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An effective procedure to explore the thermal response of living skin tissue exposed on severe thermal circumstance is proposed in this paper. The triple-layered inner structure with variable blood...

Ektacytometry has been the primary method for evaluating deformability of red blood cells (RBCs) in both research and clinical settings. This study was designed to test the hypothesis that the flow of RBCs through a network of microfluidic capillaries could provide a more sensitive assessment of the progressive impairment of RBC deformability during hypothermic storage than ektacytometry. RBC units (n = 9) were split in half, with one half stored under standard (normoxic) conditions and the other half stored hypoxically, for up to 6 weeks. RBC deformability was measured weekly using two microfluidic devices, an artificial microvascular network (AMVN) and a multiplexed microcapillary network (MMCN), and two commercially available ektacytometers (RheoScan-D and LORRCA). By week 6, the elongation indexes measured with RheoScan-D and LORRCA decreased by 5.8–7.1% (5.4–6.9% for hypoxic storage). Over the same storage duration, the AMVN perfusion rate declined by 27.5% (24.5% for hypoxic) and the MMCN perfusion rate declined by 49.0% (42.4% for hypoxic). Unlike ektacytometry, both AMVN and MMCN measurements showed statistically significant differences between the two conditions after 1 week of storage. RBC morphology deteriorated continuously with the fraction of irreversibly-damaged (spherical) cells increasing significantly faster for normoxic than for hypoxic storage. Consequently, the number of MMCN capillary plugging events and the time MMCN capillaries spent plugged was consistently lower for hypoxic than for normoxic storage. These data suggest that capillary networks are significantly more sensitive to both the overall storage-induced decline of RBC deformability, and to the differences between the two storage conditions, than ektacytometry.

To establish an automated high-throughput mimic perfusion scale-down model (SDM) in ambr® 15 system. An optimized SDM for mimic perfusion was developed in ambr® 15 system. Cell retention in ambr® 15 was realized by sedimentation and supernatant removal with a retention rate > 95%. Although the SDM couldn’t reach the viable cell density (VCD) at a bench scale bioreactor (BR), it maintained VCD at approximately 30 × 106 cells/mL with a cell bleeding rate estimated theoretically and predicted the cell specific perfusion rate (CSPR). A base-feeding strategy was developed to alleviate the pH drop during sedimentation which would adversely have an impact on cell growth, and showed an apparent cell viability improvement from 79.6% (control) to 90.1% on Day 18. The optimized SDM for mimic perfusion was employed for media screening in two cell lines. A small-scale high-throughput perfusion model in ambr® 15 was developed, optimized to improve cell viability, and as a result, utilized for media screening in two cell lines.

Radio frequency ablation (RFA) has become a popular method for the minimally invasive treatment of liver cancer. However, the success rate of these treatments depends heavily on the amount of experience the clinician possesses. Mathematical modeling can help mitigate this problem by providing an indication of the treatment outcome. Thermal lesions in RFA are affected by the cooling effect of both fine-scale and large-scale blood vessels. The exact model for large-scale blood vessels is advection-diffusion, i.e., a model capable of producing directional effects, which are known to occur in certain cases. In previous research, in situations where directional effects do not occur, the advection term in the blood vessel model has been typically replaced with the Pennes perfusion term, albeit with a higher-than-usual perfusion rate. Whether these values of the perfusion rate appearing in literature are optimal for the particular vessel radii in question, has not been investigated so far. This work aims to address this issue. An attempt has been made to determine, for values of vessel radius between 0.55 mm and 5 mm, best estimates for the perfusion rate which minimize the error in thermal lesion volumes between the perfusion-based model and the advection-based model. The results for the best estimate of the perfusion rate presented may be used in existing methods for fast estimation of RFA outcomes. Furthermore, the possible improvements to the presented methodology have been highlighted.

Using PDE-constrained optimization we introduce a parameter identification approach which can identify the blood perfusion rate from MR thermometry data obtained during the treatment with laser-induced thermotherapy (LITT). The blood perfusion rate, i.e., the cooling effect induced by blood vessels, can be identified during the first stage of the treatment. This information can then be used by a simulation to monitor and predict the ongoing treatment. The approach is tested with synthetic measurements with and without artificial noise as input data.

