In a newly formed wound, the natural fibrin network provides the first temporary matrix for tissue repair. Topical application of fibrin to a new wound may improve wound healing. A matrix of the common natural gamma ' fibrin variant may further improve wound healing because it is expected to have a different architecture and this will influence angiogenesis, because it possesses increased thrombin and factor XIII binding and decreased platelet binding, when compared with the common gamma A fibrin matrix. Our objective was to determine the effect of fibrinogen and its gamma A and gamma ' variants on angiogenesis and wound healing. We used in vitro angiogenesis models and an in vivo rat full-thickness excisional wound healing model. When comparing gamma A and gamma ' fibrin in vitro, more tube-like structures were formed on day 7 in gamma A fibrin than in gamma ' fibrin (13.83 +/- 6.12 AU vs. 6.1 +/- 1.46 AU). Wounds treated with fibrin demonstrated improved healing in vivo with more perfusion (47%+/- 3% vs. 26%+/- 4%, p<0.01 in placebo) and higher CD34 density score (2.0 +/- 0.4 vs. 2.8 +/- 0.1, p<0.01) on day 21 with fibrin matrices when compared with placebo-treated wounds. Increased perfusion was observed in gamma A fibrin-treated wounds on day 21 (53%+/- 10% vs. 41%+/- 7% for gamma ' fibrin). The other parameters showed slightly improved (not significant) wound healing with gamma A fibrin compared with gamma ' fibrin matrices. In conclusion, the use of fibrin and fibrin variant matrices offers an interesting methodology to stimulate the wound healing process.