On the microstructurally driven heterogeneous response of brain white matter to drug infusion pressure.

Delivering therapeutic agents into the brain via convection-enhanced delivery (CED), a mechanically controlled infusion method, provides an efficient approach to bypass the blood-brain barrier and deliver drugs directly to the targeted focus in the brain. Mathematical methods based on Darcy's law have been widely adopted to predict drug distribution in the brain to improve the accuracy and reduce the side effects of this technique. However, most of the current studies assume that the hydraulic permeability and porosity of brain tissue are homogeneous and constant during the infusion process, which is less accurate due to the deformability of the axonal structures and the extracellular matrix in brain white matter. To solve this problem, a multiscale model was established in this study, which takes into account the pressure-driven deformation of brain microstructure to quantify the change of local permeability and porosity. The simulation results were corroborated using experiments measuring hydraulic permeability in ovine brain samples. Results show that both hydraulic pressure and drug concentration in the brain would be significantly underestimated by classical Darcy's law, thus highlighting the great importance of the present multiscale model in providing a better understanding of how drugs transport inside the brain and how brain tissue responds to the infusion pressure. This new method can assist the development of both new drugs for brain diseases and preoperative evaluation techniques for CED surgery, thus helping to improve the efficiency and precision of treatments for brain diseases.

Insights into Infusion-Based Targeted Drug Delivery in the Brain: Perspectives, Challenges and Opportunities.

Targeted drug delivery in the brain is instrumental in the treatment of lethal brain diseases, such as glioblastoma multiforme, the most aggressive primary central nervous system tumour in adults. Infusion-based drug delivery techniques, which directly administer to the tissue for local treatment, as in convection-enhanced delivery (CED), provide an important opportunity; however, poor understanding of the pressure-driven drug transport mechanisms in the brain has hindered its ultimate success in clinical applications. In this review, we focus on the biomechanical and biochemical aspects of infusion-based targeted drug delivery in the brain and look into the underlying molecular level mechanisms. We discuss recent advances and challenges in the complementary field of medical robotics and its use in targeted drug delivery in the brain. A critical overview of current research in these areas and their clinical implications is provided. This review delivers new ideas and perspectives for further studies of targeted drug delivery in the brain.

Infusion Mechanisms in Brain White Matter and Their Dependence on Microstructure: An Experimental Study of Hydraulic Permeability.

OBJECTIVE: Hydraulic permeability is a topic of deep interest in biological materials because of its important role in a range of drug delivery-based therapies. The strong dependence of permeability on the geometry and topology of pore structure and the lack of detailed knowledge of these parameters in the case of brain tissue makes the study more challenging. Although theoretical models have been developed for hydraulic permeability, there is limited consensus on the validity of existing experimental evidence to complement these models. In the present study, we measure the permeability of white matter (WM) of fresh ovine brain tissue considering the localised heterogeneities in the medium using an infusion-based experimental set up, iPerfusion. We measure the flow across different parts of the WM in response to applied pressures for a sample of specific dimensions and calculate the permeability from directly measured parameters. Furthermore, we directly probe the effect of anisotropy of the tissue on permeability by considering the directionality of tissue on the obtained values. Additionally, we investigate whether WM hydraulic permeability changes with post-mortem time. To our knowledge, this is the first report of experimental measurements of the localised WM permeability, also demonstrating the effect of axon directionality on permeability. This work provides a significant contribution to the successful development of intra-tumoural infusion-based technologies, such as convection-enhanced delivery (CED), which are based on the delivery of drugs directly by injection under positive pressure into the brain.

Mechanochemistry of phosphate esters confined between sliding iron surfaces.

The molecular structure of lubricant additives controls not only their adsorption and dissociation behaviour at the nanoscale, but also their ability to reduce friction and wear at the macroscale. Here, we show using nonequilibrium molecular dynamics simulations with a reactive force field that tri(s-butyl)phosphate dissociates much faster than tri(n-butyl)phosphate when heated and compressed between sliding iron surfaces. For both molecules, dissociative chemisorption proceeds through cleavage of carbon-oxygen bonds. The dissociation rate increases exponentially with temperature and stress. When the rate-temperature-stress data are fitted with the Bell model, both molecules have similar activation energies and activation volumes and the higher reactivity of tri(s-butyl)phosphate is due to a larger pre-exponential factor. These observations are consistent with experiments using the antiwear additive zinc dialkyldithiophosphate. This study represents a crucial step towards the virtual screening of lubricant additives with different substituents to optimise tribological performance.

Effect of Temperature on the Deformation Behavior of Copper Nickel Alloys under Sliding.

