Biomaterials are essentially foreign to the human body and, as such, have been associated with triggering inflammation and immune reactions. Initial inflammation is necessary for wound healing and occurs when biomaterials are in contact with host tissues. The milder irritation produced includes mild to moderate pain or discomfort, such as itching. Inflammation occurs with a more severe response and presents redness, heat, swelling, pain. This is a defensive response and occurs to some degree with all resorbable materials. Inflammation only becomes a problem if it becomes prolonged (chronic) and increases in severity leading to immunologically mediated events that lead to destruction of the implants or cell/tissue death. Reviews on the inflammatory response to biomaterials are available (Anderson et al., 2008 and Slee et al., 2014) and will not be discussed here.

As foreign materials that have been introduced into the body, biomaterials would also be a potential source of infection. Biomaterials made from metals, ceramics, and polymers are now in routine clinical use and have been linked to infection (Buhmann et al., 2016 and Busscher et al., 2012). For example, approximately 60,000 deaths per year have been reported in the USA due to device-related infections from urinary catheters and central venous catheters, and those made from polyurethane have been shown to constitute an entry pathway into body for bacteria (O’Grady et al., 2002). Bacteria will compete with cells to adhere to surface of biomaterials, as many of them have similar mechanism of attachment as cells, except they are better adapted for survival on non-viable surfaces. Common bacterial infections on polymeric biomaterials come from Staphylococcus epidermidis (S. epidermidis) from skin and Staphylococcus aureus (S. aureus), which is often found on metallic biomaterials. Some of these bacteria may be resistant to antibiotics (different surface expression). These have been found on artificial hearts, synthetic vessels, joint replacement implants, fixation devices, IV catheters, urologic devices, and contact lenses (Holzapfel et al., 2013). Ceramics and metals are relatively resistant to infection, but if there are imperfections on the surface or microfractures, pathogens, such as bacteria, can establish a colony (Holzapfel et al., 2013).

A group of aliphatic polymers, such as polyethylene, polytetrafluoroethylene, polypropylene, and also polyvinylidene fluoride, have selective affinity toward endotoxins (Davies, 1999). Thus, they have the potential to facilitate the microenvironment for tissue regeneration by adsorbing the endotoxins. However, due to absence of hydrophilic ionizable groups, they cannot be used directly before further biocompatible functionalization. Charged polymers with effective functional groups can selectively bind and remove endotoxins from the systems. One such example is positively charged acrylic cellulose with DEAE or QAE functional groups that can significantly absorb endotoxins (Hou and Zaniewski, 1990). This could be an important aspect while designing advanced biomaterials for clinical translations.

More recently, biomaterials from natural sources have gained significant interest as scaffolds for promoting regeneration. In particular, the decellularization of organs and tissues to obtain scaffolds composed extracellular matrix (ECM) components have gained considerable popularity (Faulk et al., 2014). Such scaffolds have been shown to be conducive to regeneration. However, these are either derived from human cadaveric sources or from xenogeneic sources. Both sources carry a risk for pathogenic transmission. Xenogeneic scaffolds have an additional risk of inducing allergic or inflammation reactions. Bone allografts are known to transmit several deadly viruses like hepatitis, tuberculosis (TB), and human immunodeficiency virus (HIV-1) (Vincent, 2012). Similarly, corneas have been reported to transmit hepatitis B virus (HBV), rabies, cytomegalovirus (CMV), Creutzfeldt–Jakob disease (CJD), and herpes simplex virus (HSV), apart from different bacteria and fungi (Lee et al., 2007). Furthermore, heart valves have been shown to transmit TB and HBV (Zou et al., 2004). Skins from seropositive donors were associated with HIV-1 and CMV transmission (Eastlund, 1995). Therefore, critical care and appropriate safety measures, such as rigorous screening, are required during the process of transplanting decellularized organs.

