Dynamic Synthetic Biointerfaces: From Reversible Chemical

Article Cite This: Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Dynamic Synthetic Biointerfaces: From Reversible Chemical Interactions to Tunable Biological Effects Yue Ma,†,‡ Xiaohua Tian,† Lei Liu,† Jianming Pan,†,‡ and Guoqing Pan*,† Institute for Advanced Materials, School of Materials Science and Engineering, and ‡School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang, Jiangsu 212013, China

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CONSPECTUS: Dynamic synthetic biointerface is a new concept of biomaterials with smart surface properties capable of controlled display of bioactive ligands, dynamic modulation of cell-biomaterial interactions, and subsequently clever manipulation of fundamental cell behaviors like adhesion, migration, proliferation, differentiation, apoptosis, and so on. As mimics of the extracellular matrix (ECM), such molecularly dynamic biointerfaces have attracted increasing attention because of their tunable biological effects with great significance in in situ cell biology, tissue engineering, drug targeting, and cell isolation for cancer theranostics. Approaches to control bioligand presentation on materials mainly rely on surface functionalization with dynamic or reversible chemical linkers to which the ligands are tethered. Photoelectric-transformable or photocleavable chemistry, host−guest supramolecular chemistry, and multiple noncovalent interactions were initially employed for fabrication of dynamic synthetic biointerfaces. However, the external stimuli required in these systems, including electrochemical potential, electrochemical reaction, and near-infrared or UV light, are mostly invasive to living cells; and few of them are able to respond to the stimuli occurring in natural biological processes. In addition, most of current systems focused only on the control of cell adhesion, other cell behaviors like migration, differentiation and apoptosis have rarely been explored. Therefore, the development of novel synthetic biointerfaces that permit access to noninvasive control of diverse cell behaviors still represents a key challenge in biomaterials science. Our group pioneers the use of reversible covalent bonds, metal coordinative interactions, and the molecular affinity of molecularly imprinted synthetic receptors as the dynamic driving forces for the fabrication of smart biointerfaces. Several typical biological stimuli, such as glycemic volatility, body temperature fluctuations, regional disparity of pH values, and specific biomolecules, were tactfully involved in our systems. In this Account, we highlight the strategies we have used on the exploitation of dynamic synthetic biointerfaces based on the above three types of reversible chemical interactions. While our attention has been focused on biologically stimuli-responsive or other noninvasive ligand presentation, the versatility of dynamic synthetic biointerfaces in control of cell adhesion, directing cell differentiation, and targeting cell apoptosis has also been successfully demonstrated. In addition, a paradigm shift of dynamic synthetic biointerfaces from macroscopic to microscopic scale (e.g., nanobiointerfaces) was conceptually demonstrated in our research. The potential applications of these developed dynamic systems, including fundamental cell biology, surface engineering of biomaterials, scaffold-free tissue engineering, cellbased cancer diagnosis, and drug targeting cancer therapy, were also introduced, respectively. Although the development of dynamic synthetic biointerfaces is still in its infancy, we strongly believe that further efforts in this field will play a continuously and increasingly significant role in bridging the gap between chemistry and biology.

1. INTRODUCTION In the human body, the dynamic interactions between receptors at the cell membrane and ligands at the extracellular matrix (ECM) are crucial in various cellular processes.1 Changes in these interactions as a consequence of the ECM remodeling give rise to specific cell signaling and intracellular cascades, consequently triggering relevant cell behaviors like adhesion, migration, proliferation, differentiation, and apoptosis.2 To mimic the above dynamic interactions in artificial matrices, sophisticated synthetic biointerfaces, which are capable to reversible display bioactive ligands and dynamic modulating specific cell-biomaterial interactions, have attracted increasing attentions in both fundamental cell biology and tissue engineering.3−5 In addition, the controlled interactions of membrane receptors with ligands immobilized on a © XXXX American Chemical Society

biomaterial are also relevant in molecular targeting and isolation methods in medical diagnostics and therapeutics.6,7 Efficient approaches to control ligand presentation on biomaterials mainly rely on surface functionalization with responsive chemical linkers to which the bioactive ligands are tethered.4,8,9 Photoelectric-transformable or photocleavable covalent chemistry (e.g., UV-cleavable 2-nitrobenzyl esters and UV-isomerizable azobenzene groups) was initially used for this purpose. For example, the availability of bioactive peptides covalently immobilized on a surface could be switched by means of electrochemical potential,10,11 electrochemical reaction,12 near-infrared light13 and UV light.14−17 However, Received: November 28, 2018

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DOI: 10.1021/acs.accounts.8b00604 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

Figure 1. (a) Reversible covalent interactions between phenylboronic acid and cis-diol-containing molecules. (b) pH-sensitive benzoic-imine bond. (c, d) Reversibility of metal coordinative bond. (e) Schematic mechanism of molecular imprinting process for the preparation of synthetic receptor mimics.

