Commentary pubs.acs.org/accounts
Living Biomaterials Published as part of the Accounts of Chemical Research special issue “Holy Grails in Chemistry”. Mark W. Tibbitt† and Robert Langer*,†,‡ †
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States ‡ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States ABSTRACT: Convergent advances in the fields of synthetic chemistry, soft matter, molecular self-assembly, and the -omics era point to a new generation of synthetic biomaterials that are indistinguishable in form and function from biological matter. Such living biomaterials comprise a “Holy Grail” of the chemical sciences that will transform both modern medicine and materials design.
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INTRODUCTION Imagine a material-based seed that when implanted cooperates with the patient’s body to regrow a missing or damaged organ, obviating the need for transplantation and avoiding months to years of anxious wait for a cadaveric organ. Or an implant that is placed in a patient who is at-risk for developing cancer, because of genetic or lifestyle predispositions, which senses the origins of malignancy and works with the immune system to destroy aberrant cells before any clinical manifestation of disease. Or a soft prosthetic that interprets neurological communication and restores function to an intact yet nonoperative limb, bestowing a person with paralysis autonomous control of their body again. Or a patch that senses misregulated hormones or cytokines and produces, then secretes, the appropriate molecules to restore homeostasis, treating patients with diabetes or hypothyroidism. Such living biomaterials comprise a “Holy Grail” within the soft materials and biomedical communities that would transform the way medicine operates, and convergence of the chemical, physical, biological, and mathematical sciences with engineering will make them a reality in the future.
contact lenses; therapeutics are delivered in a sustained and controlled manner from polymeric implants; functional tissues are grown in synthetic scaffolds outside of the body. More recently, advances in molecular self-assembly, peptide and protein engineering, and microfabrication have introduced next-generation, “smart” biomaterials into which responsive or interactive properties have been engineered.1 Now, remotecontrolled microchips deliver therapeutic doses on-demand;2 cell culture substrates with user-tunable moduli reveal novel aspects of stem cell biology;3 shape memory implants are being created to facilitate laproscopic surgery.4 Despite the successes of biomaterials, clinical translation is still impeded, in many cases, by material fouling or rejection. The cells and tissues of the body interrogate and interact with nearly all foreign materials, eliciting some degree of immune response or a cordoning off by the foreign-body response. Few materials are capable of exchanging information with or functionally integrating into living systems, and most biomaterials merely coexist with the body. Therefore, we ultimately seek to dissolve this boundary with next-generation, living biomaterials that integrate, cooperate, and communicate with biological systems. That is, to engineer matter that perceives and adapts to its surroundings and is imbued with emergent behaviors more often ascribed to living systems.
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CLASSIC BIOMATERIALS Biomaterials comprise the broad class of synthetic matter that interfaces with biological systems and have enabled many transformative advances in modern medicine. In fact, myriad materials have been employed throughout modern history to augment the human body and treat disease. Whether opting for wood as a prosthetic toe or gold as a dental insert, biomaterials were selected initially based on mechanical properties that restore function while minimizing adverse effects. The advent of macromolecular chemistry and engineering during the 20th century, and the associated polymeric materials that are now available, have enabled a new class of rationally designed soft biomaterials. Classic soft biomaterials (i.e., those that are nonresponsive and static) pervade all aspects of modern medicine. Poor vision is corrected with hydrogel © 2017 American Chemical Society
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BIOLOGICAL MATTER As one envisions the design and fabrication of synthetic yet living biomaterials, it is natural to consider biological matter. Cells, extracellular matrix, and organs comprise some of the most complex and hierarchically functional materials known to man. As an example, human skin, a seemingly simple organ, demonstrates extreme resiliency, elasticity, and barrier properties, maintaining a separation between the outside world and Received: September 30, 2016 Published: March 21, 2017 508
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Figure 1. Chemical approaches for the synthesis of defined molecular precursors. A range of synthetic approaches exist for the fabrication of molecular constituents of living biomaterials. For example, controlled polymerizations, including ring-opening metathesis polymerization (ROMP) as a representative anionic polymerization and atom transfer radical polymerization (ATRP) as a representative radical polymerization, provide access to polymeric species with low polydispersity, defined architecture, and specific chemistry. Postpolymerization functionalization provides an additional strategy to append selected functionality to synthetic polymers via, for example, isocyanate or click chemistry among other strategies. Nucleic acid chemistry and protein engineering enables direct access to biomacromolecules. Lipid and glycochemistry provide the remaining molecules of life.
