Causes of Hypoxemia in COVID-19 Acute Respiratory Distress Syndrome: A Combined Multiple Inert Gas Elimination Technique and Dual-energy Computed Tomography Study.

BACKGROUND: Despite the fervent scientific effort, a state-of-the art assessment of the different causes of hypoxemia (shunt, ventilation-perfusion mismatch, and diffusion limitation) in COVID-19 acute respiratory distress syndrome (ARDS) is currently lacking. In this study, the authors hypothesized a multifactorial genesis of hypoxemia and aimed to measure the relative contribution of each of the different mechanism and their relationship with the distribution of tissue and blood within the lung. METHODS: In this cross-sectional study, the authors prospectively enrolled 10 patients with COVID-19 ARDS who had been intubated for less than 7 days. The multiple inert gas elimination technique (MIGET) and a dual-energy computed tomography (DECT) were performed and quantitatively analyzed for both tissue and blood volume. Variables related to the respiratory mechanics and invasive hemodynamics (PiCCO [Getinge, Sweden]) were also recorded. RESULTS: The sample (51 ± 15 yr; Pao2/Fio2, 172 ± 86 mmHg) had a mortality of 50%. The MIGET showed a shunt of 25 ± 16% and a dead space of 53 ± 11%. Ventilation and perfusion were mismatched (LogSD, Q, 0.86 ± 0.33). Unexpectedly, evidence of diffusion limitation or postpulmonary shunting was also found. In the well aerated regions, the blood volume was in excess compared to the tissue, while the opposite happened in the atelectasis. Shunt was proportional to the blood volume of the atelectasis (R2 = 0.70, P = 0.003). V˙A/Q˙T mismatch was correlated with the blood volume of the poorly aerated tissue (R2 = 0.54, P = 0.016). The overperfusion coefficient was related to Pao2/Fio2 (R2 = 0.66, P = 0.002), excess tissue mass (R2 = 0.84, P < 0.001), and Etco2/Paco2 (R2 = 0.63, P = 0.004). CONCLUSIONS: These data support the hypothesis of a highly multifactorial genesis of hypoxemia. Moreover, recent evidence from post-mortem studies (i.e., opening of intrapulmonary bronchopulmonary anastomosis) may explain the findings regarding the postpulmonary shunting. The hyperperfusion might be related to the disease severity.

High- versus Low-Flow Extracorporeal Respiratory Support in Experimental Hypoxemic Acute Lung Injury.

Rationale: In the EOLIA (ECMO to Rescue Lung Injury in Severe ARDS) trial, oxygenation was similar between intervention and conventional groups, whereas [Formula: see text]e was reduced in the intervention group. Comparable reductions in ventilation intensity are theoretically possible with low-flow extracorporeal CO2 removal (ECCO2R), provided oxygenation remains acceptable. Objectives: To compare the effects of ECCO2R and extracorporeal membrane oxygenation (ECMO) on gas exchange, respiratory mechanics, and hemodynamics in animal models of pulmonary (intratracheal hydrochloric acid) and extrapulmonary (intravenous oleic acid) lung injury. Methods: Twenty-four pigs with moderate to severe hypoxemia (PaO2:FiO2 ⩽ 150 mm Hg) were randomized to ECMO (blood flow 50-60 ml/kg/min), ECCO2R (0.4 L/min), or mechanical ventilation alone. Measurements and Main Results: [Formula: see text]o2, [Formula: see text]co2, gas exchange, hemodynamics, and respiratory mechanics were measured and are presented as 24-hour averages. Oleic acid versus hydrochloric acid showed higher extravascular lung water (1,424 ± 419 vs. 574 ± 195 ml; P < 0.001), worse oxygenation (PaO2:FiO2 = 125 ± 14 vs. 151 ± 11 mm Hg; P < 0.001), but better respiratory mechanics (plateau pressure 27 ± 4 vs. 30 ± 3 cm H2O; P = 0.017). Both models led to acute severe pulmonary hypertension. In both models, ECMO (3.7 ± 0.5 L/min), compared with ECCO2R (0.4 L/min), increased mixed venous oxygen saturation and oxygenation, and improved hemodynamics (cardiac output = 6.0 ± 1.4 vs. 5.2 ± 1.4 L/min; P = 0.003). [Formula: see text]o2 and [Formula: see text]co2, irrespective of lung injury model, were lower during ECMO, resulting in lower PaCO2 and [Formula: see text]e but worse respiratory elastance compared with ECCO2R (64 ± 27 vs. 40 ± 8 cm H2O/L; P < 0.001). Conclusions: ECMO was associated with better oxygenation, lower [Formula: see text]o2, and better hemodynamics. ECCO2R may offer a potential alternative to ECMO, but there are concerns regarding its effects on hemodynamics and pulmonary hypertension.

