Lipid-based mesophases as matrices for nanoscale reactions

Abstract

Lipidic mesophases are versatile bioorganic materials that have been effectively employed as nanoscale matrices for membrane protein crystallization, drug delivery and as food emulsifiers over the last 30 years. In this review, the focus is upon studies that have employed non-lamellar lipid mesophases as matrices for organic, inorganic and enzymatic reactions. The ability of lipidic mesophases to incorporate hydrophilic, amphiphilic and hydrophobic molecules, together with the high interfacial area of the lipidic cubic and inverse hexagonal phases has been exploited in heterogeneous catalysis as well as for enzyme immobilization. The unique nanostructure of these mesophases is the driving force behind their ability to act as templates for synthesis, resulting in the creation of highly ordered polymeric and inorganic materials with complex geometries.

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Livia Salvati Manni

Livia Salvati Manni's research interests focus on the self-assembly of amphiphilic molecules in water and ionic liquids. She obtained her PhD from University of Zurich in 2017, where she was funded by the Forschungskredit grant. Between 2017 and 2019 she was a postdoctoral researcher at ETH Zurich. Currently, she is a postdoctoral researcher in Chemistry at the University of Sydney. She has recently been awarded a SNF early postdoc mobility grant to develop her research program into the use of lipidic self-assembled nanostructures in biochemistry.

Wye-Khay Fong

Dr Wye-Khay Fong is a Lecturer in Chemistry in the Faculty of Science at the University of Newcastle. She obtained a PhD in Pharmacy at Monash University in 2013 and subsequently held two prestigious postdoctoral fellowships at ETH Zurich and Monash, and later at the Adolphe Merkle Institute. Her research focuses on the self-assembly of lipids and their use as novel matrices for biomedical applications, where she exploits the brightness of synchrotron science, light scattering and synthesis of novel amphiphiles.

Raffaele Mezzenga

Raffaele Mezzenga research focuses on the fundamental understanding of self-assembly principles in proteins, polymers, liquid crystals, food and biological colloidal systems. He has co-authored more than 300 publications. He has been a visiting Professor at the Helsinki University of Technology (now Aalto University), RMIT Melbourne, Monash University and NTU Singapore. His work has been recognized by several prestigious international distinctions such as the 2017 Fellowship and the 2013 John H. Dillon Medal of the of the American Physical Society, the 2013 Biomacromolecules/Macromolecules Young Investigator Award of the American Chemical Society, the 2011 American Oil Chemists’ Society Young Scientist Research Award, and the 2004 Swiss Science National Foundation Professorship Award.

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Introduction

Lipid molecules are a key component of life and are involved in a large number of natural phenomena. Lipid molecules are characterised by an amphiphilic nature and consequently are subject to a hydrophobic force in presence of water, resulting in their self-assembly into different mesophases.¹

Most importantly, lipid bilayers are the main constituent of cell membranes and are responsible for creating compartments that differentiate organelles and vesicles in cells. For this reason, artificially formed lipidic bilayers are good models for biological membranes. As biomimetic materials, lipid-based matrices constitute powerful tools to simulate cell environments in hosting, stabilising, and compartmentalising biomacromolecules like proteins or DNA. Consequently, these nanomaterials have been utilised as matrices for applications such as protein crystallisation,^2,3 drug delivery^4,5 and as reactions on the nanoscale.^6,7

The use of microemulsions in organic and inorganic synthesis was established in the 1980s, where microemulsions were shown to improve reaction rates and yield by firstly, enhancing the solubility of reagents and secondly, compartmentalising reagents into hydrophilic and hydrophobic phases.⁸ Compartmentalisation significantly increases the surface area available for reaction and can favourably orient reagents; additionally, surfactants can act as phase transfer agents, allowing for selective partitioning between these compartments.⁹

Over the past few decades, scientists have discovered new methods to synthesise new mesoscopic materials with regular nanostructures in processes inspired by nature such as self-organisation, replication and metamorphosis.^10,11 These bioinspired methods are largely based on using the elaborate structures formed by the self-assembly of surfactants as a templates to create complex, two and three-dimensional materials.

The focus of this review is on the use of lipidic mesophases as matrices for reactions on the nanoscale. The large majority of research reported in the literature has utilised non-lipidic surfactants. The physicochemical behaviour and the applications of these surfactants are outside the scope of this review, however some of these studies will be mentioned in order to contextualise and generalise the studies pertinent to lipidic matrices. Studies that utilise mesophases formed by other types of surfactants are excellently reviewed in ref. 8 and 12–16.