BACKGROUND AND OBJECTIVES We have developed a novel anti-vascular technique, termed photo-mediated ultrasound therapy (PUT), which utilizes nanosecond duration laser pulses synchronized with ultrasound bursts to remove the microvasculature through cavitation. The objective of the current study is to explore the potential of PUT in removing subcutaneous microvessels. STUDY DESIGN/MATERIALS AND METHODS The auricular blood vessels of two New Zealand white rabbits were treated by PUT with a peak negative ultrasound pressure of 0.45 MPa at 0.5 MHz, and a laser fluence of 0.056 J/cm2 at 1064 nm for 10 minutes. Blood perfusion in the treated area was measured by a commercial laser speckle imaging (LSI) system before and immediately after treatment, as well as at 1 hour, 3 days, 2 weeks, and 4 weeks post-treatment. Perfusion rates of 38 individual vessels from four rabbit ears were tracked during this time period for longitudinal assessment. RESULTS The measured perfusion rates of the vessels in the treated areas, as quantified by the relative change in perfusion rate, showed a statistically significant decrease for all time points post-treatment (P

The paper considers the stability property of tubes of discontinuous solutions of a bilinear system with a generalized action on the right-hand side and delay. A feature of the system under consideration is that a generalized (impulsive) effect is possible non-unique reaction of the system. As a result, the unique generalized action gives rise to a certain set of discontinuous solutions, which in the work will be called the tube of discontinuous solutions.The concept of stability of discontinuous solutions tubes is formalized. Two versions of sufficient conditions for asymptotic stability are obtained. In the first case, the stability of the system is ensured by the stability property of a homogeneous system without delay; in the second case, the stability property is ensured by the stability property of a homogeneous system with delay. These results generalized the similar results for systems without delay. © 2020 Irkutsk State University. All rights reserved.

Background: Mammography is the preferred method for the diagnosis of breast cancer. However, this diagnostic technique fails to detect tumors of small sizes, and it does not work well for younger patients with high breast tissue density. Methods: This paper proposes a novel tool for the early detection of breast cancer, which is patient-specific, non-invasive, inexpensive, and has potential in terms of accuracy compared with existing techniques. The main principle of this method is based on the use of temperature contours from breast skin surfaces through thermography, and inverse thermal modeling based on Finite Element Analysis (FEA) and a Genetic Algorithm (GA)-based optimization tool to estimate the depths and sizes of tumors as well as patient/breast-specific tissue properties. Results: The study was conducted by using a 3D geometry of patients’ breasts and their temperature contours, which were clinically collected using a 3D scanner and a thermal imaging infrared (IR) camera. Conclusion: The results showed that the combination of 3D breast geometries, thermal images, and inverse thermal modeling is capable of estimating patient/breast-specific breast tissue and physiological properties such as gland and fat contents, tissue density, thermal conductivity, specific heat, and blood perfusion rate, based on a multilayer model consisting of gland and fat. Moreover, this tool was able to calculate the depth and size of the tumor, which was validated by the doctor’s diagnosis. Published version This research was funded by Ministry of Education and Science of the Republic of Kazakhstan, AP08857347 (“Application of artificial intelligence to complement thermography for breast cancer prediction”). The APC was funded by Ministry of Education and Science of the Republic of Kazakhstan.