End-Tidal to Arterial Pco2 Ratio as Guide to Weaning from Venovenous Extracorporeal Membrane Oxygenation.

Rationale: Weaning from venovenous extracorporeal membrane oxygenation (VV-ECMO) is based on oxygenation and not on carbon dioxide elimination. Objectives: To predict readiness to wean from VV-ECMO. Methods: In this multicenter study of mechanically ventilated adults with severe acute respiratory distress syndrome receiving VV-ECMO, we investigated a variable based on CO2 elimination. The study included a prospective interventional study of a physiological cohort (n = 26) and a retrospective clinical cohort (n = 638). Measurements and Main Results: Weaning failure in the clinical and physiological cohorts were 37% and 42%, respectively. The main cause of failure in the physiological cohort was high inspiratory effort or respiratory rate. All patients exhaled similar amounts of CO2, but in patients who failed the weaning trial, [Formula: see text]e was higher to maintain the PaCO2 unchanged. The effort to eliminate one unit-volume of CO2, was double in patients who failed (68.9 [42.4-123] vs. 39 [20.1-57] cm H2O/[L/min]; P = 0.007), owing to the higher physiological Vd (68 [58.73] % vs. 54 [41.64] %; P = 0.012). End-tidal partial carbon dioxide pressure (PetCO2)/PaCO2 ratio was a clinical variable strongly associated with weaning outcome at baseline, with area under the receiver operating characteristic curve of 0.87 (95% confidence interval [CI], 0.71-1). Similarly, the PetCO2/PaCO2 ratio was associated with weaning outcome in the clinical cohort both before the weaning trial (odds ratio, 4.14; 95% CI, 1.32-12.2; P = 0.015) and at a sweep gas flow of zero (odds ratio, 13.1; 95% CI, 4-44.4; P < 0.001). Conclusions: The primary reason for weaning failure from VV-ECMO is high effort to eliminate CO2. A higher PetCO2/PaCO2 ratio was associated with greater likelihood of weaning from VV-ECMO.

Mechanical power thresholds during mechanical ventilation: An experimental study.

The extent of ventilator-induced lung injury may be related to the intensity of mechanical ventilation--expressed as mechanical power. In the present study, we investigated whether there is a safe threshold, below which lung damage is absent. Three groups of six healthy pigs (29.5 ± 2.5 kg) were ventilated prone for 48 h at mechanical power of 3, 7, or 12 J/min. Strain never exceeded 1.0. PEEP was set at 4 cmH2 O. Lung volumes were measured every 12 h; respiratory, hemodynamics, and gas exchange variables every 6. End-experiment histological findings were compared with a control group of eight pigs which did not undergo mechanical ventilation. Functional residual capacity decreased by 10.4% ± 10.6% and 8.1% ± 12.1% in the 7 J and 12 J groups (p = 0.017, p < 0.001) but not in the 3 J group (+1.7% ± 17.7%, p = 0.941). In 3 J group, lung elastance, PaO2 and PaCO2 were worse compared to 7 J and 12 J groups (all p < 0.001), due to lower ventilation-perfusion ratio (0.54 ± 0.13, 1.00 ± 0.25, 1.78 ± 0.36 respectively, p < 0.001). The lung weight was lower (p < 0.001) in the controls (6.56 ± 0.90 g/kg) compared to 3, 7, and 12 J groups (12.9 ± 3.0, 16.5 ± 2.9, and 15.0 ± 4.1 g/kg, respectively). The wet-to-dry ratio was 5.38 ± 0.26 in controls, 5.73 ± 0.52 in 3 J, 5.99 ± 0.38 in 7 J, and 6.13 ± 0.59 in 12 J group (p = 0.03). Vascular congestion was more extensive in the 7 J and 12 J compared to 3 J and control groups. Mechanical ventilation (with anesthesia/paralysis) increase lung weight, and worsen lung histology, regardless of the mechanical power. Ventilating at 3 J/min led to better anatomical variables than at 7 and 12 J/min but worsened the physiological values.