the nonphysiological external stimuli required in these systems are potentially invasive to living cells,8 thus limiting their general applicability in biosystems. Another strategy to realize dynamic ligand exposure relies on tethering bioactive ligands through congenitally reversible noncovalent bonds. Reported attempts including β-cyclodextrin- or cucurbit[n]uril-based host−guest chemistry,18−20 DNA base pair-based hydrogen bonding,21 peptide-based hydrophobic self-assembly,22,23 and polyelectrolyte-based electrostatic interactions24 have been employed for the fabrication of dynamic synthetic biointerfaces, while these noncovalent methods still have critical limitations. Reversible noncovalent bonds typically have much lower association constants in comparison to the covalent bonds, which could lead to serious leakage of the surface bioactive factors in some noncovalent systems during applications; and also, the low specificity of noncovalent interactions needs to be addressed especially as they are used in biosystems with high-demand specificity. Furthermore, from a biomimicry point of view, the above noncovalent and covalent systems are rarely able to respond to the stimuli in natural biological processes, such as glycemic volatility, body temperature fluctuations, regional pH disparity, and even specific biomolecules in biological feedback systems. It is also worth mentioning that most of the reported dynamic systems focused only on simple control of cell adhesion or release. In comparison, other cell behaviors, including migration, differentiation, and apoptosis that are very important in the biomedical field, have less been explored. Taken together, the development of dynamic synthetic biointerfaces with reversible and stable bioactivity presentation, available to noninvasive control of diverse cell behaviors, and equipped with near-physiologically stimuli-responsiveness still represents a key challenge in biomaterials science. Toward this end, our group pioneers the use of reversible covalent chemistry, coordination chemistry, and molecularly imprinted synthetic chemistry for the fabrication of dynamic biointerfaces. Besides the relatively stable and specific molecular interactions, the three chemical methods also

exhibited reversible properties. In our developed systems, several typical biological stimuli, including the sugar levels, body temperature, regional pH values, and specific biomacromolecules, were tactfully involved to trigger noninvasive cell response. In this Account, we will highlight those three representative chemical strategies for the exploitation of dynamic synthetic biointerfaces. Apart from the biologically stimuli-responsive or noninvasive ligand presentation we were concerned with, the versatility of these dynamic systems in control of cell adhesion, directing cell differentiation and targeting cell apoptosis will also be demonstrated. It is also worth mentioning that, dynamic synthetic biointerfaces with sizes from macroscopic to microscopic (e.g., nanobiointerfaces) will be conceptually presented. The potential applications, including fundamental cell biology, surface engineering of biomaterials, scaffold-free tissue engineering, cell-based cancer diagnosis, and drug targeting cancer therapy, will also be severally introduced.

2. REVERSIBLE CHEMISTRY WITH POTENTIALS IN BIOSYSTEMS In essence, the dynamic cellular processes are the results of various reversible chemistries occurred at the interfaces between cell membranes and ECMs. Hence, reversible chemical interactions are very appealing for the fabrication of dynamic synthetic biointerfaces and modulation of reversible cell-biomaterial interactions. Considering the availability and biocompatibility of synthetic systems requested in the biological applications, the following reversible, noninvasive, and in particular, biological stimuli-responsive chemical strategies attracted our great attentions. 2.1. Reversible Covalent Chemistry

Reversible (or dynamic) covalent chemistry has been extensively reported for the design of reversible or switchable functional materials.25 The most attractive ones in bioapplication are phenylboronate esters and benzoic-imine bonds, owning to their reversibility under near-physiological conB


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Figure 2. (a) Chemical structures of RGD-glycopolymer (RGD-PGAPMA) complex and the glass substrate with PBA-containing polymer brushes. (b) Schematic illustration of dynamic introduction of RGD-glycopolymer via reversible multicovalent PBA/cis-diol complexes. (c) Images of fluorescently RGD-PGAPMA-bound surface after incubation in 60 mM fructose for 1 h. (d) Sugar-triggered cell release process. (e) Cell readhesion process on the dynamic synthetic biointerface. Reproduced with permission from ref 36. Copyright 2014 American Chemical Society.

behavior modulation, and even surface engineering of the metal implants used in clinic.

ditions. Phenylboronate esters derive from phenylboronic acid (PBA) and 1,2/1,3 cis diols forming an acid-cleavable complex that can also exchange with cis diol-containing saccharides (e.g., glucose) at physiological pH value (Figure 1a).26,27 Benzoic-imine bond, stable under physiological conditions, can be hydrolyzed under mildly acidic conditions (e.g., pH < 6.5) (Figure 1b).28 Since changes in glucose levels and pH values are common in biological systems (e.g., the glycemic volatility and mildly acidic conditions in inflammatory or tumor tissues), these two types of reversible covalent chemistry are very suitable to be used as noninvasive and dynamic driving forces for the fabrication of dynamic synthetic biointerfaces.

