Harnessing Supramolecular and Peptidic Self-Assembly for the

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Harnessing Supramolecular and Peptidic Self-Assembly for the Construction of Reinforced Polymeric Tissue Scaffolds Chase B. Thompson and LaShanda T. J. Korley* Department of Macromolecular Science and Engineering, Case Western Reserve University, Cleveland, Ohio 44106, United States ABSTRACT: The repair and regeneration of the body’s tissue using polymeric materials remains a main focus of biomaterials research. While hydrogels and elastomers have shown biocompatibility and high extensibility, they lack the required toughness to host proliferating cells. As the need for robust polymeric scaffolds grows, new technologies must emerge to meet the stringent physical and biological needs of proliferating cells. To this end, the utilization of self-assembling motifs allows for the construction of versatile networks in which cells can grow. In this review, we discuss emerging techniques that harness the assembling capabilities of synthetic supramolecular and natural peptide motifs to construct mechanically robust elastomers and hydrogel scaffolds. In particular, we focus on how the design and structure impact their mechanical properties and interaction with the cellular environment.

1. INTRODUCTION Damage to the body’s tissues or vital organs can lead to injuries too great for the body alone to repair, often requiring surgery and prolonged recovery.1 In many cases, organ transplants or skin grafts are the only viable means of treatment; however, rejection of the transplanted organ and difficult surgical procedures make transplants a dangerous treatment fraught with difficulties. Transplantation of external organs into a host requires the patient to adhere to a regimen of immunosuppressants to prevent the rejection of the transplanted tissue.2 However, the possibility of selective transplantation, in which only the damaged tissue is replaced, drew the interest of researchers and surgeons and opened the door to creating platforms to which cells can adhere and proliferate more readily.3 This rudimentary platform was generally an injected cell suspension, which meant that the graft size was limited by the ability of cells to anchor themselves in the surrounding tissues to begin the repair process.3 However, in 1988, the development of the first polymeric scaffold allowed for cultured cells to be successfully implanted and grown within a rat model, displaying the ability of polymeric materials to behave as support structures during tissue repair.4 With this landmark development, a paradigm shift in tissue regeneration and repair emerged; rather than replace whole organs, the use of a mechanically robust polymer scaffold allows for cells to proliferate through the matrix within a physical polymeric support, promoting tissue repair without the need for moreinvasive surgeries. Constructing new polymer-based scaffold structures has remained an important facet of biomaterials research, and materials, such as biocompatible elastomers and hydrogels, have emerged to meet the needs of researchers. Elastomeric materials offer high extensibility and in vivo stability imparted by their loosely cross-linked or entangled polymer networks.5 Hydrogels, however, boast exceptional © XXXX American Chemical Society

biocompatibility due in part to the presence of high amounts of water in their swollen networks. Due to their generally low modulus and toughness values, the application of elastomers and hydrogels in vivo is limited to softer tissues; indeed, tissues show modulus values of around 100 Pa for soft organs such as the brain, while muscle tissues can boast modulus values of 100 kPa or more.6 With these large variances in tissue properties, fabricating appropriate scaffolds becomes a complex task. The scaffolds must be able to withstand deformations while remaining biocompatible, such that toughening mechanisms must not interfere with the proliferation of cells throughout the network.5 One approach toward toughening polymeric scaffolds is the utilization of a self-assembled architecture. Here, “selfassembly” specifically refers to directed noncovalent interactions that take place between two or more interactive “sites” on the assembling motifs. These transient linkages can be driven by ionic interactions, hydrogen bonding, π−π stacking, etc.7 To offer mechanical stability to a network, the assembled groups must exhibit noncovalent bond lifetimes that exist on experimental timescales, which can be introduced by using strong interactions (e.g., ionic bonding, metal−ligand coordination) or by having multiple, complementary interaction sites on a single molecule (e.g., hydrogen bonding, π−π stacking); it is not uncommon for these self-assembling motifs to combine two or more of these interaction types.7,8 The resultant structures exhibit unique characteristics that impact both the microscopic and macroscopic properties, including phase morphology and viscoelastic mechanics, respectively. With a wide array of architectures available, self-assembled constructs Received: February 28, 2017 Revised: April 5, 2017

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DOI: 10.1021/acs.bioconjchem.7b00115 Bioconjugate Chem. XXXX, XXX, XXX−XXX

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Figure 1. Depiction of synthetic (left) and peptide (right) self-assembled architectures.

networks. However, by including noncovalent interactions within the network, properties of polymers can be varied to result in materials that exhibit more stiffness and high crystallinity or result in extensible tough networks. While elastomers and hydrogels exhibit different characteristics and in vivo responses, both families of materials suffer from low toughness and mechanical properties reliant on cross-links, composite fillers, or double networks. However, introduction of such reinforcement strategies leads to issues such as increased or irregular in vivo degradation and hazards during materials fabrication.22 In this review, we focus on the reinforcement of tissue engineering scaffolds with self-assembling synthetic supramolecular motifs or peptide units; by introducing transient linkages, system properties can be tuned to meet the needs of the implantation site. Due to the challenges these material systems face as scaffolds, the review will be split into a discussion of self-assembly in elastomers and hydrogels. These systems’ properties and capability to reinforce the cellular environment is a consequence of their design, and each self-assembling moiety will exhibit different responses to mechanical deformation and various stimuli while also displaying unique interactions with the seeded cells and environments both in vitro and in vivo. This review reports recent technologies in the fields of self-assembling elastomeric and hydrogel-type scaffolds and discusses how the design and implementation of different self-assembling structures gives rise to unique properties.

