Development of in vitro microfluidic models to study endothelial responses to pulsatility with different mechanical circulatory support devices.

Continuous-flow ventricular assist devices (CFVAD) and counterpulsation devices (CPD) are used to treat heart failure (HF). CFVAD can diminish pulsatility, but pulsatile modes have been implemented to increase vascular pulsatility. The effects of CFVAD in a pulsatile mode and CPD support on the function of endothelial cells (ECs) are yet to be investigated. In this study, two in vitro microfluidic models for culturing ECs are proposed to reproduce blood pressure (BP) and wall shear stress (WSS) on the arterial endothelium while using these medical devices. The layout and parameters of the two microfluidic systems were optimized based on the principle of hemodynamic similarity to efficiently simulate physiological conditions. Moreover, the unique design of the double-pump and double afterload systems could successfully reproduce the working mode of CPDs in an in vitro microfluidic system. The performance of the two systems was verified by numerical simulations and in vitro experiments. BP and WSS under HF, CFVAD in pulsatile modes, and CPD were reproduced accurately in the systems, and these induced signals improved the expression of Ca2+, NO, and reactive oxygen species in ECs, proving that CPD may be effective in normalizing endothelial function and replacing CFVAD to a certain extent to treat non-severe HF. This method offers an important tool for the study of cell mechanobiology and a key experimental basis for exploring the potential value of mechanical circulatory support devices in reducing adverse events and improving outcomes in the treatment of HF in the future.

Study on the hemodynamic effects of different pulsatile working modes of a rotary blood pump using a microfluidic platform that realizes in vitro cell culture effectively.

Rotary blood pumps (RBPs) operating at a constant speed generate non-physiologic blood pressure and flow rate, which can cause endothelial dysfunction, leading to adverse clinical events in peripheral blood vessels and other organs. Notably, pulsatile working modes of the RBP can increase vascular pulsatility to improve arterial endothelial function. However, the laws and related mechanisms of differentially regulating arterial endothelial function under different pulsatile working modes are still unclear. This knowledge gap hinders the optimal selection of the RBP working modes. To address these issues, this study developed a multi-element in vitro endothelial cell culture system (ECCS), which could realize in vitro cell culture effectively and accurately reproduce blood pressure, shear stress, and circumferential strain in the arterial endothelial microenvironment. Performance of this proposed ECCS was validated with numerical simulation and flow experiments. Subsequently, this study investigated the effects of four different pulsation frequency modes that change once every 1-4-fold cardiac cycles (80, 40, 80/3, and 20 cycles per min, respectively) of the RBP on the expression of nitric oxide (NO) and reactive oxygen species (ROS) in endothelial cells. Results indicated that the 2-fold and 3-fold cardiac cycles significantly increased the production of NO and prevented the excessive generation of ROS, potentially minimizing the occurrence of endothelial dysfunction and related adverse events during the RBP support, and were consistent with animal study findings. In general, this study may provide a scientific basis for the optimal selection of the RBP working modes and potential treatment options for heart failure.

Hemodynamics of ventricular-arterial coupling under enhanced external counterpulsation: An optimized dual-source lumped parameter model.

