Exploring uncertainty in hyper-viscoelastic properties of scalp skin through patient-specific finite element models for reconstructive surgery.

Understanding skin responses to external forces is crucial for post-cutaneous flap wound healing. However, the in vivo viscoelastic behavior of scalp skin remains poorly understood. Personalized virtual surgery simulations offer a way to study tissue responses in relevant 3D geometries. Yet, anticipating wound risk remains challenging due to limited data on skin viscoelasticity, which hinders our ability to determine the interplay between wound size and stress levels. To bridge this gap, we reexamine three clinical cases involving scalp reconstruction using patient-specific geometric models and employ uncertainty quantification through a Monte Carlo simulation approach to study the effect of skin viscoelasticity on the final stress levels from reconstructive surgery. Utilizing the generalized Maxwell model via the Prony series, we can parameterize and efficiently sample a realistic range of viscoelastic response and thus shed light on the influence of viscoelastic material uncertainty in surgical scenarios. Our analysis identifies regions at risk of wound complications based on reported threshold stress values from the literature and highlights the significance of focusing on long-term responses rather than short-term ones.

Estimation of viscoelasticity of a carotid artery from ultrasound cine images and brachial pressure waveforms: Viscous parameters as a new index of detecting low plaque burden.

Viscoelasticity may be an important physical index for diagnosing vascular diseases, but wall viscosity has received less attention than elasticity due to difficulties in measurement in clinical scenarios. In this study, viscoelastic parameters were estimated from the pressure diameter relationship using carotid artery ultrasound images and brachial artery pressure waveforms of the patients. Carotid artery diameter waveforms were obtained by analyzing wall motion in ultrasound cine images, and carotid pressure waveforms were estimated from brachial waveforms using a transfer function. The estimated viscoelastic parameters quantitatively agreed with the published data, and three viscous parameters (viscous index, energy dissipation ratio, and phase lag between pressure and diameter waveforms) showed good positive correlations with each other. No significant difference in wall elasticity was found between the no plaque (NP) and low plaque (LP) groups, whereas viscous parameters were lower in the NP group than the LP group. This result suggests that the viscous parameters may be a new mechanical index for detecting early atherosclerosis.

Development and characterization of viscoelastic polydimethylsiloxane phantoms for simulating arterial wall motion.

Arterial wall viscoelasticity is likely to be a good diagnostic indicator of vascular disease, but only a few studies on the assessment of wall viscosity have been performed. Artery phantoms are manufactured using polydimethylsiloxane (PDMS) to simulate the viscoelastic characteristics of the artery wall, which depends on the wall tissue composition and progression of atherosclerosis. The viscoelastic property of PDMS is controlled by adjusting the mixture ratio of resin, curing agent, and pure silicone oil. The pressure and diameter waveforms of the artery phantom were measured to estimate the wall viscoelasticity. Elasticity is assessed using the diameter distention over the pulse pressure, and the viscosity is evaluated using the energy dissipation ratio of the pressure-diameter curve and the phase lag between the first harmonics of pressure and diameter waveforms (DP1). PDMS phantoms with resin-to-curing-agent ratios of 20:1 and 25:1 show viscoelastic characteristics similar to those of young and old human carotid arteries, respectively. Adding pure silicone oil further softens the silicone elastomer while decreasing its viscosity. The phantoms with 10:1:5 and 10:1:8 mixture ratios (resin: curing agent: silicone oil) show elasticity similar to that of the 20:1:0 and 25:1:0 ratios, respectively, albeit with a noticeable decrease in viscosity. An abrupt decrease in the phase lag (DP1) was found near the interface of the arterial phantom with different mixture ratios (20:1:0 and 10:1:5), while the change in diameter distension was negligible. DP1 may be a new index to differentiate wall tissues with similar elastic properties but different viscous behavior. The pressure diameter curve and DP1 of the phantom simulating the atherosclerosis wall can be compared with patient data and applied to clinical evaluation of plaque viscoelasticity. Computational analysis of arterial wall motion was performed using a standard linear viscoelastic model. The model parameters were determined from the measured pressure-diameter relationship, and the arterial wall motions of phantoms with different viscoelastic properties were successfully simulated. The computational model may provide a useful insight into the changes of arterial viscoelasticity caused by pathogenic wall degeneration.

