Dopamine functionalized coatings for corrosion protection of metallic implants and advanced drug delivery: a review

1 Introduction

Metallic materials are extensively employed in the fabrication of several implants. It is established fact that the structures and characteristics of the surface, for instance, morphology, stiffness, wettability, etc. play a significant role in the performance of several materials. Modification of surface is very crucial for the applied use of biomedical implants comprising devices for extensive usage such as knee and hip implants, stents, etc. as well as temporary ones like catheters (Saberi et al. 2021; Vasilev et al. 2009; Zhao et al. 2019). Because of the high concentration of chloride ions in body fluid, implants can corrode. Moreover, temperature, pH, amino acids, cells/protein may also affect rate of corrosion (Khorashadizade et al. 2021). It is essential to reflect the surface treatments for enhancing resistance to corrosion, antibacterial activity, and cytocompatiblity for the metals that are employed to generate implants. The corrosion resistance and biocompatibility can be essentially enhanced, eliminating negative effects such as physical irritation, infection, inflammation, toxic effect, and/or carcinogenetic action by formulating coatings onto the surfaces of biomaterials. Furthermore, coatings can provide medical implants with various bio-functions such as sustained drug delivery, regulation of bio-signal, antibacterial properties as well as osseointegration (Asri et al. 2017; Civantos et al. 2017; Gao et al. 2017; Li et al. 2015b; Singha et al. 2017; Vasilev et al. 2009). Actually, for certain uses, quick osseointegration is essential, so the surface of the implant must be altered to absorb bioactive materials (Marinescu et al. 2019; Yu et al. 2016). Recently, certain types of surface treatments have been suggested such as producing nano structured surfaces, which possibly will permit drug release at a settled rate or possess antibacterial activity, and enhance the other performances (Beltrán-Partida et al. 2017; Monetta and Bellucci 2014; Pawlik et al. 2017; Santo et al. 2012; Wang et al. 2017a). Due to the deposition of coatings, implant devices must be highly suitable to meet clinical desires. Intending to improve the interactions between implant materials and cells, investigators have been working to alter the material of the implant by regulating extracellular matrix components, which exhibit huge potential for such applications (Williams et al. 2006).

Recently, mussel adhesive proteins have gained high consideration due to their robust adhesive interaction with many base materials in an aqueous medium (Liu et al. 2016b; Ye et al. 2011; Zhang et al. 2017). Among those proteins, 3,4-dihydroxy-l-phenylalanine (DHPA), and lysine-enriched proteins exhibit a significant role in the unusually strong adhesion (Waite and Qin 2001).Consequently, dopamine (DA), with a comparable molecular structure to DHPA, comes to be a unique coating material. Polydopamine (PDA) can form by the oxidation of DA which could be simply deposited on nearly all kinds of organic/inorganic substrates and its thickness as well as durability can be regulated (Jia et al. 2019). PDA has achieved potential interest in the area of corrosion protection of metals and hybrid coatings with PDA have also been accepted as an efficient approach for attaining protection against surface corrosion of alloys used as implants (Singer et al. 2015; Zhou et al. 2020a). It was also verified that the PDA layer regulates the release of corrosion inhibitor as well as performs as a protecting compound between the chelating agent and corrosion products (Qian et al. 2019). Additionally, PDA owns exceptional biocompatibility and is supposed to be a very flexible reaction platform because of exclusive chemical structure which has several functional groups consists of amine, catechol, and imine that may be utilize to covalently immobilize molecules and these can adsorb metal ions. Because of its exceptional characteristics, PDA has been widely applied for modulating materials toward cellular and tissue responses (Huang et al. 2016; Liu et al. 2014a; Perikamana et al. 2015). Because of its remarkable biocompatibility and little toxicity, PDA as well as its derivatives, like PDA void capsules and many nano core–shell, are of huge attention in drug delivery (Cui et al. 2015). Besides, the unique nature of PDA has been revealed in several additional applications, such as biomolecules immobilization (Lee et al. 2009), cell adhesion and patterning (Ku et al. 2010), catalyst support/adsorbent (Liu et al. 2013c), photothermal therapy (Shi et al. 2017), antibacterial (Zeng et al. 2018), adsorption (Gan et al. 2020) etc., the specific characteristics of PDA have also led to strong research concern about its utilization as the middle layer for the adhesion for other coatings (Chen et al. 2015; Wu et al. 2016). Noteworthy, PDA has a good ability to form chelates with metal ions. It was proved that permeable nano carriers may easily form a typical chelate structure via a coordinate bond between the surface of host and ions of transition metal, in addition to those between metal ions and drugs (Zheng et al. 2013).

