Self-immolative linkers in polymeric delivery systems

There has been significant interest in the methodologies of controlled release for a diverse range of applications spanning drug delivery, biological and chemical sensors, and diagnostics. The advancement in novel substrate-polymer coupling moieties has led to the discovery of self-immolative linkers. This new class of linker has gained popularity in recent years in polymeric release technology as a result of stable bond formation between protecting and leaving groups, which becomes labile upon activation, leading to the rapid disassembly of the parent polymer. This ability has prompted numerous studies into the design and development of self-immolative linkers and the kinetics surrounding their disassembly. This review details the main concepts that underpin self-immolative linker technologies that feature in polymeric or dendritic conjugate systems and outlines the chemistries of amplified self-immolative elimination.

Dynamic recurrent neural network for system identification and control

A dynamic recurrent neural network (DRNN) that can be viewed as a generalisation of the Hopfield neural network is proposed to identify and control a class of control affine systems. In this approach, the identified network is used in the context of the differential geometric control to synthesise a state feedback that cancels the nonlinear terms of the plant yielding a linear plant which can then be controlled using a standard PID controller.

Performance statistics of a head-operated force-reflecting rehabilitation robot system

Researchers in the rehabilitation engineering community have been designing and developing a variety of passive/active devices to help persons with limited upper extremity function to perform essential daily manipulations. Devices range from low-end tools such as head/mouth sticks to sophisticated robots using vision and speech input. While almost all of the high-end equipment developed to date relies on visual feedback alone to guide the user providing no tactile or proprioceptive cues, the “low-tech” head/mouth sticks deliver better “feel” because of the inherent force feedback through physical contact with the user's body. However, the disadvantage of a conventional head/mouth stick is that it can only function in a limited workspace and the performance is limited by the user's strength. It therefore seems reasonable to attempt to develop a system that exploits the advantages of the two approaches: the power and flexibility of robotic systems with the sensory feedback of a headstick. The system presented in this paper reflects the design philosophy stated above. This system contains a pair of master-slave robots with the master being operated by the user's head and the slave acting as a telestick. Described in this paper are the design, control strategies, implementation and performance evaluation of the head-controlled force-reflecting telestick system.

Operator performance evaluation of controlled depth of field in a stereographically displayed virtual environment

Retinal blurring resulting from the human eye's depth of focus has been shown to assist visual perception. Infinite focal depth within stereoscopically displayed virtual environments may cause undesirable effects, for instance, objects positioned at a distance in front of or behind the observer's fixation point will be perceived in sharp focus with large disparities thereby causing diplopia. Although published research on incorporation of synthetically generated Depth of Field (DoF) suggests that this might act as an enhancement to perceived image quality, no quantitative testimonies of perceptional performance gains exist. This may be due to the difficulty of dynamic generation of synthetic DoF where focal distance is actively linked to fixation distance. In this paper, such a system is described. A desktop stereographic display is used to project a virtual scene in which synthetically generated DoF is actively controlled from vergence-derived distance. A performance evaluation experiment on this system which involved subjects carrying out observations in a spatially complex virtual environment was undertaken. The virtual environment consisted of components interconnected by pipes on a distractive background. The subject was tasked with making an observation based on the connectivity of the components. The effects of focal depth variation in static and actively controlled focal distance conditions were investigated. The results and analysis are presented which show that performance gains may be achieved by addition of synthetic DoF. The merits of the application of synthetic DoF are discussed.

A helmet mounted display system with active gaze control for visual telepresence

The objective of a Visual Telepresence System is to provide the operator with a high fidelity image from a remote stereo camera pair linked to a pan/tilt device such that the operator may reorient the camera position by use of head movement. Systems such as these which utilise virtual reality style helmet mounted displays have a number of limitations. The geometry of the camera positions and of the displays is generally fixed and is most suitable only for viewing elements of a scene at a particular distance. To address such limitations, a prototype system has been developed where the geometry of the displays and cameras is dynamically controlled by the eye movement of the operator. This paper explores why it is necessary to actively adjust the display system as well as the cameras and justifies the use of mechanical adjustment of the displays as an alternative to adjustment by electronic or image processing methods. The electronic and mechanical design is described including optical arrangements and control algorithms. The performance and accuracy of the system is assessed with respect to eye movement.

Head-controlled assistive telerobot with extended physiological proprioception capability

People with disabilities such as quadriplegia can use mouth-sticks and head-sticks as extension devices to perform desired manipulations. These extensions provide extended proprioception which allows users to directly feel forces and other perceptual cues such as texture present at the tip of the mouth-stick. Such devices are effective for two principle reasons: because of their close contact with the user's tactile and proprioceptive sensing abilities; and because they tend to be lightweight and very stiff, and can thus convey tactile and kinesthetic information with high-bandwidth. Unfortunately, traditional mouth-sticks and head-sticks are limited in workspace and in the mechanical power that can be transferred because of user mobility and strength limitations. We describe an alternative implementation of the head-stick device using the idea of a virtual head-stick: a head-controlled bilateral force-reflecting telerobot. In this system the end-effector of the slave robot moves as if it were at the tip of an imaginary extension of the user's head. The design goal is for the system is to have the same intuitive operation and extended proprioception as a regular mouth-stick effector but with augmentation of workspace volume and mechanical power. The input is through a specially modified six DOF master robot (a PerForceTM hand-controller) whose joints can be back-driven to apply forces at the user's head. The manipulation tasks in the environment are performed by a six degree-of-freedom slave robot (the Zebra-ZEROTM) with a built-in force sensor. We describe the prototype hardware/software implementation of the system, control system design, safety/disability issues, and initial evaluation tasks.

