Catechol Redox Reaction: Reactive Oxygen Species Generation

Chapter 10

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Catechol Redox Reaction: Reactive Oxygen Species Generation, Regulation, and Biomedical Applications Pegah Kord Forooshani, Hao Meng, and Bruce P. Lee* Department of Biomedical Engineering, Michigan Technological University, Houghton, Michigan 49931, United States *E-mail: [email protected]

Reactive oxygen species (ROS) are a group of highly reactive molecules containing oxygen. ROS are generated endogenously in different physiological processes such as metabolic system and wound healing responses. The biological responses of ROS are highly dependent on its concentration in the biological system. Natural polyphenols and catechol-containing compounds (i.e., mussel adhesive proteins, melanin, and polyphenols) demonstrate both pro- and antioxidant properties. These redox activities can be tailored to be used in various clinical applications. Here, we review the physiological generation and regulation of ROS and their effects in biological system and summarize the unique features of phenolic compounds and their incorporation into biomaterials for various biomedical applications.

Introduction Reactive oxygen species (ROS) are highly reactive chemical species resulted from the reduction of molecular oxygen (O2) (1). They are composed of one or more unpaired electrons with the tendency to interact with biological molecules including proteins and DNA (2). ROS are endogenously generated in all cell types and in a variety of physiological processes such as the respiratory chain and normal wound healing processes (3). However, excessive accumulation of © 2017 American Chemical Society Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


ROS can also lead to cellular damage as well as pathological complications such as cardiovascular, neurodegenerative, and inflammatory diseases. Our biological system generally uses two different strategies to control the oxidative stress associated with ROS, including utilizing antioxidant agents (such as ascorbate or phenolic compounds) and ROS-scavenging enzymes (such as superoxide dismutase) (4). Phenolic compounds are a member of a large family of biomaterial, which are widely distributed in nature and can be found in various animal and plant tissues. Reduction-oxidation (redox) reaction of polyphenols is an important biological process for ROS production and regulation, as well as critical functions related to the survival of the organism. For example, marine mussels produce a series of phenolic adhesive proteins (the so-called mussel foot proteins; mfps), which enable them to attach to various foreign substrates in a wet environment (5). The main constituent of these proteins is 3,4-dihydroxyphenylalanine (DOPA), which contains a catechol side chain that is responsible for the rapid curing ability and the adhesive properties of mfps (6, 7). The control of the oxidation state of catechol is critical to the adhesion and crosslinking of mfps. Similarly, natural and synthetic polyphenolic compounds (e.g., melanin and polydopamine, respectively) exhibit antioxidant property (8). Other phenolic compound such as tannins (i.e. tannic acid (TA), pyrogallol (PG), etc.) from plant tissue (e.g. oak and argan) and food resources (e.g. white and red wine) also have the similar free radical scavenging ability (9). These unique characteristics provide scientists to design various biomaterials for various biomedical applications (i.e., wound healing, antimicrobial coating, cancer treatment, etc.). Here, we first summarize endogenous production of ROS and introduce their effects on biological system. Then, we introduce various phenolic compounds and their pro-oxidant and antioxidant properties. Finally, the application of these biomaterials in wound healing, antibacterial applications, and other therapeutical applications are reviewed.