2.3. Molecularly Imprinted Synthetic Chemistry

Unlike the simple and direct covalent or coordination chemistry, molecular imprinting (MI) is a concept of supramolecular chemistry used to create artificial polymeric receptors for molecular recognition by mimicking the “lock and key” mechanism in natural receptor−ligand interactions.30,31 A typical molecular imprinting process involves the self-assembly of template molecules (i.e., the targeted molecules) and polymerizable functional monomers through either noncovalent or reversible covalent interactions (e.g., hydrogen bonding, hydrophobic interactions, ionic interactions, van der Waals forces, metal coordination interactions, and so on), the molecular assemblies subsequently being copolymerized by thermal- or photoinitiators with a suitable cross-linker. After thorough wash and removal of the templates using polar solvent, molecular recognition sites complementary in shape, size, and functionality to the template molecules are formed in the molecularly imprinted polymers (Figure 1e).32,33 This implies that molecularly imprinted polymers with affinity toward cell membrane molecules are instinctive with the potential for dynamic cell recognition.34 More importantly, the reversible molecular affinity of such synthetic receptor mimics could act as a driving force for the dynamic bioligand presentation. Furthermore, molecularly imprinted synthetic receptors could be equipped with specific stimuli-responsiveness by using smart polymer networks,35 probably endowing

2.2. Coordination Chemistry

Another potential dynamic chemistry for biosystems is the coordinative interaction. In generally, coordination between the ligands and the central atom (commonly a transition metal ion) is a type of chemical bond with bonding energy close to that of a covalent bond. Although the cleavage of a coordinative bond needs relatively complicated procedures like ligand exchange or chemical reactions, the formation of a coordination is commonly a spontaneous process, thus exhibiting “reversible” properties that allow in situ introducing and rebinding bioactivities at the metal interfaces (Figure 1c and d). In fact, metal ion coordinative complexes are universal and very important in biological systems for enzymatic reactions, metabolism, oxygen transport, storage, and so on.29 Therefore, the dynamic nature of metal coordinations also shows potential for reversible bioligand presentation, cell C


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Figure 3. (a) Mussel-inspired peptides with catechol groups (DOPA) and bioactive motifs. (b) Natural mussel foot proteins (Mfp-1). (c) Structural formula of the PBA-containing polymers on quartz slides. (d) Mussel-inspired phenylboronate-based dynamic biointerface for specific modulation of stem cell adhesion behaviors and selective isolation of tumor cells. CTCs: circulating tumor cells. (e) Time-dependent cell release from the RGD-bound surface after adding 60 mM fructose. (f) Selective tumor cell capture from a mixed cell suspension containing 1:1 MCF-7 cells (green, DiO) and HL60 cells (red, Dil). Scale bar 100 μm. Reproduced with permission from ref 37. Copyright 2018 John Wiley and Sons.

experiments confirmed our hypothesis that the sugar-sensitive, multicovalent and polymeric phenylboronate ester bonds facilitated not only the molecular binding and exchanging processes but also surface recruitment of the released molecules, thus allowing reversible cell adhesion to occur when the cell culture medium was recovered to initial physiological sugar concentration (Figure 2c−e). It is worth mentioning that the approach presented in this work is the first demonstration of reversible cell adhesion on material interface through dynamic covalent chemistry and more encouragingly, and the first example to modulate cell-biomaterial interactions by mimicking the natural biofeedback systems (e.g., human glycemic volatility). Despite the superiority of long glycopolymer chains for the formation of reversible and stable multiple phenylboronate ester bonds, the above system still involves a molecular release process, in which non-natural chemicals (i.e., the synthetic polymers or chemical linkers) are commonly nonbiocompatible and potentially harmful to cells. To this end, an biomimetic dynamic synthetic biointerface based on musselinspired peptides and PBA-containing substrate was further developed by our group (Figure 3).37 Mussel-inspired peptides (DOPA)4-Y-X, composed of a cell-binding sequence X at the C-terminus, a nonbioactive spacer sequence Y, and a tetrapeptide (DOPA)4 with multiple catechol groups at the N-terminal end, were designed and synthesized according to the Fmoc-based solid-phase peptide synthesis strategy (Figure 3a). DOPA is a catecholic amino acid (3,4-dihydroxy-L-

the resultant molecularly imprinted biointerfaces with diverse dynamic properties.

