Electrical Transducers

John Ten.J. Zhang , Kazunori Hoshino , in Molecular Sensors and Nanodevices, 2022

Capacitive Sensors

A capacitive sensor is based on measurement of changes in capacitance. In exercise, sensor designs are very similar to those of conductometric sensors. Effigy four.12 shows a schematic of the sensing principle of a typical capacitive chemical sensor. Absorption of target molecules induces ii relevant effects of changes in dielectric constant and swelling. Interdigitated electrodes every bit described for conductometric sensors are commonly used [5]. Usually measured for sensing is the impedance of the system [half-dozen], which includes the resistance of the sensitive layer as shown in the simplified circuit in Fig. four.12(b). Capacitive sensors may be categorized as a special type of conductometric sensor. The impedance of the sensor is typically constitute indirectly by incorporating the sensor into an RC circuit. Changes in the resonant frequency of an oscillator, or the level of coupling (or attenuation) of an Ac point is used for measurement.

Figure 4.12. Capacitive Chemical Sensors. (a) Schematic Showing the Working Principle of a Capacitive Chemical Sensor (from [5]). (b) Simplified Equivalent Excursion.

 From [6].

Glucose Sensors

Glucose sensors [seven–ix] are used to measure the blood glucose concentration of a patient and are an important function of managing diabetes mellitus. Type 1 and blazon 2 diabetes are the well-nigh common forms of diabetes. Type ane diabetes is usually diagnosed in children and young adults and accounts for most 5% of all diagnosed cases of diabetes. Type ii diabetes has been diagnosed in millions of Americans. Co-ordinate to diabetes written report card 2022 issued past National Eye for Chronic Disease Prevention and Wellness Promotion, 18.9% of Us adults over 65 years old are diagnosed as diabetes in 2007–2009.

Patients with Type 1 diabetes may test their blood sugar five to ten times a mean solar day in social club for them to effectively monitor their blood sugar levels. Type 2 diabetics may also consider monitoring their blood saccharide levels daily based on their risk for future health complications due to the disease. Claret glucose testing may be also needed for patients with other diseases which may bear upon the pancreas such every bit cystic fibrosis. In sports medicine, information technology is used to monitor physical weather of athletes. Normal blood glucose levels range betwixt eighty–120   mg/dL with spikes reaching upward to 250   mg/dL afterward meals. The sensor should as well exist able to mensurate the extremes in blood carbohydrate levels (between xx–500   mg/dL, or 1-30   mM) which a patient may experience during an episode of hyper or hypoglycemia and should accept a resolution of ~1   mg/dL, or ~50   µM.

The majority of claret glucose sensors, or glucose meters, are categorized every bit amperometric sensors, which will be described in this chapter. In affiliate 5, we volition talk over techniques based on optical transduction such as assimilation spectroscopy (see Section 5.5), light handful and Raman spectroscopy (see Section v.7). In chapter 7, nosotros draw examples of implantable glucose sensors (see Department 7.iii.vi).

In amperometric glucose sensors, reducing belongings of glucose is measured equally a current. Sensors comprise electrodes to measure out the current generated by an enzymatic reaction usually betwixt glucose, an enzyme, and a mediator. Use of glucose oxidase (GOx or GOD) has become the gilded standard for glucose sensing [x,xi]. The initial concept of glucose enzyme electrodes, where a thin layer of GOx was entrapped via a semipermeable membrane, was introduced by Clark and Lyons [12]. Sensing was based on the measurement of the oxygen consumed by the enzyme-catalyzed reaction

Glucose + O 2 ⟹ GO 10 Gluconic acrid + H ii O 2 Glucose + GOx ( ox ) → Gluconic acid + GOx ( red ) GOX ( red ) + 2 M ( ox ) → GOx ( ox ) + 2 M ( red ) + 2 H + ii G ( ruby-red ) → 2 M ( ox ) + 2 e −

In this method, glucose reacts with the enzyme GOx(ox). The reduced enzyme GOx(red) then reduces 2 mediator M(ox) ions to M(reddish), which is oxidized back to Grand(ox) at the electrode surface. The oxidation procedure 2 M ( red ) → ii K ( ox ) + 2 east − is measured equally the current by the electrode. However, for this type of early glucose biosensors, a high functioning potential is required to perform the amperometric measurement of hydrogen peroxide. Improved methods utilize bogus mediators instead of oxygen to transfer electrons between the GOx and the electrode [eight]. Reduced mediators are formed and reoxidized at the electrode, providing an electrical bespeak to exist measured.