BACKGROUND AND OBJECTIVE: Enhanced external counterpulsation (EECP) is a mechanically assisted circulation technique widely used in the rehabilitation and management of ischemic cardiovascular diseases. It contributes to cardiovascular functions by regulating the afterload of ventricle to improve hemodynamic effects, including increased diastolic blood pressure at aortic root, increased cardiac output and enhanced blood perfusion to multiple organs including coronary circulation. However, the effects of EECP on the coupling of the ventricle and the arterial system, termed ventricular-arterial coupling (VAC), remain elusive. We aimed to investigate the acute effect of EECP on the dynamic interaction between the left ventricle and its afterload of the arterial system from the perspective of ventricular output work. METHODS: A neural network assisted optimization algorithm was proposed to identify the ordinary differential equation (ODE) relation between aortic root blood pressure and flow rate. Based on the optimized order of ODE, a lumped parameter model (LPM) under EECP was developed taking into consideration of the simultaneous action of cardiac and EECP pressure sources. The ventricular output work, in terms of aortic pressure and flow rate cooperated with the LPM, was used to characterize the VAC of ventricle and its afterload. The VAC subjected to the principle of minimal ventricular output work was validated by solving the Euler-Poisson equation of cost function, ultimately determining the waveforms of aortic pressure and flow rate. RESULTS: A third-order ODE can precisely describe the hemodynamic relationship between aortic pressure and flow rate. An optimized dual-source LPM with three energy-storage elements has been constructed, showing the potential in probing VAC under EECP. The LPM simulation results demonstrated that the VAC in terms of aortic pressure and flow rate yielded to the minimal ventricular output work under different EECP pressures. CONCLUSIONS: The ventricular-arterial coupling under EECP is subjected to the minimal ventricular output work, which can serve as a criterion for determining aortic pressure and flow rate. This study provides insight for the understanding of VAC and has the potential in characterizing the performance of the ventricular and arterial system under EECP.

Numerical simulation analysis of multi-scale computational fluid dynamics on hemodynamic parameters modulated by pulsatile working modes for the centrifugal and axial left ventricular assist devices.

Continuous flow (CF) left ventricular assist devices (LVAD) operate at a constant speed mode, which could result in increased risk of adverse events due to reduced vascular pulsatility. Consequently, pump speed modulation algorithms have been proposed to augment vascular pulsatility. However, the quantitative local hemodynamic effects on the aorta when the pump is operating with speed modulation using different types of CF-LVADs are still under investigation. The computational fluid dynamics (CFD) study was conducted to quantitatively elucidate the hemodynamic effects on a clinical patient-specific aortic model under different speed patterns of CF-LVADs. Pressure distribution, wall shear stress (WSS), time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), relative residence time (RRT), and velocity were calculated to compare their differences at constant and pulsatile speeds under centrifugal and axial LVAD support. Results showed that pulse pressure on the aorta was significantly larger under pulsatile speed mode than that under constant speed mode for both CF-LVADs, indicating enhanced aorta pulsatility, as well as the higher peak blood flow velocity on some representative slices of aorta. Pulsatile speed modulation enhanced peak WSS compared to constant speed; high TAWSS region appeared near the branch of left common carotid artery and distal aorta regardless of speed modes and CF-LVADs but these regions also had low OSI; RRT was almost the same for all the cases. This study may provide a basis for the scientific and reasonable selection of the pulsatile speed patterns of CF-LVADs for treating heart failure patients.

Microfluidic characterization of single-cell biophysical properties and the applications in cancer diagnosis.

Single-cell biophysical properties play a crucial role in regulating cellular physiological states and functions, demonstrating significant potential in the fields of life sciences and clinical diagnostics. Therefore, over the last few decades, researchers have developed various detection tools to explore the relationship between the biophysical changes of biological cells and human diseases. With the rapid advancement of modern microfabrication technology, microfluidic devices have quickly emerged as a promising platform for single-cell analysis offering advantages including high-throughput, exceptional precision, and ease of manipulation. Consequently, this paper provides an overview of the recent advances in microfluidic analysis and detection systems for single-cell biophysical properties and their applications in the field of cancer. The working principles and latest research progress of single-cell biophysical property detection are first analyzed, highlighting the significance of electrical and mechanical properties. The development of data acquisition and processing methods for real-time, high-throughput, and practical applications are then discussed. Furthermore, the differences in biophysical properties between tumor and normal cells are outlined, illustrating the potential for utilizing single-cell biophysical properties for tumor cell identification, classification, and drug response assessment. Lastly, we summarize the limitations of existing microfluidic analysis and detection systems in single-cell biophysical properties, while also pointing out the prospects and future directions of their applications in cancer diagnosis and treatment.

Temperature-mediated diffusion of nanoparticles in semidilute polymer solutions.

