gels Review Nanocomposite Hydrogels: Advances in Nanofillers Used for Nanomedicine Arti Vashist 1,*, Ajeet Kaushik 1 , Anujit Ghosal 2, Jyoti Bala 1, Roozbeh Nikkhah-Moshaie 1, Waseem A. Wani 3, Pandiaraj Manickam 4 and Madhavan Nair 1,* 1 Department of Immunology & Nano-Medicine, Institute of NeuroImmune Pharmacology, Centre for Personalized Nanomedicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; akaushik@fiu.edu (A.K.); jbala@fiu.edu (J.B.); rnikkhah@fiu.edu (R.N.-M.) 2 School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India; [email protected] 3 Department of Chemistry, Govt. Degree College Tral, Kashmir, J&K 192123, India; [email protected] 4 Electrodics and Electrocatalysis Division, CSIR-Central Electrochemical Research Institute, Karaikudi 630006, Tamil Nadu, India; [email protected] * Correspondence: avashist@fiu.edu (A.V.); nairm@fiu.edu (M.N.) Received: 18 June 2018; Accepted: 23 August 2018; Published: 6 September 2018 Abstract: The ongoing progress in the development of hydrogel technology has led to the emergence of materials with unique features and applications in medicine. The innovations behind the invention of nanocomposite hydrogels include new approaches towards synthesizing and modifying the hydrogels using diverse nanofillers synergistically with conventional polymeric hydrogel matrices. The present review focuses on the unique features of various important nanofillers used to develop nanocomposite hydrogels and the ongoing development of newly hydrogel systems designed using these nanofillers. This article gives an insight in the advancement of nanocomposite hydrogels for nanomedicine. Keywords: biomaterials; nanocomposite hydrogels; nanomedicine; biomedical applications; carbon nanotubes; pH responsive; biosensors 1. Introduction The most emerging field of nanomedicine has come up with diverse biomedical applications ranging from optical devices, biosensors, advanced drug delivery systems, and imaging probes. In this regard, hydrogels have been intensively studied and explored [1,2]. Nanomedicine is a developing field, which deals with medical applications related to nanomaterials and biological devices. Nanomedicine showed great advancements and utilizes the change in the functionalities of nanomaterials with synergism to biological molecules. This combination of nanomaterials and biological molecules has led to the invention of unique devices, analytical tools, many novel physical therapies, and vehicles for proteins and enzymes. It is worth noting that the pace of investigation going on around the globe for hydrogels in nanomedicine is very high. The importance of nanomedicine in market has been demanding due to the unique characteristic properties arising from the application of nanotechnology. A fundamental understanding of the term “nano”, precisely with reference to nanofillers and nanoparticles, corresponds to particles with sizes ranging between 1 to 100 nm with a surrounding interfacial layer. This layer is an important and integral part of nanorange materials. This size specification affects all the properties and features of the materials. To begin with, hydrogels are the crosslinked 3D-networks of hydrophilic polymers, having great tendency to absorb large amounts of water inside them. The unique features of hydrogels include their soft porous structures, high water content, biocompatibility, and ability to absorb physiological Gels 2018, 4, 75; doi:10.3390/gels4030075 www.mdpi.com/journal/gels Gels 2018, 4, 75 2 of 15 fluids. Moreover, the presence of specific functional groups on the backbone chains of the polymeric matrices are key factors to decide their response in various environments. This unique ability of the hydrogelsGels 2018 to respond, 4, x FOR PEER to externalREVIEW stimuli makes them intelligent carriers [3]. Recent research2 of 15 shows that the development of nanomaterials, either in the form of inorganic nanoframeworks, nanogels [4,5] or nanocompositefluids. Moreover, hydrogels the presence [6]; is of the specific future functional of up-and-coming groups on the nanomedicinebackbone chains technology.of the polymeric matrices are key factors to decide their response in various environments. This unique ability of the Recent trends have suggested the development of hydrogels with the functionality of inorganic hydrogels to respond to external stimuli makes them intelligent carriers [3]. Recent research shows components.that the There development is a great of differencenanomaterials, between either ain nanocarrier the form of aloneinorganic and nanoframeworks, when it acts as nanogels a drug delivery system.