Lipid self-assembly in water is mediated by weak intermolecular forces: hydrogen bonds, electrostatic interactions, hydrophobic interactions, van der Waals interactions, and water-mediated hydrogen bonds.^17–19 In isolation, these forces are relatively insignificant, however, when combined, they influence the interaction between lipidic molecules and water and so govern their mesoscopic structural conformation.¹⁸ Lipidic mesophases are lyotropic liquid crystals that have ordered long-range nanostructure of different morphologies. The formation of different morphologies with high surface area at the hydrophilic–hydrophobic interface, together with their biomimetic nature makes lipidic nanostructures particularly appealing for heterogeneous catalysis and as templating matrices. In recent years, a better understanding of the behaviour of lipids in water has enhanced their use as nanoreactors for a plethora of reactions: organic and inorganic reactions, as well as model systems to study natural biomineralisation and enzymatic reactions.

Depending of the chemical structure of the lipid^20–22 and external conditions such as temperature, hydration level, pH, pressure etc., lipids can assemble into different geometries: from flat lipidic bilayers to curved and more complex topologies (Fig. 1).²³ The most well characterised and utilised lipid mesophase is the lamellar phase (L_α). For example, single lipid bilayers arranged in closed vesicles (liposomes) were the first matrix utilised as a nanomedicine in biomedical applications.^24,25 The lamellar phase can also exist as multilamellar systems, i.e. a sequence of planar layers intercalated with water slabs.²⁶

Fig. 1 Lipidic mesophases. From left to right lamellar phase L_α (adapted with permission from ref. 35), cubic phases Im3̄m, Pn3̄m, Ia3̄d (adapted with permission from ref. 36), inverse hexagonal phase H₂ (adapted with permission from ref. 35), and micellar cubic phases Fd3̄m and Fm3̄m (adapted with permission from ref. 37).

More recently, non-lamellar phases have attracted significant attention for their higher surface area to volume ratio and for their complex topologies; this review will focus on the use of the bicontinuous cubic phases and hexagonal phases as templates for nanoscale reactions. In the bicontinuous lipidic cubic phases (LCP), the lipid bilayer is organised following minimal surface topologies that delineate two identical and not interconnected water channels.²⁷ The most common bicontinuous surface topologies used as matrices for nanoreactors are described by the crystallographic space groups Pn3̄m, Im3̄m and Ia3̄d.²⁸ Sponge phases, which can be considered as a ‘disordered cubic phase’ as they are formed of water channels which have no long-range order,^18,29 have also been used but are less common. In hexagonal phases, lipidic monolayers are packed in micellar cylinders organised in a hexagonal pattern. They can be distinguished into direct and inverse phases according with the relative orientation of the polar head and the lipidic tail: if the tail is inside of the micelle and the polar head group is outside, the hexagonal phase is direct (H₁ phase);³⁰ if the lipidic tails are on the outside of the micelle, resulting in the formation of water cylinders packed in the hexagonal array, the phase is defined inverse (H₂ phase).³¹ Additionally, the LCP and H₂ mesophases are stable in an excess of water, which allows for the formation of structured particles with similar nanoscopic properties to the bulk phase. Particles which have a bicontinuous cubic structure or inverse hexagonal structure are known as cubosomes and hexosomes respectively and have been proposed as matrices for biomedical applications.^32–34

Lipidic mesophases have complex nanostructures which display long range order. Techniques for their identification is outside the scope of this review, however, readers are referred to the following references. By far, the most common technique for the identification of the structure and dimension of mesophases has been small angle X-ray scattering (SAXS) and cryogenic electron microscopy.^38–41 Synchrotron light sources have provided the advantage of identifying kinetics of dynamic phase changes.^42,43 Small angle neutron scattering (SANS)^43,44 and nuclear magnetic resonance (NMR) spectroscopy^45–48 techniques⁴⁹ provide the ability to identify the location of incorporated molecules around the interface of the mesophases. Rheology has also been shown to identify different symmetries depending on their viscoelastic signatures.⁵⁰

Controlling the dimensions of both the hydrophilic and hydrophobic domains affords exquisite control over the movements of the reactants, thus providing a unique matrix for hosting both organic and inorganic reactions.

