Multicompartment Systems Research Articles

Generalized Lorentzian Tensor Approach (GLTA) as a biophysical background for quantitative susceptibility mapping.

Quantitative susceptibility mapping (QSM) is a potentially powerful technique for mapping tissue magnetic susceptibility from gradient recalled echo (GRE) MRI. Herein we aim to derive the relationships between GRE signal phase and the underlying tissue microstructure and magnetic susceptibility at the cellular level. We use Maxwell's equations and a statistical approach to derive the expression for the magnetic-susceptibility-induced MR signal frequency shift of the GRE signal in single- and multicompartment systems, in which inhomogeneous magnetic field is induced by the cellular constituents (proteins, lipids, iron, etc.) distributed in intra- and extracellular spaces. We introduce the Generalized Lorentzian Tensor Approach (GLTA) that accounts for both types of anisotropy: the anisotropy of magnetic susceptibility and the structural tissue anisotropy. In the GLTA the frequency shift due to the local environment is characterized by the Lorentzian tensor L⁁ which has a substantially different structure than the susceptibility tensor χ⁁. While components of χ⁁ are simply compartmental susceptibilities "weighted" by their relative volumes, the components of L⁁ are weighted by specific numerical factors depending on tissue micro-symmetry and parameters related to the MR pulse sequence. We also provide equations bridging phenomenological and microscopic considerations. The GLTA provides a consistent background for deciphering phase data.

Molecular recognition and organizational and polyvalent effects in vesicles induce the formation of artificial multicompartment cells as model systems of eukaryotes.

Researchers have become increasingly interested in the preparation and characterization of artificial cells based on amphiphilic molecules. In particular, artificial cells with multiple compartments are primitive mimics of the structure of eukaryotic cells. Endosymbiotic theory, widely accepted among biologists, states that eukaryotic cells arose from the assembly of prokaryotic cells inside other cells. Therefore, replicating this process in a synthetic system could allow researchers to model molecular and supramolecular processes that occur in living cells, shed light on mass and energy transport through cell membranes, and provide a unique, isolated space for conducting chemical reactions. In addition, such structures can serve as drug delivery systems that encapsulate both bioactive and nonbiocompatible compounds. In this Account, we present various coating, incubation, and electrofusion strategies for forming multicompartment vesicle systems, and we are focusing on strategies that rely on involving molecular recognition of complementary vesicles. All these methods afforded multicompartment systems with similar structures, and these nanoparticles have potential applications as drug delivery systems or nanoreactors for conducting diverse reactions. The complementarity of interacting vesicles allows these artificial cells to form, and the organization and polyvalency of these interacting vesicles further promote their formation. The incorporation of cholesterol in the bilayer membrane and the introduction of PEG chains at the surface of the interacting vesicles also support the structure of these multicompartment systems. PEG chains appear to destabilize the bilayers, which facilitates the fusion and transport of the small vesicles to the larger ones. Potential applications of these well-structured and reproducibly produced multicompartment systems include drug delivery, where researchers could load a cocktail of drugs within the encapsulated vesicles, a process that could enhance the bioavailability of these substances. In addition, the production of artificial cells with multiple compartments provides a platform where researchers could carry out individual reactions in small, isolated spaces. Such a reactive space can avoid problems that occur when the environment can be destructive to reactants or products or when a diverse set of compounds difficult to obtain in a conventional reactor space are produced. Our work on these artificial cells with multicompartment structures also led us to formulate a hypothesis on the processes that possibly generated eukaryotic cells. We hope both that our research efforts will excite interest in these nanoparticles and that this research could lead to systems designed for specific scientific and technological applications and further insights into the evolution of eukaryotic cells.

Poster #S225 PREDICTING PSYCHOSIS IN A GENERAL ADOLESCENT PSYCHIATRIC SAMPLE

Gene and RNA interference therapies have significant potential for alleviating countless diseases, including many associated with the gastro-intestinal (GI) tract. Unfortunately, oral delivery of genes and small interfering RNA (siRNA) is very challenging due to the extracellular and intracellular barriers. In this review, we discuss the utilization of multi-compartmental delivery systems for oral administration of nucleic acid therapies. Some of the illustrative examples of multi-compartmental systems include solid nanoparticles-in-microsphere, solid nanoparticles-in-emulsion, and liquid nanoparticles-in-emulsion. Using type B gelatin nanoparticles encapsulated in poly(ε-caprolactone) microspheres, we have prepared nanoparticles-in-microsphere oral system (NiMOS) for gene and siRNA delivery for the treatment of inflammatory bowel disease (IBD). The results of these studies show that the multi-compartmental formulations can overcome many of the barriers for effective oral gene and siRNA delivery.

