Phase separation in polymer-based biomimetic structures containing planar membranes

Phase separation is a phenomenon underlying the complexity of the biological membrane, where both lipids and membrane-associated proteins can rearrange to form spatially separated compartments of distinct functions on all relevant size scales, ranging from molecular lengths to the dimensions of the cell itself.1,21. J. A. Ditlev, J. Mol. Cell Biol. 13, 319 (2021). https://doi.org/10.1093/jmcb/mjab0102. F. A. Heberle, J. Wu, S. L. Goh, R. S. Petruzielo, and G. W. Feigenson, Biophys. J. 99, 3309 (2010). https://doi.org/10.1016/j.bpj.2010.09.064 This complex behavior arises, in part, from the large number of diverse kinds of lipids and proteins, different ways in which these membrane components interact with each other and with the rest of the cell, and the dynamic processes that locally and dramatically change significant fractions of the membrane.33. F. A. Heberle and G. W. Feigenson, Cold Spring Harb. Perspect. Biol. 3, a004630 (2011). https://doi.org/10.1101/cshperspect.a004630 Biomimetic membranes are artificial models designed to replicate the structure and behavior of biological membranes, in order to study the complex cellular processes occurring at their surface or mediated through them, such as intracellular communication using signaling networks between nuclei and organelles,44. B. Grimm, K. Dehesh, L. Zhang, and D. Leister, Mol. Plant 7, 1071 (2014). https://doi.org/10.1093/mp/ssu073 transport of nutrients across a lipid bilayer,44. B. Grimm, K. Dehesh, L. Zhang, and D. Leister, Mol. Plant 7, 1071 (2014). https://doi.org/10.1093/mp/ssu073 or recognition processes.55. B. C. Lagerholm, G. E. Weinreb, K. Jacobson, and N. L. Thompson, Annu. Rev. Phys. Chem. 56, 309 (2005). https://doi.org/10.1146/annurev.physchem.56.092503.141211 Early models for cellular plasma membranes focused on the spatial and temporal heterogeneity of the outer and inner membrane sheets,55. B. C. Lagerholm, G. E. Weinreb, K. Jacobson, and N. L. Thompson, Annu. Rev. Phys. Chem. 56, 309 (2005). https://doi.org/10.1146/annurev.physchem.56.092503.141211 after which successful in vitro reconstitution of putative lipid-stabilized lipid raft membrane domains6,76. E. London, Curr. Opin. Struct. Biol. 12, 480 (2002). https://doi.org/10.1016/S0959-440X(02)00351-27. C. Dietrich, L. A. Bagatolli, Z. N. Volovyk, N. L. Thompson, M. Levi, K. Jacobson, and E. Gratton, Biophys. J. 80, 1417 (2001). https://doi.org/10.1016/S0006-3495(01)76114-0 directed research towards multicomponent membranes composed of mixtures of lipids. For example, in membranes composed of DSPC/DOPC/POPC/cholesterol and SM/DOPC/POPC/cholesterol, the size of compositional heterogeneities could be controlled entirely by the lipid composition.22. F. A. Heberle, J. Wu, S. L. Goh, R. S. Petruzielo, and G. W. Feigenson, Biophys. J. 99, 3309 (2010). https://doi.org/10.1016/j.bpj.2010.09.064 While lipid phase behavior in such biomimetic ternary mixtures has become a rich area of research regarding their thermotropic miscibility and phase coexistence and transitions,2,8–102. F. A. Heberle, J. Wu, S. L. Goh, R. S. Petruzielo, and G. W. Feigenson, Biophys. J. 99, 3309 (2010). https://doi.org/10.1016/j.bpj.2010.09.0648. L. S. Hirst, P. Uppamoochikkal, and C. Lor, Liq. Cryst. 38, 1735 (2011). https://doi.org/10.1080/02678292.2011.6159479. T. S. Carpenter, C. A. López, C. Neale, C. Montour, H. I. Ingólfsson, F. Di Natale, F. C. Lightstone, and S. Gnanakaran, J. Chem. Theory Comput. 14, 6050 (2018). https://doi.org/10.1021/acs.jctc.8b0049610. B. L. Stottrup, D. S. Stevens, and S. L. Keller, Biophys. J. 88, 269 (2005). https://doi.org/10.1529/biophysj.104.048439 the various membranes formed from such mixtures still suffer from poor mechanical and physicochemical stability limited by lipid content incorporated. Due to this limitation, the search for a building block able to mimic the properties of lipids and their amphiphilic nature led to the incorporation of amphiphilic diblock copolymers (DBCs), synthetic analogs of lipids,1111. P. Alexandridis and B. Lindman, Amphiphilic Block Copolymers: Self-Assembly and Applications (Elsevier, Amsterdam, The Netherlands, 2000). in order to obtain membranes less prone to mechanical or thermal damage and stable over a longer period of time.1212. J.