Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Eye prosthesis – Corneal implant
Reexamination Certificate
2001-03-30
2004-02-10
McDermott, Corrine (Department: 3738)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Eye prosthesis
Corneal implant
C623S005110
Reexamination Certificate
active
06689165
ABSTRACT:
This invention pertains to a method and device to use certain enhancer molecules tethered to an artificial surface in such a manner that the molecules retain their quaternary structure and that the surface produced promotes normal corneal epithelialization.
The Corneal Epithelium
The cornea serves several important functions for vision, e.g., refracting >80% of the incoming light onto the retina, filtering out harmful UV rays, and maintaining an optical “window.” The cornea is composed of five structural layers: the epithelium, Bowman's layer, stroma, Descemet's membrane, and endothelium. The outermost layer, the corneal epithelium, is a multi-layered structure with a complex arrangement of intercellular junctions, chemical signaling, and nerve endings. Similar to other epithelial layers throughout the body, the corneal epithelium prevents entry of pathogens, provides a barrier against fluid loss, and protects against abrasive wounding. The epithelium is separated from the external environment only by a layer of fluid, the tears.
The corneal epithelium is composed of three types of cells—the basal cells (1 layer), wing cells (1-3 layers), and squamous cells (3-4 layers)—which adhere to one another by tight cell junctions. The basal cells also form strong adhesion complexes with the underlying extracellular matrix and ultimately with Bowman's layer. Bowman's layer, the anterior-most layer of the corneal stroma, is an acellular zone consisting of collagen fibrils and associated proteoglycans which are densely woven in a random fashion into a felt-like matrix. Of the cells in the epithelium, only the basal cells have mitotic capabilities. Like all stratified epithelia in the body, the corneal epithelium is self-renewing; complete cellular turnover occurs every 5-7 days. Generally, after the basal cells undergo mitosis, the daughter cells begin to move outward toward terminal differentiation and eventual desquamation. See C. Hanna et al., “Cell production and migration in the epithelial layer of the cornea,” Arch. Ophthalmol., vol. 64, pp. 536 (1960).
Epithelial Cell Migration During Wound Healing
Natural corneal epithelialization occurs in response to a wound. Epithelial recovery following an external injury is a complex process characterized by two phases, the latent phase and the healing phase. See C. E. Crosson et al., “Epithelial wound closure in the rabbit cornea: A biphasic process,” Invest. Ophthalmol. Vis. Sci., vol. 21, pp. 464-473 (1986). These phases are thought to be initiated by the immediate expression of a nucleoprotein-encoding protooncogene (c-fos). Immediately after full-thickness wounding, the damaged cells adjacent to the wound edge lose surface microvilli. Polymorphonuclear neutrophils (PMNs) arrive via the tear film and begin the process of debriding cellular remnants. During the first six hours of epithelial debridement (latent phase), a single layer of epithelial cells at the wound margin becomes motile by forming cellular processes at the wound edge and releasing their hemidesmosomal attachments to the basement membrane. Fibronectin, the glycoprotein widely involved in cell-to-cell and cell-to-substrate interactions, is deposited from the tears onto the denuded corneal surface, along with fibrinogen and fibrin. See L. S. Fujiikawa et al., “Fibronectin in healing rabbit cornea wounds,” Lab. Invest., vol. 45, pp. 120 (1981).
