Biosensors and Invasive Monitoring in Clinical Applications Excerpt regarding Implantable Biosensors
Pages 32-35
Apr 23, 2013
by Emma P. Córcoles and Martyn G. Boutelle
5.2.4 Subcutaneous Tissue
Progress in micro-and nano-technology is transforming biosensors’ fabrication methods. The encapsulation of fluorescent sensing assay elements in microcapsules permits minimal invasive monitoring with implantable devices. (Cinnayelka and McShane 2006). Probes encapsulated by biologically localized embedding (PEBBLES) are nanoscale polymer beads specifically designed to provide minimally invasive monitoring of specific analytes in single cells (Cao et al. 2004). Quantum dots (QD) capable of binding to specific targets such as peptides, anti-bodies and nucleic acids or small-molecules can be modified for use as in vivo imaging tools. Some reviews summarized some of the issues derived by the use of QDs in biosensing, such as toxicity components and in vivo imaging, and biological applications such as cancer treatment (Xing et al. 2009), (Obonyo et al. 2010).
Intensity measurements of implanted microspheres have been used to evaluate the potential for transdermal glucose sensing (McShane et al. 2000). Nano-sized spherical biosensors have been designed combing the stablisation effect and translucent optical qualities of liposomes (Vamvakaki et al. 2005). This technology has been suggested for applications such as ‘smart tattoo’ sensors using nanoengineered alginate microsphere glucose sensors with anti-inflammatory-drug-loaded alginate microspheres to suppress inflammation at the implant site (Srivastava et al. 2011). Other techniques to quantify glucose involved the subcutaneous insertion of reagent-free fibre sensors where the detection occurs by means of attenuated total reflection spectroscopy and transmission spectroscopy (Lambrecht et al. 2006) and fluorescent hydrogel fibres that reduced inflammation response, continuously monitoring tissue levels up to 2.5 months (Heo et al. 2011). The capability of an optical glucose sensor protein to generate quantifiable fluorescence resonance energy transfer (FRET) signals for glucose monitoring has also been investigated. The biosensor presented high sensitivity, selectivity and specificity and a shelf-life of up to 3 weeks (Veetil et al. 2010). Nevertheless, studies in microspheres and nanoparticles are growing since these present the capability of forming closed-loop systems. Moreover, these systems are not limited to subcutaneous implantation and could be used in other tissues and organs. This interest in implantable optical particle sensors has led some research groups to focus on the properties of the device when in vivo and its wireless capabilities. Simulation studies have investigated microparticles implantation depths, excitation light source properties, particle characteristics, and packing density to facilitate the design of dermal implanted luminescent sensors (Long and McShane 2010). Meanwhile others are exploring programmable electronic platforms with bidirectional telemetry and wireless networking of multiple fluorescent-based biosensors for implantable chronic monitoring (Valdastri et al. 2011).
5.3 MRI Sensing Mechanism
Magnetic Resonance Image (MRI) is gaining importance as a sensing mechanism for implantable biosensors. Magnetic materials such as ferrous or ferric oxide are typically used. During short time exposures, MRI contrast agents are nontoxic and inert and accumulate in the organ of interest. In addition to this biocompatibility, the high spatial resolution positions these particles as an attractive option for in vivo diagnostics tools (Ito et al. 2005; Sandhu et al. 2010).
Magneto-elastic based biosensors have been suggested for the wireless transmission of human physiological data at capillary level. The technique consists of an external radiofrequency (RF) coil such as the one found in an MRI system, which receives and analyses the magnetic field response generated by the vibration of the magneto-elastic core of the biosensor when excited by another external magnetic field (Chanu and Martel 2007). Other procedures are based on the use of the magnetic nanoparticles (MNPs). Devices for continuous monitoring of soluble cancer biomarkers in vivo have been proposed using MNPs relaxation switches (Fig. 5.4). The nanoparticles are coated with semipermeable membranes allowing permanent implantation during biopsy (Daniel et al. 2009). Other methods load the MNPs together with drugs into alginate microspheres, which can be potentially used for biosensing simultaneously with drug delivery and MRI imaging (Joshi et al. 2011).
MRI contrast agents are particularly used in cellular imaging to investigate stroke mechanism (Hoehn et al. 2002), arthritis (Dardzinski et al. 2001) or essentially cell tracking (Yeh et al. 1995). Some of the limitations of cell tracking with MRI are the need for a large number of nanoparticles and the dilution of these by cell division (Kalish et al. 2003). New contrast agents are being investigated to overcome some of the limitations of this technique.
The reader is directed to a review on the use of magnetic nanoparticles for detection of biomolecules and cells based on magnetic resonance effects. The capabilities of diagnostic magnetic resonance technology, a detection platform based on the use of magnetic nanoparticles as proximity sensors are reviewed here (Haun et al. 2010).
A relatively new contrast agent is xenon, a noble gas and quite inert molecule, whose progress as a functionalized biosensor or contrast agent has been recently reviewed. One of the two NRM-active isotopes, 129Xe, can easily be polarized presenting remarkable NMR properties (large chemical shift range and favorable relaxation) and it is extremely sensitive to its molecular environment. Hyperpolarised xenon has been used for the detection of a range of molecular markers by means of Nuclear Magnetic Resonance (NMR) imaging and although still in its early stages, it will not be long before applications as in vivo contrast agents emerge (Schroder 2013).
5.4 Other Sensing Mechanisms
Other sensing mechanisms exploit the mechanical properties of certain materials. The degree of dislocation can be measured by using a wide range of transducers including optical laser, piezoresistive, piezoelectric and capacitive. An example is the implantable wireless glucose biosensor developed using a resonator transducer coupled to a stimuli-sensitive hydrogel trapped between a nanoporous membrane and a thin glass diaphragm. This biosensor can remotely detect the change of resonance frequency that occurs when there is a displacement of the glass diaphragm, caused by the swelling of the hydrogel, as a result of glucose molecules passing through the nanoporous membrane (Lei et al. 2006). Other studies used a chemico-mechanical sensor for continuous glucose monitoring based on the viscosity variation of a biological fluid with glucose concentration. The sensor consisted of piezoelectric crystals and flow-resistive microchannel and alumina nanoporous membrane as a size selective interface allowing monitoring of glucose for 3 days in a physiological range of blood glucose concentration (2-20 mM) (Boss et al. 2011).
Cantilever biosensors have been used to detect DNA hybridization antibody-antigen interactions, or the adsorption of bacteria. These biosensors respond to changes on their surface with a mechanical bending. Silicon or polymers cantilevers arrays were used to detect cardiac biomarkers proteins by measuring the surface stress generated by antigen-antibody molecular recognition (Arntz et al. 2003). A general introduction to the field of cantilever biosensors can be found in this review (Fritz 2008).
Gravimetric biosensors measure changes of mass loaded on the sensor surface through changes in the mechanical properties. Examples of these biosensors include surface acoustic wave (SAW) and Quartz Crystal Microbalance (QCM) and their latest progress has been reviewed recently (Voiculescu and Nordin 2012; Speight and Coooper 2012).
Although immense progress has been made in the last few years, where biocompatible materials have been used, implantable biosensors still present problems due to the biosensor fouling and the measurements inaccuracy. The reliability of these devices and the validation of the results with external offline devices is the cause of the little expansion of biosensors in clinical routines. Alternatively, sampling devices have been investigated in parallel with biosensors development for in vivo monitoring in clinical settings.
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