The development of mammalian cell perfusion cultures is still laborious and complex to perform due to the limited availability of scale-down models and limited knowledge of time- and cost-effective procedures. The maximum achievable viable cell density (VCDmax ), minimum cell-specific perfusion rate (CSPRmin ), cellular growth characteristics, and resulting bleed rate at steady-state operation are key variables for the effective development of perfusion cultures. In this study, we developed a stepwise procedure to use shake tubes (ST) in combination with benchtop (BR) bioreactors for the design of a mammalian cell perfusion culture at high productivity (23 pg·cell-1 ·day-1 ) and low product loss in the bleed (around 10%) for a given expression system. In a first experiment, we investigated peak VCDs in STs by the daily discontinuous medium exchange of 1 reactor volume (RV) without additional bleeding. Based on this knowledge, we performed steady-state cultures in the ST system using a working volume of 10 ml. The evaluation of the steady-state cultures allowed performing a perfusion bioreactor run at 20 × 106 cells/ml at a perfusion rate of 1 RV/day. Constant cellular environment and metabolism resulted in stable product quality patterns. This study presents a promising strategy for the effective design and development of perfusion cultures for a given expression system and underlines the potential of the ST system as a valuable scale-down tool for perfusion cultures.

A large number of studies indicate that blood perfusion rate in biological tissue cannot be regarded as a constant in burn and thermal therapy analysis. This provides us a motivation to investigate the transient responses in the context of generalized bio-thermoelastic theories with temperature dependent blood perfusion rate. It is difficult to obtain the analytical solutions of nonlinear governing equations due to the consideration of variable blood perfusion rate. In present work, the finite element control equations of skin tissue based on generalized bio-thermoelasticity are derived and the nonlinear thermoelastic responses of the triple-layered skin tissue are obtained in time-domain directly. The influences of variable blood perfusion rate on the responses are discussed and illustrated graphically.

Immunoglobulin preparations are medicines derived from blood used as a replacement therapy for immunodeficiencies or as an immunomodulator. While they are generally well-tolerated, side effects, rarely severe, can nevertheless occur when administered intravenously. They are usually related to an excessive perfusion rate. The recent arrival of safer products administered subcutaneously represents progress in the treatment of patients.

Biomarker development is a key clinical research need in sickle cell disease (SCD). Hemorheological parameters are excellent candidates as abnormal red blood cell (RBC) rheology plays a critical role in SCD pathophysiology. Here we describe a microfluidic device capable of evaluating RBC deformability and adhesiveness concurrently, by measuring their effect on perfusion of an artificial microvascular network (AMVN) that combines microchannels small enough to require RBC deformation, and laminin (LN) coating on channel walls to model intravascular adhesion. Each AMVN device consists of three identical capillary networks, which can be coated with LN (adhesive) or left uncoated (non-adhesive) independently. The perfusion rate for sickle RBCs in the LN-coated networks (0.18 ± 0.02 nL/s) was significantly slower than in non-adhesive networks (0.20 ± 0.02 nL/s), and both were significantly slower than the perfusion rate for normal RBCs in the LN-coated networks (0.22 ± 0.01 nL/s). Importantly, there was no overlap between the ranges of perfusion rates obtained for sickle and normal RBC samples in the LN-coated networks. Interestingly, treatment with poloxamer 188 decreased the perfusion rate for sickle RBCs in LN-coated networks in a dose-dependent manner, contrary to previous studies with conventional assays, but in agreement with the latest clinical trial which showed no clinical benefit. Overall, these findings suggest the potential utility of the adhesive AMVN device for evaluating the effect of novel curative and palliative therapies on the hemorheological status of SCD patients during clinical trials and in post-market clinical practice.

The one-dimensional hyperbolic Pennes bioheat equation under instantaneous moving heat source is solved analytically based on the Eigenvalue method. Comparison with results of in vivo experiments performed earlier by other authors shows the excellent prediction of the presented closed-form solution. We present three examples for calculating the Arrhenius equation to predict the tissue thermal damage analysis with our solution, i.e., characteristics of skin, liver, and kidney are modeled by using their thermophysical properties. Furthermore, the effects of moving velocity and perfusion rate on temperature profiles and thermal tissue damage are investigated. Results illustrate that the perfusion rate plays the cooling role in the heating source moving path. Also, increasing the moving velocity leads to a decrease in absorbed heat and temperature profiles. The closed-form analytical solution could be applied to verify the numerical heating model and optimize surgery planning parameters.