Lung Ultrasound and Electrical Impedance Tomography During Ventilator-Induced Lung Injury.

OBJECTIVES: Lung damage during mechanical ventilation involves lung volume and alveolar water content, and lung ultrasound (LUS) and electrical impedance tomography changes are related to these variables. We investigated whether these techniques may detect any signal modification during the development of ventilator-induced lung injury (VILI). DESIGN: Experimental animal study. SETTING: Experimental Department of a University Hospital. SUBJECTS: Forty-two female pigs (24.2 ± 2.0 kg). INTERVENTIONS: The animals were randomized into three groups (n = 14): high tidal volume (TV) (mean TV, 803.0 ± 121.7 mL), high respiratory rate (RR) (mean RR, 40.3 ± 1.1 beats/min), and high positive-end-expiratory pressure (PEEP) (mean PEEP, 24.0 ± 1.1 cm H2O). The study lasted 48 hours. At baseline and at 30 minutes, and subsequently every 6 hours, we recorded extravascular lung water, end-expiratory lung volume, lung strain, respiratory mechanics, hemodynamics, and gas exchange. At the same time-point, end-expiratory impedance was recorded relatively to the baseline. LUS was assessed every 12 hours in 12 fields, each scoring from 0 (presence of A-lines) to 3 (consolidation). MEASUREMENTS AND MAIN RESULTS: In a multiple regression model, the ratio between extravascular lung water and end-expiratory lung volume was significantly associated with the LUS total score (p < 0.002; adjusted R2, 0.21). The variables independently associated with the end-expiratory difference in lung impedance were lung strain (p < 0.001; adjusted R2, 0.18) and extravascular lung water (p < 0.001; adjusted R2, 0.11). CONCLUSIONS: Data suggest as follows. First, what determines the LUS score is the ratio between water and gas and not water alone. Therefore, caution is needed when an improvement of LUS score follows a variation of the lung gas content, as after a PEEP increase. Second, what determines the end-expiratory difference in lung impedance is the strain level that may disrupt the intercellular junction, therefore altering lung impedance. In addition, the increase in extravascular lung water during VILI development contributed to the observed decrease in impedance.

Mechanisms of oxygenation responses to proning and recruitment in COVID-19 pneumonia.

