Gel-forming Polymers Research Articles

Design and characterization of κ-Carrageenan:PVA hydrogels to repurpose the topical delivery of betamethasone.

Atopic dermatitis (AD) is a severe inflammatory skin disorder, affecting children and adults worldwide, and despite the several existing treatments, it is necessary to find new alternative topical therapies. Hydrogels may represent a good tool to treat AD due to their high water content, making them excellent candidates for drug delivery vehicles in skin research. This work aimed to develop and characterize hybrid hydrogels composed of gel-forming polymers (k-carrageenan and polyvinyl alcohol) for cutaneous delivery of betamethasone (up to 0.2 mg mL-1) widely used to manage AD, with high skin retention. Bergamot oil and menthol essential oils were also incorporated into the hydrogels to study their effects on penetration and retention of the corticosteroid. Rheological properties revealed the pseudoplastic behavior of the hydrogels, a favorable characteristic for skin application. Cytocompatibility towards fibroblasts and keratinocytes was determined, revealing safe usage of the hydrogel blends up to 100 mg mL-1, corresponding to 20 µg mL-1 in betamethasone, but was compromised by the presence of the essential oils in the higher hydrogel tested concentrations (50 and 100 mg mL-1). The ex vivo pig ear skin permeation assay showed that hydrogels promote betamethasone retention up to 20 % of the added dose (c.a. 10 µg) even after 24 h of permeation, independently of the use of essential oils' use in the composition, showing that they might be a good strategy to treat AD skin.

Gelatin-Sodium Alginate Hydrogels Cross-Linked by Squaric Acid and Dialdehyde Starch as a Potential Bio-Ink.

Hydrogels as biomaterials possess appropriate physicochemical and mechanical properties that enable the formation of a three-dimensional, stable structure used in tissue engineering and 3D printing. The integrity of the hydrogel composition is due to the presence of covalent or noncovalent cross-linking bonds. Using various cross-linking methods and agents is crucial for adjusting the properties of the hydrogel to specific biomedical applications, e.g., for direct bioprinting. The research subject was mixtures of gel-forming polymers: sodium alginate and gelatin. The polymers were cross-linked ionically with the addition of CaCl2 solutions of various concentrations (10%, 5%, 2.5%, and 1%) and covalently using squaric acid (SQ) and dialdehyde starch (DAS). Initially, the polymer mixture's composition and the hydrogel cross-linking procedure were determined. The obtained materials were characterized by mechanical property tests, swelling degree, FTIR, SEM, thermal analysis, and biological research. It was found that the tensile strength of hydrogels cross-linked with 1% and 2.5% CaCl2 solutions was higher than after using a 10% solution (130 kPa and 80 kPa, respectively), and at the same time, the elongation at break increased (to 75%), and the stiffness decreased (Young Modulus is 169 kPa and 104 kPa, respectively). Moreover, lowering the concentration of the CaCl2 solution from 10% to 1% reduced the final material's toxicity. The hydrogels cross-linked with 1% CaCl2 showed lower degradation temperatures and higher weight losses than those cross-linked with 2.5% CaCl2 and therefore were less thermally stable. Additional cross-linking using SQ and DAS had only a minor effect on the strength of the hydrogels, but especially the use of 1% DAS increased the material's elasticity. All tested hydrogels possess a 3D porous structure, with pores of irregular shape and heterogenic size, and their swelling degree initially increased sharply to the value of approx. 1000% during the first 6 h, and finally, it stabilized at a level of 1200-1600% after 24 h. The viscosity of 6% gelatin and 2% alginate solutions with and without cross-linking agents was similar, and they were only slightly shear-thinning. It was concluded that a mixture containing 2% sodium alginate and 6% gelatin presented optimal properties after gel formation and lowering the concentration of the CaCl2 solution to 1% improved the hydrogel's biocompatibility and positively influenced the cross-linking efficiency. Moreover, chemical cross-linking by DAS or SQ additionally improved the final hydrogel's properties and the mixture's printability. In conclusion, among the tested systems, the cross-linking of 6% gelatin-2% alginate mixtures by 1% DAS addition and 1% CaCl2 solution is optimal for tissue engineering applications and potentially suitable for 3D printing.

