Recent Progress in Synthesis, Functionalization, and

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

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Metal−Organic Framework-Templated Biomaterials: Recent Progress in Synthesis, Functionalization, and Applications Salma Begum,†,∥ Zahid Hassan,‡,∥ Stefan Bräse,‡,§ Christof Wöll,† and Manuel Tsotsalas*,†,‡ †

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Institute of Functional Interfaces, Karlsruhe Institute of Technology, Hermann-von Helmholtz-Platz 1, D-76344 Eggenstein-Leopoldshafen, Germany ‡ Institute for Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany § Institute for Toxicology and Genetics, Karlsruhe Institute of Technology, Hermann-von Helmholtz-Platz 1, D-76344 Eggenstein-Leopoldshafen, Germany CONSPECTUS: The integration of a porous crystalline framework with soft polymers to create novel biomaterials has tremendous potential yet remains very challenging to date. Metal−organic framework (MOF)-templated polymers (MTPs) have emerged as persistent modular materials that can be tailored for desired biofunctions. These represent a novel class of hierarchically structured assemblies that combine the advantages of MOFs (precisely controlled structure, enormous diversity in framework topology, and high porosity) with the intrinsic behaviors of polymers (soft texture, flexibility, biocompatibility, and improved stability under physiological conditions). Transformation of surface-anchored MOFs (SURMOFs) via orthogonal covalent crosslinking yields surface-anchored polymeric gels (SURGELs) that open up exciting new opportunities to create soft nanoporous materials. SURGELs overcome the main drawbacks of SURMOFs, such as their limited stability under physiological conditions and their potential to release toxic metal ions, a substantial problem for applications in life sciences. MOF (SURMOF)-templated polymerization processes control the synthesis on a molecular level. Additionally, the morphology of the original MOF crystal template is replicated in the final network polymers. The MOF-templated polymerization can be induced by light, a catalyst, or temperature using several types of reactions, including thiol−ene, metalfree alkyne−azide click reactions, and Glaser−Hay coupling. In the case of photoinduced reactions, the cross-linking process can be locally confined, allowing control of the macroscopic patterning of the resulting network polymer. The use of layer-by-layer (lbl) techniques in the SURMOF synthesis serves the purpose of precise, layer-selective incorporation of functionalities via the combination of the postsynthetic modification and heteroepitaxy strategies. Transforming the functionalized SURMOF into a SURGEL allows the fabrication of polymers with desired bioactive functions at the internal or external surfaces. This Account highlights our ongoing research and inspiring progress in transforming SURMOFs into persistent, modular nanoporous materials tailored with biofunctions. Using cell culture studies, we present various aspects of SURGEL materials, such as the ability to deliver bioactive molecules to adhering cells on SURGEL surfaces, applications to advanced drug delivery systems, the ability to tune cell adhesion via surface modification, and the development of porphyrin-based SURGEL thin films with antimicrobial properties. Then we critically examine the challenges and limitations of current systems and discuss future research directions and new approaches for advancing MOF-templated biocompatible materials, emphasizing the need to include responsive and adaptive functionalities into the system. We emphasize that the hierarchical structure, ranging from the molecular to the macroscopic scale, allows for optimization of the material properties across all length scales relevant for cell− material interactions.

1. INTRODUCTION

modified to create novel MOF-based composites. Remarkable progress in creating MOF composites has been made by integrating other functional materials, for instance, silica, carbon, organic polymers,4 nano- and microparticles,5 supramolecular metallopolymers,6 enzymes, and biomacromolecules.7 These have contributed new dimensions to the MOF field. Numerous studies have demonstrated the biocompatibility and biomedical applications of nanoscale MOFs,8 including

The function-led design of highly ordered structures with defined geometries and orientations through metal−ligand coordination has been an outstanding objective in diverse areas of research, and it has led to metal−organic frameworks (MOFs), metal−organic cages/polyhedra (MOCs), and related hybrid structures.1 The design of MOFs and their numerous applications have been the subject of excellent reviews.2,3 Because of their well-defined crystal structure and intrinsic porosity with narrow pore size distribution, MOF structures are regarded as excellent templates that can be postsynthetically © XXXX American Chemical Society