ROS ROS are divided into two different groups, which include radical and non-radical species (1). Reactivity of the radicals is highly dependent on their redox potential (i.e. semiquinone (SQ˙ˉ) < phenoxyl radical (PhO˙) < superoxide (O2˙ˉ) < nitrogen dioxide radical (NO2˙) < hydroxyl radical (OH˙)), due to their low reaction activation energy. Whereas, the reactivity of the non-radicals (i.e. hydrogen peroxide (H2O2), peroxynitrite (ONOOˉ) and hypochlorous acid (HOCl)) mostly depends on their reaction kinetic and activation energy. For example, H2O2 has a higher activation energy and higher reduction potential when compared to HOCl, and thus react slower than HOCl. Therefore, H2O2 is considered as a weak oxidizing agent in biological system and has poorer reactive ability with most biological molecules. This section describes the endogenous production of ROS and its biological effects. 180 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 1. ROS generation and detoxification pathway inside the body (A). Antooxidant acitivity of phenolic compound related to iron binding (B). SOD denoted to superoxide dismutase. Endogenous Production of ROS ROS is generated endogenously during the wide variety of normal metabolic processes, such as mitochondrial respiration. Additionally, there are a variety of enzymes including xanthine oxidase, nitric oxide synthase, cyclooxygenase, lipoxygenase and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase which generate ROS (10). Most of the ROS expressed in inflamed or wounded tissues are produced by NADPH oxidase (NOX) found in inflammatory cells (e.g., phagocytes) (11, 12). During the phagocytosis of invading organisms, the NOX complexes in the membrane of phagocytes are activated in a process called respiratory burst, which reduces O2 to the highly reactive O2˙ˉ (Figure 1A). The generated O2˙ˉ then is spontaneously dismutated to H2O2 and water within the extracellular spaces, catalyzed by superoxide dismutase (SOD). Due to the fact that the SOD enzyme converts the potent O2˙ˉ to the less reactive H2O2, SOD is also considered as a detoxification agent. Although H2O2 is a poor reactive ROS, it can lead to a severe biological damage through generation of hydroxyl radicals (OH˙) by Fenton reaction in the presence of iron (Fe+3), or copper (Cu+2) ions. These radicals can aggressively oxidize cellular macromolecules. H2O2 also can be converted to more reactive oxidant such as HOCl (e.g. hypochlorite 181 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


(OClˉ)) by myeloperoxidase enzyme stored inside neutrophils (professional phagocytes). The resulting reactive species are the strongest antimicrobial oxidants in neutrophils. OClˉ can then react with H2O2 and amine functional groups (RNH2) to produce chloramines (RNHCl), which is less reactive but still may have some oxidizing effects (13). In a regulated biological system, phenolic compounds such as tyrosine can be oxidized to form free radicals (i.e., phenoxyl radicals (PhO˙)), which then reversibly generate glutathionyl radical (GS˙) from the cysteine residues of glutathione (GSH) (1, 14). Additionally, autoxidation of other phenolic compounds such as DOPA or adrenaline leads to the generation of semiquinone-like radicals (SQ˙ˉ), which can then react with oxygen to form O2˙ˉ. SQ˙ˉ can also be produced through the reduction between quinone and other related phenolic compounds in the presence of reductase (i.e. flavoenzyme). Nitric oxide (NO˙) reacts with O2˙ˉ in the presence of nitric oxide synthase to form ONOOˉ, which readily reacts with carbon dioxide to form NO2 and carbonate radicals (15, 16). It can also generate OH˙ instead of carbonate radical in the absence of carbon dioxide. The tendency for NO˙ to oxidize thiols can result in damages to biological systems. Regulation of ROS ROS is a natural by-product of respiration. On the other hand, it can impose cytotoxic condition on healthy native tissue. Therefore, a protective system is required to appropriately detoxify these reactive molecules. Detoxification of ROS can occur through the enzymatic systems of an organism (10) or alternatively by endogenous antioxidants such as glutathione or antioxidants from extrinsic sources such as vitamins (e.g. ascorbic acid and vitamin E) and phenolic compounds (17, 18). Any substance that can render, delay or decrease the damaging effect of ROS on the native tissue are considered to be an antioxidant. Antioxidant activity of phenolic compounds refers to both the ability of the catechol groups to bind iron ions (i.e. disturb Fenton reaction and OH˙ generation) (Figure 1B) as well as their radical scavenging activity (i.e. acting as scarifying agent and reduce the ROS species). H2O2 which is dismutated by SOD from O2˙ˉ can further be detoxified by various enzymes including catalase, glutathione peroxidases and peroxiredoxins to water (10). The processes in which these enzymes detoxify H2O2 are reviewed in detail elsewhere (10, 19). Peroxiredoxins enzyme also has the ability to detoxify ONOOˉ (20). Malfunction in any of these enzymes can leads to excessive accumulation of ROS in an organism, leading to destructive consequences. Biological Effects of ROS in Vivo Oxidant homeostasis represents a balance between ROS production and antioxidant enzyme decomposition. The shift of homeostasis result in an oxidative stress or hypoxic stress induced cellular injury and death (Figure 2). Excessive production of ROS is highly toxic and can result in oxidative stress and cell destruction. This can end up with oxidation of many cellular 182 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


and extracellular substances, leading to premature aging, chronic inflammatory conditions, neurodegenerative diseases (e.g. Parkinson’s and Alzheimer’s) and even neoplastic transformation (e.g. cancer) (21–23). On the other hand, ROS is vital for the survival and function of various cell types. They are widely used by cells, specifically phagocytes, for defense against invading mechanism (22). They also participate in cell signaling process. In fact, it is reported that many cellular responses to hormones and growth factors need redox signaling (24, 25).

