Faculty Bibliography

ABSTRACT: The goal of this article was to illustrate the ease in which virtual surgery and computer-aided design and manufacturing can be used by the craniomaxillofacial surgeon to create tremendously accurate postoperative results and provide confidence with even the most complex three-dimensional bony reconstructions. With advancements in software technology and three-dimensional printing, our ability to plan and execute precise bony reconstruction has become a reality. With this technology, guides can be made to ensure exact bony repositioning or replacement. These guides can help guide cutting of the bone and can act as splints to precisely reposition the bone and direct plate placement. With use of these computer-aided design and manufacturing guides and the addition of guidance technology, the position of the bone can be guaranteed intraoperatively. We review our unique and advanced method in approaching some of these problems and illustrate the application of these techniques in mandibular reconstruction, orthognathic surgery, maxillofacial trauma, and temporomandibular joint reconstruction. This technology continues to evolve, and our indications for its application continue to grow. This article represents only a small portion of the types of cases in which these techniques have already been applied.

ABSTRACT: This article focuses on current practices and controversy in the area of presurgical infant orthopedics in patients born with cleft lip and palate.

ABSTRACT: There is tremendous interest in autologous fat grafting for the management of soft tissue volume deficiencies, treatment of cutaneous injuries, and regeneration of missing parts. Given its relative abundance and proximity to the surface of the skin, adipose tissue seems an excellent choice for the treatment of both congenital and acquired soft tissue defects, but the mesenchymal stem cells contained within the fat may provide unexpected opportunities for tissue replacement and repair. Although adipose transfer has been successfully used for reconstructive purposes since the end of the 19th century, numerous controversies about adipose harvesting, processing, delivery, survival, and efficacy still persist today. The purpose of this article was to highlight current practices, areas of controversy, and near-term future applications of fat grafting for reconstruction of the face.

Diabetic foot ulcers (DFUs) are a significant and rapidly growing complication of diabetes and its effects on wound healing. Over half of diabetic patients who develop a single ulcer will subsequently develop another ulcer of which the majority will become chronic non-healing ulcers. One-third will progress to lower extremity amputation. Over the past decade, the outcomes for patients with DFUs ulcers have not improved, despite advances in wound care. Successful treatment of diabetic foot ulcers is hindered by the lack of targeted therapy that hones in on the healing processes dysregulated by diabetes. Stem cells are a promising treatment for DFUs as they are capable of targeting, as well as bypassing, the underlying abnormal healing mechanisms and deranged cell signaling in diabetic wounds and promote healing. This review will focus on existing stem cell technologies and their application in the treatment of DFUs.

Lymphangiogenic cytokines such as vascular endothelial growth factor-C (VEGF-C) are critically required for lymphatic regeneration; however, in some circumstances, lymphatic function is impaired despite normal or elevated levels of these cytokines. The recent identification of anti-lymphangiogenic molecules such as interferon-gamma (IFN-gamma), transforming growth factor-beta1, and endostatin has led us to hypothesize that impaired lymphatic function may represent a dysregulated balance in the expression of pro/anti-lymphangiogenic stimuli. We observed that nude mice have significantly improved lymphatic function compared with wild-type mice in a tail model of lymphedema. We show that gradients of lymphatic fluid stasis regulate the expression of lymphangiogenic cytokines (VEGF-A, VEGF-C, and hepatocyte growth factor) and that paradoxically the expression of these molecules is increased in wild-type mice. More importantly, we show that as a consequence of T-cell-mediated inflammation, these same gradients also regulate expression patterns of anti-lymphangiogenic molecules corresponding temporally and spatially with impaired lymphatic function in wild-type mice. We show that neutralization of IFN-gamma significantly increases inflammatory lymph node lymphangiogenesis independently of changes in VEGF-A or VEGF-C expression, suggesting that alterations in the balance of pro- and anti-lymphangiogenic cytokine expression can regulate lymphatic vessel formation. In conclusion, we show that gradients of lymphatic fluid stasis regulate not only the expression of pro-lymphangiogenic cytokines but also potent suppressors of lymphangiogenesis as a consequence of T-cell inflammation and that modulation of the balance between these stimuli can regulate lymphatic function.

