Fibrous tissue consists of fibroblastic cells embedded in a hydrated extracellular matrix [Mow et al., Basic Orthopaedic Biomechanics, New York, Raven Press, 143-199 (1991)]. Fibroblasts are crucial to fibrous tissue histogenesis and maintenance [Hunziker (2000) Osteoarth. Cartil., 10:432-463]. Mature fibrous tissue only has a limited number of resident fibroblasts [Volk et al., (1999) Bone Miner. Res., 14:483-486].
There is overwhelming evidence that adult bone marrow contains mesenchymal stem cells (MSCs) that can differentiate into virtually all lineages of connective tissue cells such as osteogenic cells, chondrogenic cells, tenocytes, adipogenic cells, odontoblastic cells, etc. [Goldberg et al. (1994) Orthopedics, 17:819-821]. The MSCs' role in wound healing involves multiple phenotypic switches between fibrous, hyaline cartilage, fibro-cartilage, and bone [Einhorn (1998) Clin. Orthop., 355 Suppl., S7-S21]. The techniques of harvesting and culturing MSCs from bone marrow as well as inducing MSCs to differentiate into chondrogenic and osteogenic cell lineages in vitro and in vivo have been successful. [Alhadlaq et al. (2003) Ann. Biomed. Eng. 32(7): 911-923].
Cranial sutures are the soft connective tissues located between mineralized calvarial bones in the skull. These structures share the common feature of interosteal linkage; i.e., these fibrous tissues link bone to bone.
Cranial sutures permit the expansive growth of the brain and calvarial bones of the skull during childhood and adolescence [Enlow, (1999) In: Cohen M M Jr., MacLean R E (Eds.) Craniosynostosis: Diagnosis Evaluation and Management, New York: Raven Press. 131-156; and Mao (2002) J. Dent. Res., 81:810-816]. Cranial sutures are comprised of fibroblast-like cells derived from the neural crest [Pritchard et al (1956) J Anat 90:73-86]. Theses cells lie within a vascularization-rich matrix that is sandwiched between osteoblast-lined bone formation fronts [Opperman, (2000) Dev. Dyn., 219:472-485].
Craniosynostosis is the premature ossification and mineralization of sutures before cranial, facial, and brain growth is completed [Cohen (2000) In: Cohen M M Jr. (Ed.) Craniosynostosis: Diagnosis Evaluation and Management New York, Raven Press 81-103]. This congenital disorder arises in approximately one of every 2,500 live human births (Cohen, Ibid.). Craniosynostosis can manifest as visible craniofacial disfigurations and grossly elevated intracranial pressure leading to severe neurological disorders such as mental retardation, blindness, and seizures (Cohen, Ibid.).
At the present time, craniofacial surgery is the only alternative for correcting visible craniofacial disfigurations and relieving abnormally high intracranial pressure [Marsh (2000) In: Cohen and MacLean (Eds), Craniosynostosis: Diagnosis Evaluation and Management, Oxford University Press, New York, 292-308; Posnick, (2000) In: Cohen and MacLean (Eds), Craniosynostosis: Diagnosis Evaluation and Management, Oxford University Press, New York 269-291; and Tessier (2000) In: Cohen and MacLean (Eds Craniosynostosis: Diagnosis Evaluation and Management. Oxford University Press, New York, 228-268]. Surgeons typically perform craniotomy surgery in early childhood by physically dissecting the fused sutures in the skull and creating gaps of empirical sizes between involved calvarial bones with the hope that the surgically created gaps may accommodate all remaining brain growth and calvarial bone growth in the child (Marsh, 2000, Ibid.; and Tessier, 2000, Ibid.).
Due to the unpredictability of craniofacial growth from the time of the first surgical correction during infancy until growth completion during adolescence, surgically created gaps often re-synostose. Therefore, multiple additional surgeries may be needed to correct the re-synostosis. This problem occurs because the synostosed suture with missing fibrous interface was replaced by a surgically created gap still lacking sustainable fibrous component (Marsh, 2000, Ibid.; and Tessier, 2000, Ibid.).
Previous attempts at cranial suture transplantation have not been successful. For example, although surgical replacement of synostosed rabbit suture with an allogeneic suture graft including dura mater from the wild type rabbit permits post-operative sutural growth [Mooney et al. (2001) Cleft Palate Craniofac. J., 38:206-225]. However, this allogeneic suture transplantation approach necessitates creation of secondary bony defects, questionable donor availability and potential immune rejection when human applications are considered. Another effort to heal a surgically created defect involving the rat sagittal suture and adjacent bone by e-PEFE membrane with ruminants of suture-like structures [Marda et al. (2002) J. Craniofac. Surg., 13:453-462] suffered because it is believed that the observed suture-like structure in the defect originated from the remaining portion of the host sagittal suture. Lastly, although mechanical and chemical disturbances of surgically created calvarial defects involving at least one cranial suture lead to incomplete healing [Moss (1954) Am. J. Anat., 94:333-361] it does not appear to be a clinically applicable model because the surgically created bony gap in craniosynostosis patients should ideally be healed by the completion of craniofacial growth. As discussed hereinafter, the present invention can overcome many of these problems and can improve upon previous efforts of suture transplantation and delaying the rate of suture synostosis.