Faculty Bibliography

Craniosynostosis is the premature fusion of one or more cranial sutures. When a cranial suture fuses prematurely, skull growth is altered and the head takes on a characteristic pathological shape determined by the suture(s) that fuses. Numerous treatment options have been proposed, but until recently there were no parameters or guidelines of care. Establishing such parameters was an important step forward in the treatment of patients with craniosynostosis, but results are still assessed using radiographic measurements, complication rates, and ad hoc reporting scales. Therefore, clinical outcome reporting in the treatment of craniosynostosis is inconsistent and lacks methodological rigor. Today, most reported evidence in the treatment of craniosynostosis is level 5 (expert opinion) or level 4 (case series) data. Challenges in obtaining higher quality level 1 or level 2 data include randomizing patients in a clinical trial as well as selecting the appropriate outcome measure for the trial. Therefore, determining core outcome sets that are important to both patients and health care professionals is an essential step in the evolution of caring for patients with craniosynostosis. Traditional clinical outcomes will remain important, but patient-reported outcomes, such as satisfaction, body image, functional results, and aesthetic outcomes, must also be incorporated if the selected outcomes are to be valuable to patients and families making decisions about treatment. In this article, the authors review the most commonly used tools to assess craniosynostosis outcomes and propose a list of longitudinal parameters of care that should be considered in the evaluation, diagnosis, and treatment evaluation of a patient with craniosynostosis

Prolyl hydroxylase domain 2 (PHD2) has been implicated in several pathways of cell signaling, most notably in its regulation of hypoxia-inducible factor (HIF)-1alpha stability. In normoxia, PHD2 hydroxylates proline residues on HIF-1alpha, rendering it inactive. However, in hypoxia, PHD2 is inactive, HIF-1alpha is stabilized and downstream effectors such as vascular endothelial growth factor and fibroblast growth factor-2 are produced to promote angiogenesis. In the present study we utilize RNA interference to PHD2 to promote therapeutic angiogenesis in a diabetic wound model, presumably by the stabilization of HIF-1alpha. Stented wounds were created on the dorsum of diabetic Lepr db/db mice. Mice were treated with PHD2 small interfering RNA (siRNA) or nonsense siRNA. Wounds were measured photometrically on days 0-28. Wounds were harvested for histology, protein, and RNA analysis. Diabetic wounds treated with siRNA closed within 21+/-1.2 days; sham-treated closed in 28+/-1.5 days. By day 7, Western blot revealed near complete suppression of PHD protein and corresponding increased HIF-1alpha. Angiogenic mediators vascular endothelial growth factor and fibroblast growth factor-2 were elevated, corresponding to increased CD31 staining in the treated groups. siRNA-mediated silencing of PHD2 increases HIF-1alpha and several mediators of angiogenesis. This corresponded to improved time to closure in diabetic wounds compared with sham-treated wounds. These findings suggest that impaired wound healing in diabetes can be ameliorated with therapeutic angiogenesis

BACKGROUND: : Radiation therapy is a cornerstone of oncologic treatment. Skin tolerance is often the limiting factor in radiotherapy. To study these issues and create modalities for intervention, the authors developed a novel murine model of cutaneous radiation injury. METHODS: : The dorsal skin was isolated using a low-pressure clamp and irradiated. Mice were followed for 8 weeks with serial photography and laser Doppler analysis. Sequential skin biopsy specimens were taken and examined histologically. Tensiometry was performed and Young's modulus calculated. RESULTS: : High-dose radiation isolated to dorsal skin causes progressive changes in skin perfusion, resulting in dermal thickening, fibrosis, persistent alopecia, and sometimes ulceration. There is increased dermal Smad3 expression, and decreased elasticity and bursting strength. CONCLUSIONS: : This model of cutaneous radiation injury delivers reproducible localized effects, mimicking the injury pattern seen in human subjects. This technique can be used to study radiation-induced injury to evaluate preventative and therapeutic strategies for these clinical issues

BACKGROUND: : Distraction osteogenesis has revolutionized the treatment of craniofacial deformities, but it is limited by lengthy consolidation periods and tenuous healing in certain clinical settings, such as irradiated tissue. In this study, the authors aim to investigate whether increasing neovascularization by progenitor cell mobilization accelerates bone formation during distraction. METHODS: : Sprague-Dawley rats aged 8 weeks (n = 36) were subjected to unilateral mandibular distraction with 3-day latency, 7-day activation (0.25 mm twice daily), and 21-day consolidation periods. From the beginning of the consolidation period, animals received daily injections of either AMD3100 (bone marrow progenitor cell mobilizing agent) or sterile saline. Animals were euthanized on postoperative day 31; mandibles were harvested; and bone regeneration was assessed using micro-computed tomography, immunohistochemistry, bone morphogenetic protein-2 enzyme-linked immunosorbent assay, and mechanical testing. RESULTS: : Immunohistochemistry demonstrated that AMD3100 treatment increased vascular density and bone formation. Micro-computed tomography and dual-emission x-ray absorptiometry demonstrated that AMD3100-treated animals had improved bone generation compared with sham-treated controls. Greater force was required on three-point testing to break AMD3100-treated bone. Bone morphogenetic protein-2 expression was up-regulated with AMD3100. Interestingly, the nondistracted contralateral hemimandibles treated with AMD3100 were also stronger than sham-treated counterparts. CONCLUSIONS: : Progenitor cell mobilization improves bone regeneration in a rat distraction model. Furthermore, because this effect is seen in healthy bone and in ischemic bone healing during distraction, the mechanism is not merely related to oxygenation, but could be a phenomenon of fluid flow