Review prosthesis MDPI Functionalization of Polymers and Nanomaterials for Biomedical Applications: Antimicrobial Platforms and Drug Carriers Masoud Delfi 1,+, Matineh Ghomi 2,+, Ali Zarrabi 3,4,+ Zahra Baghban Taraghdari 6,+, Milad Ashrafizadeh 7 Tarun Agarwal 9 5,t, Reza Mohammadinejad Ehsan Nazarzadeh Zare 8,*, Vinod V. T. Padil 10,* D, Babak Mokhtari 2, Filippo Rossi 11 Giuseppe Perale 12,13, Mika Sillanpaa 14,15,16,17,Assunta Borzacchiello 18, Tapas Kumar Maiti 9,* and Pooyan Makvandi 2,18,* D 1 2 3 4 5 6 7 8 9 Department of Chemical Sciences, University of Naples “Federico II", Complesso Universitario Monte S. Angelo, Via Cintia, 80126 Naples, Italy; Masoud.delfi@unina.it Chemistry Department, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz 6153753843, Iran; ma_gh@rocketmail.com (M.G.); bmokhtari4@gmail.com (B.M.) Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey; alizarrabi@sabanciuniv.edu Center of Excellence for Functional Surfaces and Interfaces (EFSUN), Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla 34956, Istanbul, Turkey Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 76169-13555, Iran; r.mohammadinejad87@gmail.com Department of Chemical, Materials & Industrial Production Engineering, University of Naples Federico II, 80125 Naples, Italy; z.baghban@studenti.unina.it Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz 51666-16471, Iran; dvm.milad1994@gmail.com School of Chemistry, Damghan University, Damghan 36716-41167, Iran Department of Biotechnology, Indian Institute of Technology, Kharagpur 721302, India; tarun3agarwal5@gmail.com 10 Department of Nanomaterials in Natural Sciences, Institute for Nanomaterials, Advanced Technologies and Innovation (CXI), Technical University of Liberec (TUL), Studentská 1402/2, 46117 Liberec, Czech Republic Department of Chemistry, Materials and Chemical Engineering, Politecnico di Milano Technical University, 20133 Milano, Italy; filippo.rossi@polimi.it 11 12 13 14 15 56 Faculty of Biomedical Sciences, University of Southern Switzerland (USI), Via G. Buffi 13, 6900 Lugano, Switzerland; giuseppe.perale@supsi.ch Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Donaueschingenstrasse 13, 1200 Vienna, Austria Institute of Research and Development, Duy Tan University, Da Nang 550000, Vietnam; mikaetapiosillanpaa@duytan.edu.vn Faculty of Environment and Chemical Engineering, Duy Tan University, Da Nang 550000, Vietnam 16 School of Civil Engineering and Surveying, Faculty of Health, Engineering and Sciences, 17 University of Southern Queensland, West Street, Toowoomba, QLD 4350, Australia Department of Chemical Engineering, School of Mining, Metallurgy and Chemical Engineering, University of Johannesburg, P. O. Box 17011, Doornfontein 2028, South Africa 18 Institute for Polymers, Composites, and Biomaterials (IPCB), National Research Council (CNR), 80125 Naples, Italy; bassunta@unina.it * Correspondence: ehsan.nazarzadehzare@gmail.com (E.N.Z.); vinod.padil@tul.cz (V.V.T.P.); maititapask@gmail.com (T.K.M.); pooyan.makvandi@ipcb.cnr.it or Pooyanmakvandi@gmail.com (P.M.) + Equaul co-first author. Received: 21 May 2020; Accepted: 19 June 2020; Published: 23 June 2020 check for updates Abstract: The use of polymers and nanomaterials has vastly grown for industrial and biomedical sectors during last years. Before any designation or selection of polymers and their nanocomposites, Prosthesis 2020, 2, 117–139; doi:10.3390/prosthesis2020012 www.mdpi.com/journal/prosthesis Prosthesis 2020, 2 118 it is vital to recognize the targeted applications which require these platforms to be modified. Surface functionalization to introduce the desired type and quantity of reactive functional groups to target a cell or tissue in human body is a pivotal approach to improve the physicochemical and biological properties of these materials. Herein, advances in the functionalized polymer and nanomaterials surfaces are highlighted along with their applications in biomedical fields, e.g., antimicrobial therapy and drug delivery. Keywords: drug delivery; surface functionalization; antibacterial activity; antimicrobial properties; polymeric nanoparticles 1. Introduction Polymers are the most used compounds