Received: January 21, 2019

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DOI: 10.1021/acs.accounts.9b00039 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

films, or even more complex laterally and vertically structured multicomponent MOF systems with multifunctionality. In this Account, we confine our discussion to the application of surface-mounted MOFs as templates for modulating an emerging class of hierarchically structured polymeric biomaterials.

encapsulation of biomacromolecules,9 drug delivery, and other chemotherapeutic perspectives.10−12 However, the often limited stability of MOF particles or surface-anchored MOFs (SURMOFs) under physiological conditions, although beneficial for in vivo applications where clearance from the body is desired, represents a major limitation for bioactive coating or cell culture applications. Under such conditions, prolonged stability and avoidance of potentially cytotoxic metal ions is essential.13 Systematic activity/toxicity studies of MOF composites in biological settings remain scarce, especially those related to several crucial parameters such as the balance of risks versus benefits and the kinetics of absorption, biodistribution, metabolism and accumulation in tissues, excretion/removal, and toxicology (ADMET). Thus, an alternative approach should target more persistent, flexible, and biocompatible hierarchical structures. The transformation of SURMOFs to surfaceanchored polymeric gels (SURGELs) yields a new class of water-stable and, most importantly, metal-free nanoporous polymer materials that have a soft interface and controlled structure and thickness.14 In general, it is hard to control the morphology of polymer networks via conventional solution synthesis, as it usually results in randomly distributed materials. In addition, lack of solubility in common organic solvents further limits the processability of conventional polymer networks into thin films.15,16 In the MOF template approach, the polymerization is spatially confined, which leads to a defined structure, as the morphology of the parent MOF is preserved. In addition, SURMOF templates offer control over layer-selective incorporation of functionalities via the combination of postsynthetic modification (PSM) and heteroepitaxy strategies. Furthermore, locally confined macroscopic patterning of SURGEL polymers can be achieved via combination of photopatterning techniques and light-induced PSM reactions. This novel class of modular materials can be tailored with desired functions, such as adsorption selectivity, improved stability, and biocompatibility; these present tremendous potential for biotechnological applications. SURGEL nanoplatforms can be precisely structured at different length scales appropriate to bioactive functions on their surface, in pores, and as part of the templated structure (Figure 1). The SURMOF technique has great advantages, including control of the growth orientation or thin-film thickness, flexible assembly of the MOF building blocks, flexible encapsulation of the guest molecules that receive the target, designable MOF thin

1.1. MOF@Polymer Composites

The integration of MOFs with polymers yields composites/ hybrids that combine the exceptional features of MOFs with the robustness of polymers.17 Considering the possibility for enormous structural diversity and synthetic tunability, different strategies such as controlled polymerization within MOF nanochannels18,19 and interfacial polymerization20 have been introduced to form various MOF@polymer composites.21 We have introduced covalent cross-polymerization strategies exploring SURMOF assemblies as useful templates toward the design and formation of polymeric thin films. 1.2. Surfaces, Functionalization, and Their Fabrication Strategies for the Synthesis of SURMOFs

MOFs are mostly synthesized by conventional solvothermal processes that typically result in powders. Because of the insoluble and particulate form of powders, there are many challenges in their physical manipulation and processability for practical applications. This makes it difficult to integrate powders into devices, and the fabrication of multilayer systems stands as a critical obstacle.22 To overcome some of the main drawbacks of bulk-powder MOF materials, we have taken a rather different approach that uses stepwise layer-by-layer (lbl) liquid-phase epitaxy methods. On suitably functionalized substrates (e.g., gold, silicon, quartz, glass, and metal oxides), highly oriented monolithic crystals can be grown that direct the nucleation site, orientation, and structure of the deposited SURMOF (Figure 2).23 Here we describe only key elements and very briefly some landmark results in SURMOF formation. A detailed description of the surface/interface chemistry can be found in previous reviews.24−27 Layer-by-layer liquid-phase epitaxy methods, using repeated immersion and rinsing after each reactant exposure step cycle, yield highly crystalline, oriented, monolithic SURMOF thin films with smooth surfaces. The thickness of the film is controlled by the number of growth cycles. An important aspect of SURMOF growth is substrate functionalization. In this context, we studied multiple diverse molecular self-assembled monolayer (SAM) architectures. While investigating the impact of different synthesis parameters, different fabrication methods for the lbl approach were introduced, such as spraying, spincoating, and highly automated dipping robots. These offer the opportunity for upscaling to application-relevant sizes and amounts.28 1.3. Functionalization Chemistry of the Internal and External Surfaces of MOFs

