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Cerebral aneurysms are a source of neurological morbidity and mortality, most often as a result of rupture. The most common approach for treating aneurysms involves endovascular embolization using nonbiodegradable medical devices, such as platinum coils. However, the need for retreatment due to the recanalization of coil-treated aneurysms highlights the importance of exploring alternative solutions. In this study, we propose an injectable extracellular matrix-derived embolic formed in situ by Michael addition of gelatin-thiol (Gel-SH) and hyaluronic acid vinyl sulfone (HA-VS) that may be delivered with a therapeutic agent (here, RADA-SP) to fill and remodel aneurysmal tissue without leaving behind permanent foreign bodies. The injectable embolic material demonstrated rapid gelation under physiological conditions, forming a highly porous structure and allowing for cellular infiltration. The injectable embolic exhibited thrombogenic behavior in vitro that was comparable to that of alginate injectables. Furthermore, in vivo studies in a murine carotid aneurysm model demonstrated the successful embolization of a saccular aneurysm and extensive cellular infiltration both with and without RADA-SP at 3 weeks, with some evidence of increased vascular or fibrosis markers with RADA-SP incorporation. The results indicate that the developed embolic has inherent potential for acutely filling cerebrovascular aneurysms and encouraging the cellular infiltration that would be necessary for stable, chronic remodeling.
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Embolização Terapêutica , Matriz Extracelular , Aneurisma Intracraniano , Animais , Aneurisma Intracraniano/terapia , Embolização Terapêutica/métodos , Camundongos , Ácido Hialurônico/química , Gelatina/química , Masculino , HumanosRESUMO
Peripheral nerve injuries (PNIs) occur frequently and can lead to devastating and permanent sensory and motor function disabilities. Systemic tacrolimus (FK506) administration has been shown to hasten recovery and improve functional outcomes after PNI repair. Unfortunately, high systemic levels of FK506 can result in adverse side effects. The localized administration of FK506 could provide the neuroregenerative benefits of FK506 while avoiding systemic, off-target side effects. This study investigates the utility of a novel FK506-impregnated polyester urethane urea (PEUU) nerve wrap to treat PNI in a previously validated rat infraorbital nerve (ION) transection and repair model. ION function was assessed by microelectrode recordings of trigeminal ganglion cells responding to controlled vibrissae deflections in ION-transected and -repaired animals, with and without the nerve wrap. Peristimulus time histograms (PSTHs) having 1 ms bins were constructed from spike times of individual single units. Responses to stimulus onsets (ON responses) were calculated during a 20 ms period beginning 1 ms after deflection onset; this epoch captures the initial, transient phase of the whisker-evoked response. Compared to no-wrap controls, rats with PEUU-FK506 wraps functionally recovered earlier, displaying larger response magnitudes. With nerve wrap treatment, FK506 blood levels up to six weeks were measured nearly at the limit of quantification (LOQ ≥ 2.0 ng/mL); whereas the drug concentrations within the ION and muscle were much higher, demonstrating the local delivery of FK506 to treat PNI. An immunohistological assessment of ION showed increased myelin expression for animals assigned to neurorrhaphy with PEUU-FK506 treatment compared to untreated or systemic-FK506-treated animals, suggesting that improved PNI outcomes using PEUU-FK506 is mediated by the modulation of Schwann cell activity.
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Bainha de Mielina , Tacrolimo , Animais , Ratos , Tacrolimo/farmacologia , Neurônios , Uretana , Regeneração Nervosa , Amidas , Carbamatos , Ureia , ÉsteresRESUMO
Objective: Although driving simulators are powerful tools capable of measuring a wide-ranging set of tactical and operational level driving behaviors, comparing these behaviors across studies is problematic because there is no core set of driving variables to report when assessing driving behavior in simulated driving scenarios. To facilitate comparisons across studies, researchers need consistency in how driving simulator variables combine to assess driving behavior. With inter-study consistency, driving simulator research could support stronger conclusions about safe driving behaviors and more reliably identify future driver training goals. The purpose of the current study was to derive empirically and theoretically meaningful composite scores from driving behaviors of young people in a driving simulator, utilizing driving data from across a variety of driving environments and from within the individual driving environments. Method: One hundred ninety adolescent participants aged 16 years or 18 years at enrollment provided demographic data and drove in a high-fidelity driving simulator. The simulated scenario included 4 distinct environments: Urban, Freeway, Residential, and a Car Following Task (CFT). A Principal Components Analysis (PCA) was conducted on the variable output from the driving simulator to select optimal factor solutions and loadings both across the multi-environmental drive and within the four individual driving environments. Results: The PCA suggested two components from the multi-environmental simulated drive: vehicle control and speed. The individual driving environments also indicated two components: vehicle control and tactical judgment. Conclusion: These findings are among the first steps for identifying composite driving simulator variables to quantify theoretical conceptualizations of driving behavior. Currently, driving behavior and performance measured by driving simulators lack "gold standards" via driving scores or benchmarks. The composites derived in this analysis may be studied for further use where driving behavior standards are increasingly sought by clinicians and practitioners for a variety of populations, as well as by parents concerned about the readiness of their novice driving teen.