Computational study on phase lag of arterial-wall motion for assessment of plaque vulnerability.

The wall motion of atherosclerotic plaque was analyzed using a computational method, and the effects of tissue viscoelasticity, fibrosis thickness, and lipid-core stiffness on wall displacement waveforms were examined. The viscoelasticity of plaque tissues was modeled using a time Prony series with four Maxwell elements. Computational simulation of tissue indentation tests showed the validity of the proposed viscoelastic constitutive models. Decreasing the relative moduli of the viscoelastic model reduced their viscous characteristics while enhancing the stiffness of the wall, which corresponded with the effects of decreased smooth muscle cells content. A finite-element analysis was conducted for atherosclerotic wall models and wall displacement waveforms were computed. The phase difference between the first harmonics of pressure and displacement waves was selected to represent the time delay of the wall motion. As the relative modulus decreased, the wall displacement and phase lag decreased. A thinner wall and softer lipid core corresponded to a greater wall displacement and smaller phase lag. Because the phase lag of the arterial-wall motion was smaller for the plaque with a thinner cap, lower smooth muscle cells content, and softer lipid core (all features of plaques with high rupture risk), first harmonics of pressure and displacement waves can be used as an index to assess plaque vulnerability.

Effect of distal thickening and stiffening of plaque cap on arterial wall mechanics.

To investigate the effect of longitudinal variations of cap thickness and tissue properties on wall stresses and strains along the atherosclerotic stenosis, stenotic plaque models (uniformly thick, distally thickened, homogenous, and distally stiffened) were constructed and subjected to computational stress analyses with due consideration of fluid-structure interactions (FSI). The analysis considered three different cap thicknesses-45, 65, and 200 µm-and tissue properties-soft, fibrous, and hard. The maximum peak cap stress (PCS) and strain were observed in the upstream throat section and demonstrated increases of the order of 345 and 190%, respectively, as the cap thickness was reduced from 200 to 45 µm in uniformly thick models. Distal stiffening increased PCS in the downstream region; however, the overall effect of this increase was rather small. Distal thickening did not affect maximum PCS and strain values for cap thicknesses exceeding 65 µm; however, a noticeable increase in maximum PCS and corresponding longitudinal variation (or spatial gradient) in stress was observed in the very thin (45-µm-thick) cap. It was, therefore, inferred that existence of a rather thin upstream cap demonstrating distal cap thickening indicates an increased risk of plaque progression and rupture. Graphical Abstract ᅟ.

Streaming flow from ultrasound contrast agents by acoustic waves in a blood vessel model.

To elucidate the effects of streaming flow on ultrasound contrast agent (UCA)-assisted drug delivery, streaming velocity fields from sonicated UCA microbubbles were measured using particle image velocimetry (PIV) in a blood vessel model. At the beginning of ultrasound sonication, the UCA bubbles formed clusters and translated in the direction of the ultrasound field. Bubble cluster formation and translation were faster with 2.25MHz sonication, a frequency close to the resonance frequency of the UCA. Translation of bubble clusters induced streaming jet flow that impinged on the vessel wall, forming symmetric vortices. The maximum streaming velocity was about 60mm/s at 2.25MHz and decreased to 15mm/s at 1.0MHz for the same acoustic pressure amplitude. The effect of the ultrasound frequency on wall shear stress was more noticeable. Maximum wall shear stress decreased from 0.84 to 0.1Pa as the ultrasound frequency decreased from 2.25 to 1.0MHz. The maximum spatial gradient of the wall shear stress also decreased from 1.0 to 0.1Pa/mm. This study showed that streaming flow was induced by bubble cluster formation and translation and was stronger upon sonication by an acoustic wave with a frequency near the UCA resonance frequency. Therefore, the secondary radiant force, which is much stronger at the resonance frequency, should play an important role in UCA-assisted drug delivery.

Polymeric embolization coil of bilayered polyvinyl alcohol strand for therapeutic vascular occlusion: a feasibility study in canine experimental vascular models.