A claret glucose test is typically performed by pricking the finger to draw claret, which is then applied to a disposable "test-strip". Figure 4.13 shows a typical glucose meter and a test strip. Each strip includes layers of electrodes, spacers, immobilized enzymes assembled in a small package. Continued enquiry and development take worked to reduce the overall size of the sensor itself and reduce the amount of blood required for an accurate measurement (~µL).

Figure 4.13. Blood Glucose Sensor. (a) Example of a Commercial Product. (b) Composition of a Test Strip Which Includes Electrodes.

 (a) From https://world wide web.accu-chek.com/the states/; (b) from [13]. Courtesy of Roche.

The advanced glucose electrodes do non apply mediators and measures direct transfer between the enzyme and the electrode. The electrode direct transfers electrons using organic conducting materials based on charge-transfer complexes. This type of electrodes have led to needle-blazon implantable sensors for continuous blood glucose monitoring [89, 90].

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Sensor Materials, Technologies and Applications

A.Due north.M. Karim , ... South. Begum , in Comprehensive Materials Processing, 2022

xiii.twenty.2.1.1.1 CMOS-MEMS glucose sensor

This glucose sensor applies the working principle of first-generation glucose sensors by detecting the concentration of glucose oxidase (21). All the same, instead of measuring information technology through electrochemical methods, the device uses capacitive sensing to notice changes in the dielectric abiding of the textile. The capacitive sensor is formed using interdigitated composite gold and oxide electrodes placed on a silicon substrate, as shown in Figure two. Based on eqn [1], the glucose oxidase enzyme converts glucose and oxygen into gluconolactone and hydrogen peroxide. Oxygen is derived from water surrounding the sensor. When glucose is oxidized, the concentration of water decreases and the concentration of hydrogen peroxide increases, resulting in a change in the dielectric constant of the area between the sensing electrodes.

Figure 2. (a) Schematic of integrated glucose sensor. (b) Cross-section and layers of the CMOS-MEMS glucose sensor.

 Reproduced from Yang, Grand. Z.; Dai, C. L.; Hung, C. B. Fabrication of a Glucose Sensor with Oscillator Circuit Using CMOS-MEMS Technique. Microelectron. Eng. September 2022, 97, 353–356.

The dielectric constant of h2o and hydrogen peroxide is 78 and 60, respectively. Measurement of the fluctuation of dielectric constants can be detected by observing the alter in capacitance of the sensor. As shown in Figure 2, the sensing capacitors are continued to a series of odd-numbered inverters such that they form an oscillator excursion. The oscillator excursion generates a frequency output ranging from 17 to 25 MHz, depending on the sensor's capacitance.

Using this simple circuit, the alter in capacitance can at present exist easily monitored by observing the oscillator'south output since the frequency modify is proportional to the change in capacitance and thus the alter in glucose concentration. The sensitivity of the glucose sensor was nigh 1.48 MHz mM− 1.

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Textured and Porous Materials

Heidi E. Koschwanez , William M. Reichert , in Biomaterials Science (Third Edition), 2022

Porous Coatings to Improve Glucose and Oxygen Transport to Implanted Sensors

Percutaneous glucose sensors must exist removed afterward iii to seven days to forbid host inflammation, wound healing, and subsequent foreign-body encapsulation from jeopardizing sensor reliability. The strange-trunk response ultimately causes impedance of glucose and oxygen transport to the sensor, resulting in sensor signal deterioration, and oftentimes sensor failure. Methods that amend analyte (glucose, oxygen) transport to indwelling sensors could let sensors to reliably measure interstitial glucose concentrations for several weeks, as opposed to days.

Attempts to improve long-term sensor functioning have included surface chemical modification, diverse coatings (Gifford et al., 2005; Nablo et al., 2005; Shin and Schoenfisch, 2006), release of molecular mediators (Friedl, 2004; Ward et al., 2004; Norton et al., 2005), and surface topography (Wisniewski and Reichert, 2000; Wisniewski et al., 2000). The effect of surface texturing on the tissue that surrounds implanted biomaterials is well-documented for devices such as total joint arthroplasty (Bauer and Schils, 1999; Ryan et al., 2006) and percutaneous devices (Tagusari et al., 1998; Walboomers and Jansen, 2005; Kim et al., 2006).

