HDL protects against doxorubicin-induced cardiotoxicity in a scavenger receptor class B type 1-, PI3K-, and Akt-dependent manner.

Doxorubicin is a widely used chemotherapeutic with deleterious cardiotoxic side effects. HDL has been shown to protect cardiomyocytes in vitro against doxorubicin-induced apoptosis. Scavenger receptor class B type 1 (SR-B1), a high-affinity HDL receptor, mediates cytoprotective signaling by HDL through Akt. Here, we assessed whether increased HDL levels protect against doxorubicin-induced cardiotoxicity in vivo and in cardiomyocytes in culture and explored the intracellular signaling mechanisms involved, particularly the role of SR-B1. Transgenic mice with increased HDL levels through overexpression of human apolipoprotein A1 (apoA1Tg/Tg) and wild-type mice (apoA1+/+) with normal HDL levels were treated repeatedly with doxorubicin. After treatment, apoA1+/+ mice displayed cardiac dysfunction, as evidenced by reduced left ventricular end-systolic pressure and +dP/d t, and histological analysis revealed cardiomyocyte atrophy and increased cardiomyocyte apoptosis after doxorubicin treatment. In contrast, apoA1Tg/Tg mice were protected against doxorubicin-induced cardiac dysfunction and cardiomyocyte atrophy and apoptosis. When SR-B1 was knocked out, however, overexpression of apoA1 did not protect against doxorubicin-induced cardiotoxicity. Using primary neonatal mouse cardiomyocytes and human immortalized ventricular cardiomyocytes in combination with genetic knockout, inhibitors, or siRNA-mediated knockdown, we demonstrated that SR-B1 is required for HDL-mediated protection of cardiomyocytes against doxorubicin-induced apoptosis in vitro via a pathway involving phosphatidylinositol 3-kinase and Akt1/2. Our findings provide proof of concept that raising apoA1 to supraphysiological levels can dramatically protect against doxorubicin-induced cardiotoxicity via a pathway that is mediated by SR-B1 and involves Akt1/2 activation in cardiomyocytes. NEW & NOTEWORTHY We have identified an important role for the scavenger receptor class B type 1 in facilitating high-density lipoprotein-mediated protection of cardiomyocytes against stress-induced apoptosis and shown that increasing plasma high-density lipoprotein protects against the deleterious side effects of the chemotherapeutic and cardiotoxic drug doxorubicin.

Finite Element Model and Validation of Nasal Tip Deformation.

Nasal tip mechanical stability is important for functional and cosmetic nasal airway surgery. Palpation of the nasal tip provides information on tip strength to the surgeon, though it is a purely subjective assessment. Providing a means to simulate nasal tip deformation with a validated model can offer a more objective approach in understanding the mechanics and nuances of the nasal tip support and eventual nasal mechanics as a whole. Herein we present validation of a finite element (FE) model of the nose using physical measurements recorded using an ABS plastic-silicone nasal phantom. Three-dimensional photogrammetry was used to capture the geometry of the phantom at rest and while under steady state load. The silicone used to make the phantom was mechanically tested and characterized using a linear elastic constitutive model. Surface point clouds of the silicone and FE model were compared for both the loaded and unloaded state. The average Hausdorff distance between actual measurements and FE simulations across the nose were 0.39 ± 1.04 mm and deviated up to 2 mm at the outermost boundaries of the model. FE simulation and measurements were in near complete agreement in the immediate vicinity of the nasal tip with millimeter accuracy. We have demonstrated validation of a two-component nasal FE model, which could be used to model more complex modes of deformation where direct measurement may be challenging. This is the first step in developing a nasal model to simulate nasal mechanics and ultimately the interaction between geometry and airflow.

Coil Embolization of Diverticulum of Kommerell: A Targeted Hybrid Endovascular Technique.

A 57-year-old man was incidentally found to have a dissected diverticulum of Kommerell originating from aberrant origin of right subclavian artery during follow-up for treated colon cancer. A right carotid-axillary bypass was followed by embolization of aberrant artery and the diverticulum by deployment of multiple detachable coils using the Penumbra Ruby System (Penumbra, Alameda, CA). Angiography after embolization showed exclusion of flow to the aberrant artery and a patent right carotid-axillary bypass. The patient recovered uneventfully and remained well for 12 weeks after the operation, without any complications. We believe this targeted endovascular approach can avoid complications related to the coverage of thoracic aorta and reduce the risk of access vessel trauma.

