Invented by Robert J. Boock, Chris W. Dring, Dexcom Inc

The Market for Zwitterion Surface Modification for Continuous Sensors

Zwitterion-based surface modification has been demonstrated as a viable solution for continuous sensor surface chemistry. It allows hydration of the electrode, inhibiting nonspecific protein adsorption and producing optimal electrochemical impedance and low fouling.

Zwitterionic polymers (Po, pMPC and cMPC) have long been employed for surface coatings like antifouling membranes [55], while they have even been successfully employed to develop glucose sensors with long-term stability.

The market for Zwitterion surface modification

Zwitterion surface modification has emerged as a promising technology for continuous sensors such as pH sensors and blood contact sensors. It also finds application in biomedical implants, drug delivery systems, and separation membranes for protein molecules using SDS PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis).

Furthermore, zwitterion surfaces possess antifouling and antimicrobial properties comparable to cationic antimicrobial peptides, which are renowned for their outstanding antifouling and antimicrobial performance. These effects are attributed to the ion-dipole interaction between zwitterion functional groups and water molecules, leading to super hydration as well as enhanced antifouling capabilities.

Zwitterion materials boast antifouling and antimicrobial properties in addition to being highly biocompatible. They can withstand long-term circulation as well as various biological stress factors like UV light exposure, temperature extremes, acidic environments, oxidative stress and oxygen deprivation.

These properties make them an ideal surface chemistry for monitoring environmental conditions and detecting contaminants. Their versatility enables them to be applied in a variety of applications such as sensor coatings on medical devices, separation membranes, and antifouling coatings on vessels and piers.

Zwitterionic CPs (zwitterionic polymers) are becoming more and more popular as electrode materials for bioelectronics applications. Zwitterionic CPs possess the same conductive properties as conducting polymers, yet are much softer and easier to process than their inorganic counterparts. To enhance their bioelectronics performance even further, zwitterionic CPs can be modified with a grafted zwitterionic polymer brush.

This can be achieved through a two-step procedure that involves synthesizing zwitterionic moles on carbon nanotube molecules and then attaching zwitterionic polymer brushes to them. Surface modification of these CPs with zwitterionic moles helps prevent nonspecific protein adsorption, improving biocompatibility and performance for these materials.

Furthermore, zwitterionic CPs possess low sensitivity and high stability when binding salts. These qualities could be utilized to create a pH sensor that could accurately sense the pH levels in aqueous solutions under various environmental conditions and bacterial contamination.

Zwitterionic ceramic particles (CPs) are an essential class of materials in the development of continuous sensor systems. They have numerous applications, such as blood contact sensors, separation membranes and antifouling coats for medical implants. As a result, demand for surface modification with Zwitterion CPs is expected to grow significantly over the coming years.

The market for Zwitterion surface chemistry

Zwitterion surface chemistry has recently been proposed as a potential approach for creating continuous sensors for real-time detection of biomolecules. This method involves chemically altering the surface of a biosensor so as to enable label-free detection of an analyte in undiluted blood or other fluids (table 1).

These materials offer several benefits: they form strong hydration layers and inhibit self-association, helping minimize protein interaction and improving antifouling properties in biological media. Zwitterionic polymers can be produced with various monomers and crosslinkers to achieve desired functionalities and properties.

These materials are non-toxic and biodegradable, as well as being non-flammable and having excellent thermal stability – making them suitable for high temperature or low pressure applications. Furthermore, their chemical reversibility allows them to be chemically modified quickly; making them ideal for medical devices and sensors requiring rapid changes between an adsorbing agent and its degradant.

Recent publications have demonstrated the superior refractive index of zwitterionic polymers when applied as coatings on biosensors, especially when these surfaces exhibit low protein fouling and have a dry film refractive index higher than the substrate material’s (table 3).

Zwitterionic materials possess an electrostatic hydration layer on their surfaces which is much more resistant to water absorption than hydrogen bonding interactions between proteins. This enables them to be utilized for label-free detection of an analyte and highly sensitive sensitivities in various liquids, such as plasma or serum.

They possess antifouling properties in response to salts. This property is due to the ionic charge of the zwitterionic polymer and its effect on ion exchange between its zwitterionic and non-zwitterionic components of the material – known as the ‘anti-polyelectrolyte effect’. This property leads to improved wettability and reduced friction on zwitterionic surfaces, which in turn improves sensor performance when exposed to biological environments.

Zwitterionic surface coatings can be created through atom transfer radical polymerization (ATRP) and tailored for specific properties. These treatments have proven highly successful at reducing fouling and degradation of complex liquids used in medical diagnostics, biomedical sensors, and environmental monitoring applications.

