Materials from Mussel-Inspired Chemistry for Cell and Tissue

Review pubs.acs.org/Biomac

Materials from Mussel-Inspired Chemistry for Cell and Tissue Engineering Applications Sajeesh Kumar Madhurakkat Perikamana,†,‡,⊥ Jinkyu Lee,†,‡,⊥ Yu Bin Lee,†,‡ Young Min Shin,†,‡ Esther J. Lee,§ Antonios G. Mikos,*,§,∥ and Heungsoo Shin*,†,‡

Downloaded by UNIV OF NEBRASKA-LINCOLN on August 27, 2015 | http://pubs.acs.org Publication Date (Web): August 25, 2015 | doi: 10.1021/acs.biomac.5b00852

†

Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul 133-791, Republic of Korea ‡ BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul 133-791, Republic of Korea § Department of Bioengineering, Rice University, Houston, Texas 77030, United States ∥ Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas 77030, United States ABSTRACT: Current advances in biomaterial fabrication techniques have broadened their application in different realms of biomedical engineering, spanning from drug delivery to tissue engineering. The success of biomaterials depends highly on the ability to modulate cell and tissue responses, including cell adhesion, as well as induction of repair and immune processes. Thus, most recent approaches in the field have concentrated on functionalizing biomaterials with different biomolecules intended to evoke cell- and tissuespecific reactions. Marine mussels produce mussel adhesive proteins (MAPs), which help them strongly attach to different surfaces, even under wet conditions in the ocean. Inspired by mussel adhesiveness, scientists discovered that dopamine undergoes self-polymerization at alkaline conditions. This reaction provides a universal coating for metals, polymers, and ceramics, regardless of their chemical and physical properties. Furthermore, this polymerized layer is enriched with catechol groups that enable immobilization of primary amine or thiol-based biomolecules via a simple dipping process. Herein, this review explores the versatile surface modification techniques that have recently been exploited in tissue engineering and summarizes polydopamine polymerization mechanisms, coating process parameters, and effects on substrate properties. A brief discussion of polydopamine-based reactions in the context of engineering various tissue types, including bone, blood vessels, cartilage, nerves, and muscle, is also provided.

1. INTRODUCTION

research has been devoted to designing biomaterials that can provide instructive cues for cells and tissues. Cell adhesion is the preliminary step in tissue engineering, playing a major role in different cellular functions such as spreading, proliferation, migration, and differentiation. Various physiochemical interactions between cells and substrates mediate this process. Generally, cells favor adherence to surfaces that are hydrophilic or contain functional groups such as −NH2 or −COOH.11−13 To promote cell attachment or other specific tissue responses, biomolecules such as proteins, peptides, or growth factors are often introduced onto the surfaces of synthetic biomaterials.14−16 Common chemical conjugation methods include oxygen plasma treatment, chemical etching, or γ-ray irradiation.17,18 Unfortunately, these approaches tend to be timeconsuming and often necessitate complex chemical reactions, leading to surface degradation that may compromise the

Tissue engineering represents a collective approach to repair, restore or regenerate damaged tissue by bridging the gap between biology and engineering. Biomaterial scaffolds remain a crucial component, used alone as a structural support for tissue growth or employed as a delivery platform for cells or biomolecules.1−3 Various scaffold architectures have been developed, including hydrogels, porous conduits, sponges, and nanofibers, to accommodate diverse applications.4−6 They are derived from either natural or synthetic materials.7 Natural materials generally possess high biocompatibility and recognition domains for cell binding or cell-mediated degradation; however, immunogenicity, batch-to-batch inconsistency, high costs, or reduced mechanical properties often present challenges.8 On the other hand, synthetic polymers can be tailored with appropriate mechanical properties and controlled biodegradability.9 However, hydrophobicity and a dearth of cell interactive moieties can lead to undesirable cellular responses or poor integration with host tissues.10 Therefore, a major part of tissue engineering © XXXX American Chemical Society

Received: June 26, 2015 Revised: August 13, 2015

A

DOI: 10.1021/acs.biomac.5b00852 Biomacromolecules XXXX, XXX, XXX−XXX

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Biomacromolecules

Figure 1. Polydopamine application in cell and tissue engineering. (A) Various substrates can be coated with polydopamine through self-polymerization of dopamine in a weak basic buffer. Biomolecules can then be covalently immobilized onto these surfaces. (B) Applications of polydopamine-modified substrates in tissue engineering. The schematic illustrates the basic cell adhesion mechanism on polydopamine-modified surfaces and how these substrates can be employed in different tissue engineering applications. (C) The number of yearly publications on polydopamine-based cell and tissue engineering was identified through a Web of Science search using the keywords “polydopamine” and “cell/tissue engineering” on March 20, 2015.

scaffold’s mechanical properties.19−21 A portion of ongoing research is thus dedicated to formulating simple and efficient biomaterial surface modification techniques. Mussels strongly adhere to surfaces even in wet marine conditions, stemming largely from the reactive catecholcontaining compound 3,4-dihydroxyphenyl-L-alanine (DOPA) and lysine.22 Inspired by this property, Messersmith and colleagues developed an innovative surface modification method using dopamine with catecholamine functional groups.23 Dopamine undergoes oxidative self-polymerization under defined conditions, creating a polymerized layer on almost any type of material, regardless of its surface chemistry.23 Moreover,

polydopamine permits secondary reactions with biomolecules containing thiol or amine groups.23−25 Due to these outstanding properties, polydopamine has been actively employed for the last several years to modify the surfaces of many biomaterial scaffolds aimed at modulating specific cellular responses. Figure 1 illustrates polydopamine-mediated biomaterial surface modification and its related tissue engineering applications. This Review highlights polydopamine coating mechanisms, coating parameters, and surface properties of resultant substrates. The underlying mechanism of cell adhesion and cellular interactions on polydopamine-coated materials with diverse architecture including film and porous scaffolds will also be B


