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Cucurbit[n]uril -based Monodisperse Microcapsules Self - Assembled within Microfluidic Droplets: A Versatile Approach for Supramolecular Architectures and Materials Journal: Accounts of Chemical Research Manuscript ID ar-2016-00429g.R2 Manuscript Type: Article Date Submitted by the Author: 22-Nov-2016 Complete List of Authors: Liu, Ji; Melville Laboratory for Polymer Synthesis, Department of Chemistry Lan, Yang; University of Cambridge, Melville Laboratory for Polymer Synthesis, Department of Chemistry Yu, Ziyi; University of Cambridge, Chemistry Tan, Cindy; University of Cambridge, Melville Laboratory for Polymer Synthesis, Department of Chemistry; MARA University of Technology - Sarawak Campus Parker, Richard; University of Cambridge, Chemistry Abell, Chris; University of Cambridge, Chemistry Scherman, Oren; University of Cambridge, Melville Laboratory for Polymer Synthesis, Department of Chemistry ACS Paragon Plus Environment Page 1 of 20 Submitted to Accounts of Chemical Research 1 2 3 4 5 Cucurbit[n]uril-based Microcapsules Self-Assembled within Microfluidic 6 Droplets: A Versatile Approach for Supramolecular Architectures and Materials 7 Ji Liu,† Yang Lan,† Ziyi Yu,∗,‡ Cindy S.Y. Tan,†,¶ Richard M. Parker,‡ Chris Abell,∗,‡ and 8 Oren A. Scherman∗,† 9 † Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield 10 Road, Cambridge CB2 1EW, UK. 11 ‡ Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. 12 ¶Faculty of Applied Sciences, Universiti Teknologi MARA, 94300 Kota Samarahan, Sarawak, Malaysia. 13 Received November 19, 2016; E-mail: [email protected]; [email protected]; [email protected] 14 15 Conspectus disperse supramolecular microcapsules, fab- 16 ricated through the integration of traditional 17 Microencapsulation is a fundamental con- microfluidic techniques and interfacial host- 18 cept behind a wide range of daily applica- guest chemistry, specifically cucurbit[n]uril 19 tions ranging from paints, adhesives and pes- (CB[n])-mediated host-guest interactions. 20 ticides to targeted drug delivery, transport Three different strategies: colloidal particle- 21 of vaccines and self-healing concretes. The driven assembly, interfacial condensation- driven assembly and electrostatic interaction- 22 beauty of microfluidics to generate microcap- driven assembly, are classified and discussed 23 sules arises from the capability of fabricat- in details, presenting the methodology in- 24 ing mono-disperse and micron-scale droplets, which can lead to microcapsules/particles volved in each microcapsule formation pro- 25 with fine-tuned control over size, shape and cess. We highlight the state-of-the-art in 26 hierarchical structure, as well as high repro- design and control over structural complex- 27 ducibility, efficient material usage and high- ity with desirable functionality, as well as 28 throughput manipulation. The introduction promising applications, such as cargo deliv- 29 of supramolecular chemistry, such as host- ery stemming from the assembled microcap- 30 guest interactions, endows the resultant mi- sules. On account of its dynamic nature, 31 crocapsules with stimuli-responsiveness and the CB[n]-mediated host-guest complexation 32 self-adjusting capabilities, and facilitates hi- has demonstrated efficient response toward 33 erarchical microstructures with tuneable sta- various external stimuli such as UV light, 34 bility and porosity, leading to the maturity of pH change, redox chemistry, and compet- 35 current microencapsulation industry. itive guests. Herein, we also demonstrate 36 Supramolecular architectures and materi- different microcapsule modalities, which are n 37 als have attracted immense attention over the engineered with CB[ ] host-guest chemistry and also can be destroyed with the aid of 38 last decade, as they open the possibility to external stimuli, for triggered release of pay- 39 obtain a large variety of aesthetically pleas- ing structures, with myriad applications in loads. In addition to the overview of recent 40 biomedicine, energy, sensing, catalysis and achievements and current limitations of these 41 biomimicry, on account of the inherent re- microcapsules, we finally summarize several 42 versible and adaptive nature of supramolecu- perspectives in tuneable cargo loading and 43 lar interactions. As a subset of supramolecu- triggered release, directions and challenges 44 lar interactions, host-guest molecular recogni- for this technology, as well as possible strate- 45 tion involves the formation of inclusion com- gies for further improvement, which will lead 46 plexes between two or more moieties, with to substaintial progress of host-guest chem- 47 specific three-dimensional structures and spa- istry in supramolecular architectures and 48 tial arrangements, in a highly controllable materials. 49 and cooperative manner. Such highly selec- 50 tive, strong yet dynamic interactions could be 1. Introduction 51 exploited as an alternative methodology for 52 programmable and controllable engineering of supramolecular architectures and materi- The synthesis and self-assembly of polymer building 53 blocks for the construction of functional supramolecular 54 als, exploiting reversible interactions between complementary components. Through the micro-/nano-structures are a major part of the emerging 55 1,2 engineering of molecular structures, assem- field of Supramolecular Polymer Chemistry. The intro- 56 blies can be readily functionalized based on duction of non-covalent supramolecular interactions such as 57 host-guest interactions, with desirable physic- hydrogen bonding, host-guest complexation or electrostatic 58 ochemical characteristics. interactions offers great opportunities to impart novel fea- 3 59 In this account, we summarize the current tures and functions to these polymer systems. As an exam- 60 state of development in the field of mono- ple of such self-assembled architectures, microcapsules have ACS Paragon Plus Environment 1 Submitted to Accounts of Chemical Research Page 2 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment Page 3 of 20 Submitted to Accounts of Chemical Research 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment Submitted to Accounts of Chemical Research Page 4 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment Page 5 of 20 Submitted to Accounts of Chemical Research 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment Submitted to Accounts of Chemical Research Page 6 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment Page 7 of 20 Submitted to Accounts of Chemical Research 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment Submitted to Accounts of Chemical Research Page 8 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment Page 9 of 20 Submitted to Accounts of Chemical Research capsules requires future investigation, device design, and in fragment-based drug discovery. He also has research in- 1 process optimization. An important direction for future terests in developing microdroplets as a novel experimental 2 work will be expanding the range of stimuli, which can be platform, which led to the co-founding of Sphere Fluidics 3 incorporated in microcapsule formulations, featuring quanti- (2010) and Aqdot (2013). 4 tative functions and responses that can be activated in these Oren Scherman is the Director of the Melville Labora- 5 dynamic assemblies in a well-controlled manner. A future tory for Polymer Synthesis in the Department of Chemistry 6 challenge is to develop a monitoring strategy, which not only at the University of Cambridge and Professor of Supramolec- 7 controls the microcapsule integrity, but also tracks in situ ular and Polymer Chemistry. His current research projects 8 the cargoes delivery . Further in vitro and in vivo studies include the application of macrocyclic host-guest chem- 9 will be indispensable before CB[n]-based microcapsules are istry using cucurbit[n]urils in the development of novel 10 used for any biomedical applications, as most current stud- supramolecular hydrogels and microcapsules, drug-delivery 11 ies focus on the methodology of microcapsule construction systems based on dynamic hydrogels, the conservation and 12 and state-of-art techniques to trigger the structural destruc- restoration of important historical artefacts through the 13 tion with internal or external stimuli, thus release of the exploitation of supramolecular polymer chemistry and sens- 14 cargoes.