Progress in the development and use of biomaterials and artificial organs has been delayed by the serious complications of infection and exaggerated host inflammatory responses. Biomaterial implants are surrounded by an immuno-incompetent, fibro-inflammatory, integration deficient zone which is susceptible to infection due to the adherence of S. epidermidis and other bacteria, and because of host cellular and humoral immune perturbation. This proposal is directed to the investigation and moderation of those crucial problems. Our objectives are to further characterize bacterial adherence mechanisms and the cellular immune dysfunction components of biomaterial tissue interface sepsis using an integrative investigative approach to causal and therapeutic mechanisms defined in an animal model. Our objective in AIM 1 will test the effectiveness in vitro and in vivo of antibodies against bacterial adhesins in blocking colonization of biomaterials by clinically relevant strains of Staphlococcus epidermidis. These studies will indicate if the immunization of at risk groups is an effective strategy.
AIM 2 will examine the hypothesis that macrophages will preserve their oxidative and killing capacity if binding to biomaterials is minimized by surface modification.
AIM 3 will test the effectiveness of a novel in vivo mechanism to prime macrophages to express augmented killing capacity in resisting and clearing biomaterial-centered sepsis.
AIM 4 will relate the role of surface microstructure, composition and oxide ultrastructure of a systematically varied single alloy system Ti6A14V to site-specific patterns of bacterial adhesion and protein adsorption. This last objective will include antibody immunogold studies of the adsorption patterns of proteins of in vivo acquired conditioning films and relate these findings to data derived from high resolution surface analysis and bacterial adhesion. We have developed and tested an effective animal model which will be utilized to examine the ability of antiadhesin antibodies to prevent and clear biomaterial infection (AIM 1). The macrophage immune augmentation technique (AIM 3) and the biomaterial coating and conditioning studies (AIMS 2,4) will also utilize the animal model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR026957-08
Application #
2078597
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Project Start
1981-09-30
Project End
1997-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
8
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Medical Sciences Research Institute
Department
Type
DUNS #
City
Herndon
State
VA
Country
United States
Zip Code
Grainger, David W (2004) Controlled-release and local delivery of therapeutic antibodies. Expert Opin Biol Ther 4:1029-44
Poelstra, Kornelis A; Barekzi, Nazir A; Rediske, Andrea M et al. (2002) Prophylactic treatment of gram-positive and gram-negative abdominal implant infections using locally delivered polyclonal antibodies. J Biomed Mater Res 60:206-15
Barekzi, Nazir A; Felts, Adrian G; Poelstra, Kornelis A et al. (2002) Locally delivered polyclonal antibodies potentiate intravenous antibiotic efficacy against gram-negative infections. Pharm Res 19:1801-7
Poelstra, K A; van der Mei, H C; Gottenbos, B et al. (2000) Pooled human immunoglobulins reduce adhesion of Pseudomonas aeruginosa in a parallel plate flow chamber. J Biomed Mater Res 51:224-32
Felts, A G; Grainger, D W; Slunt, J B (2000) Locally delivered antibodies combined with systemic antibiotics confer synergistic protection against antibiotic-resistant burn wound infection. J Trauma 49:873-8
Rojas, I A; Slunt, J B; Grainger, D W (2000) Polyurethane coatings release bioactive antibodies to reduce bacterial adhesion. J Control Release 63:175-89
Poelstra, K A; Barekzi, N A; Slunt, J B et al. (2000) Surgical irrigation with pooled human immunoglobulin G to reduce post-operative spinal implant infection. Tissue Eng 6:401-11
Felts, A G; Giridhar, G; Grainger, D W et al. (1999) Efficacy of locally delivered polyclonal immunoglobulin against Pseudomonas aeruginosa infection in a murine burn wound model. Burns 25:415-23
Barekzi, N A; Poelstra, K A; Felts, A G et al. (1999) Efficacy of locally delivered polyclonal immunoglobulin against Pseudomonas aeruginosa peritonitis in a murine model. Antimicrob Agents Chemother 43:1609-15
Azizsoltani, E; Myrvik, Q N; Foster, L A et al. (1995) Simple technique for the preparation of silicone gel particles: the effect of silicone gel particles on oxidative responses of macrophages. J Biomed Mater Res 29:101-5

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