Topographical approaches for improving long-term sensor performance were outset proposed by Woodward (1982), who suggested that the best coating for an implanted glucose sensor was a sponge that encourages tissue ingrowth and disrupts fibrosis (Effigy I.ii.15.5). Efforts to create tissue-modifying textured coatings for implantable sensors are attractive, because their impact is non dependent on a depletable drug reservoir, dissimilar drug eluting techniques.

Effigy I.2.15.v. Example of a: (a) Medtronic MiniMed SOF-SENSOR™ glucose sensor; and (b) an experimental porous poly-L-lactic acid (PLLA) coating applied to the sensor tip for investigational purposes. Inset: ecology scanning electron microscope image of porous PLLA coating made using table salt-leaching/gas foaming with ammonium bicarbonate (NHivHCOthree).

 (Koschwanez, H. E. (2006). Unpublished data.) Courtesy of John Wiley and Sons.

A significant range of materials and pore sizes are capable of promoting angiogenesis and reducing capsule thickness (Ward et al., 2002). Geometry, rather than chemical composition, of the material appears to decide biomaterial–microvasculature interactions (Brauker et al., 1995; Sieminski and Gooch, 2000). Table I.ii.15.three summarizes leading research in the area of porosity and porous coatings for glucose sensors, including the pore size reported to yield the greatest vascularization and/or the least capsule germination around the implant. Variations in pore size and pore construction in implanted biomaterials may, however, limit the conclusions that can be fatigued about how pore size influences tissue response (Marshall et al., 2004).

Table I.2.fifteen.iii. Summary of Pore Sizes that Yielded Optimal Tissue Response (Promoted Angiogenesis and/or Reduced Capsule Thickness) Effectually Biomaterials or Glucose Sensors

Investigator Porous Material Optimal Pore Size Application and Exam Subject Duration of Investigation
Brauker et al., 1995 PTFE 5 μm Membrane implanted in rat subcutis 3 weeks
Sharkawy et al., 1998 PVA 60 μm Membrane implanted in rat subcutis 12-xvi weeks
Ward et al., 2002 ePTFE and PVA ePTFE: 1 μm
PVA: 60 μm		 Membrane implanted in rat subcutis vii weeks
Marshall et al., 2004 HEMA hydrogels 35 μm Hydrogel implanted in mouse subcutis 4 weeks
Updike et al., 2000 ePTFE 5-10 μm (Shults et al., 2006) Glucose sensor implanted in dog subcutis 162 days ∗ (best of 6 sensors)
Yu et al., 2006 Epoxy-enhanced polyurethane Not specified Glucose sensor implanted in rat subcutis 56 days ∗ (best of 9 sensors)
Gilligan et al., 2004 ePTFE Non specified Glucose sensor implanted in human subcutis 185 days ∗ (best of five sensors)

NOTE: PTFE (polytetrafluoroethylene), ePTFE (expanded polytetrafluoroethylene), PVA (polyvinyl alcohol), HEMA (hydroxyethyl methacrylate).

∗
Maximum fourth dimension sensor remained functional in vivo.

While porous biomaterials seemingly create the platonic environs for an indwelling glucose sensor, porous coatings applied to sensors have had less than ideal results. A critical cistron in sensor failure in vivo is the fibrotic capsule that forms around glucose sensors (Dungel et al., 2008). Despite porous coatings stimulating the formation of vascular networks around glucose sensors in rats, newly formed vessels within porous coatings accept been unable to overcome the diffusion barriers imparted by the collagen capsule (Dungel et al., 2008). Failing sensor sensitivity was found to correlate with increasing collagen deposition inside the sponge implant (Dungel et al., 2008). Additionally, other factors, such as mechanical stresses imposed past the percutaneously implanted sensor, may have overshadowed the angiogenic-inducing, collagen-reducing properties of porous coatings (Koschwanez et al., 2008).

Recently, homo studies (Gilligan et al., 2004) were performed using sensors covered with a porous angiogenic and bioprotective ePTFE membrane (Updike et al., 2000; Shults et al., 2006). Unfortunately, inflammation within the angiogenic layer in lxxx% of sensors, in addition to packaging failure in 60% of sensors, resulted in only 20% sensor survival after six months (Gilligan et al., 2004).

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Wireless biosensors for POC medical applications

M.S. Arefin , ... M.R. Yuce , in Medical Biosensors for Point of Intendance (POC) Applications, 2022

seven.4.1 Wireless implantable glucose biosensors

Implantable glucose sensors with interface circuits hold a corking potential for the continuous measurement and monitoring of claret glucose in patients with diabetes. The sensor tin be implanted nether the skin [iv,33,34,43,112].