A method was established to identify alterations in vascular patency and extracellular matrix integrity of decellularized porcine kidney scaffolds. These scaffolds were perfused with blood at physiologically normal (500 and 650 ml/min) and abnormal (200 ml/min) rates. Variations in venous outflow were then assessed over 24 hours. Angiographic data confirmed that standard arterial branching patterns and the integrity of the extracellular matrix were considerably disrupted. Scaffolds subjected to normal arterial perfusion rates observed drops in venous outflow across the 24 hours. These reductions rose from roughly 40% after 12 hours to 60% after 24 hours. At the end of the test period, regardless of the underlying damage that occurred, the kidneys appeared intact on the surface, and there were no apparent signs of clotting. In comparison, venous flow rates decreased by 80 to 100% across the 24 hours in acellular scaffolds subjected to a far lower perfusion rate of 200 ml/min. These kidneys also appeared intact after 24 hours of perfusion, but presented several arterial, venous, and ureteral clots. The results of this study provide insight into circumstances that limit scaffold viability and provide a simplified model to analyze other conditions that can better prepare scaffolds for long-term transplantation.

Current CHO cell production processes require an optimized space-time-yield. Process intensification can support achieving this by enhancing the productivity and improving facility utilization. The use of perfusion at the last stage of the seed train (N-1) for high cell density inoculation of the fed-batch N-stage production culture is a relatively new approach with few industry applicable examples. Within this work, the impact of the cell-specific perfusion rate (CSPR) of the N-1 perfusion and the relevance of its control for the quality of generated inoculation cells was evaluated using an automated perfusion rate (PR) control based on online biomass measurements. Precise correlations (R² = 0.99) between permittivity and viable cell counts were found up to the high densities of 100⋅106 c·mL−1. Cells from N-1 perfusion were cultivated at a high and low CSPR with 50 and 20 pL·(c·d)−1, respectively. Lowered cell growth and an increased apoptotic reaction was found as a consequence of the latter due to nutrient limitations and reduced uptake rates. Subsequently, batch cultivations (N-stage) from the different N-1 sources were inoculated to evaluate the physiological state of the inoculum. Successive responses resulting from the respective N-1 condition were uncovered. While cell growth and productivity of approaches inoculated from high CSPR and a conventional seed were comparable, low CSPR inoculation suffered significantly in terms of reduced initial cell growth and impaired viability. This study underlines the importance to determine the CSPR for the design and implementation of an N-1 perfusion process in order to achieve the desired performance at the crucial production stage.

This study aims at developing a mathematical model taking into account the effects of thermal pain sensation induced during the radiofrequency heating of neural tissues. A three-dimensional heterogeneous computational domain comprising of muscle, bone and target nerve has been considered. Importantly, the main governing equations of the multi-scale and multi-physics model are: (a) a simplified version of Maxwell’s equation utilizing a quasi-static approximation for estimating the electric field distribution, (b) the Pennes bioheat transfer equation for estimating the temperature distribution and (c) a modified Hodgkin-Huxley model for prediction of nociceptor electrophysiology. The temperature-controlled radiofrequency has been modeled on the neural tissue by utilizing the protocols applied in actual clinical practices along with taking into account the temperature-dependent electrical conductivity and blood perfusion rate. The effects of different values of preset target temperature on the treatment outcomes of nerve ablation have also been quantified. The findings of the present study would provide a priori information to the clinicians that will be beneficial during the treatment planning stage of the therapy.

Media preparation for perfusion cell culture processes contributes significantly to operational costs and the footprint of continuous operations for therapeutic protein manufacturing. In this study, definitions are given for the use of a perfusion equivalent nutrient feed stream which, when used in combination with basal perfusion medium, supplements the culture with targeted compounds and increases the medium depth. Definitions to compare medium and feed depth are given in this article. Using a concentrated nutrient feed, a 1.8-fold medium consumption (MC) decrease and a 1.67-fold increase in volumetric productivity (PR) were achieved compared to the initial condition. Later, this strategy was used to push cell densities above 100 × 106 cells/ml while using a perfusion rate below 2 RV/day. In this example, MC was also decreased 1.8-fold compared to the initial condition, but due to the higher cell density, PR was increased 3.1-fold and to an average PR value of 1.36 g L-1 day-1 during a short stable phase, and versus 0.46 g L-1 day-1 in the initial condition. Overall, the performance improvements were aligned with the given definitions. This multiple feeding strategy can be applied to gain some flexibility during process development and also in a manufacturing set-up to enable better control on nutrient addition.

