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Background The goal of cleft lip repair is a symmetrical balanced lip with minimal scar. Fat grafting is an established procedure in cosmetic and reconstructive surgery for restoration or correction of contour deformity, volume loss, and improved tissue characteristics. In this study, we evaluated the use of fat grafting in correction of cleft lip volume asymmetry. Methods We performed a retrospective analysis of our series of patients who underwent fat grafting using the Coleman technique for cleft lip volume asymmetry. Sex, age at primary repair, age at fat grafting, perioperative data, and preoperative and postoperative photographs were reviewed. Results A total of 52 children underwent fat grafting as secondary revision for both unilateral and bilateral cleft lip repair. Fat was hand suctioned from the abdominal or buttock region with a mean yield of 3.0 mL (range, 2.0-5.0 mL). An average total volume of 3.0 mL (range, 2.0-4.5 mL) of fat was injected via an intraoral incision into the philtrum, vermillion, and volume deficiencies in the vertical component of the lip for volume restoration. No complications were noted with fat harvest or with fat grafting. Mean follow-up was 48 months. Postoperative assessment revealed improved volume symmetry in all patients, and all patients or families were pleased with the results. Conclusions Fat grafting via an intraoral incision is a minimally invasive, safe, and reliable secondary procedure to improve volume asymmetries after cleft lip repairs.

In this study, the effect of pharmaceutical-grade alginates on the cell viability of human mesenchymal stem cells derived from umbilical cord was examined and their use in tissue engineering applications was evaluated. The effects of the ratio of the copolymer building blocks (guluronic and mannuronic acids) and their interactions with divalent calcium, the purity of alginates (proteins and polyphenol content), and gelation factors (calcium concentration and sol content) were examined. The high guluronic acid content in the alginates improved the viability of the human mesenchymal stem cells derived from umbilical cord and supported cell growth significantly. It was confirmed that the sol fraction of alginate reduced cell viability. Cells in the presence of alginate beads cross-linked with 50 and 100 mM calcium chloride showed maximum viability; the protein and polyphenol content of the alginates did not affect the viability of the human mesenchymal stem cells derived from umbilical cord, while the monomer ratio did have an obvious effect.

Multipotent stem cells derived from periodontal ligaments (PDLSC) and pulp of human exfoliated deciduous teeth (SHED) represent promising cell sources for bone regeneration. Recent studies have demonstrated that retinoic acid (RA) and dexamethasone (Dex) induce osteogenesis of postnatal stem cells. The objective of this study was to examine the effects of RA and Dex on the proliferation and osteogenic differentiation of SHED and PDLSC and to compare the osteogenic characteristics of SHED and PDLSC under RA treatment. SHED and PDLSC were treated with serum-free medium either alone or supplemented with RA or Dex for 21 days. The proliferation of SHED and PDLSC was significantly inhibited by both RA and Dex. RA significantly upregulated gene expression and the activity of alkaline phosphatase in SHED and PDLSC. Positive Alizarin red and von Kossa staining of calcium deposition was seen on the RA-treated SHED and PDLSC after 21 days of culture. The influences of RA on the osteogenic differentiation of SHED and PDLSC were significantly stronger than with Dex. Supplementation with insulin enhanced RA-induced osteogenic differentiation of SHED. Thus, RA is an effective inducer of osteogenic differentiation of SHED and PDLSC, whereas RA treatment in combination with insulin supplementation might be a better option for inducing osteogenic differentiation. Significantly higher cell proliferation of PDLSC results in greater calcium deposition after 3-week culture, suggesting that PDLSC is a better osteogenic stem cell source. This study provides valuable information for efficiently producing osteogenically differentiated SHED or PDLSC for in vivo bone regeneration.

Objective This report will discuss a new surgical technique for treating severe cases of macrocephaly in which the bony architecture is markedly distorted. The procedure relies on several novel surgical tools for its success that have not been previously applied to the treatment of this condition. It utilized the use of contraction osteogenesis devices, resorbable plating systems, and an age- and sex-matched computer-generated skull model, which was derived from a computed tomographic scan as a template for the new calvarium. Results In the case reported, combined use of these technologies allowed for the complete reconstruction of the calvarium down to the level of the cranial base to produce an appropriately sized skull. The skull model created a template onto which bony fragments could be placed and fixated into a normal shape using the resorbable plating system. The contraction osteogenesis devices then allowed for a slow, safe reduction of the hydrocephalus via a ventriculoperitoneal shunt over a period of several days. On completion of the contraction process, the devices served to fixate the calvarium to the cranial base during the period of bone healing. Conclusion The combination of these modalities represents a unique state-of-the-art method for the correction of severe macrocephaly without the risks of intracranial hemorrhage and provides a useful adjunct to the treatment of hydrocephalus.

Substantial evidence suggests that HOX homeobox genes regulate aspects of body development, including hair formation. We initially isolated the HOXB13 gene from human fetal skin in experiments designed to identify candidate genes that regulate scarless fetal wound healing. Although the HOX homeodomain proteins have been proposed to function as transcription factors, we have demonstrated previously that substantial fractions of the HOXB6 and HOXB4 proteins are localized to the cytoplasm throughout epidermal development. The purpose of the current study was to identify HOXB13 protein expression patterns in developing skin to elucidate potential mechanisms by which this protein might regulate aspects of tissue development and healing. HOXB13 protein expression was detected throughout the developing epidermis, with weaker signal observed in the early developing dermis. Epidermal HOXB13 signal was detected over the entire body surface, but surprisingly, essentially all of the signal was cytoplasmic in developing skin. Low-level HOXB13 protein expression was detected in adult skin and within the telogen hair follicle, and a portion of the residual signal in adult epidermis was nuclear. Expression in hyperproliferative skin conditions remained cytoplasmic with the exception of epidermis associated with Kaposi's sarcoma, which showed strong HOXB13 expression that was partially localized to the nucleus.