Figure 2. Schematic representation of antioxidant and ROS generation balance.

As an example, we summarize the various biological responses to H2O2 as this particular ROS is known to be released by phenolic compounds. The biological responses to H2O2 are highly dependent on H2O2 concentration (Table 1). Take wound healing as an example, micromolar concentration of H2O2 is secreted at the wound site once a wound is formed (26). H2O2 activates many signaling pathway and is continuously suggested as a second messenger (27, 28). Complete removal of H2O2 by catalase delayed wound healing to form incomplete eschar. The introduction of a relatively low concentration of H2O2 (102-103 µM) promoted wound healing by inducing angiogenesis (29), promoted axon regeneration (30) and mediated leukocyte recruitment. On the other hand, higher doses of H2O2 (≥ 105 µM) retarded wound healing and formed chronic wounds. H2O2 concentration between 102 to 103 µM is bacteriostatic and H2O2 at a concentration higher than 106 µM is antimicrobial (31, 32). Sustainable H2O2 (10-103) released from ascorbate acid as a function of time specifically killed cancer cells but not normal healthy cells (33). Thus, H2O2 concentration needs to be carefully monitored depending on the applications. 183 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Table 1. Biological effects correlated to the H2O2 concentration [H2O2] (µM)

Biological Effect

References

Complete removal

Delayed wound healing

(26)

102-103

Accelerated wound healing

(29)

103

Axon regeneration

(30)

103

Bacteriostatic

(32)

≥ 105

Retard wound healing

(29)

106

Antimicrobial

(31)

Sustainable release (10-103)

Kill cancer cells but safe to the normal cells

(33)

Phenolic Compounds Phenolic compounds are aromatic compounds containing one or more hydroxyl (-OH) groups linked to the aromatic ring. These compounds can be derived from various sources (i.e., mfps, plants, etc). Phenolic compounds exhibit unique antioxidant and pro-oxidant properties, and has the potential in numerous biomedical applications (i.e., antibacterial applications, cancer therapy, wound healing and treatment of neurodegenerative diseases) (34–36). Here, we introduce various phenolic compounds and their redox properties. 3,4-Dihydroxyphenylalanine (DOPA) Marine mussels secrete protein-based adhesives (mfps), which enable them to anchor to various surfaces in their wet and saline habitat (6, 7). The liquid adhesives rapidly solidify to form byssal threads and adhesive plaques to provide stable attachments for the mussels. These adhesive proteins contain a unique adhesive amino acid, 3,4-dihydroxyphenylalanine (DOPA) (37, 38). The catechol side chain of DOPA is responsible for the oxidative crosslinking capabilities and strong interfacial binding. Catechol forms strong reversible physical and irreversible covalent interaction with both organic and inorganic surfaces. Catechol form strong, reversible complexes with various metal ions (i.e., Fe+3, Cu+2, Zn+2, Mn+2, Ti+3 and Ti+4) (39–41) with different stoichiometry (i.e., mono-, bis-, and tris-complexes) (Figure 2) (42, 43). The stoichiometry of the complexes is highly dependent on pH as well as the valency of the ion and molar ratio of catechol to metal ion. Catechol-iron ion complexation has been suggested as one of the possible mechanism for the catechol’s antioxidant activity as the catechol groups can chelate iron ions and thus disrupt the Fenton reaction and OH˙ generation (Figure 1B). The triscatecholate-Fe+3 complex is very stable at a mildly basic physiological pH (i.e. Log stability constant ~40-49) (Figure 3) (9). However, the stability constant for Fe+2 ions (which participate in Fenton reaction) in a monocatecholate complex is much lower than that of Fe+3 ions (Log stability 184 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


constant of 7.95 and 20 for Fe+2 and Fe+3, respectively). Therefore, binding of the catechol as a ligand to the Fe+2 ions decreases the redox potential of iron ions and facilitate autoxidation process of the Fe+2 ions to Fe+3 in the complexes. The Fe+2 ions are oxidized in the presence of oxygen to catechol-Fe+3 complexes with a higher stability (Figure 1B). The free radical scavenging activity of catechol is another proposed pathway for its antioxidant characteristics.