Multidimensional opioid abuse deterrence using a nanoparticle-polymer hybrid formulation

Misuse of prescription opioid drugs is the leading cause of the opioid crisis and overdose-related death. Abuse deterrent formulations (ADFs) have been developed to discourage attempts to tamper with the formulation and alter the ingestion methods. However, abusers develop complex extraction strategies to circumvent the ADF technologies. For comprehensive deterrence of drug abuse, we develop tannic acid nanoparticles (NPs) that protect encapsulated opioids from solvent extraction and thermal challenge (crisping), complementing the existing formulation strategy to deter injection abuse. Here, we develop a hybrid ADF tablet (NP-Tab), consisting of iron-crosslinked tannic acid NPs encapsulating thebaine (model opioid compound), xanthan gum, and chitosan (gel-forming polymers), and evaluate its performance in common abuse conditions. NP-Tab tampered by crushing and suspended in aqueous solvents forms an instantaneous gel, which is difficult to pull or push through a 21-gauge needle. NPs insulate the drug from organic solvents, deterring solvent extraction. NPs also promote thermal destruction of the drug to make crisping less rewarding. However, NP-Tab releases thebaine in the simulated gastric fluid without delay, suggesting that its analgesic effect may be unaffected if consumed orally as prescribed. These results demonstrate that NP-Tab can provide comprehensive drug abuse deterrence, resisting aqueous/organic solvent extraction, injection, and crisping, while retaining its therapeutic effect upon regular usage.

New Biopharmaceutical Characteristics of In Situ Systems Based on Poloxamer 407.

Thermosensitive systems based on poloxamer 407 are widely used in targeted drug delivery; however, the stability of the phase transition temperature remains insufficiently studied. This article presents the results of a study on the effect of adding polyethylene glycols (PEG) with different molecular weights and some classical gel-forming polymers on the gelation temperature of thermoreversible compositions based on poloxamer 407 in a long-term experiment. The study showed a positive effect of PEG addition with average molecular weights at concentrations of 1.5-2.0%, as well as gelling agents at a concentration below the critical gelation concentration. The proposed rheological test for studying the samples' adhesion can give an indirect forecast of the composition adhesive rate. Based on the conducted studies, three experimental binary systems based on poloxamer 407 were selected, with the addition of HPMC 0.5%, sodium alginate 0.5%, and PEG 1500 1.5%. These systems are the most promising for the further development of in situ targeted drug delivery systems.

Detection of Gel-Forming Polymers via Calcium Crosslinking, Applied to the Screening of Extracellular Polymeric Substances Extracted from Biological Aggregates.

The valorization of biological aggregates through the extraction of hydrogel-forming polymers can enhance the economics and sustainability of various processes in which bacteria are involved in organic waste transformation, such as wastewater treatment. Achieving these goals requires the development of a method capable of detecting the presence of gel-forming polymers in complex mixtures containing biopolymers that are most often unknown and uncharacterized. A miniaturized screening method capable of detecting gelation via ionic crosslinking using only 1 to 3 mg of the tested samples (commercial molecules or extracellular polymeric substances, EPSs) is proposed. The method consists of calculating a percentage of reactivity (%R) through UV-vis spectra and determining the percentage of gel volume (%Vg) formed after the addition of calcium. Both factors were combined to give a gelling factor (GF), and the test was applied to pure commercial molecules (BSA, DNA, alginate (ALV), and a mixture of them), allowing the classification of the following solutions according to their gel-forming capacity: GF(ALV) > GF(ALV+DNA) > GF(BSA+ALV+DNA) > GF(BSA+ALV) > GF(DNA) > GF(BSA+DNA) > GF(BSA). As a relevant tool for screening hydrogel-forming solutions, the method was applied to the EPS extracted from aerobic granular sludge. The EPS (0.5% w/v) had a GF of 0.16 ± 0.03, equivalent to approximately half of the GF of ALV (0.38 ± 0.02 at 0.5% w/v). The developed test pushes the limits of the existing gel-detection techniques because it allows for quicker, less consuming, and more informative gelation detection through the use of simple methods that do not require sophisticated equipment.

Application of Xanthan Gum and Hyaluronic Acid as Dermal Foam Stabilizers.