which possess many advantages, such as lightweight materials, cheap, easy to produce as different products, and long durability [1]. To improve the applicability and specificity of polymers, some modifications to the particles are needed. These changes can be made in the bulk of the carrier, like incorporating Cu in nanospheres to enhance imaging and photocatalytic properties [2]. Another major site of modification is the surfaces of the polymers. Dry surface treatment techniques e.g., corona discharges [3], oxygen plasma [4], ultraviolet light-ozone [5], and cold atmospheric jet [6] have been applied for improving polymer/polymer or polymer/ceramic adhesions. To make corrections in the polymer surfaces, wettability properties of polymers can be altered to govern the adhesion of various coatings. This means the ability of the liquid for moistening the surface of a polymer, which in turn, creates different coatings on the surface. It is worth noting that polymers often have very poor wetting properties that prevent the coatings from sticking properly [7]. In this regard, surface tension plays a critical role on the surface wettability of the polymers, while low surface tension creates less wetting tendency. The attractive forces that exist on the microscopic scale of polymer surface molecules or atoms, prevent them from leaving the surface of solid/liquid materials. These forces are dependent on the binding energy of the atoms/molecules in the solid/liquid materials and cause the surface energy to disperse. For catching the high wettability on the polymer surfaces, a high concentration of polar components should be induced [8]. For improving the various properties (e.g., thermal, mechanical, and optical) of polymers, they can be combined with nanoparticles and nanofillers to form nanocomposites. Nanoparticles can modify the wetting tendency of polymer surfaces through two mechanisms. (I) Alterations of the intermolecular interactions of interfacial solid-water and enhancing the wettability of the polymer surface through modifying the chemical composition, (II) addition of some nanoparticles that can increase the hydrophobicity or water-repellence of the polymers via modification of the surface morphology (e.g., surface roughness) [9]. The physical and chemical properties of the polymer surfaces can be modified by the mentioned methodology for intimate interfacial contacts between two different phases, while these modifications have no effect on the properties of the bulk. These surface treatments show significant efficiencies such as (I) alteration of the chemical structure of polymer surfaces by free-radical reactions of the polymer surface with the surrounding gases, (II) etching of a microscopic layer or selective leaching of polymeric chains with low molecular weight, (III) polymer reinforcement by increasing the cross-links or branching of the polymer molecules, and (IV) cleaning by converting liquid or solid films/contaminants into volatile gas products [10,11]. Prosthesis 2020, 2 119 The purpose of this review is to introduce the advances in surfaces functionalization of polymer and nanomaterials and discuss their recent investigations toward antibacterial modification and drug delivery (Figure 1). Polymer chain Antimicrobial agent Antimicrobial activity DOXX Functional group for targeted delivery Drug Delivery Drug encapsulated in nanoparticle Figure 1. Surfaces functionalization of polymer and nanomaterials for antimicrobial therapy and drug delivery applications. 2. Antimicrobial Therapy Humans are always exposed to the threat of microbial infections regardless of place and time [12,13]. There are three ways to impart antimicrobial activity to a platform (Figure 2). The first is functionalization of polymers or nanomaterials with antimicrobial agents, e.g., quaternary ammonium compounds (QACs) [14,15]. These compounds have been extensively used to improve the antimicrobial efficacy of various surfaces through a contact-killing mechanism. QACs, in particular the ones possessing long alkyl chains, are mostly utilized as antimicrobial and disinfectant materials. These compounds exhibit strong toxicity against fungi and amoebas, and have