The surgical management of coronal suture synostosis routinely involves the early extirpation of the synostosed coronal suture while brain mass growth is still rapid. Frequently, however, the suturectomy sites show rapid and extensive hyperstosis and eventual resynostosis. This refusion further restricts the growing brain, increases intracranial pressure, alters craniofacial growth, and requires additional and extensive surgical procedure to correct the subsequent problem which increases patient morbidity and mortality. Recent studies have shown that developmental changes in the expression of the carious transforming Growth Factor-beta (TGF- beta) isoforms are responsible, in part, for normal cranial vault suture formation, maintenance, and eventual fusion. Over-expression of TGF-beta1 has also been noted in humans and rabbits with familial, non-syndromic craniosynostosis, and has been implicated in the production of hyperostosis, leading to synostosis of the cranial vault sutures. Perinatal treatment that interferes with TGF-beta1 production and/or function may prevent post-surgical resynostosis, decrease intracranial pressure, improve craniofacial growth, and obviate multiple surgeries in the clinical management of neonates with various synostotic conditions. The present proposal is designed to test this hypothesis in a unique rabbit model of human familial, non-syndromic craniosynostosis. The proposed research will: 1) surgically extirpate the synostosed coronal suture in 40, 10 day old New Zealand White rabbits with familial, non-syndromic craniosynostosis; 2) treat the suturectomy site in ten synostosed rabbits with either a) anti-TGF-beta1 in a slow release (35 day) collagen past vehicle, b) anti-Iggamma in a slow release (35 day) collagen paste, which will serve as the antibody control group, c) the slow release (35 day) collagen paste vehicle only, which will serve as the vehicle control group, or d) leave the remaining ten synostosed rabbits with suturectomy untreated which will serve as the sham control group; 3) quantitatively assess intracranial pressure, cranial vault growth, coronal suturectomy site bone volume, intracranial volume, brain morphology, and cranial vault shape at 10, 25, 42 and 84 days of age using serial head radiographs and 3-D CT scan reconstructions; and 4) harvest the suturectomy sites from each group at 42 and 84 days of age for histological examination and quantify the extent of coronal suturectomy site resynostosis following the various experimental manipulations using histomorphometry from serial histological preparations. The ultimate goal of this study is to provide a biological basis for future cytokine therapy protocols designed to manipulate postoperative suturectomy site reossification, decrease intracranial pressure, and ameliorate craniofacial growth deformities in human infants with familial, non-syndromic craniosynostosis.
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