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proposed the formation of coordination or chelating bonding interactions between polydopamine and metals or metal oxides.43,45 This bonding can be activated through different functional groups present in polydopamine such as carboxyl, amino, imine, phenol, or quinone.36,45 Polydopamine can also participate in a reduction reaction with noble metal ions under basic conditions.23,46 For example, Lee et al. showed that polydopamine deposition onto silver film had sufficient reductive capacity in solution and would not require other reducing agents.23 Formation of polydopamine layers on polymeric materials is expected through hydrogen bonding, π−π stacking, van der Waals interactions, and covalent reactions with different functional groups present on the molecules.47−49 Nevertheless, a simple immersion process under alkaline conditions results in the deposition of a thin polydopamine layer, which retains basic polymer properties other than surface chemistry. 2.2. Parameters Controlling Coating Processes. The polydopamine coating process normally takes place at room temperature in pH 8.5 Tris-HCl buffer. A number of studies have been conducted to identify critical parameters that can influence dopamine polymerization: coating time, initial dopamine concentration in solution, temperature, and pH of Tris-HCl. Polydopamine layer thickness has been demonstrated to reach 50 nm in approximately 24 h, and several reports suggest that it can be controlled by the total reaction time irrespective of substrate.23,50,51 On silicon substrates, the optical thickness of polydopamine coating increased linearly from 0 to 20 nm during a time interval of 0 to 8 h with the addition of freshly prepared dopamine every 15 min.51 Similarly, when poly(L-lactic-acid) (PLLA)−hemp composites were treated with dopamine for 24 and 48 h, the water contact angle decreased from 26.0 ± 1.7 to 16.9 ± 1.6.50 Quantitative analysis on the time dependency of polydopamine coating amount on poly(L-lactide-co-ε-caprolactone) (PLCL) films was performed using a micro-bicinchoninic acid assay, revealing that the amount of polydopamine increased from 0.6 g/cm2 to 177.9 g/cm2 with coating times ranging from 0 to 960 min, respectively.52 The initial concentration of dopamine in solution also influenced the kinetics of polydopamine film formation.53,54 Ball et al. discovered that changing the dopamine concentration from 0.1 to 5 g/L corresponded to a constant increase in maximal film thickness.54 Moreover, polydopamine film formation depends highly on the solution’s initial pH. Dopamine oxidationthe first step of dopamine polymerizationreadily occurs at alkaline pH.55 Shin et al. observed that the amount of coated polydopamine on PLCL meshes increased from 6.6 to 23.5 μg/mg−1 as buffer pH was tuned from 7.5 to 9.53 Similarly, polydopamine deposited on titanium substrates remarkably increased film thickness at pH 8.5 (22.05 ± 1.048 nm) versus that at pH 4.5 (0.798 ± 0.073 nm).56 While alkaline-corrosive and pH-sensitive materials may pose limitations, dopamine polymerization benefits from the flexibility of initiation by other oxidants through pH-independent mechanisms.37,44 Overall, temperature has shown relatively minimal effects on deposition kinetics compared to other parameters at the universally accepted conditions of 2 mg/mL, pH 8.5.53 One report nevertheless suggested that higher temperature coupled with vigorous stirring could increase deposition kinetics, and the resultant polydopamine layer showed a similar range of reactivity to its counterparts, which had been modified at standard conditions.57 Table 1 succinctly describes different parameters affecting polydopamine coating on substrates.


discussed. Finally, relevant examples of various polydopaminemediated tissue engineering approaches from the scientific literature are presented for different tissue types.

2. PRINCIPLES FOR MUSSEL-INSPIRED COATING 2.1. Coating Mechanism. Marine mussels bind tightly to surfaces by secreting various types of mussel adhesive proteins (MAPs) such as Mytilus edulis foot proteins (Mefp’s).26,27 Among these proteins, Mefp-1 resides in the cuticle of byssal threads and forms a hard outer sheath, which protects the collagenous inner core. Mefp-2 comprises a major component of byssal threads’ terminal adhesive plaque, while Mefp-4 located in byssal plaques links the plaques and collagenous threads. Mefp-3, Mefp-5, and Mefp-6 preferentially distribute at the adhesive interface with the substrate surface.26 Studies suggest that these proteins are highly rich in lysine and 3,4-dihydroxyphenyl-Lalanine (DOPA) and that these components may confer the observed adhesive properties.28 Recently, dopamine has piqued substantial interest in chemistry and biomedical research owing to a similar chemical structure to that of combined lysine and DOPA, as well as its adhesive potential. Dopamine constitutes one of the most abundant catecholamines in the human body that has long been investigated as a hormone or neurotransmitter, and abnormal levels have been shown to contribute to serious brain-related disorders.29 Lee et al. demonstrated that dopamine could undergo self-polymerization under basic conditions, resulting in adhesiveness to an array of materials independent of surface properties.23,30 Polydopamine has been used to coat noble metals (Au, Ag, Pt, Pd), metals with native oxide surfaces (Cu, stainless steel, NiTi), oxides (TiO2, noncrystalline and crystalline SiO2, Al2O3, Nb2O5), semiconductors, ceramics (glass, hydroxyapatite), and synthetic polymers (polystyrene (PS), polyethylene (PE), polycarbonate (PC), polyethylene terephthalate (PET), polydimethylsiloxane (PDMS), polyetheretherketone (PEEK), polyurethanes).31−35 Self-polymerization of dopamine monomers occurs at slightly alkaline pH (8.5) and spontaneously generates a black coating on the material of interest.23 It has been posited that dopamine undergoes a series of oxidation and cyclization reactions under aerobic conditions, resulting in the formation of intermediate products 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2carboxylic acid (DHICA).36 These two molecules undergo further oxidative polymerization, and covalent joining of the resultant monomers yields black-colored polydopamine in an initially colorless solution.37,38 Dreyer et al. have suggested an alternate mechanism, in which polydopamine is a supramolecular aggregate of monomers mainly consisting of 5,6-dihydroxyindoline and its dione derivatives, combined together by noncovalent interactions such as π−π stacking, charge−charge transfer, or hydrogen bonding.39 This proposal has been substantiated by other reports.40 Hong et al. noted that polydopamine layer formation occurs via physical self-assembly of unpolymerized dopamine remnants and DHI, as well as through covalent reactions between DHI monomers.41 Mechanistic details have not been entirely elucidated due to the complex involvement of numerous intermediate reactions.42,43 Nonetheless, oxidation of dopamine is essential for polydopamine layer formation, and while oxygen is most frequently used to initiate the reaction, recent reports suggest that ammonium persulfate, sodium periodate, potassium chlorate, or copper ions may also serve as oxidants.44,37 The majority of studies investigating the strong binding affinity of catechol-based molecules to metals and metal oxides have C


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hinge on coating substrate, it is nevertheless worth mentioning. Several studies on polydopamine-modified substrates using Xray photoelectron spectroscopy (XPS) or Raman spectroscopy revealed the presence of nitrogen peaks corresponding to primary amine groups present in the polydopamine structure (Figure 3A).23,53,66 When the amount of deposited polydopamine on PLCL substrates was increased from 22.4 ± 5.2 μg/cm2 to 177.9 ± 18.4 μg/cm2, the N/C ratio also increased from 0.046 to 0.125, which is close to the theoretical value of polydopamine and implies homogeneous surface modification at this particular amount. Also, peaks corresponding to CO and C−O in the PLCL backbone were dominant without or with lower amounts of polydopamine; these peaks gradually diminished with increasing deposition of polydopamine.52 Amine groups are anticipated to be favorable for biomedical applications since they confer hydrophilicity and positive charge to substrates, and furthermore, highly reactive amine groups can undergo secondary conjugation with various functional groups. Atomic force microscopic (AFM) analysis has revealed an increase in surface roughness as a function of coating time, which is attributed primarily to deposition of aggregates of polydopamine or unpolymerized dopamine through π−π bonding and van der Waals forces.52,67,36,68 As shown in Figure 3B, a transition from smooth to relatively rougher surface morphology was observed on PLCL films following polydopamine coating. AFM images showed the presence of submicron-sized polydopamine particulates distributed throughout the surface. Recently, Ponzio et al. demonstrated that adding ionic surfactants such as sodium dodecyl sulfate and hexadecyltrimethylammonium bromide during polymerization could control particle size in the solution.69 Additionally, human serum albumin modulated aggregate size during polydopamine coating.70 It has also been reported that polymerization of other small catecholamine derivatives (ex. norepinephrine) produces smoother surfaces with comparable intrinsic adhesive properties to those of polydopamine.71 Aside from surface roughness, mechanical properties can also be influenced by polydopamine. Nanoindentation studies and in silico approaches have indicated that polydopamine films possess an elastic modulus of 4.3−10.5 GPa at the highest degree of polymerization, and that these properties vary with polymerization rate.72 An increase in the Young’s modulus values of PLCL films was observed 960 min postcoating.52 When PLLA/ hemp nanofibers were modified with polydopamine, their tensile strength was greater than that of untreated samples.50 Changes in mechanical properties notably manifest after incubation times exceeding 10 h. 2.4. Reactivity of Polydopamine-Coated Surfaces. The most noteworthy feature in mussel-inspired chemistry is that polydopamine layers contain extremely reactive functional groups amenable to subsequent attachment with other