Randomized controlled trial of full and brief cognitive-behaviour therapy and wait-list for paediatric obsessive-compulsive disorder

Background: Reviews and practice guidelines for paediatric obsessive-compulsive disorder (OCD) recommend cognitive-behaviour therapy (CBT) as the psychological treatment of choice, but note that it has not been sufficiently evaluated for children and adolescents and that more randomized controlled trials are needed. The aim of this trial was to evaluate effectiveness and optimal delivery of CBT, emphasizing cognitive interventions. Methods: A total of 96 children and adolescents with OCD were randomly allocated to the three conditions each of approximately 12 weeks duration: full CBT (average therapist contact: 12 sessions) and brief CBT (average contact: 5 sessions, with use of therapist-guided workbooks), and wait-list/delayed treatment. The primary outcome measure was the child version of the semi-structured interviewer-based Yale-Brown Obsessive Compulsive Scale. Clinical Trial registration: http://www.controlled-trials.com/ISRCTN/; unique identifier: ISRCTN29092580. Results: There was statistically significant symptomatic improvement in both treatment groups compared with the wait-list group, with no significant differences in outcomes between the two treatment groups. Controlled treatment effect sizes in intention-to-treat analyses were 2.2 for full CBT and 1.6 for brief CBT. Improvements were maintained at follow-up an average of 14 weeks later. Conclusions: The findings demonstrate the benefits of CBT emphasizing cognitive interventions for children and adolescents with OCD and suggest that relatively lower therapist intensity delivery with use of therapist-guided workbooks is an efficient mode of delivery.

Production and evaluation of dry alginate-chitosan microcapsules as an enteric delivery vehicle for probiotic bacteria

This study investigates the production of alginate microcapsules, which have been coated with the polysaccharide chitosan, and evaluates some of their properties with the intention of improving the gastrointestinal viability of a probiotic (Bifidobacterium breve) by encapsulation in this system. The microcapsules were dried by a variety of methods, and the most suitable was chosen. The work described in this Article is the first report detailing the effects of drying on the properties of these microcapsules and the viability of the bacteria within relative to wet microcapsules. The pH range over which chitosan and alginate form polyelectrolyte complexes was explored by spectrophotometry, and this extended into swelling studies on the microcapsules over a range of pHs associated with the gastrointestinal tract. It was shown that chitosan stabilizes the alginate microcapsules at pHs above 3, extending the stability of the capsules under these conditions. The effect of chitosan exposure time on the coating thickness was investigated for the first time by confocal laser scanning microscopy, and its penetration into the alginate matrix was shown to be particularly slow. Coating with chitosan was found to increase the survival of B. breve in simulated gastric fluid as well as prolong its release upon exposure to intestinal pH.

Dynamic vergence telepresence system incorporating active gaze control

Visual Telepresence system which utilize virtual reality style helmet mounted displays have a number of limitations. The geometry of the camera positions and of the display is fixed and is most suitable only for viewing elements of a scene at a particular distance. In such a system, the operator's ability to gaze around without use of head movement is severely limited. A trade off must be made between a poor viewing resolution or a narrow width of viewing field. To address these limitations a prototype system where the geometry of the displays and cameras is dynamically controlled by the eye movement of the operator has been developed. This paper explores the reasons why is necessary to actively adjust both the display system and the cameras and furthermore justifies the use of mechanical adjustment of the displays as an alternative to adjustment by electronic or image processing methods. The electronic and mechanical design is described including optical arrangements and control algorithms, An assessment of the performance of the system against a fixed camera/display system when operators are assigned basic tasks involving depth and distance/size perception. The sensitivity to variations in transient performance of the display and camera vergence is also assessed.

Maximising concurrency and scalability in a consistent, causal, distributed virtual reality system, whilst minimising the effect of network delays

The development of large scale virtual reality and simulation systems have been mostly driven by the DIS and HLA standards community. A number of issues are coming to light about the applicability of these standards, in their present state, to the support of general multi-user VR systems. This paper pinpoints four issues that must be readdressed before large scale virtual reality systems become accessible to a larger commercial and public domain: a reduction in the effects of network delays; scalable causal event delivery; update control; and scalable reliable communication. Each of these issues is tackled through a common theme of combining wall clock and causal time-related entity behaviour, knowledge of network delays and prediction of entity behaviour, that together overcome many of the effects of network delay.