3. DYNAMIC BIOINTERFACES BASED ON BIOLOGICALLY RESPONSIVE COVALENT CHEMISTRY 3.1. Phenylboronate Ester Bonds

The dynamic property of phenylboronate esters was widely used for the construction of pH- and sugar-responsive systems with molecular capture/release and assembly/disassembly properties.27 Our group is one of the first that has explored the applicability of phenylboronate ester bonds for dynamic display of bioactivity and control of cell adhesion behaviors (Figure 2).36 In that study, a novel synthetic biointerface was fabricated by using a functionalized glass substrate with PBAcontaining polymer brushes and a cell adhesive peptide RGD (Arg-Gly-Asp) conjugated with a long synthetic glycopolymer chain (Figure 2a). The RGD-glycopolymer complex could be stably bound on the substrate through multicovalent interactions between the PBA groups in grafted polymer brushes and the cis-diol groups in glycopolymers. In addition, the bound RGD peptide could be released by adding the system with glucose or fructose that could exchange with glycopolymer chains (Figure 2b). In this work, the PBA/ glycopolymer complexes were chosen for RGD binding because of the reversible and stable multicovalent interactions as well as the long accessible polymer chains. Cell adhesion D


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Figure 4. (a, b) Schematic illustration of a phenylboronate-based dynamic nanobiointerface on the nanocomplex and the pH-controlled display of bioactive PBA groups for sialic acid (SA)-overexpressed tumor cells. (c) Fluorescent images of MCF-7 cells after incubation with the nanocomplexes at different pH values for 4 h. Reproduced with permission from ref 41. Copyright 2018 John Wiley and Sons.

dynamic display of tumor targeting bioactivity. When the dynamically PEGylated nanocomplexes were used for cancer therapy, the pH-responsive surface feature facilitated them escaping from the endocytosis of normal cells and phagocytes; while in the tumor region, acid-induced de-PEGylation would expose the active PBA groups for tumor cell recognition and internalization (Figure 4c), finally exhibiting tumor-targeted drug delivery and enhanced cancer cell inhibition in vivo. The positive results in this study indicated the potential of nanosized dynamic biointerfaces in nanomedicines. Form another point of view, this work also demonstrated that dynamic synthetic biointerfaces could be employed for regulating specific cell apoptosis, thus showing wider prospects in biomedical applications.

phenylalanine) that is abundant in mussel secreted proteins (Figure 3b).38 Because the catechol group in (DOPA)4 can bind with PBA through the formation of quadruple phenylboronate ester bonds, the biomimetic peptides could be efficiently bound on the PBA-containing substrate and leave the bioactive X sequence exposed for cell recognition. Similar to the above glycopolymer-based dynamic system, addition of excessive sugars (e.g., glucose or fructose) to this musselinspired system could induce the release of surface bound peptides, exhibiting a sugar-responsive presentation of bioactive ligands. To demonstrate the versatility of this dynamic biointerface, two different cell binding sequences (i.e., the cell adhesive factor RGD and the MCF-7 tumor cell targeting peptide WxEAAYQrFL39) were tactfully involved into the biomimetic peptides (Figure 3d). In vitro experiments indicated that the sugar-responsive biointerface enabled not only dynamic modulation of stem cell adhesion behaviors but also selective isolation of tumor cells (Figure 3e and f). Considering the sugar-sensitive physiological stimulus, the biomimetic nature of peptide ligands, and the flexibility in bioactivity selection, we believe that such mussel-inspired, phenylboronate-based dynamic synthetic biointerface would show promise in wider areas ranging from fundamental cell biology research to cell-based regenerative medicine and cancer diagnostics. Besides the above macroscopic systems for interfacial cell behavior modulation, micro- or nanosized biointerfaces with dynamic surface bioactivity may also exhibit wonderful properties that are desired in cancer theranostics. Owing to the mildly acidic tumor microenvironment,40 the pHresponsiveness of phenylboronate ester bonds might be useful for surface engineering of nanomaterials and modulation of targeted cancer-nanomaterial interactions. In this context, we designed a pH-sensitive phenylboronate-coordination-polymer-coated polydopamine nanocomplex decorated with catechol-capped poly(ethylene glycol) (PEG) for tumortargeted chemo-photothermal therapy (Figure 4a).41 Due to the dynamic PEGylation based on phenylboronate ester bonds, the nanocomplexes could maintain stable PEGylation at physiological condition and exhibit gradual de-PEGylation under mildly acidic condition (pH 6.5) (Figure 4b). Since PBA group is an efficient targeting ligand for sialic acid (SA)overexpressed tumor cells,42 the nanosystem could be considered as a smart synthetic nanobiointerface that enable