have found a myriad of applications, including as drug-delivery vehicles,9,10 healable polymer systems,11,12 and tissue scaffolds.13 Supramolecular polymers incorporate functionalities capable of self-assembly; these motifs are attached to the polymer backbone in a postpolymerization process or are incorporated into the monomer units before polymerization takes place. Supramolecular interactions fall into two broad categories. When two or more separate moieties are required to form the transient linkage, a complementary interaction occurs (Figure 1); the strength of these networks are, therefore, dependent on the stoichiometry between the assembling components.7,14 However, stoichiometry-independent interactions can also be achieved when a supramolecule is capable of forming an interaction with itself, resulting in self-complementary interactions (Figure 1). Inspired by nature, similar assembly can be incorporated into polymeric networks by harnessing the hierarchical arrangement of peptides.5,15,16 Peptides may be constructed from a single type of amino acid or mimic the amino acid sequences morecommonly seen in nature. These materials give rise to α-helices or β-strand structures, as dictated by the substituents on the amino acid residues (Figure 1).15 Peptides are attractive selfassembling motifs due to their programmable assembly, which yields predictable architectures upon interaction of the peptidic domains.17 Complex assemblies are achieved through the precise placement of hydrophobic, hydrophilic, or ionic amino acid species along the peptide sequence. The α-helices and βstrand structures can further assemble to form higher-order coiled coils and β-sheets, respectively, that offer structural and mechanical support to the system (Figure 1).17 Peptides have remained popular as biomaterials due to their ability to interact favorably with their in vivo environment through cell signaling via the attachment of biologically responsive sequences that can direct cell differentiation and adhesion.18 Furthermore, more complex peptide structures can be produced that exhibit higherorder structures and stimuli-responsiveness as a consequence of complex folding patterns.17,19 While such hierarchical peptides have been successfully applied to dynamic biomaterials, their use is outside the scope of this review.20 Self-assembly spans a wide array of molecules that result in different constructs and properties, allowing for tunability in the resultant scaffold properties.21 As mentioned above, conventional scaffolds suffer from low toughness values that are typically improved through the use of composites or double

2. SELF-ASSEMBLED ELASTOMERS Elastomers are attractive engineering materials due to their high extensibility and recoverable strain range. Structurally, elastomers are connected through cross-links or (in the case of thermoplastic elastomers) by loose entanglements that assist in maintaining structural integrity when deformed.22 These flexible networks exhibit glass transition temperatures (Tgs) below their application temperature, allowing for segmental mobility in the chains when stresses are applied. However, elastomeric polymers typically exhibit low toughness due to their loosely linked chain architectures, limiting their applications in vivo. To alleviate these issues without sacrificing extensibility, new methodologies, such as interpenetrating networks or nanoparticle fillers, have emerged. While these modified elastomers show marked toughness increases, they are plagued by tedious fabrication methods. B


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Figure 2. (a) Synthesis of isocyanate-terminated UPy synthon and (b) structure of chain-end (top) and chain-extended (bottom) UPyfunctionalized polymers.

resultant polymers, with many polyolefins and polyesters capable of being functionalized with a wide range of resultant properties.23,26−28 UPy has become somewhat of a model supramolecule due to its simple synthesis and strong associations in both the solid and the solution state. Further control over system properties can be achieved by slight modifications to the chain architecture; that is to say, by changing the location of the UPy moiety along the backbone. When a telechelic oligomer is functionalized with UPy units, it typically exhibits both polymeric chain extension through linear dimerization as well as the formation of UPy “clusters” that behave similarly to cross-linking junctions.29,30 These materials show microphase separation and large increases in the stiffness when compared to the precursor polymer. However, when utilized as a chain extender (similar to polyurethane systems) with isophorone diisocyanate (IPDI), the chain-centered UPy moieties (Figure 2b) are able to behave like interchain crosslinks on experimental timescales, and the resultant polymer displays characteristics similar to a soft elastomer, which is attributed to the bulky IPDI molecules preventing separating of the hard UPy phase.31 While both of these functional-PCL derivatives displayed either high stiffness or low toughness, the substantial differences in their crystallinity and mechanics allowed for in vivo responses to be accordingly tuned upon implantation through blending the two systems. Blends containing the softer, amorphous polymer showed higher cell penetration and a more-pronounced response at the interface, while the crystalline telechelic species offered higher structural integrity in the blends. Through changes in the amounts of both species, scaffold properties could be tuned to offer the required stiffness without eliciting an immunogenic response.31 Moreover, these PCL-based telechelic supramolecular materials have much lower processing temperatures; due to the transient nature of the network and the typically low molecular weight of the precursor polymers, heating them above their dissociation temperature leads to low-viscosity melts. This approach allows for the materials to be processed along with thermally sensitive materials, such as peptide sequences, without leading to degradation. Dankers et al. synthesized UPy-modified Gly−Arg−Gly−Asp−Ser (UPy− GRGDS) and Pro−His−Ser−Arg−Asn (UPy−PHSRN) and blended these peptide sequences with telechelic UPy−PCL.32 Due to the dimerization of the UPy units, the modified peptides were directly incorporated into the scaffold. When

However, the incorporation of noncovalent interactions into networks offers toughness enhancement by alleviating applied stresses through energy dissipation, with transient linkages acting as reversible sacrificial bonds. The inclusion of supramolecular groups or peptides stiffens the network through induced ordering, partially caused by microphase separation due to incompatibilities between the self-assembling moieties and the parent polymer chain. 2.1. Supramolecular Elastomers. The introduction of supramolecular functionality allows for the fabrication of elastomeric polymer networks that, due to the presence of strong transient interactions between chains, toughen the resultant material. When short or “soft” polymers are utilized, the system retains a Tg below ambient or physiological temperatures, while retaining the toughening effects of the supramolecular assembly. These systems show remarkable increases in toughness and modulus, all while retaining high extensibility.21,23 When deformed under short timescales, these supramolecular junctions behave similarly to covalent crosslinks due to the inability of the transient interactions to dissociate or relax. However, on longer timescales of deformation, the noncovalent interactions associate and dissociate many times, allowing for synergistic energy dissipation during network rearrangement.24 Even more remarkable, these deformations are largely recoverable, and many of these elastomers boast low hysteresis even when exposed to large cyclic deformations. It has not gone unnoticed that the toughness and extensibility of these elastomers could be manipulated to mimic the properties of natural tissues under cyclic loadings, such as cardiac or vascular tissues. Isocyanate-terminated 2ureido-4[1H]pyrimidinone (UPy) has been become one of the most popular supramolecular moieties in the field, due in part to the wide array of polymers to which it can be attached (Figure 2a).23 The strength of this supramolecular group lies in its bonding array: the donor−donor−acceptor−acceptor (DDAA) arrangement of the hydrogen bonding sites allows for transient network formation that is independent of stoichiometry. Moreover, stacking of the resulting UPy dimers further reinforces the network and drives phase separation into “hard” and “soft” domains. Microphase separation, driven by the crystallization of these UPy stacks, yields fiber-like phases in a matrix of the soft polymer backbone.25 Part of UPy’s versatility lies in its functional flexibility and the tunability of C