PURPOSE: To investigate the feasibility of polyvinyl alcohol (PVA) polymer coil as a new endovascular embolic agent and to gauge the related histologic response in a canine vascular model. MATERIALS AND METHODS: PVA polymer coil was fabricated by cross-linking PVA and tantalum particles. Basic properties were then studied in vitro via swelling ratio and bending diameter. Normal renal segmental arteries and wide-necked aneurysms of carotid sidewalls served as canine vascular models. Endovascular PVA coil embolization of normal renal segmental arteries (N = 20) and carotid aneurysms (N = 8) was performed under fluoroscopic guidance in 10 dogs. Degree of occlusion was assessed immediately and at 4 weeks after embolization by conventional and computed tomographic angiography. Histologic features were also graded at acute (day 1, six segmental arteries and four aneurysms) and chronic phases (week 4, 14 segmental arteries and four aneurysms) after embolization to assess inflammation, organization of thrombus, and neointimal proliferation. RESULTS: Swelling ratio declined as concentrations of cross-linking agent increased. Mean bending diameters were 2.05 mm (range, 0.86-6.25 mm) in water at 37 °C and 2.29 mm (range, 0.94-6.38 mm) in canine blood samples at 37 °C. Occlusion of normal renal segmental arteries was sustained (complete occlusion at day 1, n = 20; at week 4, n = 14), whereas immediate outcomes in carotid aneurysms (day 1, complete occlusion, n = 5; residual neck only, n = 3) were not sustained (week 4, complete occlusion, n = 1; minor recanalization, n = 1; major recanalization, n = 2). At week 4, chronic inflammatory cells predominated, with progressive organization of thrombus and fibrocellular ingrowth. All aneurysms bore full neointimal linings on the coil mass in the chronic phase. CONCLUSIONS: Vascular occlusion by PVA polymer coil proved superior in normal renal segmental arteries and feasible in surgically constructed carotid aneurysms (with packing densities ≥ 30%), constituting acceptable radiologic feasibility and histologic response.

Drug perfusion enhancement in tissue model by steady streaming induced by oscillating microbubbles.

Drug delivery into neurological tissue is challenging because of the low tissue permeability. Ultrasound incorporating microbubbles has been applied to enhance drug delivery into these tissues, but the effects of a streaming flow by microbubble oscillation on drug perfusion have not been elucidated. In order to clarify the physical effects of steady streaming on drug delivery, an experimental study on dye perfusion into a tissue model was performed using microbubbles excited by acoustic waves. The surface concentration and penetration length of the drug were increased by 12% and 13%, respectively, with streaming flow. The mass of dye perfused into a tissue phantom for 30s was increased by about 20% in the phantom with oscillating bubbles. A computational model that considers fluid structure interaction for streaming flow fields induced by oscillating bubbles was developed, and mass transfer of the drug into the porous tissue model was analyzed. The computed flow fields agreed with the theoretical solutions, and the dye concentration distribution in the tissue agreed well with the experimental data. The computational results showed that steady streaming with a streaming velocity of a few millimeters per second promotes mass transfer into a tissue.

Effects of framing coil shape, orientation, and thickness on intra-aneurysmal flow.

To study the effects of the geometrical characteristics of a framing coil on aneurysm thromboembolization efficacy, the hemodynamics in lateral aneurysms filled with coils having a different shape, orientation, and thickness were analyzed using computational fluid dynamics. The aneurysms packed with vortex and cage-shaped coils were modeled using three different coil orientations: transverse, parallel, and orthogonal. The orthogonal orientation of a vortex coil and parallel orientation of a cage-shaped coil showed higher inflow, vorticity, and wall shear stress in the dome region, which provide an unfavorable hemodynamic environment for thromboembolization. Thicker coils also produced unfavorable hemodynamic conditions compared to normal coils having the same shape, orientation, and total coil volume. Though the effects of coil shape and orientation on the hemodynamic parameters of interest were not consistent, the open area at the distal half of the mid-transverse plane of an aneurysm showed significant positive correlation with flow into the dome region and mean vorticity in the dome region. Therefore, blocking the distal mid-transverse plane of an aneurysm using coils would effectively reduce the intra-aneurysmal flow activity and provide a more efficient hemodynamic environment for thromboembolization.