The functional block diagram of an implantable microsystem for claret glucose monitoring designed past Ahmadi and Jullien is shown in Fig. 7.ten [34]. The glucose sensor is an amperometric electrochemical biosensor generating a current from the electrochemical reaction between glucose and a glucose oxidase layer on working electrode (WE). The use of iridium-oxide nanoparticles helps for the transfer of the electrons from the glucose oxidase to We. The reference electrode (RE) eliminates the potential arising from the solution medium. The counter electrode (CE) acts as a reference half-cell to supply the required current for the electrochemical reaction, whereas the We deed as a sensing one-half-prison cell to produce the current. The external reader inductively transfers power to the implantable microsystem and receives the transmitted measurement data of claret glucose concentration from the microsystem. The data transmission is performed for every 10   min using a load-shift keying modulation scheme. The interface circuit of the microsystem consists of an RF front-end excursion for receiving RF signals, rectifying, and generating the supply voltage, and a data acquisition circuit for converting the electric current from glucose sensor to pulse.

Figure 7.10. Block diagram of the implantable microsystem for continuous glucose monitoring.

 M.M. Ahmadi, G.A. Jullien, A wireless-implantable microsystem for continuous blood glucose monitoring, IEEE Transactions on Biomedical Circuits and Systems iii (2009) 169–180.

The cross-sectional view of the glucose biosensor is illustrated in Fig. 7.11. The titanium–nickel–gilt–titanium metallization is essential for the Nosotros, CE, interconnect traces, and bonding pads. The glucose oxidase on aureate acts every bit a biologically sensitive layer. The silverish metal layer at RE acts as an Ag/AgCl electrode, which generates current from the solution medium. The integrated interface circuit and the wireless transmitter are bonded on this wafer. The off-scrap components and inductive coil for energy manual are continued on this wafer. The dimension of the microsystem is 8   mm   ×   4   mm and its thickness is ane   mm.

Figure vii.eleven. Cantankerous-sectional view of the implantable microsystem and glucose sensor for continuous blood glucose monitoring.

 Thousand.Thou. Ahmadi, G.A. Jullien, A wireless-implantable microsystem for continuous blood glucose monitoring, IEEE Transactions on Biomedical Circuits and Systems 3 (2009) 169–180.

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Glucose Biosensors

Dr Dennis Fitzpatrick PhD CEng BEng(Hons) , in Implantable Electronic Medical Devices, 2022

iv.five Implantable Glucose Sensor past GlySens

The implantable glucose sensor from GlySens is a long-term implant lasting for 1 year or more than and does not crave continuous calibrations. The implant consists of an integrated glucose sensor with signal conditioning circuits, a wireless telemetry circuit, and a 1-year lifetime bombardment, all housed in a hermetically sealed titanium housing ( Effigy 4.six). The wireless radio frequency (RF) link communicates with an external receiver providing continuous glucose monitoring.

Figure 4.6. Implantable GlySens glucose sensor. Cantankerous-sectional view shows electronics module (A), telemetry transmission portal (B), bombardment (C), and sensor assortment (D) (Gough et al., 2022).

 (Reprinted with permission.)

The glucose sensor is an amperometric glucose sensor based on the detection of oxygen. The oxygen sensor incorporates dual-enzyme electrode applied science with both enzymes, glucose oxidase and catalase, immobilized in a cantankerous-linked protein gel. The catalase enzyme reduces the deactivation of the glucose oxidase enzyme in the presence of hydrogen peroxide, increasing sensor stability and effective lifetime. The reference oxygen sensor contains no enzymes.

An integrated three electrode potentiostatic circuit is used to set up the working electrode voltages and to mensurate the differential currents between the ii oxygen sensors. The sensor array consists of four working-counter platinum electrode pairs and an Ag/AgCl reference electrode, microfabricated onto the surface of an aluminum deejay measuring 12   mm in diameter. The enzymes are immobilized by cross-linking with albumin using glutaraldehyde into a gel and are covered with a protective semipermeable membrane layer of polydimethylsiloxane, reducing interference from unwanted molecules.