The nanostructures of the different mesophases determine the properties of the material, for example, rate of diffusion, rheological properties and geometries, which gives them distinctive advantages for application in structural biology, materials science and functional foods.^5,35,51 Structure determines direction, partitioning and rate of flow of reagents and products in the mesophase.^36,52,53 This property has been manipulated for the controlled release of drugs from both bulk^54–56 and dispersed^33,57,58 lipidic mesophases. Numerous studies have shown how lipid shape, composition and external environment influence the self-assembly, which has been used to great effect in on-demand drug delivery.⁵⁹

Control over the phase behaviour of these self-assembled matrices is difficult to achieve, but critical when employing these materials as reaction matrices. Lipid formulations have been designed to stabilise certain phases over a large range of temperature or composition, and different additives have been optimized to respond to defined stimuli to switch between structures and to control the lattice parameters.^4,60,61 Synthetic lipids have been designed to enlarge the library of available lipids that assemble in not lamellar phases. Unfortunately, a priori phase behaviour is still not achievable.⁶²

The control over the hydration level is of pivotal importance in controlling the size of the water channel. In the last few years, LCP with both swollen, highly hydrated water channels, as well as LCP with water channels with diameters smaller than 1 nm have been reported. This exquisite control over the size of the water channels has been achieved using charged lipidic additives,^63,64 controlled evaporation rate,⁶⁵ and the employment of synthetic lipids.⁴⁹ These advances have the potential to result in the creation of increasingly sophisticated systems where the confinement effect of the matrix on the reagents can be finely tuned spanning several orders of magnitude.

The review is divided into section which reflect the main types of reactions which have been achieved in lipidic mesophases: organic reactions, polymerisation, enzymatic reactions, ordered mesoporous materials (silica) and metallic nanoparticles and films. The final section will highlight advances in the field of self-assembled lipid systems and how they can be utilised to enhance reactions confined in lipidic mesophases.

Organic reactions

Surfactant self-assembly has been exploited to achieve new heterogeneous catalytic systems able to compartmentalise reagents in order to create nano- and microreactors for organic synthesis.⁸ While vesicles (liposomes) and lipid microemulsions have been largely used as reaction matrices,^8,66–69 non-lamellar phases have been largely unexplored.

In 2000, Vauthey et al.⁷⁰ studied Maillard reactions in structured fluids composed of monoacylglycerols, using these self-assembled structures as microreactors. It was shown that the type of reactions that could progress in LCP were more wide-ranging and achieved a higher yield compare to both inverse micellar (L₂) microemulsions and pure water. This “cubic catalyst” effect was attributed to: firstly, the partitioning of reagents to the water–lipid interface in both the LCP and L₂ resulting in the compartmentation of the reagents into a surfactant “cage”; secondly, the higher interfacial area of LCP resulted in increased yield and rate over the microemulsions, but the authors assert that is difficult to establish the role of the lipidic layer curvature in these two different models.

More recently, Duss et al.⁷¹ reported an asymmetric aldol reaction in LCP where the lipidic bilayer was used as a scaffold doped with a molecular catalyst. The guest catalyst was an amphiphilic molecule with a soluble active site attached to a lipidic tail, designed and synthesised in order to be semi-immobilised at the interface (Fig. 2). Bulk cubic phases (Pn3̄m) with different water channel sizes, and cubosomes with different geometry i.e. Pn3̄m and Im3̄m were tested as reactive recyclable scaffolds. An aldol reaction between water-soluble aldehydes and cyclohexanone was employed to achieve good organo-catalytic efficiency as well as modulation of the diastereo- and enantioselectivity. The reaction in LCP proceeded with higher yields than in water with a water-soluble catalyst. However, the best results were achieved with a lipidic catalyst that self-assembled into polydisperse micelles.

Fig. 2 Schematic representation of the LCP scaffold constituted of monoolein (1, pink) in excess of water, doped with a catalytic lipid (2, dark blue) developed by Duss et al.⁷¹ to achieve diastereo- and enantioselectivity in model aldol reactions (3 and 4 to yield 5). Figure reproduced with permission from ref. 71.

The same authors in a different study,⁶ inspired by the pioneering work of Puvvada et al.,⁷² employed palladium nanoparticles grown and embedded in different bulk and dispersed mesophases as catalysts in Suzuki–Miyaura cross-coupling reactions. In this case, the lipidic scaffold had three roles: as a reducing agent for Pd²⁺, as a template to grow monodispersed particles, and as nanostructured support for the organic reaction. The addition of cholesterol swelled the water channels of the mesophase, thereby enhancing the organic reaction. These innovative studies confirm that non-lamellar mesophase have a consistent potential as “green” reaction scaffolds and for catalysis in soft nanoconfined space as they are formed by cheap, biocompatible materials.