Optimal Electromechanical Reshaping of the Auricular Ear and Long-term Outcomes in an In Vivo Rabbit Model.

IMPORTANCE: The prominent ear is a common external ear anomaly that is usually corrected through surgery. Electromechanical reshaping (EMR) may provide the means to reshape cartilage through the use of direct current (in milliamperes) applied percutaneously with needle electrodes and thus to reduce reliance on open surgery. OBJECTIVE: To determine the long-term outcomes (shape change, cell viability, and histology) of a more refined EMR voltage and time settings for reshaping rabbit auricle. DESIGN, SETTING, AND SUBJECTS: The intact ears of 14 New Zealand white rabbits were divided into 2 groups. Group 1 received 4 V for 5 minutes (5 ears), 5 V for 4 minutes (5 ears), or no voltage for 5 minutes (control; 4 ears). Group 2 received an adjusted treatment of 4 V for 4 minutes (7 ears) or 5 V for 3 minutes (7 ears). A custom mold with platinum electrodes was used to bend the pinna and to perform EMR. Pinnae were splinted for 6 months along the region of the bend. Rabbits were killed humanely and the ears were harvested the day after splint removal. Data were collected from March 14, 2013, to July 8, 2014, and analyzed from August 29, 2013, to March 1, 2015. MAIN OUTCOMES AND MEASURES: Bend angle and mechanical behavior via palpation were recorded through photography and videography. Tissue was sectioned for histologic examination and confocal microscopy to assess changes to microscopic structure and cell viability. RESULTS: Rabbits ranged in age from 6 to 8 months and weighed 3.8 to 4.0 g. The mean (SD) bend angles were 81° (45°) for the controls and, in the 5 EMR groups, 72° (29°) for 4 V for 4 minutes, 101° (19°) for 4 V for 5 minutes, 78° (18°) for 5 V for 3 minutes, and 126° (21°) for 5 V for 4 minutes. At 5 V, an increase in application time from 3 to 4 minutes provided significant shape change (78° [18°] and 126° [21°], respectively; P = .003). Pinnae stained with hematoxylin-eosin displayed localized areas of cell injury and fibrosis in and around electrode insertion sites. This circumferential zone of injury (range, 1.3-2.1 mm) corresponded to absence of red florescence on the cell viability assay. CONCLUSIONS AND RELEVANCE: In this in vivo study, EMR produces shape changes in the intact pinnae of rabbits. A short application of 4 V or 5 V can achieve adequate reshaping of the pinnae. Tissue injury around the electrodes is modest in spatial distribution. This study provides a more optimal set of EMR variables and a critical step toward evaluation of EMR in clinical trials. LEVEL OF EVIDENCE: NA.

Quantifying Optimal Columellar Strut Dimensions for Nasal Tip Stabilization After Rhinoplasty via Finite Element Analysis.

IMPORTANCE: The contribution of columellar strut grafts (CSGs) to nasal tip support has not been determined via structural mechanics. Optimal graft dimensions have yet to be objectively determined. OBJECTIVES: To use a finite element model (FEM) of the human nose to (1) determine the effect of the CSG on nasal tip support and (2) identify how suture placement contributes to tip support. DESIGN, SETTING, AND PARTICIPANTS: A multiple-component FEM of the human nose consisting of bone, skin/soft tissue, and cartilage was rendered from a computed tomographic scan. Then, CSGs of varying sizes were created, ranging from 15 × 4 × 1 mm to 25 × 8 × 1 mm, and placed in the model between the medial crura. Two FEMs were constructed for each strut size: (1) CSGs that were physically attached to the nasal spine, medial crura, and caudal septum and (2) CSGs that were not in direct contact with these structures and free to move within the soft tissue. A control model was also constructed wherein no graft was placed. MAIN OUTCOMES AND MEASURES: Nasal tip support for each model was assessed, and the resultant distribution of von Mises stress, reaction force, and strain energy density with respect to the alar cartilages were calculated. RESULTS: Compared with the control, the reaction force increased with increasing strut volume, while the strain energy density (calculated over the alar cartilages) generally decreased with increasing CSG volume. Simulations with struts that had suture attachments along the entire length of the graft generated a larger reaction force than the models without any suture attachments. Models with anteriorly placed sutures generated reaction forces similar to that of the fully sutured model, whereas the models with posterior sutures showed reaction forces similar to the fully disconnected model. CONCLUSIONS AND RELEVANCE: Insertion of CSGs does effect the amount of force the nasal tip can withstand post rhinoplasty. Moreover, anteriorly placed sutures incur reaction forces similar to struts that are fully connected to the alar cartilage. Thus, our simulations are congruent with clinical practice in that stability increases with graft size and fixation, and that sutures should be placed along either the entire CSG or the anterior most portion for optimal support. LEVEL OF EVIDENCE: NA.