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Colloids for Nanobiotechnology

Jingyue Xu , ... Niko Hildebrandt , in Frontiers of Nanoscience, 2022

3.ii.3 QDs as FRET donors and acceptors

QDs could engage in FRET with each other as a QD-to-QD FRET organization. Compared with the common QD-to-dye and QD-to-fluorescent protein systems, a primary reward of QDs in QD-to-QD FRET sensing is their extreme photostability compared to organic dyes or fluorescent proteins, making QDs uniquely suited for longitudinal studies, where measurements or images are taken repeatedly over extended periods of fourth dimension. Their stability makes them good candidates for device-on-a-chip applications and for sensors designed for employ outside of the laboratory setting. In improver, the extraordinary effulgence of QDs, primarily due to their large absorption cross-section, yields considerable fluorescence output with relatively fewer emitters and potentially decreases the limit of detection in sensing applications. Notwithstanding, QD-to-QD FRET is challenging due to the broad, overlapping excitation spectra from the two nanocrystals, precluding selective excitation of the donor. This introduces cross talk and artificially creates a large groundwork signal, which is a major challenge in QD-to-QD FRET sensor blueprint. Due to their prominent colour and intensity changes, QD-to-QD FRET signals from heterogeneous QD samples (two different-sized, but physically comingled QDs that virtually always have the same limerick) take been more often than not adopted in sensing applications [94].

3.2.3.1 Small molecule sensing

A glucose sensor was designed using dark-green CdTe QD-Concanavalin A (Con A) conjugates and scarlet QD-NH 2-glucosamine hydrochloride conjugates as a FRET pair [95]. Con A is a lectin with high affinity to manno- and gluco-oligosaccharides, including dextran. Prefilling of the bounden sites on the CdTe QD-Con A cohabit by glucose inhibited FRET between the two QDs, assuasive for indirect sensing. This FRET-based inhibition analysis provided a fluorometric quantification method for glucose.

3.two.iii.2 Antibody/antigen sensing

Despite the large sizes of QD-antibody conjugates, two different QDs could be conjugated to an antibody and antigen and and so used within a FRET-based immunoassay format. Liu et al. used the specific bounden of IgG every bit a secondary antibody to induce an interaction between donor and acceptor QDs [96]. Antihuman CD71 monoclonal antibiotic (anti-CD71) was conjugated with red QDs and was used to label HeLa cells successfully. So green QD-labeled IgG was added to bind the red-QD-conjugated anti-CD71 on the cell surface by immunoreactions. This study not only proves that it is possible to utilize QD-to-QD FRET for studying interactions on living cell membranes, simply also shows their potential valuable awarding to screening of antibody/antigen with bioactivity detected and identification of tumor.

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Application of responsive polymers in implantable medical devices and biosensors

J. Li , ... Z. Zhang , in Switchable and Responsive Surfaces and Materials for Biomedical Applications, 2022

11.12.1 Enzyme electrode-based biosensors

Well-nigh commercialized implantable glucose sensors are based on a glucose–enzyme reaction with their products detected by an amperometric sensor. The enzyme, normally a GOX, is immobilized on an electrode to provide a redox reaction with glucose and generate a current at the electrodes. With the immobilization of the GOX, the redox polymer layer can be viewed as a glucose-responsive organisation ( Heo & Takeuchi, 2022; Wang, 2007). Commercialized implanted glucose sensors are ordinarily implanted subcutaneously with a sensor life span of less than 7   days. In addition to subcutaneous implantation, glucose sensors integrated with intravascular catheters (Armour, Lucisano, McKean, & Gough, 1990) and contact lenses (Yao, Shum, Cowan, Lähdesmäki, & Parviz, 2022) have likewise been reported. Due to the discomfort, short life bridge, and the requirement for daily calibration of electric current implantable glucose sensors, there is withal a tremendous need for improving blood glucose monitoring (Gerritsen, Jansen, & Lutterman, 1999).

The polymers that immobilize enzymes on the electrodes reply to analytes through an electron-transfer process. Different materials and their combinations have been applied on the electrodes to improve the sensitivity, biocompatibility, and lifetime of the biosensors. The redox enzymes tin can be either chemically bound inside the cross-linked polymer network or physically embedded inside the materials. Figure 11.5 shows a typical implantable glucose electrode with a sandwich construction designed for immobilizing the enzyme (Clark & Duggan, 1982). Glucose diffuses through an outer layer to accomplish the immobilized enzyme, GOX, which is placed very close to the surface of a platinum electrode. The outer layer should have a function of allowing maximum passage of oxygen and retarding the passage of glucose to control glucose diffusion. This membrane must also be biocompatible and stable in vivo. The inner layer serves equally the support for enzyme immobilization and also every bit the selective membrane for H2O2. The enzyme layer is where glucose is converted to the electoactive species H2O2.