Background Microdialysis is a clinical method used to detect ischemia after microvascular surgery. Microdialysis is easy to use and reliable, but its value in most clinical settings is hampered by a 1- to 2-h delay in the delivery of patient data. This study evaluated the effectiveness of an increase in the microdialysis perfusion rate from 0.3 to 1.0 µL/min on the diagnostic delay in the detection of ischemia. Methods In eight pigs, two symmetric pure muscle transfers were dissected based on one vascular pedicle each. In each muscle, two microdialysis catheters were placed. The two microdialysis catheters were randomized to a perfusion rate of 0.3 or 1.0 µL/min, and the two muscle transfers were randomized to arterial or venous ischemia, respectively. After baseline monitoring, arterial and venous ischemia was introduced by the application of vessel clamps. Microdialysis sampling was performed throughout the experiment. The ischemic cutoff values were based on clinical experience set as follows: CGlucose 7 mmol/L, and the lactate/pyruvate ratio > 50. Results The delay for the detection of 50% of arterial ischemia was reduced from 60 to 25 minutes, and for the detection of all cases of arterial ischemia, the delay was reduced from 75 to 40 minutes when the perfusion rate was increased from 0.3 to 1.0 µL/min. After the same increase in perfusion, the detection of 50% of venous ischemia was reduced from 75 to 40 minutes, and for all cases of venous ischemia, a reduction from 135 to 95 minutes was found. Conclusion When using microdialysis for the detection of ischemia in pure muscle transfers, an increase in the perfusion rate from 0.3 to 1.0 µL/min can reduce the detection delay of ischemia.

Bioavailability estimates the actual internal uptake or absorption of contaminants that enter the body (internal dose) and helps in providing a more accurate estimation of the human risks than the usage of total concentration. This is important for exposure assessment for children in relation to their hand-to-mouth activities. For example significant reductions of the bioavailability of long-term contaminated soils have been demonstrated using various animal models. The measurement for bioavailability involves various uncertainties for organic contaminants. It is crucial to determine the parameters that influence the results of bioavailability. This chapter provides a summary of the current state of knowledge for the determination of bioavailability for a range of organic contaminants. The information provided will be useful in facilitating further research efforts for the investigation of bioavailability of contaminants in conducting exposure assessments.

The use of benchtop bioreactors (BRs) for the development of mammalian cell perfusion cultures is expensive and time consuming, given its complexity in equipment and operation. Scale-down models, going from liter to milliliter scale, are needed to support the rapid determination of suitable operating conditions in terms of viable cell density (VCD), perfusion rate, and medium composition. In this study, we compare the performance of steady-state perfusion cultures in orbitally shaken tube and BR systems for a given Chinese hamster ovary cell line. The developed scale-down model relied on a daily workflow designed to keep the VCD constant at specific target values. This includes: cell count, removal of excessive cells (bleeding), spin down of remaining cells, harvest of cell-free supernatant, and resuspension in fresh medium. Steady-state cultures at different VCD values, medium exchange rates and working volumes were evaluated. Shake-tube perfusion cultures allowed the prediction of cell-specific growth, glucose consumption, ammonia, and monoclonal antibody production rates for much larger BRs, but not lactate (LAC) production rates. Although charge variant profiles remained comparable, different glycosylation patterns were obtained. The differences in LAC production and glycosylation probably resulted from the discontinuous medium exchange, the poor carbon dioxide removal, and the deficient pH control. Therefore, if requested by the specific process to be developed, product quality has to be fine-tuned directly in the BR system. Altogether, the developed strategy provides a useful scale-down model for the design and optimization of perfusion cultures with strong savings in time and media consumption.