The microstructural evolution in the near-surface regions of a dry sliding interface has considerable influence on its tribological behavior and is driven mainly by mechanical energy and heat. In this work, we use large-scale molecular dynamics simulations to study the effect of temperature on the deformation response of FCC CuNi alloys of several compositions under various normal pressures. The microstructural evolution below the surface, marked by mechanisms spanning grain refinement, grain coarsening, twinning, and shear layer formation, is discussed in depth. The observed results are complemented by a rigorous analysis of the dislocation activity near the sliding interface. Moreover, we define key quantities corresponding to deformation mechanisms and analyze the time-independent differences between 300 K and 600 K for all simulated compositions and normal pressures. Raising the Ni content or reducing the temperature increases the energy barrier to activate dislocation activity or promote plasticity overall, thus increasing the threshold stress required for the transition to the next deformation regime. Repeated distillation of our quantitative analysis and successive elimination of spatial and time dimensions from the data allows us to produce a 3D map of the dominating deformation mechanism regimes for CuNi alloys as a function of composition, normal pressure, and homologous temperature.

Hemiarthroplasties: the choice of prosthetic material causes different levels of damage in the articular cartilage.

BACKGROUND: Hemiarthroplasty has clear advantages over alternative procedures and is used in 20% of all shoulder joint replacements. Because of cartilage wear, the clinical outcome of hemiarthroplasty is unreliable and controversial. This paper suggests that the optimal choice of prosthetic material may reduce cartilage degeneration and improve the reliability of the procedure. The specific objectives were to assess 3 materials and assess how the severity of arthritis might affect the choice of prosthetic material. METHODS: A CoCr alloy, an AL2O3 ceramic, and a polycarbonate urethane polymer (PCU) were mechanically tested against 5 levels of human osteoarthritic cartilage (from intact to severely arthritic, n = 45). A high friction coefficient, a decrease in Young's modulus, an increase in permeability, a decrease in relaxation time, an increase in surface roughness, and a disrupted appearance of the cartilage after testing were used as measures of cartilage damage. The biomaterial that caused minimal cartilage damage was defined as superior. RESULTS: The CoCr caused the most damage. This was followed by the AL2O3 ceramic, whereas the PCU caused the least amount of damage. Although the degree of arthritis had an effect on the results, it did not change the trend that CoCr performed worst and PCU the best. DISCUSSION AND CONCLUSION: This study indicates that ceramic implants may be a better choice than metals, and the articulating surface should be as smooth as possible. Although our results indicate that the degree of arthritis should not affect the choice of prosthetic material, this suggestion needs to be further investigated.

Simulating Surfactant-Iron Oxide Interfaces: From Density Functional Theory to Molecular Dynamics.

Understanding the behavior of surfactant molecules on iron oxide surfaces is important for many industrial applications. Molecular dynamics (MD) simulations of such systems have been limited by the absence of a force field (FF), which accurately describes the molecule-surface interactions. In this study, interaction energies from density functional theory (DFT) + U calculations with a van der Waals functional are used to parameterize a classical FF for MD simulations of amide surfactants on iron oxide surfaces. The original FF, which was derived using mixing rules and surface Lennard-Jones (LJ) parameters developed for nonpolar molecules, was shown to significantly underestimate the adsorption energy and overestimate the equilibrium adsorption distance compared to DFT. Conversely, the optimized FF showed excellent agreement with the interaction energies obtained from DFT calculations for a wide range of surface coverages and molecular conformations near to and adsorbed on α-Fe2O3(0001). This was facilitated through the use of a Morse potential for strong chemisorption interactions, modified LJ parameters for weaker physisorption interactions, and adjusted partial charges for the electrostatic interactions. The original FF and optimized FF were compared in classical nonequilibrium molecular dynamics simulations of amide molecules confined between iron oxide surfaces. When the optimized FF was employed, the amide molecules were pulled closer to the surface and the orientation of the headgroups was more similar to that observed in the DFT calculations. The optimized FF proposed here facilitates classical MD simulations of anhydrous amide-iron oxide interfaces in which the interactions are representative of accurate DFT calculations.

A computational fluid dynamics approach to determine white matter permeability.