Effigy xi.five. A typical implantable glucose electrode that is responsive to glucose concentration.

Dialysis membranes from cellulose acetate (CA) are amongst the primeval substrates that have been used by Clark and Lyons (Clark & Lyons, 1962). To exclude interfering anions, a negatively charged perfluorinated ionomer Nafion™ membrane was alternatively deposited with CA on the electrode (Zhang et al., 1994). As an outer layer, Nafion™ also provides protection and improves biocompatibility. Several needle-type glucose sensors with Nafion™ layer remain functional for at least 10   days after subcutaneous implantation in dogs, without degradation of their sensitivity (Moussy, Harrison, O'Brien, & Rajotte, 1993; Moussy, Jakeway, Harrison, & Rajotte, 1994). Other examples of interference-excluding membranes include polydimethylsiloxane (PDMS) (Ertefai & Gough, 1989; Yang, Atanasov, & Wilkins, 1995), polyurethane (Moatti-Sirat et al., 1992; Pickup, Claremont, & Shaw, 1993; Yu, Long, Moussy, & Moussy, 2006), and modified CA (Qiu & Hu, 2022). These polymers allow for permeation of molecules having a like molecular weight to the analyte; interferences of sizes larger than the analyte are excluded. Durability of the biosensors can be improved using these protective membranes. For example, an epoxy-enhanced polyurethane membrane was used as the outer protective membrane of the sensor and kept operation in rats for 10–56   days (Yu et al., 2006). A glucose sensor, covered past a thin electrolyte layer, a protective layer of medical-course PDMS, and a membrane of PDMS with wells for the immobilized enzymes located over certain electrodes was capable of performing long-term monitoring of tissue glucose concentrations by wireless telemetry (Gough, Kumosa, Routh, Lin, & Lucisano, 2022). The implanted sensor was functional in a pig model for more than 1 yr, indicating pregnant progress in extending the life bridge of implantable glucose sensors (Gough et al., 2022).

An earlier study used CA as an inner layer to exclude molecules such as ascorbate, urate, and bilirubin (Clark & Duggan, 1982). The interference past small, electroactive compounds could be farther reduced by incorporating conductive polymers. Conductive polymers have been coated on the implantable glucose sensor electrodes to provide efficient transfer of electric charge produced by the biochemical reaction to an electronic circuit. The conductive polymers, usually intrinsically conducting polymers with conjugated backbones, provide loftier electron affinity and are highly susceptible to chemical or electrochemical oxidation or reduction (Singh, 2022). Using enzymes during electrochemical polymerization, enzymes can be immobilized on the electrodes with conductive polymers. For example, enzymes entrapped within films such equally polypyrrole (PPy), polyaniline, or polythiophene, prepared by electropolymerization from aqueous solutions, take been unremarkably used to prepare glucose electrodes. Similar Nafion™, some conductive polymers tin can exclude interference of molecules with sizes larger than the analyte, such equally overoxidized PPy (Rizzi, Centonze, & Zambonin, 2000), poly(o-phenylenediamine) (Malitesta, Palmisano, Torsi, & Zambonin, 1990; Sasso, Pierce, Walla, & Yacynych, 1990), and poly(quinone) (Arai, Shoji, & Yasumori, 2006; Kaku, Okamoto, Charles, Holness, & Karan, 1995). With some in vivo results for more x   days (Moussy et al., 1993, 1994), conductive polymers have shown activity, sensitivity, and selectivity, and possessed skilful immovability on glucose electrodes.