The past few years have a rapid boost in research regarding new fabrication approaches, functionalization and applications of PDA derivative nanostructures in the corrosion protection of implants and advanced drug delivery. Though, comprehensive review on the PDA modified coatings in diverse biomedical applications is still lacking. Thus, the aim of this review is to cover this gap and summarized the significance of PDA as a coating material for clinical applications. This featured review was begin by describing the polymerization process of DA and then describe the PDA as an effective coating material for corrosion protection of implants with suggested mechanism. In the same section, the beneficial effects of PDA containing coatings on corrosion protection of implants were also discussed. Characteristics and applications of PDA-modified coatings/nanoparticles were mentioned. Next, it was focused on PDA-modified nanostructures and emphasized the biocompatibility of PDA. A detail discussion about the use of PDA in advanced drug delivery was then provided.

2 Synthesis and polymerization of dopamine

It is well-known to be prepared by three usual approaches comprising solution oxidation, electro polymerization and enzymatic oxidation method (Liu et al. 2014a). The solution oxidation process is the extensively used method for PDA formation. Self-polymerization procedure is modest and no severe reaction conditions or complex instrumentation are required. Initiation of the self-polymerization reaction involves the dissolution of DA hydrochloride in a basic solution in the O₂ environment. The development of the product goes along with color change from light yellow to dark brown (Bernsmann et al. 2011). Though this method does not give suitable results when use for coating because of a lack of homogeneity. The electro polymerization process can be a better technique for retaining a preferred film thickness (Ball et al. 2012). But this process has a disadvantage as it involves electrically conductive material to perform the electropolymerization. Typically, the enzymatic oxidation technique has been favored (Batul et al. 2017) and this process possibly will produce PDA similar to the natural melanin formed by the reaction of the Tyrosinase enzyme, thus, reflected as the best method for synthesis of PDA. The fabrication of PDA nanoparticles (NPs) employing an enzymatic process was described for avoiding harsh chemical conditions (Li et al. 2015a). Further, PDA NPs having various sizes and morphology were attained by providing the most favorable reaction conditions like concentrations of urease and urea, and the temperature (Batul et al. 2017). The molecular mechanism comprised in the polymerization of DA is supposed to comprise several products formed by oxidation similar to the synthetic path of melanin (Hong et al. 2012). In aerobic and alkaline environments, the formation of DA-quinone occurs by the oxidation of DA monomer accompanied through intermolecular cyclization by 1,4-Michael type addition to produce leucodopaminechrome. Afterward, the attained leucodopaminechrome again oxidizes and rearranges to form 5,6-dihydroxyindole. Later, this 5,6-dihydroxyindole converts to produce by two paths; covalent oxidative polymerization and non-covalent self-assembly, as put forward by Hong et al. (2012). The illustrative graphics of the process is revealed in Figure 1 (Hong et al. 2012).

Figure 1:

Polydopamine synthesis takes place via two pathways: (A) an oxidative polymerization pathway that forms covalent bonds, and (B) a newly suggested pathway of physical self-assembly of dopamine and DHI (Hong et al. 2012, reproduced with permission from Wiley).

3 Polydopamine as an effective coating material for corrosion protection of implants

In recent past, DA has been considered for coating due to its robust adhesions on the surfaces of materials. Thin PDA coating onto various materials can form by self-polymerization of dopamine (Ye et al. 2011). The co-occurrence of various kinds of functional groups is supposed to involve robust interfacial PDA adhesion. Since various coating methods exist, PDA coating is simple and can be done simply by immersing a sample in an aq. alkaline dopamine solution for a certain time. Impulsive deposition of conform PDA coating happens during growth, and this primary coating could be employed without additional change or applied as a ‘primer’ onto which a successive further coating can be employed. The composition and characteristics of the secondary coating is greatly flexible, thus generating the remarkable adaptability and wide range of applications provided by PDA coatings (Ryu et al. 2018). Although, bulk properties of the materials do not alter by PDA coating, the coating can greatly change the surface properties, like morphology, chemical composition, and wettability as well as mechanical properties (Lee et al. 2007). The roughness of the surface could also be altered due to PDA adhesion. Xi et al. (2009) stated that porous polymer membranes become smoother after coating with poly(3,4-dihydroxyphenylalanine). PDA coatings are used to offer resistance against corrosion for many metals (Singer et al. 2015). Some investigations on corrosion inhibition by the use of PDA coatings have revealed that these coatings can deliberate enough corrosion resistance to metal substrates (Ding et al. 2018; Singer et al. 2015). Cheng et al. (2021) synthesized hydroxyl apatite (HAp) nanosheets with PDA surface function (PDA/HAp) by simple hydrothermal method and subsequent self-polymerization of DA and applied with epoxy matrix for corrosion protection of Q235 steel. It was detected that the PDA coating remarkably promotes the dispersion of HAp nanosheets in the epoxy coating, and acts as a corrosion inhibitor. Hong et al. (2020) studied the effect of PDA/carbon nanotubes (CNT) nanocomposite coating on the corrosion inhibition behavior of carbon steel and found that corrosion resistance of steel coated with PDA and PDA/CNT was intensely greater than those of bare samples.