Apparent exchange rate imaging in anisotropic systems

Double-wave diffusion experiments offer the possibility of probing correlation between molecular diffusion at multiple time points. It has recently been shown that this technique is capable of measuring the exchange of water across cellular membranes. The aim of this study was to investigate the effect of macroscopic tissue anisotropy on the measurement of the apparent exchange rate (AXR) in multicompartment systems. AXR data were collected from yeast and perfusion-fixated brain tissue at high angular resolution on a preclinical imaging system. The AXR was expanded for anisotropic systems by calculating scalar AXR values along the principal directions of the diffusion tensor. In yeast, both the AXR and diffusivity were rotational invariant, whereas in fixated brain tissue, the measured AXR was sensitive to the orientation of anisotropic structures. AXR, especially in white matter, was robustly estimated along the first and second principal directions of the diffusion tensor, but increasing noise was seen in the AXR estimates along the third principal direction of the diffusion tensor. Our results indicate that tissue anisotropy must be considered for AXR estimates in complex biological systems.

Mimicking the biological world: Methods for the 3D structuring of artificial cellular environments

Combining modern methods in microsystem technology with the latest advancements in the life sciences, namely those in tissue engineering and advanced cell culturing, is promoting the development of a promising toolbox for modeling biological systems. The core problem to solve using this toolbox is the design of 3D artificial cellular environments, both in fluidic systems and on solid substrates. The construction of 3D biological fluidic environments involves the use of microfluidic devices where fluid direction and behavior can be tightly regulated in a geometrically constrained environment for advanced cell cultivation. This is used in modern cultivation devices, such as bioreactors and multicompartment systems, including systems with integrated multielectrode arrays in both 2D and 3D. The construction of 3D cell cultures on substrates involves various fabrication techniques that use different polymers and biopolymers processed by micromachining, chemical pattern guided cell cultivation, photopolymerization, and organ printing methods. These methods together have the potential to create an artificial system with the complete hierarchical, geometrical, and functional organization found in an actual biological system. In this review, we describe representative developments in this research area and the fusion of formerly unrelated disciplines that are generating new beneficial applications in life sciences.

The influence of coating on release of paracetamol from the multi-compartment systems

A multi-compartment system enables modification of medicinal substance release. Nine series of multi-compartment systems were prepared, where each contained 5 minitablets. Application of different envelopes (OPADRY II WHITE and ACRYL EZE – PINK), coating the individual minitablets and complete multi-compartment systems, allowed for modeling medicinal substance release from the tested drug forms. Dissolution test of paracetamol was tested. The results were processed using the Statistica 9.0 (StatSoft, USA).

Adaptive all the way down: Building responsive materials from hierarchies of chemomechanical feedback

A living organism is a bundle of dynamic, integrated adaptive processes: not only does it continuously respond to constant changes in temperature, sunlight, nutrients, and other features of its environment, but it does so by coordinating hierarchies of feedback among cells, tissues, organs, and networks all continuously adapting to each other. At the root of it all is one of the most fundamental adaptive processes: the constant tug of war between chemistry and mechanics that interweaves chemical signals with endless reconfigurations of macromolecules, fibers, meshworks, and membranes. In this tutorial we explore how such chemomechanical feedback - as an inherently dynamic, iterative process connecting size and time scales - can and has been similarly evoked in synthetic materials to produce a fascinating diversity of complex multiscale responsive behaviors. We discuss how chemical kinetics and architecture can be designed to generate stimulus-induced 3D spatiotemporal waves and topographic patterns within a single bulk material, and how feedback between interior dynamics and surface-wide instabilities can further generate higher order buckling and wrinkling patterns. Building on these phenomena, we show how yet higher levels of feedback and spatiotemporal complexity can be programmed into hybrid materials, and how these mechanisms allow hybrid materials to be further integrated into multicompartmental systems capable of hierarchical chemo-mechano-chemical feedback responses. These responses no doubt represent only a small sample of the chemomechanical feedback behaviors waiting to be discovered in synthetic materials, and enable us to envision nearly limitless possibilities for designing multiresponsive, multifunctional, self-adapting materials and systems.