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Bioconjugate Chemistry seeded with cells, the scaffold showed vascularization and macrophage infiltration likely caused by the integrin-binding peptides present in the scaffold. Utilizing UPy in such a manner allows for the simple incorporation of peptides in these networks and could facilitate the production of compatiblized supramolecular scaffold “blends” that forego the need to synthesize complicated block copolymers or covalently grafting peptides to a polymer chain.33−36 If an increase in the overall polymer molecular weight is desired, utilization of pendant supramolecular groups allows for similar increases in mechanical response without the need for telechelic polymers.37 This functionalization strategy allows for the mechanics to be dictated by the amount of UPy incorporated. For example, Chen et al. attached UPy to pendant hydroxyl groups along the backbone of poly(sebacoyl diglyceride) to yield toughened elastomers.40 By changing the amount of UPy attached to the reactive sites, the stiffness and extensibility of the elastomer could be tuned due to the transient cross-links that form between the pendant UPy motifs. Furthermore, Feldman et al. showed that the bulk relaxation properties in such pendant-functionalized elastomers is largely dependent on the spacing of the UPy groups along the backbone, and “clustering” the supramolecular units dramatically increases the relaxation times in such materials, impacting important properties, such as stress relaxation or creep, of such networks.41 Due to the reversible nature of the supramolecular linkages, there is a constant association− dissociation equilibrium occurring in which these supramolecular groups can rearrange and interact freely on experimental timescales, making these elastomers potential candidates for vascular or cardiac stints.5,21 While UPy has certainly dominated the field of supramolecular scaffold materials, these elastomers are not limited to hydrogen bonding motifs; ionic interactions have also been explored as a route to self-assembly. The incorporation of ionic interactions can be generated by a simple proton transfer between carboxylic acids and amines. In one example of such an elastomer, Daemi and colleagues constructed an ionic polyurethane from a PCL block chain-extended with cationic Nmethyldiethanolamine (MDEA) reacted with alginate.42 Compared to a nonionic PU control, the ionic networks showed marked improvements in mechanical properties, displaying a nearly 7-fold increase in Young’s modulus and significant increase in strain-at-break in networks with a 1:1 ratio between the cationic MDEA groups and anionic alginate carboxylate groups. These networks exhibited low hysteresis even after exposure to 100 deformation cycles (Figure 3a), experiencing little viscous loss that is uncharacteristic of typical “linear” systems; these supramolecular PU materials also exhibit exemplary deformation recovery with complete restoration after only 5 s (Figure 3b). While degradation of elastomers can be complicated due to the slow rate of hydrolysis, the in vitro degradation of the ionic polyurethane in the presence of Lipase enzymes nearly matched that of the polyurethane control. This phenomenon was attributed to the degradation-accelerating MDEA moiety. These degradation characteristics open up avenues for designing ionic supramolecules with tunable biodegradation rates. The inclusion of transient linkages into elastomeric species has been shown to increase toughness and stability without harming the biocompatibility of these networks. The low immunogenic responses elicited by these materials make them promising candidates for implants in load-bearing tissue regions

Figure 3. Mechanical properties of the ionic polyurethane elastomers showing their hysteresis behavior (a) and deformation recovery of the supramolecular PU sample compared to a PU control (b). Reproduced in part with permission from ref 42. Copyright 2016 Elsevier.

due to their mechanical stability. UPy is a model compound for the development of such tissue platforms, but other noncovalent interactions, such as ionic bonding, are emerging as viable platforms for the development of biocompatible elastomers. Further studies on material interactions with biological tissues, as well as more-in-depth studies on the in vivo stability of these elastomers at physiological temperatures, are required due to the high temperature dependence of transient linkages on the environmental conditions.43 Moreover, modeling and theoretical approaches to supramolecular chain behavior have offered insight into toughening mechanisms and potential new methods for fabrication of scaffold platforms. For instance, it has been shown that the introduction of covalent cross-links into such supramolecular materials increases the activation energy of the hydrogen bonding groups, such as UPy, while offering more opportunities for control of material properties. 37 Here, we have shown that, by incorporating supramolecules into elastomeric materials, enhancements in toughness can be achieved. Though supramolecular elastomers incorporating hydrogen bonding or electrostatic interactions have shown improved mechanical properties and desirable biocompatibility, there are still many unexplored avenues for the construction of these scaffolds. Other assembly routes, such as metal−ligand coordination or π−π stacking, have shown significant promise promise as healable supramolecular elastomers, but a focus in the area of tissue engineering scaffolds has been limited.38,39 2.2. Peptide−Polymer Conjugate Elastomers. Peptide incorporation has also piqued researchers’ interests as a route to elastomer reinforcement. Due to their spontaneous ordering into well-defined arrays, peptides are strong candidates for fabricating versatile biocompatible elastomers. For example, copolymers of poly(L-lysine) and PCL−poly(ethylene oxide) (PEO) yielded tough elastomers that showed desirable wettability when spun into nanofibers.44 The utilization of amino acid units, such as β-alanine, allowed for associations between neighboring amide groups to build “stacks” of D