Figure 3. Coordination of catechol with metal ions to form mono-, bis-, and tris-complexes.

Pro-oxidant activity of catechol stems from its oxidation to form semiquinone and quinone by one- and two-electron oxidation, respectively. During the oxidation of catechol, a considerable amount of ROS such as O2˙ˉ and H2O2 is generated (Figure 4) (34, 44). The oxidation occurs in the presence of oxygen molecules in a basic aqueous solution (i.e., autoxidation) or with the addition of either enzymatic (e.g. tyrosinase, peroxidase) or chemical (e.g., periodate) oxidants (5, 45). During the autoxidation of catechol, a sustained release of 102-103 µM H2O2 was observed for over 48 h (34). On the other hand, during the chemical oxidant (i.e., NaIO4) induced oxidation and crosslinking of polymer-bound catechol, a significantly lower amount of H2O2 (102 µM during the first 24 hrs) was reported (46). This lower amount of generated H2O2 was attributed to the entrapment of the ROS and its contribution towards catechol crosslinking and polymerization, which can take over 8 hrs to reach completion (47).

Figure 4. Generation of H2O2 from the oxidation and polymerization of catechol. 185 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Melanin and Polydopamine Melanin is a polyphenolic biomaterial composed of tyrosine, DOPA, and their derivatives as well as their oxidation products. Melanin ubiquitously exists in nature and has various functions in different organisms (48). Melanin can function as a protective agent for microorganisms (e.g. fungi and bacteria) against various external stresses such as ROS, ultraviolet light irradiation and high temperature. Melanin also serves as pigment found in human hair and skin (49). Melanins have interesting physical and chemical characteristics (i.e. strong adhesion to various substrates, photoabsorbing and strong antioxidant properties), which make them suitable choice for various applications. This could be the reason behind the production of a synthetic melanin, polydopamine, as the extracted melanin from biological sources usually results in contamination (50, 51). Polydopamine is synthesized through the autoxidation and polymerization of dopamine in a process similar to melanin formation (8). The structure of the polydopamine and the mechanism of formation still largely unclear, but its properties (i.e., antioxidant properties) mimic those of naturally derived melanin (8). Polydopamine contains many phenolic groups, which impart polydopamine with the ability to scavenge free radicals through an electron-transfer reaction (52). During the polymerization process, polydopamine deposits onto various type of surfaces including noble metals, inert polymers and ceramic (8), with different geometry and sizes (53, 54). As the coating layer is very thin (10-8-10-9 m), the geometry and structure of the functionalized substrates remain mostly unchanged (55). Polydopamine coating remains reactive and can be further modified with various functional groups (i.e., -NH2, -SH, etc.) or metal ions (54, 56). Its stability in aqueous environment also contributes to this property and provides a facile method for the attachment of these functional groups. Polydopamine is a suitable anchoring groups for binding a wide range of protein, enzyme and other biological molecules to various surfaces for biotechnology applications (57). Biological molecules such as growth factors also are grafted on the coated implant devices to enhance biocompatibility, cell viability and proliferation (58). Additionally, various antifouling polymers (e.g. PEG) can be grafted on the coated surfaces to design a surface with strong antifouling properties which prevent nonspecific attachment of bacteria and cell (8). polydopamine also can be coated on various nano-sized materials as a sacrificial template to form polydopamine nanoparticles (NPs) after removing the template (59, 60). For example, Polydopamine coated on nanoparticle templates is used to produce capsules for drug delivery application (61, 62). The capsules have tunable size and wall thickness and can be loaded with different drugs (e.g. anticancer drugs). Alternatively, polydopamine NPs have been prepared without template through neutralization of acidic dopamine with sodium hydroxide which followed by subsequent autoxidation in air (63). The nanoparticles demonstrated excellent biocompatibility to HeLa cells and good antioxidant ability.