Because of the maturation of the synthesis methodologies, characterization capabilities, and postsynthetic structural and functional tunability, MOFs (SURMOFs) are emerging as modular materials that can be tailored for numerous applications. The functionality and diversity of a MOF (SURMOF) can arise from its innate physical/chemical properties or can be introduced through PSM.29 PSM has been instrumental for introducing desired functionalities within the main molecular skeleton after the MOF lattice is assembled. PSM can be used to introduce functionality selectively to the

Figure 1. Design of SURMOF-templated hierarchically structured biomaterials. B


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Figure 2. Schematic of liquid-phase epitaxy (or heteroepitaxy)/layer-by-layer SURMOF synthesis on a self-assembled monolayer (SAM). Step cycles indicate repeated immersion and rinsing after each reactant exposure. The illustration shows how a MOF can become anchored onto a SAM. Reproduced with permission from ref 23. Copyright 2016 Wiley-VCH.

Figure 3. Schematic illustration of MOF postsynthetic functionalization on the internal surfaces (small molecules diffuse in the pores) and external surfaces (larger molecules attach to the outer surfaces). PSM can be achieved through covalent bonds at the organic linkers (right) or coordinative bonds to the metal nodes (left).

inner pore surfaces30 or external surfaces10 via covalent bond formation at the linkers and coordinate bond functionalization at the metal nodes (Figure 3). To fully utilize the PSM strategy for biomedical applications, simple and mild reaction conditions are favorable since most biomolecules are thermally and/or chemically sensitive.31,32 By means of such simple reactions in PSM, even multistep tandem transformation protocols have been achieved within MOFs, generating peptides with enzyme-like complexity.33 The lbl approach in SURMOF synthesis offers the additional possibility of layer-selective incorporation of desired functionalities in the inner pores or at external surfaces via the combination of PSM and heteroepitaxy strategies.34

2. DESIGN AND DEVELOPMENT OF MOF-TEMPLATED POLYMERIC MATERIALS In this section, we describe the design principles and procedures for transforming MOFs into flexible soft polymer materials via covalent cross-linking postsynthetic modifications. 2.1. Synthetic Approaches and Design Principles of Molecular Building Blocks

The judicious selection of metal clusters and specifically designed organic building blocks are of utmost relevance for modulating the topology and desired properties of the resulting hybrid framework structures.35,36 The geometry of the organic building unit determines the topology and enables tuning of the C


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Figure 4. (a) Some representative organic linkers with azide or alkyne tagging used as building blocks. (b) Thiol- or alkyne-tagged molecules used as secondary cross-linkers (CLs).

Figure 5. (a) Schematic of the SURMOF-to-SURGEL postsynthetic polymerization process. Reproduced from ref 14. Copyright 2013 American Chemical Society. (b) Orthogonal functional sites, such as azides and alkoxys within the linker backbone, interact with CL molecules to covalently interconnect the MOF structure via click reaction mechanisms.

employed to coordinate to the metal ions/clusters and form the MOF structure, while orthogonal functional sites, such as azides, alkoxys, and alkynes within the linker backbone (Figure 4), can interact with cross-linker molecules to covalently interconnect the MOF structure via a wide range of reaction mechanisms.

size and porosity; hence, each imparts characteristic properties to the resulting MOF.37 For postsynthetic polymerization, several functional groups intended for a specific task need to be attached to a single molecular linker unit. Carboxylic acid moieties are usually D


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Figure 6. Shape-controlled transformation of MOFs to polymer gels: AzoMOF (AzM) to cross-linked MOF (CLM) and finally to MOF-templated polymer (MTP). Reproduced with permission from refs 41, 42, and 44. Copyright 2013 American Chemical Society, 2017 Wiley-VCH, and 2018 Royal Society of Chemistry, respectively.

Figure 7. Strategy for the formation of molecular textiles. A schematic of the heteroepitaxial sandwich-layer SURMOF system is shown. Reproduced with permission from ref 49. Copyright 2017 Nature Publishing Group.