Implications of leaky boundaries for compartmentalised control of pathogens: A modelling case study for bacterial kidney disease in Scottish salmon aquaculture

Compartmentalisation is the focusing of disease control measures on valued and epidemiologically isolatable populations. However, pathogens may transmit across compartment boundaries and undermine local control measures. Bacterial kidney disease (BKD) affects both salmon and trout farms and a compartmentalised management programme has been adopted for Scotland with BKD more rigorously controlled in salmon farming regions. Undetected subclinical infection is an important uncertainty in BKD management. An existing epidemiological model has been adapted to assess the impact of external infection on the salmon compartment. The model has been modified to split infection pressure between exogenous (input) and endogenous (internal) spread, keeping the total infection pressure required to maintain the observed prevalence at steady-state. Model results suggest that BKD's persistence in salmon is dependent on input from trout or other external sources, even though these inputs are rare. Inputs also make it impossible to remove all risk of BKD occurring in salmon, although exclusion of BKD may be possible for long periods. BKD prevalence in salmon is likely to change in response to changes in other compartments, but any response will be less than linear. By far the largest predicted increases in BKD in Scottish salmon would occur if movement controls were to be lifted from salmon farms that are known to be infected. The model should have wider application to situations where pathogens are being eradicated from, or controlled within, specific compartments of multi-compartment systems and can be used to guide the appropriate balance between intensity of boundary and internal controls to minimise disease occurrence in control compartments.

Multicompartment Particle Assemblies for Bioinspired Encapsulated Reactions

In recent years, interest in mimicking the complex hierarchical architectures and functionalities of biological systems and associated spatially confined reactions has led to the design and synthesis of a range of multicompartment particles. Multicompartmentalization allows the incorporation of a range of structures in a single particle, thus allowing optimization of physicochemical properties of the assembly (e.g., permeability, stability, stimuli-response) and various multiple, spatially separated reactions. In this Perspective, we describe particle-based multicompartment systems, detailing the building blocks and assembly approaches employed to produce each subcompartmentalized system. The properties that contribute to the performance of multicompartment systems in diverse applications are also discussed, with a focus on coupled enzymatic reactions in confined volumes. The challenges associated with these assemblies for encapsulated reactions are identified and further directions and plausible developments in the field are suggested.

ChemInform Abstract: Interaction of Vesicles: Adhesion, Fusion and Multicompartment Systems Formation

AbstractReview: 69 refs.

Interaction of Vesicles: Adhesion, Fusion and Multicompartment Systems Formation

In this review, interactions of selected vesicles, induced either by molecular recognition or by electrostatic interactions, for the simulation of cell-cell and cell-drug interaction processes are discussed. In order of increasing complexity, examples of vesicles adhesion are presented at first, followed by recognition experiments in which fusion takes place. This differentiation in behavior was primarily attributed to the structural features of interacting vesicular pairs primarily affected by concentration and lateral phase separation of the anchored recognizable groups. In certain cases, fusion is accompanied by multicompartmentalization of the obtained aggregates. In connection with the formation of these multicompartment systems, it was proposed that an analogous mechanism could be operating in the evolution of eukaryotes during the symbiosis of prokaryotes.

Antibiotic stability in commercial peritoneal dialysis solutions: influence of formulation, storage and duration

Peritoneal dialysis (PD)-associated peritonitis is treated by administration of antibiotics mixed with the PD solution. Data on antibiotic stability for solutions in current use are limited. The aim of this study was to determine the stability of cefepime, cephazolin and ampicillin in three commercial PD solutions. Antibiotics were added to the non-glucose compartment of the Gambro (Gambrosol®) and Fresenius (Balance®) multi-compartment systems and Baxter (Dianeal®) single-compartment (glucose 2.5%) PD solutions in a sterile suite. Antibiotic stability over 3 weeks was determined using both a bioassay of bacterial inhibition and antibiotic concentrations. The influence on stability and sterility of storage conditions was determined. The bioassay demonstrated the stability of all antibiotics for 9 days at room temperature and 3 weeks when refrigerated, except ampicillin in the Gambro solution, which displayed no bioactivity after 4 days. However, a ceiling effect in bacterial inhibition at higher antibiotic concentrations limited the ability of the bioassay to detect antibiotic degradation at relevant concentrations. Antibiotic concentrations varied with time but were comparable to the bioassay and supported stability in refrigerated solutions, except ampicillin in the Gambro solution. No bacterial contamination, marked colour change or precipitation occurred. This study supports the stability of cephazolin and cefepime in all three PD solutions and ampicillin in only the Baxter and Fresenius PD solutions. Antibiotic stability studies should ideally be conducted prior to registration and marketing of new PD solutions.

