Supramolecular Biomaterials Matthew J

REVIEW ARTICLE PUBLISHED ONLINE: 18 DECEMBER 2015 | DOI: 10.1038/NMAT4474 Supramolecular biomaterials Matthew J. Webber1,2†, Eric A. Appel1,3†, E. W. Meijer4,5,6 and Robert Langer1,2,7,8,9* Polymers, ceramics and metals have historically dominated the application of materials in medicine. Yet rationally designed materials that exploit specific, directional, tunable and reversible non-covalent interactions offer unprecedented advantages: they enable modular and generalizable platforms with tunable mechanical, chemical and biological properties. Indeed, the reversible nature of supramolecular interactions gives rise to biomaterials that can sense and respond to physiological cues, or that mimic the structural and functional aspects of biological signalling. In this Review, we discuss the properties of several supramolecular biomaterials, as well as their applications in drug delivery, tissue engineering, regenerative medicine and immu- nology. We envision that supramolecular biomaterials will contribute to the development of new therapies that combine highly functional materials with unmatched patient- and application-specific tailoring of both material and biological properties. ressures arising from the increasing incidence of cancer and crosslinked materials12. Supramolecular biomaterials leverage motifs degenerative diseases, coupled with a focus to increase the qual- based on supramolecular chemistry in order to produce functional Pity of life for patients, have inspired the development of smarter materials that have applications in therapy, diagnostics or devices and more creative healthcare solutions. The use of biomaterials — to advance healthcare. The specific benefits of supramolecular bio substances that are not foods or drugs and that are in contact with materials arise from the nature of these supramolecular interactions, tissues or biological fluids1,2 — has a long history dating back thou- which confer control over properties in a reversible, highly tunable, sands of years to early wood prostheses3. In modern times, clinical dynamic and modular fashion. Supramolecular biomaterials may uses of biomaterials have included the application of metals, ceram- also enable biomimetic recapitulation of native biological signalling ics and polymers to augment, repair or replace diseased, damaged or structural cues13 (Fig. 1). As such, supramolecular biomateri- or defective tissues. Over the past several decades, materials have als provide a diverse toolbox that could help to address important been ubiquitous in the practice of medicine and have transformed unmet medical needs. orthopaedic joint replacement, vascular grafting, plastic surgery, dental augmentation and bone fusion and fixation, among many Synthesis of supramolecular biomaterials other clinical practices. Materials have also been used in the context Generally speaking, and on the basis of their supramolecular forma- of tissue engineering as scaffolds and delivery depots for cell-based tion mechanisms, supramolecular biomaterials fall into two broad regenerative medicine4,5. Traditional biomaterials offer the possi- classes (Fig. 2): materials prepared from one-dimensional (that is, bility of preparing structural analogues to native tissue, but their high-aspect-ratio) assemblies of molecular stacking motifs (Box 1), capacity to recapitulate native functional dynamics is limited. and materials prepared through chain extension of oligomers or The development of next-generation biomaterials must include through crosslinking of polymeric precursors by specific supra- strategies to improve both structural and functional recapitulation molecular recognition motifs (Box 2). The design of each of these of native tissue. In this regard, materials designed using supra classes of supramolecular biomaterials requires an understanding molecular principles could have broad impact for use in the body. of the nature of the underlying non-covalent interactions that give Supramolecular chemistry — defined as ‘chemistry beyond the mol- rise to different supramolecular motifs. In preparing these materials, ecule’6–9 — is based on the rational design of specific, directional, a number of specific, directional, non-covalent moieties have been tunable, reversible, non-covalent molecular recognition motifs that developed. These are based on ordered non-covalent interactions exploit hydrogen bonding, metal chelation, hydrophobic inter such as hydrogen bonding, metal–ligand coordination, host–guest actions, π–π interactions, and/or van der Waals interactions. These complexation and electrostatic interactions. Each interaction can motifs can be leveraged to create supramolecular materials whose be characterized by its equilibrium association constant (Keq) and properties follow from the dynamic nature of their constituents10,11, binding kinetics, which is defined by the rate constants of associa- and thereby contribute distinct and useful properties that have thus tion (ka) and dissociation (kd). Within every supramolecular material far been unrealized in traditional biomaterials. Although individu- there exists a complex interplay between each of these parameters, as ally the non-covalent interactions that give rise to supramolecular well as their binding mode, so that even when considering the same materials are weak, the summation and directionality of these inter- general non-covalent interaction (such as a hydrogen bond), each actions leads to materials with mechanical properties that were of these specific parameters must be considered in order to realize thought to be uniquely reserved for macromolecules and covalently predictable material properties. The mechanisms of interaction that 1David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. 2Department of Anesthesiology, Boston Children’s Hospital, Boston, Massachusetts 02115, USA. 3Department of Materials Science & Engineering, Stanford University, Stanford, California 94305, USA. 4Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands. 5Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands. 6Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands. 7Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. 8Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. 9Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. †These authors contributed equally to this work. *e-mail: [email protected] NATURE MATERIALS | VOL 15 | JANUARY 2016 | www.nature.com/naturematerials 13 © 2015 Macmillan Publishers Limited. All rights reserved REVIEW ARTICLE NATURE MATERIALS DOI: 10.1038/NMAT4474 a c natural biodegradation, and the possibility to mimic the structural Tunable Responsive and functional aspects of native matrix elements. [ ][ ] ka Keq == [ ] kd A different bioinspired strategy to create supramolecular biomaterials has been developed using de novo engineering of recombinant protein-derived molecular recognition motifs in order to crosslink polymers or recombinant polypeptides. Early work in this b d area demonstrated the feasibility of the strategy with designed syn- Modular Biomimetic thetic proteins incorporating leucine-zipper domains along with non-structured flexible domains40,41. More specific protein-based interactions, such as molecular recognition through engineered Cell membrane receptor receptor–ligand motifs, have also been leveraged as crosslinking Biomaterial scaold domains within synthetic polymeric or recombinant protein back- Displayed bioactive group bones42,43. Although these types of materials have not commonly been discussed in the context of supramolecular materials, the spe- Figure 1 | Supramolecular biomaterials are tunable, modular, responsive cific, directional, tunable and strong nature of these non-covalent and biomimetic, as a result of the specific, dynamic, interchangeable and molecular recognition motifs resemble those of materials based reversible motifs used in their design. a–d, Examples of the ways in which on more typical supramolecular chemistry. Approaches based on the properties of supramolecular biomaterials could interface with a cell recombinant engineered proteins benefit from the use of naturally (such properties would also provide benefits across a number of other derived building blocks, similar to small-molecule oligopeptide gela- biomedical applications). Tunable nature of the affinity between molecular tors, whereas recombinant production of polypeptides can produce recognition motifs (a). Modularity enables the ‘mix-and-match’ creation of high-molecular-weight building blocks with discrete mass exploit- supramolecular biomaterials with, for example, conserved self-assembling ing the same established preparation and purification methods used motifs and variable bioactive groups (b). Supramolecular biomaterials can in the bioengineering of protein therapeutics. also respond to physiological cues if, for instance, they are engineered with One of the most recognizable motifs in supramolecular chem- enzyme-degradable segments (c). Supramolecular materials that exhibit istry is the macrocyclic host–guest interaction. One such macro-

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