2.2. Fundamentals and Mechanism of SURMOF-to-SURGEL Postsynthetic Polymerization in Confined Nanospaces

These mechanisms include Glaser−Hay coupling and thiol−ene or azide−alkyne “click” modifications. The organic linker molecules with reactive side groups (at least two) serve as monomers, thus enabling the preparation of covalently cross-linked polymeric networks with a well-defined structure, as the monomers are preorganized in the SURMOF. PSM of SURMOFs via click chemistry, including azide−alkyne cycloaddition38 and the photoinduced thiol−ene reaction, is a versatile and highly reliable synthetic tool in the fabrication of structures that would be difficult to obtain via direct synthesis routes.39

Inspired by controlled enzymatic polymerization in biosystems, the understanding of reactions in confined spaces has been a long-standing aspiration. With the advent of pioneering studies on crystal cross-linking of bulk-powder azide-MOF (“clickable MOF”)40 via polymerization of the organic ligands within the MOF using multifold acetylene-tagged molecules, a new dimension has been opened for the exploration of MOFs and the fabrication of novel polymers. Sada and co-workers introduced polymerization (crystal cross-linking) between host monomers immobilized in open frameworks and guest monomers freely mobile in the nanopores.41 After demetalation E


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Figure 8. Grafting of RGD-containing oligopeptide onto a SURGEL using photoinduced thiol−yne click chemistry. (left) Scheme of the SURGEL framework. Organic linkers (blue) connect through the multifunctional cross-linking molecules (black) with remaining alkyne moieties (green). (right) Surface-modified SURGEL via thiol−yne click reaction. Adapted with permission from ref 58. Copyright 2016 Wiley-VCH.

with acid treatment, the cross-linked MOFs are converted into polymer gel materials that preserve the shape of the parent MOF. We extended this postsynthetic polymerization to SURMOF thin films using copper-free click modifications with a multifold alkyne-tagged trimethylolethane tripropiolate (TMETP) cross-linker (CL).14 Metal ion extraction yields a homogeneous, entirely metal-free thin polymer film called a SURGEL (Figure 5).

investigations examined stimuli-responsive photoluminescence behavior43 and boxlike, well-defined, hollow gel capsules with a cubic shape reflecting heterostructures based on core−shell MOF crystals (Figure 6e).44 For the boxlike hollow gel capsules, epitaxial growth of two isostructural coordination polymers was applied, and these were then selectively cross-linked. In a similar manner, the crystal cross-linking method allowed control of various size scales from nanometer to centimeter; for instance, fabrication of nano- and microsized gel particles with a cubic shape from cyclodextrin MOFs was achieved.45 Taking advantage of step-by-step epitaxial growth techniques on modified surfaces, we previously prepared different types of SURGEL-based materials. We investigated their applications in conductive polymers by covalently linking a ferrocenyl derivative into the pores of the SURGELs using thiol−yne postsynthetic modification.46 MOF material fabrication for application to energy conversion, high proton conductivity, bioelectronics, water electrolysis, batteries, fuel cells, and sensors has been growing.47 We demonstrated that nanoporous polymer thin films, formed by transforming SURMOFs to SURGELs, exhibit excellent proton conductivity with high ductility and pronounced water stability.48 These record high values are attributed to the highly ordered polymer network structure containing regularly spaced carboxylic acid groups upon crosslinking and subsequent removal of metal ions. We recently demonstrated an innovative approach for molecular weaving of highly oriented crystalline coordination networks onto a modified gold surface via epitaxial growth (Figure 7).49

2.3. Micro- and Nanofabrication and Tuning of the Structure and Function of Cross-Linked Polymer Gels

Controlling nanostructures at different scales enables control over their physicochemical properties and ultimately determines their effectiveness for desired applications. Size and shape are two typical parameters for tailoring the properties of nanomaterials. Sada and co-workers41 reported a series of polymer gels with controlled sizes and shapes, e.g., cube, truncated octahedron, and octahedron derived from azido-MOFs (Zn, Cu, and Zr metal ions). These were preassembled with biphenyland terphenyl-based organic linkers. The cross-linked polymer gels and their structures were characterized in detail, reflecting fine control over the nanostructure, size, and shape preservation of the corresponding parent MOFs, as illustrated in Figure 6a−c. The same group recently reported crystal cross-linking of a pillared-layer MOF (AzPLMOF).42 By cross-linking, the AzPLMOF crystals were converted into polymer gels that retained the crystal rectangular prism shape and size. The gel materials exhibited an anisotropic swelling phenomenon upon solvent impregnation (Figure 6d). In similar approaches, F