Foams are increasingly popular in the field of dermatology due to their many advantages such as easy spreading, good skin sensation, and applicability in special skin conditions. One of the critical points of foam formulation is the choice of the appropriate stabilizing ingredients. One of the stability-increasing strategies is retarding the liquid drainage of liquid films from the foam structure. Therefore, our aim was the application of different hydrogel-forming polymers in order to retain the stabilizing liquid film. Dexpanthenol and niacinamide-containing foams were formulated, where xanthan gum and hyaluronic acid were used as foam-stabilizing polymers. Amplitude (LVE range) and frequency sweep (G’, G”, tanδ, and frequency dependency) were applied as structure- and stability-indicating rheological parameters. The rheological data were compared with the results of the cylinder method, microscopical images, and the spreadability measurements. The application of the gel-forming polymers increased the stability of the dermal foams (increased LVE range, G’ values, and decreased frequency dependency). These results were in correlation with the results of the cylinder and spreadability tests. It was concluded that in terms of both foam formation and stability, the combination of xanthan gum and dexpanthenol can be ideal.

Mucin O-glycans are natural inhibitors of Candida albicans pathogenicity.

Mucins are large gel-forming polymers inside the mucus barrier that inhibit the yeast-to-hyphal transition of Candida albicans, a key virulence trait of this important human fungal pathogen. However, the molecular motifs in mucins that inhibit filamentation remain unclear despite their potential for therapeutic interventions. Here, we determined that mucins display an abundance of virulence-attenuating molecules in the form of mucin O-glycans. We isolated and cataloged >100 mucin O-glycans from three major mucosal surfaces and established that they suppress filamentation and related phenotypes relevant to infection, including surface adhesion, biofilm formation and cross-kingdom competition between C. albicans and the bacterium Pseudomonas aeruginosa. Using synthetic O-glycans, we identified three structures (core 1, core 1 + fucose and core 2 + galactose) that are sufficient to inhibit filamentation with potency comparable to the complex O-glycan pool. Overall, this work identifies mucin O-glycans as host molecules with untapped therapeutic potential to manage fungal pathogens.

Optimization of the Elasticity and Adhesion of Catechol- or Dopamine-Loaded Gelatin Gels under Oxidative Conditions.

The synthesis of surgical adhesives is based on the need to design glues that give rise to strong and fast bonds without cytotoxic side effects. A recent trend in surgical adhesives is to use gel-forming polymers modified with catechol groups, which can undergo oxidative crosslinking reactions and are strongly adhesive to all kinds on surfaces in wet conditions. We previously showed that blending gelatin with catechol can yield strong adhesion when the catechol is oxidized by a strong oxidant. Our previous work was limited to the study of the variation in the sodium periodate concentration. In this article, for an in-depth approach to the interactions between the components of the gels, the influence of the gelatin, the sodium periodate and dopamine/(pyro)catechol concentration on the storage (G′) and loss (G″) moduli of the gels, as well as their adhesion on steel, have been studied by shear rheometry. The hydrogels were characterized by infrared and UV-Vis spectroscopy and the size of their pores visualized by digital microscopy and SEM after freeze drying but without further additives. In terms of adhesion between two stainless steel plates, the optimum was obtained for a concentration of 10% w/v in gelatin, 10 mM in sodium periodate, and 20 mM in phenolic compounds. Below these values, it is likely that crosslinking has not been maximized and that the oxidizing environment is weakening the gelatin. Above these values, the loss in adhesiveness may result from the disruption of the alpha helixes due to the large number of phenolic compounds as well as the maintenance of an oxidizing environment. Overall, this investigation shows the possibility to design strongly adhesive hydrogels to metal surfaces by blending gelatin with polyphenols in oxidative conditions.

Interactions of Crosslinked Polyacrylic Acid Polyelectrolyte Gels with Nonionic and Ionic Surfactants.