Table 1. Effects of Coating Parameters on Polydopamine Coating Efficiency parameters coating time dopamine concentration in solution temperature pH


oxidation

effects on coating efficiency

reference

• longer coating time increases coating efficiency • higher initial solution concentration increases coating efficiency

23,50−52

• higher temperature increases coating efficiency • pH ≤ 4.5 − limited coating • pH 7 − moderate level of coating • pH 8.5 − highest coating efficiency • pH ≥ 11−unstable coating • higher oxidation rate increases coating efficiency

54,57

53,54

54−56

37,44

2.3. Properties of Polydopamine-Coated Surfaces. The majority of biomaterial surface modifications presently in use alter a host of substrate characteristics, including wettability, chemical composition, surface morphology, and mechanical properties.58,59 Thus, it is important to emphasize prominent substrate changes that occur during polydopamine coating. As depicted in Figure 2A, a color change to dark brown or black serves as the primary indicator of catechol oxidation and subsequent dopamine polymerization. This gradual transition manifested after 1 h of polydopamine coating on PLCL films and further darkened over the course of 16 h. Increased hydrophilicity independent of the underlying substrate’s surface chemistry represents another major change in surface properties following polydopamine coating.23,60,61 For example, when polydopamine was deposited on polytetrafluoroethylene (PTFE) or PDMS substrates, the water contact angle decreased from 108.5° to 58.7° and from 104.4° to 65.5°, respectively.62 Likewise, polydopamine-coated titanium lowered the water contact angle from 68.6° to 44.3°.63 In another study, the water contact angle of polydopamine-modified PLGA nanofibers was notably decreased as compared to unmodified PLGA nanofibers (Figure 2B). Ku et al. observed that the water contact angle of polydopamine-modified PCL nanofibers plummeted to 0°, and that these values were comparable to gelatin-modified PCL nanofibers, yielding a super hydrophilic nanofiber surface.64 Of note, hydrophilicity can be tuned by controlling the amount of polydopamine deposited on the surface. Hydrophilic substrates are generally favored for cell attachment relative to their hydrophobic counterparts and can be leveraged for cell adhesion-based approaches in tissue engineering. Changes in hydrophilicity and surface chemistry have been widely employed to confirm surface modification by polydopamine.65 While the composition of surface modification does not

Figure 2. Changes in substrate properties observed following polydopamine modification. (A) The color of PLCL films darkened as coating time was increased from 0 to 16 h, indicating catechol oxidation via dopamine polymerization. (B) A decrease in water contact angle was measured after PLGA nanofibers were coated with dopamine, indicating greater hydrophilicity. D


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Figure 3. Changes in substrate properties observed following polydopamine modification. (A) XPS wide scan spectra of PLLA nanofibers with varying polydopamine coating times: 0 h (PLLA), 4 h (PD−PLLA-4h), and 8 h (PD−PLLA-8h). Polydopamine-modified samples displayed a peak corresponding to nitrogen (N 1s), attributed to the primary amine of polydopamine. In addition, an increase in peak characteristics was observed following extension of polydopamine coating time from 4 to 8 h. (B) AFM images compare surface roughness of a pristine PLCL film and a polydopamine-modified PLCL (PD−PLCL) film, which increased with the addition of polydopamine.

Figure 4. Different aspects of cellular adhesion on polydopamine-modified substrates. (A) HUVECs cultured on polydopamine (PDA)-coated glass, PDMS, silicone rubber (SR), PTFE, and PE substrates. PDA-coated substrates demonstrated significantly higher cell viability compared to those on gelatin-modified substrates. Reprinted from ref 64, Copyright 2010, with permission from Elsevier. (B) Confocal images of hMSCs cultured on uncoated and coated PLLA (PD−PLLA) revealed localized paxillin distribution and well-developed actin fibers, indicating enhanced cell adhesion on polydopamine-modified substrates after 12 h of culture (Scale bar: 100 μm). Reprinted from ref 91, Copyright 2012, with permission from Elsevier. (C) Immunofluorescence images highlighted that HUVECs grown on polydopamine modified PCL readily maintained their phenotype, with strong positive expression of endothelial markers vWF and VE-cadherin. Reprinted from ref 99, Copyright 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, with permission from John Wiley & Sons. (D) HT1080 cells adhered specifically to polydopamine-micropatterned regions on PDMS substrates. Actin (red) and nuclei (blue). Reprinted with permission from ref 112. Copyright 2010 American Chemical Society.

biomolecules. In earlier reports, molecules bearing nucleophilic functional groups such as amines and thiols were shown to react with catechol through Michael addition or Schiff base reactions.24,48 Pioneering work from Lee et al. suggested that

many types of biomolecules could be immobilized onto different substrates using polydopamine chemistry in a nearly substrateindependent manner. For example, polydopamine-coated glass, polystyrene, and indium tin oxide immobilized with thiolated E


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Table 2. Controlling Cellular Responses through Polydopamine-Mediated Surface Modification cell type

adhesion (±)

myoblast myoblasts myoblasts hMSCs hMSCs hMSCs HUVECs HUVECs HUVECs HUVECs HUVECs SMCs hNSCs hNSCs hADSCs chondrocytes chondrocytes MC3T3-E1 cells HT1080 cells NIH-3T3 MC3T3-E1 MC3T3-E1 cells

(+) (+) (+) (+)

(+) (+) (+) (+) (+) (−) (+) (+) (+) (+) (+) (+) (+)

(+)

proliferation (±)

(+) (+) (+) (+) (+) (+) (+) (+) (−) (+) (+) (+)

(+)

substrate

surface properties

reference

liposomes pNiPAAm glass,PLL/liposomes PLLA PLGA PLLA PLCL PLCL PCL SS Ti stent Ti stent PLGA PLGA PLGA PU,PCL,PLGA,PLLA E-jetting PCL Ti implant PDMS

PD PD PD PD BMP-7/PD BMP-2/PD VEGF/PD RGD, bFGF/PD heparin/PD mPEG-NH2,VEGF/PD heparin-PLL NP/PD heparin-PLL NP/PD NGF,GDNF/PD YIGSR,RGD/PD BMP-2/PD fibronectin/PD collagen type II/PD collagen/PD PD

116 117 118 91 119 66 120 102 121 122 123 123 124 124 125 89 126 103 112

3D-PCL scaffold

PD/HA

65

bFGF: basic fibroblast growth factor; BMP-2: bone morphogenetic protein-2; BMP-7: bone morphogenetic protein-7; E-jetting: electrohydrodynamic printing; GDNF: glial cell line-derived neurotrophic factor; HA: hydroxyapatite; hADSC: human adipose-derived stem cell; hMSC: human mesenchymal stem cell; hNSC: neural stem cell; HUVEC: human umbilical vein endothelial cell; HUVEC: human umbilical vein endothelial cell; mPEG-NH2: amino-terminated polyethylene glycol NGF: nerve growth factor; NP: nanoparticle; PCL: poly(ε-caprolactone); PD: polydopamine; PDMS: polydimethylsiloxane; PLCL: poly(L-lactide-co-ε-caprolactone); PLGA: poly(DL-lactic-co-glycolic acid); PLL: poly(L-lysine); PLLA: poly(L-lactic acid); pNIPAAm: poly(N-isopropylacrylamide); PU: polyurethane; RGD: arginine-glycine-aspartic acid; SMCs: Smooth muscle cells; SS: stainless steel; Ti: titanium; VEGF: vascular endothelial growth factor; YIGSR: tyrosine-isoleucine-glycine-serine-arginine.