Some biopolymers, and in particular, polysaccharides, have inherent anti-inflammatory properties. For example, chitosan, a linear polysaccharide composed of randomly distributed β-(1–4)-linked d-glucosamine and N-acetyl-d-glucosamine derived from crustacean shells, has long been reported to have anti-inflammatory properties. Song et al. studied the anti-inflammatory effects of the chitosan–gelatin hybrid materials cross-linked with genipin. They concluded that the anti-inflammatory effects of genipin could be due to its effect on the NO/iNOS pathway and inhibition of the mRNA expression of COX-2 and IL-6 within activated macrophages (Song et al., 2011). Chitosan-based materials are believed to be anti-inflammatory based on their ROS scavenging properties (Je and Kim, 2006). Other biopolymers, primarily polysaccharides from plants, such as mushrooms (Elsayed et al., 2014) and seaweed (Rodrigues et al., 2012 and Park et al., 2011), are being examined for their anti-inflammatory properties. It is possible for these in the future to be tested as biomaterials.

Polyethylene glycol (PEG) and its nano-conjugated derivatives have also been shown to possess anti-inflammatory properties (Dobrovolskaia and McNeil, 2007). For example, PEG has been hybridized by incorporation of peptides, such as GRGDSPG, to form hydrogels with anti-inflammatory properties. GRGDSPG-containing peptides have been reported to protect MIN6 mouse pancreatic islet-derived cells from cytokine-induced cell death when functionalized to encapsulate these cells. These peptide-containing hydrogels in conjunction with the interleukin-1 receptor inhibitory peptide (IL-1RIP) FEWTPGWYQPY-NH2 were particularly effective in protecting the islet cells (Su et al., 2010).

Implantation of tectonic patches made from interpenetrating networks of collagen and 2-methacryloyloxyethyl phosphorylcholine (MPC) into three patients in a small hospital-based study under compassionate use revealed that this material was able to stably restore the integrity of the damaged corneas of patients with chronic ulceration or erosion of the epithelium due to stroma damage, thereby relieving patients from pain, discomfort, and photophobia (Buznyk et al., 2015). MPC has also been shown to have anti-inflammatory properties in other systems. For example, MPC-polymer has been shown to be useful for oral care. It protects from oral infection by preventing the adherence of periodontal pathogen and succeeding inflammatory reaction and, thus, protects gingival epithelium to maintain oral epithelial function (Yumoto et al., 2015).

Hyaluronic acid (HA) hydrogels have been widely used as scaffolds for promoting regeneration because of their reported anti-inflammatory nature (Nakamura et al., 2004; Hirabara et al., 2013). TNF-α antibody-conjugated HA hydrogels have been shown to reduce IL-1β concentration and macrophage infiltration when applied to burn wounds. This, in turn, reduced the thickness of the non-viable tissue (Friedrich et al., 2014). HA-based scaffolds with mesenchymal stem cells completely eliminated the inflammatory process when transplanted in pig models of myocardial infarction (Muscari et al., 2013).

To reduce the foreign body reaction (FBR), plasmid-encoded or virus-encapsulated IL-10 can efficiently downregulate the inflammatory response against collagen scaffolds, when transplanted subcutaneously in rats (Van Putten et al., 2009; Holladay et al., 2012). Combined glycosaminoglycan high sulfated hyaluronan with collagen scaffold reduced the secretion of pro-inflammatory cytokines and increased the anti-inflammatory cytokines, when macrophages were cultured on the implants (Kajahn et al., 2012) in in vitro-mimicked conditions of sterile tissue injury.

Not all biomaterials in clinical use are inherently anti-inflammatory in nature. However, they have been used to deliver a wide variety of therapeutic agents that were developed to control inflammation. The need for delivery agents stems from the fact that most therapeutic agents on their own fail to achieve a high enough local concentration to exert their effects. One approach to address this problem is the use of biomaterials as delivery agents and reservoirs for the therapeutic agent(s) and, in particular, provide sustained release of effective concentrations for prolonged periods of time. For example, the incorporation of stromal cell-derived factor-1 alpha (SDF-1α) into PLGA scaffolds reduced inflammation when transplanted into the subcutaneous cavity of Balb/C mice to improve both the tissue response and regenerative potential of tissue engineering scaffolds by reducing the local inflammation. It decreased the number and responses of mast cell near the implants together with reduced expression of IL-1α, IL-6, and TNF-α and increased VEGF expression (Thevenot et al., 2010).