A long-term follow-up study of patients who underwent bilateral mandibular distraction is presented, and the results of patients with Treacher Collins syndrome and Nager syndrome are compared with results for other forms of congenital micrognathia. It was hypothesized that the factors responsible for the predetermined, syndrome-specific shape of the mandible in patients with Treacher Collins and Nager syndromes would alter the long-term results of linear (uniplanar) distraction of the mandible. Thus, over time, the mandibles would remodel to preoperative form while maintaining the increase in volume. To investigate this hypothesis, all patients treated with bilateral mandibular distraction who had at least 1.5 years of follow-up, including satisfactory cephalometric examinations, were retrospectively reviewed. Two groups were identified. Group 1 (n = 6) were Treacher Collins and Nager syndrome patients (ages, 2 to 13 years; mean, 5.2 years) and group 2 (n = 6) included other forms of bilateral, congenital micrognathia (ages, 1.5 to 19 years; mean, 8.4 years). Serial cephalometric measurements were recorded before distraction, after distraction, and at least 18 months after distraction. Mandibular mean linear distraction distance (as recorded on the device) averaged 24.5 mm in group 1 and 26.2 mm in group 2. In group 1, the antegonial angle (angle from the mandibular plane to the top of the antegonial notch) decreased after distraction by 3.8 degrees, and the antegonial notch height was reduced by 1.6 mm. The posttreatment morphologic change was modified significantly over time, with a 3.7-degree increase of the antegonial angle and a 1.2-mm deepening of the antegonial notch. In group 2, the immediate reduction in height of the antegonial notching was subtler; however, long-term recurrence of the antegonial notching was also observed. At the end of distraction, the mean group 1 gonial angle became 8 degrees more obtuse. In contrast, patients in group 2 developed a more acute angle (mean, 8 degrees). The mandibles of the Treacher Collins syndrome patients (group 1) maintained their more obtuse postdistraction gonial angle during the period of follow-up, whereas over time this change was reversed in group 2 patients. In conclusion, experience with bilateral mandibular distraction has demonstrated that long-term determination of mandibular form is more complex than either the amount of distraction or the direction of the distraction vector. The underlying genotype and the musculoskeletal milieu must be taken into account when planning distraction, as these factors tend to remodel the mandible into its preoperative shape over time, despite the fact that the increased mandibular volume and projection are maintained.

The HOX homeodomain proteins are fundamental regulators of organ and tissue development, where they are thought to function as transcription factors, and HOX gene expression has been associated with numerous types of cancers. Previous studies have demonstrated that enforced expression of the HOXB4 protein transforms cultured fibroblasts and leads to a selective expansion of the hematopoietic stem cell pool, suggesting that this protein might play a role in cellular proliferation. In support of this concept, we now show that enforced expression of HOXB4 in human neonatal keratinocytes results in increased cellular proliferation and colony formation as well as decreased expression of the alpha-2-integrin and CD44 cell surface adhesion molecules. We previously have reported HOXB4 gene expression in the basal and suprabasal layers of developing human skin and now show extensive HOXB4 mRNA in psoriatic skin and basal cell carcinoma. In fetal human skin HOXB4 protein expression was both nuclear and cytoplasmic within epidermal basal cells and in hair follicle inner and outer root sheath cells, whereas strong nuclear signals were observed in the bulge region. In adult skin, HOXB4 protein expression was both nuclear and cytoplasmic, but was predominantly localized to the intermediate and differentiated cell layers. In contrast to the striking gradient patterns of HOX gene and protein expression previously described in developing spinal cord and limb, HOXB4 protein was uniformly detected in all regions of the fetal and adult skin. Although little HOXB4 signal localized to proliferative cell layers, as marked by proliferating cell nuclear antigen (PCNA) staining, in normal adult epidermis, nuclear HOXB4 protein expression substantially overlapped with PCNA-positive cell in a series of samples of hyperproliferative skin. Taken together, these data suggest that nuclear HOXB4 protein may play a role in the regulation of cellular proliferation/adhesion in developing fetal human epidermis and in hyperproliferation conditions, including cancers, in adult epidermis. Published 2002 Wiley-Liss, Inc.

Distraction osteogenesis has evolved as a mainstream surgical technique for lengthening and augmentation of the hypoplastic mandible. As clinical experience accumulated, there developed the need to "mold" the bony regenerate to avoid the development of postdistraction malocclusion and to achieve the desired craniofacial form. Although the potential to mold the regenerate has important clinical implications, the safety and efficacy of such an acute manipulation of the bony regenerate form have not yet been investigated in the laboratory. The purpose of this study was to determine if the distraction regenerate could be molded and result in a bony union. Four adult female dogs underwent bilateral mandibular distraction with an external multiplanar device (Stryker, Osteonics). After a latency period of 5 days, the mandibles underwent linear (anteroposterior) and angular (superoinferior) distraction to produce an anterior open bite of approximately 30 degrees. At the conclusion of the distraction procedure, the distraction sites were molded to close the open bite. In two dogs, the maneuver was performed over 3 days by changing the angulation of the devices (gradual molding), and in the other two dogs, molding was achieved with a single movement (acute molding). In the latter, the distraction devices were adjusted and reapplied to allow for anatomical fixation during the consolidation period of 49 days. According to the research protocol, the mandibles were assessed serially by cephalograms and computed tomography (CT) scans. All dogs survived the study without complications. The bony regenerate was easily molded in both groups to close the surgically created open bite. After molding, all the regenerates showed CT scan evidence of solid bone (consolidation), which was classified as "extended" on the Hamanishi scale. After the dogs were killed and soft tissue was removed, the regenerate seemed to be robust on gross examination without any evidence of fibrous nonunion. In addition, histological study of the regenerate confirmed the bony union. The study demonstrates that the mandible can be successfully molded into a desired anatomical position immediately after distraction without producing a fibrous union. Furthermore, it has been demonstrated that the bony regenerate is sufficiently malleable before consolidation to undergo either acute or gradual angular molding without disturbing osteogenic potential. The ability to mold the regenerate without the fear of creating a fibrous union or destroying bony potential provides the surgeon the capability to optimize the dental occlusion and mandibular form as part of the distraction treatment process.

