Use of Hydrogels in Brain Applications

In the last decades, an exponential and rapid evolution has been seen in hydrogel studies. This all started when for the very first-time hydrogels were used in eye surgery. Hydrogels made their way in the medical application because of its biodegradable nature. Now a day’s hydrogels applications can be found in many fields including contact lenses, wearable sensors for muscular activities, biodegradables hydrogels for reconstructive surgery and many more. All of these classes have been continuous studies with time to improve the efficiency and filed of applications. Beside all these applications, recently hydrogels were used for tissue engineering especially as a scaffold for stem cells. It was found that hydrogels play an important role in brain application including the treatment of brain tumors. This review covers the use of hydrogels in brain applications. Figure 1: Schematic of a hydrogel network having mesh size ξ and polymeric chain molecular mass Mc [13]. Global Journal of Engineering Sciences Volume 4-Issue 3 Citation: Haider Butt. Use of Hydrogels in Brain Applications. Glob J Eng Sci. 4(3): 2020. GJES.MS.ID.000587. DOI: 10.33552/GJES.2020. 04.000587. Page 2 of 7 Hydrogels can be classified into two categories; i) physically cross-linked, ii) chemically cross-linked. Chemically cross-linked hydrogels are insoluble in water unless the covalent bond in the network is broken first [10]. The network of physical hydrogels is formed by the non-covalent cross-linking of monomers, e.g., electrostatic interaction [11]. Usually, hydrogels are inert in nature which makes hydrogels one of the best candidates to be used as biomaterials [12]. The response of hydrogels depends on their composition, degree of cross-linking and type of cross-linking. Tailoring these properties may allow us to synthesize applicationbased hydrogels. Mesh size is an important factor that determines the space available for external particles to enter or leave the hydrogel network and is controlled by the degree of cross-linking [13] (see Figure 1). There are certain properties of hydrogel structures that are hunted when being used for sensing applications; i) the degree of wetness and inertness of the structure that makes it qualified to be a hydrogel, ii) the degree of sensitivity or response to the external stimuli like change in swelling, and iii) the diffusion control of particles through their polymeric structures [14-16]. The theory of swelling needs to be understood which is essential for sensing applications of hydrogels. The following section will describe the swelling theory of hydrogels. In hydrogel network, osmotic pressure is created by the hydrophilicity of monomers which results in the swelling of structure upon contact with water [17]. The swelling occurs in three stages; i) first the water diffuses into the structure, ii) after hydration, the polymer chains relax, and iii) lastly, they expand upon relation [17,18]. There is a limit to which hydrogels can absorb water. This limit or so-called equilibrium is attained when the osmotic pressure becomes equal to the elastic counteractive forces of polymeric chains in hydrogel structure. The expansion stops at this equilibrium state. When osmotic pressure changes due to any kind of activity, for example by breakage of bond or change in pH value, the equilibrium is disturbed which results in the swelling or shrinking of hydrogel structure to stabilize. Flory & Rehner [19,20] have described the theory of swelling in detail using the free energy and chemical potential of hydrogels. The response of hydrogels, when they encounter external stimuli, is in the form of volume-phase transitions (VPT) which occurs due to sudden changes in the hydrogel network. These sudden changes are the product of molecular interactions with the external particles or stimuli. Therefore, it can be stated that the stimulus determines the response mechanism of hydrogels. There are several types of hydrogels that respond differently to different stimuli. Most researched hydrogels are those that respond to pH changes leading to volume-phase transitions. Consider having a system where we have a hydrogel that has a pH value equal to pKa (acidic nature) and an environment having a pH value greater than pKa. This difference results in the deprotonation of the hydrogel, causing a negative charge to appear on polymeric chains or functional groups attached to the monomers to be more accurate which leads to the repulsion of polymeric chains and hence the swelling of the network. An example of this mechanism can be found with poly (methacrylic acid) (PMAA) structure [21]. However, if this ionized acidic network is protonated or the pH of the environment is lowered than the pH of the network, the structure returns from the swollen state to its initial state because of the reduction of electrostatic repulsive forces between the ions on the polymeric chains. Similar behavior exists in the hydrogel structures with cationic functional groups (basic nature), but in an opposite fashion [22]. Status of Development Hydrogel sensors were reported for the detection of Glutamate in vivo [23]. Glutamate is one of the most important excitatory neurotransmitters in the brain. Osmium is recycled through a chemical reaction and acts as an electron transfer mediator. These sensors were hydrogel-based second generation sensors. They were obtained using carbon fiber which used redox mediator wired coating. They were reported previously reported by Kulagina et al. [24]. Anesthetized rats were used for this experiment. It was found that a very less amount of glutamate oxides was used in these sensors when compared to the first-generation sensors. In 2009, a wearable brain cap was reported in the 4th International IEEE EMBS Conference on Neural Engineering [25]. This cap showed the ability to measure electroencephalogram (EEG) signals. Unlike other caps that use electric contact, this cap doesn’t require any electric contact with the head. Hydrogel materials were used for cap manufacturing. These contacts do not need any electric contact between its surface and scalp. On the other hand, these contacts are flexible, and their integration is easy in the wearable cap. This cap plays a vital role in the basic braincomputer interfaces (BCI) system (See Error! Reference source not found (a). On the other hand, Error! Reference source not found (b). highlighted one reference approach using contactless electrodes. The electrode used an electro-active hydrogel, polyacrylamide hydrogel (PAAM), for sensing and modulation of the sensor. This work provided a solution to the uncomfortable attachment of caps for the BCI system to monitor the EEG signal by reducing the attachment procedure and time consumption. Right after this, another detailed report was published by the same authors with the same results in 2010 [26]. One of the milestones for the usage of hydrogel for brain applications was reported by Shen [27]. A new technique for the imaging of a brain, called Clear Lipid-exchanged, Anatomically Rigid, Imaging/immunostaining compatible, Tissue hydrogel (CLARITY), was developed in Stanford University. This technique made it possible to get the whole image of a mouse brain and make it possible to label a lot of molecules. This technique involved the use of hydrogel to remove fat lipid layer without disrupting the cell structure and hold the rest of the components in place. This process is called hydrogel-hybrid tissue formation. This is done by the formation of formaldehyde-acrylamide fixative-generated hydrogel mesh. By using this cellular lipid is removed using sodium dodecyl sulfate [28]. This makes the whole brain transparent to light but also permeable to molecules (Figure 2).