The market for Zwitterion anchors

Zwitterion is an innovative sensor technology that is rapidly making its mark in the sensor world. This polycarboxylate surface was engineered for immobilizing negatively charged biomolecules such as DNA, carbohydrates or proteins with low pI values.

To be effective, a sensor system must create an effective covalent bond between the biomolecule and its target. A common solution is pre-concentrating the biomolecule on a solid surface before attaching it to the sensor; however, this method may be problematic when the biomolecule has highly variable size or composition.

A more reliable approach is to modify the sensor surface itself. This can be accomplished using in-solution or on-chip techniques which offer precise control of layer structure, grafting density, polymer length etc., while also guaranteeing that zwitterionic polymers are securely attached to the sensor substrate.

Materials have been tested, from zwitterionic carboxylic acids (CB) and phosphorylcholine to a trio of polymers. The most successful and aesthetically pleasing combination was poly-glycidyl methacrylate (polyGMA) combined with concentration-polarization enhanced polysulfone (SPE). For best results, two stages were used grafting procedure wherein thin layer of PolyGMA was first laid over PA before SPE was applied on top.

The market for Zwitterion self-assembly

Continuous sensors require high selectivity and inertness towards nonspecific protein binding, as well as a surface compatible for multiple molecular substrates and an effective functional unit that can capture specific proteins. This task becomes particularly daunting in nanoscale sensors where different molecular groups can be combined to form functional units covering an extensive surface area.

When designing a sensor, several factors need to be taken into account: material chemistry of the element; surface materials; and anchor properties. Many anchor choices are insufficient for miniaturized sensors due to their materials-specific nature and cannot bind securely across all elements.

When designing a sensor, the first factor to consider is its chemisorption strength. To guarantee long-lasting functionality of the sensor, multiple irreversibly bound anchors must be coupled to each spacer in order to prevent non-specific adsorption on the surface due to desorption of spacers.

Zwitterionic anchors can provide the solution here, as they bind water molecules more electrostatically than hydrogen bonds do and thus prevent nonspecific protein adsorption on the surface. Furthermore, these materials have excellent antifouling qualities due to their hygroscopicity and ability to form hydration layers which prevent biofilm formation.

These materials come in various chemistries, with the most promising being those based on sulfobetaine or carboxybetaine, which have demonstrated remarkable antifouling properties against protein adsorption (Gao et al., 2010; Jiang and Cao, 2010). Further, sulfobetaine-based zwitterionic materials can be immobilized on polydopamine-activated polymer membranes through Michael addition for even greater antifouling capabilities in complex biological media.

Zwitterionic materials are highly hydrophilic, enabling them to be grafted onto membranes through Michael addition to enhance antifouling properties against biofilm formation. According to Zhang et al. (2006), these membranes could resist protein adsorption of up to 0.3 ng cm-2 (Feng et al.). Recently, Feng et al. created an impressive polydopamine (PDA)-engineered biointerface and then immobilized it with sulfobetaine mecharylate (SBMA) through Michael addition for undetectable protein absorption on its surface.

The Dexcom Inc invention works as follows

Devices can be used to measure the concentration of analytes, such as glucose, in a host. A sensor can be used to produce a signal that indicates the concentration of an analyte. The sensor may also include a sensing membrane. The sensing membrane contains a diffusion resistance domain that controls the flux of the analyte through it. One or more zwitterionic substances and a base polymer containing both hydrophilic as well as hydrophobic areas make up the diffusion resistance domain.

Background for Zwitterion surface modification for continuous sensors

Electrochemical sensor are used in medicine and chemistry to determine the concentration or presence of biological analytes. These sensors can be used to monitor the glucose levels of diabetic patients or detect lactate in critical care events. There are many sensors that can continuously detect and quantify blood analytes such as glucose and blood sugar.

However, drift in the sensor’s sensitivity in-vivo is a major performance problem for continuous glucose sensors. Sensors made up of polymer membranes that have hydrophobic or hydrophilic elements can drift by rearrangement. This could be done to bring more hydrophilic component to the surface, or to make it easier to access hydrophilic ones during membrane hydration. In-vivo sensors that have improved surface wetting are desirable.

Additionally in-vivo sensors can be coated for targeted drug/biologic distribution. The drug or biologic that is being delivered is usually coated on the sensor’s surface. It should release in-vivo in controlled and predictable manner. In-vivo sensors that allow for the controlled release of drugs or biologics to subjects’ blood or tissues upon implant are desirable.

In-vivo sensors can also be affected by non-specific protein adsorption or cell adhesion. In-vivo sensors can also trigger inflammatory reactions such as tissue fibrosis and leukocyte activation. This could adversely affect sensor performance. In-vivo sensors should have surface treatments that resist cell adhesion and protein adsorption, and/or decrease the host’s inflammatory response.

