Physiologic Timeline of Cranial-Base Suture and Synchondrosis Closure.

BACKGROUND: Fusion of cranial-base sutures/synchondroses presents a clinical conundrum, given their often unclear "normal" timing of closure. This study investigates the physiologic fusion timelines of cranial-base sutures/synchondroses. METHODS: Twenty-three age intervals were analyzed in subjects aged 0 to 18 years. For each age interval, 10 head computed tomographic scans of healthy subjects were assessed. Thirteen cranial-base sutures/synchondroses were evaluated for patency. Partial closure in greater than or equal to 50 percent of subjects and complete bilateral closure in less than 50 percent of subjects defined the fusion "midpoint." Factor analysis identified clusters of related fusion patterns. RESULTS: Two hundred thirty scans met inclusion criteria. The sutures' fusion midpoints and completion ages, respectively, were as follows: frontoethmoidal, 0 to 2 months and 4 years; frontosphenoidal, 6 to 8 months and 12 years; and sphenoparietal, 6 to 8 months and 4 years. Sphenosquamosal, sphenopetrosal, parietosquamosal, and parietomastoid sutures reached the midpoint at 6 to 8 months, 8 years, 9 to 11 months, and 12 years, respectively, but rarely completed fusion. The occipitomastoid suture partially closed in less than or equal to 30 percent of subjects. The synchondroses' fusion midpoints and completion ages, respectively, were as follows: sphenoethmoidal, 3 to 5 months and 5 years; spheno-occipital, 9 years and 17 years; anterior intraoccipital, 4 years and 10 years; and posterior intraoccipital, 18 to 23 months and 4 years. The petro-occipital synchondrosis reached the midpoint at 11 years and completely fused in less than 50 percent of subjects. Order of fusion of the sutures, but not the synchondroses, followed the anterior-to-posterior direction. Factor analysis suggested three separate fusion patterns. CONCLUSIONS: The fusion timelines of cranial-base sutures/synchondroses may help providers interpret computed tomographic data of patients with head-shape abnormalities. Future work should elucidate the mechanisms and sequelae of cranial-base suture fusion that deviates from normal timelines.

Intravenous and Intra-amniotic In Utero Transplantation in the Murine Model.

In utero transplantation (IUT) is a unique and versatile mode of therapy that can be used to introduce stem cells, viral vectors, or any other substances early in the gestation. The rationale behind IUT for therapeutic purposes is based on the small size of the fetus, the fetal immunologic immaturity, the accessibility and proliferative nature of the fetal stem or progenitor cells, and the potential to treat a disease or the onset of symptoms prior to birth. Taking advantage of these normal developmental properties of the fetus, the delivery of hematopoietic stem cells (HSC) via an IUT has the potential to treat congenital hematologic disorders such as sickle cell disease, without the required myeloablative or immunosuppressive conditioning required for postnatal HSC transplants. Similarly, the accessibility of progenitor cells in multiple organs during development potentially allows for a more efficient targeting of stem/progenitor cells following an IUT of viral vectors for gene therapy or genome editing. Additionally, IUT can be used to study normal developmental processes including, but not limited to, the development of immunologic tolerance. The murine model provides a valuable and affordable means to understanding the potential and limitations of IUT prior to pre-clinical large animal studies and an eventual clinical application. Here, we describe a protocol for performing an IUT in the murine fetus through intravenous and intra-amniotic routes. This protocol has been used successfully to elucidate the necessary conditions and mechanisms behind in utero hematopoietic stem cell transplantation, tolerance induction, and in utero gene therapy.

Relaxin affects the dentofacial sutural tissues.

This is a report of an exploratory study of how the hormone relaxin might modulate the remodeling of connective tissue within the craniofacial sutures and periodontal tissues. Relaxin is a hormone that was discovered to be produced by the pregnant female. It is responsible for the relaxing of the pubic symphysis; the birth canal is widened for parturition. It has also been shown to have effects on other areas of the body, including ligaments and regions containing collagen and fibroblastic activity. Twenty-one Swiss retired-breeder mice were used to: 1) immunohistochemically demonstrate the presence of relaxin within the sutures; 2) demonstrate its effects on the integrity of the suture-like tissues; and 3) assay its effects on protease activity. Relaxin in concentrations of 250 and 500 ng/ml was used in the treated samples and allowed to incubate in complete tissue culture for 24 h. The results indicate the presence of relaxin within the cranial suture. Histological observations revealed definite changes in the collagen fibril arrangement in the PDL - from being dense and highly organized with a perpendicular direction between tooth and bone to randomly organized and loose, lacking any direction between tooth and bone. An elevation in the protease activity was evident in the relaxin-treated samples. This naturally occurring hormone might be used as an adjunct to orthodontic therapy as it appears to have the capacity to alter the physical properties of the connective tissue within sutures, gingival tissue, and the PDL. Potential indications for use include instances of sutural and soft tissue adaptation of orthopedic expansion in non-growing patients by a reduction in the tension of the stretched soft tissue envelope following orthognathic surgery (particularly the expanded palatal mucosa), periodontal ligament remodeling during or after tooth movement promoting stability, rapid gingival tissue remodeling during space closure in extraction sites, and by a decrease in the amount of scar tissue formation following frenectomies.