Dynamic Covalent Polymers for Biomedical Applications Cite This: Mater
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MATERIALS CHEMISTRY FRONTIERS View Article Online REVIEW View Journal | View Issue Dynamic covalent polymers for biomedical applications Cite this: Mater. Chem. Front., 2020, 4,489 a b c d Yan Zhang, * Yunchuan Qi, Se´bastien Ulrich, * Mihail Barboiu * and be Olof Ramstro¨m * The rapid development of supramolecular polymer chemistry and constitutional dynamic chemistry over the last decades has made tremendous impact on the emergence of dynamic covalent polymers. These materials are formed through reversible covalent bonds, endowing them with adaptive and responsive features that have resulted in high interest throughout the community. Owing to their intriguing properties, such as self-healing, shape-memory effects, recyclability, degradability, stimuli- responsiveness, etc., the materials have found multiple uses in a wide range of areas. Of special interest is their increasing use for biomedical applications, and many examples have been demonstrated in Received 25th September 2019, recent years. These materials have thus been used for the recognition and sensing of biologically active Accepted 26th November 2019 compounds, for the modulation of enzyme activity, for gene delivery, and as materials for cell culture, DOI: 10.1039/c9qm00598f delivery, and wound-dressing. In this review, some of these endeavors are discussed, highlighting the many advantages and unique properties of dynamic covalent polymers for use in biology and rsc.li/frontiers-materials biomedicine. 1. Introduction a Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214122, During the last decades, dynamic covalent chemistry has P. R. China. E-mail: [email protected] emerged as a powerful means to generate controlled molecular b Department of Chemistry, University of Massachusetts Lowell, One University Ave., systems and networks, designed self-processes, and complex Published on 03 12 2019. Downloaded 2021-10-07 5:20:59. Lowell, MA 01854, USA. E-mail: [email protected] 1–5 c Institut des Biomole´cules Max Mousseron (IBMM), CNRS, Universite´ de Montpellier, architectures. It expands the adaptive features of supra- ENSCM, Montpellier, France. E-mail: [email protected] molecular chemistry to the molecular level,6 thereby forming d Institut Europe´en des Membranes, Adaptive Supramolecular Nanosystems Group, a constitutional dynamic chemistry encompassing dynamically University of Montpellier, ENSCM, CNRS, Place Euge`ne Bataillon, CC 047, interchanging connections between different components.5,7 F-34095, Montpellier, France. E-mail: [email protected] e Department of Chemical and Biomedical Sciences, Linnaeus University, Compared to supramolecular interactions, component reshuf- SE-39182 Kalmar, Sweden fling through dynamic covalent bonds usually needs physical or Yan Zhang received her BSc degree Yunchuan Qi graduated from from Central South University, Shaanxi Normal University in P. R. China. In 2013, she obtained 2014 and received his MSc in 2017 her PhD degree from the Royal from Beijing Normal University. Institute of Technology, Sweden, HestartedhisPhDresearchin under the supervision of Prof. Olof Prof. Olof Ramstro¨m’s group at Ramstro¨m. After a postdoctoral University of Massachusetts Lowell period at the Institut Europe´en des in 2017, focusing on dynamic Membranes (IEM), Montpellier, covalent polymers. France, with Dr Mihail Barboiu, she is now a professor at Jiangnan University, School of Pharmaceutical Yan Zhang Sciences,P.R.China.Hercurrent Yunchuan Qi research is focused on biomaterials based on dynamic covalent polymers. This journal is © The Royal Society of Chemistry and the Chinese Chemical Society 2020 Mater. Chem. Front., 2020, 4, 489--506 | 489 View Article Online Review Materials Chemistry Frontiers chemical triggers and takes longer time, but stronger, optimal multivalent effects, resulting in higher binding affinity compared connections can generally be established, leading to responsive to their corresponding monomers, a feature that is especially systems with controllable stability under different conditions useful in biorecognition. or in the presence of stimuli. These features are often of A number of summarizing accounts on the topic of dynamic advantage, and have led to applications in a range of areas, covalent polymers have been reported, however generally such as organic synthesis, catalysis, materials sciences, and emphasizing their preparations, physicochemical nature, and biomedicine.8–11 applications as self-healing materials, shape-memory matrices, Dynamic covalent polymers (dynamers) are polymeric struc- stimuli-responsive structures, etc.10,18–22 However, in parallel to tures in