Inside the enzyme layer, GOX has been immobilized through cross-linked albumin, synthetic hydrogels (Guiseppi-Elie, 2022), and conductive polymers (Singh, 2022). Hydrogels are commonly used materials applied to the electrodes to immobilize enzymes and/or provide biocompatibility, permeability, and fouling resistance. PolyHEMA and its copolymers are among the earliest hydrogels to be applied on electrodes (Shaw, Claremont, & Pickup, 1991). To improve porosity, hydrophilicity, or biocompatibility, iii-dihydroxypropyl methacrylate (DHPMA) (Wang et al., 2008; Yu et al., 2008), Northward-vinyl pyrrolidone (Heineman, 1993), vinyl booze (Vaddiraju, Singh, Burgess, Jain, & Papadimitrakopoulos, 2009), ethylene glycol (Quinn, Pathak, Heller, & Hubbell, 1995), 2-methacryloyloxyethyl phosphorylcholine (MPC) (Chen et al., 1992), and carboxybetaine (Yang, Xue, Carr, Wang, & Jiang, 2022; Zhang et al., 2009) have all been applied. These hydrogels are ionically merely not electronically conductive and usually demonstrate high interfacial impedances. Conductive polymers are incorporated into the hydrogel network to meliorate the stimuli responsiveness and reduce interfacial electrical impedances (Heller, 2006) (Guiseppi-Elie, 2022). Incorporating an osmium complex within the hydrogel network could as well improve the redox efficacy (Kenausis, Taylor, Katakis, & Heller, 1996; Mano, Mao, & Heller, 2005).

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Strategies to improve the hemocompatibility of biodegradable biomaterials

P. Mulinti , ... A.E. Brooks , in Hemocompatibility of Biomaterials for Clinical Applications, 2022

x.4.three Polymer hybrids

Implantable sensors, including glucose sensors, play a meaning office in electric current medical practice; nonetheless, their indwelling lifetime is frequently limited by protein adsorption, which progresses to a chronic FBR. Although several groups have tried coating these sensors with a variety of synthetic polymers such as PU, poly(2-methoxyethyl acrylate), and PVA [ 110], their durability is even so express. A material that is compatible with blood while even so allowing bespeak molecule (e.one thousand., glucose) send is needed. Recently, a polyester fabric was coated with a biodegradable PGA sheet and implanted in a rat model. Equally the PGA degraded, cells deposited their extracellular matrix, much of which is collagen, on the polyester cloth. This hybrid textile was decellularized, and its mechanical compliance and hemocompatibility were evaluated, revealing a material that resisted platelet adhesion and thrombus germination [111].

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Molecular Events at Tissue–Biomaterial Interface

Themis R. Kyriakides , in Host Response to Biomaterials, 2022

Molecular strategies to enhance angiogenic responses

Specific applications, such every bit glucose sensors and tissue engineered constructs, have increased dependence on angiogenesis. Interestingly, prolonged inflammation is oft associated with persistent angiogenic responses merely this is not the example with implanted biomaterials. Feasibly, this relative subtract in angiogenesis is due to loss of production of pro-angiogenic factors by late stage macrophages or sequestration of these factors exterior of the avascular fibrous capsule, where an increased angiogenic response is often seen. Alternatively, excessive deposition of angiogenesis inhibitors during matrix production could also negatively influence angiogenesis. Regardless of the mechanism, the result is inefficient transport of molecules from microcirculation to the implant. Several groups have attempted to increment the number and stability of vessels in the FBR. Such strategies include delivery of pro-angiogenic factors such equally VEGF, PDGF, and MCP-ane, which found the majority of neovascularization approaches ( Jay et al., 2022; Richardson et al., 2001; Brudno et al., 2022; Klueh et al., 2005). Furthermore, the secretion and sequestration of angiogenic factors by the ECM can exist replicated closely past modulating their release. This controlled release could be accomplished by engineering chemical or enzymatic susceptibilities that allow for spatial and temporal control of release. In add-on, engineered enzyme (MMP)-sensitive hydrogel systems were shown to stimulate vascular germination (Seliktar et al., 2004; Kraehenbuehl et al., 2008). Alternatively, targeting the expression of anti-angiogenic factors, such as TSP2 or prolyl hydroxylase domain protein ii (PHD2), was shown to enhance vessel density in the FBR (Kyriakides et al., 2001a; Nelson et al., 2022). Specifically, it was shown that gene-activated matrix delivery of an antisense TSP2 cDNA enhanced blood vessel formation and altered collagen fibrillogenesis in mouse subcutaneous implant models. Similarly, Figure five.7 shows delivery of PHD2-specific siRNA from a porous polyester urethane (PEUR) scaffold that resulted in sustained increased blood vessel formation associated with increased VEGF and bFGF.

Figure 5.7. Sustained silencing of PHD2 increases angiogenesis within PEUR tissue scaffolds. CD31 staining was significantly increased inside PHD2 scaffolds at day fourteen and day 33 (calibration=200   μm, vessels announced red, nuclei are counterstained purple with hematoxylin, and the white space represents residual PEUR scaffold). (F) Micro-CT images visually demonstrate the increased vasculature within the PHD2-NP scaffolds.