Computational study of particle size effects on selective binding of nanoparticles in arterial stenosis.

In order to elucidate particle size and wall shear effects on the selective binding of nanoparticles to vessel wall, particle binding to the wall of arterial stenosis was computationally analyzed using a transport and reaction model. The attachment rate constant was modeled as a function of shear rate and particle size. The results showed that it had a positive correlation with the shear rate for particles smaller than 600 nm and a negative correlation with the shear rate for particles larger than 800 nm. Small size particles showed high binding selectivity in the stenosis region for the normal and shear-activated wall, whereas large particles showed high binding selectivity in the low and oscillatory zone for the shear-activated wall.

Development of endovascular vibrating polymer actuator probe for mechanical thrombolysis: in vivo study.

In this study, we propose a new method for the enhancement of intraarterial thrombolysis by use of an endovascular vibrating polymer actuator probe (VPAP), which is fabricated from an ionic polymer metal composite (IPMC) actuator. The endovascular VPAP was fabricated by combining 0.8 × 0.8 × 10 mm3 IPMC samples, 0.22 mm × 50 cm copper wires, and 40 cm of Teflon tube. The purpose of this study was to evaluate the thrombolysis efficiency of an endovascular VPAP in a dog model. Both renal arteries of the enrolled dogs (n = 5) were used in the current study. A distal portion of the renal artery in a mongrel dog was occluded by a blood clot from autologous venous whole blood. Intraarterial thrombolysis was performed by use of a VPAP without the actuation force (control group), by a VPAP-only (VPAP-only group), or with a combination of recombinant tissue plasminogen activator (rtPA) and a VPAP (VPAP + rtPA group). The thrombolysis efficiency was evaluated by the modified Thrombolysis in Myocardial Infarction (TIMI) grading system based on the consensus between two radiologists. The grading scales were compared according to each intraarterial thrombolysis method. The VPAP + rtPA and VPAP-only groups showed a significantly higher thrombolysis efficiency than did the control group (p < 0.05). The VPAP-only group also showed a significantly higher thrombolysis efficiency than did the control group (p < 0.05). The VPAP+ rtPA group showed a significantly higher thrombolysis efficiency than did the VPAP-only group (p < 0.05). The use of an endovascular VPAP was a feasible and useful method for intraarterial thrombolysis, and it enhanced the thrombolysis efficiency when combined with the thrombolytic agent rtPA.

Computational analysis of blood clot dissolution using a vibrating catheter tip.

We developed a novel concept of endovascular thrombolysis that employs a vibrating electroactive polymer actuator. In order to predict the efficacy of thrombolysis using the developed vibrating actuator, enzyme (plasminogen activator) perfusion into a clot was analyzed by solving flow fields and species transport equations considering the fluid structure interaction. In vitro thrombolysis experiments were also performed. Computational results showed that plasminogen activator perfusion into a clot was enhanced by actuator vibration at frequencies of 1 and 5 Hz. Plasminogen activator perfusion was affected by the actuator oscillation frequencies and amplitudes that were determined by electromechanical characteristics of a polymer actuator. Computed plasminogen activator perfused volumes were compared with experimentally measured dissolved clot volumes. The computed plasminogen activator perfusion volumes with threshold concentrations of 16% of the initial plasminogen activator concentration agreed well with the in vitro experimental data. This study showed the effectiveness of actuator oscillation on thrombolysis and the validity of the computational plasminogen activator perfusion model for predicting thrombolysis in complex flow fields induced by an oscillating actuator.

Hemodynamics of cerebral aneurysms: computational analyses of aneurysm progress and treatment.

The progression of a cerebral aneurysm involves degenerative arterial wall remodeling. Various hemodynamic parameters are suspected to be major mechanical factors related to the genesis and progression of vascular diseases. Flow alterations caused by the insertion of coils and stents for interventional aneurysm treatment may affect the aneurysm embolization process. Therefore, knowledge of hemodynamic parameters may provide physicians with an advanced understanding of aneurysm progression and rupture, as well as the effectiveness of endovascular treatments. Progress in medical imaging and information technology has enabled the prediction of flow fields in the patient-specific blood vessels using computational analysis. In this paper, recent computational hemodynamic studies on cerebral aneurysm initiation, progress, and rupture are reviewed. State-of-the-art computational aneurysmal flow analyses after coiling and stenting are also summarized. We expect the computational analysis of hemodynamics in cerebral aneurysms to provide valuable information for planning and follow-up decisions for treatment.

