Faculty Bibliography

Purpose: Cutaneous radiation injury occurs during the treatment of cancer, or in rare environmental exposure. As the acute wound heals, fibrosis is induced and extracellular matrix (ECM) is deposited. The fibrotic pathway is mediated by the transforming growth factor-beta (TGF-beta) cascade, and is dependent on Smad3, a transcription factor for ECM. We characterized gene expression of this cascade after radiation injury and performed in vitro and in vivo gene silencing of Smad3 in an attempt to reverse the fibrotic pathway. Methods: Wild-type murine dermal fibroblasts were irradiated with 20Gy and harvested at serial time-points. RT-PCR was performed for known regulators and mediators of fibrosis. Smad3 was silenced by transfection with siRNA. For the in vivo experiment, dorsal skin of wild-type mice was irradiated with 45 Gy. Five weeks later, siRNA was applied to the fibrotic areas for one week. Skin was harvested and tissue analyzed by RT-PCR and Western blotting, as well as tissue tensiometry, which quantitatively measures rigidity. Results: Following irradiation, there was a steady increase in mRNA expression of Smad3, TGFbeta, and ECM genes collagen 1A1, metalloprotease2, and tissue inhibitor of metalloprotease-1, with peak expression at 12-24 hours. Inhibition of Smad3 with siRNA significantly decreased expression of Smad3, TGFbeta, and ECM genes. In the mouse model, topical treatment with siRNA again significantly decreased expression of these genes. Tensiometry demonstrated decreased stiffness in Smad3 siRNA treated skin, with a Young's modulus nearer to normalcompared to untreated and nonsense siRNA treated skin. Conclusion: Following initiation of the fibrotic pathway by radiation, Smad3 siRNA treatment both in vitro and in vivo effectively reversed gene expression. Furthermore, cutaneous Smad3 inhibition mitigated radiation-induced fibrotic stiffening. These findings suggest a therapeutic role for Smad3 silencing for cancer patients treated with radiation as well as those accidentally exposed to radiation

Calcium phosphate-based bioactive ceramics in various physical and chemical formulations have been extensively utilized as biomaterials for bone regeneration/conduction. However, the determination of their in vivo temporal behavior from the short to long term in humans has been a challenge due to the lack of physical reference for morphologic and morphometric evaluation. The present study evaluated bone morphology and morphometry (bone-to-implant contact [BIC]) around plasma-sprayed hydroxyapatite (PSHA)-coated endosseous implants that were retrieved due to prosthetic reasons while successfully in function at the posterior region of the jaws from as early as 2 months to approximately 13 years after a 6-month healing period after placement. Bone morphology was evaluated by light microscopy, and BIC was determined using computer software. Irrespective of the time in vivo, lamellar bone was observed in close contact with the implant PSHA-coated surface and between plateaus. BIC ranged from approximately 35-95%, was highly directional, and Haversian-like osteonic morphology between plateaus was observed for most implants. The PSHA coating was present with little variation in thickness between the samples retrieved regardless of time in vivo.

BACKGROUND: Composite tissue allotransplantation may have different immunosuppressive requirements and manifest different complications compared with solid organ transplantation. We developed a non-human primate facial composite tissue allotransplantation model to investigate strategies to achieve prolonged graft survival and immunologic responses unique to these allografts. METHODS: Composite facial subunits consisting of skin, muscle, and bone were heterotopically transplanted to mixed lymphocyte reaction-mismatched Cynomolgus macaques. Tacrolimus monotherapy was administered via continuous intravenous infusion for 28 days then tapered to daily intramuscular doses. RESULTS: Five of the six animals treated with tacrolimus monotherapy demonstrated rejection-free graft survival up to 177 days (mean, 113 days). All animals with prolonged graft survival developed posttransplant lymphoproliferative disorders (PTLD). Three animals converted to rapamycin after 28 days of rejection of their allografts, but did not develop PTLD. Genotypic analysis of PTLD tumors demonstrated donor origin in three of the five analyzed by short-tandem repeats. Sustained alloantibodies were detected in rejecting grafts and absent in nonrejecting grafts. CONCLUSIONS: Tacrolimus monotherapy provided prolonged rejection-free survival of composite facial allografts in a non-human primate model but was associated with the development of a high frequency of donor-derived PTLD tumors. The transplantation of a large volume of vascularized bone marrow in composite tissue allografts may be a risk factor for PTLD development.

Obstetrical brachial plexus palsy is commonly attributed to excessive traction applied to the baby's neck during a difficult delivery. The majority of infants with brachial plexus palsy recover spontaneously within the first 3 months of life. However, in 10 to 30 percent of cases, the recovery is incomplete. Global palsy and the absence of biceps muscle function at 3 months of age have been adopted as the main indications for early brachial plexus microsurgery. In late cases or when primary reconstruction has not yielded satisfactory results, secondary reconstruction will intervene as an enhancement of a specific functional deficit or of the overall function of the upper extremity. In this article, the authors review the history of obstetrical brachial plexus palsy, the epidemiology and cause, and the indications for and the timing of surgery. The current diagnostic modalities and clinical evaluation of plexus injuries are also considered. The advances in electrophysiology, myelography, and computed tomographic scanning and magnetic resonance imaging are presented, all of which are important diagnostic modalities that facilitate a more accurate diagnosis. Obstetrical brachial plexus injuries may require multistaged reconstructive procedures, including neurolysis, resection of neuromas, identification of intraplexus and extraplexus donor nerves, selective neurotizations, selective nerve transfers, and nerve grafting. Finally, the various secondary procedures in terms of anatomical location in the upper extremity are described. Whatever the reports and results, the complex doctrine of obstetrical brachial plexus palsy continues to evolve with notable functional outcomes, but return to normal function remains a challenge for the future

PURPOSE: The objective of this study was to evaluate the bone response to a nanothickness bioceramic ion beam-assisted deposition (IBAD) on endosteal implants in a canine model. MATERIALS AND METHODS: Alumina-blasted/acid-etched (control) and IBAD-modified (test) implants were characterized by scanning electron microscopy, X-ray photoelectron spectroscopy + ion beam milling, thin-film mode X-ray diffraction, and atomic force microscope. The implants were surgically placed in four dogs' proximal tibiae and remained for 2 and 4 weeks in vivo. Oxytetracycline (10 mg/kg) was administered for bone labeling 48 hours prior to euthanization. Following euthanization, nondecalcified thin sections were prepared for UV and transmitted light microscopy. The amount of bone labeling was evaluated along the length and away from the implant surface by means of a computer software. The % bone-to-implant contact (BIC) was determined for each specimen. One-way analysis of variance at 95% level of significance along with Tukey's post hoc multiple comparisons were utilized for statistical evaluation. The characterization showed Ca- and P-based amorphous coatings with a 20- to 50-nm thickness. RESULTS: In vivo results showed a significant increase in general and site-specific (to 0.5 mm from the implant surface) bone activity for the 4-week test implants compared with the control implants. Bone activity levels decreased as a function of distance from the implant surface for all groups. No significant differences in BIC were observed between groups. CONCLUSIONS: This study showed that both surfaces were biocompatible and osteoconductive and that a time-dependent increase in osteoactivity occurred around the test implants.