PURPOSE: This study aimed at investigating the mechanisms underlying the oxygenation response to proning and recruitment maneuvers in coronavirus disease 2019 (COVID-19) pneumonia. METHODS: Twenty-five patients with COVID-19 pneumonia, at variable times since admission (from 1 to 3 weeks), underwent computed tomography (CT) lung scans, gas-exchange and lung-mechanics measurement in supine and prone positions at 5 cmH2O and during recruiting maneuver (supine, 35 cmH2O). Within the non-aerated tissue, we differentiated the atelectatic and consolidated tissue (recruitable and non-recruitable at 35 cmH2O of airway pressure). Positive/negative response to proning/recruitment was defined as increase/decrease of PaO2/FiO2. Apparent perfusion ratio was computed as venous admixture/non aerated tissue fraction. RESULTS: The average values of venous admixture and PaO2/FiO2 ratio were similar in supine-5 and prone-5. However, the PaO2/FiO2 changes (increasing in 65% of the patients and decreasing in 35%, from supine to prone) correlated with the balance between resolution of dorsal atelectasis and formation of ventral atelectasis (p = 0.002). Dorsal consolidated tissue determined this balance, being inversely related with dorsal recruitment (p = 0.012). From supine-5 to supine-35, the apparent perfusion ratio increased from 1.38 ± 0.71 to 2.15 ± 1.15 (p = 0.004) while PaO2/FiO2 ratio increased in 52% and decreased in 48% of patients. Non-responders had consolidated tissue fraction of 0.27 ± 0.1 vs. 0.18 ± 0.1 in the responding cohort (p = 0.04). Consolidated tissue, PaCO2 and respiratory system elastance were higher in patients assessed late (all p < 0.05), suggesting, all together, "fibrotic-like" changes of the lung over time. CONCLUSION: The amount of consolidated tissue was higher in patients assessed during the third week and determined the oxygenation responses following pronation and recruitment maneuvers.

COVID-19 pneumonia: pathophysiology and management.

Coronavirus disease 2019 (COVID-19) pneumonia is an evolving disease. We will focus on the development of its pathophysiologic characteristics over time, and how these time-related changes determine modifications in treatment. In the emergency department: the peculiar characteristic is the coexistence, in a significant fraction of patients, of severe hypoxaemia, near-normal lung computed tomography imaging, lung gas volume and respiratory mechanics. Despite high respiratory drive, dyspnoea and respiratory rate are often normal. The underlying mechanism is primarily altered lung perfusion. The anatomical prerequisites for PEEP (positive end-expiratory pressure) to work (lung oedema, atelectasis, and therefore recruitability) are lacking. In the high-dependency unit: the disease starts to worsen either because of its natural evolution or additional patient self-inflicted lung injury (P-SILI). Oedema and atelectasis may develop, increasing recruitability. Noninvasive supports are indicated if they result in a reversal of hypoxaemia and a decreased inspiratory effort. Otherwise, mechanical ventilation should be considered to avert P-SILI. In the intensive care unit: the primary characteristic of the advance of unresolved COVID-19 disease is a progressive shift from oedema or atelectasis to less reversible structural lung alterations to lung fibrosis. These later characteristics are associated with notable impairment of respiratory mechanics, increased arterial carbon dioxide tension (P aCO2 ), decreased recruitability and lack of response to PEEP and prone positioning.

Role of Fluid and Sodium Retention in Experimental Ventilator-Induced Lung Injury.

Background: Ventilator-induced lung injury (VILI) via respiratory mechanics is deeply interwoven with hemodynamic, kidney and fluid/electrolyte changes. We aimed to assess the role of positive fluid balance in the framework of ventilation-induced lung injury. Methods: Post-hoc analysis of seventy-eight pigs invasively ventilated for 48 h with mechanical power ranging from 18 to 137 J/min and divided into two groups: high vs. low pleural pressure (10.0 ± 2.8 vs. 4.4 ± 1.5 cmH2O; p < 0.01). Respiratory mechanics, hemodynamics, fluid, sodium and osmotic balances, were assessed at 0, 6, 12, 24, 48 h. Sodium distribution between intracellular, extracellular and non-osmotic sodium storage compartments was estimated assuming osmotic equilibrium. Lung weight, wet-to-dry ratios of lung, kidney, liver, bowel and muscle were measured at the end of the experiment. Results: High pleural pressure group had significant higher cardiac output (2.96 ± 0.92 vs. 3.41 ± 1.68 L/min; p < 0.01), use of norepinephrine/epinephrine (1.76 ± 3.31 vs. 5.79 ± 9.69 mcg/kg; p < 0.01) and total fluid infusions (3.06 ± 2.32 vs. 4.04 ± 3.04 L; p < 0.01). This hemodynamic status was associated with significantly increased sodium and fluid retention (at 48 h, respectively, 601.3 ± 334.7 vs. 1073.2 ± 525.9 mmol, p < 0.01; and 2.99 ± 2.54 vs. 6.66 ± 3.87 L, p < 0.01). Ten percent of the infused sodium was stored in an osmotically inactive compartment. Increasing fluid and sodium retention was positively associated with lung-weight (R 2 = 0.43, p < 0.01; R 2 = 0.48, p < 0.01) and with wet-to-dry ratio of the lungs (R 2 = 0.14, p < 0.01; R 2 = 0.18, p < 0.01) and kidneys (R 2 = 0.11, p = 0.02; R 2 = 0.12, p = 0.01). Conclusion: Increased mechanical power and pleural pressures dictated an increase in hemodynamic support resulting in proportionally increased sodium and fluid retention and pulmonary edema.