the ability to envelop viruses as well [15,16]. Another example that can be mentioned in this context is the surface modification of polysaccharides using QACs. Due to the available functional groups of polysaccharides, they are known as abundant renewable bio-substrates. For instance, glycidyl trimethyl ammonium chloride grafted cellulose and chitosan films have been investigated extensively as antibacterial surfaces [17-19]. Prosthesis 2020, 2 Alive microbes 3 2 Using antimicrobial platforms Dead microbes Antimicrobial agent Antimicrobial drug Surface functionalized nanoparticle/polymer Drug delivery systems ww Antimicrobial nanoparticle Polymer chain Nanocomposite 120 Figure 2. Schematic illustration of three ways of antimicrobial activity in a platform: (left panel) surface functionalization of nanoparticles/polymers, (middle panel) drug delivery system, and (right panel) fabrication of nanocomposite. The second approach is fabrication composites by adding fillers such as metal-based nanomaterials like Ag nanoparticles [20–22]. Silver has been used for wound healing soon after its discovery as an effective antimicrobial agent. It can be used as a solid state (powder) or even salt solutions for wound treatment [23,24]. Although it has been used for a very long time, the exact mechanism of action of silver nanoparticles remained partially unknown. The antimicrobial activities of Ag NPs can be divided into four steps: approaching to the bacterial surface, disruption of the cell wall of the bacteria and its membrane through changing its permeability, exerting toxicity effects and oxidative stress by producing ROS and free radicals, and modulation of signal transduction pathways [25]. The last method is encapsulation of antimicrobial drugs or biomolecules such as gentamicin. The drug is a potent broad-spectrum antibiotic with high toxicity efficacy against various Gram-positive and Gram-negative organisms [26]. Regarding the killing strategy, there are two main strategies to confront bacteria: (I) releasing of antibacterial agents on the infected sites and (II) attaching to surfaces containing antibacterial compounds (contact-killing). In the latter strategy, surface modification of metallic or polymeric surfaces is performed to attach various agents with antibacterial activities to make direct contacts with microorganisms. To increase the antimicrobial efficacy, implant functionalization using antimicrobial peptides (AMPs) has been introduced to be a very practical technique. An interesting example in this respect, a polydopamine coated Ti substrate was conjugated with AMPs through a click chemistry reaction (Figure 3). The AMPs show resistance against the infection of different types of microbes including bacteria and fungi. They can penetrate the bacterial cell membrane and damage the drug-resistant bacteria vigorously. The surfaces functionalized by AMP showed high microbicidal effects with low cytotoxicity [27]. Prosthesis 2020, 2 (b) AMP: KRWWKWWRR Surface a HO Dopamine Dopamine: HO OH OH 2-Bromoisobutyryl bromide: Ti-PDA Br Surface b 2-Bromoisobutyryl bromide Br Br Ti-Br Surface c NH NIPAM Ti-pNIPAM Surface f NH NaN Br N3 N3 Ti-Na Surface d NaN Ti-PNIPAM-N₁ Surface g Substrate glass, polymer, metal SEBS bead SEBS chain NH H₂N PraAMP: KRWWKWWRR HO PDA layer: NH2 HO PraAMP PraAMP NIPAM: H₂N H₂N Ti-AMP Surface e HN- H₂N H₂N Ti-PNIPAM-AMP Surface h SEBS/p-xylene/decanol (polymer/solvent/nonsolvent) 346 Dry decanol (nonsolvent) Solvent evaporation NH p-xylene (solvent) 121 Figure 3. (a) Schematic of preparation of antibacterial implants through conjugation of antimicrobial peptides (AMPs) on Ti substrate. Reprinted with permission from [27]. (b) Schematic of preparation of biocompatible and antibacterial surfaces by superhydrophobic coating of styrene-b-(ethyleneco- butylene)-b-styrene elastomer (SEBS) on different substrates. Reprinted with permission from [28]. There are some ceramic nanocompounds, e.g., SiO2 nanoparticles, that do not possess antimicrobial activity yet have been modified to generate microbicidal materials. As an example, Makvandi et al. have functionalized silica nanoparticles with quaternary ammonium methacrylate blended with