[4,5] The or capacity nanocomposite for drug hydrogels encapsulation, [6]; is the future its stability, of up-and-coming and effectiveness nanomedicine of technology. delivery vehicles are excessivelyRecent enhanced trends when have wesuggested consider the development nanocomposite of hydrogels hydrogels with as the drug functionality delivery of systems. inorganic Thecomponents. development There of is inorganic-organic a great difference frameworksbetween a nanocarrier with soft alone hydrogel and when networks it acts isas thea drug demand of today’sdelivery materials. system. Clay The nanocomposite capacity for drug hydrogels encapsulatio weren, its innovative stability, and gels effectiveness developed of by delivery Haraguchi in vehicles are excessively enhanced when we consider nanocomposite hydrogels as drug delivery 2002 [7].systems. These nanocomposite hydrogels exhibited superior properties, including mechanical and swelling/deswellingThe development features of inorganic-or when comparedganic frameworks to conventional with soft hydrogel hydrogels. networks This is study the demand came to be a breakthroughof today’s in materials. the world Clay of nano nanocompositecomposite hydrogels hydrogels. were innovative Nanocomposite gels developed hydrogels by Haraguchi are simply the cross-linkedin 2002 three-dimensional [7]. These nanocomposite networks hydrogels formed exhibi inted the superior presence properties, of nanostructures. including mechanical These and structures are formedswelling/deswelling either by physical features or chemical when compared crosslinking. to conv Physicalentional hydrogels. linkages areThis formed study came through to be hydrogen a breakthrough in the world of nanocomposite hydrogels. Nanocomposite hydrogels are simply the bonding or via hydrophobic or ionic interactions. Chemical crosslinking occurs by the formation of cross-linked three-dimensional networks formed in the presence of nanostructures. These structures covalentare bonds, formed which either are by veryphysical strong. or chemical These nanocomposite crosslinking. Physical hydrogels linkages are are capable formed of through changing their propertieshydrogen depending bonding upon or via external hydrophobic stimuli. or Theionic nanoparticles interactions. Chemical are added crosslinking to the hydrogel occurs by matrix the either by absorbingformation these of covalent nanoparticles bonds, which inside are thevery matrix strong. These or dispersing nanocomposite them hydrogels homogeneously are capable inside of the hydrogelchanging matrix their and alsoproperties by entrapping depending nanoparticles upon external insidestimuli. the The hydrogel nanoparticles matrix. are Theseadded nanoparticlesto the act as nanofillershydrogel matrix inside either the matrix, by absorbing which causesthese nanopa great enhancementrticles inside the in intrinsicmatrix orand dispersing extrinsic them properties homogeneously inside the hydrogel matrix and also by entrapping nanoparticles inside the hydrogel of the hydrogel matrix. The nanofiller addition to the hydrogel matrix contributes to the unique matrix. These nanoparticles act as nanofillers inside the matrix, which causes great enhancement in propertiesintrinsic of hydrogels and extrinsic and properties enhances of the hydrogel their applications matrix. The nanofiller in microfluidics, addition to the sensors, hydrogel and matrix actuators. Moreover,contributes the nanocomposite to the unique properties hydrogels of arehydrogels being and applied enhances in catalysis, their applications development in microfluidics, of membranes used forsensors, separation, and actuators. water purification, Moreover, andthe nanocomposite other various hydrogels biomedical are applications. being applied This in catalysis, diversity exists becausedevelopment these nanocomposites of membranes can used be for designed separation, in variouswater purification, forms, such and asother thick various and biomedical thin membranes, applications. This diversity exists because these nanocomposites can be designed in various forms, uneven sheets, hollow tubes, and bellows (Figure1). such as thick and thin membranes, uneven sheets, hollow tubes, and bellows (Figure 1). Figure 1.FigureNanocomposite 1. Nanocomposite hydrogels hydrogels gels with with various various shapes: shapes: (a) thin ( afilm,) thin (b) sheet, film, ( (cb) uneven) sheet, sheet, (c) uneven (d) hollow tube, and (e) bellows. Reprinted with permission from Reference [8]. Copyright 2007 Elsevier. sheet, (d) hollow tube, and (e) bellows. Reprinted with permission from Reference [8]. Copyright 2007 Elsevier. Gels 2018, 4, 75 3 of 15 2. Various Nanofillers Used for Designing Nanocomposite Hydrogels Gels 2018, 4, x FOR PEER REVIEW 3 of 15 Hydrogels are covalently or physically crosslinked networks and hence, usually have