A Finite Element Model to Simulate Formation of the Inverted-V Deformity.

IMPORTANCE: Computational modeling can be used to mimic the forces acting on the nasal framework that lead to the inverted-V deformity (IVD) after surgery and potentially determine long-range outcomes. OBJECTIVE: To demonstrate the use of the finite element method (FEM) to predict the formation of the IVD after separation of the upper lateral cartilages (ULCs) from the nasal septum. DESIGN, SETTING, AND PARTICIPANTS: A computer model of a nose was derived from human computed tomographic data. The septum and upper and lower lateral cartilages were designed to fit within the soft-tissue envelope using computer-aided design software. Mechanical properties were obtained from the literature. The 3 simulations created included (1) partial fusion of the ULCs to the septum, (2) separation of the ULCs from the septum, and (3) a fully connected model to serve as a control. Forces caused by wound healing were prescribed at the junction of the disarticulated ULCs and septum. Using FEM software, equilibrium stress and strain were calculated. Displacement of the soft tissue along the nasal dorsum was measured and evaluated for evidence of morphologic change consistent with the IVD. MAIN OUTCOME AND MEASURES: Morphologic changes on the computer models in response to each simulation. RESULTS: When a posteroinferior force vector was applied along the nasal dorsum, the areas of highest stress were along the medial edge of the ULCs and at the junction of the ULCs and the nasal bones. With full detachment of ULCs and the dorsal septum, the characteristic IVD was observed. Both separation FEMs produced a peak depression of 0.3 mm along the nasal dorsum. CONCLUSIONS AND RELEVANCE: The FEM can be used to simulate the long-term structural complications of a surgical maneuver in rhinoplasty, such as the IVD. When applied to other rhinoplasty maneuvers, the use of FEMs may be useful to simulate the long-term outcomes, particularly when long-term clinical results are not available. In the future, use of FEMs may simulate rhinoplasty results beyond simply morphing the outer contours of the nose and allow estimation of potentially long-term clinical outcomes that may not be readily apparent. LEVEL OF EVIDENCE: NA.

Finite Element Model Analysis of Cephalic Trim on Nasal Tip Stability.

IMPORTANCE: Alar rim retraction is the most common unintended consequence of tissue remodeling that results from overresection of the cephalic lateral crural cartilage; however, the complex tissue remodeling process that produces this shape change is not well understood. OBJECTIVES: To simulate how resection of cephalic trim alters the stress distribution within the human nose in response to tip depression (palpation) and to simulate the internal forces generated after cephalic trim that may lead to alar rim retraction cephalically and upward rotation of the nasal tip. DESIGN, SETTING, AND PARTICIPANTS: A multicomponent finite element model was derived from maxillofacial computed tomography with 1-mm axial resolution. The 3-dimensional editing function in the medical imaging software was used to trim the cephalic portion of the lower lateral cartilage to emulate that performed in typical rhinoplasty. Three models were created: a control, a conservative trim, and an aggressive trim. Each simulated model was imported to a software program that performs mechanical simulations, and material properties were assigned. First, nasal tip depression (palpation) was simulated, and the resulting stress distribution was calculated for each model. Second, long-term tissue migration was simulated on conservative and aggressive trim models by placing normal and shear force vectors along the caudal and cephalic borders of the tissue defect. RESULTS: The von Mises stress distribution created by a 5-mm tip depression revealed consistent findings among all 3 simulations, with regions of high stress being concentrated to the medial portion of the intermediate crus and the caudal septum. Nasal tip reaction force marginally decreased as more lower lateral cartilage tissue was resected. Conservative and aggressive cephalic trim models produced some degree of alar rim retraction and tip rotation, which increased with the magnitude of the force applied to the region of the tissue defect. CONCLUSIONS AND RELEVANCE: Cephalic trim was performed on a computerized composite model of the human nose to simulate conservative and aggressive trims. Internal forces were applied to each model to emulate the tissue migration that results from decades of wound healing. Our simulations reveal that the degree of tip rotation and alar rim retraction is dependent on the amount of cartilage that was resected owing to cephalic trim. Tip reaction force is marginally reduced with increasing tissue volume resection. LEVEL OF EVIDENCE: NA.