Development of endovascular vibrating polymer actuator probe for mechanical thrombolysis: a phantom study.

In this study, we propose a new method for enhancement of intraarterial thrombolysis using an ionic polymer-metal composite (IPMC) actuator. The purpose of this study was to test the mechanical thrombolysis efficiency of IPMC actuators and evaluate the endovascular vibrating polymer actuator probe for mechanical thrombolysis in a phantom model; 2 × 1 × 15 mm (2 mm in width, 1 mm in thickness, and 15 mm in length) and 0.8 × 0.8 × 10 mm (0.8 mm in width, 0.8 mm in thickness, and 10 mm in length) IPMC actuators were fabricated by stacking five and four Nafion-117 films, respectively. We manufactured the endovascular vibrating polymer actuator probe, for which thrombolysis efficiency was tested in a vascular phantom. The phantom study using 2 × 1 × 15 mm IPMC actuators showed that 5 Hz actuation is the optimal frequency for thrombolysis under both 2 and 3 V, when blood clot was not treated with rtPA, and when exposed to rtPA, IPMC actuators under the optimized condition (3 V, 5 Hz, and 5 min) significantly increased the thrombolysis degree compared with control and other experimental groups (p < 0.05). In addition, 0.8 × 0.8 × 10 mm IPMC actuators also revealed a significantly higher thrombolysis degree under the optimized condition than the control and rtPA only groups (p < 0.05). Finally, the fabricated probe using 0.8 × 0.8 × 10 mm IPMC actuators also incurred higher thrombolysis degree under the optimized condition than the control and rtPA only groups (p < 0.05). A vibrating polymer actuator probe is a feasible device for intravascular thrombolysis, and further study in an animal model is warranted.

Computational analysis of nanoparticle adhesion to endothelium: effects of kinetic rate constants and wall shear rates.

Various nanoparticles have been developed as imaging probes and drug carriers, and their selectivity in binding to target cells determines the efficacy of these functionalized nanoparticles. Since target cells in different arterial segments experience different hemodynamic environments, we study the effects of wall shear rate waveforms on particle binding. We also explore the effects of the kinetic rate constant, which is determined by particle design parameters, on particle binding. A transport and reaction model is used to evaluate nanoparticle binding to the substrate in a laminar flow chamber. Flow and particle concentration fields are solved by using a computational fluid dynamics. The particle binding rate increases as the mean value of wall shear increases, and the amplitudes of sinusoidal shear waveform do not affect the bound particle density profiles significantly. Particle binding rates increase with the rate constant of attachment (k(A)), and are more sensitively affected by low k(A) values and less by k(A) values higher than 1 × 10⁻6 m s⁻¹. Since binding selectivity is affected by k(A) and the wall shear rate, the results of this study can be used for designing functionalized nanoparticles targeting for the specific cells that experience a specific shear rate.

Current status of nanoparticle-based imaging agents for early diagnosis of cancer and atherosclerosis.

Endothelium plays a vital role in various vascular functions, and its dysfunction is a key underlying process closely related to diverse array of diseases such as atherosclerosis and tumor. Therefore, early detection of endothelial dysfunction at the functional or molecular level is of high importance for effective therapy. Recent advances in nanotechnology and our understanding in cellular and molecular biology have provided various biomedical imaging modalities and nanosized multimodal imaging agents. Multimodal nanoparticles that encompass the targeting ligands and magnetic/optical imaging labels enable us to visualize the pathophysiological process of various diseases using multiple imaging techniques. To visualize the specific pathogenic process at the molecular level, the imaging probe needs to be surface-functionalized with specific affinity ligands such as monoclonal antibodies (mAb). Combining the functional imaging agents along with therapeutic drugs has great potential for effective early detection, accurate diagnosis, and treatment of disease. The current review will highlight the application of various nanoparticle-based imaging agents and their recent developments in diagnosing endothelium dysfunction with a special emphasis on atherosclerosis and cancer.