 Reprinted with permission from Nelson et al. (2014).

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Glucose Biosensors—Recent Advances in the Field of Diabetes Management

Frank Davis , Séamus P.J. Higson , in Micro Fuel Cells, 2009

vi.10 Commercial Biosensors

At present, the commercial glucose sensors market is dominated by the dispensable market, with about devices currently utilizing the mediated electrochemical detection of glucose [1, 3, 254]. A major factor in this dominance is the availability of an inexpensive reliable engineering science for fabrication of the disposable sensor strips. Screen press is a mature technology especially suitable for depositing enzyme electrodes [3, 254]. A wide diversity of inks containing catalysts, mediators, and reference standards such as Ag/AgCl are commercially bachelor from a variety of suppliers. The ease of scaling upward the screen-printing process to mass product levels enables economies of scale to apply and thus reduces the costs of individual electrodes. Medisense (at present Abbott), for example, at the time of writing produces over a billion sensor strips per yr [three, 254] with other major suppliers including Lifescan and Roche Diagnostics.

The mediated detection of glucose is at present a mature technology and the primary focus of commercial research appears to be more into the supporting engineering science. Currently the monitoring of glucose requires lancing of a finger to produce a drib of blood, a process which when repeated on a regular basis can be both painful and distressing. Technologies such every bit the Pelikan® device, which simply require microliter blood volumes [i], have been developed to reduce the amount of blood needed to minimize these problems. However, other means take too been studied to remove the necessity for invasive procedures.

A diversity of techniques take been applied in attempts to measure out glucose levels in interstitial fluid. Laser ablation, ultrasonic techniques, and opposite iontophoresis accept all been studied and have been shown to be capable of removing interstitial fluid, thereby allowing testing [i, 3, 254]. However, whether this technique really gives reliable data is still controversial. It is yet uncertain whether glucose levels in interstitial fluid follow blood glucose levels closely plenty. Should at that place be a rapid rise or drib in blood glucose and it not be followed quickly enough past respective changes in the levels in interstitial fluid, a patient could suffer glycemia with bereft warning. Other fluids such as urine, tears, or sweat accept been suggested; nevertheless, as still no large scale commercial device product has been launched and at the time of writing, the home testing market place is all the same dominated by techniques that crave removal of a driblet of blood [254].

For patients who require closer monitoring of blood glucose than periodic sampling allows, in that location is the possibility of using an implanted needle-blazon sensor for continuous or near continuous glucose monitoring, even when the patient is asleep. Commercial implantable glucose sensors are available, ordinarily consisting of an implanted sensor combined with a minor monitoring and logging device. A subcutaneously implantable device, the CGMS® (Continuous Glucose Monitoring Arrangement) has been commercialized by Minimed (world wide web.minimed.com). The glucose biosensor probe is inserted just beneath the skin, usually in the abdomen, and can exist used to monitor glucose for up to 72   h and provide a reading every v   min. Traditional claret sampling of glucose is used to calibrate the device. Other information such as meal times and exercise periods can besides exist recorded using the device and all data so downloaded to a personal estimator.

For many diabetes type 1 sufferers, life involves a constant round of glucose testing and insulin injections. Externally worn insulin pumps accept been developed, such as those by Medtronic (www.minimed.com). These have the advantage that they remove the demand for injections by introducing insulin subcutaneously through a canella. When coupled together with a glucose biosensor, this provides an opportunity for the device to inject insulin "on need." This was the start device of its type to receive FDA approving [1]. At present, commercial devices commonly tin only be used for a few days at a time without maintenance, and injection and sensing sites need to be changed regularly. An implanted device which automatically responds to changes in glucose levels would in event act every bit an bogus pancreas so as to enhance the quality of life for many millions of people.

The preferred type of biosensor would be a noninvasive, wearable device which continuously monitored glucose. Devices of this type such as Glucowatch, produced by Cygnus, accept been released but have all the same to make a successful major impact on the market.

A variety of other methods have been proposed to measure glucose which do not involve use of biological moieties in whatsoever fashion. These prevarication outside the scope of this chapter but have been reviewed elsewhere [3, 254]. These methods include apply of spectroscopic techniques such as near-infrared spectroscopy and use of chemical binders for glucose such as boronic acids or molecularly imprinted polymers. However, every bit still none of these methods has been shown to work with sufficient reliability for utilize in a commercial sensor.

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