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Figure 9. (a) Schematic of the locally confined attachment of rhodamine-SH to the linker of Zn2(BA-BDC)2(dabco) SURMOFs using a photomask with a hexagonal pattern and (b) fluorescence microscopy images of the SURMOF that clearly show the hexagonal pattern of the photomask. Reproduced from ref 50. Copyright 2017 American Chemical Society. (c) Fluorescence microscopy image of the SURGEL thin film showing the line pattern of the region functionalized with fluorescently labeled RGD-thiol by light-induced thiol−yne reaction using a line pattern photomask and (d) fluorescence intensity trace along a line perpendicular to the patterned stripes. Reproduced with permission from ref 58. Copyright 2016 Wiley-VCH.

postsynthetic thiol−ene click modifications with the multitopic thiol cross-linkers. Upon irradiation with UV light to initiate the thiol−ene click reaction, the linker molecules covalently connect with the thiol CLs within the pores. In the last step, the metal ions are removed, yielding the porous polymer gel. The use of light-triggered reactions in combination with photomasks or other photopatterning techniques allows the reaction to be locally confined, leading to patterned gel structures of virtually any size and shape.

Multi-heteroepitaxial SURMOFs were assembled from different types of linkers to fabricate single fabric layers consisting of interwoven one-dimensional polymer strands. In this case, as depicted in Figure 7, no cross-linker was involved. Instead, the “arms” connecting the docking points to the primary layer linker were designed in such a way that homocoupling was possible. The preorganized terphenyl backbones bearing bis(acetylenebiphenyl) side groups were homopolymerized via the Glaser− Hay reaction, which linked the individual long strands crossing each other (very much like weft and warp in a woven textile from a loom) into interwoven covalent polymer networks. X-ray diffraction studies revealed that this topochemical reaction leaves the MOF backbone fully intact. By sandwiching these linkers between two sacrificial MOF thin films (shown in light gray), multi-heteroepitaxial and crystalline systems were obtained. The obtained 2D fabric can be disassembled into individual polymer strands using ultrasonication. After dropcasting of the diluted solution on a smooth Si substrate, the single strands can be unambiguously identified using scanning electron microscopy and atomic force microscopy. We recently described the localized conversion of both singlecrystal MOFs and surface-anchored SURMOFs on a goldcoated silica substrate into a novel type of network polymer gel via light-induced click chemistry.50 The organic linker, containing allyloxy side chains, acts as a functional moiety for

3. BIOFUNCTIONALIZATION AND EMERGING APPLICATIONS OF SURGELS The modular approach and controlled synthesis of hierarchically structured nanomaterialscombined with the ability to functionalize with peptides, proteins, and drugs to mimic biocompatible media or interfacesis of growing interest for applications in biology and medicine.51−53 Recently, various nanosystems including but not limited to micelles, dendrimers, liposomes, polymer brushes, nanogels, nanotubes, and nanocomposites have been proposed for biomedical applications.54−56 Their properties, such as stability, shape, size, surface chemistry, surface charge, mechanical strength, and porosity, can vary significantly in the different systems and need to be considered for the desired application.55 Recently we demonstrated a new type of hierarchically structured polymer networks, G


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Figure 10. (top) Schematic showing the design of MOF growth around magnetic core particles (MagMOF) via layer-by-layer heteroepitaxy: (a) MOF growth of Cu(BA-TPDC); (b) loading of blue dye molecules via click reaction; (c) MOF growth of Cu(TPDC); (d) MOF growth of Cu(BA-TPDC); (e) loading of red dye molecules via click reaction. (bottom) Confocal microscopy images of the dye-functionalized multishell MOF-coated nanoparticles using different filters: (f) blue channel; (g) red channel; (h) overlay of the red and blue channels. Adapted from ref 61. Copyright 2015 American Chemical Society.

namely SURGELs, that can be tailored for desired biofunctions. Merging of SURGELs with biology-relevant molecules through covalent postsynthetic polymerization leads to exciting new opportunities compared with randomly oriented bulk systems, i.e., control over the network structure and density of functional groups on the surface.57 The nanofabrication capabilities of synthetic polymer materials and evaluations of their biological functions can help to advance biomedical applications with therapeutic goals.