Handheld-Level Electromechanical Cartilage Reshaping Device.

We have developed a handheld-level multichannel electromechanical reshaping (EMR) cartilage device and evaluated the feasibility of providing a means of cartilage reshaping in a clinical outpatient setting. The effect of EMR on pig costal cartilage was evaluated in terms of shape change, tissue heat generation, and cell viability. The pig costal cartilage specimens (23 mm × 6.0 mm × 0.7 mm) were mechanically deformed to 90 degrees and fixed to a plastic jig and applied 5, 6, 7, and 8 V up to 8 minutes to find the optimal dosimetry for the our developed EMR device. The results reveal that bend angle increased with increasing voltage and application time. The maximum bend angle obtained was 70.5 ± 7.3 at 8 V, 5 minutes. The temperature of flat pig costal cartilage specimens were measured, while a constant electric voltage was applied to three pairs of electrodes that were inserted into the cartilages. The nonthermal feature of EMR was validated by a thermal infrared camera; that is, the maximum temperate of the flat cartilages is 20.3°C at 8 V. Cell viability assay showed no significant difference in cell damaged area from 3 to 7 minutes exposure with 7 V. In conclusion, the multichannel EMR device that was developed showed a good feasibility of cartilage shaping with minimal temperature change.

Tangential Bicortical Locked Fixation Improves Stability in Vancouver B1 Periprosthetic Femur Fractures: A Biomechanical Study.

OBJECTIVES: The biomechanical difficulty in fixation of a Vancouver B1 periprosthetic fracture is purchase of the proximal femoral segment in the presence of the hip stem. Several newer technologies provide the ability to place bicortical locking screws tangential to the hip stem with much longer lengths of screw purchase compared with unicortical screws. This biomechanical study compares the stability of 2 of these newer constructs to previous methods. METHODS: Thirty composite synthetic femurs were prepared with cemented hip stems. The distal femur segment was osteotomized, and plates were fixed proximally with either (1) cerclage cables, (2) locked unicortical screws, (3) a composite of locked screws and cables, or tangentially directed bicortical locking screws using either (4) a stainless steel locking compression plate system with a Locking Attachment Plate (Synthes) or (5) a titanium alloy Non-Contact Bridging system (Zimmer). Specimens were tested to failure in either axial or torsional quasistatic loading modes (n = 3) after 20 moderate load preconditioning cycles. Stiffness, maximum force, and failure mechanism were determined. RESULTS: Bicortical constructs resisted higher (by an average of at least 27%) maximum forces than the other 3 constructs in torsional loading (P < 0.05). Cables constructs exhibited lower maximum force than all other constructs, in both axial and torsional loading. The bicortical titanium construct was stiffer than the bicortical stainless steel construct in axial loading. CONCLUSIONS: Proximal fixation stability is likely improved with the use of bicortical locking screws as compared with traditional unicortical screws and cable techniques. In this study with a limited sample size, we found the addition of cerclage cables to unicortical screws may not offer much improvement in biomechanical stability of unstable B1 fractures.

Long-term in vivo electromechanical reshaping for auricular reconstruction in the New Zealand white rabbit model.

OBJECTIVES/HYPOTHESIS: To demonstrate the dosimetry effect of electromechanical reshaping (EMR) on cartilage shape change, structural integrity, cellular viability, and remodeling of grafts in an in vivo long-term animal model. STUDY DESIGN: Animal study. METHODS: A subperichondrial cartilaginous defect was created within the base of the pinna of 31 New Zealand white rabbits. Autologous costal cartilage grafts were electromechanically reshaped to resemble the rabbit auricular base framework and mechanically secured into the pinna base defect. Forty-nine costal cartilage specimens (four control and 45 experimental) successfully underwent EMR using a paired set of voltage-time combinations and survived for 6 or 12 weeks. Shape change was measured, and specimens were analyzed using digital imaging, tissue histology, and confocal microscopy with LIVE-DEAD viability assays. RESULTS: Shape change was proportional to charge transfer in all experimental specimens (P < .01) and increased with voltage. All experimental specimens contoured to the auricular base. Focal cartilage degeneration and fibrosis was observed where needle electrodes were inserted, ranging from 2.2 to 3.9 mm. The response to injury increased with increasing charge transfer and survival duration. CONCLUSIONS: EMR results in appropriate shape change in cartilage grafts with chondrocyte injury highly localized. These studies suggest that elements of auricular reconstruction may be feasible using EMR. Extended survival periods and further optimization of voltage-time pairs are necessary to evaluate the long-term effects and shape-change potential of EMR. LEVELS OF EVIDENCE: NA.