It was examined by Wang et al. (2019c) that the anticorrosion and micro tribological performances of Ti–6Al–4V were improved under dry and SBF lubrication by grafting silane, graphene oxide (GO) with DA coating on the alloy surface and the adhesive layer APTES-DA-GO shows improved properties than those of the without DA. A polyfunctional composite coating consists of PDA, dicalcium phosphate dihydrate (DCPD), and collagen (Col) was fabricated by a two-step chemical method to improve the corrosion resistance and biocompatibility of magnesium alloys. The outcomes exhibited that the PDA/DCPD/Col coating considerably enhanced the corrosion resistance and biomineralization capacity of magnesium alloys (Guo et al. 2020). Comparable results were also revealed by Chen et al. (2015). They demonstrated that the hybrid TiO₂/PDA coated magnesium revealed considerably lower corrosion current density and an unusually low degradation rate up to 21 days in PBS in comparison to samples only coated with TiO₂ and without coating. Pan et al. (2016) modified AZ31B alloy by the heating treatment with alkali followed by the self-assembly of 3-phosphonopropionic acid, APTES, and DA correspondingly so as to increase the resistance to corrosion and biocompatibility of the surface. The rate of corrosion reduced to several orders after the self-assembly medication of the surface. Zhang et al. (2021) prepared a hybrid coating of nitrogen-doped carbon dots (N–CDs) with PDA on Mg alloy using electro-deposition by dip coating procedure. Produced N–CDs were divided by three kinds of molecular sieves with average pore sizes of 3.0, 6.0, and 8.0 nm to get different particle sizes of N–CDs. They found that the corrosion resistance behavior of the N–CDs coatings was improved with the rise of particle size. A clear self-healing performance was also obtained on the surface coated with N–CDs with PDA. The effect of self-healing of the N–CDs (8.0 mm)/PDA hybrid coating was noteworthy as compared to bare Mg alloy. This effect creates due to PDA diffusion and extension from the nearby surface (Qian et al. 2019) and thus hybrid coating of N–CDs with PDA increase the corrosion resistance of magnesium alloy. Coating with PDA improves the corrosion resistance, as well as results in self-healing behavior. Carangelo et al. (2019) applied a PDA layer to raise adhesion between the substrate metal and exterior organic coating for AZ31 magnesium alloy. The outcomes confirmed a reduction of the metal degradation rate when PDA was applied as an interlayer assuming a synergistic effect when it was applied along with the organic coating. Singer et al. (2015) also used PDA to check Mg corrosion, and enhanced the application of Mg alloy for biomedical use. They established that the dipping of Mg specimens in a solution of DA at an angle of 0° for 2 h caused protection towards corrosion in 0.1 M NaOH solution. Moreover, a pH of 8 or 10 with an analogous of 1 or 2 mg/mL DA concentration was essential for ideal corrosion resistance. Besides, considering such ideal conditions, better resistance to corrosion was attained by using DME medium at 37 °C. Table 1 characterizes the summary of research on the corrosion resistance performance of PDA modified coatings onto different metallic implants.

Zhou et al. (2020a) used the hydrothermal method on Mg alloy for the development of HAp coatings and applied PDA as the intermediate layer and found that the thick hydroxyapatite coating with PDA unusually enhanced the corrosion resistance behavior of magnesium alloy. Additionally, the PDA containing HAp coating revealed exceptional stability in SBF, thus resolving the issue of easy peeling of the HAp coating. This also exhibited improved biocompatibility as compared to only HAp coating. In the initial 24 h, the values of pH of the uncoated samples and coated with pure HAp rose quickly, and the pH has become stable in the end at the value of about 9.06 and 8.21 (Figure 2) (Zhou et al. 2020a). However, negligible pH variations were detected for the samples with PDA-induced HAp coating, which further indicate the slight corrosion of samples having a coating with PDA. In the surface morphology analysis, it was observed that after 7 days immersion of samples, extensive cracks and corrosion pits were observed on the uncoated AZ31 alloy as shown in Figure 3a (Zhou et al. 2020a). The surfaces of coating with HAp and HAp/PDA were covered with bulky particles, and only small corrosion was detected (Figure 3b and c) (Zhou et al. 2020a). Benzotriazole (BTA) as a corrosion inhibitor was loaded in mesoporous SiO₂ particles by Qian et al. (2019) and a PDA layer was wrapped on the surface of silica particles. Later the fabricated inorganic nanocapsule was added to the waterborne alkyl coating. Release of BTA was regulated by PDA sensitive to pH. The released BTA and dissolved PDA produce complexes with iron oxide to heal defects and prohibited additional corrosion (Qian et al. 2019). All of the results found so far specify that the coating having PDA is a promising approach to reduce the corrosion of metallic biomaterials (Table 1).