Glioblastomas represent a challenging problem with an extremely poor survival rate. Since these tumour cells have a highly invasive character, an effective surgical resection as well as chemotherapy and radiotherapy is very difficult. Convection-enhanced delivery (CED), a technique that consists in the injection of a therapeutic agent directly into the parenchyma, has shown encouraging results. Its efficacy depends on the ability to predict, in the pre-operative phase, the distribution of the drug inside the tumour. This paper proposes a method to compute a fundamental parameter for CED modelling outcomes, the hydraulic permeability, in three brain structures. Therefore, a bidimensional brain-like structure was built out of the main geometrical features of the white matter: axon diameter distribution extrapolated from electron microscopy images, extracellular space (ECS) volume fraction and ECS width. The axons were randomly allocated inside a defined border, and the ECS volume fraction as well as the ECS width maintained in a physiological range. To achieve this result, an outward packing method coupled with a disc shrinking technique was implemented. The fluid flow through the axons was computed by solving Navier-Stokes equations within the computational fluid dynamics solver ANSYS. From the fluid and pressure fields, an homogenisation technique allowed establishing the optimal representative volume element (RVE) size. The hydraulic permeability computed on the RVE was found in good agreement with experimental data from the literature.

Effective Diffusion and Tortuosity in Brain White Matter.

Patients affected by glioblastomas have a very low survival rate. Emerging techniques, such as convection enhanced delivery (CED), need complex numerical models to be effective; furthermore, the estimation of the main parameters to be used to instruct constitutive laws in simulations represents a major challenge. This work proposes a new method to compute tortuosity, a key parameter for drug diffusion in fibrous tissue, starting from a model which incorporates the main white matter geometrical features. It is shown that tortuosity increases from 1.35 to 1.85 as the extracellular space width decreases. The results are in good agreement with experimental data reported in the literature.

Models and tissue mimics for brain shift simulations.

Capturing the deformation of human brain during neurosurgical operations is an extremely important task to improve the accuracy or surgical procedure and minimize permanent damage in patients. This study focuses on the development of an accurate numerical model for the prediction of brain shift during surgical procedures and employs a tissue mimic recently developed to capture the complexity of the human tissue. The phantom, made of a composite hydrogel, was designed to reproduce the dynamic mechanical behaviour of the brain tissue in a range of strain rates suitable for surgical procedures. The use of a well-controlled, accessible and MRI compatible alternative to real brain tissue allows us to rule out spurious effects due to patient geometry and tissue properties variability, CSF amount uncertainties, and head orientation. The performance of different constitutive descriptions is evaluated using a brain-skull mimic, which enables 3D deformation measurements by means of MRI scans. Our combined experimental and numerical investigation demonstrates the importance of using accurate constitutive laws when approaching the modelling of this complex organic tissue and supports the proposal of a hybrid poro-hyper-viscoelastic material formulation for the simulation of brain shift.

Electronic remote blood issue combined with a computer-controlled, automated refrigerator for major surgery in operating theatres at a distance from the transfusion service.

BACKGROUND: The difficulty of supplying red blood cells within an adequate time to patients undergoing surgery is a known problem for transfusion services, particularly if the operating theater is located at some distance from the blood bank. The consequences frequently are that more blood is ordered than required; several units are allocated and issued; and unused units must be returned to the blood bank. Some sparse reports have demonstrated that remote blood issue systems can improve the efficiency of issuing blood. STUDY DESIGN AND METHODS: This study describes a computer-controlled, self-service, remote blood-release system, combined with an automated refrigerator, installed in a hospital at which major surgery was performed, located 5 kilometers away from the transfusion service. With this system, red blood cell units were electronically allocated to patients immediately before release, when the units actually were needed. Two 2-year periods, before and after implementation of the system, were compared. RESULTS: After implementation of the system, the ratio of red blood cell units returned to the transfusion service was reduced from 48.9% to 1.6% of the issued units (8852 of 18,090 vs. 182 of 11,152 units; p < 0.0001), and the issue-to-transfusion ratio was reduced from 1.96 to 1.02. An increase in the number of transfused red blood cell units was observed, probably mainly due to changes in the number and complexity of surgical procedures. No transfusion errors occurred in the two periods. CONCLUSION: The current results demonstrate that the remote blood-release system is safe and useful for improving the efficiency of blood issue for patients in remote operating theatres.

Tribological properties of PVA/PVP blend hydrogels against articular cartilage.

This research investigated in-vitro tribological performance of the articulation of cartilage-on- polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) blend hydrogels using a custom-designed multi-directional wear rig. The hydrogels were prepared by repeated freezing-thawing cycles at different concentrations and PVA to PVP fractions at a given concentration. PVA/PVP blend hydrogels showed low coefficient of friction (COF) values (between 0.12 ± 0.01 and 0.14 ± 0.02) which were closer to the cartilage-on-cartilage articulation (0.03 ± 0.01) compared to the cartilage-on-stainless steel articulation (0.46 ± 0.06). The COF increased with increasing hydrogel concentration (p = 0.03) and decreasing PVP content at a given concentration (p < 0.05). The cartilage-on-hydrogel tests showed only the surface layers of the cartilage being removed (average volume loss of the condyles was 12.5 ± 4.2mm3). However, the hydrogels were found to be worn/deformed. The hydrogels prepared at a higher concentration showed lower apparent volume loss. A strong correlation (R2 = 0.94) was found between the COF and compressive moduli of the hydrogel groups, resulting from decreasing contact congruency. It was concluded that the hydrogels were promising as hemiarthroplasty materials, but that improved mechanical behaviour was required for clinical use.