3.2. Benzoic-Imine Bonds

Benzoic-imine is a mildly acid-cleavable covalent bond, while normal cellular processes commonly do not involve pH changes in the surrounding ECM environment. Thus, the pH-responsiveness of benzoic-imine bonds are rarely used to fabricate dynamic synthetic biointerfaces for the control of cell adhesion and growth behaviors, and so does the pH-sensitivity of phenylboronate ester bonds. To overcome such restriction, we likewise begun to pay attention to the concept of nanosized biointerfaces because of their potential to dynamically modulate the cancer-nanomaterial interactions under mildly acidic tumor microenvironment and improve the efficiency of nanomaterials for cancer therapy.43,44 Similar but not identical to the concept of the phenylboronate-based dynamic nano-biointerface, we designed a mesoporous antitumor nanoplatform that was dynamically immobilized with the bioactive antitumor drug doxorubicin (DOX).43 The antitumor nanoplatform was fabricated by conjugating the amino-containing DOX molecules on the pore outlets of a benzaldehyde-functionalized mesoporous silica nanoparticle through pH-sensitive benzoic-imine bonds (Figure 5a). In this design, a pH-responsive dynamic nanobiointerface was involved in the nanosystem and used for controlled release of bioactive antitumor drug DOX (Figure 5b). Under normal physiological condition, the nanoplatform is stable; in case of being at mildly acidic tumor tissue (pH 6.5), DOX molecules could be efficiently released form the pore channels to interact with surrounding tumor tissue, leading to rapid tumor cell apoptosis. In vitro and E


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and disulfide) for the intelligentialization of nanomaterial surfaces and apply them in broader biomedical applications.

4. DYNAMIC BIOINTERFACES BASED ON METAL COORDINATION CHEMISTRY Metal coordinations naturally exist in metalloproteins (e.g., hemoglobin, cytochromes, carboxypeptidases, and matrix metalloproteinases), which are crucial to the biofunctions like enzymatic reactions, metabolism, oxygen transport, and storage.29 These biologically existing interactions thus are relatively more biocompatible than nonbiological chemical bonds. To fabricate a coordinative biointerface for dynamic control of cell behaviors in a biocompatible manner, metal ions and bioligands should be rationally selected according to these natural coordinations in biosystems. Considering that Mg2+ is a proadhesive divalent cation that can coordinate and activate metal-ion-dependent adhesion site in integrins,45 Kang et al. reported a switchable synthetic biointerface for dynamic and combinatorial presentation of integrin-binding cell-adhesive moieties (i.e., RGD peptide and Mg 2+ ) through the spontaneous and convertible coordination between Mg2+ and bisphosphonate (BP) ligands (Figure 6).46 A BP-coated gold nanoparticle (BP-AuNP) on a substrate was first prepared to allow in situ self-assembly of cell adhesive Mg-BP complexes on it via Mg2+-BP coordination. Another cell adhesive moiety RGD peptide was further in situ coordinatively assembled on the substrates to form a dual active RGD-BP-Mg2+-BP nanocomplex. Since ethylenediaminetetraacetic acid (EDTA)-based Mg2+ chelation allows in situ disassembly of Mg2+-BP complexes, the resultant biointerface exhibited reversible cell adhesion and release. After subcutaneous implantation of (BP-AuNP)-grafted substrates into mice and injection of BP and Mg2+, EDTA, or RGD-BP and Mg2+ on the substrates, in situ Mg-BP assembly (“ON”), reversible Mg BP disassembly (“ON → OFF”), and RGD BP Mg assembly (“Dual ON”) could be respectively demonstrated in vivo. Furthermore, the “Dual ON” RGD-BP-Mg2+-BP nanocomplex could greatly tune and promote focal adhesion and spreading both in vitro and in vivo. Therefore, the modular nature of this coordination-based dynamic biointerface shows the potential

Figure 5. Benzoic-imine-based dynamic nano-biointerface as antitumor nanoplatform. (a) Dynamic doxorubicin (DOX) and benzaldehyde complex via pH sensitive benzoic imine bond. (b) Schematic illustration of the nanobiointerface with dynamic DOX conjugation on mesoporous nanoparticle. (c) Enhanced nanoparticles accumulation in the tumor regions and (d) improved tumor inhibition (reduced tumor tissue size). Reproduced with permission from ref 43. Copyright 2017 John Wiley and Sons.

in vivo results both confirmed the advantages of this pHresponsive nano-biointerface, i.e., acid-enhanced tumor cell uptake, specific nanoparticles accumulation in tumor regions, and improved cancer therapy outcomes (Figure 5c and d). This work, together with the above phenylboronate-based nanosystem, jointly suggested that the dynamic nanobiointerfaces are very useful in the design of smart nanomaterials with controlled cancer-targeting ligands and antitumor bioactive molecules for cancer therapy. Not only that, the paradigm shift from macroscopic to microscopic also inspire us to explore more potential reversible covalent bonds (e.g., acylhydrazone

Figure 6. Switchable biointerface (a) for dynamic and combinatorial presentation of cell-adhesive moieties RGD-BP-Mg2+-BP nanocomplex through coordination between Mg2+ and bisphosphonate (BP) ligands and (b) for the regulation of cell adhesion and release. (c) Quantification of the adhered cell density in vivo. Reproduced with permission from ref 46. Copyright 2018 John Wiley and Sons. F