the body under a range of environmental conditions and deformation loads. At the same time, this hierarchical and multicomponent material is extremely sensitive, spatially resolving and communicating information about external forces, topography, and temperature. Yet, in a reductionist view, this structurally complex and multifunctional organ is nothing more than a complex assemblage of macromolecules, lipids, small molecules, and aqueous fluids. Biological systems are comprised entirely of molecules and molecular assemblies, which are not themselves alive. The choreographed interplay between these molecular components is sufficient to generate the critical and varied functions of the skin. In fact, any biological material can be viewed in this way; biological matter is governed by the same chemistry, physics, and thermodynamics as every other molecular system. Yet, it is clear that the complexity in structure and function of biological matter is beyond that of current synthetic systems. Major distinguishing features between biological and synthetic matter are the scope and precision of molecular building blocks as well as the tailored intermolecular interactions found in biological systems. The molecules of life include macromolecules (e.g., nucleic acids, proteins, and glycans) of precise molecular weights, lipids, and small molecules, as well as
inorganic salts and metals. Directional and dynamic interactions between these molecular building blocks that are relatively simple on the molecular scale give rise to the emergent behaviors that support and drive biological function as well as the wide range of physical properties and biochemical functionality observed in nature. As we continue to decode the molecular interactions and complexity of biological systems and combine this with our ability to design and synthesize precise and complex macromolecules, we begin to possess the tools and understanding that are needed to design and assemble macromolecular matter imbued with living behavior.
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CHEMICAL TOOLS In order to realize this aim, we need synthetic tools and assembly methods to precisely define how macromolecular systems form and interact. As stated above, there is nothing that prohibits, a priori, the design and fabrication of synthetic materials that recapitulate the emergent functions of life and even communicate with biological matter. In fact, similar concepts of living soft matter were anticipated by Hermann Staudinger, the father of macromolecular science, in the closing paragraphs of his 1953 Nobel Lecture.5 Yet, we are still limited by our inability to make certain molecular precursors and by 509
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Figure 2. Molecular interactions for the controlled assembly of living biomaterials. In order to fabricate living biomaterials that can adapt and respond to changing environments, their assembly should rely on a range of directional and dynamic interactions. These include, but are not limited to, hydrogen bonding as demonstrated by ureido-pyrimidinone (UPy) dimerization and DNA base-pairing, electrostatic interactions through π−π stacking or ionic interactions, and entropically driven processes such as micelle formation or shape controlled assembly. In addition, higher level interactions can be engineered into molecular assemblies to provide a broader range of response kinetics and thermodynamic equilibria. These include host−guest interactions through adamantane and cyclodextrin pairs; metal−ligand coordination via iron or zinc centered species; as well as tailored peptide self-assembly that can form β-sheet fibers.
the difficulty in predicting how macromolecular systems will assemble and interact. Active collaboration between chemists, engineers, biologists, physicists, clinicians, theoreticians, and materials scientists is needed to converge upon the design and implementation of living biomaterials. To reach this end, this emerging field will draw upon synthetic chemists and engineers to provide access to the required (macro)molecular building blocks as well as physicists, theoreticians, and materials scientists to generate conceptual frameworks for the design and assembly of living matter and how it will respond to and interact with biological systems. Synthetic chemistry, biochemistry, and engineering provide access to a wide range of tailored molecular constitutents (Figure 1). Controlled polymerizations (e.g., RAFT, ATRP, and ROMP) and postpolymerization functionalization provide unprecedented control over macromolecular architecture and chemical functionality. Nucleic acid chemistry and automated synthesis enable researchers to construct tailored sequences of DNA or RNA outside of a cell. Protein engineering enables the facile production of large quantities of specific proteins by transfecting bacteria or mammalian cells with a prescribed genetic sequence. Lipid chemistry and glycochemistry provide
access to the additional building blocks of life and inform how multicomponent molecules behave and work together to compartmentalize life and speciate interactions. Bio-orthogonal chemistry supplies the tools to perform precise chemical synthesis of many of these species in complex aqueous media. In addition to synthetic access, the fields of molecular selfassembly, including supramolecular chemistry and colloid science, provide methods and frameworks to precisely engineer intermolecular interactions and multiscale organization (Figure 2). Intermolecular forces (e.g., hydrogen bonding, van der Waals interactions, entropic driving forces, π−π stacking, and ionics) can be designed into macromolecular species to define how they assemble and interact. More complex assembly approaches, such as host−guest interactions and metal−ligand coordination, have been used to form responsive polymer networks.6,7 Peptide self-assembly reveals how molecular design of constituent species can be be employed alone to spontaneously assemble functional materials.8 Recently, templated oligonucleotides were conjugated to sequence-defined synthetic polymers to fabricate a range of supramolecular cages through nucleic acid base pairing and hydrophobic interactions.9 In general, weak yet multivalent interactions that are 510
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Accounts of Chemical Research directional and noncovalent are sufficient to drive emergent behavior, when properly designed. In addition to advanced synthetic capabilities, the field is benefiting from the development of computational algorithms to understand and predict how complex (macro)molecular media interact and assemble. Improvements in these predictive capabilities (e.g., with respect to thermodynamic and kinetic fidelity) will allow us to design and model multicomponent, living biomaterials in silico in order to inform synthetic approaches. As an example, de novo protein design has been leveraged to engineer a functional and selective transmembrane ion transporter.10 In addition, biomaterials will benefit from advances in synthetic biology and genetic engineering, and the corresponding -omics era, that are decoding the rules of life and handing us the keys to manipulate and design biological matter selectively.