In a first embodiment, a device for measuring an analyte concentration is provided. The device comprises: a sensor that generates a signal associated to a concentration of analyte, and a sensing membrane over the sensor. The sensing membrane includes a bioprotective layer that interfaces with the biological fluid that contains the analyte. The bioprotective domain in devices of this type includes a base polymer that has both hydrophilic as well as hydrophobic regions, and one or more zwitterionic compound, precursors or derivatives thereof.

In some embodiments, bioprotective domain includes up to 0.1, 0.0.2, 0.3 and 0.4, respectively, or 0.5, 1, 2 or 5% wt. zwitterionic substances, precursors or derivatives.

In some embodiments, the precursors or derivatives of zwitterionic substances, zwitterionic compounds or derivatives thereof include a betaine compound or precursor, or derivative thereof. Some embodiments of the zwitterionic substances, precursors, and derivatives thereof include a carboxyl-, sulfo-, or phosphorbetaine compound, precursor or derivative. Some embodiments of the zwitterionic substances, precursors, and derivatives thereof include one or more from the following: cocamidopropyl, oleamidopropyl, octyl sulfobetaines, caprylyl sulfobetaines, lauryl sulfobetaines, myristyl sulfobetaines, palmityl sulfobetaines, stearylcholine, poly(sulfobetainesulfobetainesulfobetainesulfobetainesulfobetainesulfobetybetainesulfobetainesulfobetainesulfobetainesulfobetainesulfabetainesulfobetainesulfobetainesulfobetainesulfobetainesulfidybetainesulfobetaine), sulfobetaine), sulfobetaine), sulfobetaine), sulfobe One or more of the zwitterionic compound or derivatives thereof may be one or more from the group consisting poly(carboxybetaine), poly(sulfobetaine), or precursors or derivatives thereof.

It is important to note that the above list of zwitterionic substances is not complete and is not meant to be exhaustive. It is possible that others suitable zwitterionic substances may be recognized by skilled persons in the art. Further examples of zwitterionic compounds, precursors or derivatives of them include phosphorylcholine and phosphoryl ethanolamine, as well as phosphatidylethanolamine, serine, phosphatidylethanolamine, and their precursors or derivatives.

In some embodiments the base polymer includes at least one of the following polymers: epoxies. polyolefins. polysiloxanes. polyethers. acrylics. polyesters. carbonates. A polyurethane copolymer is also used in some similar embodiments. Some embodiments include polyurethane as the base polymer.

In some embodiments, the sensor also includes a diffusion resistance domain that controls a flow of therethrough. In some embodiments, the bioprotective domain is part of a unitary bioprotective/diffusion resistance domain.

In some embodiments, the sensing cell also contains an enzyme domain that includes an enzyme from one of the following groups: glucose oxidase or glucose dehydrogenase; galactose oxidease; cholesterol oxidase; amino acid oxidase; alcohol oxidase. lactate oxidase. and uricase. The enzyme in some other embodiments is glucose oxidase.

In some embodiments, a sensor includes an electrode.

In some embodiments, a device can be configured to continuously measure an analyte concentration.

In some embodiments the analyte may be glucose

In a second embodiment, a device for measuring an analyte concentration is provided. The device comprises: a sensor that generates a signal related to a concentration of an Analyte, and a sensing membrane over the sensor. The sensing membrane includes a bioprotective area that interfaces with the biological fluid to be measured. The bioprotective domain in devices of this type comprises a polyampholytic monomer with both hydrophilic as well as hydrophobic regions.

In some embodiments, the monoampholytic polymer includes at least one of the following polymers: epoxies. A polyurethane copolymer is also used in some similar embodiments. Some embodiments of the polyampholytic polymer include polyurethane.

In some instances, the polyampholytic monomer may contain up to 0.1, 0.0.2, 0.3 and 0.4, or 0.5, 1, 2,, or 5% wt monomers containing charged end groups. Some embodiments have approximately equal numbers of anionic and cationic end groups in the polyampholytic polymer. Some embodiments have more cationic than anionic end group in the polyampholytic polymer. In some embodiments, the number cationic end group in a polyampholytic polymer is greater than that of anionic.

In some embodiments, the sensor also includes a diffusion resistance domain that controls a flow of therethrough. In some embodiments, the bioprotective domain is part of a unitary bioprotective/diffusion resistance domain.

In some embodiments, the sensing cell also contains an enzyme domain that includes an enzyme from one of the following groups: glucose oxidase or glucose dehydrogenase; galactose oxidease; cholesterol oxidase; amino acid oxidase; alcohol oxidase. lactate oxidase. and uricase. The enzyme in some other embodiments is glucose oxidase.

In some embodiments, a sensor includes an electrode.

In some embodiments, a device can be configured to continuously measure an analyte concentration.

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