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Thrombosis and intimal hyperplasia have remained the major failure mechanisms of small-diameter vascular grafts used in bypass procedures. While most efforts to reduce thrombogenicity have used a biochemical surface modification approach, the use of local mechanical phenomena to aid in this goal has received somewhat less attention. In this work, the mechanical, fluid transport, and geometrical properties of a layered and porous vascular graft are optimized within a porohyperelastic finite element framework to maximize self-cleaning via luminal reversal fluid velocity (into the lumen). This is expected to repel platelets as well as inhibit the formation of and/or destabilize adsorbed protein layers thereby reducing thrombogenic potential. A particle swarm optimization algorithm was utilized to maximize luminal reversal fluid velocity while also compliance matching our graft to a target artery (rat aorta). The maximum achievable luminal reversal fluid velocity was approximately 246 µm/s without simultaneously optimizing for host compliance. Simultaneous optimization of reversal flow and compliance resulted in a luminal reversal fluid velocity of 59 µm/s. Results indicate that a thick highly permeable compressible inner layer and a thin low permeability incompressible outer layer promote intraluminal reversal fluid velocity. Future research is needed to determine the feasibility of fabricating such a layered and optimized graft and verify its ability to improve hemocompatibility.
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Modelos Cardiovasculares , Enxerto Vascular , Animais , Artérias , Prótese Vascular , Complacência (Medida de Distensibilidade) , RatosRESUMO
Improved materials for peripheral nerve repair are needed for the advancement of new surgical techniques in fields spanning from oncology to trauma. In this study, we developed bioresorbable materials capable of producing repeated electric field gradients spaced 600 µm apart to assess the impact on neuronal cell growth, and migration. Electrically conductive, biphasic composites comprised of poly (glycerol) sebacate acrylate (PGSA) alone, and doped with poly (pyrrole) (PPy), were prepared to create alternating segments with high and low electrically conductivity. Conductivity measurements demonstrated that 0.05% PPy added to PSA achieved an optimal value of 1.25 × 10-4 S/cm, for subsequent electrical stimulation. Tensile testing and degradation of PPy doped and undoped PGSA determined that 35-40% acrylation of PGSA matched nerve mechanical properties. Both fibroblast and neuronal cells thrived when cultured upon the composite. Biphasic PGSA/PPy sheets seeded with neuronal cells stimulated for with 3 V, 20 Hz demonstrated a 5x cell increase with 1 day of stimulation and up to a 10x cell increase with 3 days stimulation compared to non-stimulated composites. Tubular conduits composed of repeated high and low conductivity materials suitable for implantation in the rat sciatic nerve model for nerve repair were evaluated in vivo and were superior to silicone conduits. These results suggest that biphasic conducting conduits capable of maintaining mechanical properties without inducing compression injuries while generating repeated electric fields are a promising tool for acceleration of peripheral nerve repair to previously untreatable patients.