The temperature is often a critical factor affecting the diffusion of nanoparticles in complex physiological media, but its specific effects are still to be fully understood. Here, we constructed a temperature-regulated model of semidilute polymer solution and experimentally investigated the temperature-mediated diffusion of nanoparticles using the particle tracking method. By examining the ensemble-averaged mean square displacements (MSDs), we found that the MSD grows gradually as the temperature increases while the transition time from sublinear to linear stage in MSD decreases. Meanwhile, the temperature-dependent measured diffusivity of the nanoparticles shows an exponential growth. We revealed that these temperature-mediated changes are determined by the composite effect of the macroscale property of polymer solution and the microscale dynamics of polymer chain as well as nanoparticles. Furthermore, the measured non-Gaussian displacement probability distributions were found to exhibit non-Gaussian fat tails, and the tailed distribution is enhanced as the temperature increases. The non-Gaussianity was calculated and found to vary in the same trend with the tailed distribution, suggesting the occurrence of hopping events. This temperature-mediated non-Gaussian feature validates the recent theory of thermally induced activated hopping. Our results highlight the temperature-mediated changes in diffusive transport of nanoparticles in polymer solutions and may provide the possible strategy to improve drug delivery in physiological media.

Visualization of Cell Membrane Tension Regulated by the Microfilaments as a "Shock Absorber" in Micropatterned Cells.

The extracellular stress signal transmits along the cell membrane-cytoskeleton-focal adhesions (FAs) complex, regulating the cell function through membrane tension. However, the mechanism of the complex regulating membrane tension is still unclear. This study designed polydimethylsiloxane stamps with specific shapes to change the actin filaments' arrangement and FAs' distribution artificially in live cells, visualized the membrane tension in real time, and introduced the concept of information entropy to describe the order degree of the actin filaments and plasma membrane tension. The results showed that the actin filaments' arrangement and FAs' distribution in the patterned cells were changed significantly. The hypertonic solution resulted in the plasma membrane tension of the pattern cell changing more evenly and slowly in the zone rich in cytoskeletal filaments than in the zone lacking filaments. In addition, the membrane tension changed less in the adhesive area than in the non-adhesive area when destroying the cytoskeletal microfilaments. This suggested that patterned cells accumulated more actin filaments in the zone where FAs were difficult to generate to maintain the stability of the overall membrane tension. The actin filaments act as shock absorbers to cushion the alternation in membrane tension without changing the final value of membrane tension.

A mathematical model for intracellular NO and ROS dynamics in vascular endothelial cells activated by exercise-induced wall shear stress.

Vascular endothelial cells (ECs) residing in the innermost layer of blood vessels are exposed to dynamic wall shear stress (WSS) induced by blood flow. The intracellular nitric oxide (NO) and reactive oxygen species (ROS) in ECs modulated by the dynamic WSS play important roles in endothelial functions. Mathematical modeling is a popular methodology for biophysical studies. It can not only explain existing cell experiments, but also reveal the underlying mechanism. However, the previous mathematical models of NO dynamics in ECs are limited to the static WSS induced by constant flow, while arterial blood flow is a periodic pulsatile flow with varying amplitude and frequency at different exercise intensities. In this study, a mathematical model of intracellular NO and ROS dynamics activated by dynamic WSS based on the in vitro cell experiments is developed. With the hypothesis of the viscoelastic body, the Kelvin model is adopted to simulate the mechanosensors on EC. Thus, the NO dynamics activated by dynamic shear stresses induced by constant flow, pulsatile flow, and oscillatory flow are analyzed and compared. Moreover, the roles of ROS have been considered for the first time in the modeling of NO dynamics in ECs based on the analysis of cell experiments. The predictions of the proposed model coincide fairly well with the experimental data when ECs are subjected to exercise-induced WSS. The mechanism is elucidated that WSS induced by moderate-intensity exercise is most favorable to NO production in ECs. This study can provide valuable insights for further study of NO and ROS dynamics in ECs and help develop appropriate exercise regimens for improving endothelial functions.

A sensorless, physiologic feedback control strategy to increase vascular pulsatility for rotary blood pumps.