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REGENERATIVE MEDICINE As living synthetic biomaterials emerge, a major area of emphasis will be their use in tissue engineering and regenerative medicine. During development or as the body heals, biological matter adapts and evolves to respond to the changing conditions, providing cells with a range of cues that guide morphogenesis, homeostasis, or healing. We still lack materials for the ex vivo culture of mammalian cells that capture realistic extracellular matrix-like dynamics and multifunctionality as well as tissue-like adaptability and cell−matrix crosstalk. Instead of simply serving as a support for cell growth and then going away, we now aim to design materials that provide cues dynamically and in a responsive manner to cells and nascent tissues as they develop. An early example of this class of living scaffolds was engineered such that a cellular dictated mechanism regulated peptide presentation depending on cell state, enhancing stem cell differentiation and tissue maturation (Figure 3a).11 More recently, scaffolds whose mechanics were designed to change over time have been employed to enhance cardiomyocyte maturation and investigate fibrotic disease.12,13 In addition, implantable materials are being engineered to integrate functionally with the body following implantation. For instance, tailored chemical modification of alginate has enabled cell-laden hydrogels to avoid rejection and produce insulin functionally for up to 6 months in non-human primates, reversing the clinical manifestations of diabetes.14 While these “stealth” materials may enable clinicians to place synthetic materials in the body without fear of rejection, we ultimately seek materials that adapt to the body after implantation. This may include a cartilage implant that restores pain-free function to an arthritic patient in the short term and over time forms a seemless interface with the surrounding tissue or an implant that nucleates tissue growth and disappears as functional neotissue forms. In order for these tissue engineering approaches to function, we likely need to think beyond monolithic materials and design synthetic systems composed of multiple components (e.g., polymers, peptide nanofibers, glycosaminoglycans, native or engineered proteins, and polysaccharides). Complementary work that is dissecting the structure and proteomic complexity of biological materials may further inform the design of living biomaterials. Finally, incorporating the ability to harvest and use energy from the surrounding biological milieu is critical, as complex functionality is rarely passive and requires a directional flow of energy.
Figure 3. Examples of living biomaterials. (a) Responsive scaffolds for the three-dimensional culture of mesenchymal stem cells have been designed to present an adhesive peptide while the stem cell remains latent (red cell) but releases the ligand in response to protease expression as the stem cell becomes activated and differentiates toward a chondrocyte lineage (green cell). Redrawn with permission from ref 11. Copyright 2008 Elsevier. (b) A microneedle-based, transdermal patch has been engineered that senses and responds to local glucose concentration, releasing insulin only when needed during hyperglycemia. Redrawn with permission from ref 16. Copyright 2015 National Academy of Sciences. (c) Artificial skin has been fabricated that converts mechanical force into electrical signal, which may be transmitted to biological organs. Redrawn with permission from ref 22. Copyright 2016 Nature Publishing Group. (d) Protocells have been synthesized from lipid vesicles and RNA molecules that will begin to manifest basic functions of living cells, such as autonomous protein production and self-replication. Redrawn with permission from ref 28. Copyright 2013 AAAS.