Polymerisation

Chemically engineered lipids have been synthesised to control their assembly into different geometries. The dynamic ability to switch between mesophases in response to an external stimulus is of fundamental importance for several applications but, at the same time, could impede the use of such systems in situations in which one phase is desired and it is difficult or impossible to control the environmental conditions, such as pH, temperature or hydration level. Thus, the polymerisation of self-assembled lipids would preserve qualities such as topology of the lipidic bilayer, nanostructure and diffusion of solutes within the mesophase. A few reviews address the molecular design of lipids with different polymerisable motifs and their position within the lipidic tail.^73,74

Similar materials have been successfully prepared via polymerisation of detergents that form cubic or hexagonal structures, and that were cross linked retaining the geometry and resulting in stable polymeric materials with an organized template.^13,14,75,76 In recent years, the development of new applications of nanostructured organic materials has increased the popularity of polymerisable surfactants (mostly detergents) to create films⁷⁷ and membranes^78,79 with high surface area and uniform pore sizes. Examples of possible applications are in water filtration,^80,81 heterogenous catalysis,⁸² enhancement of photoluminescence⁸³ and the creation of breathable, vapor-resistant membranes.⁸⁴

In lipid-based nanomaterials, two main types of reactions have been demonstrated: the polymerisation of the lipidic tails of lipids in the non-lamellar mesophases, and the polymerisation of soluble compounds within the water channel.

The stabilisation of different lipidic mesophases through the polymerisation of lipidic chains has been shown to preserve the topology of the self-assembled systems. O’Brien et al. succeeded in cross-linking the lipids around the water channels of both LCP and H₂, thereby maintaining the desired morphology in a broad range of temperatures. For this purpose, lipids like phosphoethanolamines,^85,86 mono- and diacylglycerols^87,88 were designed and synthesised with a polymerisable dienoyl group on the lipidic chain in proximity to the polar headgroup. In cases in which the polymerisation was overly efficient, the cross liked material was insoluble in solvents.^85,86 In other cases where the lipids were not completely cross linked, the thermal stability of the original Ia3̄d phase was improved.⁸⁷ It is expected that the ability of the crossed-linked mesophases to be solvent resistant and stable in refluxing organic solvents, opens up the possibility to use these structures as reactors in presence of different organic solvents, exploiting their innate high surface area and ability to confine substrates.^82,85,86

A polymerised hexagonal columnar nanostructure (Fig. 3A) was achieved by Feng et al.,⁸⁹ utilising a core molecular template of plant-derived polymerisable fatty acids. After the vertical alignment of the cylinders by a surface-confinement method, the lipids were polymerised into an oriented hexagonal phase, in order to create membranes with a controlled porosity, long-range order and a nanometric channel size.

Fig. 3 (A) Core templated, oriented H₂ phase, successfully polymerised in a stable matrix. The orientation and the geometry are retained after the removal of the core templating agent as visible from the SAXS patterns. Figure adapted with permission from ref. 89. (B) TEM picture with scale bar of 100 nm of a portion of a polymerised cubosome. Figure adapted with permission from ref. 90.

Polymerised cubosomes were achieved by Yang et al. utilising a synthesised polymerisable monoacylglycerol, 3-(2,4,13-(E,E)-tetradecatrienoyl)-sn-glycerol (Fig. 3B). The bulk phase was dispersed in the presence of Poloxamer 407 in excess of water to form cubosomes and then polymerised via photo or redox initiators. The resulting crossed linked cubosomes were resistant to excess of surfactant solutions such as Triton X-100.⁹⁰ This stability is the main innovation of these crossed linked particles as they are expected to be useful nanostructured materials for applications that require stability in solvents or in broad temperature ranges.⁹¹

In order to capture the complex topology of the liquid crystalline mesophases, a few studies have focused on the polymerisation of soluble monomer within the water channels. The attempts to preserve the structure and obtain a polymer with the geometry and the characteristics of the water channels of the original liquid crystalline moulds have led to new materials with complex nanostructures. The use of lyotropic liquid crystals as templating matrices for the polymerisation of monomers within the water channels has been largely explored for non-lipidic surfactant based mesophases.^14,92,93 We hypothesise that this can be easily extrapolated for lipidic matrices as many of the general finding valid for surfactants can be applied to lipid-based amphiphiles. A few studies report the photochemical^94,95 and thermal⁹⁶ polymerisation of acrylamide in detergent based mesophases with different nanostructure i.e. H₂, LCP and L_α.