processes using bone morphogenic protein-2 (BMP-2) and alkaline phosphatase (ALP), specifically in the aspects of biomolecule immobilization efficiency, release behavior, and bioactivity. While neither method affected biomolecule activity, it was suggested that the one-step and two-step process may be more appropriate for higher and lower concentrations of biomolecules, respectively.86

hyaluronic acid (HA) exhibited bioactivity when M07e cells were cultured on them.23,25 Thus far, DNA, cells, minerals, drugs, peptides, and proteins have been functionalized onto polydopamine modified substrates for diverse applications.73−77 Wood et al. generated DNA microarrays by combining polydopaminecoated gold films with amino-functionalized single-stranded DNA, and the resulting product had excellent stability and bioactivity for detecting biomolecules with the aid of surface plasmon resonance (SPR) imaging.78 In another example, coating self-assembled diphenylalanine nanowires with polydopamine prior to incubation in simulated body fluid led to uniform mineralization and successful attachment of preosteoblast cells.79 A two-step process is typically employed to immobilize cell adhesive peptides or growth factors for tissue engineering applications.80−83 The scaffold is immersed in a dopamine solution at defined conditions, then incubated with a solution of biomolecules.23 To expand usage from primarily amine and thiolbased molecules, Kang et al. accomplished both steps simultaneously.84 The devised immobilization strategy also proved less time-consuming and more effective for oxides, noble metals, synthetic polymers, and ceramics, along with molecules of diverse size ranges (102 to 106 Da) and chemistries (carboxyl, amine, thiol, quaternary ammonium, catechol groups). It may additionally permit functionalization of higher biomolecule concentrations on a given surface area; for example, available reactive quinone groups might be limited for ad-layer formation in the two-step process, whereas molecules could potentially react with quinone groups throughout the thickness of polydopamine films in the one-step strategy. Various reports have in turn demonstrated the utility of the one-step process and its biofuctionality.85,86 Nijhuis et al. compared one- and two-step

3. CELLULAR INTERACTIONS WITH POLYDOPAMINE-COATED SURFACES 3.1. Cell Adhesion on Polydopamine-Coated Substrates and Resulting Behaviors. Most synthetic polymers used in cell culture and tissue engineering lack cell-binding moieties and are often hydrophobic,87 therefore necessitating surface modification to improve cell adhesion. Polydopamine has received a great deal of attention because its application as a coating permits materials to be endowed with various chemical functionalities and 3D architectures. Ku et al. showed that polydopamine effectively promoted cell adhesion and proliferation on various synthetic polymers (Figure 4 A).64 Several biomaterial substrates highly resistant to cell adhesion (PE, PTFE, silicone rubber, PDMS, and glass) were layered with polydopamine, and their adhesive properties were subsequently compared to gelatin-coated counterparts in the presence of human umbilical cord vascular endothelial cells (HUVECs). Microscopic observations revealed that polydopamine-covered substrates not only improved initial cell attachment but also led to greater HUVEC proliferation and development of stable cytoskeletal structures. F


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3.2. Mechanism of Cell Adhesion on PolydopamineCoated Substrates. The following distinct mechanisms purportedly govern cell adhesion on biomaterial surfaces: (1) chemical functional groups on these biomaterial surfaces undergo weak binding with glycoproteins and proteoglycans presented by the cell membrane through electrostatic interactions or van der Waals force, referred to as nonspecific cell adhesion, and (2) protein adsorption forms a thin layer of cell-adhesive protein domains on these biomaterial surfaces which binds to transmembrane integrin receptors, defined as specific cell adhesion.98 In general, gas-plasma treatment of culture surfaces confers hydrophilicity and positive charge. Serum proteins adsorb to these modified substrates, thereby allowing cell attachment via binding to integrin receptors on the cell membrane. Even under serum-free conditions, cell adhesion and other metabolic functions that require specific binding can still be enhanced by conjugating ECM molecules, such as collagen, fibronectin, laminin, heparin sulfate, or HA. To fully appreciate polydopamine-based strategies, one must understand how cell adhesion is controlled on these types of surfaces. Ku et al. postulated that effective immobilization of serum proteins on polydopamine-coated substrates regulates cell behavior on synthetic substrates. This study found that proteins adsorbed onto polydopamine-coated surfaces maintained a conformation that enabled stable cell adhesion. Consequently, Shin et al. investigated the mechanism underlying cell interactions with polydopamine modified PLCL films.52 C2C12 myoblast adhesion to substrates fabricated under different coating times was analyzed in the presence and absence of serum proteins in culture medium. Under serum-free conditions, cell attachment remained low, and no statistical difference was noted between groups with different coating time. Conversely, the addition of serum significantly increased cell adhesion on polydopamine-coated surfaces, suggesting that serum proteins preferentially adsorbed onto the surface mediate cell adhesion, as opposed to direct interaction between the polydopamine layer and cells, which is consistent with the previous report by Ku and colleagues.64 Interestingly, a contradicting study showed that polydopamine helped orchestrate attachment and spreading of HUVECs in the absence of serum. These processes were likely influenced by the interaction of cell-secreted fibronectin and integrin α5β1.99 Furthermore, HUVECs retained their phenotypic traits, as evidenced by positive expression of endothelial cell markers (vWF and VEcadherin) (Figure 4C). Additional inquiry is nevertheless warranted to unravel the mechanism of cell adhesion and exploit it in tissue engineering strategies. 3.3. Immobilization of Biomolecules onto Polydopamine-Coated Substrates for Cell Adhesion. Cellular interactions with biomaterials used in tissue engineering may be enhanced by polydopamine coating alone or together with subsequent immobilization of cell adhesive ECM biomolecules, which is a more prominent strategy for improving biocompatibility.100,101 Specifically, polydopamine can serve as a bridging chemical for ad-layer formation of different cell adhesive moieties through covalent interaction between catechol and amine or thiol groups present on biomolecules.80,83,85,102 Various polymer substrates have been modified with polydopamine and subsequently functionalized with multiple adhesion peptide sequences derived from fibronectin, laminin, or growth factors. Yang and colleagues demonstrated that various cell adhesive moieties enhanced the attachment and proliferation of human neuronal stem cells, in addition to directing neuronal differ-