Role of total lung stress on the progression of early COVID-19 pneumonia.

PURPOSE: We investigated if the stress applied to the lung during non-invasive respiratory support may contribute to the coronavirus disease 2019 (COVID-19) progression. METHODS: Single-center, prospective, cohort study of 140 consecutive COVID-19 pneumonia patients treated in high-dependency unit with continuous positive airway pressure (n = 131) or non-invasive ventilation (n = 9). We measured quantitative lung computed tomography, esophageal pressure swings and total lung stress. RESULTS: Patients were divided in five subgroups based on their baseline PaO2/FiO2 (day 1): non-CARDS (median PaO2/FiO2 361 mmHg, IQR [323-379]), mild (224 mmHg [211-249]), mild-moderate (173 mmHg [164-185]), moderate-severe (126 mmHg [114-138]) and severe (88 mmHg [86-99], p < 0.001). Each subgroup had similar median lung weight: 1215 g [1083-1294], 1153 [888-1321], 968 [858-1253], 1060 [869-1269], and 1127 [937-1193] (p = 0.37). They also had similar non-aerated tissue fraction: 10.4% [5.9-13.7], 9.6 [7.1-15.8], 9.4 [5.8-16.7], 8.4 [6.7-12.3] and 9.4 [5.9-13.8], respectively (p = 0.85). Treatment failure of CPAP/NIV occurred in 34 patients (24.3%). Only three variables, at day one, distinguished patients with negative outcome: PaO2/FiO2 ratio (OR 0.99 [0.98-0.99], p = 0.02), esophageal pressure swing (OR 1.13 [1.01-1.27], p = 0.032) and total stress (OR 1.17 [1.06-1.31], p = 0.004). When these three variables were evaluated together in a multivariate logistic regression analysis, only the total stress was independently associated with negative outcome (OR 1.16 [1.01-1.33], p = 0.032). CONCLUSIONS: In early COVID-19 pneumonia, hypoxemia is not linked to computed tomography (CT) pathoanatomy, differently from typical ARDS. High lung stress was independently associated with the failure of non-invasive respiratory support.

Ligand-Mediated Nanocrystal Growth.

A microfluidic platform combined with a deterministic model accounting for surface ligands reveals precious insights into the nanocrystal formation process. The comparison of on-line kinetic information with model predictions enables the derivation of temperature-dependent kinetic parameters for the CdSe model system. This fully generalizable approach represents a step forward toward a quantitative prediction of the nanocrystal size distribution, enabling the control and optimization of process performance and material properties.

Growth and Aggregation Regulate Clusters Structural Properties and Gel Time.