Ström et al.^97,98 added hydrophobic and hydrophilic polymerisable additives, divinylbenzene or acrylamide, to the surfactant–water mixture. The polymerisation was induced by photoinitiation and produced cubic polymers, with retention of the structure and the water mobility, as confirmed by SAXS and NMR self-diffusion studies. Quantification of the amount of reactant polymerised by dissolution of the lipidic phase and the isolation of the polymer were successfully achieved, however structure identification of the surfactant free polymer by SAXS was unsuccessful.

Additionally, studies on surfactant phase behaviour suggest that the aggregation of the polymer is localised in the grain boundaries.⁹⁴ For this reason, it is essential to find an area of the phase diagram in which the chosen liquid crystalline phase is stable in presence and absence of the monomer in order to macroscopically avoid phase separation. Systematic studies show that the structure of the obtained polymer depends on the type of monomer, crosslinking density, kinetics, monomer and surfactant concentration, and can be varied systematically to result in different pore morphologies and a broad size range varying from hundreds of nanometers to micrometers.^95,96,99 As can be seen, many molecular and macroscopic aspects must be taken into account in order to obtain a nanostructured material with long-range order.

Enzymatic reactions

The immobilisation of biological enzymes onto substrates has been used to control and improve the preservation, locality, recovery, observed activity, specificity of selectivity of an enzyme for application in both synthesis and biosensing.¹⁰⁰ Many enzymes that are central to physiological functions are centred at the interface or within the cell membrane.^101,102 As such, it has been established that the nanostructure, fluidity and symmetry of the lipid membrane influence enzyme functionality,^103–105 where more open structures (i.e. LCPs) allow for a higher specific activity of the enzyme.¹⁰⁶ The viability of enzymes has been established in LCPs. A wide range of hydrophilic^107–110 and membrane^111–118 proteins in their native form have been incorporated into the cubic phase, whilst maintaining the bicontinuous cubic nanostructure and protein activity for prolonged times.^119,120 Native proteins have also been successfully reconstituted in inverse hexagonal phases.¹²¹ In most cases, enzymes immobilised in LCPs maintain classical Michaelis–Menten kinetics, but can differ due to the confinement of enzyme in the mesophase (Fig. 4A).⁷ The ability to maintain the function of these catalytic centres led to their development as matrices for the detection of biological components.

Fig. 4 The properties of lipid mesophases makes them ideal matrices for the immobilisation of enzymes for reactions on the nanoscale. (A) the amphiphilic nature of the lipid bilayer of the cubic phase maintains the native structure and therefore activity of membrane proteins such as fructose dehydrogenase (FDH) as compared to a water soluble enzyme, horseradish peroxidase (HRP). Reproduced with permission from ref. 112. As the lipidic cubic phase is isotropic, reactions catalysed by immobilised enzymes that cause a change in optical properties make them ideal for biosensing for: (B) the detection of glucose where 1 – buffer solution, 2 – 10 mM, 3 – 5 mM, 4 – 2.5 mM, 5 – 1 mM and & 6 – blood plasma (5.1 mM glucose); reproduced with permission from ref. 122, and (C) schematic of bacteria detection via development of birefringent crystals in LCP. Reproduced with permission from ref. 131.

The immobilisation of enzymes into LCP and the detection of the subsequent formation of substrate have been engineered for use as matrices for biosensors. The first use of these materials for biosensing was reported by Wallin et al. who immobilised glucose oxidase into ethoxylated fatty alcohol (C_16–18(OCH₂CH₂)₈₀OH) and water as a simple glucose monitor of both solutions and blood plasma, where the enzyme immobilised within the mesophase maintained a higher amount of its original activity than in solution (Fig. 4B).¹²² Razumas et al. immobilised various enzymes into a monoolein cubic phase for the amperometric detection of β-D-glucose and L-lactate, and pH-sensitive urea and creatinine.¹²³ In these types of amperometric biosensors, the aqueous domains of the lipidic cubic phase matrix provide a double benefit: firstly, these water-soluble proteins can be confined in a stable manner, and secondly, the substrates and products can easily flow into and out of the bulk water depending on the size and topology of the water channels.^112,124 Since their introduction, enzymes confined into LCP have been utilised in a vast range of electrochemical biosensors¹²⁵ including glucose,¹²⁶ fructose,¹²⁷ cholesterol,¹²⁸ dioxygen monitoring¹²⁹ and hydrogen peroxide.¹³⁰