Costochondral grafting for reconstruction of the Pruzansky type III mandible has given variable results. Lengthening of the rib graft by means of distraction had been advocated when subsequent growth of the grafted mandible is inadequate. This retrospective study reviews a series of patients with mandibular costochondral grafts who underwent subsequent distraction osteogenesis of the graft. A retrospective review identified two patient groups: group 1 consisted of individuals (n = 9) who underwent costochondral rib grafting of the mandible followed by distraction osteogenesis several months later at a rate of 1 mm/day. Group 2 consisted of patients with Pruzansky type II mandibles who had distraction osteogenesis without prior rib grafting (n = 9). The biomechanical parameters, orthodontic treatment regimens, and complications were examined versus patient age and quality of the rib graft. Distraction osteogenesis was successfully performed in six of the rib graft patients (group 1) and in all of the group 2 individuals. On the basis of the Haminishi scale, the computed tomographic scan appearance of the regenerate was classified as "standard or external" in six of the group 1 patients and as either "agenetic" or "pillar" (fibrous union) in the remaining three patients. In group 1, the average device was expanded 23 mm (range, 20 to 30 mm). Group 2 mandibular distraction results were all classified as either standard or external, and there was an average device expansion of 22.4 mm (range, 16 to 30 mm). The length of consolidation averaged 12.6 weeks in group 1, compared with 8.5 weeks in the traditional mandibular distraction patients (group 2). The mean shift of the dental midline to the contralateral side was 2.5 mm in group 1 versus 4.0 mm in group 2. Complex multiplanar and transport distractions were successfully performed on grafts of adequate bony volume. All four patients in group 1 with tracheostomies were successfully decannulated after consolidation. Rib graft distraction complications included pin tract infections in two patients, hardware failure with premature pin pullout in one patient, and evidence of fibrous nonunions in three young patients with single, diminutive rib grafts. In group 2, there were no distraction failures. Distraction osteogenesis can be successfully performed on costochondral rib grafts of the mandible; however, the complication rate is higher than in non-rib-graft patients. Performing the technique on older, more cooperative individuals seems to reduce this risk. In addition, placement of a double rib graft or an iliac bone graft of sufficient volume to create a neomandible with greater bone stock is an absolute requirement to decrease the risk of fibrous nonunion and provide a bone base of sufficient size for retention of the distraction device and manipulation of the regenerate.

Hyponatremia after cranial vault remodeling has been noted in a pediatric patient population. If left untreated, the patients may develop a clinical hypoosmotic condition that can lead to cerebral edema, increased intracranial pressure, and eventually, to central nervous system and circulatory compromise. The hyponatremia has traditionally been attributed to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH); however, in our patients the treatment has been resuscitation with normal saline as opposed to fluid restriction (the accepted treatment of SIADH), thus placing the diagnosis of SIADH in question. Patients who developed hyponatremia after intracranial injury or surgery were, until recently, grouped together as having SIADH. However, there are diagnosis and treatment differences between SIADH and another distinct but poorly understood disorder that is designated cerebral salt wasting syndrome (CSW). CSW is associated with increased urine output and increased urine sodium concentration and volume contraction, and it is frequently seen after a central nervous system trauma. We therefore developed a prospective study to evaluate the cause of the sodium imbalance.Ten consecutive pediatric patients who underwent intracranial surgery for various craniosynostotic disorders were postoperatively monitored in the pediatric intensive care unit for hemodynamic, respiratory, and fluid management. The first four patients were evaluated for electrolyte changes and overall fluid balance to determine the consistency with which these changes occurred. The remaining six patients had daily (including preoperative) measurement of serum electrolytes, urine electrolytes, urine osmolarity, serum antidiuretic hormone (ADH), aldosterone, and atrial natriuretic hormone (ANH). All patients received normal saline intravenous replacement fluid in the postoperative period. All of the patients developed a transient hyponatremia postoperatively, despite normal saline resuscitation. Serum sodium levels as low as 128 to 133 mEq per liter (normal, 137 to 145 mEq per liter) were documented in the patients. All patients had increased urine outputs through the fourth postoperative day (>1 cc/kg/h). The six patients who were measured had an increased ANH level, with a peak value as high as 277 pg/ml (normal, 25 to 77 pg/ml). ADH levels were low or normal in all but one patient, who had a marked increase in ADH and ANH. Aldosterone levels were variable. On the basis of these results, all but one patient showed evidence of CSW characterized by increased urine output, normal or increased urine sodium, low serum sodium, and increased ANH levels. The other patient had similar clinical findings consistent with CSW but also had an increase in ADH, thus giving a mixed laboratory picture of SIADH and CSW. The association of CSW to cranial vault remodeling has previously been ignored. This study should prompt reevaluation of the broad grouping of SIADH as the cause of all hyponatremic episodes in our postoperative patient population. An etiologic role has been given to ANH and to other, as yet undiscovered, central nervous system natriuretic factors. All of the patients studied required normal saline resuscitation, a treatment approach that is contrary to the usual management of SIADH. These findings should dictate a change in the postoperative care for these patients. After cranial vault remodeling, patients should prophylactically receive normal saline, rather than a more hypotonic solution, to avoid sodium balance problems.