Electromechanical reshaping of ex vivo porcine trachea.

OBJECTIVES: The trachea is a composite cartilaginous structure particularly prone to various forms of convexities. Electromechanical reshaping (EMR) is an emerging technique used to reshape cartilaginous tissues by applying electric current in tandem with imposed mechanical deformation to achieve shape change. In this study, EMR was used to reshape tracheal cartilage rings to demonstrate the feasibility of this technology as a potentially minimally invasive procedure to alter tracheal structure. STUDY DESIGN: Controlled laboratory study using ex vivo porcine tracheae. METHODS: The natural concavity of each porcine tracheal ring was reversed around a cork mandrel. Two pairs of electrodes were inserted along the long axis of the tracheal ring and placed 1.5 millimeters from the midline. Current was applied over a range of voltages (3 volts [V], 4V, and 5V) for either 2 or 3 minutes. The degree of EMR-induced reshaping was quantified from photographs using digital techniques. Confocal imaging with fluorescent live and dead assays was conducted to determine viability of the tissue after EMR. RESULTS: Specimens that underwent EMR for 2 or 3 minutes at 4V or 5V were observed to have undergone significant (P < .05) reshaping relative to the control. Viability results demonstrated that EMR reshaping occurs at the expense of tissue injury, although the extent of injury is modest relative to conventional techniques. CONCLUSION: EMR reshapes tracheal cartilage rings as a function of voltage and application time. It has potential as a minimally invasive and cost-efficient endoscopic technology to treat pathologic tracheal convexities. Given our findings, consideration of EMR for use in larger ex vivo tracheal segments and animal studies is now plausible.

Rethinking nasal tip support: a finite element analysis.

OBJECTIVE: We employ a nasal tip finite element model (FEM) to evaluate contributions of two of the three major tip support mechanisms: attachments between the upper and lower lateral cartilages and attachment of the medial crura to the caudal septum. STUDY DESIGN: The nasal tip FEM computed stress distribution and strain energy density (SED) during nasal tip compression. We examined the impact of attachments between the upper and lower lateral cartilages and the attachment of the medial crura to the caudal septum on nasal tip support. METHODS: The FEM consisted of three tissue components: bone, cartilage, and skin. Four models were created: A) control model with attachments present at the scroll and caudal septum; B) simulated disruption of scroll; C) simulated disruption of medial crura attachments to caudal septum; and D) simulated disruption of scroll and medial crura attachments to caudal septum. Spatial distribution of stress and SED were calculated. RESULTS: The keystone, intermediate crura, caudal septum, and nasal spine demonstrated high concentration of stress distribution. Across all models, there was no difference in stress distribution. Disruption of the scroll resulted in 1% decrease in SED. Disruption of the medial crura attachments to the caudal septum resulted in 4.2% reduction in SED. Disruption of both scroll and medial crural attachments resulted in 9.1% reduction in SED. CONCLUSION: The nasal tip FEM is an evolving tool to study structural nasal tip dynamics and demonstrates the loss of nasal tip support with disruption of attachments at the scroll and nasal base. LEVEL OF EVIDENCE: N/A.

In-depth analysis of pH-dependent mechanisms of electromechanical reshaping of rabbit nasal septal cartilage.