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Figure 7. (a, b) Two mussel-derived peptides with catechol groups and bioactive motifs. (c) Spontaneous surface peptide engineering on medial Ti screw though the coordinations between the TiO2 and catechol groups. (d) Rapid peptide coating on a TiO2 substrate. (e) Enhanceed ALP activity and (f) calcium deposition on the peptide-treated substrate in vitro indicated the efficient improvement of osteogenesis. (g) Representative histological images indicated the enhanced osteogenesis at the surface of Ti implants in vivo. Reproduced with permission from ref 48. Copyright 2016 American Chemical Society. (h) Schematic illustration of the coordination-based biointerface on Ti implant for the regulation of interfacial cell differentiation. Reproduced with permission from ref 49. Copyright 2018 American Chemical Society.

(DOPA)4-G4-YGFGG, both consisting of a catechol-containing (DOPA)4 sequence, a quadriglycine G4 placeholder and a bioactive peptide sequence (i.e., cell adhesive peptide RGDS or osteogenic growth peptide YGFGG) (Figure 7a and b).48 The mussel-derived peptides can spontaneously and stably bind on medical Ti implants via strong coordinations between the catechol groups and TiO2 layer of the implant (Figure 7c and d). Due to the synergy of cell adhesive peptide RGD and osteogenic peptide YGFGG in osteoblast differentiation, the peptide-functionalized Ti surfaces exhibited significantly improved cell adhesion, proliferation, osteogenesis in vitro (Figure 7e and f). More importantly, the peptide-functionalized Ti screws exhibited enhanced osseointegration and improved mechanical stability in vivo (Figure 7g). The results successfully demonstrated the superiority of coordinationbased synthetic biointerfaces for the biofunctionalization of metal implants, which will direct interfacial stem cell differentiation into the osteoblasts (Figure 7h). We also successfully applied this mussel-inspired peptide-coordination strategy for Ti implants under clinically challenging conditions (e.g., osteoporotic and wear-debris-induced osteolytic models49,50), showing efficient inhibition of the interfacial osteoclastogenesis. These studies further verified the potential of dynamic coordination chemistry for surface bioengineering of medical metal implants. Although the reversibility of these systems needs further explorations, the spontaneous nature of

for in situ introduction of multiple bioactivities to regulate diverse cellular functions (e.g., cell adhesion, migration, and even differentiation) in vivo. Further inspired by the spontaneity and renewability of metal coordinations, we considered to apply coordination chemistry for surface bioengineering of clinical metal implants. The motivation derived from (1) the bioinertness and low bioactivity of metal implants (e.g., Ti and its alloys) that probably cause implant loosening and failure of the implant in orthopedics and dentistry; (2) the complexity of traditional chemical strategies for the introduction of bioactive ligands on metal implants, such as tedious chemical reactions, nonbiocompatible chemical linkers as well as sophisticated techniques and instruments;47 (3) the potential coordination between metals and biomolecules with functional groups (e.g., bioactive peptide or proteins). In this context, well-designed coordinative strategies for surface introduction of desired bioactivity on metal implants may show remarkable superiority, owing to the direct, spontaneous, and renewable interactions between bioactive molecules and metal surfaces. In other words, the dynamic property of a coordination-based biointerface may overcome most of the common drawbacks of metal implants in clinic. To demonstrate the potential of coordination chemistry in surface engineering of metal implants, we designed two musselderived bioactive peptides (DOPA) 4 -G 4 -GRGDS and G


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Figure 8. (a, b) Strategy to fabricate cell adhesive peptide RGDS-imprinted biointerface with thermoresponsive affinity. (c) Gradual cell release from the thermoresponsive biointerfaces at 20 °C. (d) Noninvasive harvesting an intact cell sheet from the biointerface at 20 °C. Reproduced with permission from ref 54. Copyright 2013 John Wiley and Sons.

adhesive protein fibronectin (FN).51,52 Similarly, Wu et al. reported an ovalbumin protein-imprinted multilevel membrane for cell adhesion and detachment.53 However, the recognition properties in these studies were relatively weak, compromising the end objectives of the study. More importantly, these systems lacked a dynamic mechanism for modulating cellmaterial interactions, e.g. obtaining transformation of the cell adhesive behaviors by reversible protein binding. To address this problem, we prepared a novel MI-based biointerface for reversible cell adhesion that relied on a poly(N-isopropylacrylamide) (PNIPAm)-based hydrogel layer with thermoresponsive affinity toward a cell adhesive peptide RGDS (Figure 8).54 The thermoresponsive hydrogel layer was designed with high RGDS affinity at physiological temperature 37 °C and low RGDS affinity as the temperature was decreased. With RGDS peptide binding at 37 °C, the imprinted hydrogel layer showed excellent cell adhesion behavior, and more excitingly, the adhered cells could be rapidly release at 20 °C due to the temperature-triggered release of RGDS peptides and surface wettability changes. To the best of our knowledge, this was the first sample that successfully used molecularly imprinted synthetic receptor for modulating dynamic cell-material interactions. Moreover, the near-physiological temperaturestimulus used in this system indicated the control of cell adhesion behaviors was realized in a noninvasive manner.

coordination chemistry still endows the coordination-based synthetic biointerfaces with semidynamic properties, e.g., postbiofunctionalization or bioactivity regeneration by in situ injection of the peptide ligands. In short, the concept of coordination-based semidynamic synthetic biointerfaces involved in this work would provide a facile, safe and effective means for improving clinical outcome of metal medical implants.