When particles undergo aggregation, very often they form structures that can be described with fractal geometry concepts. The spatial organization of the particles embedded in these aggregates, quantified by means of their fractal dimension, plays a key role in the clusters' diffusion and aggregation process. Fractal dimensions are typically known for some specific, ideal aggregation scenarios, such as for diluted diffusion limited cluster aggregation (DLCA) or reaction limited cluster aggregation (RLCA). The situation becomes significantly more complicated as soon as the initial particle concentration increases and fractal-dimension changing phenomena, such as particle growth, occur. In this frame, the aim of the present work is twofold: (i) to investigate the clusters' spatial organization in a scenario where growth and aggregation occur simultaneously and (ii) to assess the corresponding aggregation kinetics. To this end, an ad hoc Monte Carlo model has been developed. Both DLCA and RLCA regimes have been explored at several initial primary particle concentrations and for different growth rates. The results were discussed in terms of the characteristic times of growth (τG) and aggregation (τA), as well as the rate at which the structural properties change, vR. It was then possible to propose empirical correlations in the form dm = dm (vR) and tgel = tgel (τA, τG) to relate the evolution of the mass mobility exponent dm and the gel times to the simultaneously occurring processes of growth and aggregation.

Effects of Coalescence on Shear-Induced Gelation of Colloids.

Shearing lyophobic colloidal suspensions can lead to aggregation, followed by gelation, if the formed clusters grow to sizes large enough to percolate. If the temperature is set over the glass transition temperature of the suspended material, the particles embedded in the same aggregate start to coalesce with one another. Coalescence occurs to the finite viscosity of the particles' material, which leads to material diffusion from particle to particle. The driving force of this process is the reduction of the particle-dispersant interface and, as a consequence, the decrease the center-to-center separation of the particles. This leads to decreased cluster size, and hence a delayed gelation. Simultaneously, coalescence reinforces the particle-particle bonds formed upon aggregation, leading to clusters that are able to resist higher hydrodynamic forces before breaking up, hence leading to faster gelation. These two competing effects, combined with the natural complexity of colloidal aggregation makes it rather difficult to understand and predict which trend becomes dominant. In the present work, the shear-induced gelation of model polymeric colloidal systems with different glass transition temperatures has been studied. Starting with their interaction potential we investigate the impact of temperature on the gel time in concentrated suspensions (φ = 5%) under steady shear, followed by the effect of temperature on the stress-resistance of fully destabilized clusters under agitation. The results of the present work allow for a systematic view and deepened understanding of the factors governing shear-induced gelation in the presence of coalescence.

Kinetics of Monoclonal Antibody Aggregation from Dilute toward Concentrated Conditions.

Gaining understanding on the aggregation behavior of proteins under concentrated conditions is of both fundamental and industrial relevance. Here, we study the aggregation kinetics of a model monoclonal antibody (mAb) under thermal stress over a wide range of protein concentrations in various buffer solutions. We follow experimentally the monomer depletion and the aggregate growth by size exclusion chromatography with inline light scattering. We describe the experimental results in the frame of a kinetic model based on population balance equations, which allows one to discriminate the contributions of the conformational and of the colloidal stabilities to the global aggregation rate. Finally, we propose an expression for the aggregation rate constant, which accounts for solution viscosity, protein-protein interactions, as well as aggregate compactness. All these effects can be quantified by light scattering techniques. It is found that the model describes well the experimental data under dilute conditions. Under concentrated conditions, good model predictions are obtained when the solution pH is far below the isoelectric point (pI) of the mAb. However, peculiar effects arise when the solution pH is increased toward the mAb pI, and possible explanations are discussed.

Viscosity scaling in concentrated dispersions and its impact on colloidal aggregation.

Gaining fundamental knowledge about diffusion in crowded environments is of great relevance in a variety of research fields, including reaction engineering, biology, pharmacy and colloid science. In this work, we determine the effective viscosity experienced by a spherical tracer particle immersed in a concentrated colloidal dispersion by means of Brownian dynamics simulations. We characterize how the effective viscosity increases from the solvent viscosity for small tracer particles to the macroscopic viscosity of the dispersion when large tracer particles are employed. Our results show that the crossover between these two regimes occurs at a tracer particle size comparable to the host particle size. In addition, it is found that data points obtained in various host dispersions collapse on one master curve when the normalized effective viscosity is plotted as a function of the ratio between the tracer particle size and the mean host particle size. In particular, this master curve was obtained by varying the volume fraction, the average size and the polydispersity of the host particle distribution. Finally, we extend these results to determine the size dependent effective viscosity experienced by a fractal cluster in a concentrated colloidal system undergoing aggregation. We include this scaling of the effective viscosity in classical aggregation kernels, and we quantify its impact on the kinetics of aggregate growth as well as on the shape of the aggregate distribution by means of population balance equation calculations.