In another study, the efficiency of neuronal differentiation of pheochromocytoma 12 (PC12) cells was investigated on tissue culture plates layered with either polydopamine or gelatin. Polydopamine-coated substrates promoted better PC12 cell adhesion and spreading, decreased apoptosis, and enhanced neuronal differentiation when combined with nerve growth factor (NGF) treatment.88 PCL, PLA, and PLGA films required less than 4 min of dopamine incubation to increase chondrocyte adhesion by 1.35−2.69 fold compared to uncoated controls.89 Polydopamine coating also influenced cell morphology and spreading.52,62 Actin bundles were elongated on polydopaminemodified PTFE and glass.62 Consistent with the aforementioned report, Shin et al. observed a steady expansion of projected cell area (2.3 ± 0.3 × 103 μm2 to 2.7 ± 0.5 × 103 μm2) of C2C12 myoblasts on PLCL films when polydopamine coating time was increased from 5 to 960 min.52 Additionally, most cells displayed polygonal structures and focal adhesion points at their filophodia on coated films while remaining round on uncoated ones. These outcomes illustrate how surface chemistry can modulate cellular structure and cytoskeleton organization to encourage specific cell functions and long-term survival. For tissue engineering applications, biocompatible materials have been designed to present diverse 3D structures. In particular, electrospun nanofibers have been widely employed in tissue engineering due to their ease of fabrication and structural resemblance to components of the native extracellular matrix. Polydopamine modification has been mainly used to improve surface properties of synthetic polymer-based nanofibers, being advantageous in terms of simplicity, inexpensiveness, low cytotoxicity, and minimal changes in mechanical properties. Human mesenchymal cells (hMSCs) cultured on polydopamine-PLLA nanofiber scaffolds showed significant improvements in adhesion and proliferation (Figure 4B).90,91 In another study, H9c2 myoblasts showed the greatest extent of adherence, spreading, and proliferation on polydopamine-PLCL nanofibrous matrices immobilized with gelatin.92 A handful of investigations have employed either polydopamine alone or in conjugation with other cell adhesive biomolecules for tuning cell behavior on nanofibers.53,93 Recently, Xie et al. employed polydopamine to bind calcium phosphate minerals to PCL fibers, and this strategy improved scaffold mechanical properties, making them more amenable for bone tissue engineering.94 In addition to nanofibers, 3D scaffolds hold tremendous promise by mimicking complex tissue architecture; however, limited cellular infiltration due to poor hydrophilicity and a sparse number of cell adhesive moieties at the scaffold interior present major obstacles. The addition of polydopamineimmobilized hydroxyapatite to 3D printed PCL scaffolds created a hydrophilic interior, permitting preosteoblasts to more effectively infiltrate and adhere.65 In another study, polydopamine modification of 3D polyurethane constructs led to increased chondrocyte proliferation, as well as increased glycosaminoglycan secretion.89 Yan et al. observed that culturing MC3T3 cells on polydopamine-coated carbon nanotubes resulted in apatite deposition and good cytocompatibility.95 In a separate study, PDMS beads modified with polydopamine demonstrated excellent hydrophilicity and cell attachment.96 When gelatin was functionalized via polydopamine onto porous titanium alloys, the resulting substrate was conducive for periosteum-derived cells.97 Table 2 summarizes representative cellular responses to polydopamine-coated materials with various chemical functional groups and 3D structures. G


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Biomacromolecules Table 3. Polydopamine-Mediated Approaches for Tissue Regeneration soft tissue

approach

tissue

function

substrate

surface properties

reference

in vitro

blood vessel

antiplatelet effect (+) HUVEC spreading, viability, CD31 marker (+) actin bundles (+) vWF (+),VE-cadherin (+) HUVEC migration (+) hNSC differentiation(+) neural activity (+) cytotoxicity (−) Adhesion (+) cytotoxicity (−), thrombresistance (+)

316L SS PLCL PCL PLCL PS, PLGA electrode, Insulators liposome pNIPAAm hydrogel cobalt−chromium alloy stent PCL, PLLA E-jetting PCL Ti stent PLGA PLGA Ti substrate (PLGA)-[Asp-PEG]n PLGA PLLA

mPEG-NH2, VEGF/PD VEGF/PD PD RGD, bFGF/PD NGF,GDNF,YIGSR,RGD/PD PLL/PD PD PD heparin/PD

122 120 99 102 124 134 116 117 130

fibronectin/PD collagen type II/PD heparin-PLL NP/PD BMP-7/PD BMP-2/PD HA, BMP-2/PD BMP-2, HA/PD BMP-7, BMP-2/PD BMP-2/PD

89 126 123 119 125 149 150 119,125 66

neural muscle

cartilage


hard tissue

in vivo in vitro

blood vessel bone

in vivo

bone

chondrocyte differentiation (+) chondrogenesis (+) hemocompatibility (+), anti-inflammation (+) hMSC differentiation (+) hADSC differentiation (+), mineralization (+) MG63 cells differentiation (+) rBMSCs differentiation (+) bone regeneration (+) in calvarial defects bone regeneration (+) in calvarial defects

bFGF: basic fibroblast growth factor; BMP-2: bone morphogenetic protein-2; BMP-7: bone morphogenetic protein-7; E-jetting: electrohydrodynamic printing; GDNF: glial cell line-derived neurotrophic factor; HA: hydroxyapatite; hADSC: human adipose-derived stem cell; hMSC: human mesenchymal stem cell; hNSC: neural stem cell; HUVEC: human umbilical vein endothelial cell; HUVEC: human umbilical vein endothelial cell; mPEG-NH2: amino-terminated polyethylene glycol; NGF: nerve growth factor; NP: nanoparticle; PCL: poly(ε-caprolactone); PD: polydopamine; PDMS: polydimethylsiloxane; PLCL: poly(L-lactide-co-ε-caprolactone); PLGA: poly(DL-lactic-co-glycolic acid); PLL: poly(L-lysine); PLLA: poly(L-lactic acid); pNIPAAm: poly(N-isopropylacrylamide); PU: polyurethane; rBMSCs: rabbit-derived bone marrow stromal cells; RGD: arginine-glycine-aspartic acid; SMCs: Smooth muscle cells; SS: stainless steel; Ti: titanium; VEGF: vascular endothelial growth factor; vWF: von Willebrand factor; YIGSR: tyrosine-isoleucine-glycine-serine-arginine.

entiation.83 Lee et al. prepared polydopamine-coated PLCL films exhibiting RGD peptides concurrently with basic fibroblast growth factor (bFGF) with the intent of using them as vascular grafts. The small peptides readily reacted with polydopamine and regulated endothelial cell functions.102 Another group employed titanium substrates covalently modified with collagen and tested for adhesion, proliferation, and osteogenic differentiation of MC3T-E1 cells. Polydopamine was shown to facilitate effective and uniform immobilization of collagen.103 Another study revealed that using an intermediate layer of polydopamine to modify titanium surfaces with gelatin showed good uniformity and excellent stability, along with enhanced cell adhesion.97 Because polydopamine coating and subsequent biomolecule immobilization comprise a relatively facile and stable procedure, these approaches are attractive for cell-based tissue engineering applications. 3.4. Spatial Regulation of Cell Adhesion Using Polydopamine-Coated Substrates. Human tissues consist of multicellular components, and oftentimes, different cell populations arranged in a spatially defined manner. Thus, tremendous efforts have been dedicated to recapitulate these unique hierarchical patterns, given that the ability to dictate the position of individual cells on biomaterial surfaces may be extremely beneficial for studying heterotypic cell interactions, as well as for fulfilling the functional commitment of specialized cells to replace damaged tissues.104 Recent advances in microfabrication technology have enabled researchers to simulate these conditions in vitro in a more controlled fashion.105,106 Cell adhesive molecules are typically patterned on substrates such that cells attach solely to those selective regions.107,108 Contemporary micropatterning methods, such as photolithography, microcontact printing, and microfluidic patterns, largely suffer from difficulties in maintaining bio-