OBJECTIVES/HYPOTHESIS: Electromechanical reshaping (EMR) involves reshaping cartilage by mechanical deformation and delivering electric current to the area around the bend axis, causing local stress relaxation and permanent shape change. The mechanism of EMR is currently unclear, although preliminary studies suggest that voltage and application time are directly related to the concentration and diffusion of acid-base products within the treated tissue with little heat generation. This study aims to characterize local tissue pH changes following EMR and to demonstrate that local tissue pH changes are correlated with tissue damage and shape change. STUDY DESIGN: Ex vivo animal study involving EMR of rabbit nasal septal cartilage and biochemical estimation of tissue pH changes. METHODS: The magnitude and diffusion of acid-base chemical products in control (0V, 2 minutes), shape change (4V, 4 minutes; 6V, 1, 2, 4 minutes; 8V, 1, 2 minutes), and tissue damage (8V, 4, 5 minutes; 10V, 4, 5 minutes) parameters following EMR are approximated by analyzing local pH changes after pH indicator application. RESULTS: There is a direct relationship between total charge transfer and extent of acid-base product diffusion (P <0.05). A "pH transition zone" is seen surrounding the bend apex above 8V, 2 minutes. Colorimetric analysis suggests that small local pH changes (10(-8) hydrogen ions) are at least partly implicated in clinically efficacious EMR. CONCLUSIONS: These results provide additional insight into the translational applications of EMR, particularly the relationship among pH changes, shape change, and tissue injury, and are integral in optimizing this promising technology for clinical use.

Nasal tip support: a finite element analysis of the role of the caudal septum during tip depression.

OBJECTIVES/HYPOTHESIS: Although minor and major tip support mechanisms have been described in detail, no quantitative models exist to provide support for the relative contributions of the structural properties of the major alar cartilage, the fibrous attachments to surrounding structures, and the rigid support structures in an objective manner. STUDY DESIGN: The finite element method was used to compute the stress distribution in the nose during simple tip compression, and then identify the specific anatomic structures that resist deformation and thus contribute to tip support. Additionally, the impact of caudal septal resection on nasal tip support was examined. METHODS: The computer models consisted of three tissue components with anatomically correct geometries for skin and bone derived from computed tomographic data. Septum, upper lateral cartilages, and major alar cartilages were fitted within the model using three-dimensional computer-aided design software. Five-millimeter nasal tip compression was performed on the models with caudal septal resection (3 and 5 mm) and without resection to simulate palpation, then the resulting spatial distribution of stress and displacement was calculated. RESULTS: The von Mises stress in the normal model was primarily concentrated along the medial crural angle. As caudal septum length was reduced, stress was redistributed to adjacent soft tissue and bone, resulting in less force acting on the septum. In all models, displacement was greatest near the intermediate crura. CONCLUSIONS: These models are the first step in the comprehensive mechanical analysis of nasal tip dynamics. Our model supports the concept of the caudal septum and major alar cartilage providing the majority of critical load-bearing support.

In vivo laser cartilage reshaping with carbon dioxide spray cooling in a rabbit ear model: a pilot study.

BACKGROUND/OBJECTIVES: Similar to conventional cryogen spray cooling, carbon dioxide (CO2) spray may be used in combination with laser cartilage reshaping (LCR) to produce cartilage shape change while minimizing cutaneous thermal injury. Recent ex vivo evaluation of LCR with CO2 cooling in a rabbit model has identified a promising initial parameter space for in vivo safety and efficacy evaluation. This pilot study aimed to evaluate shape change and cutaneous injury following LCR with CO2 cooling in 5 live rabbits. STUDY DESIGN/MATERIALS AND METHODS: The midportion of live rabbit ears were irradiated with a 1.45 µm wavelength diode laser (12 J/cm(2)) with simultaneous CO2 spray cooling (85 millisecond duration, 4 alternating heating/cooling cycles per site, 5 to 6 irradiation sites per row for 3 rows per ear). Experimental and control ears (no LCR) were splinted in the flexed position for 30 days following exposure. A total of 5 ears each were allocated to the experimental and control groups. RESULTS: Shape change was observed in all irradiated ears (mean 70 ± 3°), which was statistically different from control (mean 37 ± 11°, P = 0.009). No significant thermal cutaneous injury was observed, with preservation of the full thickness of skin, microvasculature, and adnexal structures. Confocal microscopy and histology demonstrated an intact and viable chondrocyte population surrounding irradiated sites. CONCLUSIONS: LCR with CO2 spray cooling can produce clinically significant shape change in the rabbit auricle while minimizing thermal cutaneous and cartilaginous injury and frostbite. This pilot study lends support for the potential use of CO2 spray as an adjunct to existing thermal-based cartilage reshaping modalities. An in vivo systematic evaluation of optimal laser dosimetry and cooling parameters is required.

Ex vivo investigations of laser auricular cartilage reshaping with carbon dioxide spray cooling in a rabbit model.

