Peptide-coated implants and methods for producing same

Details Peptide-coated implants and methods for producing same Peptide-coated implants and methods for producing same

1999-11-22

2001-08-28

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S422000, C623S001490, C623S002420, C623S003290, C623S008000, C623S011110

Reexamination Certificate

active

06280760

ABSTRACT:

The invention relates to implants of a general nature for the human and animal body, which are coated with peptides which are able to selectively mediate the adhesion of specific cells in the particular environment of the implant. In particular, the invention relates to implants coated with RGD peptides and processes for their preparation.
The invention is based on the principle of targeted adhesion stimulation of selected cell species to surface coatings of biomaterials in general and implants in particular for the purpose of tissue-selective, accelerated and enhanced integration thereof after surgical insertion into the appropriate tissue.
In this manner, various surface parts of an implant can be coated with and made available to various peptides mediating cell adhesion, in particular RGD peptides, which take account of the specific tissue environment into which the implants are inserted.
In this manner, moreover, with respect to tissue engineering the generation of “intelligent” biohybrid organs which carry the biological information for organ regeneration is possible by self-organization by means of specific activation of various cell species by various peptides in different regions of the implant surface.
The term “peptides according to the invention” in the following includes, if not stated otherwise or additionally, all peptides which are able to mediate cell adhesion. Among these, especially those are intended which contain the amino acids arginine (R), glycine (G) and aspartic acid (D) one after the other (RGD peptides). Examples of suitable RGD peptides and suitable peptides not containing RGD are mentioned further below. Furthermore included are corresponding peptides which do not contain the RGD sequence, but nevertheless affect cell adhesion. In the widest sense, the invention also includes non-peptide compounds which qualitatively have the same biological activity as said peptide compounds.
Biomaterials or implants in the sense according to the invention are designated as materials which can be introduced into the human or animal body in order to restore the function of the corresponding functionally damaged natural tissue. These include, for example, hip endoprostheses, artificial knee joints, jaw implants, tendon replacements, skin replacements, vascular prostheses, heart pacemakers, artificial heart valves, breast implants, stents, catheters and shunts.
The integration behaviour of implants in the body still proves problematical. The tissue integration of the materials often proceeds too slowly and too incompletely in order to produce a mechanical stability of the tissue/biomaterial bonding which is adequate for functionality. The composition of the implant surface, which on account of its inadequate interfacial compatibility or biocompatibility prevents an active absorption of surrounding healthy tissue or cells, is often causally responsible for this. This complicates the formation of a stable tissue-implant boundary layer and thus leads to inadequate tissue integration, which in turn results in loosening, tissue resorption, infections, inflammations, allergies, microthrombi formation (restenosis). As a result, revision interventions for the replacement of the implants (e.g. hip endoprostheses, jaw implants, catheters or external fixators) and thus renewed surgical interventions become necessary (Malchau and Herberts, 1996, Prognosis of the Total Hip Arthoplasty, 63. Annual Meeting of the American Academy of Orthopaedic Surgeons, Atlanta; Haddad et al, 1996, The Journal of Bone and Joint Surgery, 78-B:546-549; Collinge et al., 1996, Pin Tract Infections).
Moreover, in particular in the case of hip endoprostheses, so-called aseptic implant loosening proves problematical in which bone cells and thus bony tissue do not, as desired, form the direct connection to the biomaterial, but fibroblasts and connective tissue occur as interfering elements. As a consequence, the prosthesis is lined by connective tissue instead of bony tissue, the resulting stability of the prosthesis-connective tissue bond not being adequate to meet the mechanical demands on the force transmission of an artificial hip joint. As a result, this can lead to loosening of the prosthesis (Pilliar et al., 1986, Clin. Orthop., 208:108-113) and likewise necessitates revision. A further example of undesirable cell types adhering to implants are blood platelets, which can lead to the formation of microthrombi and thus to impaired implant integration (Phillips et al., 1991, Cell 65, 359).
The lack of integrability of biomaterials or implants into the body has a particularly serious effect in the case of complete replacement organs, since here the different cell types come into contact with the implant and the necessary integrability should be targeted. In order to avoid extremely complicated transplantation procedures with the aid of other patients, it is attempted, for example, to accomplish the therapy of functional failure of liver, pancreas, kidney and spleen more and more frequently in the field of tissue engineering by means of so-called biohybrid organs, which consist of carrier materials which are covered with living cells and can be implanted as a functional unit. In most cases, for this purpose functional, healthy cells are included or encapsulated in vitro in resorbable or non-resorbable membranes and transplanted into the patient as artificial biohybrid organs or hollow organs (for example: Lim et al., 1980, Science 210, 908-912; Altman et al., 1982, Horm. Met. Res. Suppl. 12, 43-45; Zekorn et al., 1989, Transplantation Proceedings 21, 2748-2750; Altman et al., 1982, Horm. Met. Res. Suppl. 12, 43-45; EP 0 504 781 B1). However, here too the problems described of the fibrous ensheathing with associated lack of nutrient supply to the transplants, immunological defence reactions due to cell release from the capsules and the formation of blood clots on account of the thrombogenicity of the material surfaces very often occur.
It is known to stimulate the tissue integration of biomaterials/implants by coating thereof with peptides which mediate cell adhesion. For this purpose, on the one hand, those peptides which contain the tripeptide amino acid sequence arginine-glycine-aspartic acid (RGD), or their non-peptide analogues and, on the other hand, cell adhesion-mediating, non-RGD-containing peptides (for examples see below), or their non-peptide analogues, which, as is known, as integral constituents of many proteins, inter alia of the extracellular matrix (e.g. collagen type I, fibronectin, laminin, vitronectin, entactin, osteopontin, thrombospondin) or of the blood clotting cascade (fibrinogen, von Willebrand factor) function as central recognition patterns for the adhesion of eukaryotic cells (e.g.: Pierschbacher and Ruoslahti, 1984; Nature, 309:30-33; Yamada, 1991, J. Biol. Chem., 266:12809-12812). The sequences defined according to the invention are recognized and bound by the respective receptors on the cell surface, the integrins. Since the adhesion of cells to the corresponding proteins is mediated by a large number of different integrins, the integrin expression pattern of a cell species is crucial for their adhesion properties to these proteins. The made-to-measure design and the synthesis of mostly short-chain peptides equipped with the appropriate sequences, which can bind selectively and specifically only to certain integrins, make possible the targeted activation of only those cell species which express these integrins. Thus, for example, RGD peptides are known which bind selectively to alpha
v
-integrin receptors and thus are preferably able to stimulate the binding (adhesion) of alpha
v
beta
3
-/alpha
v
beta
5
-bearing cells (osteoblasts, osteoclasts, endothelial cells) without simultaneously being able to stimulate the adhesion of undesirable cell species, e.g. &agr;
IIb
&bgr;
3
-bearing blood platelets (Haubner et al., 1996, 7, Am. Chem. Soc., 118:7461). In contrast, other RGD peptides show a reverse effect and preferably bind to &agr;
IIb
&bgr;
3
-integrin receptors, thus exh

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