molecule reactivity since they require harsh processes. In such scenarios, polydopamine offers abundant freedom in terms of its ease of use, structural stability, and substrate-independent adhesive properties. In an initial approach, microcontact printing of polydopamine took place on several poly(ethylene glycol) (PEG)-treated substrates, including glass, polystyrene (PS), and PDMS.109 Various cell types (NIH 3T3, Escherichia coli, Staphylococcus epidermidis) adhered exclusively to polydopamine-patterned regions on these substrates and exhibited normal morphology and alignment along the direction of the patterns. In addition, Chien et al. studied the versatility of polydopamine-based methods on cell patterning. They developed polydopamine patterns on PDMS stamps that easily imprinted onto different substrates, including glass, silicon, gold, polystyrene, and PEG via microcontact printing. The reactivity of imprinted polydopamine and the potency of biomolecule immobilization for secondary reactions was confirmed through culturing L929 cells, protein immobilization, conjugation of thiol- or amine-containing molecules, and immobilization of gold nanoparticles.110 Another strategy leveraged polydopamine as a glue to bond PDMS microfluidic channels to poly(2,2dimethoxy nitrobenzyl methacrylate-r-methyl methacrylate-rpoly(ethylene glycol) methacrylate) (PDMP) films, largely retaining their surface properties. Notably, protein micropatterns and gradients could be generated within the microfluidic channels.111 Ku et al. also utilized a microfluidic approach to pattern polydopamine on PDMS, and different cell lines (NIH3T3, MC3T3-E1, and HT1080) were able to selectively attach and align themselves according to the micropatterns (Figure 4D).112 For cell patterning, selecting a cell-repellant surface is important because hydrogels cross-linked with highly hydrophilic polymers are generally nonadhesive to proteins and cells. H


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Figure 5. Representative in vitro/in vivo results from polydopamine-coated scaffolds. (A) An untreated vascular titanium stent (top) caused severe thrombosis and hyperplasia, while a vascular stent coated with polydopamine (bottom) was biocompatible in vivo. Reprinted with permission from ref 123. Copyright 2014 American Chemical Society. (B) Hippocampal neurons were cultured on a polydopamine-modified surface (top) and a poly(Llysine)-polydopamine linked surface (bottom). The bottom image shows well-proliferated and linked neural structures. Reprinted from ref 134, Copyright 2011, with permission from Elsevier. (C) Phase contrast highlighted chondrocyte proliferation on untreated (left) and polydopamine-treated (right) surfaces. Reprinted from ref 89, Copyright 2011, with permission from Elsevier. (D) Micro-CT revealed that PD-PLLA-BMP-2 scaffolds promoted greater bone regeneration than did unmodified PLLA nanofibers. TEM showed biocompatibility of polydopamine-coated nanofibers via the strong interaction of endogenous cells with regenerated collagen (Col; collagen, NF; PLLA nanofiber, PD; polydopamine layer).66

polydopamine-coated regions.114 Shi and co-workers prepared grooved parafilm substrates via photolithography, and these polydopamine-modified surfaces displayed robust cell adhesion and proliferation in defined regions, as compared to control groups.115

On the downside, these materials are inert to common chemical reactions employed in biomaterial surface modification, thereby requiring alternative techniques. Polydopamine has been effective in simplifying these cumbersome tasks. Poly(vinyl alcohol) (PVA) hydrogels subjected to microcontact printing with polydopamine using PDMS stamps successfully led to patterning of HeLa cells, human embryonic kidney cells, HUVECs, and prostate cancer cells.113 Single cells could even be confined by the specified patterns. Moreover, cocultures of HUVECs and HeLa cells maintained their respective spatial patterns. In another study, Sun et al. modified the surfaces of antifouling oligo(ethylene glycol)-terminated self-assembled monolayers with polydopamine through microcontact printing and microfluidic-based methods, yielding substrates bearing discrete patterns of cultured cells selectively adherent to

4. APPLICATIONS IN TISSUE ENGINEERING Tissue engineering represents a highly interdisciplinary field integrating cells, materials, and bioactive factors. Biomaterials that provide suitable biochemical and physiochemical cues have garnered substantial interest for both ex vivo and in vivo tissue regeneration approaches. However, they often need special surface treatments to overcome issues such as low biofuctionality, toxicity, or immunogenicity.127 In many instances, I


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suspended in culture medium frequently lack adequate physiochemical stimulation to initiate signaling cascades that promote proliferation and differentiation and often fail to survive post-transplantation.133 Hence, culturing NSCs on biomaterial scaffolds that can provide the necessary physiochemical signals for cell survival and differentiation would be immensely promising. Kang et al. modified common neural interfaces (gold, glass, platinum, indium tin oxide, and liquid crystal) using polydopamine and covalently linked PLL.134 Primary neuronal cells seeded on these modified surfaces exhibited excellent network formation and viabilities (Figure 5B). This same study also reported successful recordings of neuronal signals on polydopamine-modified gold electrode microelectrode arrays (MEAs), revealing the possible application of polydopaminebased materials toward developing neural interface platforms. In another work, polydopamine was used to functionalize PS and PLGA surfaces with cell adhesive peptides and glial cell-line derived neurotrophic factor (GDNF), with NSC differentiation and proliferation on these substrates shown to be comparable or greater than on Matrigel. These results indicated that polydopamine modification could potentially circumvent safety concerns associated with nonchemically defined platforms (ex. Matrigel).124 PCL nanofibers functionalized with RE-1 silencing transcription factor (REST) via polydopamine promoted neuronal differentiation of primary mouse neural progenitor cells while lowering glial cell differentiation.135 Muscle tissue engineering aims to reconstruct skeletal muscle loss resulting from injury, congenital defects, or tumor ablations.136 Muscle cells possess relatively limited ability to regenerate under in vivo conditions.137 Thus, muscle tissue engineering strategies mainly focus on recapitulating the native environment using biomaterial scaffolds in combination with autologous cells. Toward this end, numerous strategies have been pursued to improve interactions between materials and muscle cells.138,139 For example, polydopamine-coated liposomes led to higher myoblast viability and uptake efficiency compared to unmodified ones.116 Lynge et al. demonstrated that myoblasts adhered and proliferated on polydopamine-coated glass slides.118 These cells were also shown to successfully internalize fluorescently labeled zwitterionic liposomes coated with polydopamine, with the highest fluorescence intensity concentrated near the nuclei. In another study, poly(N-isopropylacrylamide) (pNiPAAm) hydrogels modified with polydopamine exhibited favorable properties for myoblast adhesion with negligible effect on the polymer’s intrinsic thermoresponsive characteristics.117 Recently, Ku et al. demonstrated that myogenic protein expression and myoblast fusion were upregulated on polydopamine−PCL nanofibers compared to their unmodified counterparts.140 Electrospun PLCL fibers functionalized with RGD peptides through polydopamine also stimulated adhesion and proliferation of C2C12 myoblasts and could potentially be used as a cardiac patch.53 Although surface modification of biomaterials using polydopamine is relatively nascent in muscle tissue engineering, preliminary research suggests that muscle cells interact highly with polydopaminemodified surfaces with no evidence of cytotoxicity. Consequently, polydopamine may be a promising tool for altering the surface of various materials for muscle tissue engineering. Unlike the majority of tissues, cartilage is avascular and has limited intrinsic regenerative capacity. Replacement or reconstruction thereby proves challenging when undermined by pathological conditions.141 The versatility and high reactivity of polydopamine has been utilized for modifying different