Fragmentation of amyloid fibrils occurs in preferential positions depending on the environmental conditions.

Understanding the mechanism of amyloid fibril breakage is of fundamental importance in various research fields including biomedicine and bionanotechnology. The aim of this work is to clarify the impact of temperature and agitation speed on the fibril breakage rate constant, which depends both on the fibril length as well as on the position of fragmentation along the fibril longitudinal axis. In particular, we intend to discriminate between three fibril fragmentation mechanisms: erosion (i.e., breakage occurs preferentially at the ends of the fibril), random (i.e., breakage occurs with the same likelihood at any position), or central (i.e., breakage occurs preferentially at the center of the fibril). To do so, we compare the time evolution of the fibril length distribution followed with atomic force microscopy with simulations from a kinetic model based on population balance equations (PBE). In this frame, we investigate the breakage mechanism of insulin fibrils, which turns out to be affected by the operative conditions employed. Moreover, we compare our findings with literature data obtained with ß-lactoglobulin and ß2-microglobulin. It is observed that high temperature drives the breakage toward an erosion mechanism, while a high agitation rate rather induces a central breakage.

Mathematical modeling of PLGA microparticles: from polymer degradation to drug release.

The present work is focused on the development and the validation of a mechanistic model describing the degradation of drug-loaded polylactic-co-glycolic acid microparticles and the drug release process from such devices. Microparticles' degradation is described through mass conservation equations; the application of population balances allows a detailed description of the hydrolysis kinetics, which also takes into account the autocatalytic behavior that characterizes bulk eroding polymers. Drug release considers both drug dissolution and the diffusion of dissolved active principle through the polymeric matrix. The diffusion of oligomers, water, and drug is assumed to follow Fickian behavior; the use of effective diffusion coefficients takes into account the diffusivity increase due to polymer hydrolysis. The model leads to a system of partial differential equations, solved by means of the method of lines. The model predictions satisfactorily match with different sets of literature data, indicating that the model presented here, despite its simplicity, is able to describe the key phenomena governing the device behavior.

Colloidal stability of polymeric nanoparticles in biological fluids.

Estimating the colloidal stability of polymeric nanoparticles (NPs) in biological environments is critical for designing optimal preparations and to clarify the fate of these devices after administration. To characterize and quantify the physical stability of nanodevices suitable for biomedical applications, spherical NPs composed of poly-lactic acid (PLA) and poly-methyl-methacrylate (PMMA), in the range 100-200 nm, were prepared. Their stability in salt solutions, biological fluids, serum and tissue homogenates was analyzed by dynamic light scattering (DLS). The PMMA NPs remained stable in all fluids, while PLA NPs aggregated in gastric juice and spleen homogenate. The proposed stability test is therefore useful to see in advance whether NPs might aggregate when administered in vivo. To assess colloidal stability ex vivo as well, spectrophotofluorimetric analysis was employed, giving comparable results to DLS.

Eye-hand coordination in rhythmical pointing.

The authors investigated the relation between hand kinematics and eye movements in 2 variants of a rhythmical Fitts's task in which eye movements were necessary or not necessary. P. M. Fitts's (1954) law held in both conditions with similar slope and marginal differences in hand-kinematic patterns and movement continuity. Movement continuity and eye-hand synchronization were more directly related to movement time than to task index of difficulty. When movement time was decreased to fewer than 350 ms, eye-hand synchronization switched from continuous monitoring to intermittent control. The 1:1 frequency ratio with stable pi/6 relative phase changed for 1:3 and 1:5 frequency ratios with less stable phase relations. The authors conclude that eye and hand movements in a rhythmical Fitts's task are dynamically synchronized to produce the best behavioral performance.