186 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Polyphenols Polyphenols are biomolecules derived from different plant tissues or organic food sources (i.e., wine, green tea, etc.) that contain various amounts of catechol and gallol (1,2,3-trihydroxyphenyl) functional groups (64, 65). They have various biological functions, which include photoabsorbance, structural support, pigmentation and defense mechanism against different external stresses (66). Additionally, these compounds exhibit diverse physical and chemical properties (i.e., metal ion complexation, free radical scavenging activity), which contribute to their antioxidant activities (67). Additionally, they have significant structural similarities with biomaterials like DOPA and dopamine and exhibit strong interfacial binding properties with various surfaces (64). Polyphenol coatings can be formed through the oxidation and polymerization process similar to that of polydopamine formation. Oxidation of the polyphenols at an alkaline pH, leads to oligomerization which results in the reduction of polyphenols’ solubility and ultimately result in their precipitation on a surface substrate (64). This reaction has been used in leather and tea industries (68). In contrast with the polydopamine coating, which has a dark color and is expensive due to the cost of dopamine, polyphenol-based coatings are significantly less expensive and colorless, which make them potentially suitable for applications such as cosmetic, antimicrobial and free radical scavenging coatings (64). Various polyphenols (e.g. tannic acid (TA), pyrogallol (PG), epigallocatechin (EGC), epicatechin gallate (ECG), epigallocatechin gallate (EGCG), catechin (Ctn), catechol, hydroxyhydroquinone (HHQ)) have demonstrated the ability to polymerized to form stable coatings (Table 2) (65). Diversity of these precursors can lead to designing advanced coatings with tailorable physical and chemical properties. As most of the polyphenols that exhibited the ability to form surface coatings contain catechol functional groups, catechol is considered as a necessary component for coating formation. However, there are some catechol-contained polyphenols (e.g. quercetin and gallic acid) that were unable to form a coating under similar conditions (64, 65). Polyphenols have the ability to be deposited on a wide variety of organic and inorganic surfaces, including metals (i.e., gold, stainless steel, titanium oxide (TiO2)), ceramics, and polymers (e.g., polytetrafluoroethylene, polycaprolactone) (64, 65). Some of them (i.e. TA, PG, EGCG, Ctn and catechol) can be deposited onto surfaces with different topographies such as polymer meshes and porous foams (65). The coating formation is strongly pH dependent; therefore, small changes in pH can significantly affect the ability of phenols to form a coating. For each polyphenol, the pH should normally be less than the first phenolic pka. The stability and thickness of the coatings are dependent on the type of the substrates, pH and presence of the ester functional groups on the phenolic precursor (65). The precursor concentration and incubation time also affect the thickness of the PGand TA-derived coatings on TiO2 and gold surfaces (64).



Table 2. Summary of coating precursors, their plant sources and chemical structure.



The polyphenol coatings derived from TA and PG are reported to have antibacterial properties (64). These coatings reduced the viability of both gram-negative (Pseudomonas aeruginosa, P. aeruginosa) and gram-positive (Staphylococcus aureus, S. aureus) strains by more than 30-fold when compared to non-coated surfaces. At the same time, these polyphenol-coated surfaces did not exhibit cytotoxic effect towards fibroblasts. Antifouling polymers such as PEG can be grafted on the surfaces coated TA and PG which demonstrated strong resistance to cells and bacteria attachments. Unlike PG, TA also shows significant ROS scavenging ability like other phenolic compounds. TA also can be used for producing capsules through TA-metal ion complexation (69). The resulted metal-phenolic network (MPN) capsules have high stability at natural pH (i.e. catechol-metal ion complexation forms with high stoichiometry), while they disassembled at acidic condition (i.e. the stoichiometry is reduced) which resulted in rapid releasing of the loaded drug. Antioxidant Properties of Phenolic Compounds Polydopamine and other polyphenols are known as antioxidants based on their free-radical scavenging ability (Figure 5) (63, 70). Irons enhanced ROS production and oxidative stress environment (9). Polyphenols can chelate iron ions, which significantly decrease the generation of ROS (71). This antioxidant property of polyphenols can protect the cells from ROS-induced cytotoxicity. Biomaterials coated with polydopamine have been demonstrated to improve their cyto-compatibility (72, 73). The pro- and anti-oxidant properties of polydopamine coatings are highly dependent on its redox state. Polydopamine film under its reduced state has pro-oxidant activity, while polydopamine film under its oxidized state has antioxidant activity (74). Polydopamine nanoparticles synthesized under alkaline pH demonstrated a size and concentration dependent free radical scavenging property (63).