Continuous flow rotary blood pumps (RBP) operating clinically at constant rotational speeds cannot match cardiac demand during varying physical activities, are susceptible to suction, diminish vascular pulsatility, and have an increased risk of adverse events. A sensorless, physiologic feedback control strategy for RBP was developed to mitigate these limitations. The proposed algorithm used intrinsic pump speed to obtain differential pump speed (ΔRPM). The proposed gain-scheduled proportional-integral controller, switching of setpoints between a higher pump speed differential setpoint (ΔRPM Hr ) and a lower pump speed differential setpoint (ΔRPM Lr ), generated pulsatility and physiologic perfusion, while avoiding suction. The switching between ΔRPM Hr and ΔRPM Lr setpoints occurred when the measured ΔRPM reached the pump differential reference setpoint. In-silico tests were implemented to assess the proposed algorithm during rest, exercise, a rapid 3-fold pulmonary vascular resistance increase, rapid change from exercise to rest, and compared with maintaining a constant pump speed setpoint. The proposed control algorithm augmented aortic pressure pulsatility to over 35 mmHg during rest and around 30 mmHg during exercise. Significantly, ventricular suction was avoided, and adequate cardiac output was maintained under all simulated conditions. The performance of the sensorless algorithm using estimation was similar to the performance of sensor-based method. This study demonstrated that augmentation of vascular pulsatility was feasible while avoiding ventricular suction and providing physiological pump outflows. Augmentation of vascular pulsatility can minimize adverse events that have been associated with diminished pulsatility. Mock circulation and animal studies would be conducted to validate these results.

Fabricating a multi-component microfluidic system for exercise-induced endothelial cell mechanobiology guided by hemodynamic similarity.

Generating precise in vivo arterial endothelial hemodynamic microenvironments using microfluidics is essential for exploring endothelial mechanobiology. However, a hemodynamic principle guiding the fabrication of microfluidic systems is still lacking. We propose a hemodynamic similarity principle for quickly obtaining the input impedance of the microfluidic system in vitro derived from that of the arterial system in vivo to precisely generate the desired endothelial hemodynamic microenvironments. First, based on the equivalent of blood pressure (BP) and wall shear stress (WSS) waveforms, we establish a hemodynamic similarity principle to efficiently map the input impedance in vivo to that in vitro, after which the multi-component microfluidic system is designed and fabricated using a lumped parameter hemodynamic model. Second, numerical simulation and experimental studies are carried out to validate the performance of the designed microfluidic system. Finally, the intracellular Ca2+ responses after exposure to different intensities of exercise-induced BP and WSS waveforms are measured to improve the reliability of EC mechanobiological studies using the designed microfluidic system. Overall, the proposed hemodynamic similarity principle can guide the fabrication of a multi-component microfluidic system for endothelial cell mechanobiology.

A high-throughput microfluidic device inspired by the Wheatstone bridge principle for characterizing the mechanical properties of single cells.

The mechanical properties of single cells have been recognized as biomarkers for identifying individual cells and diagnosing human diseases. Microfluidic devices based on the flow cytometry principle, which are not limited by the vision field of a microscope and can achieve a very high throughput, have been extensively adopted to measure the mechanical properties of single cells. However, these kinds of microfluidic devices usually required pressure-driven pumps with a very low flow rate and high precision. In this study, we developed a high-throughput microfluidic device inspired by the Wheatstone bridge principle for characterizing the mechanical properties of single cells. The microfluidic analogue of the Wheatstone bridge not only took advantage of flow cytometry, but also allowed precise control of a very low flow rate through the constricted channel with a higher input flow rate generated by a commercially available pressure-driven pump. Under different input flow rates of the pump, the apparent elastic moduli and the fluidity of osteosarcoma (U-2OS) cells and cervical carcinoma (HeLa) cells were measured by monitoring their dynamic deformations passing through the bridge-channel with different sizes of rectangular constrictions. The results showed that the input flow rate had little effect on measuring the mechanical properties of the cells, while the ratio of cell radius to effective constriction radius was different, i.e., for U-2OS cells it was 1.20 and for HeLa cells it was 1.09. Under this condition compared with predecessors, our statistic results of cell mechanical properties exhibited minimal errors. Furthermore, the cell viability after measurements was kept above 90% that demonstrated the non-destructive property of our proposed method.

