The implantation of artificial devices and organs is always accompanied by the traumatic disruption of tissue. Long term success is currently hampered by an unacceptable incidence of infection in the inflamed tissue around the prosthesis. This proposal is designed to investigate one aspect of the pathogenesis of such infection. We will examine the in vitro and in vivo interaction of selected prosthetic biomaterials with cellular and humoral components of the traumatic wound. We hypothesize that contact between certain biomaterials and neutrophils and/or plasma will cause initial activation and resultant depletion of the host defenses against infection. The activation and resultant depletion of the host defenses against infection. The activation of the cellular (neutrophilic) component will result in release of activated intermediates of oxidative metabolism and of lysosomal constituents which can induce tissue necrosis. Concomitantly, the interaction will render the neutrophil incapable of effective further response to infection. Additionally, we hypothesize that activation of the humoral component will cause utilization and depletion of complement components necessary for effective host-microbe interaction. Specifically, the proposed work will characterize the changes that take place in neutrophil and plasma as a result of in vitro exposure to those biomaterials commonly used in prosthetic devices; then, using an animal model, we will determine whether or not these defects also are produced around prosthetic biomaterial in vivo. The study will further document that these defects are associated with increased infectivity in the periprosthetic space in proportion to the observed activation and subsequent impairment of neutrophil and plasma function. Modification of the biomaterials by coating them with substances (laminin, fibronectin, vitronectin, capillary endothelial cells) known to be less damaging to neutrophils or less activating to complement will then be carried out. Unmodified and modified biomaterials can then be compared with respect to the damage induced by contact with cellular and humoral host defenses in vitro as well as their infectivity of the periprosthetic space in vivo. This investigation should not only enhance our understanding of the mechanisms of postimplantation infections but it should also help in the design and predictive testing of future biomaterials by providing in vitro correlates of infectivity.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM041734-02
Application #
3300093
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1989-12-01
Project End
1992-11-30
Budget Start
1990-12-01
Budget End
1991-11-30
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Green, Jerril; Doughty, Lesley; Kaplan, Sandra S et al. (2002) The tissue factor and plasminogen activator inhibitor type-1 response in pediatric sepsis-induced multiple organ failure. Thromb Haemost 87:218-23
Kaplan, S S; Simmons, R L (2001) Effect of plasma and matrix proteins on defensin-induced impairment of phagocytic killing by adherent neutrophils. J Biomed Mater Res 57:1-7
Kaplan, S S; Heine, R P; Simmons, R L (1999) Defensins impair phagocytic killing by neutrophils in biomaterial-related infection. Infect Immun 67:1640-5
Doughty, L; Carcillo, J A; Kaplan, S et al. (1998) Plasma nitrite and nitrate concentrations and multiple organ failure in pediatric sepsis. Crit Care Med 26:157-62
Doughty, L; Carcillo, J A; Kaplan, S et al. (1998) The compensatory anti-inflammatory cytokine interleukin 10 response in pediatric sepsis-induced multiple organ failure. Chest 113:1625-31
Kaplan, S S; Lancaster Jr, J R; Basford, R E et al. (1996) Effect of nitric oxide on staphylococcal killing and interactive effect with superoxide. Infect Immun 64:69-76
Kaplan, S S; Basford, R E; Jeong, M H et al. (1996) Biomaterial-neutrophil interactions: dysregulation of oxidative functions of fresh neutrophils induced by prior neutrophil-biomaterial interaction. J Biomed Mater Res 30:67-75
Wong, H R; Carcillo, J A; Burckart, G et al. (1996) Nitric oxide production in critically ill patients. Arch Dis Child 74:482-9
Doughty, L A; Kaplan, S S; Carcillo, J A (1996) Inflammatory cytokine and nitric oxide responses in pediatric sepsis and organ failure. Crit Care Med 24:1137-43
Kaplan, S S (1994) Biomaterial-host interactions: consequences, determined by implant retrieval analysis. Med Prog Technol 20:209-30

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