Chapter 1: Chemoresponsive Materials: Introduction, Overview, Promises

Chemoresponsive materials ideally combine sensors and actuators in the same unit. Living systems are regulated and thus maintained by responses to chemical signals, without the need for separate sensor and actuator devices. Living organisms are intrinsically both responsive and adaptive to external stimuli. A good example is the regulation of the insulin level for diabetics: man-made devices have relied until now mostly on measurement of glucose in blood and subsequent administration of insulin by injections. A smart solution, which is discussed in several chapters of the present book, is the use of a material which directly delivers insulin as a function of the continuously monitored glucose level in the blood. Like in nature one can hope to realize sensors and actuators within the same material, thus allowing self-regulating systems, or, in probably the most important application, selective drug delivery and targeting. How manifold applications of smart materials are for drug release is visible in many places of the book, such as in Chapter 2 by Schalley et al., 4 by Adams et al., 6 by Paulusse et al., 7 by Miyata, 8 by Payne et al., 9 by Harada et al., 10 by Löwik et al., 11 by Wickramasinghe et al., 13 by Vallet-Regí and Colilla, particularly for antitumor drugs, and 14 by Carrasco et al.

Many chemoresponsive materials are discussed in separate chapters of the present book, but not all could find their place. A number of these are therefore mentioned in this chapter; this applies in particular to systems that until now have mostly been described in solution, and played an essential role in the development of related smart materials. Also several new materials have only recently been shown on a larger scale to hold much promise for performance as both sensors and actuators.

Applications of chemoresponsive materials also encompass rapidly developing fields such as molecular electronics;¹  even cleaning of paintings can be improved with gels responsive to the surface.²  Most sensors are based on chemoresponsive materials, which encompass traditional systems such as induced optical changes, piezoelectric devices like quartz balances loaded with suitable receptor compounds (see Chapter 16 by Lvova et al.), or surface plasmon resonance (SPR), or photonic crystals.³  Many advanced techniques of industrial and environmental importance rely on responsive smart materials, such as separation with membranes (see Chapter 11 by Wickramasinge), or those for surface modification (see Chapter 6 by Paulusse et al.).

The common feature of smart or “intelligent” materials is their ability to change their properties upon stimulation by external signals. Chemomechanical materials change volume and/or size by chemical stimulation (Chapter 2). Interestingly there exists also the reverse, namely materials that convert mechanical forces into chemical reactions⁴  (see Chapter 17 by Göstl et al.). Besides stimulation by change of the chemical environment, which is the theme of the present book, application of voltage, light, temperature, pressure, electric or magnetic fields is commonly used for the design of such materials.^5,6 

Smart materials responding to the chemical environment appeared rather late in the literature; the earliest demonstration of a macroscopic material change by external stimuli goes back to 1950, when scientists from different fields reported pH-induced stressable mechanical changes with a crosslinked polyacrylic acid polymer (Figure 1.1).⁷ 

Ground breaking systems for chemically induced movements (see Chapter 15 by Shioi et al.) in the form of switches or even machines were first developed for complexes in solution. As they are not commonly regarded as materials they will be briefly discussed only in this chapter. Their development presented a most significant progress in chemistry in the last decades, which in 2017 was recognized by three Nobel prizes.

Fraser Stoddart was the first to introduce the ingenious use of rotaxanes⁸  on which movement can be triggered by pH changes or redox reaction (Figure 1.2).⁹  In acid the complexation of the –⁺NH₂– ion with the crown ether dominates, under neutral conditions it is that with the permanently charged –⁺NR– ion.

With ligands that dimerize around a Fe²⁺ complex as linker one can obtain linear polymers with an average of ∼3000 repeating units, with a total length of several nanometres. The long poly[c2]daisy chains can amplify nanomotions of rotaxanes over several orders of magnitude, as in the single elements the contour lengths with the protonated part at B (15.9 μm) and at the B unprotonated part (9.4 μm) differ by 6.5 μm (Figure 1.3).⁹ 

Jean-Piere Sauvage opened up another fascinating way to design molecular machines by transition metal coordination.¹⁰  The presence of e.g. copper or zinc ions can in suitable rotaxanes lead to gliding motions of both threads along one another (Figure 1.4). With redox-active metals such as copper one can also trigger motions by oxidation/reduction cycles (see also Chapter 9 by Harada et al.).

Ben Feringa introduced the use of cis–trans isomerization in chiral overcrowded alkenes for unidirectional molecular motors induces by light, or e.g. by palladium (Figure 1.5).¹¹  Photochemical and thermal E/Z isomerization in optically active asymmetric biaryls were shown to lead to four different states and could be used to drive by light a unidirectional rotation around the central double bond.

Supramolecular machines of the rotaxane type can be trapped within silica nanoparticles (SNPs, see also Chapter 13 by Vallet-Regi et al.), or mounted on a silica film and operate there as if they were in solution.¹²  Such mechanized silica nanoparticles (MSNPs) contain a solid support, a cargo or drug payload, and an external machinery. Figure 1.6 shows a typical combination of (a) linear stalks anchoring rotaxanes to the surfaces of the SNPs, (b) gating rings in the form of macrocycles which encircle the stalks and trap the cargo, (c) an alternative ring binding site or weak, cleavable point along all the stalks that are susceptible to some specific stimulus such as an acid and force the rings to distance themselves from the pores, which then release the cargo, and (d) stoppers at the ends of the stalks.

The rapid development of supramolecular chemistry in the last decades has paved the way to whole families of chemoresponsive materials by implementation of selective binding sites within suitable polymers.¹³  Such responsive host–guest systems are most often based on macrocycles such as cyclodextrins, crown ethers, cyclophanes, calixarenes and cucurbiturils, or also on foldamers.¹⁴  Cyclodextrins play a prominent role here due to their availability and large chemical variability,¹⁵  as shown in particular in Chapter 9 by Harada et al. and in several other chapters.