In cell toxicity studies of both functionalized and unfunctionalized SURGELs, no toxicity was observed. The influence of the RGD functionalization was determined by comparing the adhesion and spreading behavior of CAL72 cells on the SURGEL surfaces. The number of cells adhering to the RGDmodified substrates was substantially larger than that to the pristine SURGEL substrates. In addition, the mean cell area, i.e., the cell spreading, was significantly larger on the functionalized SURGELs. Consistent with these experiments, we showed by microfluidic shear force assays that the cells’ attachment was already moderate on the pristine SURGEL and increased significantly with the RGD biofunctionalization. These experiments show that by functionalization of the SURGEL substrates with biomolecules such as RGD, we can tune the cell−material interactions. Our investigations showed no cytotoxic effects of the SURGEL and efficient mediation of the adhesion of osteoblast-like cells. Using a photomask (hexagon pattern) for light-activated thiol−yne and thiol−ene reactions, we demonstrated the locally confined functionalization of SURGELs with rhodamine and RGD, as depicted in Figure 9, to further expand the intrinsic variability of SURGEL systems for targeted biofunctionalization.

3.1. Tuning Cell Adhesion by Surface Modification

As a proof of principle for surface biofunctionalization of SURGELs, we attached the short peptide sequence arginine− glycine−aspartic acid (RGD) to favor cell adhesion via a specific interaction with the integrin receptors of the cell membrane.58 RGD is well-known for inducing the adhesion of osteoblasts onto implanted surfaces and improving bone formation. The proof of concept was performed in vitro using the osteoblast-like CAL72 cell line. The sequence SKGSS serves as a hydrophilic linker, and the C-terminal cysteine carries the thiol moiety in its side chain that reacts in the thiol−yne-based SURGEL functionalization. The linker is incorporated into the peptide in order to enhance its solubility in water and to increase the distance of the bioactive sequence RGD to the functionalized surface in order to improve the accessibility of the RGD peptide for cells. Two approaches are suitable for surface functionalization: (i) attachment to the carboxylic acid groups that formerly were coordinated to the metal centers and (ii) use of the remaining alkyne moieties from the cross-linking reaction. The remaining triple bonds were utilized by the metal-free thiol−yne click reaction for surface biofunctionalization (Figure 8).

3.2. Advanced Delivery System Particles (MagGel)

The combination of SURMOFs with nanoparticles can lead to architectures with remarkable optical, magnetic, electrical, and catalytic properties.59 The lbl approach enables coating of (magnetic) particles of different sizes with a uniform MOF shell, which we introduced as the MagMOF system.60 The sequential use of two different linkers, one bearing additional azide functionalities, allows us to selectively functionalize only the defined layers in the resulting core−shell−shell system, e.g., via 1,3-dipolar cycloaddition with alkyne-tagged dye molecules.61 H


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Figure 11. (top) Schematic of hierarchically structured shell-on-shell MOF particles and their transformation into MagGEL capsules. (bottom) Schematic of pH-triggered swelling and the release of dye from the magGel capsule, as confirmed by emission spectra. Adapted from ref 61. Copyright 2015 American Chemical Society.

Figure 12. Schematic representation and fluorescence microscopy images of P. putida pJN::GFP bacteria after 24 h of incubation in the presence of SURGEL substrates. Reproduced from ref 14. Copyright 2013 American Chemical Society.

The synthesis strategy and structure of these core−multishell particles is depicted in Figure 10. The inner blue and outer red shells of these core−shell−shell particles can be visualized by confocal microscopy (Figure 10, bottom). Combining multishell MagMOFs with the SURGEL approach allows us to create capsule systems with defined properties. In this approach, the inner shell serves as a reservoir for guest molecules while the outer shell is converted to a polymer network. This porous outer shell serves as a membrane with permeability for the encapsulated guest molecules that can

be adjusted by changing the pH of the surrounding medium. An increase in the pH leads to swelling of the gel shell (Figure 11). 3.3. Cell Culture Substrate

The ability to control the structure and surface chemistry of biomaterials on a molecular level is crucial for optimizing material performance.12 We demonstrated the huge potential of SURGELs as substrates for cell culture studies by studying the delivery of biomolecules to the interior of cells adhering to the SURGEL surface.14 The SURGEL was loaded with arabinose (a small sugar molecule), and subsequently, the substrate was I