Evaluation of the performance of Ca-deficient hydroxyapatite (CDHA)/MgF2 bilayer coating on biodegradable high-purity magnesium in a femoral condyle defect model in rabbits.

The two most critical factors in promoting the clinical translation of magnesium (Mg) are reducing its degradation rate and improving its osteogenesis. In this study, a Ca-deficient hydroxyapatite (CDHA)/MgF2 bilayer coating was prepared on high-purity magnesium (HP Mg) rods by fluorination and hydrothermal treatment. Scanning electron microscope showed that the thickness of the bilayer coating was 3.78 µm and that the surface morphology was nanoscale. In an in vivo experiment on femoral condyle defects in rabbits, the serum magnesium ion levels of rabbits were always in the normal range after surgery, and the liver and kidney functions were not abnormal, which indicated that the CDHA/MgF2 bilayer coating has good biosafety. Micro-CT showed that the CDHA/MgF2 bilayer coating significantly reduced the degradation rate of the HP Mg rods and enhanced the promotion of bone formation. Hard tissue sections showed that the CDHA/MgF2 bilayer coating gave the bone tissue a tight contact interface with the HP Mg rod and improved the bone mass. Immunohistochemistry showed that the expression of vascular endothelial growth factor and BMP-2 was more obvious. These results confirm that the CDHA/MgF2 bilayer coating can improve the properties of HP Mg and provide a basis for the further transformation of HP Mg in the future. It also provides a new reference for the surface modification of magnesium metal.

A passive pump-assisted microfluidic assay for quantifying endothelial wound healing in response to fluid shear stress.

There as an urgent need to quantify the endothelial wound-healing process in response to fluid shear stress to improve the biological and clinical understanding of healing mechanisms, which is of great importance for preventing healing impairment, chronic wounds, and postoperative in-stent restenosis. However, current experimental platforms not only require expensive, cumbersome, and powered pumping devices (to, e.g., generate cell scratches and load shear stress stimulation) but also lack quantitative controls for quantitative analysis. In this paper, a passive pump-assisted microfluidic assay is developed to quantify endothelial wound healing in response to fluid shear stress. Our assay consists of passive constant-flow pumps based on the siphon principle and a three-inlet microfluidic chip for cell wound-healing experiments. We also propose a method for quantitatively adjusting cell scratch size by controlling trypsin flow. Both numerical simulations and fluorescein experiments validate the effectiveness of this method. Moreover, we use the designed microfluidic assay to successfully generate cell scratches, load a 12-h shear stress of 5 dyn/cm2 to the cells, and observe wound healing. The results indicate that the healing of a cell scratch is significantly accelerated under the stimulation of shear stress. In conclusion, our passive pump-assisted microfluidic assay shows versatility, applicability, and the potential for quantifying endothelial wound healing in response to fluid shear stress.