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Bioconjugate Chemistry hydrogen bonds and reinforce the elastomeric networks. Through the utilization of stiff, aromatic precursors, hairpinlike turns forced the formation of parallel β-sheets.45,46 To gain better insight into the mechanical properties offered by peptides, Rathore and Sogah incorporated four or six alanine (Ala) segments into a PEG-based multiblock copolymer (Mn ≈ 20 kDa).47 The resultant elastomers had high β-sheet contents and displayed Young’s modulus values as high as 750 MPa when spun into fibers, although the resultant stiffness afforded by the high amounts of peptide lead to lowered extensibility. The high stiffness of these materials can be attributed to the intermolecular binding of the β-sheets, yielding hydrogen bonding “clusters” that were resistant to the applied stresses. Demonstrating the importance of secondary structure content, Tanaka and co-workers utilized poly(β-benzyl-Laspartate) (PBLA) to construct PBLA−PEO−PBLA triblock copolymers that showed variations in their mechanical properties upon annealing the films at 70 °C.48 At this temperature, melting of the central PEO block allowed for structural rearrangement of the α-helical segments into βsheets. The increase in β-sheet content led to an overall decrease in the PEO crystallinity, increasing the strain at break of the material by more than double that of the as-cast films; the presence of the stable β-sheets also gave rise to an overall increase in film toughness. In our own group, peptides have been utilized to synthesize a library of peptidic polyurethane-urea and polyurea systems that exhibit improved toughness in both linear and covalently crosslinked systems. Inspired by the “hard” and “soft” segments displayed in spider silk, triblock poly(benzyl-L-glutamate)− block-poly(dimethylsiloxane)−block-poly(benzyl-L-glutamate) (PBLG−b−PDMS−b−PBLG) was chain-extended with either a crystalline or an amorphous hard segment (HS) and 1,4butanediol, exhibiting microphase-separated morphologies with increased domain spacing upon inclusion of the peptide.49 The formation of β-sheets was also detected in the peptide conjugate elastomers utilizing wide-angle X-ray scattering (WAXS), showing that the spontaneous ordering of PBLG units was not suppressed even when coupled to the polymer, likely due to the phase incompatibility and unhindered mixing of peptide species in the melt or solution. When an amorphous HS was incorporated, three distinct morphological phases corresponding to the HS, soft segment (SS), and the peptide units were detected. These peptide-modified systems exhibited an increase in Young’s modulus but reduced extensibility when compared to neat polyurethane controls, which was attributed to the rigid β-sheet domains behaving as stiff, crystalline segments within the network that, under deformation, contribute to the HS mechanics. To enhance modulus without sacrificing elongation, non chain-extended polyurea networks containing copolymers of either poly(β-benzyl-L-aspartate) (PBLA) or poly(ε-carbobenzyloxy-L-lysine) (PZLY) utilizing PDMS as the central block were fabricated.50 In the polyurea networks containing five amino acid units, the stable formation of β-sheets yielded stiffer materials attributed to the mechanical stability of the intermolecular hydrogen bonds. However, as the amount of peptide increased from 5% to 20% by weight, the hard segment microstructure shifted from short, globular fibers to long, densely packed fibers, leading to an overall increase in mechanics (Figure 4). When the difunctional hexamethylene diisocyanate HS was replaced with an analog triisocyanate, covalently cross-linked networks were achieved; these networks

Figure 4. Morphology transformation in PBLA and PZLY peptide− PDMS linear triblock elastomers with increasing peptide chain length. Reproduced in part with permission from ref 50. Copyright 2014 Royal Society of Chemistry.

further restricted the mobility of the SS and the incorporated peptide, forcing it into parallel β-sheets (Figure 5).51 These materials exhibited a globular microstructure due to the restricted mobility upon introduction of the covalent crosslinks. The absence of antiparallel β-sheets and a fiber morphology allowed for 40 wt % of PBLA to be incorporated into the network, increasing the modulus and toughness without sacrificing material extensibility. These changes in mechanics can be attributed to the globular morphology; without the formation of a continuous fiber network as seen in the linear triblock systems, the system was more extensible due to the continuous SS formed by the cross-linked PDMS. These networks show promise as cell scaffolds with similar versatility E


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Figure 5. Structure of the linear and network non chain-extended peptide−polymer triblock polyurea elastomers. Reproduced with permission from ref 51. Copyright 2017 American Chemical Society.

introduced through covalent or physical linkages, seeded cells can freely diffuse throughout the system, adhere to growth factor expressions or other cells, and proliferation and tissue repair can take place without interference from the supporting polymer. However, while hydrogels show great promise in tissue repair applications, they are often plagued by low mechanical properties.56,57 In this way, directed self-assembly in hydrogels enables the strengthening of the network through transient interactions. However, whereas self-assembling elastomers require only that the transient interactions exist in high concentrations and with adequate experimental lifetimes to offer reinforcement, hydrogels must overcome another obstacle: water. Water disrupts hydrogen bonding interactions, one of the most-common pathways for inducing self-assembly into polymer systems. A question that arises when designing these hydrogels (and one of the first aspects of supramolecular design for these networks) is how to allow for the polymer to swell in water without compromising the lifetime and stability of the supramolecular interactions. However, despite this caveat, self-assembling hydrogels have shown great potential as tissue scaffolds and new methods to fabricate these materials are emerging rapidly. 3.1. Supramolecular Hydrogels. Incorporation of supramolecular interactions into hydrogel networks allows for improved structural and mechanical stability to be achieved without the need for challenging preparative processes or potentially toxic in vivo cross-linking methods.55 In supramolecular systems, assembly occurs within water in two primary methods: either the utilized self-assembly mechanisms are insensitive to the presence of water or they are sufficiently “shielded” to prevent water from penetrating their structure and disrupting the assemblies. Being one of the simplest routes to induce supramolecular assembly, ionic interactions have been utilized to fabricate supramolecular hydrogels, commonly from biopolymers such as chitosan and alginate due to the presence of ionizable groups along their backbones.58−61 These polymers show good biocompatibility, but suffer from network inhomogeneities caused by rapid cross-linking of ionic species, and instabilities

in these systems as observed in supramolecular elastomers. By altering the polymer chain architecture, changes to in vivo degradation and mechanical properties can be modified without sacrificing the hierarchical arrangements of the peptides. The incorporation of peptides into elastomeric tissue scaffolds allows for the construction of stable, tough networks that mimic the hierarchical structures seen in naturally occurring proteins, allowing for the incorporation of tunable amounts of α-helical and β-sheet structures. These elastomers display energy dissipation and toughening mechanisms induced by the phase separation of the peptide segments from the polymer matrix architectures that show a weaker dependence on temperature up until the dissociation or degradation of the ordered peptide segments. Moreover, the application of modeling studies allows for the morphology and chain packing of these peptide−polymer conjugates to be determined, giving insight into potential mechanical properties in such systems. Johnson et al. used coarse-graining modeling to determine the morphological transitions of PBLGA−PDMS−PBLGA and PDMS−PBLGA−PDMS triblock copolymers, defining the impacts of chain connectivity, functional group sterics, and block sizes on the final morphology of the elastomeric systems.52 The application of these parameters into other peptidic elastomers could redefine the final morphology and, as a consequence, the resultant mechanics. While these peptide− polymer conjugates display a wide array of properties and architectures, the actual inclusion of these elastomers in vitro or in vivo has been largely unexplored.