A new stochastic approach to multi-compartment pharmacokinetic models: probability of traveling route and distribution of residence time in linear and nonlinear systems

Drug kinetics in human has been studied from both deterministic and stochastic perspectives. However, little research has been done to systematically determine the probability for a drug molecule to follow a specific traveling route. Recently a method was developed to estimate this probability and the probability density function of residence time in linear systems. In this paper, we provide a rigorous proof of the main results of the previous paper and extend the method to nonlinear multi-compartment systems. A novel concept of compartment expansion is introduced to facilitate the development of our method. This formulation resolves computational difficulties associated with nonlinear systems, allowing for direct estimation of the probability intensity coefficients, and subsequently the transition probability and probability density function of the residence time. With such expansion of the methodology, it becomes both practical and feasible to apply it in the real-world drug development where drug disposition patterns are often nonlinear. The method can be used to estimate drug exposure at any site of interest, thus may help us to gain better understanding about the impact of drug exposure on efficacy and safety.

Fractional kinetics in multi-compartmental systems

Fractional calculus, the branch of calculus dealing with derivatives of non-integer order (e.g., the half-derivative) allows the formulation of fractional differential equations (FDEs), which have recently been applied to pharmacokinetics (PK) for one-compartment models. In this work we extend that theory to multi-compartmental models. Unlike systems defined by a single ordinary differential equation (ODE), considering fractional multi-compartmental models is not as simple as changing the order of the ordinary derivatives of the left-hand side of the ODEs to fractional orders. The latter may produce inconsistent systems which violate mass balance. We present a rationale for fractionalization of ODEs, which produces consistent systems and allows processes of different fractional orders in the same system. We also apply a method of solving such systems based on a numerical inverse Laplace transform algorithm, which we demonstrate that is consistent with analytical solutions when these are available. As examples of our approach, we consider two cases of a basic two-compartment PK model with a single IV dose and multiple oral dosing, where the transfer from the peripheral to the central compartment is of fractional order α<1, accounting for anomalous kinetics and deep tissue trapping, while all other processes are of the usual order 1. Simulations with the studied systems are performed using the numerical inverse Laplace transform method. It is shown that the presence of a transfer rate of fractional order produces a non-exponential terminal phase, while multiple dose and constant infusion systems never reach steady state and drug accumulation carries on indefinitely. The IV fractional system is also fitted to PK data and parameter values are estimated. In conclusion, our approach allows the formulation of systems of FDEs, mixing different fractional orders, in a consistent manner and also provides a method for the numerical solution of these systems.

DNA-mediated self-assembly of artificial vesicles.

BackgroundAlthough multicompartment systems made of single unilamellar vesicles offer the potential to outperform single compartment systems widely used in analytic, synthetic, and medical applications, their use has remained marginal to date. On the one hand, this can be attributed to the binary character of the majority of the current tethering protocols that impedes the implementation of real multicomponent or multifunctional systems. On the other hand, the few tethering protocols theoretically providing multicompartment systems composed of several distinct vesicle populations suffer from the readjustment of the vesicle formation procedure as well as from the loss of specificity of the linking mechanism over time.Methodology/Principal FindingsIn previous studies, we presented implementations of multicompartment systems and resolved the readjustment of the vesicle formation procedure as well as the loss of specificity by using linkers consisting of biotinylated DNA single strands that were anchored to phospholipid-grafted biotinylated PEG tethers via streptavidin as a connector. The systematic analysis presented herein provides evidences for the incorporation of phospholipid-grafted biotinylated PEG tethers to the vesicle membrane during vesicle formation, providing specific anchoring sites for the streptavidin loading of the vesicle membrane. Furthermore, DNA-mediated vesicle-vesicle self-assembly was found to be sequence-dependent and to depend on the presence of monovalent salts.Conclusions/SignificanceThis study provides a solid basis for the implementation of multi-vesicle assemblies that may affect at least three distinct domains. (i) Analysis. Starting with a minimal system, the complexity of a bottom-up system is increased gradually facilitating the understanding of the components and their interaction. (ii) Synthesis. Consecutive reactions may be implemented in networks of vesicles that outperform current single compartment bioreactors in versatility and productivity. (iii) Personalized medicine. Transport and targeting of long-lived, pharmacologically inert prodrugs and their conversion to short-lived, active drug molecules directly at the site of action may be accomplished if multi-vesicle assemblies of predefined architecture are used.