Transverse mandibular distraction osteogenesis involves moving the osteotomized segments of the mandible in either a varus or valgus direction. This maneuver allows for widening of the bigonial distance or for a lateral shift of an asymmetric mandibular midline. During this process, a significant amount of torque is placed on the mandibular condyles, because they act as the pivot point for the mandibular translation. Although standard linear distraction osteogenesis induces transient, reversible changes in the temporomandibular joint, it is not known what effect the varus and valgus stresses of transverse distraction have on the temporomandibular joint. We therefore designed a study to document the temporomandibular joint changes following various degrees of transverse distraction. Bilateral transverse mandibular distraction was performed on 10 adult, female mongrel dogs using an external, multiplanar mandibular distraction device. The distraction protocol was as follows: (1) complete osteotomy at the angle of the mandible, (2) 5-day latency period, (3) distraction rate of 1 mm/day, (4) rhythm of one turn per day, (5) linear activation 16 to 30 mm bilaterally, and (6) 8-week consolidation period. A variety of varus and valgus distraction vectors were applied to the mandible only after 10 mm of initial linear distraction had been achieved. Posteroanterior and lateral cephalograms were performed throughout the entire process. Pre-distraction and post-consolidation computed tomographic scans were also performed. Changes in mandibular conformation, axis of rotation, temporomandibular joint structure, and glenoid fossa changes were directly assessed by evaluating the postmortem craniofacial skeleton. The findings were compared with those of normal, age-matched mongrel dog skulls. Significant remodeling changes were observed in the temporomandibular joints of all animals involved in the study. The mandibular condyles demonstrated varying degrees of flattening and erosion at all contact points with the craniofacial skeleton. In some cases, the condyle became part of the distraction regenerate process and was hypertrophied in all dimensions. The condyles were frequently displaced out of the glenoid fossa, particularly on the side in the direction of varus distraction. When the latter occurred, a new fossa was created on the undersurface of the zygomatic arch. Varying degrees of mandibular rotation in the sagittal plane were also observed, which led to abnormal torquing of the condyles in the coronal plane, depending on whether the axis of rotation occurred primarily around the condyle or around the distraction regenerate zone.In conclusion, transverse mandibular distraction is an effective means of producing a varus or valgus shift in the gonion relative to the midsagittal plane. However, unlike linear or angular mandibular distraction, transverse distraction has a multitude of nontransient effects on the temporomandibular joint. Therefore it must be emphasized that in clinical practice, transverse distraction should be used cautiously. One must also be aware that such a maneuver in distraction can have negative effects on the temporomandibular joint.

The human fetus is capable of healing cutaneous wounds without scar up to the third trimester of development This process of tissue repair is more akin to newt limb regeneration than classic adult scar forming wound repair. Regeneration of the newt limb is dependent on neural input in its early stages. This study was an attempt to determine whether a similar dependence on neural input exists for mammalian fetal wounds to heal without scar. The left hind limb of six fetal lambs was denervated during the early second trimester of development (day 55; term = 145 days). Two weeks after denervation, the animals were again exposed to create bilateral incisional and 6-mm-diameter excisional wounds on their innervated right and denervated left lower extremities. Five days after creation of these defects, the wounds were examined for alterations in repair. Four fetal lambs survived, and three were suitable for evaluation. There were marked alterations in wound healing seen after denervation. Excisional wounds on the innervated side contracted and decreased their surface area by 14 percent. In contrast, the denervated wounds not only failed to contract, but increased in size by 60 percent. Changes in the incisional wounds were equally distinctive. Innervated incisional wounds healed completely without scar and had a wound breaking strength comparable to that of normal skin (Table I). In contrast, two of the three denervated incisional wounds dehisced and failed to heal, even in the regions where the skin was approximated by suture. The third denervated incisional wound did heal but with a significant amount of scar. Electron microscopy confirmed this finding by clearly demonstrating thickened and irregular collagen deposition in the extracellular matrix of all the denervated incisional specimens. In summary, like the regenerating newt limb, scarless fetal skin wound repair requires neural stimulation for tissue regeneration to occur. Therefore, in the mammal, the primary regulator for this unique type of tissue repair may have a central neural, rather than a local, tissue origin.

The purpose of this study was to develop a methodology to quantify osseous, ocular, and periocular fat changes caused by correction of orbital hypertelorism to test the hypothesis that there is a quantitatively predictable relationship between the movement of the osseous orbit and that of the ocular globe. A retrospective review was performed of 10 patients who were status post unilateral or bilateral transcranial medial orbital translocation, for whom there were archival digital data for preoperative and postoperative (mean interval = 30 months) three-dimensional computed tomographic (CT) scans. In addition to standard demographic and surgical data, the clinical preoperative and postoperative interpupillary and intermedial canthal distances were recorded. By using a computer graphics workstation, the CT digital data were registered to four surgically unaltered anatomic fiducial points to allow longitudinal quantitative comparisons. The following three-dimensional measurements were made for each patient preoperatively and postoperatively: interdacryon and interocular centroid distances, and on a standard series of three horizontal and two vertical planes, the position of the medial and lateral orbital walls, and the thickness of the medial and lateral periorbital fat (20 orbits). CT digital distances were compared with similar clinical distances when possible. The age at operation ranged from 4.0 to 12.5 years (mean, 6.6 years). The reduction in interdacryon distance exceeded the reduction in intercentroid distance (mean interdacryon change = -5.3 mm versus mean intercentroid change = -2.7 mm). Although there was a strong correlation between the amount of reduction of the lateral orbital wall and intercentroid distances, there was only a moderate correlation between the reduction in the intercentroid distance and that of the medial orbital wall. Similarly, there was a moderate correlation between the decrease in thickness of the lateral periorbital fat and the reduction of intercentroid distance but not of the medial orbital fat. In conclusion, medial translocation of the orbit does not produce equivalent movement of the ocular globe; neither the intermedial canthal nor the interdacryon distance is a useful predictor of ocular centroid position; and if the goal of hypertelorism operation is reduction of interocular distance, then CT measurement of globe intercentroid distance is essential for outcome assessment.

