inhibiting on blocking the integration of these surfaces with surrounding articular cartilage following implantation. In particular, partial- or full-thickness defects in articular cartilage are especially difficult to treat because mechanical fixation by sutures results in further damage to the surrounding cartilage without resulting in firm fixation of the implant. The use of tissue glues such as fibrin or cyanoacrylate formulations, may result in initial fixation of the implant, but may also inhibit or block the cellular processes leading to the bridging of the interface. The invention described herein provides a method for improving the integration of such solid constructs into the surrounding host tissue by incorporating a suspension of cells or cell-microcarrier aggregates at the interface of the implanted and surrounding host tissue, thereby stimulating the integration of the implanted and host tissues.
Prior Art Patents
Masuda (U.S. Pat. No. 6,197,061) is for a method of preparing a transplantable cartilage matrix and its method of production. Autologous chondrocyte implantation is taught. Cell culture takes place in alginate beads. Cell culture can take place over a period of 7 to 14 days or longer.
Vacanti et al (U.S. Pat. No. 6,027,744) teach methods for generating new tissue using a hydrogel and tissue precursor cells delivered to a support and allowing the gel-cell composition to solidify within the support structure.
SUMMARY OF THE INVENTION
The herein disclosed invention proposes several alternative methods for implanting tissue into a body cavity for the purpose of repairing the cavity. The methods employ in combination, for example, a solid aggregate of cells and microcarrier particles and a fluid composition of cells and microcarrier particles. In use the fluid composition serves to better fix the solid aggregate in the cavity to be repaired. These alternative methods are described in detail in the figures and description set forth herein.
Definition of abbreviations used herein:
TGF-&bgr;—Transforming Growth Factor-&bgr;
BMP—Bone Morphogenetic Protein
PDGF—Platelet Derived Growth Factor
FGF—Fibroblast Growth Factor
DESCRIPTION OF THE INVENTION
Contemplated in this invention is the implantation of a combination of (1) cell-microcarrier aggregates or cell-scaffold or cell-free biomaterial formulations in a solid implantable format; and (2) cells or cell-microcarrier aggregates in an injectable format. In this context, a “solid” implant is a non-porous material that retains its shape during handling. A solid implant may contain a high content of water if the water is substantially retained in the implant, such as in cartilage or other connective tissue, for example. A solid implant may be produced, for example, by culturing cells in a porous scaffold until the pores of the scaffold become filled with a tissue-like matrix. For example, in one embodiment, the solid implant may be first implanted to fill the majority of the cavity receiving the implant, and then a suspension of cells or of cell-microcarrier aggregates in the injectable format, with or without the addition of gelling materials to promote rapid gelling in situ, may be injected into spaces surrounding the solid implant or on the outer surface of the solid implant and surrounding tissue in order to fill the remaining space around the solid implant and/or to secure the solid implant in the site and/or to promote rapid adherence and/or integration of the solid implant and/or provide a covering for the implant to surrounding tissues. Alternatively, the injectable formulation may first be applied to the site intended to receive the implant, then the solid implant construct may be inserted into the site. In this embodiment, the injectable formulation may serve to seat the solid construct into the defect, thereby helping to fix the implant in place and to promote future integration of the implant with the surrounding tissue(s). Finally, the injectable formulation may be coated onto the solid implant prior to implantation.
Also contemplated in this invention is that the cellular composition of the injectable component may differ from that of the solid component. For example, the solid implant may result from the culturing of chondrocytes, thereby resulting in an implant having cartilage p
Bloom Leonard
Domb Abraham J.
Fink David J.
Frondoza Carmelita G.
Hungerford David S.
Armstrong Westerman & Hattori
Barrett Thomas
McDermott Corrine
The Johns Hopkins University
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