The initiation of lateral migration of epithelial cells over the wound signifies the onset of the healing phase. In association with the proteins fodrin and vinculin, the assembly and disassembly of intracellular actin filaments provides cytoskeletal locomotive support during this pre-mitotic stage of the healing phase. Adhesion of the migrating epithelial monolayer to the stroma is thought to be mediated by the glycoprotein fibronectin. See S. Hiraki et al., “Biochemical and histological findings on the effect of fibronectin in rabbits with experimental corneal disorders,” Arzneim-Forch/Drug Res., vol. 40, pp. 1336-1340 (1990). Fibronectin contains both cell-specific binding sequences and a binding region for heparin sulfate and type IV collagen (basement membrane components). Fibronectin is thought to provide a temporary subepithelial matrix on which the epithelial cells can migrate, in repetitive cycles during which the cells cleave their attachments, advance, and then form new attachments. Plasmin, generated by urokinase-like plasminogen activator (uPA), is thought to cleave the fibronectin at the basal cell surface to release the leading edge of the epithelium. See M. Berman, “The pathogenesis of corneal epithelial defects,” In
Healing Processes in the Cornea,
(Beuerman et al. eds), Portfolio Publishing Company, The Woodlands, Tex. (1989). After about 24 hours, the migrating epithelial cells begin to proliferate, and the epithelium attaches to the basement membrane more firmly via newly synthesized hemidesmosomes and associated type VII collagen containing anchoring filaments. See I. K. Gipson et al., “Anchoring fibrils form a complex network in human and rabbit cornea,” Invest. Ophthalmol. Vis. Sci., vol. 28, pp. 212-220 (1987). The anchoring filaments pass through the basement membrane and are contiguous with anchoring fibrils that terminate as anchoring plaques in Bowman's layer. See I. K. Gipson et al., 1987; and T. Nishida et al., “Expression of fibronectin receptors in corneal epithelial cells,” In: Healing Processes in the Cornea (Beuerman R W, Crosson C E, Kaufman H E (eds)), Portfolio Publishing Company, The Woodlands, Tex. (1989). The proteins laminin, K-laminin, talin, integrin, and kalinin also play roles in the attachment of the epithelium to the stroma. See L. M. Sorokin et al., “Developmental regulation of the laminin &agr;5 chain suggests a role in epithelial and endothelial cell maturation,” Dev. Biol., vol. 189, pp. 285-300(1997); L. S. Grushkin-lerner et al., “Expression of integrin receptors on plasma membranes of primary corneal epithelial cells is matrix specific,” Exp. Eye Res. vol. 64, pp. 323-334 (1997); M. P. Marinkovich et al., “The dermal-epidermal junction of human skin contains a novel laminin variant,” J. Cell Biol., vol. 119, pp. 696-703 (1992); A. Horowitz et al., “Interaction of plasma membrane fibronectin receptor with talin: a transmembrane linkage,” Nature, vol. 320, pp. 531-533 (1986); T. Paallysaho et al., “Epithelial cell-substrate adhesion in the cornea: Localization of actin, talin, integrin and fibronectin,” Exp. Eye Res., vol. 52, pp. 261-267 (1991); and P. Rousselle et al., “An epithelium-specific basement membrane adhesion molecule that is a component of anchoring filaments,” J. Cell Biol., vol. 114, pp. 567-576 (1991).
Although much is known about the factors that make up the adhesion complexes, the precise sequence by which these adhesion complex components are assembled is still unknown. Certain growth factors, such as EGF, FGF, and TGF-&bgr;, enhance the rate of epithelial wound healing, and human epithelial growth factor (EGF) has been specifically shown to induce a dose-dependent increase in epithelial replication in the epithelial stem cells of the corneoscleral limbus. See M. Grant et al., “Effects of epidermal growth factor, and transforming growth factor-&bgr; on corneal cell chemotaxis,” Invest. Ophthalmol. Vis. Sci., vol. 33, pp. 3292-3301 (1992); S. E. Wilson et al., “Fibroblast growth factor-1 receptor messenger RNA expression in corneal cells,” Cornea, vol. 12, pp. 249-254(1993); and S. E. Wilson et al., “EGF, basic FGF and TGF beta-1 messenger RNA production in rabbit corneal epithelial cells,” Invest. Opthalmol. Vis. Sci., vol. 33, pp. 1987-1995 (1992).
Both laminin and fibronectin are multifunctional extracellular matrix proteins that play a central role in cell adhesion and migration. Expression of integrin receptors for both of these proteins has been shown to occur within hours of the ligands being detected in the matrix. See L. S. Grushkin-Lerner et al., “Expression of integrin receptors on plasma membranes of primary corneal epitheli
Bi Jingjing
Jacob Jean T.
Board of Supervisors of Louisana State University and Agricultur
Davis Bonnie J.
Matthews William H.
McDermott Corrine
Runnels John H.
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