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Regeneração Nervosa , Nervo Isquiático , Humanos , Ratos , Animais , Células PC12 , Regeneração Nervosa/fisiologia , Nervo Isquiático/lesões , Estimulação Elétrica , Condutividade Elétrica , PirróisRESUMO
Poly(dimethylsiloxane) (PDMS) has been used in a wide range of biomedical devices and medical research due to its biostability, cytocompatibility, gas permeability, and optical properties. Yet, some properties of PDMS create critical limitations, particularly fouling through protein and cell adhesion. In this study, a diallyl-terminated sulfobetaine (SB-diallyl) molecule was synthesized and then directly mixed with a commercial PDMS base (Sylgard 184) and curing agent to produce a zwitterionic group-bearing PDMS (PDMS-SB) hybrid that does not require a complex or an additional surface modification process for the desired end product. In vitro examination of antifouling behavior following exposure to fresh ovine blood showed a significant reduction in platelet deposition for the PDMS-SB hybrid surface compared to that of a PDMS control (p < 0.05, n = 5). The manufacturability via soft lithography using the synthesized polymers was found to be comparable to that for unmodified PDMS. Bonding via O2 plasma treatment was confirmed, and the strength was measured and again found to be comparable to the control. PDMS-SB microfluidic devices were successfully fabricated and showed improved blood compatibility that could reduce channel occlusion due to clot formation relative to PDMS control devices. Further, gas (CO2) transfer through a PDMS-SB hybrid membrane was also tested with a proof-of-concept microchannel device and shown to be comparable to that through the PDMS control.
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Incrustação Biológica , Dispositivos Lab-On-A-Chip , Animais , Incrustação Biológica/prevenção & controle , Adesão Celular , Dimetilpolisiloxanos , Polímeros , Impressão , OvinosRESUMO
Capillary rarefaction is a hallmark of right ventricle (RV) failure. Mesenchymal stromal cell (MSC)-based therapy offers a potential treatment due to its pro-angiogenic function. However, the impact of RV tissue mechanics on MSC behavior is unclear, especially when referring to RV end-diastolic stiffness and mechanical anisotropy. In this study, we assessed MSC behavior on electrospun scaffolds with varied stiffness (normal vs failing RV) and anisotropy (isotropic vs anisotropic). In individual MSCs, we observed the highest vascular endothelial growth factor (VEGF) production and total tube length in the failing, isotropic group (2.00 ± 0.37, 1.53 ± 0.24), which was greater than the normal, isotropic group (0.70 ± 0.15, 0.55 ± 0.07; p < 0.05). The presence of anisotropy led to trends of increased VEGF production on normal groups (0.75 ± 0.09 vs 1.20 ± 0.17), but this effect was absent on failing groups. Our findings reveal synergistic effects of RV-like stiffness and anisotropy on MSC pro-angiogenic function and may guide MSC-based therapies for heart failure.
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Células-Tronco Mesenquimais , Fator A de Crescimento do Endotélio Vascular , Anisotropia , Ventrículos do Coração/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVE: The aim of the study is to describe a model of care and outcomes for placenta accreta spectrum (PAS) implemented in the context of a community based non-academic health system. STUDY DESIGN: The program for management of PAS includes a multidisciplinary team approach with protocols for ultrasound assessment, diagnosis, and surgery. The program was implemented in the two largest private hospitals in the Twin Cities, Minnesota, United States. Maternal and fetal outcomes as well as cost were compared for histopathologic confirmed PAS cases before (2007-2014, n = 41) and after (2015-2017, n = 26) implementation of the PAS program. RESULTS: Implementation of the PAS program was associated with ICU admission reductions from 53.7 to 19.2%, p = 0.005; a decrease of 1,682 mL in mean estimated blood loss (EBL) (p = 0.061); a decrease in transfusion from 85.4 to 53.9% (p = 0.005). The PAS program also resulted in a (non-significant) decrease in both surgical complications from 48.8 to 38.5% (p = 0.408) and postoperative complications from 61.0 to 42.3% (p = 0.135). The total cost of care for PAS cases in the 3 years after implementation of the program decreased by 33%. CONCLUSION: The implementation of a model of care for PAS led by a perinatology practice at a large regional non-academic referral center resulted in reductions of ICU admissions, operating time, transfusion, selected surgical complications, overall postoperative complications, and cost. KEY POINTS: · Implementation of a PAS care model resulted in reduced ICU admissions from 53.7% to 19.2%.. · Patient safety increased by reducing blood loss, transfusions and postoperative complications.. · This model decreased operating time, as well as total cost of care by 33%..