Figure 2:

The pH values of SBF with AZ31 alloy, HAp and Hap-PDA coating (Zhou et al. 2020a, reproduced with permission from Elsevier).

Figure 3:

Surface morphology of AZ31 alloy (a); HAp (b); Hap-PDA (c) after 7 days of immersion in SBF (Zhou et al. 2020a, reproduced with permission from Elsevier).

4 Mechanism of corrosion protection

Numerous studies have explored that PDA coating combined with NPs have exceptional barrier properties against metal corrosion. Different mechanisms have been suggested for synergistic effect of PDA with NPs. Chen et al. (2015) have studied the corrosion protection mechanism for Mg using TiO₂ with PDA coating. It was demonstrated that for coated Mg the rate determining step is the ionic pathway which is attributed to the coating barrier and check electrolyte penetration into the substrate (Liu et al. 2014b). The protective efficacy of the sandwiched PDA/TiO₂ layer against corrosion is illustrated schematically in Figure 4 (Chen et al. 2015). It has shown that the rate determining step of corrosion process has changed to be electrical pathway due to the insulating PDA layer. Moreover, surface resistivity measurement found that samples with Mg/PDA/TiO₂ are relatively insulating while Mg/TiO₂ showed detectable resistance value. As a result, the cathodic reaction is suppressed effectively because of the delayed arrival of electrons from the anode and the overall corrosion rate slows down. The coating quality with respect to homogeneousness and denseness might also consider partly for the reduced corrosion/degradation rate of the metal.

Figure 4:

Schematic illustration of sandwiched polydopamine layer to enhance corrosion protection of TiO₂ coated Mg: (a) without sandwiched PDA layer; (b) with sandwiched PDA layer (Chen et al. 2015, reproduced with permission from Elsevier).

Chen et al. (2020) demonstrated that 8-HQ/GO coating was modified by PDA in order to prevent leakage of corrosion inhibitor for AZ31b magnesium alloy. A sandwich-like structure (GO/8-HQ/PDA) enables long-term stable storage of corrosion inhibitor in the protective matrix. The sandwich structure protects the activity and structural integrity of the corrosion inhibitor (8-HQ). The corrosion inhibitor of the GO/8-HQ/PDA sandwich structure cuts off the ion exchange between the metal alloy and the electrolyte solution, which hinders the electrochemical corrosion of the metal. It was also stated that the PDA increases the hydrophobicity of the composite and has a certain physical barrier function, successfully preventing direct contact of electrolyte solution. Moreover, PDA also makes a denser epoxy (EP) matrix with fewer defects and voids in the coating which inhibit the diffusion of corrosive medium. Therefore, the GO/8-HQ/PDA-EP coating with hydrophobicity has improved anticorrosion properties (Hu et al. 2021). ZnO/PDA coating was used for corrosion protection of Ti6Al4V alloy by Hu et al. (2021). It was demonstrated that PDA and ZnO/PDA coatings were able to effectively block the corrosive ions from coming into contacting with the Ti6Al4V substrate, thereby improving the corrosion resistance of Ti6Al4V alloy.

5 PDA-modified nanoparticle

PDA nanoparticles can prepare mainly under basic condition by the polymerization of DA. Several substrates, with coating of a PDA films, have attained great interest in various fields. Because of its good adhesion property and the existence of active functional groups on its surface, PDA is able to be formed in numerous nanostructures. Various techniques have been employed to prepare PDA NPs subject to the demand of size or particular use. PDA nanoparticles with sizes from 50 to 400 nm can be fabricated by regulating the factors like a solvent, reaction time, and pH (Yan et al. 2013). Synthesis of PDA in various shapes and dimensions is possible like thin films, core–shell structures, hollow capsules, and surface coatings (Cui et al. 2015). PDA NPs can be applied as the core as well as several polymers and active species can bring together as the shell, hence providing core–shell nanocomposites for a certain application. Furthermore, it can also act as a stabilizing and reducing agent for additional fictionalization. PDA contains a high level of hydroxyl and amine components, and is thus applied to construct core–shell Fe₃O₄ polydopamine (Fe₃O₄@PDA) nanohybrid which can be employed in many applications as shown in Figure 5 (Liu et al. 2013). Zeng and coworkers (2014) developed versatile theranostic agents, such as lipid-Au NP@PDA nanocomposite. To offer effective diagnosis and PTT for hepatocellular carcinoma, these nanohybrids were deliberated for targeted MRI and computed X-ray to mammography dual-mode imaging. PDA coating is typically employed to conquer certain disadvantages of other NPs. Such as, PDA can be applied as a protector to block mesoporous silica NPs (MSNs) pores which are loaded with cationic amphiphilic drugs like desipramine and doxorubicin. PDA also worked as a pH-responsive cover at the cavity of the pore, and thus permits an organized drug release whereas hindering the initial burst release profile (Chang et al. 2016; Zheng et al. 2014). Zheng and coworkers suggested MSNs functionalized with the amine group followed by polymerization of DA (Zheng et al. 2015). PDA thin layer was made in the limited area of mesopores because of interactions between quinone groups of PDA and altered amine groups of MSNs by Michael type addition and/or Schiff base reactions. Because of benefit of the binding ability of PDA with catechol, several coordination complexes having metal ions and anthracyclines (e.g., doxorubicin (DOX)) were also formulated, such as catechol–metal–drug structures like MSN@PDA-Zn and MSN@PDA-Fe particles, which again inspected for pH responsive drug release. Their illustrative diagram for drug loading and release is revealed in Figure 6 (Zheng et al. 2015).