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Figure 13. (top) Schematic of the porphyrin SURMOF-to-SURGEL transformation. (bottom) Porphyrin SURGEL thin films with antimicrobial potential toward E. coli, as demonstrated by fluorescence microscopy images showing green-fluorescent living bacteria and red-fluorescent dead bacteria. Adapted from ref 63. Copyright 2018 American Chemical Society.

organism, and high antibacterial activity against pathogens was demonstrated.

exposed to genetically modified bacteria that express green fluorescent protein (GFP) in the presence of arabinose. The induction of GFP expression is highly site-specific, as it occurs only for bacteria that are in direct contact with the SURGEL substrate (Figure 12). For these studies, two different types of gene-modified bacteria model organisms were used: Escherichia coli pJN::GFP and Pseudomonas putida pJN::GFP. After incubation of P. putida pJN::GFP cells for 24 h, only those bacteria attached to the surface of the arabinose-loaded SURGEL exhibit GFP-specific fluorescence. In contrast, bacteria in the broth supernatant and bacterial cells adhering to unloaded SURGEL showed only marginal GFP fluorescence.

4. CURRENT CHALLENGES AND FUTURE DIRECTIONS 4.1. Current Limitations, Translation Potential, and Application-Based Design Considerations

The high flexibility of the SURGEL approach enables the creation of hierarchically structured films that contain multiple active components at defined positions via loading and surface functionalization with bioactive molecules. Despite the progress in SURGEL biomaterials, they are still in their infancy, and certain challenges that limit their practical potential in biological settings and translational work remain. Multiple studies are needed to address current limitations. (1) A systematic study of the structure−activity/toxicity relationship of MOF-templated materials via high-throughput screening approaches is needed. (2) SURGEL materials enable optimal physical, chemical, and certain mechanical properties that can be deployed in nanodevice fabrication; however, for practical applications, upscaling using an automated synthesis approach is still lacking. Optimized synthesis conditions for SURMOFs to achieve ultrasmooth surfaces and low defect densities via, e.g., ultrasonication therefore need to be included in SURGEL synthesis protocols.64 (3) Because of the almost unlimited possibilities in synthesizing molecular components, biologically active compounds, and nano- and microstructures, computational methods should be employed to identify the most promising components and structures.

3.4. Integration of Antimicrobial Activity into MOF-Templated Biomaterials

Porphyrin-containing polymers are a promising class of materials for photodynamic antimicrobial chemotherapy by visible light, as they can generate reactive oxygen species (ROS) with very high local concentrations.62 To create porphyrincontaining SURGELs, we employed selectively functionalized porphyrin linkers bearing two carboxylate and two azido groups. Using the lbl method by subsequent spray coating, we prepared structurally well-defined azidoporphyrin SURMOFs.63 Afterward, the assembled SURMOFs were immersed into a crosslinker solution to covalently cross-link the porphyrin SURMOFs via click reaction with the azido groups. By treatment with EDTA solution, the metal ions were removed, resulting in waterstable porphyrin polymer thin films (Figure 13). Porphyrin-based SURGEL films were investigated for their antimicrobial potential by probing their visible-light-promoted singlet O2 generation. The visible-light-promoted antibacterial properties of the prepared porous porphyrin polymer thin films were evaluated using cultures of Gram-negative E. coli as a model

4.2. Future Research Directions

The microenvironment in biological tissue is structurally and dynamically complex. In addition to having a hierarchical structure, materials designed to interact with tissue or to act as an advanced cell culture scaffold need to be responsive to the J


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Accounts of Chemical Research microenvironment.65 Dynamically responsive materials must respond to small and specific stimuli within the vicinity of a cell or tissue via targeted, timed release of bioactive molecules or via degradation and remodeling of their structure.66 Integrating smart functions that are able to remotely respond to various stimuli, such as temperature, light, pH, and stress conditions, would provide new application possibilities. Thus, the integration of dynamic functions such as azobenzene switches67 or dynamic covalent bonds68 and continued fundamental advancements in molecular engineering, combined with functional studies, will broaden and deepen the knowledge and applicability of MOF-based biomaterials. PSM is particularly appealing to integrate flexible molecules capable of dynamic motion within 3D frameworks, since it allows precise alignment of the molecules in space while preserving their flexible and dynamic nature. The experimental insight gained by developing more complex MOF-based materials has generated high demand for in silico modeling of these materials. Because of the huge possibilities offered by the numerous molecular components; bioactive functions; and 1D, 2D, and 3D structures, this clearly represents an important step forward. We anticipate that capitalizing on the rational design and functionalization of MOF-based biomaterials will be rewarding in countless ways, for fundamental understanding as well as for thus-far-unrealized therapeutic impact.