3. SELF-ASSEMBLY IN HYDROGELS In terms of biocompatible scaffolds, hydrogels have dominated the field due to their stable, swollen structures that offer mechanical reinforcement without hindering the transport of vital nutrients through the network.53,54 Typically, hydrogels consist of either water-soluble synthetic or biologically derived polymers covalently cross-linked through a wide variety of reactions, resulting in a swollen, continuous network.55 Consisting mostly of water, these materials exhibit desirable biocompatibility and cell penetration. When growth factors are F


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Figure 6. Live−dead assay of chondrocytes seeded on to different weight percent of assembled terpyridine gels (scale bar: 200 μm). Reproduced with permission from ref 70. Copyright 2015 Elsevier.

when submerged in an aqueous environment, such as those found in vivo, can lead to mechanical instabilities.58,59 However, their ease of fabrication has given rise to their incorporation into networks, where cross-linking is induced by either a dual cross-linking or double network approach.55,62−64 These materials are advantageous in that their mechanical properties can be tuned through the addition of more or fewer crosslinking counterions, which effectively increases or decreases the cross-linking density of the networks, respectively. These materials have found application as supports for the growth of axons and neurites.65,66 Among the primary noncovalent reactions utilized in supramolecular chemistry, metal−ligand complexation interactions encompass materials with some of the largest variations in binding strengths.67,68 From a design perspective, this presents both advantages and challenges; the choice of a metal center when designing such systems will dictate the assembly of the system and the timescale of the association dynamics between ligands and the metal center. With a seemingly infinite number of possible ligand and metal center combinations, metal−ligand coordination shows promise as a tunable platform for tissue repair.67 Indeed, the tough, stable nature of such gels has been utilized to construct a versatile bioadhesive to assist in the repair of trauma such as organ leaks and fistulas in a minimally invasive procedure.69 To design such an adhesive gel, gelatin was complexed with Fe3+ to encourage complexation between the iron particles and the many potential binding sites on the gelatin (carbonyls, hydroxyls, secondary amines, etc.). Further modification of pendant carboxylic acid groups with dopamine allowed for even stronger iron binding to occur. These materials showed little cytotoxicity and degraded in vivo after 14 days with the low amount of iron (∼68 mg Fe3+ per 1 mL of gel) being removed by iron-binding proteins. Taking the cytocompatibility of iron-based metallo complexes further, Wang et al. developed a tissue scaffold from 8-arm star PEG end-functionalized with terpyridine.70 When stoichiometric amounts of iron were present, successful binding of Fe2+

particles was achieved. These gels showed structural tunability dependent on the presence of the iron particles; nanogels or hydrogels could be formed favorably depending on the concentration of the components in water as well as the metal/ligand ratio. Cytotoxicity was low for these gelatin-Fe3+ gel complexes, but an interesting caveat in the design of these materials was observed (Figure 6). When chondrocytes were seeded onto materials that had an excess of uncomplexed terpyridine, cell death was evident due to the tendency of the free terpyridine moieties to sequester trace metals from the cell environment. An excess of Fe2+ did not prove to be cytotoxic, although lower DNA concentrations were noted in the seeded chondrocytes. This behavior only existed in systems in which the presence of intentional free terpyridines were used; once the iron complexes formed, no further metals were leached from their environment. While these metal−ligand gels form tough hydrogel networks, their development is still in its infancy and requires further research. A second route to designing supramolecular groups for use in hydrogels is to effectively “shield” the transient interactions from the surrounding water network through effective placement of hydrophobic groups on or around the self-assembling moieties. For instance, UPy, while hydrogen bonding and heavily affected by the presence of water, could be incorporated into hydrogels when hydrophobic spacer groups were placed between the UPy functionality and the water-soluble polymer backbone, allowing for these noncovalent interactions to exist in a hydrophobic microenvironment. This shielding has been introduced both by adding hydrophobic spacers between the UPy synthon and by placing bulky nonpolar substituents directly onto the pyrimidine ring. While substituting adamantyl groups onto the ring structure aids in stabilizing hydrogen bonding in polar aprotic solvents, there is still significant weakening of the associations as indicated by an upfield shift of the amine proton peaks in 1H nuclear magnetic resonance (NMR) spectroscopy.71 The pendant attachment of adamantylsubstituted UPy was shown to induce stable hydrogel G


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adjusted by using α, β, or γ CDs that have six, seven, or eight saccharide groups, respectively, allowing for tuning of guest selectivity.76 These macrocyclic structures form their supramolecular networks in a complementary manner by encasing a compatible “guest” molecule into their hydrophobic core. While these resulting hydrophobic interactions between the guest and CD are typically weaker than interactions seen in hydrogen bonding or coordination materials,75,76 the innate biocompatibility of CD makes it an advantageous supramolecular functional group. The hydroxyl groups along the molecule’s surface allow for the functionalization of the CD with a wide variety of groups, including acrylates and carboxylic acids, which allow for the facile incorporation of the CD into polymeric networks. One favorable aspect of CD complexes is the ability of the hydrophobic core to incorporate a wide array of guest molecules. For instance, the inclusion of aromatic peptide residues (e.g., tyrosine) allows for the binding of CDs to biomolecules, such as gelatin. Furthermore, these inclusions allow for the binding of CDs to native tissues like collagen for increased tissue adhesion. For instance, Feng and co-workers formed hydrogels from polymerized β-CD acrylate and gelatin.77 The CD functional groups encapsulated the aromatic residues on the gelatin backbone and formed stable hydrogels after the polymerization of the acrylated β-CD under UV. The CD moieties improved adhesion to the surrounding tissues by binding aromatic residues from the collagen. Furthermore, the low binding affinities of CD analogues show potential for the slow release of drugs or other small molecules throughout the proliferating network. Both synthetic guests, such as naphthalene derivatives, and natural products such as triterpenoids have been used to develop CD-based hydrogels, offering a wide array of binding constants and hydrogel mechanics.78,79 However, while CDs remain as one of the most versatile supramolecular chemistries, they are plagued by low binding constants, which require high concentrations of binding agents to ensure adequate mechanical stability. To combat low binding strengths, cucurbit[n]urils (CB[n]) (Figure 8) have gained traction. Named for their unique pumpkin-like shape, these hosts boast broader inclusion cavities and high binding stability compared to CD hydrogels and bind guest molecules through a similar inclusion mechanism into a hydrophobic pocket. However, the presence of the ureidocarbonyl rim also leads to preferential binding of cationic species. As an example, CB[6]-functionalized hyraluronic acid (HA) formed physical cross-links with diaminohexane-modified HA due to the incorporation of the protonated amine into the interior of the CB macrocycle.80,81 Such CB-based hydrogel networks show great versatility in their in vivo applications. For example, cell adhesion to the network (and, therefore, the proliferation of the cells) can be improved by incorporating c(RGDyK)-modified CB into the hydrogel upon mixing, and sustained drug release can be achieved through similar conjugation methods.80,81 With a wide range of potential host and guests available to these systems, these systems can be tuned to meet the needs of the implantation site, allowing for tissue regeneration in a minimally invasive manner. However, while CBs show much higher binding constants than CDs, their solubility in water is limited: while CB[5] and CB[7] show good solubility in neutral water, CB[6] and CB[8] require acidic conditions to fully solubilize.14,82 Yet, these materials show remarkable increases in toughness when incorporated

