Fibrin gels and their clinical and bioengineering applications

Abstract

Fibrin gels, prepared from fibrinogen and thrombin, the key proteins involved in blood clotting, were among the first biomaterials used to prevent bleeding and promote wound healing. The unique polymerization mechanism of fibrin, which allows control of gelation times and network architecture by variation in reaction conditions, allows formation of a wide array of soft substrates under physiological conditions. Fibrin gels have been extensively studied rheologically in part because their nonlinear elasticity, characterized by soft compliance at small strains and impressive stiffening to resist larger deformations, appears essential for their function as haemostatic plugs and as matrices for cell migration and wound healing. The filaments forming a fibrin network are among the softest in nature, allowing them to deform to large extents and stiffen but not break. The biochemical and mechanical properties of fibrin have recently been exploited in numerous studies that suggest its potential for applications in medicine and bioengineering.

Figure 1

Scanning electron micrograph of 1 mg l⁻¹ human fibrinogen polymerized by 1 U ml⁻¹ thrombin at pH 7.4 and 150 mM NaCl. Full width of the figure is 62.5 μm.

Figure 2

(a–c) Schematic of the structure of fibrin monomers and their assembly into protofibrils.

Figure 3

Strain stiffening of fibrin gels under shear deformation. Dynamic shear storage moduli measured with a strain-controlled rheometer at different maximal strain amplitudes are shown for 6 mg ml⁻¹ human fibrinogen polymerized under coarse clotting conditions (filled circles), and for 5% polyacrylamide polymerized with ammonium persulphate and TEMED (open circles) by standard methods. Detailed methods are given in Storm et al. (2005).

Figure 4

Schematics for two different mechanisms of strain stiffening. (a) Semiflexible polymers linked at ends in network junctions lose configurational entropy as their end-to-end distances are increased or decreased from their resting lengths during shear deformation. Filaments with intrinsically nonlinear force elongation relationships resist more strongly when they are stretched more to the limit at which the end-to-end distance equals their contour length. Adapted from MacKintosh et al. (1995). (b) Stiff filaments deform initially by bending at small strains and then by stretching at larger strains when their end-to-end vectors align in the shear field. In this mode, fibres with linear force–extension relationships produce strain stiffening in networks owing to the geometrical changes as they align in shear. Adapted from Onck et al. (2005).