Mechanisms regulating lymphedema pathogenesis remain unknown. Recently, we have shown that lymphatic fluid stasis increases endogenous danger signal expression, and these molecules influence lymphatic repair (Zampbell JC, et al. Am J Physiol Cell Physiol 300: C1107-C1121, 2011). Endogenous danger signals activate Toll-like receptors (TLR) 2, 4, and 9 and induce homeostatic or harmful responses, depending on physiological context. The purpose of this study was to determine the role of TLRs in regulating tissue responses to lymphatic fluid stasis. A surgical model of lymphedema was used in which wild-type or TLR2, 4, or 9 knockout (KO) mice underwent tail lymphatic excision. Six weeks postoperatively, TLR KOs demonstrated markedly increased tail edema compared with wild-type animals (50-200% increase; P < 0.01), and this effect was most pronounced in TLR4 KOs (P < 0.01). TLR deficiency resulted in decreased interstitial and lymphatic transport, abnormal lymphatic architecture, and fewer capillary lymphatics (40-50% decrease; P < 0.001). Lymphedematous tissues of TLR KOs demonstrated increased leukocyte infiltration (P < 0.001 for TLR4 KOs), including higher numbers of infiltrating CD3+ cells (P < 0.05, TLR4 and TLR9 KO), yet decreased infiltrating F4/80+ macrophages (P < 0.05, all groups). Furthermore, analysis of isolated macrophages revealed twofold reductions in VEGF-C (P < 0.01) and LYVE-1 (P < 0.05) mRNA from TLR2-deficient animals. Finally, TLR deficiency was associated with increased collagen type I deposition and increased transforming growth factor-beta1 expression (P < 0.01, TLR4 and TLR9 KO), contributing to dermal fibrosis. In conclusion, TLR deficiency worsens tissue responses to lymphatic fluid stasis and is associated with decreased lymphangiogenesis, increased fibrosis, and reduced macrophage infiltration. These findings suggest a role for innate immune responses, including TLR signaling, in lymphatic repair and lymphedema pathogenesis.

This study aimed to investigate the mechanisms that coordinate lymphangiogenesis. Using mouse models of lymphatic regeneration and inflammatory lymphangiogenesis, we explored the hypothesis that hypoxia inducible factor-alpha (HIF-1alpha) is a central regulator of lymphangiogenesis. We show that HIF-1alpha inhibition by small molecule inhibitors (YC-1 and 2-methyoxyestradiol) results in delayed lymphatic repair, decreased local vascular endothelial growth factor-C (VEGF-C) expression, reduced numbers of VEGF-C(+) cells, and reductions in inflammatory lymphangiogenesis. Using transgenic HIF-1alpha/luciferase mice to image HIF-1alpha expression in real time in addition to Western blot analysis and pimonidazole staining for cellular hypoxia, we demonstrate that hypoxia stabilizes HIF-1alpha during initial stages of wound repair (1-2 wk); whereas inflammation secondary to gradients of lymphatic fluid stasis stabilizes HIF-1alpha thereafter (3-6 wk). In addition, we show that CD4(+) cell-mediated inflammation is necessary for this response and regulates HIF-1alpha expression by macrophages, as CD4-deficient or CD4-depleted mice demonstrate 2-fold reductions in HIF-1alpha expression as compared to wild-types. In summary, we show that HIF-1alpha is a critical coordinator of lymphangiogenesis by regulating the expression of lymphangiogenic cytokines as part of an early response mechanism to hypoxia, inflammation, and lymphatic fluid stasis.-Zampell, J. C., Yan, A., Avraham, T., Daluvoy, S., Weitman, E. S., Mehrara, B. J. HIF-1alpha coordinates lymphangiogenesis during wound healing and in response to inflammation.

BACKGROUND: : The senior author routinely performs primary nasal reconstruction with every cleft lip repair. This addresses the nasal tip asymmetry and simplifies the definitive secondary rhinoplasty in adolescence. METHODS: : A retrospective chart review was completed of all unilateral cleft secondary rhinoplasties performed by the senior author. The indications for secondary rhinoplasty were examined, anatomical features of the nose at the time of operation were documented, and the reconstructive techniques used were recorded. RESULTS: : From 2001 to 2009, the senior author performed 116 secondary rhinoplasties in patients with a previously repaired unilateral cleft lip. The senior author performed 44 of the initial cleft lip repairs (group A). A Dibbell rhinoplasty was required in 26 percent, a Potter rhinoplasty was required in 5 percent, a Tajima inverted-U incision was required in 70 percent, and an alar base resection was required in 53 percent. For those patients who did not undergo cleft lip repair with primary rhinoplasty by the senior author, 60 percent required a Dibbell rhinoplasty, Potter rhinoplasty was not used, 76 percent required a Tajima inverted-U incision, and 64 percent required an alar base resection. Group A had significantly greater dome symmetry when comparing the cleft side to the noncleft side (p = 0.001). Nostril apex height was also more symmetrical in group A (p = 0.105). CONCLUSION: : Primary nasal reconstruction performed with cleft lip repair as described by the senior author makes the nasal tip more symmetric and requires less complex intervention at the time of definitive secondary rhinoplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE:: Therapeutic, IV.