Faculty Bibliography

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

Bony defects in the craniomaxillofacial skeleton remain a major and challenging health concern. Surgeons have been trying for centuries to restore functionality and aesthetic appearance using autografts, allografts, and even xenografts without entirely satisfactory results. As a result, physicians, scientists, and engineers have been trying for the past few decades to develop new techniques to improve bone growth and bone healing. In this review, the authors summarize the advantages and limitations of current animal models; describe current materials used as scaffolds, cell-based, and protein-based therapies; and lastly highlight areas for future investigation. The purpose of this review is to highlight the major scaffold-, cell-, and protein-based preclinical tools that are currently being developed to repair cranial defects

BACKGROUND: Mandibular distraction has evolved from the use of external to the use of intraoral and semiburied devices. The authors highlight the evolution of the semiburied technique. The authors evaluate advantages and limitations, and report perioperative events for external and semiburied techniques to establish the indications for selection of the different devices. METHODS: A retrospective review was conducted of patients undergoing mandibular distraction at the New York University Langone Medical Center from the authors' introduction of mandibular distraction in May of 1989 to June 30, 2009. Perioperative events were stratified into three groups: minor incidents, moderate incidents, and major incidents. RESULTS: A total of 211 mandibular distraction procedures were performed: 129 external procedures on native bone, 37 external procedures on grafted bone, and 45 semiburied procedures on native bone. Minor incidents were more common with the semiburied device (62 percent) compared with external devices on native (26 percent) and grafted (38 percent) bone. There were fewer moderate incidents with the semiburied device (18 percent) than with the external device on native (22 percent) and grafted (30 percent) bone. In contrast to the external technique, no major incidents were seen with semiburied distraction. CONCLUSIONS: The semiburied device reduces scarring and has the mechanical advantages of being applied directly to the bone, less vulnerable to dislodgment, and more favorable for a vertical vector. However, its use requires more bone stock and it has the disadvantage of requiring a second operation for removal. Semiburied distraction is safe, reliable, and indicated for lengthening of the hypoplastic mandible where there is adequate bone stock for its attachment

Diabetes is characterized by several poorly understood phenomena including dysfunctional wound healing and impaired vasculogenesis. p53, a master cell cycle regulator, is upregulated in diabetic wounds and has recently been shown to play a regulatory roles in vasculogenic pathways. We have previously described a novel method to topically silence target genes in a wound bed with small interfering (si)RNA. We hypothesized that silencing p53 results in improved diabetic wound healing and augmentation of vasculogenic mediators. Paired 4-mm stented wounds were created on diabetic db/db mice. Topically applied p53 siRNA, evenly distributed in an agarose matrix, was applied to wounds at postwound day 1 and 7 (matrix alone and nonsense siRNA served as controls). Animals were sacrificed at postwound days 10 and 24. Wound time to closure was photometrically assessed, and wounds were harvested for histology, immunohistochemistry, and immunofluorescence. Vasculogenic cytokine expression was evaluated via Western blot, reverse transcription-polymerase chain reaction, and enzyme-linked immunosorbent assay. The ANOVA/t-test was used to determine significance (p</= 0.05). Local p53 silencing resulted in faster wound healing with wound closure at 18+/-1.3 d in the treated group vs. 28+/-1.0 d in controls. The treated group demonstrated improved wound architecture at each time point while demonstrating near-complete local p53 knockdown. Moreover, treated wounds showed a 1.92-fold increase in CD31 endothelial cell staining over controls. Western blot analysis confirmed near-complete p53 knockdown in treated wounds. At day 10, VEGF secretion (enzyme-linked immunosorbent assay) was significantly increased in treated wounds (109.3+/-13.9 pg/mL) vs. controls (33.0+/-3.8 pg/mL) while reverse transcription-polymerase chain reaction demonstrated a 1.86-fold increase in SDF-1 expression in treated wounds vs. controls. This profile was reversed after the treated wounds healed and before closure of controls (day 24). Augmented vasculogenic cytokine profile and endothelial cell markers are associated with improved diabetic wound healing in topical gene therapy with p53 siRNA