Figure 5. Schematic representation of antioxidant properties of polydopamine coated substrate and polydopamine nanoparticles (NPs). 189 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

Delivery of ROS for Therapeutic Applications The therapeutic applications of ROS are highly dependent on the concentration of ROS (Table 2 for H2O2). Here we summarized ROS generating and regulating phonic biomaterials for various biomedical applications (i.e., wound healing, antimicrobial, cancer treatment, Parkinson’s disease treatment).


Wound Healing Mussel inspired moisture-resistant adhesives have been widely studied in wound healing (75), tendon repair (76), and cell engineering applications (77). The oxidative crosslinking of catechol is critical in the curing the adhesive and form interfacial bonding with the tissue surfaces (46). Our lab recently captured H2O2 production during the autoxidation and oxidative crosslinking process of catechol (34, 46). When these adhesives were implanted subcutaneously, the released H2O2 promoted localized M2 macrophages polarization. Unlike the pro-inflammatory response demonstrated by M1 macrophages, M2 macrophages are responsible for regulatory and anti-inflammatory responses, which are critical in promoting tissue regeneration (78, 79). Therefore, the H2O2 production from the mussel inspired materials could potentially be modulated for wound healing application. The released H2O2 drastically reduced cell viability under typical cell culture conditions. However, doping the cell culture media with an antioxidant enzyme (e.g., catalase) drastically increased cell viability, indicating that the released H2O2 is main source of cytotoxicity in culture for catechol-based adhesives. Exposing primary fibroblasts to H2O2 also upregulated the production of antioxidants (e.g., peroxiredoxin 2) (46). Rat tendon fibroblasts were more sensitive to a relatively lower amount of released H2O2 when compared to the rat dermal fibroblasts, due to the fact that tendon is exposed to a hypoxic environment in vivo. As such, the application of ROS in different tissues and biological systems needs to be carefully monitored due to their different responses to ROS. Anti-Bacterial Effect Polydopamine films or nanoparticles are versatile substrate which can be further modified by polymers, proteins and metal ions, or encapsulated drugs and metal ions to impart these materials various applications (8, 57, 80). For antimicrobial studies, polydopamine surfaces were modified with quaternary amine or low molecular weight lipopeptide analogue (81), antibacterial enzyme lysostaphin (82), and metal ions (silver and copper) (83). Additionally, ROS was produced during the oxidation of dopamine to form polydopamine. Recently, the antimicrobial property of the ROS produced from polydopamine surfaces is believed to contribute at least partly to the antimicrobial activity (83). However, the mechanism of ROS production during polymerization of dopamine and its antimicrobial properties has not well studied. Recently, it was reported that over 7 mM of H2O2 was produced over 48 hrs during the polymerization of dopamine (34). This reported amount of H2O2 was significantly higher when compared to autoxidation of catechol, suggesting that the crosslinking of the catechol 190 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

amine contributed to additional H2O2 production. The release of H2O2 may have contributed to the observed antimicrobial properties of polydopamine coating.