Mandibular distraction has been performed at the authors' institution for the past 10 years on a variety of craniofacial anomalies. This article reviews the experience with distraction and outlines the authors' treatment algorithms based on patient age and pathology. The roles of distraction versus conventional orthognathic surgery are reviewed. The need for preoperative surgical planning and postoperative orthodontic therapy is emphasized.

Objective The purpose of this study was to determine if endoscopic techniques could be used to repair an epithelialized lip cleft with accuracy and with an outcome comparable to fetuses treated through an open hysterotomy. Interventions and Results In contrast to previous open fetal cleft lip repairs in the same model, none of the five fetuses reported here had a good aesthetic result. Although there was no evidence of scar histologically, the edges of the lip were poorly approximated. The epithelial lining and underlying dermis of the wound margins were notably inverted. The orbicularis oris muscle, which had been reapproximated, appeared thin and hypoplastic. Most of the vermilion elements were poorly aligned, and in one animal, there was a complete dehiscence of the repair. Conclusions In a more representative model of cleft lip that is not an acute lip wound, in utero endoscopic suture repair of the ovine lip gave a poor result using current technology. Only a meticulously performed, multilayered, open repair of a cleft appears to give a good cosmetic and functional outcome. Further studies to improve the endoscopic repair as our technology advances are therefore warranted.

Several animal models have been designed in the past to analyze the pathophysiology and management of craniosynostosis, very few of which were intrauterine. Those that were interuterine had problems with either a short gestation or limited availability that prevented most researchers from using them in treatment analysis. We desired to create a biologically sound intrauterine model of craniosynostosis, using an animal with a long gestation and an early calvarial bone formation, which was easy to manipulate in utero, that could be created by any researcher studying this disorder. Using biologic data available regarding growth factors thought to be involved in bone growth and cranial suture closure, we developed a new in utero fetal lamb model for the study of craniosynostosis. Ten 70-day gestation fetal lambs (term gestation 140 days) received a midline coronal incision to expose both coronal sutures. The entire right coronal suture was then excised along with a 4-mm bony margin. In each animal, the site was packed with 25 mg of demineralized sheep bone powder augmented with 50 microg of bone morphogenetic protein-2 (BMP-2) and 1 microg of poly-transforming growth factor-beta. The scalp was closed, and the sheep were returned to the uterus until either 90 or 140 days of gestation. Complete fusion of the right coronal suture occurred in all fetuses by 90 days gestation. In every animal, right-sided frontal bone flattening and supraorbital rim elevation were evident. Histologic analysis showed bony synostosis at the suture site without evidence of suture regeneration. By 140 days, this isolated suture fusion led to marked craniofacial abnormalities including right supraorbital rim elevation, significant frontal bone flattening, a decrease in the anterior-posterior length of the cranial vault, and flattening of the cranial base. In conclusion, we have developed a new model for the study of the secondary effects induced by the process of cranial suture fusion, which produces abnormalities seen in naturally occurring cases of isolated right coronal suture synostosis. In addition, this model confirms that isolated coronal suture fusion alone can lead to the multiple cranial and facial abnormalities seen with this disorder, even in the absence of associated cranial base suture fusions.

The spatial and temporal deployment of HOX homeobox genes along the spinal axis and in limb buds during fetal development is a key program in embryonic pattern formation. Although we have previously reported that several of the HOX homeobox genes are expressed during murine skin development, there is no information about developmental expression of HOX genes in human skin. We have now used reverse transcriptase polymerase chain reaction, in conjunction with a set of degenerate oligonucleotide primers, to identify a subset of HOX genes that are expressed during human fetal skin development. In situ hybridization analyses demonstrated that there were temporal and spatial shifts in expression of these genes. Strong HOXA4 expression was detected in the basal cell layers of 10 wk fetal epidermis and throughout the epidermis and dermis of 17 wk skin, whereas weak signal was present in the granular layer of newborn and adult skin. The expression patterns of HOXA5 and HOXA7 were similar, but their expression was weaker. In situ hybridization analysis also revealed strong HOXC4 and weaker HOXB7 expression throughout fetal development, whereas HOXB4 was expressed at barely detectable levels. Differential HOX gene expression was also observed in developing hair follicles, and sebaceous and sweat glands. None of the HOX genes examined were detected in the adult dermis.

Several case reports have demonstrated that microplates migrate intracranially when used in the reconstruction of the neonatal craniofacial skeleton. We conducted a study to analyze the validity of this finding, to calculate the rate of intracranial plate migration, and to compare the migration of microplates to standard surgical wire. We hypothesized that, because of constant bone generation and resorption in the developing cranial skeleton, both microplates and wires would migrate and resorption in the developing cranial skeleton, both microplates and wires would migrate intracranially. Bilateral supraorbital osteotomies were performed in five 6-week-old Yucatan minipigs. The right side was repaired by fixating the bone segment with 32-gauge stainless steel wire. The left side was fixed with two microplates (Leibinger Corp, Dallas, TX). The pigs were monitored for 6 months. During this time each pig was injected with a fluorescent bone dye on the first day of each month. One pig was killed at 3 months and used for midpoint comparison. We found that both microplates and wires migrated intracranially in these neonatal pigs. None of the plates or wires penetrated the dura, but several pieces of hardware from each group migrated far enough to rest directly on the dural surface. The rate of plate and wire migration also varied slightly among animals, but the mean rate remained relatively constant at 0.91 mm/month. Computed tomographic scans and morphometric analysis revealed no significant difference between the fracture healing and facial growth of the microplate and wire sides. We conclude that the biology of bone deposition in the calvarium causes any stationary foreign body on the surface of the skull to migrate intracranially in the neonate.