BACKGROUND:: Pediatric temporomandibular joint (TMJ) dysfunction, resulting from either soft tissue or skeletal disorders, may be congenital or acquired. Congenital TMJ disorders are uncommon. Here we review our experience with pediatric TMJ disorders and propose a new classification system. METHOD:: Clinical records, cephalograms, computed tomography, magnetic resonance images, and pathologic specimens of all pediatric patients (< 18 years) with trismus or restricted mandibular excursion from 1976-2008 were reviewed. Cases were stratified according to soft tissue or skeletal pathology; skeletal abnormalities were further characterized as intra- or extra-capsular. RESULTS:: 38 patients, ranging in age from 1 day to 18 years of age at diagnosis, were identified with TMJ disorders. Ten cases (26.3%) were due to soft tissue pathology. The remaining 28 cases (73.7%) were due to skeletal pathology, consisting of 14 congenital and 14 acquired cases (50% each). Acquired skeletal deformities included 12 (85.7%) intracapsular ankyloses and 2 (16.7%) extracapsular ankylosis (extra-articular bone blocks). Congenital skeletal deformities accounted for 5 (35.7%) intracapsular ankyloses and 9 (64.3%) extracapsular ankyloses. CONCLUSION:: On initial survey, the data are consistent with published reports that attribute TMJ dysfunction to acquired pathology (i.e., trauma and infection). However, we observed a significantly higher percentage (50%) of congenital TMJ skeletal disorders than previously reported. Most congenital cases involved extracapsular pathology (i.e., coronoid hypertrophy); only a minority of cases had glenocondylar fibro-osseous fusion (i.e., intracapsular ankyloses). Since the diagnosis and classification of TMJ disorders determines treatment options, we provide a new classification that characterizes the extent of capsular involvement

OBJECTIVE: Radiotherapy, an essential modality in cancer treatment, frequently induces fibrotic processes in the skin, including accumulation of extracellular matrix. Transforming growth factor-beta is essential in regulating extracellular matrix gene expression and is dependent on Smad3, an intracellular mediator/transcription factor. Our study characterized the genetic expression involved in extracellular matrix accumulation during radiation-induced fibrosis. We performed Smad3 gene silencing in an attempt to abrogate the effects of radiation. STUDY DESIGN: Laboratory research. SETTING: University laboratory. SUBJECTS AND METHODS: C57 murine dermal fibroblasts were irradiated with 20 Gy RNA isolated (0, 6, 12, 24, 48, 72 hours postirradiation) and mRNA analyzed (reverse transcriptase polymerase chain reaction) for known regulators (Smad3, interleukin-13 [IL-13]), tumor necrosis factor-alpha [TNF-alpha]) and mediators of fibrosis (collagen 1A1 [Col1A1]), TGF-beta, matrix metalloprotease-1 and -2 (MMP-1, MMP-2), and tissue inhibitor of metalloprotease-1 (TIMP-1). Smad3 gene expression was silenced using siRNA in an effort to restore an unirradiated gene profile. RESULTS: Following irradiation, there was a steady increase in mRNA expression of Smad3, IL-13, TGF-beta, Col1A1, MMP-2, TIMP-1, with peak at 12 to 24 hours and subsequent decline by 72 hours. TNF-alpha expression remained elevated throughout. MMP-1 showed minimal expression initially, which decreased to negligible by 72 hours. Inhibition of Smad3 significantly decreased expression of Col1A1, TGF-beta, MMP-2, and TIMP-1. IL-13 and TNF-alpha expression was not affected by Smad3 silencing. CONCLUSION: We have characterized the early-phase mRNA expression profiles of the major mediators of radiation-induced fibrosis. Smad3 siRNA effectively abrogated the elevation of Col1A1, TGF-beta, TIMP-1, and MMP-2. IL-13 and TNF-alpha were unaffected by Smad3 silencing and appear to be minor regulators in fibrosis. These findings suggest a therapeutic rationale for Smad3 silencing in vivo