Figure 5:

Fe₃O₄@PDA as a flexible NPs platform for (A) responsive drug delivery; (B) catalytic support; and (C) carbon adsorbents (Liu et al. 2013, reproduced with permission from ACS).

Figure 6:

Schematic design of the process for fabricating polydopamine-coated MSNs for drug loading and release (Zheng et al. 2015, reproduced with permission from ACS).

6 Characteristics and applications of PDA-modified coatings/NPs

PDA modified coatings/NPs have numerous applications as schematic illustration is given in Figure 7. In this section we are discussing some of them as follows:

Figure 7:

Schematic illustration of applications of PDA modified coatings/NPs.

7 Biocompatibility and biodegradability of PDA

For any biomaterial that likely to be implanted directly into the human body, it is essential to figure out the possibilities for explicit level of toxicity and also adverse effects (Bakhtiari et al. 2021). PDA occurs naturally and has an extensive distribution in humans and other living organisms. PDA is a favorable material for biomedical use because of its satisfactory biocompatibility. In-vitro and in-vivo stability and biocompatibility of gold NPs coated with PDA shell (GNP@PDA) were studied by Liu et al. (2013b). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay recognized that GNP@PDA (with up to 20 mg L⁻¹ concentration of gold) did not show any apparent cytotoxicity on HepG2 cells. Nurunnabi et al. (2013) employed graphene quantum dots as the core and revealed the in-vivo cytotoxicity of PDA-coated dots. Obtained findings exhibited that the PDA coating can diminish blood toxicity and inflammation which was shown by uncoated dots. Biosafety and in-vivo cytotoxicity of hollow PDA nanocapsules were investigated by Tan et al. (2016) and show that ionic liquid/PDA nanocomposites have excellent biocompatibility. Zhou et al. (2020a) examined the cell viability of the cells of bare and HAp/PDA coated AZ31 alloy and found that the samples having HAp/PDA have excellent cytocompatibility as shown in Figure 8 (Zhou et al. 2020a). It was detected that after cell culture of 1 day, no specimens exhibited cytotoxicity, and the cell durability rate was about more than 70 %. After three and 5 days of incubation, it was obtained that both the coatings extracts, with and without PDA, enhanced the proliferation of osteoblast cells because of the action of HAp. After 5 days, the PDA/HAp coated cell durability rate touched 120 %, which might be owing to superior protection of the substrate that inhibits the additional ions from entering the culture medium. Thus, it was established that such composite coatings are much better for the development and proliferation of osteoblast cells.

Figure 8:

Viability of MC3T3-E1 cells cultured with AZ31extract, pure HAp and PDA-Hap (Zhou et al. 2020a, reproduced with permission from Elsevier).