formation, although rheological data showed they exhibited low modulus values.72 However, utilization of hydrophobic spacers (12 methyl groups) between the water-soluble PEG chain and methyl-substituted UPy groups promoted continuous network formation and phase-separated morphologies in mono- and dual-functional UPy networks with pH-sensitive architecture.73 Taking it one step further, utilizing chain-extended UPy flanked by the same 12 methyl spacers on either side of the moiety allowed for tough hydrogel networks to be produced.74 These materials showed remarkable toughness and low hysteresis values, even when exposed to strains of 300%, which was attributed to the nonpolar microphase separation in the functionalized PEG. Even upon hydration, these materials retain their structure due to the hydrophobicity of these supramolecular motifs, as shown by in situ scanning transmission electron microscopy images showing the network evolution and retention of hydrophobic pockets containing the majority of the supramolecular interactions (Figure 7).

Figure 7. Scanning transmission electron micrographs showing structural evolution of chain-extended UPy hydrogels. (a) Dry gels (scale bar 200 nm), (b) gel as it begins to swell (scale bar 50 nm), and (c) fully swollen gel (scale bar 200 nm). Reproduced with permission from ref 74. Copyright 2014 American Chemical Society.

Host−guest interactions similarly allow for assembly to occur in water due to the hydrophobic interior of the enveloping “host” molecules, such as cyclodextrins or cucurbit[n]urils, where n is the number of glycoluril groups in the ring, that permit these interactions to occur even in in an aqueous environment (Figure 8). Cyclodextrins (CD) are a family of cyclic oligosaccharides that have drawn significant attention due to their stability, availability, and many pathways for chemical modification.75 Inclusion of guest molecules into a CD host is based upon the size of the guest (i.e., whether it physically fits inside of the cavity) and hydrophobic interactions between the organic guest and the host cavity. The cavity size can be H


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Figure 8. General chemical structures and shapes of CB and CD motifs.

degradation times through enzymatic cleavage of the amide linkages along the peptide units.85 In the body, peptides are formed from complex amino acid sequences, which result in well-defined hierarchical structures that offer structural stability and mechanical reinforcement; the utilization of similar amino acid sequences on these polymer−peptide conjugates can offer toughness to the resultant hydrogel networks without having to isolate entire proteins. Jing et al. demonstrated this by utilizing a peptide sequence derived from human fibrin and fabricating peptide−PEG−peptide triblock copolymers.86 The specific sequence allowed for the formation of α-helical coils that formed bundles akin to physical cross-links upon swelling. The resulting chains were able to form stable hydrogels in phosphate buffer at concentrations as low as 8 wt %; furthermore, they showed shear modulus values between 0.6 and 2.5 kPa for the 8 and 12 wt % gels, respectively. Similarly, the utilization of specific collagen-mimetic peptide sequences can be utilized to fabricate toughened hydrogels through the formation of triple helices.87,88 For example, Lee and colleagues utilized a collagen mimetic peptide sequence of repeating triplets of proline−hydroxyproline−glycine capped with a tyrosine residue (Pro−Hyp−Gly)n−Tyr to create triple helix structures.87 After functionalization of the N-terminus with an acrylate group, photopolymerization of the modified peptide sequence with poly(ethylene oxide)diacrylate (PEODA) yielded a hydrogel that showed increased retention of type I collagen. Furthermore, when seeded with chondrocytes, these hydrogels displayed up to an 83% increase in glycosaminoglycan and a 103% increase in collagen content, which was partially attributed to the hydrogels proficiently mimicking the cells’ natural environment. By taking advantage of the unique thermal properties of different peptide assemblies, temperature responses can also be programmed into these materials as a means of inducing gelation, taking advantage of hierarchical transitions of the αhelical structures into mechanically robust β-sheets. For instance, Chiang et al. prepared a hydrogel with a central poly(propylene oxide) (PPO)−block−PEG−block−PPO and peripheral peptides consisting of alanine (Ala), phenylalanine (Phe), and either aspartic acid (Asp) or its protected derivative,

into hydrogels, so they will likely continue to gather interest from researchers.14,82 With the differences in CD and CB[n]-based systems in mind, construction of host−guest hydrogels requires careful materials selection; while the toughness increases offered by the CB family of host molecules may prove advantageous, CD molecules show not only full water solubility, but are also capable of interacting with a wider array of compounds, including biopolymers. Because CB[n] hosts boast stronger binding of appropriate guests, these units are more suited for application as load-bearing tissue scaffolds. However, CDs still show remarkable biocompatibility and adhesion to surrounding tissues, making them suitable material constructs for implantation into non load-bearing areas or regions where softer matrices are required, such as in neural tissue regeneration. With a variety of self-assembling motifs available, supramolecular hydrogels have access to a range of binding constants and, as a result, mechanical properties. While these systems show good biocompatibility, the strength of the transient interactions at physiological temperatures requires more indepth studies. Utilizing a model hydrogel exhibiting both covalent and noncovalent cross-links, Hu et al. demonstrated the effects of temperature on the supramolecular network.83 As the network temperature was increased, significant decreases in Young’s modulus and the lifetime of the physical network were observed. These significant changes upon heating could heavily impact the lifetime and stability of the hydrogels in vivo. 3.2. Peptidic Hydrogels. Peptides are attractive materials for building self-assembling hydrogels; some of the highly ordered architectures derived from peptide units exist in aqueous environments naturally, so their incorporation into hydrogel networks is a logical choice. The use of peptides in hydrogels relies primarily on their hierarchical arrangements and the natural hydrophobicity of certain amino acid residues to allow for persistent self-assembly. The hydrophobicity of the peptide residues shield the hydrogen bonding residues of the amide linkages, yielding swollen, toughened networks.84 The incorporation of peptidic units provides biodegradable handles on the hydrogel network, allowing for tunable and defined I