Nonequilibrium Molecular Dynamics Simulations of Organic Friction Modifiers Adsorbed on Iron Oxide Surfaces.

For the successful development and application of lubricants, a full understanding of the nanoscale behavior of complex tribological systems is required, but this is difficult to obtain experimentally. In this study, we use nonequilibrium molecular dynamics (NEMD) simulations to examine the atomistic structure and friction properties of commercially relevant organic friction modifier (OFM) monolayers adsorbed on iron oxide surfaces and lubricated by a thin, separating layer of hexadecane. Specifically, acid, amide, and glyceride OFMs, with saturated and Z-unsaturated hydrocarbon tail groups, are simulated at various surface coverages and sliding velocities. At low and medium coverage, the OFMs form liquidlike and amorphous monolayers, respectively, which are significantly interdigitated with the hexadecane lubricant, resulting in relatively high friction coefficients. At high coverage, solidlike monolayers are formed for all of the OFMs, which, during sliding, results in slip planes between well-defined OFM and hexadecane layers, yielding a marked reduction in the friction coefficient. When present at equal surface coverage, OFMs with saturated and Z-unsaturated tail groups are found to yield similar structure and friction behavior. OFMs with glyceride head groups yield significantly lower friction coefficients than amide and particularly carboxylic acid head groups. For all of the OFMs and coverages simulated, the friction coefficient is found to increase linearly with the logarithm of sliding velocity; however, the gradient of this increase depends on the coverage. The structure and friction details obtained from these simulations agree well with experimental results and also shed light on the relative tribological performance of these OFMs through nanoscale structural variations. This has important implications in terms of the applicability of NEMD to aid the development of new formulations to control friction.

Soft Tissue Phantoms for Realistic Needle Insertion: A Comparative Study.

Phantoms are common substitutes for soft tissues in biomechanical research and are usually tuned to match tissue properties using standard testing protocols at small strains. However, the response due to complex tool-tissue interactions can differ depending on the phantom and no comprehensive comparative study has been published to date, which could aid researchers to select suitable materials. In this work, gelatin, a common phantom in literature, and a composite hydrogel developed at Imperial College, were matched for mechanical stiffness to porcine brain, and the interactions during needle insertions within them were analyzed. Specifically, we examined insertion forces for brain and the phantoms; we also measured displacements and strains within the phantoms via a laser-based image correlation technique in combination with fluorescent beads. It is shown that the insertion forces for gelatin and brain agree closely, but that the composite hydrogel better mimics the viscous nature of soft tissue. Both materials match different characteristics of brain, but neither of them is a perfect substitute. Thus, when selecting a phantom material, both the soft tissue properties and the complex tool-tissue interactions arising during tissue manipulation should be taken into consideration. These conclusions are presented in tabular form to aid future selection.

Attenuation of the dynamic yield point of shocked aluminum using elastodynamic simulations of dislocation dynamics.

When a metal is subjected to extremely rapid compression, a shock wave is launched that generates dislocations as it propagates. The shock wave evolves into a characteristic two-wave structure, with an elastic wave preceding a plastic front. It has been known for more than six decades that the amplitude of the elastic wave decays the farther it travels into the metal: this is known as "the decay of the elastic precursor." The amplitude of the elastic precursor is a dynamic yield point because it marks the transition from elastic to plastic behavior. In this Letter we provide a full explanation of this attenuation using the first method of dislocation dynamics to treat the time dependence of the elastic fields of dislocations explicitly. We show that the decay of the elastic precursor is a result of the interference of the elastic shock wave with elastic waves emanating from dislocations nucleated in the shock front. Our simulations reproduce quantitatively recent experiments on the decay of the elastic precursor in aluminum and its dependence on strain rate.

Dynamic response of liquid-filled catheter systems for measurement of blood pressure: precision of measurements and reliability of the Pressure Recording Analytical Method with different disposable systems.