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A 67-year-old female presented with 2 weeks of right eye pain, redness, and diplopia. An orbital mass was found on magnetic resonance imaging (MRI), and biopsy revealed Merkel cell carcinoma (MCC). She had no primary head or neck lesion and no previous history of MCC. Positron emission tomography (PET) scan showed hypermetabolic subcutaneous lesions of the lower extremity andmultiple osseous lesions of the axial and appendicular skeleton. She received palliative external radiation of 20 Gy in 5 fractions to the orbit. After discussing immunotherapy, she opted for comfort care and expired 1 month later. To the best of our knowledge, this is only the third case of MCC with distant metastasis to the orbit and the first case in which the patient had no previous diagnosis of MCC and no known primary tumor.
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Ongoing investigations in wound repair bring new opportunities and challenges for creating novel composite engineered biomaterials. Efforts have been directed toward using different combinations of biomaterials with the goal of providing an ideal biomimetic substitute for native tissue. A universal formula using collagen, fibroin and a synthetic polymer is proposed. By modifying the ratio of the building blocks, the composite material can be fabricated to match the mechanical property of different types of tissues and be further tuned to carry desirable physical and biological function. The results should provide composite engineered materials comparable to native tissue in order to repair and regenerate a variety of wounds and tissues.
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Materiais Biocompatíveis , Alicerces Teciduais , Regeneração , Engenharia Tecidual , CicatrizaçãoRESUMO
Our review in the 2008 volume of this journal detailed the use of mechanical circulatory support (MCS) for treatment of heart failure (HF). MCS initially utilized bladder-based blood pumps generating pulsatile flow; these pulsatile flow pumps have been supplanted by rotary blood pumps, in which cardiac support is generated via the high-speed rotation of computationally designed blading. Different rotary pump designs have been evaluated for their safety, performance, and efficacy in clinical trials both in the United States and internationally. The reduced size of the rotary pump designs has prompted research and development toward the design of MCS suitable for infants and children. The past decade has witnessed efforts focused on tissue engineering-based therapies for the treatment of HF. This review explores the current state and future opportunities of cardiac support therapies within our larger understanding of the treatment options for HF.
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Circulação Assistida/instrumentação , Circulação Assistida/métodos , Cardiologia/tendências , Insuficiência Cardíaca/terapia , Coração Auxiliar , Adulto , Circulação Assistida/tendências , Engenharia Biomédica/métodos , Cardiologia/métodos , Criança , Pré-Escolar , Humanos , Lactente , Desenho de Prótese , Ensaios Clínicos Controlados Aleatórios como Assunto , Engenharia Tecidual/métodosRESUMO
The growing field of regenerative rehabilitation has great potential to improve clinical outcomes for individuals with disabilities. However, the science to elucidate the specific biological underpinnings of regenerative rehabilitation-based approaches is still in its infancy and critical questions regarding clinical translation and implementation still exist. In a recent roundtable discussion from International Consortium for Regenerative Rehabilitation stakeholders, key challenges to progress in the field were identified. The goal of this article is to summarize those discussions and to initiate a broader discussion among clinicians and scientists across the fields of regenerative medicine and rehabilitation science to ultimately progress regenerative rehabilitation from an emerging field to an established interdisciplinary one. Strategies and case studies from consortium institutions-including interdisciplinary research centers, formalized courses, degree programs, international symposia, and collaborative grants-are presented. We propose that these strategic directions have the potential to engage and train clinical practitioners and basic scientists, transform clinical practice, and, ultimately, optimize patient outcomes.
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Medicina Regenerativa/tendências , Reabilitação/tendências , Certificação , Congressos como Assunto , Currículo , Bolsas de Estudo , Humanos , Medicina Regenerativa/educação , Reabilitação/educaçãoRESUMO
Degradable metallic stents, most commonly composed of Mg-based alloys, are of interest as an alternative to traditional metallic stents for application in cardiac and peripheral vasculature. Two major design challenges with such stents are control of the corrosion rate and acute presentation of a nonthrombogenic surface to passing blood. In this study, several types of sulfobetaine (SB)-bearing biodegradable polyurethanes were developed and assessed as physical, chemical, and combination-type coatings for a model degradable Mg alloy, AZ31. For physical coatings, poly(ester sulfobetaine)urethane ureas, PESBUUs were synthesized using variable monomers that allowed the incorporation of a varying extent of carboxyl groups. Introduction of the carboxyl groups was associated with faster polymer degradation time. Simple physical coating of PESBUUs reduced macro- and microscopic thrombogenic deposition together with good stability of the coating attachment compared to a control coating of polylactic- co-glycolic acid. For PESBUUs incorporating carboxyl groups (PESBUUs-COOH), these groups could be converted to siloxane groups (PESBUUs-Si), thus creating polymers that could be surface reacted with the oxidized or phytic acid treated AZ31 surface. Chemical (silanization) attachment of these polymers reduced underlying alloy corrosion rates, but following the salination reaction with physical coating most reduced corrosion rates and protected the surface better from the consequences of oxidation occurring under the coating, such as blistering. The application of a multilayered coating approach using a sulfobetaine-based biodegradable elastomer thus offers options for degradable metallic stent design where thromboresistance is desired in combination with a means to control both polymeric coating degradation rates and underlying alloy corrosion rates.