Calixarenes and related macrocycles can serve on a broad basis for sensing.¹⁶  Their use as smart material¹⁷  has been advanced for example with calix[4]arene derivatives bearing guanidinium groups and hydrophobic tails R (such as R = n-C₈H₁₇, see Figure 1.7) for gene delivery into cells, driven by binding of the guanidinium groups to the DNA phosphodiester backbone and the hydrophobic interaction of the tails R with the cell membrane.¹⁸ 

Cucurbit[n]urils are (Figure 1.7) macrocyclic host molecules with variable symmetric barrel-like “pumpkin” shape and cavities, which, depending on their size, can accommodate two guest molecules, are used as versatile sensors. They are also the basis for the design of smart materials, for instance for drug formulation and controlled drug delivery, or for self-healing materials.^19,20  Thus, cucurbit[n]urils can serve as self-healing structures, which are liquid-like before processing and can after injection be converted into a free-standing solid-like network (Figure 1.8). Upon release of the polymer payloads from the cucurbit[n]urils by thermal treatment the paired complementary polymers come into contact as host–guest partners, and by dynamic gelation give a moulded shape.²¹ 

Biomaterials also can exhibit properties that change in response to environmental stimuli, and hold promise for many applications; Chapters 7–10 of the this book contain interesting examples for smart materials from nature. In particular proteins offer structures with a large variety of responsive elements.²²  As illustrated in Figure 1.9 proteins can exhibit typical responses as function of their amino acids; thus, their pH sensitivity depends on the presence of charged amino acids such as histidine, aspartic acid, and glutamic acid. Temperature-triggered aggregation followed by enzyme-mediated cleavage may be used for drug delivery, etc.

The fascinating ability of DNA to control by sequence-specific binding the assembly of materials and the placement of each component within those was recognized early on.²³  Figure 1.10 shows the possible diverse DNA architectures with ensuing topologies such as dendrimer, hybrids with functional moieties, arrays, polyhedrons, crystals and hydrogels.²⁴  DNA hydrogels, resulting from the multi-direction extension of DNA strands from branched DNA allow applications such as tissue engineering, wound dressing, as well as drug and gene delivery.²⁵ 

DNA microgels can encapsulate drugs such as the anticancer drug doxorubicin (DOX) and release at lower pH. A cocoon-like DNA nanogel, or “DNA nanoclew”, was synthesized by assembling long single-stranded DNA by using rolling-circle amplification (RCA). Conjugating folate into the nanoclew building blocks enabled the realization of cell-specific targeting. When embedded with an acid-responsive DNase I nanocapsule, the nanoclews can release loaded DOX at lower pH (Figure 1.11).²⁶ 

Living materials as a basis for smart functions only appeared in 2000, but rapidly gained much attention.²⁷  One way is to incorporate cells into polymer layers, thus taking advantage of their native properties in making living functional surface capable of self-cleaning or of antibiotic-releasing. A particular promising strategy is to implement or modify proteins or enzymes within living cells, in order to produce molecular building blocks, direct their hierarchical organization, or convert their function.

For instance Escherichia coli was equipped with a mercury-responsive promoter, generating mercury-absorbing biofilms that could detect and sequester Hg²⁺ ions.²⁸  Programmable and printable Bacillus subtilis biofilms were engineered as living materials, by introducing multiple enzymes through genetic fusion or post-modification.²⁹  Organophosphate hydrolase, which converts the pesticide paraoxon into less harmful paranitrophenol, was fused to TasA to obtain a catalytic biofilm. This was subsequently co-cultured with another strain that contained AuNP-functionalized TasA to further degrade paranitrophenol to the much less toxic p-aminophenol (Figure 1.12).

Several smart materials emerged only in the last few years and found applications as chemoresponsive polymers, for which reason they are mentioned here, but only with a few examples.

Graphenes are a class of recently most often used materials, not only for sensing, but also as smart materials for e.g. drug delivery.³⁰  The high surface-area-to-volume ratio of these two dimensional or three dimensional hybrids allows them to be loaded with large quantities of anticancer and other bioactive compounds, and their use for targeted drug delivery, with low toxicity due to their carbon structure. Figure 1.13 illustrates how cisplatin-loaded graphene foams can be degraded either with reactive oxygen radicals or hydrolytic enzymes; the degradation leads moreover to the formation of carbon dioxide without toxic metabolites.³¹  Nanotubes, an all-carbon modification like graphene, find enhanced use as sensors,³²  but also for drug delivery.³³ 

A multitude of chemoresponsive materials are already known for applications such as sensors, artificial muscles, molecular machines, actuators for process control, separations, tissue engineering, self-healing surfaces, electronics and drug delivery. The size and shape of the materials can be adopted to any desired dimension; this allows modification of both sensitivity and speed of the response. In future such devices could serve as nanorobots, even as injectable or implantable therapeutics systems. Hybrid multi-functional self-adapting materials can be integrated into multi-compartmental systems, allowing simultaneous control by chemical and biological stimuli, light, temperature and other environmental factors. Electrochemical methods,³⁴  based e.g. on conducting polymers, also hold promise for drug delivery, as do methods such as surface plasmon resonance (SPR),³⁵  which lend themselves to miniaturization and automatization. Atomic force microscopy (AFM) or scanning force microscopy (SFM), or chemical force microscopy (CFM) allows the measurement of forces between e.g. drugs and proteins on a single molecule scale; they already play a significant role for drug discovery,³⁶  but also for characterization of conformations changes induced by drugs.³⁷  Promising applications also concern drug delivery.³⁸