V6

• Transport of oxygen and nutrients

• Removal of waste products

• Exchange of messenger substances

• Immune system

• Regulation of body temperature

• Interactions with blood

  • Blood contacting devices have great differences concerning intensity, function and demand

  • Immediate exposure to all host defences

• Impact on body

  • Local effects

  • Incompatibility reactions also affect remote and vital organs

“Property of a material/device that permits it to function in contact with blood without inducing adverse (schädliche) reactions.“

—> Hemocompatibility is a prerequisite (Vorraussetzung) for materials/devices used in biomedical products

• Protein Adsorption

• Coagulation cascade

• Cell Adhesion

• Proteins are a major constituent of plasma

• Cell adhesion is mediated by protein adsorption

• The dynamics of protein adsorption are related to the chemical and physical properties of the surface and the proteins.

• Rapid adsorption of plasma proteins onto artificial surfaces is the initiating event in thrombus formation

  • Activation of coagulation cascade and the complement system

• Adhesive proteins: fibrinogen, von Willebrand factor (vWF)

• The coagulation cascade is a complex system responsible for the formation blood clots.

  • Activation of a series of clotting factors enumerated by roman numerals (I, II, V, etc.)

  • Each factor is an enzyme that speeds up the breakdown of another protein. Initially, each factor is an inactive form of the enzyme

  • When a clotting factor becomes activated, it is denoted with an “a” (Ia, IIa, Va, etc)

• Coagulation consists of three pathways, the extrinsic, intrinsic, and common pathways

• Extrinsic pathway: initiates when there is injury to the endothelial tissue

• Intrinsic pathway: initiates when blood is exposed to negatively charged surfaces leading to the activation complex of factor XII, high-molecular-weight kininogen, and prekallikrein.

• Adhesion of platelets and leukocytes leads to their activation

• Platelets:

  • Fibrinogen and vWF are the major proteins responsible for platelet adhesion

  • Platelet activation leads to the amplification of the coagulation cascade

• Leukocytes:

  • Adhesion via fibrinogen

  • Platelet adhesion also promotes leukocyte adhesion

  • Adhesion of leukozytes further promotes release of substances that enhance platelet activation and the activation of the coagulation cascade

• The complement system refers to a group of plasma proteins called the complement proteins, which are produced in the liver, and act collectively to help destroy pathogens.

• Complement proteins circulate in the blood in their inactive state

• In medical devices, the complement system is activated by the adsorption of proteins

  • For example, adsorption of antibodies

• Promotes the adhesion and activation of leukocytes

• Closely linked to the coagulation cascade • the activation of one, leads to the activation of the other

Complement activation:

• Considerable variation in shear stress within one device

  • Regions of high and low shear stresses depending on size, placement and geometric configuration

  • Bifurcations, joints/connection, expansions can lead to vorticity

• Hemodynamic conditions can vary depending on the patient’s actions

  • For example, shear and turbulence can increase drastically during exercise

• Immune system does not respond to biological materials

  • Ideally, implanted materials are non-immunogenic or „invisible“ to the body

• However, Non-biologic materials often exhibit:

  • Clotting

  • Foreign body reaction

—> The basis for these reactions and responses are the presence and adsorption of proteins to the surface of materials

—>Which proteins adsorb to the surface determine the nature of the response to these materials

• In reality, Langmuir isotherms are only applicable for a reversible adsorption processes

  • Protein adsorption to biomaterials is generally an irreversible process

• Isotherm data from protein adsorption studies often appear to fit well the Langmuir isotherm model

• Effects that explain the Langmuir-like adsorption:

  • “Spreading” of the proteins over the surface upon adsorption due to surface-induced unfolding and denaturation

  • Degree of spreading dependent of protein stability and protein-surface interactions

  • Displacement due to competitive adsorption of other proteins (Vroman effect)

• Protein adsorption is irreversible if no other proteins are present

• Proteins can replace each other at the surface

• Different proteins have different affinities for a surface:

  • Proteins with stronger affinity can displace proteins with a weaker affinity

• Residence time and conformational changes determine activation process

• Protein adsorption can only occur spontaneously (at constant pressure and temperature) if the Gibbs energy G of the system decreases.

• Any interaction leading to the reduction in the free enery state of the system will lead to protein adsorption

• Spontaneous dehydration and subsequent aggregation of non-polar components in an aqueous environment

• Contact between water molecules are much more favorable than contacts between non-polar groups or between a nonpolar group and water

—> Hydrophobic interaction is characterized by a large entropy increase

• Physiological solutions contain a high concentration of salt ions

• Dissociated ions complexate with charged groups in proteins and in material surfaces

• Interaction between protein and material lead to the displacement of counter ions to the bulk solution

• The entropy increase is the driving force for adsorption

• Negatively charged surfaces attract activated blood proteins which initiate the coagulation cascade.

• However, positively charged surfaces may also trigger coagulation.

  
  

—> Coagulation and complement activation are minimized at charge-neutral, strongly water-binding surfaces