PDA coating can also provide the osteogenic property for orthopedic implants by subsequent modification using HA or bioactive molecules having osteogenic functions (Jia et al. 2019). Gan et al. (2022) have fabricated a mussel-inspired Col/PDA/HA hydrogel scaffold mimicking the native ECM of cartilage. The PDA/HA complex incorporated-hydrogel scaffold with catechol moieties exhibited better cell affinity than bare negatively-charged HA incorporated scaffold. Additionally, the PDA/HA complex provide the scaffold with immunomodulation ability, which protect the expression of inflammatory cytokines and effectively activated the polarization of macrophages toward M2 phenotypes. The in-vivo results revealed that the mussel-inspired Col/PDA/HA hydrogel scaffold has strong cartilage inducing ability to promote cartilage regeneration. In addition, the Col/PDA/HA hydrogel scaffolds exhibited excellent cytocompatibility and cell affinity favoring cell adhesion, spreading, and proliferation. To demonstrate this, BMSCs were seeded on this scaffold and cultured in a basic stem cell maintenance medium. Figure 9 shows the in-vitro cytocompatibility evaluation of the hydrogel scaffolds (Gan et al. 2022). As revealed in Figure 9a and b, only few cells were attached on the Col/HA scaffold. On the contrary, many cells were observed on the surface of hydrogel scaffold having Col/PDA and Col/PDA/HA (Figure 9c and d). Maximum cells on the Col/PDA and Col/PDA/HA hydrogel scaffolds displayed characteristic spindle-like morphology as shown in magnified images of Figure 9c and d, confirmed that the PDA constituent present in the scaffolds facilitate cell adhesion and spreading. The cellular morphology on different hydrogel scaffolds was again verified by F-actin cytoskeleton staining. BMSCs cultured on the Col/PDA/HA and Col hydrogel scaffolds exhibit more elongated cell morphology with extensive actin filaments that linked adjacent cells (Figure 9e). On the other hand, the cells on the Col/HA hydrogel scaffold were dispersive, and some of cells exhibit spherical morphology with less spreading areas (Figure 9f). Then, the cell proliferation was further investigated via MTT assay for 1, 3, and 5 days. Figure 9g revealed that the proliferation of the BMSCs is higher for scaffolds having PDA, indicating that PDA has good biocompatibility. These results confirmed that the PDA functionalization could increase the cell affinity of HA, and as a result the Col/PDA/HA hydrogel scaffold had better cell affinity to promote the proliferation of BMSCs. Chuah et al. (2015) used BMSC culture and applied a series of PDA concentrations increasing from 0 to 1.0 % (w/v) was coated on the native Polydimethylsiloxane (PDMS) substrates for 24 h and assessed for the initial cell adhesion as well as the prolonged cell proliferation. When the native PDMS surface was coated with PDA at various concentrations, they observed at least a 40-fold increase in cell adhesion as compared to the uncoated PDMS surfaces which was strong evidence suggesting that the presence of PDA facilitated initial cell adhesion. Table 2 revealed summary of research on the biocompatibilty analysis of PDA modified coatings onto different metallic implants.

Figure 9:

In-vitro cytocompatibility evaluation of the hydrogel scaffolds (a–d) CLSM images of live/dead stained BMSCs on the four kinds of hydrogel scaffolds (Col, Col/HA Col/PDA, and Col/PDA/HA) after 3 days of culturing in primary medium. Live and dead cells were stained green and red, respectively. (e) Phalloidin (red) and DAPI (blue) staining of BMSCs on Col, Col/HA and Col/PDA/HA hydrogel scaffolds on day 3. (f) Quantitative analysis of spreading area of BMSCs on various hydrogel scaffolds. (g) MTT assay of the proliferation of BMSCs on hydrogel scaffolds after 1, 3, and 5 days of culturing in primary medium (Gan et al. 2022, reproduced with permission from Elsevier).

8 Summary of advantages and limitations of PDA modified coatings

PDA surface coating has attracted intensive attentions in surface engineering. The functional groups in PDA can perform as active sites for covalent modification with preferred molecules (Hu et al. 2014; Wang et al. 2013). PDA modified surfaces and NPs can be used in various applications as discussed. However, traditional immersion dopamine polymerization strategy has some drawbacks in morphology control, low chemical stability, low dopamine conversion and wastewater discharge. In addition, during the PDA polymerization process, the possibility of having unreacted dopamine (Hong et al. 2012) and excess tris buffer (Vecchia et al. 2013) could be unavoidably added to the coating. As a result, the physicochemical properties of final PDA coating can be altered. In the case of having unreacted dopamine in the final structure, the resulting PDA coating starts to show cytotoxic effects (Hong et al. 2012). However, in other conditions, incorporation of –CH₂–OH groups from Tris buffer could provide to PDA significant antibacterial properties (Patel et al. 2018). To avoid Tris buffer incorporation (Bernsmann et al. 2011; Vecchia et al. 2014) another buffer can be used, such as amine-free organic ones or inorganic solvents, but on the other hand, this can enhance the creation of PDA aggregates (Ryu et al. 2018). Another limitation is the roughness and the thickness because thickness is dependent on dopamine concentration. To reduce the roughness, it has suggested decreasing the immersion time of the substrate (Han et al. 2012).

9 Advanced drug delivery

As reflected before, PDA has been extensively used for the alteration of surface and functionalization of several materials. In this segment, we chiefly focus on applications of PDA coating in drug delivery systems. Effective surface alteration of drug-interactive ligands is a vital area of material treatment to create the performance of nanocarriers and regulate their drug interaction. DA has gained high attention in drug delivery mainly after finding the reduced toxicity of PDA modified biomaterials (Hong et al. 2011). PDA has been suggested as a worthy material for drug delivery due to the π–π stacking interactions between the rich aromatic rings of PDA and the backbones of drugs which is also aromatic. A combined nanocarrier system involving the s porous structure and PDA to load and release of hydrophilic drugs is described by Zheng et al. (2015). The MSN@PDA nanocarriers can significantly adsorb hydrophilic drugs with good loading abilities assisted by the π–π stacking interactions. PDA thin coating on the pore surfaces substantially increases both drug loading regarding the high capacity of drug loading and release ability in respect of constant release, in the aqueous phase for aromatic molecules through non-covalent π–π stacking interactions.