polydopamine-based materials have facilitated superb adhesion of cells and biomolecules, and have therefore been extensively explored for tissue engineering applications. The following sections discuss polydopamine in the context of engineering different tissues, with Table 3 providing an organized summary. In addition, the potential immune responses and inflammatory reactions following implantation of polydopamine-coated materials are also discussed. 4.1. Engineering Soft Tissues. The prevalence of cardiovascular diseases in contemporary society has led to heightened demand for synthetic vascular grafts to replace damaged blood vessels.128,129 Polydopamine was initially employed for pre-endothelialization on graft surfaces, since endothelial cells promote vascular network formation by releasing factors that regulate thrombogenesis/fibrinolysis and platelet activation/inhibition. In one study, HUVEC cell adhesion, proliferation, and viability on PCL nanofibers surface-functionalized with polydopamine were compared to those modified with gelatin. HUVECs on polydopaminemodified PCL nanofibers exhibited well-developed actin bundles and positively expressed endothelial cell markers (PECAM-1 and vWF). Moreover, polydopamine coatings showed a high efficiency of endothelial cell adhesion on various nonadherent surfaces such as PDMS, silicone rubber, PTFE, and PE.64 More recently, polydopamine has been used to conjugate different biomolecules that influence endothelial cell function. Luo et al. modified 316L stainless steel with polydopamine and then immobilized amino-terminated polyethylene glycol (mPEGNH2) or vascular endothelial growth factor (VEGF). The surface coating ensured successful functionalization, as evidenced by reduced antiplatelet adhesion and greater endothelial cell proliferation.122 Similarly, PLCL elastomers immobilized with VEGF via polydopamine exhibited significantly enhanced proliferation, migration, and higher expression of cell markers, such as CD31.120 Multiple bioactive molecules that could trigger endothelial cell functions, including RGD-containing peptides and bFGF, were also incorporated. The stability of immobilized biomolecules on polydopamine-coated substrates was confirmed, and synergistic or independent effects were observed to enhance cell adhesion, proliferation, and migration of endothelial cells over 14 days in vitro.102 These results collectively support that polydopamine serves as a promising tool for controlling the surface properties of vascular grafts. Furthermore, polydopamine has been involved in engineering heparin-modified substrates to confer antithrombogenic properties to vascular grafts.121 Bae et al. assessed the thrombo-resistant and endothelialization outcomes of dopamine-mediated heparin (HPM) coating on stents. Results suggested that this facile coating approach could improve both endothelialization and thrombo-resistant properties of otherwise bare stents.130 In another study, Liu and co-workers immobilized heparin/poly-Llysine (PLL) nanoparticles onto polydopamine-coated titanium stent surfaces to regulate and maintain intravascular biological responses within the normal range following device implantation. Biomolecules retained stability (14 to 28 days) on the surface, allowing for hemocompatibility and anti-inflammation. Furthermore, coated stents inhibited smooth muscle cell (SMC) proliferation and promoted endothelial cell growth without thrombus formation or intimal hyperplasia (Figure 5A).123 Neural stem cells (NSCs) have shown excellent selfregenerative capacity toward neural cells, thereby offering a promising cell source to mitigate the issue of self-recovery of native neural-like cells and glial cells.131,132 Pure NSCs J


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factors in vivo complicates direct administration, polydopaminemediated surface immobilization of growth factors on biomaterials has been attempted to mitigate the aforementioned issue. Following implantation in a murine model, PLGA nanofibers functionalized with bone-forming peptide 1 (BFP1) via polydopamine showed higher bone formation and greater distribution of regenerated collagen.119 In another study, adipose-derived stem cells were cultured on polydopaminemodified 3D PLGA scaffolds immobilized with BMP-2 derived peptides and transferred to a murine model, which promoted bone regeneration at the defect site.125 Similarly, polydopaminecoated PLLA nanofibers were stably functionalized with BMP-2. When the samples were exposed to physiological conditions in vitro for 28 days, nearly 90% of the growth factor was retained on the surface of nanofibers, implying strong covalent binding of BMP-2 to the polydopamine layer. When implanted into criticalsized cranial defects in mice, almost 80% bone regeneration was observed (Figure 5D, top side), and this result was particularly noteworthy due to the low BMP-2 concentration used (25 ng/ defect). Further microscopic analysis revealed the stability of polydopamine nanofiber surfaces and interaction between the modified nanofibers and host ECM (Figure 5D, bottom side).66 Enamel and dentin are major calcified components of dental tissue consisting of significant amounts of minerals with an organic matrix (mainly collagen) and water. Polydopamine coating has been utilized for mineralization of enamel and dentin since catecholamine moieties present in polydopamine exhibit high affinity to minerals and show accelerated hydroxyapatite crystal growth.145 In a study by Zhou et al., dental slices containing both enamel and dentin were coated with polydopamine and immersed in a supersaturated solution of calcium and phosphate for several days.151 Characterization of surface properties using scanning electron microscope (SEM) and Xray powder diffraction (XRD) revealed that the polydopamine coating greatly enhanced dentin mineralization despite no observed differences in enamel mineralization. These results suggest that polydopamine can bind to the collagen matrix and thus provide a new nucleation site for mineral deposition of dentin. In dental tissue engineering, polydopamine has also been applicable to root canal treatments, in which a strong adhesion of filling materials to the root canal wall is essential. Chen et al. evaluated the bonding efficiency of glass-fiber posts with polydopamine to root dentin using a push-out test.152 The results demonstrated significantly enhanced bond strength of polydopamine-treated samples compared to that of untreated controls, implying that surface modification with polydopamine may improve the adhesive strength of filling materials to the root canal wall. 4.3. Tissue Compatibility. Injury caused from surgically implanting a biomaterial elicits an immunological response that can affect the quality of tissue regeneration. Hence, it is of paramount importance to design biomaterials that can appropriately modulate these immune reactions to prevent rejection by the body.153 Initial concerns over polydopamine arose from the finding that unpolymerized dopamine particles may be cytotoxic.154,155 Hong et al. conducted a detailed study using quantum dots and polydopamine-coated PLLA films and discovered that the unpolymerized portion was not released from the polydopamine layer. The same report speculated that polydopamine prevented toxic ion release from quantum dots and positively altered the surface energy of PLLA films, thus avoiding the inflammatory response of these otherwise hydro-