A PLLA scaffold releasing Ibuprofen was shown to reduce IL-6 and TNF-α expression leading to decreased inflammatory responses and improved muscle regeneration (Yuan et al., 2014). Dexamethasone incorporated hydrogels reduced TNF-α and IL-6 expression from macrophages that ultimately reduced inflammatory response in lipopolysaccharide-stimulated primary mouse macrophages in vitro (Ito et al., 2007). Gelatin hydrogels incorporating mixed immunosuppressive triptolide-micelles and bone morphogenic protein-2 (BMP-2) downregulated the expression of pro- and anti-inflammatory cytokines, including IL-6 and IL-10, and reduced local inflammation responses and enhanced bone regeneration in rat model (Ratanavaraporn et al., 2012).

Although a plethora of potential delivery systems have been reported, only a few anti-inflammatory drug delivery materials are currently used in the clinic. One of these is a system for sustained delivery of dexamethasone (Ozurdex, Allergan Inc., Irvine, CA, USA). The implant is introduced into the posterior segment of the patient’s eyes with various pathologic conditions, including diabetic macular edema, non-infectious intermediate uveitis, and birdshot chorioretinopathy, and has been shown to exhibit a good safety profile and promising results in edema and inflammation control (Cao et al., 2014; Dugel et al., 2015; Walsh and Reddy, 2016). Further clinical trials are ongoing to confirm these initial results (ClinicalTrials.gov identifier: NCT01801774, NCT02736175, and NCT02547623).²

Just like there are biomaterials with innate anti-inflammatory behavior, there are biomaterials that have intrinsic anti-infective properties, and there are those that are effective as carriers of antibacterial and antiviral agents or other bioactives developed to combat infectious agents. There is a wide range of these and only a selected few examples are provided below. Biomaterials containing sulfated groups are known to have anti-infective properties. These include antibacterial as well as antiviral properties. The best-known are the marine-derived sulfated polysaccharides derived from brown seaweeds (Phaeophyceae such as Fucus, Laminaria, and Ascophyllum). These macromolecules include alginates and fucoidans (Berteau and Mulloy, 2003; Marguerite, 2014).

Among the properties attributed to fucoidans is its antiviral activity (Damonte et al., 2004). Fucoidans isolated contain mainly O-sulfated α-l-fucosides but they also contain acetyl groups and other types of saccharides and proteins (Morya et al., 2012). Our group had examined the possibility of reproducing the antiviral properties of fucoidans in synthetic mimics and confirmed that the sulfation was essential for activity against viruses, such as Herpes Simplex Virus serotype 1 (HSV-1) (Tengdelius et al., 2014). However, we also found that the activity of synthetic fucoidan was similar to that of other sulfated polysaccharides, such as heparin and dextran sulfate, while non-sulfated control synthetic fucoidans or polyacrylamide did not block viral activity. We, further, showed that synthetic O-sulfated fucoidans blocked HSV-1 activity during the viral adsorption step, reacting with viral particles to prevent their entry into cells (Tengdelius et al., 2014). More recently, we examined the anti-HSV-1 efficacy of another fully synthetic sulfated biomaterial, polystyrene sulfonate [poly(sodium 4-styrenesulfonate) (PSS)]. We developed theranostic contact lenses, i.e., contact lenses that could detect and modulate HSV-1 infection. Here, PSS was used as coatings to effectively provide antiviral activity (Mak et al., 2015).

A wide range of nanomaterials, from carbon nanotubes (CNTs) and fullerenes to dendrimers and metal nanoparticles has been shown to have intrinsic anti-infective properties against bacteria, viruses, and other pathogens (reviewed in Rai et al., 2015). Table 1 provides a list of various nanoparticle systems and their reported antimicrobial (antibacterial) activities.

