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STRUCTURES HAVING COATED
INDENTATIONS
RELATED APPLICATIONS
The present application claims benefit of priority of 5 provisional patent application serial No. 60/126,545, filed Mar. 26, 1999.
FEDERAL GOVERNMENT FUNDING
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This invention was made with government support under grant number 9872882 awarded by the National Science Foundation. The government has certain rights in the invention.
FIELD OF THE INVENTION 15
The present invention is related to structures, such as implantable medical devices, that have an indented surface, and methods for making the same.
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BACKGROUND OF THE INVENTION
The present invention provides biomedical structures, and methods for their manufacture, having indentations that are selectively coated with a substance having a desirable ^ property, such as a substance possessing a desired biological activity. For example, medical devices that are implanted into an animal body, such as the human body, often stimulate a so-called "foreign body reaction" which produces a fibrous capsule around the implanted device. The fibrous capsule 3Q impedes vascular communication between the body and the implanted device leading to additional, fibrous encapsulation that reduces the effectiveness and working life of the device. Thus, for example, there is a need for implantable, medical devices that have one or more surfaces adapted to 3J promote cellular communication (such as vascularization) with the cells of the body into which the medical device is implanted.
SUMMARY OF THE INVENTION
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In one aspect the present invention provides indented structures (such as biomedical structures) comprising indentations that are coated with at least one biologically active substance. The indented structures of the invention each comprise (a) a body defining a plurality of indentations, 45 substantially all of the plurality of indentations comprising a surface layer comprising a biologically active substance; and (b) a body surface, wherein each of the plurality of indentations opens onto the body surface through a plurality of openings, and wherein the biologically active substance is 50 not substantially present on the body surface. Examples of structures of the present invention include medical devices (such as devices that provide substrates and/or frameworks for culturing cells, tissues or organs in vitro or in vivo), including medical devices that are completely or partially 55 implantable into a living body. The surface layer of the indentations (or at least some of the indentations) of the medical devices of the invention may comprise biologically active substances, such as proteins, that promote the growth of cells into and/or within the indentations, thereby promot- go ing the acceptance of the implanted device by the living body, or achieve some other desired response.
In another aspect, the present invention provides methods for making indented structures (such as biomedical structures) comprising indentations that are coated with at 65 least one biologically active substance. The methods of this aspect of the invention include the steps of (a) treating a
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structure, comprising a body and a body surface, to form a plurality of indentations in the body, each of the plurality of indentations (1) opening onto the body surface through a plurality of openings, and (2) further defining an indentation surface; and (b) forming a layer on at least some of the indentation surfaces, the layer comprising a biologically active substance, provided that the layer is not formed on a substantial portion of the body surface. The methods of the invention can be used, for example, to make medical devices (completely or partially implantable into a living body) comprising indentations wherein the indentations (or a portion thereof) are coated with one or more biologically active substances, such as proteins, that enhance a desired biological reaction in use, such as promotion of the growth of cells into and/or within the indentations, thereby promoting the acceptance of the device by the living body.
As more fully discussed herein, the structures and methods of the present invention can be used in any situation where there is a need to stimulate the growth of specific cell, tissue and/or organ types, or to promote some other biological function. For example, structures of the invention can be used to promote vascular communication between an implanted medical device and the surrounding tissue.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing aspects and many of the attendant advantages of this invention will become more readily appreciated as the same become better understood by reference to the following detailed description, when taken in conjunction with the accompanying drawings, wherein:
FIG. 1 shows a perspective view of an indented structure of the invention.
FIG. 2 shows a cross-section of an indentation defined by an indented structure of the invention.
FIG. 3 shows a cross-section of an indented structure of the invention that includes several representative configurations of indentations.
FIG. 4 shows a cross-section of an indented structure of the invention attached to a substrate structure.
FIG. 5 shows a cross-section of an indented structure of the invention that includes several body layers.
FIG. 6A shows a substrate that can be treated in accordance with the methods of the invention to form an indented structure of the invention.
FIG. 6B shows the substrate of FIG. 6A which has been treated to form a plurality of indentations.
FIG. 6C shows the treated substrate of FIG. 6B wherein the surface of the indentations have been coated with a layer comprising at least one biologically active substance.
FIG. 7A shows a cross-section of an indentation defined by an indented structure of the invention.
FIG. 7B shows the indentation of FIG. 7A wherein the indentation surface has been coated with a layer of polymer.
FIG. 7C shows the coated indentation of FIG. 7B wherein the polymer layer has been coated with a layer that comprises at least one biologically active substance.
FIG. 8 shows the attachment of a protein (shaded ovals) to amine groups via an ethylene glycol diglycidyl ether linker.
DETAILED DESCRIPTION OF THE
PREFERRED EMBODIMENT
In one aspect the present invention provides indented structures that each comprise (a) a body defining a plurality
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of indentations, substantially all of the plurality of indentations comprising a surface layer comprising a biologically active substance; and (b) a body surface, wherein each of the plurality of indentations opens onto the body surface through a plurality of openings, and wherein the biologically 5 active substance is not substantially present on the body surface.
The phrase "substantially all of the plurality of indentations comprising a surface layer comprising a biologically active substance", and grammatical equivalents thereof, 1° means more than 50% of the indentations, preferably more than 75% of the indentations, more preferably more than 90% of the indentations, and most preferably more than 99% of the indentations comprise a surface layer comprising a biologically active substance. In one embodiment of the :5 indented structures of the invention, 100% of the plurality of indentations comprise a surface layer comprising a biologically active substance.