As a rapid, point-of-care analysis tool, the enzyme-catalysed crystallisation of substrate within an optically isotropic cubic phase has provided a simple visual indicator for a positive or negative biochemical reaction. LCP are isotropic in nature and so do not exhibit birefringence when observed in between cross-polarisers, whereas crystallised substrates exhibit birefringence. Vallooran et al. exploited this effect in order to detect biomarkers (glucose and cholesterol) and antigens (E. Coli., Malaria, HIV and Ebola).¹³¹ The presence of these biomarkers resulted in the formation of hydrogen peroxide (H₂O₂) via the presence of oxidase enzymes; H₂O₂ then activated a cascade reaction via the activation of an additional immobilised enzyme, horseradish peroxidase, which subsequently activated the crystallisation of different organic substrates. The crystallisation of the organic substrates resulted in quantifiable amounts of birefringence and so a positive result. In the case of the detection of antigens, horseradish peroxidase was directly attached to the corresponding antibody, where detection of the antigens in the presence of H₂O₂ resulted in crystallisation and thus, a quantifiable amount of birefringence (Fig. 4C). As matrices for biosensing, the unique nanostructure of the LCP has three key functions: maintenance of the native structure of enzyme, flow of substrate and product to/from the enzyme and ideal optical properties.^112,124,132

Recently, enzymes immobilised in lipidic mesophases have also been used as matrices for the immobilisation of enzymes for synthesis. The synthesis of carbohydrates by aldolase confined in LCP was found to be three-times more efficient than in solution, attributed to both the ability of the protein to maintain its native conformation in the LCP nanostructure, and the compartmentalisation of the substrate and products.¹³³ In this case, the structure of the LCP plays a key role in the maintenance and enhancement of activity of enzymes immobilised within the mesophase.

Reactions catalysed by enzymes encapsulated in dispersed liquid crystalline phases have also been demonstrated. The immobilisation of a large enzyme, β-galactosidase, was achieved within a lipid sponge phase in order to enhance the stability and the hydrolysis of lactose to its component monosaccharides.¹³⁴ To our knowledge, enzyme immobilisation in lipidic cubosomes has not been achieved, however, La et al. utilised polymeric cubosomes formed by the self-assembly of amphiphilic block copolymers to covalently immobilise maleimide-activated horseradish peroxidase (HRP, 44.1 kDa); the kinetic action of HRP was found to be comparable to values of HRP in free solution.¹³⁵ In the same way as the bulk, the structure of dispersed mesophases maintains the activity of the enzyme and influences the flow of substrate and product.

Ordered mesoporous materials (silica)

Mesoporous materials possess attractive properties, such as high surface areas, tuneable pore sizes and shapes, various structures, and a multitude of compositions. Of these materials, silica is one of the most frequently studied inorganic frameworks due to their tetra-connected covalent bonds. Mesoporous silica has been extensively studied for application in a wide range of fields, ranging from biomedical (drug delivery and biosensors) to industrial (catalysis, sorption, gas sensing, ion exchange, optics, photovoltaics, coatings and separation materials) as they are chemically inert, thermally stable, inexpensive and have high surface area which makes them promising materials.^136–138 Of particular interest are mesoporous silica nanomaterials; these materials contain pores with diameters between 2 and 50 nm, resulting in the augmentation of the surface area thus enabling new functions.^139,140

In general, mesoporous silica matrices are produced by the following reaction: a solubilised silica source, e.g. tetraethylorthosilicate (TEOS) or silicate solutions, forms the solid silica matrix via the formation of sequential Si–O–Si bonds in a polycondensation process (eqn (1)).

–Si(OH) + –Si(OH) ⇌ –Si–O–Si–(s) + H₂O(l) (1)

The ability to form mesoporous silica matrices with long range order was established by using liquid crystal structures formed by concentrated surfactant systems as templates in a patent in 1969 leading to the birth of the field in 1992.^141,142 The seminal paper by Kresge et al. in 1992 was highlighted in the collection, “150 years of Nature” as one of the “10 extraordinary Nature papers” as it is considered a significant breakthrough in materials science which triggered an explosion of research into mesoporous materials.^142,143 Since then, it has been shown that the structure, thickness and porosity of the mesoporous silica is intimately linked to the physicochemical properties and concentration of the surfactant.^{142,144–148} The assembly process is controlled by silica precursors condensing around the polar headgroups of the surfactants, resulting in the formation of layers of silica at the interface of the micelles (Fig. 5A). This process is controlled by electrostatic interactions between the inorganic ions in solution, the charged surfactant head groups and inorganic counterions.^149–151 As a consequence of the silica forming, phase transitions have also been observed in the templating matrix.¹⁵² It has been proposed that the final morphology of the mesoporous materials is influenced by the competition mainly between the free energy of mesostructure self-assembly (ΔG) and the colloidal surface free energy (F).¹⁵³

Fig. 5 (A) General mechanism of mesoporous silica templating. Adapted with permission from ref. 151. B (top) TEM image of mesoporous silica films formed using MO based templates; (bottom) 2D Fourier transforms for data in top images. Adapted with permission from ref. 172.

