Faculty Bibliography

Chronic post-surgical lymphedema is common condition that afflicts nearly 2 million Americans. In the USA, it is most commonly encountered in the upper extremities of patients who have undergone axillary lymph node dissection for breast cancer. Lymphedema has a significant negative effect on cosmesis, limb function, and overall quality of life. Despite the impact of this condition, very little is known about how to effectively prevent or treat lymphedema. While therapeutic options for chronic extremity lymphedema remain limited, several surgical approaches have been suggested. These include techniques aimed at reducing limb volume, as well as techniques that aim to reconstitute disrupted lymphatic channels. Operations proposed to re-establish lymphatic continuity include lymphatico-venous anastomoses, lymphatico-lymphatico anastomoses, and tissue transfer.

INTRODUCTION: While several studies report that bone morphogenetic proteins (BMPs) and vascular endothelial growth factor (VEGF) can act synergistically to improve bone tissue engineering, others suggest that VEGF inhibits osteogenesis. The purpose of these experiments was therefore to evaluate the effect of dual transfection of these growth factors and potential mechanisms of interaction on gene expression and osteogenesis in vitro and in vivo. METHODS: Marrow-derived mesenchymal stem cells (MSCs) were exposed to recombinant VEGF protein or transfected with adenoviruses encoding BMP2, VEGF, or LacZ in a variety of ratios. Alterations in gene and protein expression in vitro as well as bone formation in vivo were assessed. RESULTS: MSC exposure to AdV-VEGF or recombinant VEGF inhibited BMP2 mRNA expression, protein production, and MSC differentiation. Coculture experiments revealed that BMP2 suppression occurs through both an autocrine and a paracrine mechanism, occurring at the transcriptional level. Compared to controls, cotransfection of VEGF and BMP2 transgenes prevented ectopic bone formation in vivo. CONCLUSION: VEGF is a potent inhibitor of BMP2 expression in MSCs, and supplementation or overexpression of VEGF inhibits osteogenesis in vitro and ectopic bone formation in vivo. Strategies to utilize MSCs in bone tissue engineering therefore require careful optimization and precise delivery of growth factors for maximal bone formation.

Lymphedema is a complication of cancer treatment occurring in approximately 50% of patients who undergo lymph node resection. Despite its prevalence, the etiology of this disorder remains unknown. In this study, we determined the effect of soft tissue fibrosis on lymphatic function and the role of transforming growth factor (TGF)-beta1 in the regulation of this response. We determined TGF-beta expression patterns in matched biopsy specimens collected from lymphedematous and normal limbs of patients with secondary lymphedema. To determine the role of TGF-beta in regulating tissue fibrosis, we used a mouse model of lymphedema and inhibited TGF-beta function either systemically with a monoclonal antibody or locally by using a soluble, defective TGF-beta receptor. Lymphedematous tissue demonstrated a nearly threefold increase in the number of cells that stained for TGF-beta1. TGF-beta inhibition markedly decreased tissue fibrosis, increased lymphangiogenesis, and improved lymphatic function compared with controls. In addition, inhibition of TGF-beta not only decreased TGF-beta expression in lymphedematous tissues, but also diminished inflammation, migration of T-helper type 2 (Th2) cells, and expression of profibrotic Th2 cytokines. Similarly, systemic depletion of T-cells markedly decreased TGF-beta expression in tail tissues. Inhibition of TGF-beta function promoted lymphatic regeneration, decreased tissue fibrosis, decreased chronic inflammation and Th2 cell migration, and improved lymphatic function. The use of these strategies may represent a novel means of preventing lymphedema after lymph node resection.