In order to identify homeobox genes which may regulate skin development and possibly mediate scarless fetal wound healing we have screened amplified human fetal skin cDNAs by polymerase chain reaction (PCR) using degenerate oligonucleotide primers designed against highly conserved regions within the homeobox. We identified three non-HOX homeobox genes, MSX-1, MSX-2, and MOX-1, which were differentially expressed in fetal and adult human skin. MSX-1 and MSX-2 were detected in the epidermis, hair follicles, and fibroblasts of the developing fetal skin by in situ hybridization. In contrast, MSX-1 and MSX-2 expression in adult skin was confined to epithelially derived structures. Immunohistochemical analysis of these two genes suggested that their respective homeoproteins may be differentially regulated. While Msx-1 was detected in the cell nucleus of both fetal and adult skin; Msx-2 was detected as a diffuse cytoplasmic signal in fetal epidermis and portions of the hair follicle and dermis, but was localized to the nucleus in adult epidermis. MOX-1 was expressed in a pattern similar to MSX early in gestation but then was restricted exclusively to follicular cells in the innermost layer of the outer root sheath by 21 weeks of development. Furthermore, MOX-1 expression was completely absent in adult cutaneous tissue. These data imply that each of these homeobox genes plays a specific role in skin development.

We have developed a new in vivo model for the study of fetal wound healing. Fetal ICR mice (total gestation, 21 days) received a full-thickness incisional wound in the hind limb at gestational day 14 (N = 100). The wound was made with a 28.5-gauge needle that was passed transplacentally into the amniotic cavity. The wounds were analyzed histologically on postoperative days 0, 1, 3, and 5 by hematoxylin-eosin and Mallory's trichrome stains. Once the wounding technique was mastered, the overall mortality rate for this model was 20% by postwounding day 5. Each fetus healed their wound without scar by postwounding day 3. In 3 animals, 5 microliters of human transforming growth factor beta 1 (25 micrograms per microliter) was injected into the wound site, resulting in scar and an inflammatory cell infiltrate, indicating that the 14-day-gestation fetal mouse can be manipulated if necessary. This model offers the advantages of an in vivo system that can be studied at an early gestational age. Furthermore, it is inexpensive, easy to manipulate, and can be studied with commercially available murine probes.

This study was designed to evaluate hydroxyapatite paste (BoneSource; Leibinger Corp., Dallas, TX) as an alloplastic implant for supraorbital and malar augmentation. Ten male Sprague-Dawley rats had cylindrical onlay implants made of the hydroxyapatite cement placed above their left orbits on the supraorbital rim. Size-matched Medpor implants were placed similarly on the right side. To test the utility of this new material in the midface, hydroxyapatite paste and Medpor implants were also placed in the right malar regions of a different set of rats. The implants were left in situ for 6 months and examined for evidence of bone ingrowth, infection, migration, resorption, and detrimental effects on the surrounding tissue. All hydroxyapatite cement implants provided excellent soft tissue projection and demonstrated steadfast adherence to the adjacent bone. The surface of the hydroxyapatite implant in contact with the native bone demonstrated evidence of native bony ingrowth into approximately 12% of the implant. There was no evidence of implant migration or gross infection. There was no bony resorption below the hydroxyapatite paste, but four of the Medpor implants showed evidence of this in the underlying bone. Only one negative aspect to the use of hydroxyapatite cement paste as an onlay implant was identified. Two of the supraorbital and one of the malar hydroxyapatite implants had approximately 20 to 25% volume loss during the experimental period (P = 0.05). Overall, the vast majority of the implants retained their original form. We concluded that hydroxyapatite paste may possibly be used to effectively augment bone in the supraorbital and malar regions. Its biocompatibility, excellent bony adherence, and tendency to be replaced by natural bone may make it suitable for the aesthetic patient. The possible resorptive aspects of the material need to be evaluated further.

The present study was designed to assess the utility and validity of standard prenatal ultrasonography in identifying individuals with coronal suture synostosis by examining sutural abnormalities before the development of secondary craniofacial dysmorphologies. An Accusson 128 XP ultrasound machine was used to scan the coronal sutures of 31 twenty-five-day-old fetuses (term = 31 days) from four timed-pregnant New Zealand White rabbits with simple, nonsyndromic craniosynostosis. Each mother was sedated with general anesthesia, and the gravid uterine horns were exposed via a laparotomy procedure. The fetal calvariae were examined using a no. 7 transducer at 7.0 mHz. Each coronal suture was scanned using ultrasonography by first identifying bregma (the anterior fontanelle) at the intersection of the sagittal, interfrontal, and coronal sutures and then following the coronal sutures laterally. Seventeen of the 31 fetuses were diagnosed with unilateral or bilateral coronal suture fusion. In fetuses with synostosis, the suture was echolucent and patent in the midline but then rapidly tapered off to fused bone as it progressed laterally. This finding is in accordance with the natural history of the synostotic foci and coronal suture fusion progression in these rabbits. In addition, the sagittal and interfrontal sutures in each synostotic rabbit appeared wider along their course compared with normal. This reflects early enhanced compensatory transverse growth resulting from the anteroposterior growth restrictions from coronal suture fusion. No other cranial shape abnormalities were recognizable at this stage of fetal development. The validity of the ultrasound diagnoses was tested by direct ex utero inspection of 9 of the 17 synostotic fetuses. Gross morphological examination showed that 8 of 9 rabbit fetuses (89%) had fused coronal sutures. Statistical analysis revealed no significant difference (chi 2 = 0.22, P > 0.05) between the diagnostic accuracy of standard ultrasonography and direct examination. In conclusion, we have shown that standard ultrasonography of the calvarial sutures, in the absence of other craniofacial malformations, may be a feasible method of diagnosing simple, nonsyndromic craniosynostosis in utero, a condition that is typically missed during routine prenatal ultrasonic screening examinations.