PURPOSE: We aimed to compare the effects of a blood pressure transducer system specifically manufactured to limit underdamping artifacts with those of a standard system on hemodynamic parameter estimation and accuracy. MATERIALS AND METHODS: Forty-three consecutive patients undergoing vascular surgery at the University of Florence, Italy, were included. Arterial blood pressure signal was simultaneously registered with 2 MostCare monitors, connected to the artery either by a standard transducer or a specific transducer manufactured to avoid underdamping artifacts (Resonance Over-Shoot Eliminator [R.O.S.E.]; Becton Dickinson, Becton Drive, NJ). Patients were divided into 2 groups: absence (C group) or presence (R group) of underdamping/resonance artifacts of blood pressure signal. Systolic blood pressure, cardiac index, maximal pressure/time ratio (dP/dt(MAX)), and cardiac cycle efficiency were recorded every 30 seconds for 30 minutes. A total of 2675 measurements were performed with 34.9% incidence of underdamping/resonance artifacts. RESULTS: All hemodynamic parameters showed clinically acceptable differences in the C group; in contrast, the results differed greatly in the R group between standard and R.O.S.E. transducer (systolic blood pressure bias, 16.7 mm Hg; cardiac index bias, 0.24 L min(-1) m(-2); dP/dt(MAX) bias, 0.92 mm Hg/ms; cardiac cycle efficiency bias, 0.018 units). CONCLUSIONS: Underdamping/resonance artifacts frequently affect blood pressure measurement in operating rooms and intensive care units and cause severe overestimation of systolic blood pressure and incorrect estimation of hemodynamic parameters when the pulse contour method is used.

Cardiac output by arterial pulse contour: reliability under hemodynamic derangements.

Pulse contour methods (PCM) for the measurements of cardiac output (CO) are gaining popularity in intensive care settings but their reliability during hemodynamic instability has been questioned. Pressure-recording-analytical-method (PRAM) is a newly developed uncalibrated hemodynamic monitor and its capability in measuring CO during hemodynamic instability is still under investigation. Dobutamine (2.5 and 5 microg/kg/min), vasoconstriction (arginine-vasopressin 4, 8 and 16 IU/h), hemorrhage (-10%, -20%, -35%, and -50% of the theoretical volemia), and volume resuscitation were induced in eight swine. CO by means of thermodilution (CO(ThD)), transesophageal echocardiography (CO(TEE)) and PRAM (CO(PRAM)) were contemporarily registered. R(2), bias, and percentage error were used to compare the methods. Comparison between CO(PRAM) and CO(ThD) resulted in: r(2)=0.87; bias=-0.006 l/min; precision=+/-0.87 l/min; percentage error=22.8%. Comparison between CO(PRAM) and CO(TEE) resulted in: r(2)=0.85; bias=-0.007 l/min; precision=+/-0.86 l/min; percentage error=22%. Sub-group analysis revealed disagreement between methods only during the last two steps of hemorrhage: CO(PRAM) vs. CO(ThD): r(2)=0.67, bias=-0.37 l/min, precision=+/-1.04 l/min, limits of agreement=-1.39+0.66 l/min, and percentage error=45%; CO(PRAM) vs. CO(TEE): r(2)=0.38, bias=0.4 l/min, precision=+/-1.42 l/min, limits of agreement=-0.99+1.79 l/min, and percentage error=62%. PRAM resulted to be accurate in measuring CO during hemodynamic stability, tachycardia, and vasoconstriction. When volemia was reduced by >35%, disagreement between methods was observed.

Bisphosphonate-associated osteonecrosis of the jaw: a review of 35 cases and an evaluation of its frequency in multiple myeloma patients.

Over a period of 28 months, we observed five cases of osteonecrosis of the jaw (ONJ) in cancer patients treated with bisphosphonates (BP) at our institution. This prompted us to undertake a retrospective, multicenter study to analyse the characteristics of patients who exhibited ONJ and to define the frequency of ONJ in multiple myeloma (MM). We identified 35 cases in Gruppo Italiano Studio Linfomi centers during the period 2002 - 05. The median time from cancer diagnosis to the clinical onset of ONJ was 70 months. In these 35 cases of ONJ, 24 appeared 20 - 60 months after starting BP treatment. The time for the onset of ONJ was significantly shorter for patients treated with zoledronic acid alone than for those treated with pamidronate followed by zoledronic acid. The frequency of ONJ in the MM group during the study period was 1.9%, although the nature of the present study may have resulted in an underestimation of ONJ cases. Our analysis strongly suggested an association between the use of BP and the occurrence of ONJ, although we were unable to identify any definite risk factors with a retrospective study. The most frequently ONJ-associated clinical characteristics were chemotherapy treatment, steroid treatment, advanced age, female sex, anemia, parodonthopaties/dental procedures and thalidomide (in the case of MM patients).