Laser cartilage reshaping (LCR) with cryogen spray cooling is a promising modality for producing cartilage shape change while reducing cutaneous thermal injury. However, LCR in thicker tissues, such as auricular cartilage, requires higher laser power, thus increasing cooling requirements. To eliminate the risks of freeze injury characteristic of high cryogen spray pulse rates, a carbon dioxide (CO2) spray, which evaporates rapidly from the skin, has been proposed as the cooling medium. This study aims to identify parameter sets which produce clinically significant reshaping while producing minimal skin thermal injury in LCR with CO2 spray cooling in ex vivo rabbit auricular cartilage. Excised whole rabbit ears were mechanically deformed around a cylindrical jig and irradiated with a 1.45-µm wavelength diode laser (fluence 12-14 J/cm(2) per pulse, four to six pulse cycles per irradiation site, five to six irradiation sites per row for four rows on each sample) with concomitant application of CO2 spray (pulse duration 33-85 ms) to the skin surface. Bend angle measurements were performed before and after irradiation, and the change quantified. Surface temperature distributions were measured during irradiation/cooling. Maximum skin surface temperature ranged between 49.0 to 97.6 °C following four heating/cooling cycles. Significant reshaping was achieved with all laser dosimetry values with a 50-70 °C difference noted between controls (no cooling) and irradiated ears. Increasing cooling pulse duration yielded progressively improved gross skin protection during irradiation. CO2 spray cooling may potentially serve as an alternative to traditional cryogen spray cooling in LCR and may be the preferred cooling medium for thicker tissues. Future studies evaluating preclinical efficacy in an in vivo rabbit model are in progress.

Implantation of allogenic synovial stem cells promotes meniscal regeneration in a rabbit meniscal defect model.

BACKGROUND: Indications for surgical meniscal repair are limited, and failure rates remain high. Thus, new ways to augment repair and stimulate meniscal regeneration are needed. Mesenchymal stem cells are multipotent cells present in mature individuals and accessible from peripheral connective tissue sites, including synovium. The purpose of this study was to quantitatively evaluate the effect of implantation of synovial tissue-derived mesenchymal stem cells on meniscal regeneration in a rabbit model of partial meniscectomy. METHODS: Synovial mesenchymal stem cells were harvested from the knee of one New Zealand White rabbit, expanded in culture, and labeled with a fluorescent marker. A reproducible 1.5-mm cylindrical defect was created in the avascular portion of the anterior horn of the medial meniscus bilaterally in fifteen additional rabbits. Allogenic synovial mesenchymal stem cells suspended in phosphate-buffered saline solution were implanted into the right knees, and phosphate-buffered saline solution alone was placed in the left knees. Meniscal regeneration was evaluated histologically at four, twelve, and twenty-four weeks for (1) quantity and (2) quality (with use of an established three-component scoring system). A similar procedure was performed in four additional rabbits with use of green fluorescent protein-positive synovial mesenchymal stem cells for the purpose of tracking progeny following implantation. RESULTS: The quantity of regenerated tissue in the group that had implantation of synovial mesenchymal stem cells was greater at all end points, reaching significance at four and twelve weeks (p < 0.05). Tissue quality scores were also superior in knees treated with mesenchymal stem cells compared with controls at all end points, achieving significance at twelve and twenty-four weeks (3.8 versus 2.8 at four weeks [p = 0.29], 5.7 versus 1.7 at twelve weeks [p = 0.008], and 6.0 versus 3.9 at twenty-four weeks [p = 0.021]). Implanted cells adhered to meniscal defects and were observed in the regenerated tissue, where they differentiated into type-I and II collagen-expressing cells, at up to twenty-four weeks. CONCLUSIONS: Synovial mesenchymal stem cells adhere to sites of meniscal injury, differentiate into cells resembling meniscal fibrochondrocytes, and enhance both quality and quantity of meniscal regeneration.

Electromechanical reshaping of costal cartilage grafts: a new surgical treatment modality.