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DRUG DELIVERY Another major research area that will benefit from the design of living biomaterials is drug delivery. The body constantly exchanges soluble and insoluble chemicals to communicate and regulate biochemical function, including hormone secretion to maintain metabolism and body temperature, growth factor expression during organogenesis, and cytokine secretion in response to infection. Modern pharmaceuticals work to intervene with these pathways as well as at the cell signaling level to direct the body back to homeostasis. Work within the drug delivery field over the past several decades has provided clinicians with a wide range of controlled release technologies: polymeric implants control the release of drugs over the course of months to years; nanoparticles deliver functional nucleic acids to specific tissue of interest; and contraceptive hormones are released from intravaginal rings.15 Current work focuses on “smart” or living drug delivery systems that listen and respond to the needs of biological systems. Such technologies will be able to sense disease in its earliest form, communicate its presence outside of the body to clinicians, and treat it before any damage is done. As an example, a transdermal microneedle patch was recently 511
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Accounts of Chemical Research developed that sits patiently on the skin until it senses a misregulation in glucose levels and then secretes insulin in response to aid in the management of diabetes (Figure 3b).16 Developments in the field of nanotechnology continue to produce an array of nanoscale delivery vehicles capable of discerning between pathological and healthy tissue through passive and active targeting. This critical design criterion serves to increase the efficacy of a range of therapeutics, while mitigating off-target damage and morbidity. Additionally, materials have been designed to interact with the immune system both to “recruit and train” dendritic cells to enhance vaccine efficacy as well as to sequester metastatic tumor cells, mitigating the formation of lethal metastatic lesions.17,18 Advances in synthetic biology have enabled the design of bacterial-based therapeutics that colonize hypoxic tumor regions specifically and then synchronously express several molecules (engineered to induce immune cell activation, apoptosis, and cell lysis), providing a synergistic effect with chemotherapy on the suppression of tumor growth.19 Proteaseresponsive nanotechnologies have been assembled to inform clinical treatment. In one instance, nanoparticles release a tag in the presence of cancer cells providing a simple cancer biomarker that can be detected in the urine.20 In another example, a nanoscale fluorophore has been designed to only light up in the presence of cancerous cells guiding tumor resection surgeries.21 The era of living therapeutics will require ongoing collaboration with biologists and clinicians to identify early markers of disease as well as to develop a more robust understanding of how to augment the immune system to address morbidity.
active behavior. 26 In addition, engineered systems of autocatalytic, organic reactions within a microfluidic device demonstrated emergent bistable and oscillatory behavior.27 The origin of life constitutes one of the physical world’s most profound transitions, wherein matter assumed the attributes of life: molecular assemblages that continually regenerate, replicate, and evolve. As our ability to engineer soft matter has advanced, researchers are now able to construct from base components protocells, composed of lipid vesicles and RNA molecules, that behave as minimal living systems (Figure 3d).28 In parallel, molecular biologists are deconstructing bacterial genomes to a minimum basis set of life, including the design and synthesis of a functional, 57-codon genome.29 As these systems can harvest energy more efficiently from biochemical sources and generate specific molecules in response to primed signals, they present a great resource for the advancement of living biomaterials.
SOFT ELECTRONICS Another hallmark of life is the ability to transmit signals electronically over long distances, often achieved by the nervous system. In this vein, living biomaterials will incorporate aspects of the emerging field of soft or bioelectronics. An advance in this area has been the fabrication of artificial skin that is responsive to external touch, transducing physical force into electrical signal (Figure 3c).22 In addition, piezoelectric devices have been designed to harness power from mechanical motion or organs to power medical implants.23 Complex prostheses equipped with electronic sensors have been engineered, not only to restore function but to enable amputees to perform intricate activities, such as ballroom dance.24 Electronics incorporated into hydrogel-based wound coatings have been demonstrated to monitor and treat infection during wound healing.25 Future advances in soft electronics will engender living biomaterials that store and transmit information over longer distances, communicate with external devices outside of the body, and harness excess energy to remain powered.
Corresponding Author
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CONCLUSION The lines between biological and synthetic matter continue to dissolve. We now possess the tools to synthesize nearly any molecule of interest and to predict how intermolecular interactions lead to emergent behavior. These engineered systems increasingly adopt the manifestation of biological systems. The coming years will see a targeted growth in the design of living biomaterials that functionally cooperate and communicate with the body to diagnose, treat, and prevent disease.
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AUTHOR INFORMATION
*E-mail:
[email protected]. Phone: +1 (617) 253 3107. ORCID
Mark W. Tibbitt: 0000-0002-4917-7187 Robert Langer: 0000-0003-4255-0492 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS R.L. thanks the National Institutes of Health (NIH) for funding support (Grant R37EB000244). M.W.T. thanks the NIH for funding support through a Ruth L. Kirschstein National Research Service Award (F32HL122009). The authors thank H. Ragelle and O.S. Fenton for critical feedback on the manuscript.
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REFERENCES
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ARTIFICIAL LIFE Finally, active research in the areas of artificial life and synthetic biology will further advance the design and implementation of living biomaterials. While this field has classically arisen out of molecular biology and biochemistry laboratories, there is increasing interest within the physics and chemistry communities to contribute to the study of artifical life. Recent work has investigated emergent complexity and information content of two-component droplet systems, highlighting how simple physical phenomena in soft matter systems alone can manifest 512
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