Structural Features of Interacting Complementary Liposomes Promoting Formation of Multicompartment Structures

The structural features of complementary liposomes and factors favoring formation of multicompartment systems are investigated. Specifically, liposomal formulations consisting of PEGylated unilamellar liposomes with guanidinium moieties located at the distal end of polyethylene glycol (PEG) chains interact with complementary multilamellar liposomes bearing phosphate moieties. Furthermore, the number of PEG chains attached to the unilamellar interface of the liposomes is enhanced by incorporating PEGylated cholesterol in their bilayer. While molecular recognition of the liposomes is the driving force for initiating multicompartmentalization, it is the enhanced PEGylation at the liposomal interface that synergistically promotes fusion resulting in large and well-formed multicompartment systems. A mechanism is proposed according to which initial adhesion of the liposomes, followed by reorganization of their membrane lipids, leads to giant bilayer aggregates incorporating large liposomes.

A Full-Scale Prototype Multisensor System for Damage Control and Situational Awareness

The U.S. Naval Research Laboratory has developed a real-time, remote detection system for damage control and situational awareness, called “Volume Sensor”, as part of the Advanced Volume Sensor Task, an important element of the U.S. Navy’s Office of Naval Research, Future Naval Capabilities program, Advanced Damage Countermeasures. The objective of the Advanced Volume Sensor Task was to develop an affordable detection system that could identify shipboard damage control conditions and provide real-time threat level information for damage control events (such as flaming and smoldering fires, explosions, pipe ruptures, flooding, and gas releases) while eliminating the false alarms typical of fire detection systems in industrial environments. The approach was to build a multisensor, multicriteria system from low cost commercial-off-the-shelf hardware components integrated with intelligent software and data fusion algorithms. Two multicompartment prototype Volume Sensor systems were constructed at NRL and tested with a series of simulated damage control events at the Navy’s full-scale fire test facility, the ex-USS Shadwell in Mobile Bay, AL. Results from this test series indicate that the Volume Sensor Prototypes performed as well or better than commercial video image detection and point-detection systems in critical quality metrics for fire detection while also providing additional situational awareness for flooding scenarios, fire suppression system activations, and gas release events.

Neurochemical Oscillations in the Basal Ganglia

This work represents an attempt to elucidate the neurochemical processes in the basal ganglia by mathematical modelling. The correlation between neurochemistry and electrophysiology has been used to construct a dynamical system based on the basal ganglia's network structure. Mathematical models were constructed for different physical scales to reformulate the neurochemical and electrophysiological behaviour from synapses up to multi-compartment systems. Transformation functions have been developed to transit between the different scales. We show through numerical simulations that this network produces oscillations in the electrical potentials as well as in neurotransmitter concentrations. In agreement with pharmacological experiments, a parameter sensitivity analysis reveals temporary changes in the neurochemical and electrophysiological systems after single exposure to antipsychotic drugs. This behaviour states the structural stability of the system. The correlation between the neurochemical dynamics and drug-induced behaviour provides the perspective for novel neurobiological hypotheses.

Stochastic biological modelling in the presence of multiple compartments

The application of concurrent calculi to the formalisation of biological systems constitutes a promising approach to the analysis of biological phenomena in silico. The peculiar nature of such systems inspired the introduction of specific features in biologically-oriented calculi, such as compartments to model more faithfully their highly organised structure. In this paper we present S π @, a conservative extension of the stochastic π -calculus which allows an intuitive and concise formalisation of multi-compartment systems with dynamic structure, despite retaining the simplicity of the original π -calculus. The possibility to encode into S π @ several bio-inspired, compartmentalised languages demonstrates its expressive power and flexibility. The calculus is accompanied by an extended version of Gillespie’s stochastic simulation algorithm, able to handle multiple compartments with varying volumes. An enhanced formalisation of the algorithm is also presented, in order to provide efficient simulation in the presence of a high number of compartments and reactions.

BISEN: Biochemical Simulation Environment

The Biochemical Simulation Environment (BISEN) is a suite of tools for generating equations and associated computer programs for simulating biochemical systems in the MATLAB computing environment. This is the first package that can generate appropriate systems of differential equations for user-specified multi-compartment systems of enzymes and transporters accounting for detailed biochemical thermodynamics, rapid equilibria of multiple biochemical species and dynamic proton and metal ion buffering. The software and a user manual (including several tutorial examples) are available at bbc.mcw.edu/BISEN.