OBJECTIVES/HYPOTHESIS: Needle electrode-based electromechanical reshaping (EMR) is a novel, ultra-low-cost nascent surgical technology to reshape cartilage with low morbidity. EMR uses direct current to induce mechanical relaxation in cartilage that is first deformed into a required geometry, which in turn leads to permanent shape change. The objective of this study was to determine the effect of EMR voltage and time on the shape change of costal cartilage grafts. STUDY DESIGN: EMR of ex vivo porcine costal cartilage. METHODS: Graft specimens obtained from the central core of porcine costal cartilage were bent at a 90-degree angle with a custom jig and then reshaped via EMR. The effects of voltage (3-7 V) and application time (1-5 minutes) on the amount of shape change were systematically examined. Bend angles were analyzed using analysis of variance and paired t tests to determine significant reshaping times at each voltage setting. RESULTS: There is a threshold for voltage and time above which the retention of bend angle is statistically significant in treated specimens compared to the control (P < .05). Above the threshold of 3 V, shape retention initially increased with application time for all voltages tested and was then observed to reach a plateau. Shape retention was noted to be greatest at 6 V without a rise in temperature. CONCLUSIONS: EMR provides a novel method to bend and shape costal cartilage grafts for use in facial plastic surgery. A low voltage can reshape cartilage grafts within several minutes and without the heat generation. This study demonstrates the feasibility of EMR and brings this minimally invasive procedure closer to clinical implementation.

Needle electrode-based electromechanical reshaping of cartilage.

Electromechanical reshaping (EMR) of cartilage provides an alternative to the classic surgical techniques of modifying the shape of facial cartilages. The original embodiment of EMR required surface electrodes to be in direct contact with the entire cartilage region being reshaped. This study evaluates the feasibility of using needle electrode systems for EMR of facial cartilage and evaluates the relationships between electrode configuration, voltage, and application time in effecting shape change. Flat rabbit nasal septal cartilage specimens were deformed by a jig into a 90° bend, while a constant electric voltage was applied to needle electrodes that were inserted into the cartilage. The electrode configuration, voltage (0-7.5 V), and application time (1-9 min) were varied systematically to create the most effective shape change. Electric current and temperature were measured during voltage application, and the resulting specimen shape was assessed in terms of retained bend angle. In order to demonstrate the clinical feasibility of EMR, the most effective and practical settings from the septal cartilage experimentation were used to reshape intact rabbit and pig ears ex vivo. Cell viability of the cartilage after EMR was determined using confocal microscopy in conjunction with a live/dead assay. Overall, cartilage reshaping increased with increased voltage and increased application time. For all electrode configurations and application times tested, heat generation was negligible (<1 °C) up to 6 V. At 6 V, with the most effective electrode configuration, the bend angle began to significantly increase after 2 min of application time and began to plateau above 5 min. As a function of voltage at 2 min of application time, significant reshaping occurred at and above 5 V, with no significant increase in the bend angle between 6 and 7.5 V. In conclusion, electromechanical reshaping of cartilage grafts and intact ears can be effectively performed with negligible temperature elevation and spatially limited cell injury using needle electrodes.

Low-dose oral sirolimus reduces atherogenesis, vascular inflammation and modulates plaque composition in mice lacking the LDL receptor.

BACKGROUND AND PURPOSE: Chronic proliferative responses of different vascular cell types have been involved in the pathogenesis of atherosclerosis. However, their functional role remains to be established. Sirolimus reduces neointimal proliferation after balloon angioplasty and chronic graft vessel disease. These studies were undertaken to investigate the effects of this anti-proliferative drug on atherogenesis. EXPERIMENTAL APPROACH: Low-density lipoprotein receptor-deficient (LDL r-KO) mice on a cholesterol-rich diet were randomized to receive placebo or sirolimus (0.1; 0.3; or 1 mg.kg(-1)) in their diet for 8 or 16 weeks. RESULTS: In both studies, plasma levels of the drug increased in a dose-dependent fashion, animals gained weight normally and, among groups, plasma lipids levels did not differ significantly. Compared with placebo, plasma levels of interleukin-6, monocyte chemoattractant protein-1, interferon gamma, tumour necrosis factor alpha and CD40, and their mRNA levels in aortic tissue were significantly reduced in sirolimus-treated mice. This effect resulted in a significant and dose-dependent reduction in atherosclerotic lesions, in both the root and aortic tree. Also these lesions contained less monocyte/macrophages and smooth muscle cells, but more collagen. CONCLUSIONS AND IMPLICATIONS: The present results demonstrated that at low doses, sirolimus was an effective and safe anti-atherogenic agent in the LDL r-KO mice. It attenuated the progression of atherosclerosis and modulated the plaque phenotype by reducing the pro-inflammatory vascular responses typical of the disease.