Cancer Therapy Polyphenols selectively trigger the cancer cells apoptosis but they are safe to the normal cells (84). Ribonucleotide reductase (RR) is an enzyme with a lower expression in the normal cells. RR are expressed more prominently in tumor cells and are considered as a target chemotherapy for cancers (85, 86). Polyphenol acts as a free radical scavenger to effectively inhibit RR (87). Gallic acid (GA) has demonstrated strong efficiency toward killing human HL-60 promyelocytic leukemia cells. GA significantly increased the ROS levels in the cancer cells (i.e., lung cancer cells (84), hepatocellular carcinoma cells (88), and prostate cancer cells (89)), which resulted in the apoptosis of these cancer cells. Additionally, production of H2O2 during auto-oxidation of the polyphenols induced cancer cells apoptosis, and the efficacy was dependent on the H2O2 concentration (90, 91). Parkinson’s Disease Parkinson’s disease (PD) is a neurological disorder with the degeneration of Dopaminergic neurons (92). The reason for the specific loss of dopaminergic neurons in the PD patients is still unknown. One accepted mechanism is the ROS generation during the autoxidation of dopamine into semiquinone which forms an oxidative stress environment. Additionally, the neural system of PD patients contained a higher concentration of ion (93). Elevated ion concentrations enhanced the generation of ROS, which overwhelms the natural antioxidant system to trigger neural cells apoptosis (71). Additionally, oxidative stress may inhibit the cells from protein degradation through the imbalance of the ubiquitin-proteasome system (94). One method for treating PD is to supplement L-DOPA to the PD patients. The dose of L-DOPA to treat PD is still controversial. Accumulation of L-DOPA was considered to elevate the ROS production in the neural system which induced side effects for the PD patients (95). On the other hand, polyphenol is considered as an antioxidant as well as an iron chelator. Therefore, the polyphenols can chelate the accumulated irons in the neural system to relief the oxidative stress in the PD patients (71). ROS Production and Other Biomaterials ROS can be triggered to be produced intracellularly due to diseases, infection, wounding and also mechanical manipulation of the tissue during surgical implantation of biomaterials (10). Additionally, biomaterial itself can exogenously produce ROS or it can induce intracellular production of these reactive specie. 2-hydroxy-ethyl methacrylate is a cytotoxic degradation product of dental cements and adhesives and it has been demonstrated to induce the generation of intracellular ROS in human pulp fibroblast, human gingival epithelial S–G cells and mouse macrophages (96–98). Triethylene glycol dimethacrylate is another dental adhesive monomer which induce cell death through apoptosis and necrosis 191 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


(99). Several studies have been performed to understand the possible signaling pathway involving cell death after administration of these monomers, to control ROS over-generation. Alternatively, biomaterials can exhibit antioxidant properties through the incorporation of ROS scavenging compounds or enzymes. Coenzyme Q10 (also known as ubiquinone) is a benzoquinone derivative naturally found in most cells. This enzyme is a strong antioxidant with free radical scavenging ability which play a role in oxidative stress protection and reduction of mitochondrial ROS production (100–102). Coenzyme Q10 incorporated into different polymer systems (e.g. poly (lactic-co-glycolic acid), poly (ethylene glycol), polycaprolactone, and triphenylphosphonium bromide), have been shown to have the ability to scavenge ROS at the levels greater than the enzyme itself (103–105).

Summary and Future Outlook ROS have multitudes of biological functions which are highly dependent on their concentration. Phenolic compounds and their derivatives demonstrated both pro- and anti-oxidant properties depending on the states of the phenolic side chains. ROS induced oxidative stress is the main factor to trigger cell apoptosis when the antioxidant enzyme system is impaired. Polydopamine and other polyphenols under oxidized state function as antioxidants to scavenge the free radicals as well as chelate the irons to decrease the ROS generation. The modulation of ROS production can be used for different biomedical applications including wound repair, cancer, antimicrobial and Parkinson’s diseases treatment. Mussel inspired biomaterials with catechol moiety has been widely studied for their application in wound healing, tendon repair, cell engineering and drug delivery. The oxidation of catechol into highly reactive quinone is an important pathway to harden the adhesive and forming strong interfacial bindings. Therefore, the ROS production during the curing process need to be carefully assessed. Our lab has studied the H2O2 production during autoand oxidant-mediated oxidation (34, 46). The concentration of H2O2 can be modulated from several micromolar to millimolar. Therefore, the application of persistently generation of ROS from mussel inspired adhesives can potentially lead to new mussel inspired biomaterials. Additionally, most existing studies are concentrated on using DOPA or its derivatives as bioadhesives and crosslinking precursors and there are limited studies on tailoring the unique redox properties of the catechol-functionalized polymers for promoting wound healing or PD treatment (34, 46, 106). Therefore, future materials that focus on tuning the redox chemistries of catechol and polyphenols will potentially lead to novel biomaterials with improved therapeutic outcomes.

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