Identification of a peptide ligand recognizing dysfunctional endothelial cells for targeting atherosclerosis.

Targeting ligands to dysfunctional or activated endothelial cells overlying atherosclerotic plaques could provide tools for selective drug delivery to atherosclerotic lesions. To identify peptides selectively targeting dysfunctional endothelial cells, a phage library was screened against tumor necrosis factor-alpha (TNF-alpha) activated bovine aortic endothelial cells (BAECs). Five rounds of biopanning were carried out and the phage clones selected were examined for their DNA inserts. A phage clone displaying the CLWTVGGGC sequence occurred most frequently and was found to bind specifically to TNF-alpha activated BAECs over untreated cells. On the other hand, bindings of the phage clone to human umbilical vein endothelial cells, lymphatic endothelial cells, and epithelial cells were minimal. Flow cytometric and fluorescence microscopic studies showed the preferential binding of the CLWTVGGGC peptide to TNF-alpha activated BAECs compared to untreated cells. In vivo studies demonstrated selective homing and co-localization of the CLWTVGGGC peptide to dysfunctional endothelial cells overlying atherosclerotic plaques in low-density lipoprotein receptor-deficient mice. These results demonstrate that the CLWTVGGGC peptide could specifically recognize dysfunctional endothelial cells at atherosclerotic plaques and be used as a targeting ligand for drug delivery and imaging of atherosclerosis.

A new atherosclerotic lesion probe based on hydrophobically modified chitosan nanoparticles functionalized by the atherosclerotic plaque targeted peptides.

We developed a new imaging probe for atherosclerotic lesion imaging by chemically conjugating an atherosclerotic plaque-homing peptide (termed the AP peptide) to hydrophobically modified glycol chitosan (HGC) nanoparticles. The AP peptide was previously discovered by using an in vivo phage display screening method. HGC nanoparticles were labeled with the near-infrared (NIR) fluorophore Cy5.5, yielding nanoparticles 314 nm in diameter. The binding characteristics of nanoparticles to cytokine (TNF-alpha)-activated bovine aortic endothelial cells (BAECs) were studied in vitro under static conditions and in a dynamic flow environment. AP-tagged HGC-Cy5.5 nanoparticles (100 microg/ml, 2 h incubation) bound more avidly to TNF-alpha-activated BAECs than to unactivated BAECs. Nanoparticles were mostly located in the membranes of BAECs, although some were taken up by the cells and were visible in the cytoplasm, suggesting that the AP peptides in HGC nanoparticles retained target selectivity for activated BAECs. Binding selectivity of AP-tagged HGC-Cy5.5 nanoparticles was also studied in vivo. NIR fluorescence imaging demonstrated that AP-tagged HGC-Cy5.5 nanoparticles bound better to atherosclerotic lesions in a low-density lipoprotein receptor-deficient (Ldlr(-/-)) atherosclerotic mouse than to such lesions in a normal mouse. These results suggest that the newly designed AP-tagged HGC-Cy5.5 nanoparticles may be useful for atherosclerotic lesion imaging, and may also be employed to elucidate pathophysiological changes, at the molecular level, on atherosclerotic endothelium.

Whole blood clot dissolution: in vitro study on the effects of permeation pressure.

Dissolution of a blood clot in thrombolytic procedure is affected by permeation of a thrombolytic agent into a clot, and permeation of plasminogen activator into a clot is dependent on the permeation pressure. A controlled experimental study on the effects of permeation pressure on clot lysis was carried out. The effects of intra-thrombus perfusion on thrombolyis were also explored. In vitro clot lysis tests were performed for perfusion pressures of 0, 1, and 10 kPa. Two perfusion media were used: buffer and urokinase solution. Clot lysis by diffusion was enhanced in urokinase solution compared with buffer solution, but the effects of perfusion medium were not significant in pressurized perfusion. Clot lysis was accelerated with the perfusion pressure in the early stage of perfusion, but the pressure effect on thrombolysis was not significant in the later stage (after 2 h). Intra-thrombus perfusion was more efficient in clot lysis than surface perfusion was. It is suggested that fluid flow inside the thrombus should be the most important factor in thrombolytic therapy.