Medical device and methods of use

Details Medical device and methods of use Medical device and methods of use

2000-12-04

2004-11-02

Nguyen, Dave T (Department: 1632)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C623S066100, C435S320100, C424S450000

Reexamination Certificate

active

06812217

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to medical devices (e.g., implantable pulse generators) that include a polymer and a polynucleotide. Preferably, the medical device can be used to prevent or treat medical device-associated infections. In some aspects of the present invention, the medical devices carry a polynucleotide that encodes an antimicrobial peptide and inhibits the growth of pathogens. In other aspects of the present invention, the medical devices carry eukaryotic cells (e.g., endothelial cells) that express an antimicrobial peptide and inhibit the growth of pathogens.
BACKGROUND
The insertion of implants has become a widely accepted and often life-saving procedure. The past few years have seen a dramatic increase in the variety and numbers of medical devices. It is estimated that currently world-wide there are some 6,000 distinct types or generic groups of medical devices, and some 750,000 or more brands and models, ranging from very simple devices to very complex systems. A study in 1989 estimated that world-wide approximately 1,000,000 implants are performed annually; the number of additionally used catheters for diagnostic and therapeutic means exceeds this number considerably.
Infection is the most feared, if not the most serious complication of the numerous devices and materials inserted. Treatment of such infections is difficult and most often infection is irreversible, requiring in many cases complete removal of the catheter or implant. Technological refinements in materials and design and increasing surgical experience generally lowers the incidence of infectious complications; however, infection remains a constant cause of morbidity and mortality.
The impact and clinical importance of implant-related infections may be more appreciated considering several factors. One important factor is the millions of patients in whom prostheses of one sort or another are present. Another important factor is the severity of illness that results from device-related infections. In most instances, infection involving a totally implanted device results in function-loss and the need for surgical removal in order to achieve a cure. Depending on the device type, e.g., with prosthetic heart valves or vascular grafts, mortality is high following infection. A third factor is the economic consequences that are measured in the costs of making the diagnosis and in treating a device-related infection. It is estimated that the costs of treating an infected joint prosthesis exceed four- to sixfold the costs of the original prosthetic joint replacement.
Approaches to reduce device-related infections initially were focused on improvements of the surgical technique, including modification of the operating room area and the use of prophylactic antibiotics at the time of surgery. Despite the introduction of these meticulous aseptic measures the occurrence of device-related infections could not be completely eliminated.
An alternative approach is to focus on the implant itself, and consequently on modification of the device to enhance infection-resistance by providing surfaces on the device that promote appropriate integration of the surrounding tissue(s) with the device surface. The underlying concept is that encouraging rapid colonization and integration of the device surface with tissue cells protects the implant surface from bacterial colonization.
A considerable amount of attention and study has been directed toward preventing colonization of bacterial and fungal organisms on the surfaces of orthopedic implants by the use of antimicrobial agents, such as antibiotics, bound to the surface of the materials employed in such devices. The objective of such attempts has been to produce a sufficient bacteriostatic or bactericidal action to prevent colonization. Practice of the prior art coating methods results in an orthopedic implant or medical device wherein the effectiveness of the coating can diminish over time. After insertion of the medical device or orthopedic implant, the antibiotics can leach from the surface of the device into the surrounding environment. Moreover, bacterial pathogens have become increasingly resistant to commonly used antibiotics. In some cases, there are no remaining first-line options for therapy. A recently published trend analysis on bacterial pathogens isolated from blood in England and Wales from 1990 to 1998 showed an upward trend in total numbers of reports of bacteraemia. The five most cited organisms accounted for over 60% of reports each year. There was a substantial increase in the proportion of reports of
Staphylococcus aureus
resistant to methicillin,
Streptococcus pneumoniae
resistance to penicillin and erythromycin, and
Enterococcus faecalis
and
Enterococcus faecium
resistance to vancomycin.
Antimicrobial peptides are a type of antibiotic. The first antimicrobial peptides were identified in 1939 by Dubos who demonstrated that ‘an unidentified soil bacillus’ produced antibacterial compounds that could prevent pneumococcal infections in mice (Boman et al., “Antimicrobial Peptides,” Ciba Foundation Symposium, John Wiley and Sons, Chicester (1994)). In the 1960s, a bee venom toxin and a peptide in frog skin were claimed to be antibacterial. Since then, antimicrobial peptides have been isolated from insects (cecropins from the moth
Hyalophora cecropia
and
Drosophila melanogaster
, insect defensins from the fleshflies
Phormia terranovae
and
Sacrophaga peregrina
), from the skin of the African clawed frog
Xenopus laevis
(magainins), from the horse shoe crab (tachyplesins), and mammalian granulocytes (defensins), macrophages (murine microbicidal proteins), and platelets (thrombocidins). Their widespread distribution is remarkable and makes it highly likely that these components play an important protective role as a first line of defense against infections. Although antimicrobial peptides vary considerably in length, almost all of them are of cationic nature.
In humans, numerous antimicrobial peptides have been isolated and characterized from multiple sources, including neutrophils (also referred to in the art as polymorphonuclear leukocytes), T cells, bronchoalveolar lavage, platelets, plasma, wound fluid, and various organs. Furthermore, over the past few years a range of antimicrobial peptides have been found in epithelial tissue of airways, urogenital tissue, skin, and intestine. These findings suggest that host defense by means of antimicrobial peptides might be more general than ever was assumed initially.
Antimicrobial peptides are able to kill a wide variety of gram-positive and gram-negative bacteria. At least three sequential events are required for target cell lysis: membrane binding; permeabilization; and finally damaging of DNA. It is believed that after binding to the cell membrane, the antimicrobial peptides form voltage-dependent channels in the lipid bilayers of the cell membrane. The amphiphatic nature of antimicrobial peptides makes them soluble in aqueous media and promotes their ability to insert in membranes. The net positive charge on antimicrobial peptides favors interactions with negatively charged lipid head groups, and provides an initial driving force for insertion of an antimicrobial peptide into a membrane. Moreover, this mechanism of action is one which bacteria have difficulty evading by developing resistance.
TABLE 1
Documents cited herein.
U.S. Patents:
U.S. Pat. No.
Inventor(s)
Issue Date
4,944,659
Labbe et al.
Jul. 31, 1990
5,077,056
Bally et al.
Dec. 31, 1991
5,674,722
Mulligan et al.
Oct. 7, 1997
5,877,302,
Hanson
Mar. 2, 1999
5,993,850
Sankaram et al.
Nov. 30, 1999
International Patent Applications:
Application No.
Inventor(s)/Applicant(s)
WO 96/28841
Smela et al.
WO 96/34417
Smela et al.
Other documents:
Ausubel, R.M., ed. Current Protocols in Molecular Biology (1994)
Boman et al., “Antimicrobial Peptides,” Ciba Foundation Symposium,
John Wiley and Sons, Chicester (1994)
Dichek et al.,
Mol. Biol. Med.
, 8 257-266 (1991)
Genbank Accession Nos:
NM_021010,
AJ277280,
AF295370,
AJ237673,
AF21

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