Journey of Hydrogels to Nanogels: A Decade After

ARTI VASHIST, AJEET KAUSHIK, ANUJIT GHOSAL, ROOZBEH NIKKHAH-MOSHAIE, ATUL VASHIST, RAHUL DEV JAYANT AND MADHAVAN NAIR

1.1 The Journey of Hydrogels

The remarkable invention of crosslinked hydroxyethylmethacrylate (HEMA) hydrogels was a ground-breaking innovation for biomaterials scientists around the globe, which led to the future golden era of research for the next generations. The pioneering work carried out by Lim and Sun in 1980, and later by Yannas and co-workers, showed the potential applications of calcium alginate microcapsules utilised for cell encapsulation as well as the utilisation of the natural polymers collagen and shark cartilage in a hydrogel matrix for dressings for artificial burns. The beneficial aspects of hydrogels for therapeutics led to their clinical use. The ability of these soft materials to provide spatial and temporal control in handling the release of bioactives and various therapeutic interventions is exceptional. Their existence in various forms such as injectable forms, patch or thin film forms, viscous gel forms, and nanocomposite forms of hydrogels make them more desirable for various biomedical applications. Research has been conducted to understand the underlying mechanism for their design so that the drug delivery and release conditions can be modulated. Figure 1.1 demonstrates a histogram showing the immense exponential increase in the research and publication regarding hydrogels that has been done in the past 50 years.

The emerging research on inorganic nanoparticle-based adsorbents, drug delivery carriers and sensor formulations having a three dimensional network has come up with remarkable advantages over conventional nanocarriers and other carriers such as metal oxide nanoparticles, polymeric nanoparticles, liposomes, dendrimers, exosomes, etc. The major advantages of the nanogel-based systems in comparison to nanospheres, that have polymeric dense cores, is that they show the capability to encapsulate diverse therapeutic interventions, proteins, and bioactives (enzymes, DNA/RNA). The first nanogels were synthesized by the promising research group of Kabanov et al. and they developed a chemical crosslink using the polymers poly(ethylene glycol) (PEG) and polyethylenimine (PEI) and used the nanogels for oligonucleotide delivery. Figure 1.2 shows some therapeutic utilisations of hydrogels that are used on a on regular basis for various applications like a substitute for skin application, drug encapsulated hydrogels, hydrogels for burn treatments, sensor applications and many others.

The first physically crosslinked nanogels were reported by the pioneering group of Akiyoshi et al., showing the self-assembly of cholesterol-bearing polysaccharides in water using the self-organization of amphiphilic polymers. The journey of hydrogel research over the following ten years has been commendable in terms of the translation of hydrogels to the market and various other achievements (Figure 1.3). The vast absorbing capacity of hydrogels of physiological fluids and their compatibility towards the cellular environment makes them ideals candidates to be used for various purposes. The era of hydrogels began with the invention of HEMA hydrogels and then various natural and synthetic polymers were exploited in the following years utilising various synthetic approaches. The exceptional swelling capacity and porous structures were utilised by various research groups to translate this hydrogel-based research to clinics. Click chemistry, supramolecular interactions and self-assembly processes were selected to design better hydrogels.

Various biomedical applications were covered utilising bulk hydrogels in diverse forms and certain challenges were raised. The next sections will highlight major limitations imposed by the hydrogels and the upsurge in demand of nanogel-based systems. High quality drug delivery carriers, imaging tools, and diagnostics were in demand with the emergence of biocompatible hydrogel systems.

1.2 Driving Force for Designing the Nanogels

Recently, the realm of nanotechnology and the advances in the design of nano-formulations have come up with innovative biomaterials. These nanoformulations are emerging with advanced features and escaping all the demerits of the bulk hydrogel technology (Figure 1.4). The expensive synthesis of hydrogels is being replaced by cheap, easy and fast synthesis procedures.

Traditionally utilised natural polymers with low mechanical strength are being replaced by synthetic polymers and this inhibits the chances of passing on viruses from animal-derived materials. The extensive need for sterilization and the low loading capacity of therapeutics into the hydrogel systems are being replaced by nanoscale gels with exceptionally high loading efficiency. The surgical implantation of the hydrogel device was one of the major limitations of the hydrogel-based drug delivery systems. This drawback was overcome by the invention of injectable hydrogels and nanogels which can be delivered to the humans intravenously or intraperitoneally. The high...