which the units are linked through reversible covalent the rich development of new dynamic materials bestowed with bonds, thus in principle giving rise to constitutional dynamics.12–15 multiple functionalities and able to operate under a wide range Such dynamic polymers show intriguing malleability, self-healing, of conditions, biomedical applications have increasingly and shear-thinning effects, as well as tunable mechanical and become a target. optical properties.16,17 Moreover, when based on repeating In this review, we provide a short background on dynamic units of embedded functional groups, they often display polymer features, preparation, and distinctive properties, that will help the reader to focus on the biomedical applications of this new type of adaptive systems. Extensive studies have been directed in recent years with the goal and control molecular Se´bastien Ulrich carried out his structure and to generate related biofunctions in fully adaptive PhD with Prof. Jean-Marie Lehn synthetic systems. A range of intriguing examples will be (Universite´ de Strasbourg, France), described, involving different aspects of gene and drug delivery, and post-docs with Prof. Harry L. enzyme activation, recognition of bioactive compounds, cell Anderson (Oxford University, UK) culture and delivery, as well as antibacterial and wound- and Prof. Eric T. Kool (Stanford dressing materials. University, CA, USA). In 2011 he joined the group of Prof. Pascal Dumy, first in Grenoble, then in 2. Synthesis of dynamic covalent Montpellier, France where he was polymers recruited by the CNRS in 2012 to develop his current research In addition to selecting suitable main-chain (backbone) and Se´bastien Ulrich interests in the field of supra- potential side-chain structures, the key step in preparing molecular bioorganic chemistry. dynamic polymers is the inclusion of elements carrying the In 2017, he was awarded the ability to form dynamic covalent bonds. The features of the CNRS Bronze Medal. various reversible bond types have to be considered in great Published on 03 12 2019. Downloaded 2021-10-07 5:20:59. Mihail Barboiu graduated from Olof Ramstro¨m received his MSc University Politehnica of Bucharest and PhD degrees from Lund and received his PhD in 1998 from Institute of Technology/Lund the University of Montpellier, University, Sweden. After a before being post-doctoral period at the Louis Pasteur researcher at the University University, Strasbourg, France, Louis Pasteur in Strasbourg. He he returned to Sweden and the is CNRS Research Director at the Royal Institute of Technology, Institut Europeen des Membranes Stockholm. He is currently active in Montpellier and Fellow of at University of Massachusetts, Royal Society of Chemistry. Since Lowell, USA, and Linnaeus 2014 he is also Extraordinary University, Sweden. Mihail Barboiu Professor in Sun-Yat-sen University Olof Ramstro¨m in Guangzhou, China. A major focus of his research is Dynamic Constitutional Chemistry toward Dynamic Interactive Systems: adaptive biomimetic membranes, delivery devices etc. author of more than 280 scientific publications, 3booksand22chaptersand420conferencesandlectures.DrBarboiu has received in 2004 the EURYI Award in Chemistry and in 2015 the RSC Surfaces and Interfaces Award for the Development of Artificial Water Channels. 490 | Mater. Chem. Front., 2020, 4, 489--506 This journal is © The Royal Society of Chemistry and the Chinese Chemical Society 2020 View Article Online Materials Chemistry Frontiers Review detail, as they are essential to ensure sufficient structural control Disulfide formation and exchange reactions are also frequently and functionality of the final polymeric structures. Especially for to construct dynamic polymers.31 Both anionic (thiolate) and applications in the biomedical area, the exchange rates and radical pathways can in this case lead to disulfide recomposition. biocompatibility of the reversible reactions can be critical. With Intheformercase,aredoxbalancebetweenthiolateanddisulfide a judicious selection and design of the building blocks, their species leads to exchange. Concerning the radical pathway, light arrangement in a preferred order is in principle possible, thereby or radical initiators can cause S–S bond cleavage, leading to obtaining materials with desired functions. disulfide scrambling following radical recombination. Similarly, Se–Se and Se–N bonds can be used in reversible, radical-based 2.1. Types of reversible reactions used for the construction of exchange processes.32,33 Such disulfide-linked polymers have, for dynamic polymers example, been developed to target cysteine groups in biological Kinetically unstable bond types leading to reversibility and systems, leading to degradation of the polymers