The morphology and stability of surfactant-loaded polyelectrolyte gels are of great interest for a variety of personal care, cosmetic, and pharmaceutical products. However, the mechanisms of surfactant interactions with gel-forming polymers are poorly understood and experimentally challenging. The aim of this work is to explore in silico the specifics of surfactant absorption within polyelectrolyte gels drawing on the examples of typical non-ionic octaethylene glycol monooctyl ether (C8E8) and anionic sodium dodecyl sulfate (SDS) surfactants and polyacrylic acid modified with hydrophobic sidechains mimicking the practically important Carbopol polymer. Using the systematically parameterized coarse-grained dissipative particle dynamics models, we generate and characterize the equilibrium conformations and swelling of the polymer films in aqueous solutions with the surfactant concentrations varied up to the critical micelle concentration (cmc). We discover the striking difference in interactions of Carbopol-like polymers with nonionic and ionic surfactants under mildly acidic conditions. The sorption of C8E8 within the polymer film is found substantial. As the surfactant concentration increases, the polymer film swells and, close to cmc, becomes unstable due to the formation and growth of water pockets filled with surfactant micelles. Sorption of SDS at the same bulk concentrations is found much lower, with only about 1% of surfactant mass fraction achieved at cmc. As the SDS concentration increases further, a lamellae structure is formed within the film, which remains stable. Reduced swelling and higher stability indicate better prospects of using SDS-type surfactants with Carbopol-based gels in formulations for detergents and personal care products.

Crossover of Rate-Limiting Process in Plasma Gel Growth by Contact with Source of Gelator.

Plasma is regarded as a solution of precursor polymers specifically transformed to gel-forming polymers by a reaction with initiators. We developed a theory for the gel growth dynamics of plasma induced by contact with a source of gelators that are yielded by the initiation. In developing the theory, we combined the Ginzburg–Landau type dynamics with the gelator diffusion dynamics expressed by the moving boundary picture. The theory predicts the crossover of the rate-limiting process in the time course of the thickness of the gel layer X from the energy-limited process expressed by to the diffusion-limited process expressed by , where t is the time elapsed from when the plasma comes into contact with the source of gelators. A demonstration experiment was performed by placing a tissue factor coating plate as the initiator in plasma. Log–log plot of X vs. t showed a crossover as predicted by the theory, and the parameters characterizing plasma were determined.

Designing 3D printable cementitious materials with gel-forming polymers

This work explores the use of hydrogel-forming polymers as printing aids for cement-based pastes. The principal results suggest an inverse relationship between gel and paste rheology and printability. The preferred gel is mechanically stiff, while the preferred printing paste is malleable and retains shape. The results, which include printability indexes (PI), mix formulation factors, and rheological measurements, form a framework for selection of gel-based printing aids and can be used as a basis for quality control of three-dimensional (3D) printed objects. Such gel-forming polymers may reduce the need for more complex admixture packages as printing aids.

Natural polymers for vaginal mucoadhesive delivery of vinegar, using design of experiment methods

Background/Aim. Vinegar is one of the main international traditional nutraceuticals, and it has been used as a vaginal health protectant due to vagina pH balance maintenance and antimicrobial properties. Since the main form of vinegar is liquid, it is difficult to apply vaginally due to its short retention. The aim of this study was to design a vaginal mucoadhesive gel made of vinegar. Methods. Xanthan gum and tragacanth were utilized as natural gel-forming polymers. The effects of xanthan gum and tragacanth on mucoadhesion strength and drug release of the gel formulations were optimized using a 3 level (32) factorial design. Several physico-chemical properties of the gel formulations, including gel viscosity, lubricity, scanning electron microscopy (SEM) images of hydrogel chains, and chain release kinetic, were also investigated. Results. It was found that tragacanth possessed a statistically significant effect on release rate control (p-value = 0.0027), while both tragacanth and xanthan gum had a significant effect (p-value = 0.0001 and 0.0017, respectively) on mucoadhesion property. Formulation F7 with 5% xanthan gum and 1% tragacanth (mucoadhesion = 0.4632 N and re-lease rate = 88.8% in 6 hours) considered as the optimum formulation with some modifications. Conclusion. Xanthan gum and tragacanth can be considered as appropriate natural polymers for vaginal drug delivery.

Ionogenic gel-forming (co)polymers of N-vinyl succinimide, N-vinylsuccinamic and acrylic acids grafted on starch

Gel-forming (co)polymers of N-vinylsuccinimide, N-vinylsuccinamic and acrylic acids grafted on starch were obtained using an initiating redox system or as a result of 60Co gamma irradiation. The dependence of the level of sorption properties (co)of polymers relative to bioactive compounds (BAC), their water absorption and swelling on the conditions of the (co) polymerization process has been determined. The ability of composite copolymers to high moisture absorption, binding and prolonged release of BAC and the possibility of their use for biomedical purposes has been established.

An Active and Soft Hydrogel Actuator to Stimulate Live Cell Clusters by Self-folding.

