Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving hydrolase
Patent
1999-03-08
2000-07-11
Weber, Jon P.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving hydrolase
C12Q 137
Patent
active
060871202
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The invention is in the field of diagnostics and relates to a new diagnostic technique in medicine. More specifically it is concerned with the measurement of activation of an immunologic system in blood, the complement system, when blood is contacting a foreign body surface (biomaterial).
BACKGROUND OF THE INVENTION
Medical devices are frequently used in contact with blood in blood banks, cardiovascular applications, organ replacement and vascular surgery. These devices are made from plastics, metals or modified tissue and have in common that they activate the natural host defence mechanism of blood by a foreign body reaction (FIG. 1). One of the direct effects of blood with such a foreign surface is clotting, which is prevented by anticoagulants. The other effect is activation of the immune system, which cannot be prevented pharmacologically.
This immune response is effected by the complement system, a number of serum proteins consisting of components, activators, stabilizers and inhibitors. The complement system initiates chemotaxis and activation of leucocytes, is essential for phagocytosis of microorganisms and is capable of killing bacteria directly by inducing cell lysis. An implanted foreign body surface could also be attacked by the complement system. In view of the wide-reaching biologic effects of the complement system, the consequences of uncontrolled complement activation would be devastating (1-4). Continued activation of the sequence attracts leukocytes which release lysosomal enzymes as a byproduct of phagocytosis, which in turn cause necrosis of normal tissue (5-8).
Normally, tight controls are in effect which regulate the complement system to protect host tissue. The cascade is naturally moderated by the instability of the enzymes formed. Once a component is activated, failure to combine with its substrate within milliseconds cause it to decay. In addition, several plasma inhibitors are present to control the cascade. However, during the use of medical devices these regulatory mechanisms appear often inadequate due to the unnatural surface. Therefore, testing of complement activation by materials used for the construction of medical devices is needed to ensure the use of materials with as low complement activation as possible.
THE COMPLEMENT SYSTEM (FIG. 2)
Activation of the complement system can occur via two distinct routes--the classical and the alternative pathway. The end result of complement activation is cytolysis, although this is probably not the major function of complement. In the course of complement activation, biologically active factors are released. These factors enhance the immune response by directing neutrophil migration, promoting immune adherence, increasing vascular permeability, and interacting with other inflammatory systems.
The classical pathway components are designated C1g, C1r, C1s, C4, C2, C3, C5, C6, C7, C8, C9. The alternative pathway components are designated Factor B, Factor D, Properdin, H and I.
Initiation of the classical pathway begins when antibody binds antigen. C1g binds the altered Fc region of IgG or IgM that has bound antigen. Upon binding, C1r activates C1s which initiates the activation unit by cleaving a peptide from both C4 and C2. C1s thus cleaves C4 into C4a and C4b and C2 into C2a and C2b. C2a binds to C4b forming C4b2a. C4b2a, the C3 convertase, is a proteolytic enzyme. It cleaves C3 into C3b, which may bind to the activating surface, and C3a which is released into the fluid phase (9). C3 convertase has the ability to cleave many C3 molecules. This could result in the deposition of a large number of C3b molecules on the activating surface. However, due to the labile nature of C3b, very few molecules actually bind. C4b2a3b, the C5 convertase, is formed when C3 is cleaved. C5 convertase, also an enzyme, can cleave many C5 molecules into C5a and C5b.
The alternative pathway provides natural, non-immune defense against microbial infections. In addition, this pathway amplifies antibody-antigen reactions.
Alternative path
REFERENCES:
Labarre et al., "Strategy for in vitro Evaluation of the Interactions Between Biomaterials and Complement System", J. Appl. Biomat., vol. 4, No. 3, pp. 231-240, 1993.
De Haan Jacob
Van Oeveren Willem
HaemoProbe B.V.
Weber Jon P.
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