biomaterial scaffolds, leading to excellent adhesion and proliferation of chondrocytes through immobilization of serum adhesive proteins such as fibronectin on polydopamine surfaces (Figure 5C). Polydopamine-coated 3D polyurethane scaffolds better stimulated chondrocyte secretion of glycosaminoglycans than did unmodified structures.89 Another work described the incorporation of polydopamine for collagen grafting on 3D PCL scaffolds fabricated by electro-hydrodynamic printing. Chondrocytes cultured on these materials readily attached and maintained healthy phenotypes by producing cartilage-like ECM.126 Despite the limited number of polydopamine-based studies in cartilage tissue engineering, the simple functionalization steps and high biocompatibility of this method may be influential for long-term clinical effects in cartilage regeneration. 4.2. Engineering Hard Tissues. Bone confers structural support to the human body, and bone loss arising from many clinical issues, such as traumatic injury, osteoporosis, or osteoarthritis, may therefore be particularly detrimental.142 A major aspect of bone tissue engineering focuses on developing biomaterials used either alone or in combination with cells or biomolecules to trigger bone formation in vivo.143,144 Polydopamine has influenced the adhesion and osteogenic differentiation of different cell types in vitro.65,75,91 Rim and co-workers observed that hMSC adhesion and proliferation on polydopamine-modified PLLA nanofibers was significantly greater than on unmodified ones. Likewise, these cells demonstrated higher ALP activity, upregulation of osteogenic markers, and calcium deposition.91 When rat osteoblasts were cultured on different biodegradable polymer films (PCL, PLLA, and PLGA), their adhesion and proliferation increased by several fold when polydopamine was introduced onto the substrates.75 Ryu et al. discovered that catechol groups in polydopamine could enhance hydroxyapatite nucleation by concentrating calcium ions at the interface.145 Because the coating process is relatively simple, it has been extensively exploited to facilitate mineralization on different materials.146−148 In one instance, polydopaminemediated mineralization was leveraged to improve the mechanical properties of PCL nanofibers, which yielded values for stiffness, ultimate tensile strength, and toughness closer to that of native bone.94 Higher biomolecule immobilization capability on polydopamine surfaces has also been used in enhancing in vitro osteogenic differentiation. For example, BMP-2 immobilized on titanium alloy modified with hydroxyapatite and polydopamine displayed favorable release profiles, increasing adhesion, proliferation, and ALP activity of human osteosarcoma MG63 cells, as well as upregulating the expression of osteogenic markers.149 Additionally, Pan et al. functionalized RGDcontaining (K)16GRGDSPC peptides, osteoconductive hydroxyapatite (HAp) nanoparticles, and osteoinductive BMP-2derived P24 peptides onto (PLGA)-[Asp-PEG]n scaffolds, and the resultant bioactive substrates enhanced the osteogenic differentiation of rabbit bone marrow-derived stromal cells.150 Aside from in vitro work, polydopamine has also been utilized in select in vivo studies. Lee et al. noted the enhanced bone regenerative capacity of polydopamine-modified PLLA nanofibers compared to their unmodified counter-parts in a mouse calvarial defect model. The coating was speculated to have improved attachment of progenitor cells to scaffolds and eventually resulted in higher bone regeneration.90 Delivering specific growth factors to the defect site constitutes a classical therapeutic approach, given that bone formation is mediate by a milieu of these biomolecules. Because rapid dissolution of growth K


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Biomacromolecules phobic, degradable surfaces.156 These results suggest that polydopamine has minimal adverse effects in vivo. In another study, polydopamine-coated nanofibers implanted in mouse cranial defects showed the stable presence of a coated polydopamine layer, and further microscopic analysis revealed that host cells and regenerated collagen fibers closely interacted with the polydopamine surface throughout the nanofiber region with no signs of inflammation (Figure 5D, bottom side).66 Furthermore, applications of polydopamine in the area of medical devices have been explored. Gao et al. developed heparin-immobilized PLLA membranes coated with polydopamine for hemodialysis, and in vitro experiments showed significant clearance of urea and lysozymes while 90% of BSA was retained, suggesting that surface heparinization through polydopamine improved material hemocompatibility and decreased the hemolysis ratio.157 To mitigate issues of thrombosis and restenosis associated with commercial vascular stents, in situ regeneration of the endothelium has been widely attempted. While most studies focus on endothelial cell growth, long-term success also hinges on antithrombotic activity and competitive interactions between smooth muscle cells (SMCs) and endothelial cells (ECs).158 Yang et al. developed a nanotubular titanium oxide (TiO2) system containing the thrombin inhibitor bivalirudin (BVLD), which remained stable on the polydopamine-coated surfaces for at least two months. These substrates largely inhibited thrombin activity and platelet adhesion while enhancing HUVEC adhesion and growth.159 The above studies denote polydopamine’s contribution to the biocompatibility of implanted materials, which could expand their usage in translational endeavors. 4.4. Other Materials Derived from Mussel-Inspired Chemistry in Tissue Engineering. Although polydopamine is mostly used for surface modification of prefabricated materials, it has also been exploited via both covalent and noncovalent interactions in the fabrication of hydrogels, which serve as carriers for cells or therapeutic molecules such as growth factors and morphogens relevant to tissue engineering. As mentioned earlier, amine or thiol-terminated molecules can cross-link with polydopamine through Michael addition or Schiff base reactions. For example, HA conjugated with dopamine and reacted with thiol-end-capped pluronic F127 produced a cross-linked composite hydrogel through a catechol−thiol reaction.160 Catechol chemistry has also been employed for fabricating PEG, heparin, or poly(ethylenimine) hydrogels for various applications.30,161 In one study, coacervate hydrogels of polydopamine-conjugated HA and lactose-modified chitosan were formed through electrostatic interactions between anionic and cationic polymers and Michael addition of catechol molecules at alkaline pH.162 These cross-linking strategies not only improved hydrogel stability, but also generated highly favorable cell culture substrates with minimal cytotoxicity. Alginate hydrogels fabricated with polydopamine cross-linkers possessed better physical and mechanical properties compared to their calcium ion-cross-linked counterparts. Furthermore, in vitro studies demonstrated higher cell viability on these catecholfunctionalized alginate hydrogels.163 Similarly, neural stem cells showed excellent attachment and viability on HA-catecholfunctionalized substrates.164 Physical and chemical cross-linking methods generally used in hydrogel synthesis have limitations in terms of stability, mechanical properties, reagent toxicity, and unfavorable reaction conditions for biomolecules. In contrast, polydopamine cross-linking confers high stability, tunable mechanical properties, and limited toxicity. Highly reactive

catechol molecules can also be utilized for secondary conjugation of cell adhesive peptides or growth factors.

5. CONCLUSIONS AND FUTURE PERSPECTIVES Despite a relatively short history since its introduction into the cell and tissue engineering community, polydopamine modification boasts many advantages, among them being ease-of-use, versatility, and high stability under physiological conditions. When applied as a coating on biomaterials, polydopamine can alter surface properties, such as chemical functionality, hydrophilicity, roughness and/or mechanical properties. Moreover, a growing body of evidence supports that polydopamine-coated surfaces can enhance in vitro cell adhesion, spreading, and proliferation, as well as in vivo tissue growth. Another attractive characteristic of polydopamine is its presentation of catechol groups, which permits secondary reactions with a variety of biomolecules at near physiological conditions, thereby ensuring retention of bioactivity. Such versatility in chemical reactions makes a polydopamine-based approach unique as a universal platform to tackle cumbersome problems in engineering different tissue types. However, a more thorough understanding of dopamine oxidation and polymerization mechanisms is warranted to advance the field toward more controllable surface modifications. Although numerous in vitro studies have reported effective adhesion, proliferation, and differentiation of different cell types on polydopamine-modified materials, the long-term in vivo toxicity and fate of polydopamine layers remain largely unknown. Some preliminary studies have confirmed that no unpolymerized dopamine is released in vivo, and that the stable polydopamine layer remains intact postimplantation. Some questions that have yet to be addressed are whether biomaterial degradation may detach the polydopamine layer or how the body will respond to polydopamine particles or oligomeric dopamine. Nevertheless, polydopamine has emerged as a powerful, bioinspired tool for surface modification and for readily immobilizing biomolecules. Summarily, greater insights on polymerization mechanisms and prolonged in vivo fate will expand the application of polydopamine in cell and tissue engineering.

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AUTHOR INFORMATION

Corresponding Authors

*Tel: +1-713-348-5355; Fax: +1-713-348-4244; E-mail: mikos@ rice.edu (A.G.M.). *Tel: +82-2-2220-2346; Fax: +82-2-2298-2346; E-mail: hshin@ hanyang.ac.kr (H.S.). Author Contributions ⊥

These authors equally contributed to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS H.S. acknowledges support from a Yonam Professor Fellowship through the LG Yonam Foundation. A.G.M. acknowledges support from the National Institutes of Health for research towards the development of biomaterials for tissue engineering applications (R01 AR048756, R01 CA180279, and R21 AR067527). E.J.L. acknowledges support from a National Science Foundation Graduate Research Fellowship. L


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