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the University of Rostock in Germany. After undertaking an IBS Postdoctoral Fellowship at the Centre for Self-assembly and Complexity, POSTECH, he held a faculty position at the University of Nizwa. Since 2017, he has been associated with the Institute of Organic Chemistry (IOC) and the IFG at KIT. His recent research centers on the synthesis and design of synthetic materials. Stefan Bräse is a Professor of Chemistry at the IOC and Director of the Institute of Toxicology and Genetics (ITG) at KIT. He studied in Göttingen, Bangor (U.K.), and Marseille and received his Ph.D. in 1995. After postdoctoral appointments at Uppsala University and the Scripps Research Institute, he began his independent research career at RWTH Aachen in 1997. After Habilitation in 2001, he moved to the University of Bonn as a Professor for Organic Chemistry, and since 2003 he has been a Professor at the IOC at KIT. His research interests include methods in drug discovery (including drug delivery), combinatorial chemistry toward the synthesis of biologically active compounds, and nanotechnology. Christof Wöll has been the Director of the Institute of Functional Interfaces at KIT (since 2009) and is renowned in the area of solid-state chemistry and particularly for contributions to the field of surface science. He studied Physics at the University of Göttingen and received his Ph.D. in 1987 at the Max Planck Institute of Dynamics and SelfOrganization. In 1996, he took over the chair for Physical Chemistry at the University of Bochum and remained there until 2009, where he founded the Collaborative Research Center SFB 588. His research activities focus on fundamental processes in surface physics and surface chemistry, in particular the development of techniques for the characterization of molecular adsorbates, oxide surfaces, and metal− organic frameworks (MOFs and SURMOFs).

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: +49 721 608-28107. Fax: +49 721 608-23478.

Manuel Tsotsalas is leading a Helmholtz Young Investigator group hosted at the IFG and IOC and is the PI of SFB 1176 “Molecular Structuring of Soft Matter” at KIT. He studied Chemistry and obtained his Ph.D. at the University of Münster. After a postdoctoral stay at Kyoto University, he joined the IFG in 2013. His research interests focus on the interfacial synthesis and hierarchical structuring of porous polymers and their application as novel nanomembranes and bioactive surface coatings.

ORCID

Christof Wöll: 0000-0003-1078-3304 Manuel Tsotsalas: 0000-0002-9557-2903 Author Contributions ∥ S. Begum and Z. Hassan contributed equally. All of the authors approved the final version of the manuscript.

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Funding

ACKNOWLEDGMENTS We gratefully acknowledge our several students, colleagues, and collaborators, whose names are listed as coauthors in the articles we have cited from our institutes, for their intellectual contributions over the years to our research on SURMOF nanobiomaterials.

The German Research Foundation (formally the Deutsche Forschungsgemeinschaft) is acknowledged for financial contributions. M.T. acknowledges the Helmholtz Association’s Initiative and Networking Fund (Grant VH-NG-1147). The author team is part of the Cooperative Research Center (SFB) 1176 “Molecular Structuring of Soft Matter” (Projects C5 and C6) at KIT, which has been funded by the German Research Foundation.

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Notes

REFERENCES

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The authors declare no competing financial interest. Biographies Salma Begum studied at the University of Leipzig with Prof. Harald Krautscheid and the Institute for Integrated Cell−Material Sciences (WPI-iCeMS) with Prof. Suzumu Kitagawa at Kyoto University in Japan. After earning her Ph.D. in Materials Science in 2015, she moved to the Institute of Functional Interfaces (IFG) at Karlsruhe Institute of Technology (KIT) as a Postdoctoral Associate. Currently, her research interest lies in the synthesis and self-assembly of nanoscale objects and functional bionanomaterials, coordination polymers, and SUR(MOF) thin films. Zahid Hassan studied Chemistry at the HEJ Research Institute of Chemistry at Leibniz University of Hannover and received his Ph.D. at K


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