The hydrogels are widely used in various applications, and their successful uses depend on controlling the mechanical properties. In this study, we present an advanced strategy to develop hydrogel actuator designed to stimulate live cell clusters by self-folding. The hydrogel actuator consisting of two layers with different expansion ratios were fabricated to have various curvatures in self-folding. The expansion ratio of the hydrogel tuned with the molecular weight and concentration of gel-forming polymers, and temperature-sensitive molecules in a controlled manner. As a result, the hydrogel actuator could stimulate live cell clusters by compression and tension repeatedly, in response to temperature. The cell clusters were compressed in the 0.7-fold decreases of the radius of curvature with 1.0 mm in room temperature, as compared to that of 1.4 mm in 37 °C. Interestingly, the vascular endothelial growth factor (VEGF) and insulin-like growth factor-binding protein-2 (IGFBP-2) in MCF-7 tumor cells exposed by mechanical stimulation was expressed more than in those without stimulation. Overall, this new strategy to prepare the active and soft hydrogel actuator would be actively used in tissue engineering, drug delivery, and micro-scale actuators.

Gamma scintigraphic evaluation of floating gastroretentive tablets of metformin HCl using a combination of three natural polymers in rabbits.

The present research was aimed at formulating a metformin HCl sustained-release formulation from a combination of polymers, using the wet granulation technique. A total of 16 formulations (F1–F16) were produced using different combinations of the gel-forming polymers: tamarind kernel powder, salep (palmate tubers of Orchis morio), and xanthan. Post-compression studies showed that there were no interactions between the active drug and the polymers. Results of in vitro drug-release studies indicated that the F10 formulation which contained 5 mg of tamarind kernel powder, 33.33 mg of xanthan, and 61.67 mg of salep could sustain a 95% release in 12 hours. The results also showed that F2 had a 55% similarity factor with the commercial formulation (C-ER), and the release kinetics were explained with zero order and Higuchi models. The in vivo study was performed in New Zealand White rabbits by gamma scintigraphy; the F10 formulation was radiolabeled using samarium (III) oxide (153Sm2O3) to trace transit of the tablets in the gastrointestinal tract. The in vivo data supported the retention of F10 formulation in the gastric region for 12 hours. In conclusion, the use of a combination of polymers in this study helped to develop an optimal gastroretentive drug-delivery system with improved bioavailability, swelling, and floating characteristics.

Effect of Sodium alginate in Combination With HPMC K 100 M in Extending the Release of Metoprolol Succinate from its Gastro-Retentive Floating Tablets

Abstract: Aim of work: The aim of present study was to convert Metoprolol Succinate (MS) into Gastro Retentive Floating Tablet (GRFT) and simultaneously to determine the effect of Sodium Alginate (SA) in combination with HPMC K 100M in extending the release of MS. Method: The drug- excipients compatibility studies of MS and the polymers were carried by FTIR studies. The effervescent GRFT of MS was prepared by non aqueous wet granulation. All Formulations were evaluated for pre-compression, post-compression, in vitro buoyancy and accelerated stability studies: for the best formulation for 3 months. Results: The drug- excipients compatibility studies reveals that MS and the polymers used are compatible. Evaluation parameters were within the acceptable limits for all formulations. In-vitro dissolution studies, showed the formulation F4 having the combination of 20% HPMC K100M and 10% SA is exhibiting better extended release up to 12 h, with a Floating Lag Time (FLT) of 20 s, Total Floating Time (TFT) and Matrix Integrity (MI) maintained up to 12 h than other formulations. Regression Coefficients of Zero order and Higuchi equations suggested the drug release follows Zero order and is predominantly by diffusion respectively. The Diffusion exponent (n) of Korsmeyer-Peppas model suggested the release mechanism is by non- Fickian transport. DSC studies further confirmed the drug is in the same state even in the optimized formulation F4 with out interacting with the polymers and excipients in the formulation. Accelerated stability studies indicate no significant differences in the optimized formulation F4. Conclusion: In conclusion, by optimizing the right ratios of the release-retarding gel-forming polymers HPMC K100M and SA, GRFT of MS with a better extended release up to 12 h was formulated. Key words: Gastro retentive floating tablets (GRFT), HPMC K100M, In vitro buoyancy studies, Metoprolol Succinate (MS), Sodium alginate.