BACKGROUND: Recent reports have demonstrated that lymphedema can occur after even minor pertubation of the axillary region such as sentinel lymph node biopsy (SLNB). The impact of breast reconstruction on the development of lymphedema, however, remains unknown. Therefore, the purpose of this study was to determine the impact of immediate tissue expander breast reconstruction on the risk of developing lymphedema. MATERIALS AND METHODS: We identified patients who had undergone mastectomy with SLNB or SLNB and axillary lymph node dissection (ALND) with or without breast reconstruction using our prospectively maintained lymphedema and breast reconstruction databases. The development of lymphedema was evaluated prospectively using arm measurements and a validated questionnaire. Associations between variables were examined. Logistic regression was used to examine the association of reconstruction on prevalence of lymphedema while adjusting individually for BMI, age, and weight gain after surgery. RESULTS: Characteristics of patients with or without reconstruction were similar except for age, BMI, and weight gain since surgery. Median follow-up was 5 years. Among patients treated with mastectomy with SLNB or SLNB/ALND, those undergoing reconstruction had a lower rate of measured lymphedema than those who did not (5% vs. 18%, P < .0004). The reconstructed group also had fewer patients with both measured and self-reported lymphedema (3% vs. 12%, P < .002). Differences in the rates of measured lymphedema between groups persisted following univariate logistical regression for differences in age, BMI, and weight gain. CONCLUSIONS: Tissue expander breast reconstruction in patients undergoing SLNB or SLNB/ALND does not increase the risk of developing measured or perceived lymphedema.

Strain rate dependence of the mechanical response of hard tissues has led to a keen interest in their dynamic properties. The current study attempts to understand the high strain rate characteristics of rabbit femur bones. The testing was conducted using a split-Hopkinson pressure bar equipped with a high speed imaging system to capture the fracture patterns. The bones were also characterized under quasi-static compression to enable comparison with the high strain rate results. The quasi-static compressive moduli of the epiphyseal and diaphyseal regions were measured to be in the range of 2-3 and 5-7GPa, respectively. Under high strain rate loading conditions the modulus is observed to increase with strain rate and attains values as high as 15GPa for epiphyseal and 30GPa for diaphyseal regions of the femur. The strength at high strain rate was measured to be about twice the quasi-static strength value. A large number of small cracks initiated on the specimen surface close to the incident bar. Coalescence of crack branches leading to fewer large cracks resulted in specimen fragmentation. In comparison, the quasi-static failure was due to shear cracking.

Since the founding of the osseointegration concept, the characteristics of the interface between bone and implant, and possible ways to improve it, have been of particular interest in dental and orthopaedic implant research. Making use of standardized tools of analysis and terminology, we present here a standardized characterization code for osseointegrated implant surfaces. This code describes the chemical composition of the surface, that is, the core material, such as titanium, and its chemical or biochemical modification through impregnation or coating. This code also defines the physical surface features, at the micro- and nanoscale, such as microroughness, microporosity, nanoroughness, nanotubes, nanoparticles, nanopatterning and fractal architecture. This standardized classification system will allow to clarify unambiguously the identity of any given osseointegrated surface and help to identify the biological outcomes of each surface characteristic.

OBJECTIVE: this study aimed to histomorphologically and histomorphometrically evaluate the in vivo response to three variations in the resorbable blasting media (RBM) surface processing in a rabbit femur model. STUDY DESIGN: screw root form implants with 3.75 mm in diameter by 8 mm in length presenting four surfaces (n=8 each): alumina-blasted/acid-etched (AB/AE), bioresorbable ceramic blasted (TCP), TCP + acid etching, and AB/AE + TCP were characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The implants were placed at the distal femur of 8 New Zeland rabbits, remaining for 2 weeks in vivo. After sacrifice, the implants were nondecalcified processed to 30 micro m thickness slides for histomorphology and bone-to-implant contact (BIC) determination. Statistical analysis was performed by one-way ANOVA at 95% level of significance considering implant surface as the independent variable and BIC as the dependent variable. RESULTS: SEM and AFM showed that all surfaces presented rough textures and that calciu-hosohate particles were observed at the TCP group surface. Histologic evaluation showed intimate interaction between newly formed woven bone and all implant surfaces, demonstrating that all surfaces were biocompatible and osseoconductive. Significant differences in BIC were observed between the AB/AE and the AB/AE + TCP, and intermediate values observed for the TCP and TCP + Acid surfaces. CONCLUSION: irrespective of RBM processing variation, all surfaces were osseoconductive and biocaompatible. The differences in BIC between groups warrant further bone-implant interface biomechanical characterization.

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.