Maximising concurrency and scalability in a consistent, causal, distributed virtual reality system, whilst minimising the effect of network delays

The development of large scale virtual reality and simulation systems have been mostly driven by the DIS and HLA standards community. A number of issues are coming to light about the applicability of these standards, in their present state, to the support of general multi-user VR systems. This paper pinpoints four issues that must be readdressed before large scale virtual reality systems become accessible to a larger commercial and public domain: a reduction in the effects of network delays; scalable causal event delivery; update control; and scalable reliable communication. Each of these issues is tackled through a common theme of combining wall clock and causal time-related entity behaviour, knowledge of network delays and prediction of entity behaviour, that together overcome many of the effects of network delays.

Microencapsulation of probiotics for gastrointestinal delivery

The administration of probiotic bacteria as nutraceuticals is an area that has rapidly expanded in recent years, with a global market worth $32.6 billion predicted by 2014. Many of the health promoting claims attributed to these bacteria are dependent on the cells being both viable and sufficiently numerous in the intestinal tract. The oral administration of most bacteria results in a large loss of viability associated with passage through the stomach, which is attributed to the high acid and bile salt concentrations present. This loss of viability effectively lowers the efficacy of the administered supplement. The formulation of these probiotics into microcapsules is an emerging method to reduce cell death during GI passage, as well as an opportunity to control release of these cells across the intestinal tract. The majority of this technology is based on the immobilization of bacteria into a polymer matrix, which retains its structure in the stomach before degrading and dissolving in the intestine, unlike the diffusion based unloading of most controlled release devices for small molecules. This review shall provide an overview of progress in this field as well as draw attention to areas where studies have fallen short. This will be followed by a discussion of emerging trends in the field, highlighting key areas in which further research is necessary.

Describing Earth system simulations with the Metafor CIM

The Metafor project has developed a common information model (CIM) using the ISO19100 series for- malism to describe numerical experiments carried out by the Earth system modelling community, the models they use, and the simulations that result. Here we describe the mechanism by which the CIM was developed, and its key properties. We introduce the conceptual and application ver- sions and the controlled vocabularies developed in the con- text of supporting the fifth Coupled Model Intercomparison Project (CMIP5). We describe how the CIM has been used in experiments to describe model coupling properties and de- scribe the near term expected evolution of the CIM.

CLSM method for the dynamic observation of pH change within polymer matrices for oral delivery

If acid-sensitive drugs or cells are administered orally, there is often a reduction in efficacy associated with gastric passage. Formulation into a polymer matrix is a potential method to improve their stability. The visualization of pH within these materials may help better understand the action of these polymer systems and allow comparison of different formulations. We herein describe the development of a novel confocal laser-scanning microscopy (CLSM) method for visualizing pH changes within polymer matrices and demonstrate its applicability to an enteric formulation based on chitosan-coated alginate gels. The system in question is first shown to protect an acid-sensitive bacterial strain to low pH, before being studied by our technique. Prior to this study, it has been claimed that protection by these materials is a result of buffering, but this has not been demonstrated. The visualization of pH within these matrices during exposure to a pH 2.0 simulated gastric solution showed an encroachment of acid from the periphery of the capsule, and a persistence of pHs above 2.0 within the matrix. This implies that the protective effect of the alginate-chitosan matrices is most likely due to a combination of buffering of acid as it enters the polymer matrix and the slowing of acid penetration.

Janus PEG-based dendrimers for use in combination therapy: controlled multi-drug loading and sequential release

The increasing use of drug combinations to treat disease states, such as cancer, calls for improved delivery systems that are able to deliver multiple agents. Herein, we report a series of novel Janus dendrimers with potential for use in combination therapy. Different generations (first and second) of PEG-based dendrons containing two different “model drugs”, benzyl alcohol (BA) and 3-phenylpropionic acid (PPA), were synthesized. BA and PPA were attached via two different linkers (carbonate and ester, respectively) to promote differential drug release. The four dendrons were coupled together via (3 + 2) cycloaddition chemistries to afford four Janus dendrimers, which contained varying amounts and different ratios of BA and PPA, namely, (BA)2-G1-G1-(PPA)2, (BA)4-G2-G1-(PPA)2, (BA)2-G1-G2-(PPA)4, and (BA)4-G2-G2-(PPA)4. Release studies in plasma showed that the dendrimers provided sequential release of the two model drugs, with BA being released faster than PPA from all of the dendrons. The different dendrimers allowed delivery of increasing amounts (0.15–0.30 mM) and in exact molecular ratios (1:2; 2:1; 1:2; 2:2) of the two model drug compounds. The dendrimers were noncytotoxic (100% viability at 1 mg/mL) toward human umbilical vein endothelial cells (HUVEC) and nontoxic toward red blood cells, as confirmed by hemolysis studies. These studies demonstrate that these Janus PEG-based dendrimers offer great potential for the delivery of drugs via combination therapy.