In addition to the capacity of molecular binding, another significant characteristic of PDA depends on its chemical structure that combines catechol with transition metal ions with a high binding potential to construct variable coordination complexes (Liu et al. 2014a). The high coordination ability of C=O and C–O bonds in anthracycline drugs (such as DOX) with metal ions is well recognized at pH 7.4 under physiological conditions (Zheng et al. 2013). A catechol-metal-drug design was formed by Zheng et al. (2015) by taking benefit of the coordination bonding between catechol and metal ions, and between metal ions and DOX. PDA capsules have also been broadly investigated in pH arbitrate drug delivery (Yu et al. 2009). The occurrence of acid-labile hydrazone bond results in a substantial release in acidic condition as revealed in Figure 10 (Cui et al. 2012). This pH-activated mechanism of release might improve the healing efficiency and diminish the essential ramification in drug delivery. Yu et al. (2009) estimated the loading and release performance of Rh6G as a pH function in various solvents, like aq. buffer and ethyl alcohol (Yu et al. 2009). Rh6G uptake was substantial in aq. solution at high pH, though it was almost impermeable in ethanol. Though, a noteworthy Rh6G release was detected in ethyl alcohol. Adversely, no release was detected in aq. solution with expose to various pH and enhanced temperatures. In an aqueous solution, the loading was done by high osmotic pressure outside. At low pH, the protonation of amino groups occurs and hence the PDA shell becomes positively charged resulting in the repulsion of Rh6G, while at high pH, the catechol groups of PDA became negatively charged and firmly attracted the cationic Rhodamine dye. The Rh6G diffusion occurs in ethanol due to the huge osmotic pressure inside the capsule. This characteristic of PDA capsules might be useful, particularly in drug delivery. A negative charge appears at PDA at high pH because phenolic groups become deprotonated, whereas, at small pH, –NH₂ groups contribute to the positive charge due to protonation. Assuming that catechol-metal-drug bonds are quite firm under neutral conditions but not in acidic, one may suppose a pH-regulate release of DOX loaded on MSN@PDA-Mⁿ⁺ particles. It was shown that dropping the pH to 4.4 enhanced the release of DOX (Zheng et al. 2015). PDA has broadly been examined for chemotherapy and PTT in the forms of NPs as well as nano-capsules. Ho and Ding prepared PDA NPs with variable particle sizes and estimated the pH-controlled loading and release of Camptothecin (anticancer drug) (Ho and Ding 2013). Likewise, PDA NPs were verified as a spacious nano-reservoir for loading of antibiotic Rifampicin drug too (Tamanna and Yu 2016). These particles loaded with the drug were recognized to be very stable in acidic condition for about 3 days. NPs of Fe₃O₄@PDA core–shell were also examined for the pH-meditated drug delivery of Bortezomib (BTZ) (Liu et al. 2013c). The controlled release behavior of this drug based on the reversible covalent bond between boronic acid of BTZ and catechol groups of PDA. The release was detected at acidic pH only because of the breaking of covalent bonds. In the same way, in cancer therapy, the release of DOX by PDA-coated magnetic NPs had also been evaluated (Mrowczynski et al. 2016). Further, for the binding and intracellular delivery of an anticancer drug, a comparable method was adapted by Cui et al. (2012). Concisely, a conjugate of polymer-drug was designed by thiolated polymethacrylic acid and maleimide derivative of DOX. Binding of this conjugate was done by development with PDA capsules by Michael-type addition in basic pH and the drug release rate was observed at various pH environments.

Figure 10:

Immobilization and pH-responsive release of Dox from PDA capsules (red spots indicate the drug) (Cui et al. 2012, reproduced with permission from ACS).