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After more than 22 years of research challenges and innovation, the heart valve tissue engineering paradigm still attracts attention as an approach to overcome limitations which exist with clinically utilized mechanical or bioprosthetic heart valves. Despite encouraging results, delayed translation can be attributed to limited knowledge on the concurrent mechanisms of biomaterial degradation in vivo, host inflammatory response, cell recruitment, and de novo tissue elaboration. This study aimed to reduce this gap by evaluating three alternative levels at which lability could be incorporated into candidate polyurethane materials electroprocessed into a valve scaffold. Specifically, polyester and polycarbonate labile soft segment diols were reacted into thermoplastic elastomeric polyurethane ureas that formed scaffolds where (1) a single polyurethane containing both of the two diols in the polymer backbone was synthesized and processed, (2) two polyurethanes were physically blended, one with exclusively polycarbonate and one with exclusively polyester diols, followed by processing of the blend, and (3) the two polyurethane types were concurrently processed to form individual fiber populations in a valve scaffold. The resulting valve scaffolds were characterized in terms of their mechanics before and after exposure to varying periods of pulsatile flow in an enzymatic (lipase) buffer solution. The results showed that valve scaffolds made from the first type of polymer and processing combination experienced more extensive degradation. This approach, although demonstrated with polyurethane scaffolds, can generally be translated to investigate biomaterial approaches where labile elements are introduced at different structural levels to alter degradation properties while largely preserving the overall chemical composition and initial mechanical behavior.
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Materiais Biocompatíveis/química , Próteses Valvulares Cardíacas , Teste de Materiais , Poliésteres/química , Poliuretanos/química , Animais , SuínosRESUMO
Physical cues are decisive factors in extracellular matrix (ECM) formation and elaboration. Their transduction across scale lengths is an inherently symbiotic phenomenon that while influencing ECM fate is also mediated by the ECM structure itself. This study investigates the possibility of enhancing ECM elaboration by topological cues that, while not modifying the substrate macro scale mechanics, can affect the meso-scale strain range acting on cells incorporated within the scaffold. Vascular smooth muscle cell micro-integrated, electrospun scaffolds were fabricated with comparable macroscopic biaxial mechanical response, but different meso-scale topology. Seeded scaffolds were conditioned on a stretch bioreactor and exposed to large strain deformations. Samples were processed to evaluate ECM quantity and quality via: biochemical assay, qualitative and quantitative histological assessment and multi-photon analysis. Experimental evaluation was coupled to a numerical model that elucidated the relationship between the scaffold micro-architecture and the strain acting on the cells. Results showed an higher amount of ECM formation for the scaffold type characterized by lowest fiber intersection density. The numerical model simulations associated this result with the differences found for the change in cell nuclear aspect ratio and showed that given comparable macro scale mechanics, a difference in material topology created significant differences in cell-scaffold meso-scale deformations. These findings reaffirmed the role of cell shape in ECM formation and introduced a novel notion for the engineering of cardiac tissue where biomaterial structure can be designed to both mimick the organ level mechanics of a specific tissue of interest and elicit a desirable cellular response.