Ginkgo biloba L. extract prevents steroid-induced necrosis of the femoral head by rescuing apoptosis and dysfunction in vascular endothelial cells via the PI3K/AKT/eNOS pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba L. extract (EGb) is one of the world's most extensively used herbal medicines. Due to the diverse pharmacological properties of EGb, it has been used in the treatment of neurological illnesses, as well as cardiovascular and cerebrovascular ailments. However, the effect and pharmacological mechanism of EGb on steroid-induced necrosis of the femoral head (SINFH) are still unclear. AIM OF THE STUDY: SINFH remains a challenging problem in orthopedics. Previous investigations have shown that EGb has the potential to reduce the occurrence of SINFH. The goal was to determine the effect and mechanism of EGb in preventing SINFH by inhibiting apoptosis and improving vascular endothelial cells (VECs) functions. MATERIALS AND METHODS: CCK-8, nitric oxide (NO) production and flow cytometry were used to determine the cell apoptosis and function. The scratch and angiogenesis tests assessed migration and tube formation. Western blot analysis detected the expressions of apoptosis-related proteins and PI3K/AKT/eNOS pathway-related proteins. Apoptosis and angiogenesis were also detected treated with the inhibitors. A mouse model of SINFH was established. Paraffin section was used to determine the necrotic pathology and apoptosis. Vessels in the femoral heads were assessed by immunofluorescence staining. RESULTS: When stimulated by methylprednisolone (MPS), cell viability, NO generation and tube formation were decreased, the apoptotic rate increased. Simultaneously, MPS decreased the expression levels of p-PI3K, p-AKT, and p-eNOS. EGb increased the expression levels of these proteins, restrained apoptosis, and restored cell functions. The addition of the inhibitors decreased anti-apoptotic effect and angiogenesis. In addition, when compared to the model mice, there were fewer empty lacunae and normal trabecular arrangement after taking different doses of EGb. The protective effect was also confirmed by the vascular quantitative analysis in vivo. CONCLUSION: This study established that EGb increased endothelial cell activity and inhibited apoptosis and function loss induced by MPS, elucidating the effect and molecular mechanism of EGb on early SINFH.

Vortex evolution patterns for flow of dilute polymer solutions in confined microfluidic cavities.

Flow instability in confined cavities has attracted extensive interest due to its significance in many natural and engineering processes. It also has applications in microfluidic devices for biomedical applications including flow mixing, nanoparticle synthesis, and cell manipulation. The recirculating vortex that characterizes the flow instability is regulated by the fluid rheological properties, cavity geometrical characteristics, and flow conditions, but there is a lack of quantitative understanding of how the vortex evolves as these factors change. Herein, we experimentally study the flow of dilute polymer solutions in confined microfluidic cavities and focus on a quantitative characterization of the vortex evolution. Three typical patterns of vortex evolution are identified in the cavity flow of dilute polymer solutions over a wide range of flow conditions. The geometrical characteristics of the cavity are found to have little effect on the patterns of vortex evolution. The geometry-independent patterns of vortex evolution provide us an intuitive paradigm, from which the interaction and competition among inertial, elastic and shear-thinning effects in these cavity-induced flow instabilities are clarified. These results extend our understanding of the flow instability of complex fluids in confined cavities, and provide useful guidelines for the design of cavity-structured microfluidic devices and their applications.

Learning Asynchronous Boolean Networks From Single-Cell Data Using Multiobjective Cooperative Genetic Programming.

Recent advances in high-throughput single-cell technologies provide new opportunities for computational modeling of gene regulatory networks (GRNs) with an unprecedented amount of gene expression data. Current studies on the Boolean network (BN) modeling of GRNs mostly depend on bulk time-series data and focus on the synchronous update scheme due to its computational simplicity and tractability. However, such synchrony is a strong and rarely biologically realistic assumption. In this study, we adopt the asynchronous update scheme instead and propose a novel framework called SgpNet to infer asynchronous BNs from single-cell data by formulating it into a multiobjective optimization problem. SgpNet aims to find BNs that can match the asynchronous state transition graph (STG) extracted from single-cell data and retain the sparsity of GRNs. To search the huge solution space efficiently, we encode each Boolean function as a tree in genetic programming and evolve all functions of a network simultaneously via cooperative coevolution. Besides, we develop a regulator preselection strategy in view of GRN sparsity to further enhance learning efficiency. An error threshold estimation heuristic is also proposed to ease tedious parameter tuning. SgpNet is compared with the state-of-the-art method on both synthetic data and experimental single-cell data. Results show that SgpNet achieves comparable inference accuracy, while it has far fewer parameters and eliminates artificial restrictions on the Boolean function structures. Furthermore, SgpNet can potentially scale to large networks via straightforward parallelization on multiple cores.

Finite-Horizon Optimal Control of Boolean Control Networks: A Unified Graph-Theoretical Approach.