Fe₃O₄@PDA NPs were also applied for the release of DOX. These NPs were prepared by Wu et al. (2018b) with a size of approximately 50–60 nm (Figure 11a–c) (Wu et al. 2018b) and were then loaded into natural killer (NK) cells. They accompanied in-vivo tests with Fe₃O₄@PDA labeled NK cells, which indicate that the application of external magnetic fields could improve the accretion of NPs in the area of the tumor and remarkably prevent the progress of a tumor. Not only single Fe₃O₄ NPs, but PDA was also employed to modify Fe₃O₄ NPs clusters (Figures 11D and E) (Liu et al. 2017). A core–shell nanohybrid with super-paramagnetic Fe₃O₄ NPs clusters as the core and PDA as the shell (SPION cluster/PDA) was prepared by Wu et al. (2015). The diameter of the nanocomposite was about 50 nm and the PDA layer was about 4 nm. It was then applied to kill cancer cells due to its photothermal effect, and it exhibited improved photothermal property in comparison to magnetic clusters without coating. It may be ascribed to the collective photothermal conversion ability of crystallized Fe₃O₄ and the layer of PDA. Tan et al. (2016) prepared the hollow PDA NPs loading with ionic liquids (ILs/PDA) and revealed as therapeutic agents for antitumor application in vivo by tumor microwave thermal therapy (MWTT). Both in-vivo and in-vitro experiments verified that ILs/PDA nanocomposites had positive sensitization effect to MWTT. ILs/PDA nanocomposites have a superb microwave heating efficiency under an ultra low microwave power irradiation. Because of the specific drug loading pattern of PDA, the bonding between drugs and PDA tends to weaken in the acidic and high glutathione (GSH) micro environment of tumor, causing drug releasing in a pH and GSH responsive approach, hence achieving profile of tissue-targeted controlled drug release (Mandriota et al. 2019).

Figure 11:

(A) Schematic illustration of a 3D molecular model. Characteristic TEM images displaying (B) size distribution of Fe₃O₄@PDA NPs and (C) Fe₃O₄@PDA NPs with a PDA thickness of 10.4 nm (Wu et al. 2018, reproduced with permission from RSC). TEM images of (D) pristine Fe₃O₄ nanoclusters and (E) Fe₃O₄@PDA nanoclusters (Liu et al. 2017, reproduced with permission from RSC).

Spiky gold NPs (SGNPs) coated with PDA were suggested by Nam et al. (2018). PDA coating have verified to conquer the limitation of instability of SGNPs on the basis of serving as a surface passivation layer. Ample of NPs have been applied as adjuvant and antigen carriers to enhance the immunogenicity of subunit vaccines. Though, it is still a challenge to make vaccine delivery and adjuvant nanosystem with both adequate biocompatibility and substantial activation effect of immune responses. As a nature-inspired biomaterial with superb molecular loading ability, PDA modification provides the NPs with high biocompatibility as well as improved antigen and adjuvant anchoring efficiency (Le et al. 2019; Wang et al. 2019b). Liu et al. (2016a) suggested the synthesis of pathogen-mimicking PLGA@PDA-HBsAg-CpG NPs for vaccine hepatitis B surface antigen delivering. PDA based surface functionalization provide the PLGA core with morphology to mimic pathogen structure and the loading of CpG.

The loading ability of NPs working as drug carrier is a significant factor and it is improved by PDA modification. Due to the presence of catechol and quinone moieties in rich quantity, that offers the potential to either attach functional molecules onto the NPs by physical or chemical bonding, PDA modification can enhance drug loading ability (Lee et al. 2007; Wang et al. 2018). It was proposed that self-assembly zeolitic imidazolate frameworks (ZIFs) coated with PDA-PCM where DOX was encapsulated in pores of ZIF, used for thermo-chemotherapy against cancer. PDA coating not only enhanced biocompatibility but also the degradability can be precisely regulated. PDA also employed photothermal transfer activity for realizing near IR controlled drug release (Wu et al. 2018a). The bonding between PDA and drugs is likely to weaken in the acidic and high glutathione (GSH) condition. Consequently, PDA is able to attach drugs at neutral pH but releasing them at lower pH (typically in tumor cite/ inflamatory area), so as drug releasing in a pH and also GSH responsive manner (Mandriota et al. 2019; Sherif et al. 2019).

10 Conclusions and outlook

PDA has unusually strong adhesion ability and can form films on most of the solid surfaces. Hence, PDA exhibits high potential as an intermediate for coating material to corrosion protection of implants. Owing to its excellent biocompatibility, unique drug loading capacity, and strong photothermal conversion capacity, several PDA-modified NPs have also been preferred as drug carriers. The use of chemical analogs of dopamine results further expands the properties and applications of PDA coatings. Hybrid PDA coatings have given excellent results in the area of biomedical applications. Dopamine/PDA comprises plentiful functional moieties like amine, phenolic, hydroxyl groups, and π–π stacking structures. Consequently, PDA can be combined and co-deposit with an extensive range of compounds via, coordination, hydrogen bond, electrostatic, and hydrophobic interactions. The biocompatibility, osseointegration, cell adhesion, and proliferation of implants can be enhanced through PDA-modified coating. PDA modified NPs have excellent drug loading ability and releasing of drug could be easy. However, for further clinical application, the study of biodistribution of PDA modified NPs in vivo and long-term toxicity is needed. In depth understanding of the interactions between cell like osteoblasts, stem cells, and immune cells, and PDA-modified orthopedic implants is also essential. In addition, the interaction between PDA and ECM, which in turn will affect cell behaviors and functions, should also be investigated.