The work is devoted to the study of the effect of interval hypoxic training on the state of microcirculation of the skin in rats in the experiment. The study was conducted on white male Wistar rats weighing 70 g ±10%. In order to study the state of the dynamic characteristics of blood microcirculation, a change in blood perfusion of the tissue was considered. A non-invasive method for quantifying microvascular perfusion was used. The results showed that inhibition of microcirculation up to 50 % was observed in comparison to this value before exposure during the formation of a compensatory reaction of the body to a hypoxic effect on the 7–14th day of the experiment. It was noted that the predominant role in the regulation of the microvasculature belongs to the passive regulation factor of microcirculation which is characterized by the involvement of blood vessels in the microvasculature due to periodic changes in blood volume in the vessel together with an increase in the arithmetic mean perfusion rate. Thus, experimentally modulated hypobaric exposure, changes the volume of blood in arterioles that is determined by a pulse wave.

The Heat Transfer Rate (HTR) of tissue is a major problem in controlling the brain tissue temperature under laser therapy to remove a tumor. For the planning, Planning, according to research (7), to set HTR of the brain tissue provides the result of the cerebral blood flow (CBF) by applying the tissue residue curves of dynamic susceptibility in contrast to magnetic resonance imaging (DSC-MRI) with gadolinium (Gd). The research created a map of heat transfer for every temperature level for brain tissue CBF by studying the samples of Glioblastoma and Meningioma tissues in the two HTR diagrams. This research, studied five sample patients by using perfusion of multiple lesions diffuse enhancement (n = 1), irregular enhancement (n = 1), and ring enhancement( n = 3). The perfusion rate from CBF of the samples was compared with the database. The result, of the HTR value HTR, at a brain tissue temperature of 34°C to 43 °C had the same result as from the analysis of the tumor; HTR increases around the rim of the tumor while the value inside is low. Another result was the HTR inside the tumor was high, while the HTR at the rim was low. The HTR data could be used to simulate tissue under the equation of bio-heat transfer.

The relationship between dynamic infrared (IR) thermal images and blood perfusion rate of the tongues of anaemia patients was investigated. Blood perfusion rates at multiple locations on the tongues of 62 anaemia patients and 70 control subjects were measured. For both groups of subjects, dynamic IR thermal images were also recorded within 16 s after the mouth opened. The results showed that the blood perfusion rates at different sites (apex, middle, left side and right side) on the tongues in anaemia patients (3.49, 3.71, 3.85 and 3.77 kg/s m−3) were significantly lower than those at the corresponding sites in control subjects (4.45, 4.66, 4.81 and 4.70 kg/s m−3). After the mouth opened, the tongue temperature decreased more rapidly in anaemia patients than in control subjects. To analyse the heat transfer mechanism, a transient heat transfer model of the tongue was developed. The tongue temperatures in anaemia patients and control subjects were calculated using this model and compared to the tongue temperatures measured by the IR thermal imager. The relationship between the tongue surface temperature and the tongue blood perfusion rate was analysed. The simulation results indicated that the low blood perfusion rate and the correlated changes in anaemia patients can cause faster temperature decreases of the tongue surface.

Lentiviral vectors (LVs) are promising tools for gene therapy. However, scaling up the production methods of LVs in order to produce high-quality vectors for clinical purposes has proven to be difficult. In this article, we present a scalable and efficient method to produce LVs with transient transfection of adherent 293T cells in a fixed-bed bioreactor. The disposable iCELLis bioreactors are scalable with a large three-dimensional (3D) growth area range between 0.53 and 500 m2, an integrated perfusion system, and a controllable environment for production. In this study, iCELLis Nano (2.67–4 m2) was used for optimizing production parameters for scale-up. Transfections were first done using traditional calcium phosphate method, but in later runs polyethylenimine was found to be more reliable and easier to use. For scalable LV production, perfusion rate control by measuring cell metabolite concentrations in the bioreactor leads to higher productivity and reduced costs. Optimization of cell seeding density for targeted cell concentration during transfection, use of low compaction fixed-bed and lowering the culture pH have a positive effect on LV productivity. These results show for the first time that iCELLis bioreactor is scalable from bench level to clinical scale LV production., published version, peerReviewed