Many of the reported syntheses have utilised lyotropic liquid crystals formed by aqueous mixtures of cationic surfactants, e.g. cetyltrimethylammonium,^{151,154–156} amphiphilic block copolymers,^157,158 non-ionic surfactants,^159–163 and anionic surfactants.¹⁶⁴ The resulting structure of the mesoporous silica can be tuned through the use of cosolvents, surfactant blends and by changing the aqueous environment such as pH and salt concentration.^165,166 The nanostructured silica matrices can subsequently be used as a support matrix for metallic nanocomposites.¹⁶⁷ A number of very comprehensive reviews on the formation of mesoporous silica via surfactant templating provide a good insight into their formation.^168–170

Few studies have utilised lipid-based liquid crystals as a template for creating mesoporous materials. To our knowledge, the first mesoporous material formed by lipidic cubic phase templating was reported in 2001: the formation of mesoporous alumina with a pore size of 38 Å, which corresponds well to the pore size of the aqueous channels formed by monoolein and water (35 Å).¹⁷¹ Spicer et al. report large 100 μm silica cubosomes formed by coating a large cubosome with silica sol, evaporating the water to consolidate the silica, and dissolving the cubosome, though, the composition of the cubosome template remains unclear.³² Moreover, in both these brief communications, it is not clear whether the resulting material maintained the original symmetry of the lipidic mesophase. In 2011, mesoporous silica films were achieved by Dunphry et al. through the use of LCP (MO) templates and evaporation-induced self-assembly (Fig. 5B), where the pore size of both the LCP and subsequent silica film was enlarged through the use of cetyltrimethylammonium bromide.¹⁷² The ability to modulate the water channel size by the incorporation of charged additives resulting in increased mesoporous silica pore size demonstrates the advantage of using LCP as matrices for templating.

Phospholipid-based mesophases have also been utilised. A twisted multilamellar hybrid silica mesophase was obtained by Seddon et al., in which the lipid bilayers were intercalated with thin sheets of amorphous silica.¹⁷³ This hybrid mesostructure involved the co-assembly of phospholipids containing polymerizable diacetylinic groups with the in situ synthesis of silica by acid hydrolysis and condensation of TEOS. In a systematic study, a wide range of phospholipids of varying lipid tail length, number of acyl groups and headgroup type, was utilised to produce silica and hybrid thin films with 1D, 2D and 3D long range order.¹⁷⁴ The acyl tails were found to be the main determinant of whether total phase separation between silica and lipid during film assembly occurred; and the headgroups determined the suppression or enhancement of siloxane framework reactivity. The phase separation issue was overcome through the use of a co-surfactant¹⁷⁵ or lipids without a phosphatidyl headgroup.¹⁷² Mixed phospholipid/surfactant systems have also been used to form mesoporous silica with sponge phase structure for hosting enzymes.¹⁷⁶

As can be seen by these studies, controlling the composition of the lipidic mesophase ultimately determines the structure and porosity of the resulting mesoporous silica matrices.

Metallic nanoparticles and films

As seen in the preceding sections, the biomimetic method of utilising surfactant-based soft templating for the crystallisation of inorganic composites in order to generate new organic–inorganic materials was established in the late 80's and early 90's.^10,177 Most of the work in the field has employed non-lipidic amphiphiles to generate the lyotropic liquid crystalline templates.^178–180 Possibly the most explored method is the formation of films via electrodeposition of metal salts in the aqueous compartment of non-lipidic surfactant based liquid crystalline phases, resulting in metal films with uniform nanostructures and high specific surface areas; these materials have been employed for catalysis,¹⁸¹ enhanced electrical connectivity,¹⁷⁹ and for the formation of semiconducting superlattices.¹⁸⁰ In some cases, a double templating strategy was employed to produce highly ordered materials, where a hard silica template was generated from a surfactant template and then used to create mesoporous metals through deposition.^182–184 For a more focused review on mesoporous metals by soft templating the reader is directed to Yamauchi et al.¹⁶