5. DYNAMIC BIOINTERFACES BASED ON MOLECULARLY IMPRINTED SYNTHETIC CHEMISTRY In comparison to the “finiteness” of reversible covalent and coordinative interactions that have been discovered, molecular imprinting (MI) technology can provide molecularly tunable affinity in analogy with natural receptor−ligand interactions. In theory, the imprinting process can be used to tailor reversible interactions toward any kind of ligands, including small molecules, peptides, and even proteins.30 Thus, a MI-based dynamic synthetic biointerface could be easily fabricated by directly surface imprinting a bioactive ligand (e.g., cell adhesive peptide or protein) that can bind specifically to the cell membrane receptors. The groups of Ciardelli and Kazuhiko first studied the cell adhesion or proliferation behaviors on MIbased biointerfaces with molecular affinity toward a cellH


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Figure 9. (a) Generation of epitope-imprinted biointerface (EIB) for dynamic control of cell adhesion. (b) Binding isotherms for the epitope peptide to EIB and NIB (i.e., the control nonimprinted biointerface) in PBS. (c) Selective binding toward different peptides. (d) Fluorescence intensity changes of the FITC-epitope bound surfaces after incubation in PBS. (e) Fluorescence images of the surfaces (e1, e3) with FITC-epitope and (e2, e4) without FITC-epitope after 12 h incubation in PBS. Scale bar 500 μm. (f) Epitope peptide-induced changes of cell release on the epitope-imprinted biointerface (EIB). Scale bar 50 μm. Reproduced with permission from ref 55. Copyright 2017 John Wiley and Sons.

epitope recognition sites and release it via epitope peptidetriggered molecular exchanging mechanism (Figure 9c and d). In vitro experiments showed that, cells could specifically adhere on the RGD-bound surface, while the addition of an appropriate amount of the epitope peptide to the cell culture medium could induce a gradual transition of cell morphology from spread-out shape to round shape and a release of them in 4.5 h (Figure 9f). These results again demonstrated the feasibility of molecularly imprinted synthetic receptors for the fabrication of dynamic synthetic biointerface. More excitingly in this work, the cell behaviors could be regulated by specific biomolecule that could be presupposed during the epitope imprinting process. As compared to the limited chemical means to achieve dynamic ligand presentation, such molecularly tunable dynamic system may unlock new applications in in situ cell biology, cell-based diagnostics and regenerative medicine.

Further in this study, the MI-based dynamic biointerface was innovatively used as a highly efficient system for harvesting intact cell sheets, thus showing the promise in cell-based and scaffold-free tissue engineering. A critical issue worth mentioning in the above system is the poor accessibility of the bound peptides or proteins embedded in the above MI-based biointerfaces, which greatly decreased the efficiency of surface bioactivity presentation and the subsequent cell recognition. Taking the biomolecular imprinting strategy one step further, we recently employed an epitope imprinting strategy for dynamically display bioligands on the material interface and reversibly control cell adhesion behaviors (Figure 9a).55 The epitope imprinting process referred to the use of a terminal short peptide sequence (i.e., the epitope) of an RGD-containing long peptide as the template for surface imprinting, thus allowing the surface to bind the terminal epitope peptide and free up the bioactive RGD sequence in the opposite end for cell recognition. To obtain high affinity, benzamidine-bearing monomer and carboxyl-containing epitope peptide were chosen to enhance imprinting efficiency, in view of the strong and reversible electrostatic interaction in benzamidine-carboxylate complex. Isothermal adsorption experiments revealed that the epitopeimprinted biointerface (EIB) exhibited excellent peptide selectivity and high association constant (Ka = 9.75 × 107 M−1) that is comparable to the nature receptors (Figure 9b and c). Qualitative and quantitative analysis on the fluorescence binding experiments demonstrated that the EIB could stably bind to the epitope peptide through surface

6. CONCLUSIONS AND OUTLOOK Dynamic synthetic biointerface is an emerging frontier in biomaterial science for the purpose of chemical mimicking the dynamic properties of ECMs. The paradigmatic examples discussed in this Account mainly highlight the reversible chemical strategies we recently used for the exploitation of smart biointerfaces with noninvasive and reversible bioligand presentation. Apart from the traditional host−guest supramolecular and photoelectric chemistry, reversible covalent chemistry, metal coordination chemistry and molecularly imprinted synthetic chemistry have emerged as new driving I