The phrase "the biologically active substance is not substantially present on the body surface", and grammatical 20 equivalents thereof, means that less than 50%, preferably less than 25%, more preferably less than 10%, and most preferably less than 1% of the amount of biologically active substance(s) present in and/or on the indented structure is present on the body surface. In one embodiment of the 25 indented structures of the invention, the body surface of the indented structure comprises less than 0.5% of the biologically active substance present in the structure. Typically, biologically active substance(s) present in the indentation surface layer is covalently attached thereto, while biologi- 30 cally active substance(s) present on the body surface is non-covalently attached thereto.
As used herein, the term "indentation", or "indentations", includes indentations that partially penetrate a structure, and 3J indentations that penetrate all the way through a structure (as exemplified in FIG. 3 herein).
As used herein, the phrase "a medical device", and grammatical equivalents thereof, means a device that is completely or partially implanted into a living body during 40 the course of normal operation of the device.
FIG. 1 shows one embodiment of the indented structures of the present invention wherein indented structure 10 comprises a body 12 having an upper surface 14, a lower surface 16, a first end 18, a second end 20, a first face 22 and 45 a second face 24. In the embodiment shown in FIG. 1, structure body 12 defines a plurality of indentations 26 which extend from upper surface 14 to lower surface 16 and completely penetrate structure body 12, each of indentations 26 comprising a first opening 28, defined by upper surface 50 14, a second opening 30, defined by lower surface 16, and an indentation surface 32. As shown more clearly in FIG. 2, indentation surface 32 is coated with a layer 34 that comprises at least one type of biologically active substance, such as a biologically active protein or peptide. 55
Indentations 26 can have a variety of configurations in addition to the columnar configuration shown in FIG. 1 that completely penetrates structure body 12. FIGS. 3 and 4 show other, representative examples of acceptable configurations of indentations 26, including: indentation 26a that is 60 a columnar configuration that partially penetrates structure body 12, indentation 26b that is a curved configuration that partially penetrates structure body 12, indentation 26c that is a curved configuration that completely penetrates structure body 12 and indentation 26d that is a groove defined by body 65 12. Indentations 26 can penetrate structure body 12 at any desired angle.
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Layer 34 on indentation surface 32 can comprise any biologically active substance, or combinations thereof. Representative examples of biologically active substances that can be used to form layer 34 include, but are not limited to: growth factors (such as fibroblast growth factors, platelet derived growth factors, transforming growth factors, insulin-like growth factors, nerve growth factors, vascular endothelial growth factors, hematopoietic growth factors and epidermal growth factors); stimulators of vasculogenesis (i.e., stimulate the formation of new blood vessels) including vascular growth factors, angiogenin, and osteonectin; stimulators of the growth of other types of tissue, such as epidermal growth factor and bone morphogenic proteins; extracellular matrix proteins, such as collagens, thrombospondins, osteopontin, osteonectin, vitronectins, laminins, or one or more functional domains of the foregoing proteins. Representative examples of useful functional domains include cellular attachment domains that recognize cell-surface molecules, such as integrins. Additionally, biologically active fragments of molecules such as elastin, glycosaminoglycans (such as hyaluronic acid) and dermatan sulfate, can be used to form layer 34. Non-protein, biologically active molecules that can be used to form layer 34 include antibiotics, drugs utilized to treat diabetes and antisense oligonucleotides.
Thus, for example, layer 34 of indentation surface 32 can include one or more stimulators of vasculogenesis that promote the growth of blood vessels into and/or within indentations 26, thereby reducing the tendency of the surrounding tissue (when structure 10 is implanted into a living body) to mount a foreign body reaction. In some embodiments of indented structures 10 of the invention, some indentations 26 are coated with one or more types of biologically active substance(s), while other indentations 26 are coated with different types of biologically active substance(s).
Layer 34 covers at least a portion of indentation surface 32 of at least some of indentations 26. Layer 34 may cover all of indentation surface 32 of all of indentations 26. In this context, the term "cover all of indentation surface 32" means that greater than 95%, preferably greater than 98%, more preferably greater than 99%, most preferably 100% of the surface area of indentation surface 32 is covered with layer 34. Additionally, in this context, the term "all of indentations 26" means greater than 95%, more preferably greater than 98%, most preferably 100% of indentations 26 include layer 34.
In one embodiment, indentations 26 have an average, maximum diameter in the range of from about 1 micron to about 100 microns, more preferably about 50 microns, and penetrate structure 10 to a depth of from about 1 micron to about 2 millimeters, more preferably from about 1 micron to about 500 microns.
Indented structures 10 can be made from any suitable material, including polymers, metals and composites. Representative examples of polymers useful for making structures 10 include, but are not limited to: polypropylene, polyethylene, polyurethane, polyester, polytetrafluoroethylene (PTFE), poly(lactic acid), poly(glycolic acid), polystyrene, polycarbonate, polyethylene glycol (PEG), fluoropolymers, collagen, poly(galactic acid), polyethylene terephthalate (PET), poly(dioxanone), poly(trimefhylene carbonate) copolymers, poly (e-caprolactone) homopolymers and copolymers, polyanhydrides, polyorthoesters, and copolymers of any of the foregoing. Representative examples of metals useful for making indented structures 10 include, but are not limited to: steel, titanium and NiTi smart
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