A new method has been developed for the closed reduction of minimally displaced, noncomminuted zygomatic arch fractures that is minimally invasive and precludes the use of nonresorbable materials such as plates and wires in the repair. Twenty rats received simple, minimally displaced right-sided zygomatic arch fractures under general anesthesia. In 10 animals these fractures were treated with closed reduction through a temporal approach (Gillies method) to reapproximate the fractured segments. In the second group of 10, immediately after the closed fracture reduction, 1 ml of hydroxyapatite cement paste (BoneSource, Leibinger Corp., Dallas, TX) was injected through a 14-gauge needle into and around the fracture site. This paste, which is remodeled into bone over time, hardens into a plaster-like substance within 20 minutes of mixing. The majority of the paste was placed on the medial aspect of the fracture to act as a buttress between the fractured zygoma and the temporalis muscle lying on the greater wing of the sphenoid. This served to support the fracture by "casting" the bone and preventing it from collapsing medially. Nine of the 10 fractures treated with the hydroxyapatite paste healed completely without evidence of zygomatic displacement or malunion. One fracture had mild displacement of the fractured segment but good bone healing between the fractured sides. No adverse effects were noted in the temporalis muscle of these animals, and mastication was normal. Five of the 10 treated with closed reduction alone also had a good result. Of the remaining 5 fractures 2 had a mild to moderate bony deformity as a result of improper alignment during fracture healing. The other 3 did not heal and, therefore, formed a fibrous nonunion at the fracture site. We concluded that closed reduction of simple zygomatic fractures can be performed if the fracture site is held in place with a stabilizing material such as a hydroxyapatite cement paste.

Background: Cardiac procedures in exteriorized fetuses or assisted by fetoscopy require monitoring capabilities not attended by conventional maternal transabdominal echocardiography.

The chronic pain syndrome encompassed by the term RSD is poorly understood. The confusion is caused in large part by frequent misdiagnosis and excessive use of sympatholytic procedures in inappropriate circumstances. Recently, pain specialists have redefined the specific criteria for regional pain syndromes having sympathetic maintaining factors, emphasizing application of placebo testing in diagnosis and attention to anatomic principles in pharmacologic and surgical treatment. The authors believe that three-phase bone scanning is a valuable adjunct to clinical judgment in making the proper diagnosis. Current thinking suggests that sympathetic maintained pain exists but that it may comprise only approximately 10% of regional pain cases. Once the appropriate diagnosis is made, classically described sympatholytic procedures are reasonably used. Alternative techniques, such as spinal cord stimulation, may have an important role in refractory cases of sympathetically maintained pain.

Fetal transesophageal and intracardiac echocardiography by utilizing ultrasound technology permits accurate definition of cardiac anatomy in fetal sheep. Because fetal transesophageal echocardiography is less invasive than intracardiac echocardiography, it has the potential to serve as a monitoring tool for currently developed open and fetoscopic fetal cardiac interventions.

A case of ocular duplication with complex craniofacial and central nervous system anomalies is described. The anomaly is termed triopia because the child's most overt and distinguishing feature was three eyes: the left orbit contained two globes with independent ocular adnexa; the right orbit contained one normal appearing and functioning globe. Computer assisted medical imaging was used to define, in vivo, the intra- and extracranial soft and hard tissue anomalies: the cerebral hemisphere ipsilateral to the ocular duplication was also duplicated. Possible bases for this anomaly include duplication of primordia for the eye and secondary prosencephalon.

Fracture fixation using adhesive is a promising alternative in craniofacial surgeries, replacing the plates and screws system. The advantages include the ease of application and avoidance of drilling holes that may weaken the bone and cause fractures. In this study the bond strengths of selected adhesives were evaluated and compared with resorbable plates and screws. Four adhesives, octyl-cyanoacrylate, N-butyl-cyanoacrylate, a novel methyl-methacrylate, and a novel cyanoacrylate derivative, were tested for their microtensile and shear bond strengths. The bone samples were cut into rectangular bars and bonded with selected adhesives for microtensile testing. For the shear bond test, paired bars were bonded at the overlap, while two other sets of bars were attached by a Lactosorb plate using either adhesive or screws. Data were analysed by analysis of variance (ANOVA). The microtensile bond strengths of N-butyl-cyanoacrylate, novel cyanoacrylate derivative, and novel methyl-methacrylate derivative were significantly greater than octyl-cyanoacrylate. When bone sections were fixed with resorbable plates and adhesives, shear bond strength was significantly greater for N-butyl-cyanoacrylate than plate and screws, while the bond strengths of other adhesives were comparable with the plate and screws. N-Butyl cyanoacrylate was shown to have the greatest potential for fixation of fractured bone in craniofacial surgical applications.

A total of 14 patients were enrolled in the study at cervical vertebral maturation stage CVM2. Bilateral FDA approved miniplates (Bollard plates) were surgically inserted in the infrazygomatic crests of the maxilla and between the canine and the lateral incisor in the anterior mandible. The patients were treated by intermaxillary elastics for an average of 16 months. Cephalometric analysis was done before, during and at the end of the treatment. Intraoral and extraoral photographs were taken for comparisons. In this study, we analyze the effect of maxillary advancement in patients with class III skeletal malocclusions using a nonosteotomy technique that produces combined maxillary advancement and mandibular retraction using bone anchored Bollard plates (Tita-Link, Brussels, Belgium). We evaluate the change in WITS appraisal and ANB values for each patient before and after treatment. OMaxillary hypoplasia is frequently found in Class III Malocclusion patients O Traditional Treatment options include use of protraction face mask anchored to dentition or a more invasive Le Fort osteotomy OBone Anchored Maxillary Protraction devices provide skeletal anchorage O Requires active sutures in growth phase, skeletal anchorage buttress and remodeling of adjacent bone OLess invasive than osteomies