-F. Le Meins, C. Schatz, S. Lecommandoux, and O. Sandre, Mater. Today 16, 397 (2013). https://doi.org/10.1016/j.mattod.2013.09.002 Polymers are compounds of choice for the fabrication of biomimetic textured surfaces due to their varied chemical and mechanical properties. Additionally, by careful choice of the hydrophilic (A) and hydrophobic (B) blocks in a diblock copolymer, as well as by adjusting their length and biocompatibility to form biomimetic structures, it was possible to obtain a physicochemical resemblance of the lipid molecule using block copolymers.13,1413. W. Meier, C. Nardin, and M. Winterhalter, U.S. patent 6,723,814B2 (20 April 2004).14. M. Stolzenburg, C. Elbek, S. Mentzel, and K. H. Nielsen, DK patent 178227B1 (7 September 2015). Initial attempts to incorporate them into membranes involved the titration of DBCs into solutions of lipids or their mixtures, using the protocols previously employed for the assembly of lipid structures, leading to hybrid assemblies containing a low content of DBCs.1515. J. Kowal, D. Wu, V. Mikhalevich, C. G. Palivan, and W. Meier, Langmuir 31, 4868 (2015). https://doi.org/10.1021/acs.langmuir.5b00388 The gradual adjustment of these protocols led to hybrid biomimetic membranes based on block copolymers and diverse biomolecules,1616. A. Krywko-Cendrowska, S. di Leone, M. Bina, S. Yorulmaz-Avsar, C. G. Palivan, and W. Meier, Polymers 12, 1003 (2020). https://doi.org/10.3390/polym12051003 such as lipids, proteins, nucleic acids, and small molecules, e.g., metabolites or natural products. While phase separation in biomimetic hybrid membranes containing lipid mixtures with block copolymers has been well known for over two decades, reports on phase separation in fully synthetic planar membranes are scarce. In a recent report, the recreation of a lipid bilayer and the reconstitution of the natural phase separation has been achieved using a mixture of two different DBCs, PDMS-b-PMOXA, and PEO-b-PEHOx.1717. M. Bina et al., Nano Lett. 22(13), 5077-5085 (2022). https://doi.org/10.1021/acs.nanolett.2c00332 The concept of the research was based on the analogy to lipid bilayers based on lipid mixtures, but using only synthetic amphiphilic molecules. In this article, we review recent developments in the formation of biomimetic membranes based on block copolymers, leading to phase separation. We attempt to define the membrane and its phase separation and the parameters and conditions decisive for its reconstitution into a membrane, such as chemical compatibility, hydrophobic mismatch, chemical composition, presence of lipid molecules, polymer crystallinity, and copolymer architecture. Next, we briefly list the methods to obtain such inhomogeneous membranes, and we further exemplify the occurrence of phase separation in planar membranes, in particular, obtained on a solid support and quasiplanar membranes contained in giant unilamellar vesicles (GUVs), as model structures for free-standing planar biomimetic membranes (Fig. 1). GUVs are self-assembled, three-dimensional structures commonly used as basic cell and cell membrane models, sized between 1 and 100 μm.1818. T. Bhatia, P. Husen, J. Brewer, L. A. Bagatolli, P. L. Hansen, J. H. Ipsen, and O. G. Mouritsen, Biochim. Biophys. Acta, Biomembr. 1848, 3175 (2015). https://doi.org/10.1016/j.bbamem.2015.09.020 In this review, we consider hybrid and synthetic GUVs of 1 μm in diameter and above, from which size the strain due to the curvature of the membrane can be neglected on a local scale.1818. T. Bhatia, P. Husen, J. Brewer, L. A. Bagatolli, P. L. Hansen, J. H. Ipsen, and O. G. Mouritsen, Biochim. Biophys. Acta, Biomembr. 1848, 3175 (2015). https://doi.org/10.1016/j.bbamem.2015.09.020 Therefore, the membrane can be considered as a free-standing architecture that is in two-dimensional form1919. E. Jenkins et al., J. Cell Sci. 132, jcs219709 (2018). https://doi.org/10.1242/jcs.219709 and that can contain different domains as in the case of solid-supported membranes. Due to the above, we exclude both synthetic20,2120. J. Lin, J. Zhu, T. Chen, S. Lin, C. Cai, L. Zhang, Y. Zhuang, and X.-S. Wang, Biomaterials 30, 108 (2009). https://doi.org/10.1016/j.biomaterials.2008.09.01021. B. M. Tande, N. J. Wagner, and M. E. Mackay, C. R. Chim. 6, 853 (2003). https://doi.org/10.1016/j.crci.2003.08.004 and hybrid lipid micelles2222. T. P. T. Dao et al., Langmuir 33, 1705 (2017). https://doi.org/10.1021/acs.langmuir.6b04478 because of the lack of hollow space in the interface, and due to the size not large enough, as well as hybrid lipid-polymer vesicles and synthetic polymersomes, the phase separation of which has been covered by recent reviews.22–2422. T. P. T. Dao et al., Langmuir 33, 1705 (2017). https://doi.org/10.1021/acs.langmuir.6b0447823. T. P. T. Dao, F. Fernandes, M. Er-Rafik, R. Salva, M. Schmutz, A. Brûlet, M. Prieto, O. Sandre, and J.-F. Le Meins, ACS Macro Lett. 4, 182 (2015). https://doi.org/10.1021/mz500748f24. D. Liu, H. Sun, Y. Xiao, S. Chen, E. J. Cornel, Y. Zhu, and J. Du, J. Controlled Release 326, 365 (2020). https://doi.org/10.1016/j.jconrel.2020.07.018

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