This article investigates the finite-horizon optimal control (FHOC) problem of Boolean control networks (BCNs) from a graph theory perspective. We first formulate two general problems to unify various special cases studied in the literature: 1) the horizon length is a priori fixed and 2) the horizon length is unspecified but finite for given destination states. Notably, both problems can incorporate time-variant costs, which are rarely considered in existing work, and a variety of constraints. The existence of an optimal control sequence is analyzed under mild assumptions. Motivated by BCNs' finite state space and control space, we approach the two general problems intuitively and efficiently under a graph-theoretical framework. A weighted state transition graph and its time-expanded variants are developed, and the equivalence between the FHOC problem and the shortest-path (SP) problem in specific graphs is established rigorously. Two algorithms are developed to find the SP and construct the optimal control sequence for the two problems with reduced computational complexity, though technically, a classical SP algorithm in graph theory is sufficient for all problems. Compared with existing algebraic methods, our graph-theoretical approach can achieve state-of-the-art time efficiency while targeting the most general problems. Furthermore, our approach is the first one capable of solving Problem 2) with time-variant costs. Finally, a genetic network in the bacterium E. coli and a signaling network involved in human leukemia are used to validate the effectiveness of our approach. The results of two common tasks for both networks show that our approach can dramatically reduce the running time. Python implementation of our algorithms is available at GitHub https://github.com/ShuhuaGao/FHOC.

Infinite-Horizon Optimal Control of Switched Boolean Control Networks With Average Cost: An Efficient Graph-Theoretical Approach.

This study investigates the infinite-horizon optimal control (IHOC) problem for switched Boolean control networks with an average cost criterion. A primary challenge of this problem is the prohibitively high computational cost when dealing with large-scale networks. We attempt to develop a more efficient approach from a novel graph-theoretical perspective. First, a weighted directed graph structure called the optimal state transition graph (OSTG) is established, whose edges encode the optimal action for each admissible state transition between states reachable from a given initial state subject to various constraints. Then, we reduce the IHOC problem into a minimum-mean cycle (MMC) problem in the OSTG. Finally, we develop an algorithm that can quickly find a particular MMC by resorting to Karp's algorithm in the graph theory and construct an optimal switching control law based on state feedback. The time complexity analysis shows that our algorithm, albeit still running in exponential time, can outperform all the existing methods in terms of time efficiency. A 16-state-3-input signaling network in leukemia is used as a benchmark to test its effectiveness. Results show that the proposed graph-theoretical approach is much more computationally efficient and can reduce the running time dramatically: it runs hundreds or even thousands of times faster than the existing methods. The Python implementation of the algorithm is available at https://github.com/ShuhuaGao/sbcn_mmc.

Raman Spectroscopic Characterization of Polymerization Kinetics of Cyanoacrylate Embolic Glues for Vascular Embolization.

Endovascular glue embolization is a minimally invasive technique used to selectively reduce or block the blood supply to specific targeted vessels. Cyanoacrylate glues, mixed with radiopaque iodized oil, have been widely used for vascular embolization owing to their rapid polymerization rate, good penetration ability and low tissue toxicity. Nevertheless, in clinical practice, the selection of the glue-oil proportion and the manual injection process of mixtures are mostly based on empirical knowledge of operators, as the crucial physicochemical effect of polymerization kinetics has rarely been quantitatively investigated. In this study, the Raman spectroscopy is used for studying the polymerization kinetics of n-butyl-cyanoacrylate-based glues mixed with an iodized oil. To simulate the polymerization process during embolization, glue-oil mixtures upon contact with a protein ionic solution mimicking blood plasma are manually constructed and their polymerization kinetics are systematically characterized by Raman spectroscopy. The results demonstrate the feasibility of Raman spectroscopy in the characterization of polymerization kinetics of cyanoacrylate-based embolic glues. The polymerization process of cyanoacrylate-based mixtures consists of a fast polymerization phase followed by a slow phase. The propagation velocity and polymerization time primarily depend on the glue concentrations. The commonly used 50% mixture polymerizes 1 mm over ∼21.8 s, while it takes ∼51 min to extend to 5 mm. The results provide essential information for interventional radiologists to help them understand the polymerization kinetics of embolic glues and thus regulate the polymerization rate for effective embolization.