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Bioconjugate Chemistry β-benzyl-L-aspartate.89 When the peptide units contained the protected β-benzyl-L-Asp moiety, the polymer chains formed microgels due to the largely α-helical formations (Figure 9).

peptides may enhance material properties by adding additional transient interactions, issues with fabrication arise as overall hydrophilicity of the gel decreases. In addition, constructing painstakingly sequenced peptides requires the use of solidphase synthesis techniques, which typically yield limited amounts of material for use and potentially introduces scalability obstacles for future expansion of such materials. 3.3. Self-Assembling Low-Molecular-Weight Hydrogelators. One subclass of hydrogels consists entirely of selfassembling small molecules that organize into columnar stacks (Figure 10).90 These low-molecular-weight hydrogelator

Figure 9. Wet cell TEM micrographs showing the formation of microgels due to the formation of α-helices (top) and the long-range fiber morphology developed by the β-sheet systems (bottom) upon heating to 35 °C. Reproduced from ref 89. Copyright 2013 American Chemical Society.

However, when Asp was utilized more β-sheets were formed. These β-sheets showed structural transitions at 35 °C corresponding to the formation of nanofibrils as imaged in wet-cell transmission electron microscopy (TEM) (Figure 9). The formation of these fibers corresponded to the conversion of α-helices to the more hydrophobic β-sheets; the application of heat disrupted the hydrogen bonding assemblies between the carboxylic acid units on Asp, allowing for the hydrophobic interactions to dominate the peptide units. This shift in assembly facilitated β sheet aggregation, forming a continuous fiber network through the gel. Because the transition occurs near physiological temperatures, these materials may be utilized as injectable hydrogels in in vivo applications, resulting in more noninvasive strategies for introducing scaffolds. The introduction of peptides into hydrogel networks provides directed assembly of these units into hierarchical secondary structures, improving mechanics depending on parameters, such as increased chain length of the peptidic units or temperature. While these gels show great promise as tissue scaffolds due to the natural biocompatibility of incorporated peptides and their well-studied assembly, these materials are still limited (as with other systems) in their toughness by the swollen network. An interesting balance must be struck between the presence of hydrophilic polymers and the self-assembling peptides units. While incorporating more

Figure 10. Depiction of the formation of supramolecular nanofibers through the application of a stimulus (cooling after dissolution at an elevated temperature).

(LMWHG) assemblies span their aqueous environment as nanofibers; as they expand, overlap of these nanofibers leads to pseudoentanglements that produce the viscoelastic gel. Typically, this gel phase forms in the presence of a stimulus. Temperature formation is most common, whereby heating the system dissolves the gel, and the 3D network forms upon cooling, yielding a continuous, fibrillar network. However, other stimuli have arisen in popularity to induce gelation. For instance, pH-sensitive hydrogelators were fabricated by incorporating different amino acid units onto a cyclohexane base.91 By changing the available functional groups (e.g., carboxylic acid, imidazole, etc.), the pKa values of the gelator are altered, and gelation occurs upon neutralization of the acidic or basic functional groups, which eliminates the electrostatic repulsions between gelator molecules. All of the gelling species showed gel−sol transitions dependent upon temperature and pH, and were shown to be noncytotoxic in preliminary studies. Similarly, von Gröning and co-workers noted pH sensitivity in J


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time-consuming. For many LMWHGs, gel lifetime can present itself as an issue because the nanofibers can precipitate out of the solution; many solutions to this issue have been proposed, such as the addition of nongelling “stabilizers”, to promote an increase in the lifetime of the gels.97,98 The addition of supporting structures allows for stability to be increased without loss of the dynamic nature of the gel networks. In one example, water-soluble acrylate monomers were polymerized in a gelator solution to yield a pseudointerpenetrating network (pseudo-IPN) structure. Other examples of reinforcing LMWHG networks with covalent hydrogels show that the mechanical properties of these systems can be enhanced without sacrificing stimuli responsiveness.99 3.4. Peptide-Based Gelators. While amino acid residues are commonly incorporated into LMWHGs to tune the number of hydrogen bonding residues, hydrophobic interactions, and/or π−π stacking (e.g., phenylalanine), short peptide sequences (one to five amino acids) have also garnered interest as hydrogel precursors. In their simplest form, these systems consist of a hydrophobic motif that forms the nanofiber core and a short peptide sequence that acts to both strengthen the nanofiber through specific interactions that vary between amino acids. Simpler gels commonly utilize 9-flurenylmethyloxycarbonyl (Fmoc) or napthalene groups, while more-complex structures allow for stimuli-responsive breakdown of the fibrillar gel network through decomposition of the hydrophobic motif upon exposure of the system to certain stimuli, such as UV radiation or oxidation.100−102 When designing the peptide segment to attach to the hydrophobic motif, Orbach et al. observed that the presence and placement of aromatic amino acids in the peptide aid assembly and stabilization of the resultant hydrogel.103 The assembly of these gels has been attributed to the presence of π−π stacking between the amino acid residues and hydrophobic motif, strengthening the assembled fiber stacks.103,104 Such simple, robust systems that are capable of forming stable nanofibers are attractive tissue scaffolds due to their natural biocompatibility and mechanical stability. To increase the efficacy of these hydrogels, researchers have incorporated cell-signaling peptide motifs directly into the network, allowing for the gelators to specifically interact with proliferating cells and increasing overall viability by better mimicking the cells’ natural environment.102,105 To tune biological activity without modifying the dipeptide gel, Zhou et al. co-assembled Fmoc−diphenylalanine (Fmoc− FF) and Fmoc−RGD; the resultant hydrogel exhibited higher cell viability as the concentration of Fmoc−RGD increased compared to the neat Fmoc−FF system.106 Surprisingly, the presence of Fmoc−RGD within the co-assembled gel enhanced the overall mechanics despite the inability of Fmoc−RGD to form stable individual gels at biological conditions, indicating complex interactions between the two gelators. Although cell adhesion has been improved in these less complex gelators, it can be challenging to match the mechanical response to native tissues. One strategy has been to introduce polymer additives, such as dextran, PEO, and sodium alginate, to tune the mechanics and gel stability while maintaining biocompatibility.107,108 An additional level of tunability is achieved with the inclusion of longer peptide motifs capable of directed β-sheet assembly. As such, peptide amphiphiles (PA) have emerged as morecomplex peptidic hydrogel precursors. Extensive reviews on the design and characteristics of PAs have been previously published, and here, we focus on their use in scaffolds,