Postoperative resynostosis and secondary craniofacial growth abnormalities are common sequelae after craniofacial surgery. It has been suggested that an overexpression of transforming growth factor-beta2 (Tgf-beta2) may be related to craniosynostosis and contribute to postoperative resynostosis. Interference with Tgf-beta2 function using neutralizing antibodies may inhibit resynostosis and improve postoperative craniofacial growth; the present study was designed to test this hypothesis. Twenty-nine New Zealand white rabbits with bilateral coronal suture synostosis were used: 1) suturectomy controls (n=9); 2) suturectomy with nonspecific, control IgG antibody (n=9); and 3) suturectomy with anti-Tgf-beta2 antibody (n=11). At 10 days of age, a 3 mm x 15-mm coronal suturectomy was performed. The sites in groups 2 and 3 were immediately filled with 0.1 cc of a slow resorbing collagen gel mixed with either IgG (100 microg/suture) or anti-Tgf-beta2 (100 microg/suture). Three-dimensional computed tomography scan reconstructions of the skulls and cephalographs were obtained at 10, 25, 42, and 84 days of age. Computed tomography scan data revealed patent suturectomy sites and significantly (P

Objective To present the first clinical use of a new bioabsorbable material, poly (D,L) lactic acid (PDLLA), in pediatric cranial-vault remodeling procedures. This discussion will highlight the benefits and detriments of PDLLA in comparison with currently used absorbable plating systems. Design This was a case study documenting the first North American case in which PDLLA was used to treat craniosynostosis. Materials and Methods Evaluation of pure PDLLA, a copolymer product of the mixture of poly L-lactic acid and its D-isomer, was used in an 8-month-old boy with a severe phenotypic expression of sagittal craniosynostosis. No signs of elevated intracranial pressure were present, and the neurological examination did not show impairments. Total cranial-vault remodeling with the “hung-span” technique was performed. The Resorb X system, containing 2.2-mm screws and 0.6- to 1-mm-thick plates, was used to stabilize the reconstructed cranial vault. Results No surgical complications occurred. The preoperative cranial index measured 62. The scaphocephalic appearance of the skull was eliminated, and the cranial index was normalized to 77. The screws and plates were less palpable than other plating systems. Twelve months postoperatively, none of the plates and screws were identifiable by external palpation. Conclusion Resorb X has been successfully used in the treatment of sagittal craniosynostosis. Its rapid rate of resorption and lower profile make it an advantageous system for pediatric skull reconstruction. This represents the first use of this product in the United States for any pathology.

The alignment of the alveolar segments creates the foundation upon which excellent results of lip and primary nasal surgery are dependent in the repair of the cleft lip and palate patient. The purpose of this article is to illustrate the step-by-step fabrication process of the nasoalveolar molding appliance used to direct growth of the alveolar ridge, lips, and nose in the presurgical treatment of cleft lip and palate. As a result of this appliance, the primary surgical repair of the nose and lip heals under minimal tension, thereby reducing scar formation and improving the esthetic result.

In contrast to adult cutaneous wound repair, early gestational fetal cutaneous wounds heal by a process of regeneration, resulting in little or no scarring. Previous studies indicate that down-regulation of HoxB13, a member of the highly conserved family of Hox transcription factors, occurs during fetal scarless wound healing. No down-regulation was noted in adult wounds. Here, we evaluate healing of adult cutaneous wounds in Hoxb13 knockout (KO) mice, hypothesizing that loss of Hoxb13 in adult skin should result in enhanced wound healing. Tensiometry was used to measure the tensile strength of incisional wounds over a 60-day time course; overall, Hoxb13 KO wounds are significantly stronger than wild-type (WT). Histological evaluation of incisional wounds shows that 7-day-old Hoxb13 KO wounds are significantly smaller and that 60-day-old Hoxb13 KO wounds exhibit a more normal collagen architecture compared with WT wounds. We also find that excisional wounds close at a faster rate in Hoxb13 KO mice. Biochemical and histochemical analyses show that Hoxb13 KO skin contains significantly elevated levels of hyaluronan. Because higher levels of hyaluronan and enhanced wound healing are characteristics of fetal skin, we conclude that loss of Hoxb13 produces a more "fetal-like" state in adult skin.

With the modern emphasis on minimally invasive therapies, the concept of distraction is being applied in the treatment of craniosynostosis. Although specific genetic mutations have been identified in craniosynostotic patients, changes in the gene expression induced by cranial distraction have not yet been explored. The effects of cranial distraction on hedgehog and patched-1 expression were evaluated in a rabbit model for craniosynostosis. Rabbits (n = 8) were divided into four groups: affected rabbits, wild-type rabbits, affected rabbits subject to cranial distraction, and wild-type rabbits subject to distraction. Perisutural tissue was examined using immunohistochemistry in four areas: suture, endosteum, periosteum, and osteocytes, for the expression of Indian hedgehog, sonic hedgehog, and desert hedgehog and their receptor, patched-1. Two experimental groups were compared: (1) wild-type before distraction to wild-type after distraction, and (2) synostotic before distraction to synostotic after distraction. Distraction produced several variable and interesting changes in hedgehog protein presence. In wild-type rabbits, the predominant effect was a mild decrease in Indian hedgehog levels. Sonic and desert hedgehog and patched-1 protein levels were unchanged. In synostotic rabbits, the predominant effect of distraction was to decrease Indian hedgehog, sonic hedgehog, and patched-1 protein levels. This was especially true in the periosteum and endosteum. Cranial distraction of normal and affected rabbits differentially changed both the expression levels and patterns of the hedgehog and patched-1 proteins in the cranial tissues examined. These results suggest that molecular and genetic parameters of distraction and bone response may be different in craniosynostotic individuals, which may influence treatment protocols in these patients.