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Ovines are a common animal model for the study of cardiovascular devices, where consideration of blood biocompatibility is an essential design criterion. In the ovine model, tools to assess blood biocompatibility are limited and continued investigation to identify and apply additional assays is merited. Toward this end, the thrombelastograph, clinically utilized to assess hemostasis, was used to characterize normal ovine parameters. In addition, platelet labeling with biotin was evaluated for its potential applicability to quantify ovine platelet life span. Mean ovine thrombelastograph values were reaction-time: 4.9 min, K-time: 2 min, angle: 64.1°, maximum amplitude: 68.6mm, actual clot strength: 11.9 kd/s, and coagulation index: 1.5. Reaction time was significantly shorter and maximum amplitude, actual clot strength, and coagulation index were all significantly higher when compared to normal human thrombelastograph values suggesting some hypercoagulability of sheep blood. Biotinylation and reinfusion of ovine platelets allowed temporal tracking of the labeled platelet cohort with flow cytometry. These data indicated a mean ovine platelet life span of 188h with a half-life of 84h. The collection of these parameters for normal ovines demonstrates the applicability of these techniques for subsequent studies where cardiovascular devices may be evaluated and provides an indication of normal ovine values for comparison purposes.
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Plaquetas/fisiologia , Ovinos/sangue , Tromboelastografia , Animais , Biotinilação , Feminino , Citometria de Fluxo , Masculino , Valores de ReferênciaRESUMO
OBJECTIVE: One of the rate-limiting barriers within the field of vascular tissue engineering is the lengthy fabrication time associated with expanding appropriate cell types in culture. One particularly attractive cell type for this purpose is the adipose-derived mesenchymal stem cell (AD-MSC), which is abundant and easily harvested from liposuction procedures. Even this cell type has its drawbacks, however, including the required culture period for expansion, which could pose risks of cellular transformation or contamination. Eliminating culture entirely would be ideal to avoid these concerns. In this study, we used the raw population of cells obtained after digestion of human liposuction aspirates, known as the stromal vascular fraction (SVF), as an abundant, culture-free cell source for tissue-engineered vascular grafts (TEVGs). METHODS: SVF cells and donor-paired cultured AD-MSCs were first assessed for their abilities to differentiate into vascular smooth muscle cells (SMCs) after angiotensin II stimulation and to secrete factors (eg, conditioned media) that promote SMC migration. Next, both cell types were incorporated into TEVG scaffolds, implanted as an aortic graft in a Lewis rat model, and assessed for their patency and composition. RESULTS: In general, the human SVF cells were able to perform the same functions as AD-MSCs isolated from the same donor by culture expansion. Specifically, cells within the SVF performed two important functions; namely, they were able to differentiate into SMCs (SVF calponin expression: 16.4% ± 7.7% vs AD-MSC: 19.9%% ± 1.7%) and could secrete promigratory factors (SVF migration rate relative to control: 3.1 ± 0.3 vs AD-MSC: 2.5 ± 0.5). The SVF cells were also capable of being seeded within biodegradable, elastomeric, porous scaffolds that, when implanted in vivo for 8 weeks, generated patent TEVGs (SVF: 83% patency vs AD-MSC: 100% patency) populated with primary vascular components (eg, SMCs, endothelial cells, collagen, and elastin). CONCLUSIONS: Human adipose tissue can be used as a culture-free cell source to create TEVGs, laying the groundwork for the rapid production of cell-seeded grafts.