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Accounts of Chemical Research forces for dynamic display of the bioactive ligands. By rational molecular design, the dynamic synthetic biointerfaces could also be endowed with diverse biofunctions (e.g., regulating cell adhesion, directing cell differentiation and targeting cell apoptosis) and tunable sizes from macroscopic to microscopic (e.g., dynamic nano-biointerfaces). These advances greatly expanded the potentials of dynamic synthetic biointerfaces in areas ranging from fundamental cell biology to various biomedical applications, including regenerative medicine, biomaterial engineering, cancer diagnosis and therapy. In essence, the cellular processes are the results of a series of chemical interactions. Thus, the integration of reversible chemistry in dynamic synthetic biointerfaces is of great importance for scientists to study and mimic the biochemical processes in biosystems. Despite the tremendous progress in this field, dynamic synthetic biointerfaces is an area still in its infancy. Further efforts need to be done on the exploration of new chemistries, new biological responsiveness, and new biofunctions in the future concept of dynamic synthetic biointerfaces. Some dynamic chemical bonds like the pH-responsive acylhydrazones, glutathione-sensitive disulfide bonds, and matrix metalloproteinase (MMP)-cleavable peptide bonds have not been studied yet, while these novel chemistries may show unpredictably new biofunctions during the modulation of cellbiomaterials interactions. For instance, nanomaterials with pHand glutathione-responsive surface properties are very attractive in nanomedicine; and MMP-sensitive biointerfaces could be used to study the mechanism of ECM remodeling process, thus being very useful in tissue engineering and regenerative medicine. Molecularly imprinted synthetic chemistry also needs to be further explored, in particular, the bioactive molecular imprinting. MI-based biointerfaces with dynamic molecular affinity toward bioactive molecules like the growth factors are very appealing for the control of stem cell fate and are highly desired in regenerative medicine. In addition, an evolution of these ECM mimics from 2D to 3D level is urgently needed for advanced biomedical applications. Integration of dynamic bioactivity presentation into the 3D networks of tissue engineering scaffolds may endow these biomaterials with properties and functions closer to a natural ECM. We strongly believe that, with the development of chemical science and material engineering technology, dynamic synthetic biointerfaces will play a continuously and increasingly significant role in bridging the gap between chemistry and biology.

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Jiangsu University, China. Her research interests include molecular imprinting, polymer chemistry and biomaterials. Xiaohua Tian is currently a Ph.D. candidate in the Institute for Advanced Materials, School of Materials Science and Engineering, Jiangsu University. Her research interests mainly focus on the development of smart materials and interfaces for biomedical application. Lei Liu received his Ph.D. degree in National Center for Nanoscience and Technology, China and performed his postdoctoral research in iNANO, Aarhus University, Denmark. He is now a full professor and the deputy director of Institute for Advanced Material, School of Material Science and Engineering, Jiangsu University. His research interests focus on peptide self-assembly, peptide-based nanomaterial and related biomedical applications. Jianming Pan was awarded his Ph.D. degree in Environmental Engineering by Jiangsu University in 2012. He is now a full professor in the School of Chemistry and Chemical Engineering, Jiangsu University. His research interests include polymer chemistry, molecular imprinting, specific separation, and electrochemical (bio)sensors. Guoqing Pan is currently a full professor in the Institute for Advanced Materials, School of Materials Science and Engineering, Jiangsu University. He obtained his Ph.D. degree (2011) in Polymer Chemistry and Physics from Nankai University, China. He has been supported by the EU “Horizon-2020″ action as a Marie-Curie Individual Research Fellow (2015) in Malmö University, Sweden. His research interests encompass dynamic biointerfaces, molecular imprinting, synthetic polymers, and biomaterials as well as functional and intelligent nanomaterials for biomedical applications.

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ACKNOWLEDGMENTS We greatly acknowledge the financial support from the National Natural Science Foundation of China (21875092, 21574091, and 21706099), the Natural Science Foundation of Jiangsu Province (BK20160056 and BK20160491), the “Six Talent Peaks” program of Jiangsu Province (2018-XCL013), and China Postdoctoral Science Foundation funded project (2018M642174).

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AUTHOR INFORMATION

Corresponding Author

*Fax/Tel: +86-511-88783268. E-mail: [email protected]. cn. ORCID

Lei Liu: 0000-0002-6265-9412 Guoqing Pan: 0000-0001-5187-796X Notes

The authors declare no competing financial interest. Biographies Yue Ma completed her Ph.D. thesis in Polymer Chemistry and Physics (2014) at Nankai University, China. She is now a research assistant in the School of Chemistry and Chemical Engineering, J


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