Implant-associated infections are of major concerns in orthopedic surgery requiring a high rate of knee and hip revisions and joint replacements. The implant materials provide an ideal environment for bacterial growth, acquired at the time of surgery or at a later stage. The goal of this proposal is to develop peptide-based multifunctional molecules that can self-assemble on implant surfaces and simultaneously induce antimicrobial effects directly on the site through their inherent programmable functions. Following the nucleation of pathogens at the implant surface, antibiotic penetration into the biofilm can be weak resulting in various detrimental effects for healthy implant-tissue integrations such as poor vascularization of the bone. Some of the current treatments may even include implant removal, antibiotic therapy and, only after along recovery period, re-implantation. In the combat of implant-associated infections, there is an urgency to develop new strategies that can be preventive specifically at the implant site. Among the most attractive preventive strategies would be to provide an antimicrobial activity at the implant site without impairing the osseous-integration. The major prerequisite to realize this approach is by modifying the surface biochemistry of the implant via immobilization of biologically active molecules. Conventional immobilization methods, however, are only applicable to a limited range of materials and require the presence of specific functional groups and synthetic pathways. Using combinatorially-selected solid-binding peptides we tailor multifunctional properties with nanoMolar affinities through computational biology tools. We recently engineered peptide sequences that are specific to titanium based implant material, successfully coupled them with antimicrobial peptides, and tested their bactericidal efficacy. Our preliminary studies suggest that peptides engineered as bi-functional molecules can assemble on the implant materials and inducing potent antimicrobial effects. Here, we propose to explore the potential of controlling cell-surface interactions through programmable functional biomolecules that can induce predictable antimicrobial property at the implant/bio interface. The designed chimeric peptides, composed of individual domains for binding and self assembly on the implant surfaces and having antimicrobial property, will be grafted onto carrier proteins that are robust and stable for use as molecular antimicrobial combater to prevent infection. Once developed, the proposed technology will be modular with high efficacy potentially having a broad range of applications including drug delivery at the site of orthopedic surgery.

Public Health Relevance

Implant-associated infections are of major concerns in orthopedic surgery requiring a high rate of knee and hip revisions and joint replacements. The implant materials provide an ideal environment for bacterial growth, acquired at the time of surgery or at a later stage. The goal of this proposal is to develop peptide-based multifunctional molecules that can self-assemble on implant surfaces and simultaneously induce antimicrobial effects directly on the site through their inherent programmable functions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AR062249-01
Application #
8228799
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Panagis, James S
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$208,575
Indirect Cost
$73,575
Name
University of Washington
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Yazici, H; Fong, H; Wilson, B et al. (2013) Biological response on a titanium implant-grade surface functionalized with modular peptides. Acta Biomater 9:5341-52