their own hydrogels when carboxylic acid residues were introduced on the periphery of the gelator molecule.92 The assembly and the resultant length of the nanofibers could be tuned by changes in the ionic strength or pH of the environment, which resulted in either increased or decreased Coulombic repulsions between carboxylate anions to yield shorter or longer 1D stacks, respectively. Other gels that require mild gelation conditions can incorporate ions into their structure. Buerkle et al. utilized a guanosine derivative to induce gelation when biologically relevant sodium concentrations are present.93 Moreover, these same motifs formed gels in Dulbeco’s modified Eagle’s medium (DMEM) at concentrations as low as 0.5 wt %, and, by adding 1 wt % gelatin, cell adhesion and proliferation was demonstrated throughout the gel thickness. As with hydrogels, diffusion of cells and nutrients throughout the media is not impeded by the presence of the low concentration of gelator species, partially explaining their high biocompatibility. Gelators displaying aromatic benzene cores are attractive motifs because of the strengthened interactions due to the presence of both hydrogen bonding and π−π stacking between these structures. C2 gelators display two substituents para to one another, while C3 gelators are defined by three substituents in the meta positions.94 It was shown that by modifying the lengths of ethylene glycol chains on a C2 benzene gelator, the wettability of the fiber could be modified; the morehydrophobic LMWHG showed greater propensity for wetting by proteins, such as bovine serum albumin (BSA).95 This high wettability allowed for greater cell adhesion (and increased proliferation) to be achieved in both 2D and 3D environments, offering insight into gelator design. C3 benzene gelators have also shown similar protein adhesion behavior. Müller and colleagues demonstrated the adherence and interaction of antibiotin antibodies and streptavidin protein with a biotinmodified benzene tricarboxamide (BTA) derivative through Förster resonance energy transfer (FRET) studies.96 By functionalizing the proteins with acceptor fluorophore Cy3, the emission spectrum of the hydrogelators could be overlapped with the absorption spectrum of the fluorescentmodified proteins. Gratifyingly, the donor emission from the functional BTA decreased while there were marked increases in the acceptor emission of Cy3, highlighting the fact that the proteins were interacting closely with the columnar stacks. These protein interactions show great promise for encouraging cell adhesion and proliferation in the gel network. The incorporation of LMWHGs into biomaterials to provide suitable conditions for cell proliferation and growth offers platforms that provide a stable, mechanically robust environment for tissue repair without hindering the transport of oxygen or other nutrients within the 3D network. When designing these materials, it is important to note how gelation is induced to form continuous nanofibers. Although heat is the most common, researchers have more recently strived to develop methodologies that allow for gelation to occur under mild pH changes, the exposure of the gel solution to light, or through more-exotic pathways like enzyme-driven gelation. While structurally stable, the resultant gels are easily deformed and exhibit low toughness. However, increases in gel strength can be introduced through chemical and architectural modification of the network. Increases in the number of noncovalent interaction sites along the molecule would result in increases in the strength of the transient network, but additional synthetic steps can be cumbersome or K


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Bioconjugate Chemistry ORCID

specifically their formation of nanofibers, to create stable hydrogels.109−111 PAs generally contain peptide sequences and hydrophobic alkane groups (most commonly long alkyl tails). In designing these PAs, it has been noted that only the peptide residues closest to the hydrophobic tail interact to form βsheets, with the outermost head groups strictly responsible for solubility in the aqueous media.110,112 Chemical changes to the outermost groups can be harnessed to design molecules with pH responsiveness or cell-signaling capabilities.109,113−115 These PAs have been applied to tissue engineering applications with low regenerative capabilities, such as the brain. By the mimicking of the extracellular matrix (ECM) mechanics, neural growth can be stimulated by adhesion to the PA, serving as a tunable approach to elicit specific biological responses.109,116 For instance, by modulating the stiffness of the hydrogel network through use of a “stiff” linear PA and a “soft” branched PA, Sur et al. showed that the differentiation and growth of hippocampi neurons could be tuned through the stiff and soft PA gels with softer gels leading to the formation of longer neurites.117 In a second example, co-assembly of PA moieties was achieved by mixing oppositely charge PA solutions, each one bearing different peptide sequences on their head groups to regulate cell adhesion, migration, and differentiation; this assembly strategy promoted synergistic differentiation of neural stem cells into active neurons. In this section, we have discussed peptide gelators ranging from simple dipeptide hydrogels to the more complex PAs. In both types of systems, assembly and biological activity depends on the structural organization of the applied chemical motifs, balancing hydrophilic and hydrophobic interactions. The interplay between hydrophobic and hydrophilic interactions within peptides yields unique and tunable hydrogel characteristics driven by structural complexity, promoting nanofiber formation to gel their aqueous environment, while also offering the added flexibility of chemical modification. Incorporation of cell-signaling motifs within the nanofiber opens up pathways to direct growth and differentiation of the cultured cells, mimicking the native ECM. However, as the use of these tissue scaffolds continues to expand, a deeper understanding of assembly pathways is needed to better predict the relationship between the peptide sequence and the resultant gel properties.118−122

LaShanda T. J. Korley: 0000-0002-8266-5000 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Science Foundation (NSF, DMR-1608441). ABBREVIATIONS UPy, ureidopyrimidinone; PCL, poly(caprolactone); PEG, poly(ethylene glycol); PEO, poly(ethylene oxide); PA, peptide amphiphile; LMWHG, low-molecular-weight hydrogelators

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4. CONCLUSIONS AND OUTLOOK Here, we have outlined recent strategies to construct selfassembling tissue scaffolds that are applied as toughened elastomers and gels. These materials offer tunable mechanics and structures as well as the potential for stimuli responsive characteristics, resulting in versatile tissue scaffolds that can be modified to meet the needs of their implant sites. As these materials continue to be applied as cell growth platforms, their assembly pathways and in vivo stability are critical to ensuring that the material functionality matches the site of application. From a material perspective, an understanding of the cellmaterial interactions of these self-assembling motifs will guide future design of scaffolds that more closely match the functionality of native tissue.

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