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Tecido Adiposo/irrigação sanguínea , Bioprótese , Implante de Prótese Vascular/instrumentação , Prótese Vascular , Músculo Liso Vascular/transplante , Miócitos de Músculo Liso/transplante , Células Estromais/transplante , Engenharia Tecidual/métodos , Adulto , Angiotensina II/farmacologia , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aorta Abdominal/cirurgia , Implante de Prótese Vascular/métodos , Diferenciação Celular , Movimento Celular , Separação Celular , Células Cultivadas , Feminino , Humanos , Lipectomia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Fenótipo , Ratos Endogâmicos Lew , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Fatores de Tempo , Alicerces TeciduaisRESUMO
Imaging of angiogenesis receptors could provide a sensitive and clinically useful method for detecting neovascularization such as occurs in malignant tumors, and responses to antiangiogenic therapies for such tumors. We tested the hypothesis that microbubbles (MB) tagged with human VEGF121 (MBVEGF) bind to the kinase insert domain receptor (KDR) in vitro and angiogenic endothelium in vivo, and that this specific binding can be imaged on a clinical ultrasound system. In this work, targeted adhesion of MBVEGF was evaluated in vitro using a parallel plate flow system containing adsorbed recombinant human KDR. There was more adhesion of MBVEGF to KDR-coated plates when the amount of VEGF121 on each MB or KDR density on the plate was increased. MBVEGF adhesion to KDR-coated plates decreased with increasing wall shear rate. On intravital microscopic imaging of bFGF-stimulated rat cremaster muscle, there was greater microvascular adhesion of MBVEGF compared to that of isotype IgG-conjugated control MB (MBCTL). To determine if MBVEGF could be used to ultrasonically image angiogenesis, ultrasound imaging was performed in mice bearing squamous cell carcinoma after intravenous injection of MBVEGF. Ultrasound videointensity enhancement in tumor was significantly higher for MBVEGF (17.3 ± 9.7 dB) compared to MBCTL (3.8 ± 4.4 dB, n = 6, p < 0.05). This work demonstrates the feasibility of targeted ultrasound imaging of an angiogenic marker using MBVEGF. This approach offers a noninvasive bedside method for detecting tumor angiogenesis and could be extended to other applications such as molecular monitoring of therapeutic angiogenesis or antiangiogenic therapies in cardiovascular disease or cancer.
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Meios de Contraste/química , Neovascularização Patológica/diagnóstico , Fator A de Crescimento do Endotélio Vascular/química , Fator A de Crescimento do Endotélio Vascular/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C3H , Microbolhas , Imagem Molecular/métodos , Neovascularização Patológica/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Ultrassonografia/métodos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Although a variety of synthetic materials have been used to reconstruct tissue defects, these materials are associated with complications such as seromas, fistulas, chronic patient discomfort, and surgical site infection. While alternative, degradable materials that facilitate tissue growth have been examined. These materials can still trigger a foreign body inflammatory response that can lead to complications and discomfort. MATERIALS AND METHODS: In this report, our objective was to determine the effect of placing a pedicled omental flap under a biodegradable, microfibrous polyurethane scaffold serving as a full-wall thickness replacement of the rat abdominal wall. It was hypothesized that the presence of the omental tissue would stimulate greater vascularization of the scaffold and act to reduce markers of elevated inflammation in the patch vicinity. For control purposes, a polydimethylsiloxane sheet was placed as a barrier between the omental tissue and the overlying microfibrous scaffold. Both groups were sacrificed 8 wk after the implantation, and immunohistological and reverse transcription polymerase chain reaction (RT-PCR) assessments were performed. RESULTS: The data showed omental tissue placement to be associated with increased vascularization, a greater local M2/M1 macrophage phenotype response, and mRNA levels reduced for inflammatory markers but increased for angiogenic and antiinflammatory factors. CONCLUSIONS: From a clinical perspective, the familiarity with utilizing omental flaps for an improved healing response and infection resistance should naturally be considered as new tissue engineering approaches that are translated to tissue beds where omental flap application is practical. This report provides data in support of this concept in a small animal model.
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Parede Abdominal/cirurgia , Inflamação/prevenção & controle , Omento/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Complicações Pós-Operatórias/prevenção & controle , Retalhos Cirúrgicos/irrigação sanguínea , Alicerces Teciduais , Parede Abdominal/irrigação sanguínea , Implantes Absorvíveis , Animais , Feminino , Inflamação/etiologia , Omento/irrigação sanguínea , Poliuretanos , Ratos , Ratos Endogâmicos LewRESUMO
Male signals that provide information to females about mating benefits are often of low reliability. It is thus not clear why females often express strong signal preferences. We tested the hypothesis that females can distinguish between males with preferred signals that provide lower and higher quality direct benefits. In the field cricket, Gryllus lineaticeps, females usually prefer higher male chirp rates, but chirp rate is positively correlated with the fecundity benefits females will receive from males only for males that have experienced low quality diets. We paired females with muted males that were maintained on low or high nutrition diets, during the interactions we broadcast a replacement high chirp rate, and we observed whether females mated with the assigned male. Females were more likely to mate when paired with low nutrition males. These results suggest that females have evolved assessment mechanisms that allow them distinguish between males with preferred signals that provide high quality benefits (low nutrition males with high chirp rates) and males with preferred signals that provide low quality benefits (high nutrition males with high chirp rates).