RGTA are chemically defined compounds which proved to be very potent healing agents in various tissue repair models including skin, muscle and nerve. These chemicals are believed to protect endogenously released heparin-binding growth factors and enhance their bioavailability during healing. In craniotomy defects that do not heal spontaneously in adults, RGTA promoted dose-dependent skull closure. The aim of this work was to characterize, in the same model, the events associated with wound closure by studying the expression of the osteoblastic phenotype and the distribution of some matrix proteins during RGTA11-induced bone healing. Craniotomy defects in rats were implanted with collagen plasters soaked in a solution of RGTA11 (1.5 micrograms per piece). The skulls were removed 30 days after wounding, a stage of almost complete bone filling in treated samples. Bone formed only at the edges of the defect in controls, while it formed also at the center in the form of nodules in the treated samples. RGTA11 modified the amount and distribution of the tissues including bone in the wounds. In some RGTA11-treated samples, skull closure by bone occurred and the median suture was restored. In the treated defects, alkaline phosphatase-positive (osteoprogenitor) cells were far more numerous and were distributed differently. Type I and III collagen and fibronectin deposition was markedly enhanced in the bone compartment of the wounds. Secretory osteoblasts released type III collagen. Osteocalcin expression was enhanced by RGTA11. RGTA11 thus modified the healing pattern by increasing both the cellularity and the synthesis of a bone-competent extracellular matrix, thereby restoring the original anatomy of the skull. Flat bone regeneration can be triggered in adults through developmental events (i.e. nodule formation, secretion of type III collagen by osteoblasts, suture restoration...) that are no longer operative in the wounds of mature individuals.