Lipidic mesophases have been less explored. In 1994, Puvvada et al.⁷² employed LCP as a reactive matrix to produce palladium (Pd) nanoparticles. The particles were synthesised in the lipidic matrix via the reduction of a Pd salt to Pd⁰ by the glycerol head group of monoolein. In this way, the resulting Pd nanoparticles that were formed inside the water channels possessed a diameter similar to the water channel size, with excellent monodispersity. In two recent studies, Akbar et al.^185,186 developed two methods for producing platinum (Pt) nanowires (Fig. 5). In the first study, an electrodeposition method in a Fd3̄m cubic phase was used to create a highly homogenous nanowire network with a high electrochemical surface area as determined by cyclovoltammetry (Fig. 6A–C).¹⁸⁵ In a subsequent study, ultrathin uniform platinum nanowires were obtained by using chemical reduction via galvanic displacement in a H₂ phase lipidic matrix composed mainly of phytantriol (Fig. 6D).¹⁸⁶

Fig. 6 (A–C) Simulated Fd3̄m phases superimposed onto TEM images of nanostructured Pt Fd3̄m single diamond electrodes with scale bars of 50 nm (a), 10 nm (b), and 100 nm (c). Adapted with permission from Akbar et al.¹⁸⁵ (D) schematic of the templating mechanism. Formation of the self-assembled lipidic mesophase, followed by metal electrodeposition and formation of the Pt nanowires. Reproduced with permission from ref. 186; (E and F) structure of the Pn3̄m templating mesophase, where the grey region is occupied by the lipid bilayer and the green one by water, and corresponding Im3̄m platinum structure obtained by electrodeposition. Reproduced with permission from ref. 187.

Lipidic mesophases on solid supports have been used to produce nanostructured metallic films. By using a Pn3̄m lipidic cubic phase template on a gold foil support, Richardson et al.¹⁸⁷ obtained a Fd3̄m nanostructured aligned metallic film via the deposition of Pt. The authors attribute this change in geometry to the capping of one of the channels of the cubic phase near the gold surface, and the subsequent asymmetric deposition of Pt in one of the two water channels as confirmed by their in situ SAXS study.¹⁸⁸ They also explain the alignment of the resulting platinum film as an interfacial effect on the lipidic cubic phase deposited on the solid support: while the lipids domains are disordered, an alignment is achieved at the interface, resulting in aligned platinum films.¹⁸⁷ The same change in geometry from a Pn3̄m lipidic cubic phase to a Fd3̄m templated metallic (Bi₂Te₃) nanostructure was observed from Burton et al. in the formation of bismuth sulphide 3D structures.¹⁸⁹

Perspectives

Lipidic mesophases are readily available and environmentally friendly matrices that can be implemented as natural and reusable matrices for reactions on the nanoscale. Recent advances in the field have demonstrated that the structure of mesophase is easily tunable by controlling environmental factors (temperature, hydration, pH) as well as molecular dimensions of the surfactant; a trait that can be used advantageously to enhance nanoscale reactions. It is envisaged that the exquisite control over structure and size of the water channels will lead to the creation of new nanostructured materials and consequently, better control over organic and enzymatic reactions. The highly regular structure of the matrix will allow also for mass production with fewer defects and a low impact on environment.

One limitation to the development of nanostructured particles is the control over particle size. It is envisaged that the use of templating will overcome this shortcoming.

Proof of concept studies have shown the effect of different diffusion rates and mesophase geometry on reactions in lipidic mesophases, however, the effect of the water channel size and lipidic bilayer curvature on the rate and yield of in-meso reactions is still to be optimised and understood, especially for systems where confinement plays an important role. The employment of these matrices for enantioselective reactions opens the question: what is the effect of confinement on enantio- and diasteroselectivity? The generalisability of these rules is of pivotal importance for the implementation of mesophases in scalable reactions.

The implementation of lipids for the creation of nanostructured polymers is still under development, and the optimisation of the process to avoid phase separation during polymerisation seems to be the most important factor to achieve regular structures that can conserve the template geometry. On the other hand, the possibility to cross-link lipids in a certain geometry opens up the opportunity to implement these materials in applications that require fixed geometry and lattice parameters, including their use as reactors for reactions in organic solvents.

Cubic and hexagonal structures have unique optical and electrical properties. The development of structurally aligned mesophases that have defined geometry, high porosity and surface area pave the way to the possibility of direct fabrication of novel 2D and 3D structures, and thus, may bring new opportunities and advances in the fields of electrocatalysis and optoelectronics.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Livia Salvati Manni acknowledges financial support from the Professor J. A. Schofield fund.

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