The best-known metallic nanoparticles with antibacterial activity are the silver nanoparticles (AgNPs) and silver in general. These are known for their antibacterial and antiviral properties. Use of silver in medical implants has a long history of medical use. Colloidal silver has been approved for wound treatment since the 1920s and registered as a bactericidal substance since 1954 (Nowack et al., 2011; Reidy et al., 2013). New solutions combine regeneration and antimicrobial effects to allow faster and safer recovery from injury. Silver containing wound dressings include Acticoat^®, a commercial wound dressing utilizing nanocrystaline silver (Khundkar et al., 2010), Actisorb^®, which contains a silver-nylon cloth, and Calgitrol Ag^® that utilizes silver-alginate (Simon et al., 2016). Silver ions have been shown to have toxicity on cells and also in vivo. However, it has been shown that silver nanoparticles produced as naked particles and coated with collagen or LL-37 peptide have reduced cytotoxicity on human skin epidermal cells compared to ionic silver (Alarcon et al., 2015). However, they were effective against bacteria tested, such as S. aureus (strain ATTC 25923), S. epidermidis (strain Se19), Escherichia coli (strain CFT073), and Pseudomonas aeruginosa (strain PA01). Methicillin-resistant S. epidermidis (MRSE) and methicillin-resistant S. aureus (MRSA) have been reported to be successfully inhibited by “NanoSilver” embedded bone cement in an in vitro model with human osteoblasts, whereas similar cement with gentamicin could not able to prevent the infection with such resistant strains (Alt et al., 2004). Within our group, we have developed simple composite collagen-based hydrogels that have included silver nanoparticles with antibacterial properties as corneal implants (Alarcon et al., 2016).

Nanoparticles and their different composites have also had antiviral activity (Table 1). They have now been shown to interact with the HIV-1 virus in a size-dependent manner possibly through the gp120 subunit of the viral envelope glycoprotein (Di Gianvincenzo et al., 2010; Lara et al., 2010).

Like antibiotics, however, resistance to silver has been found in bacteria. The reports, to date, point to the resistance being plasmid-based, and not all bacteria examined have been shown to harbor these plasmids. Overall, the incidence of silver resistance remains low compared to antibiotic resistance (Griffith et al., 2015).

Nanoparticles have also been used as carriers for bioactives and antiviral drugs. For example, silver and gold coated with sulfated ligands developed have been shown to exert their anti-HIV activity by inhibiting the binding of HIV gp120 on the host cell receptors at early stage of viral replication (Di Gianvincenzo et al., 2010; Lara et al., 2010). Several studies have evaluated the potential antiviral efficacy of antiviral drug delivery systems against HIV-1 infection (Bowman et al., 2008; Mahajan et al., 2010; Chiodo et al., 2014; Bastian et al., 2015) or HBV, showing promising results in terms of enhanced antiviral potency or efficiency in delivery of the drugs/peptides used. Zhang et al. showed that adefovir dipiroxil (ADV), a nucleotide analog with potent antiviral activity against chronic HBV, loaded in solid lipid NPs significantly lowered HBV DNA levels compared with free ADV (Zhang et al., 2008).

We have previously reported collagen implants containing silica nanoparticles releasing LL37 peptide that has anti-HSV-1 antiviral properties (Lee et al., 2014). Other more sophisticated composite biomaterials have been developed as local antibiotic carriers system that offer regulated release of antibiotics in specific tissues and implant. An example of such biomaterials is TiO₂-NiFe₂O₄ nanoparticle system that comprise particles with photocatalytic shells and magnetic cores, to form removable antimicrobial photocatalyst system that can be extracted from the sprayed surface (infected region) after exposure (Rana et al., 2005). Biocompatible, injectable polymeric carriers, e.g., Pluronic^® F127 that can respond in situ to physiological stimuli have also been developed for controlled drug release (Simões et al., 2012). To combat with the increasing concern of antibiotic resistance, composite nanosystems that combine conventional antibiotics with nanoparticles have been reported to successfully inhibit drug resistant microbes compared with antibiotics alone (Campoccia et al., 2010). Several approaches are going on with antibiotic-loaded biomaterials for local infection prophylaxis, and one such example that is available for use in the clinic is poly(d,l-lactide) (PDLLA) coating. The idea is to turn an implant into a drug delivery device.³

We have summarized the different functional aspects and the major concern in developing the biomaterials for their successful clinical translation (Figure 1).