Controlled release behavior and characterization of ropinirole hydrochloride using multi-layer formulation

In this paper, we report cost-effective and simply achievable extended release formulations of ropinirole hydrochloride (RP) by forming coating layers with well-known polymers. The upper and bottom coating layers were composed of one of gel-forming polymers such as PEG, PVP, and HPMC, respectively, designed to control drug release profile. The core tablet is prepared by wet granulation method with RP and HPMC (150 K). The multi-layer tablet showed much slower release behavior than that of commercially available once-diary formulation (REQUIP PD®, 4 mg, GSK) in the pH 1.2 conditions regardless of coated polymers, and zero order release profiles of RP were observed in the pH 6.8 dissolution conditions, which is nearly identical to dissolution profile of REQUIP PD®. These results indicate that the formation of multi-layer tablet is one of promising strategies for extended release formulation of RP, in addition, better bioavailability is expected due to minimized dissolution profiles of RP in low pH.

Preparation and Characterization of a Gastric Floating Dosage Form of Capecitabine

Gastrointestinal disturbances, such as nausea and vomiting, are considered amongst the main adverse effects associated with oral anticancer drugs due to their fast release in the gastrointestinal tract (GIT). Sustained release formulations with proper release profiles can overcome some side effects of conventional formulations. The current study was designed to prepare sustained release tablets of Capecitabine, which is approved by the Food and Drug Administration (FDA) for the treatment of advanced breast cancer, using hydroxypropyl methylcellulose (HPMC), carbomer934P, sodium alginate, and sodium bicarbonate. Tablets were prepared using the wet granulation method and characterized such that floating lag time, total floating time, hardness, friability, drug content, weight uniformity, and in vitro drug release were investigated. The sustained release tablets showed good hardness and passed the friability test. The tablets' floating lag time was determined to be 30–200 seconds, and it floated more than 24 hours and released the drug for 24 hours. Then, the stability test was done and compared with the initial samples. In conclusion, by adjusting the right ratios of the excipients including release-retarding gel-forming polymers like HPMC K4M, Na alginate, carbomer934P, and sodium bicarbonate, sustained release Capecitabine floating tablet was formulated.

Aerobic sludge granulation: A tale of two polysaccharides?

Aerobic sludge granules are suspended biofilms with the potential to reduce the cost and footprint of secondary wastewater treatment. Attempts to answer how and why they form leads to a consideration of the role of their extracellular polymeric substances (EPS) in determining their physical and microbiological properties. The exopolysaccharide components of this matrix, in particular, have received attention as putative structural, gel-forming agents. Two quite different exopolysaccharides have been proposed as the gel-forming constituents, with their gel properties clearly different from those of activated sludge EPS. This review aims to address the question of whether more than one gel-forming exopolysaccharide exist in granules. Based on the available structural data, it seems likely that they are different gel-forming polymers and their differences are not artifacts of the analytical methods used. Nonetheless, both proposed structural gel polymers are extracted and purified based on procedures selecting for anionic polar polysaccharides soluble at high pH, and both contain hexuronic acids. Granulation does not result from EPS synthesis by any single microbial population, nor from production of a single exopolysaccharide. Future studies using solvents suitable for recalcitrant polysaccharides are likely to reveal important structural roles for other polysaccharides. It is hoped that this article will serve as a guide for subsequent studies into understanding the roles of exopolysaccharides in aerobic granular sludge.

A Dynamic Covalent, Luminescent Metallopolymer that Undergoes Sol-to-Gel Transition on Temperature Rise

The condensation of linear diamine and dialdehyde subcomponents around copper(I) templates in the presence of bulky trioctylphosphine ancillary ligands gave a linear, conjugated polymeric material in DMSO solution. This polymer solution was observed to undergo sol-to-gel transition as the temperature was raised to 140 °C, in contrast with the behavior of most gel-forming polymers, which do so upon cooling. We attribute the sol-to-gel transition to the formation of Cu(I)N(4) cross-links as the equilibria 2[Cu(I)N(2)P(2)] ⇄ [Cu(I)N(4)] + [CuP(n)](+) + (4 - n)P favor the right-hand side at higher temperatures. The material was also observed to exhibit thermochromism and photoluminescence, with the color and intensity of both absorption and emission exhibiting temperature dependence. This material thus responds predictably to combinations of stimuli (heat, light, mechanical shear) in an interconnected way, as is required to generate complex function.