Bigels

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Alyssa Francavilla	--	3031	2023-11-11 21:16:00	\|
2	format	Jason Zhu	Meta information modification	3031	2023-11-13 07:00:33	\|

This entry is adapted from the peer-reviewed paper 10.3390/gels9080648

Bigels have been mainly applied in the pharmaceutical sector for the controlled release of drugs or therapeutics. However, these systems, with their intricate structures, hold great promise for wider application in food products. Besides their classical role as carrier and target delivery vehicles for molecules of interest, bigels may also be valuable tools for building complex food structures. In the context of reducing or even eliminating undesirable (but often highly functional) food components, current strategies often critically affect food structure and palatability. The production of solid fat systems that are trans-fat-free and have high levels of unsaturated fatty acids is one of the challenges the food industry currently faces.

bigels hydrogels organogels controlled release

1. Introduction

Bigels, also referred to as biphasic or hybrid gels, are an emerging class of soft materials composed of two discrete gel phases, typically a hydrogel and an organogel, where both gel phases contribute to the physical properties of the material ^[1]. Physicochemical characteristics, rheological properties and delivery capabilities of individual hydrogels ^[2]^[3]^[4] and organogels ^[5]^[6]^[7]^[8]^[9] have been extensively reported ^[10]. The insights gained on individual gels will aid in designing bigels with specific properties. Despite being combined, the resulting bigel structures retain some of the characteristics of the individual systems, while also often resulting in functional enhancements over the individual parts ^[1]^[11]. Bigels benefit from having both hydrophilic and lipophilic phases, making them suitable to encapsulate and deliver both hydrophilic and lipophilic active agents. In topical applications, organogels have been reported to hydrate the stratum corneum, improving the penetration of drugs into the skin ^[12]. Additionally, bigels are often easy to prepare, spread and wash ^[1]^[11]^[12]. By combining two gel phases with different structures and at different proportions, both the physicochemical and release properties can be tuned. The system’s physical stability can also be improved due to the entrapment of both liquid phases within a network (in comparison to an emulgel, which has only one structured phase) ^[6]^[13]^[14]. Due to the vast tunability of the systems and the parameters that can be modulated throughout the production process, bigel properties are currently difficult to predict. Hence, in-depth studies on structure–function relationships are needed ^[13].

Depending on the distribution of the individual gel phases (organogel and hydrogel) within the bigel, these systems can be classified as (1) organogel-in-hydrogel (O/H), (2) hydrogel-in-organogel (H/O), or (3) complex (bicontinuous/semibicontinuous/matrix-in-matrix) structures (Figure 1) ^[1]^[11]. O/H bigels have thus far been the most extensively studied. Recently, H/O and complex bigels have also received more attention ^[15]^[16]. Besides their specific composition, the phase distributions of the components can also contribute to the physicochemical and release properties of bigels, which will be explored in the following sections.

Figure 1. Schematic illustration of organogels, hydrogels, and bigel matrices. Illustration created with biorender.com.

2. Composition and Production Methods

Bigels have been produced via two main methods, where (i) the molten organogel and hydrogel are combined at high shear followed by gel setting, or (ii) both gels are prepared and allowed to set prior to high-shear mixing (Figure 2) ^[1]. The preparation of the individual gels is generally a simple process wherein the hydrogelator/organogelator is dispersed/dissolved into the liquid phase. Then, the gelling mechanism is triggered based on the gelator’s requirements.

Figure 2. Flow diagram for bigel production via two main mixing methods. (i) Individual hydrogels/organogels are set, and then combined by high shear mixing. (ii) The bigel is produced via high shear mixing of the hydrogel and organogel. Illustration created with biorender.com.

Gelators can be classified based on their molecular weight as either low or high molecular weight or polymeric gelators ^[7]^[9]. Low-molecular-weight (<1 kDa) gelators (LMWG) are able to self-assemble through noncovalent bonds at concentrations as low as 2%. These physical interactions lead to large aggregates that interweave and cause the gelation of the matrix through chemical crosslinking ^[7]^[9]. These networks can either be strong or weak ^[7]. High-molecular weight (>2 kDa) gelators, or polymeric gelators, typically gel at lower concentrations (<2%) than LMWGs. Gels of high molecular weight organogelators can be both physical (non-covalent interactions) or chemical (crosslinked) gels ^[7]^[9]. Most LMWG identified to date perform better in non-polar solvents ^[17]. Therefore, the most commonly used hydrogelators are polymeric, although hydrophilic LMWGs have been identified ^[18]. In drug delivery, gelators only require biocompatibility, but for food applications, they must be edible and approved for food use by the relevant regulatory agencies. In both hydro- and organogels, gelator selection is important to obtain the proper desired qualities of the gel.

Chemical organogels are less sensitive to temperature due to the formation of a supramolecular polymer network through non-covalent bonds ^[9]. However, organogels (especially physical organogels) typically undergo solid-to-liquid transitions when the temperature is above their sol-to-gel transition temperature ^[7]. According to the literature, numerous organogelators have been used to formulate bigels, including sorbitan esters (e.g., sorbitan monostearate and sorbitan monopalmitate), monoglycerides and fatty acids, waxes, lecithin, and others ^[1]. The liquid phases used are also subject to regulatory approval. While the liquid phase options for pharmaceutical applications are relatively broad, the organic liquid phases acceptable for food bigel formulation are largely restricted to vegetable and seed oils (e.g., canola, sesame, olive oil). Typically, organogelation occurs by heating the liquid phase/organogelator mixture to a required temperature, prior to cooling the mixture to obtain the gel.

Polymers for hydrogelation can be natural, semi-synthetic, or synthetic. Regardless of their origin, all should be able to form a polymer network that can bind large quantities of water ^[19]. Natural polymers such as chitosan, gellan, pectin, xanthan gum, guar gum, starch, locust bean gum, alginate, agarose, collagen, and gelatin have previously been used for bigel production ^[1]^[19]. Synthetic polymers like carbomers, poloxamer, polyvinyl alcohol, polyethylene oxide, and polyacrylic acid have also been used to produce tunable hydrogels. Still, these polymers do not have applications in food-grade bigels ^[1]. Finally, semi-synthetic polymers such as methylcellulose and hydroxypropyl methylcellulose (HPMC), have also been utilized in bigel preparation ^[1]. Hydrogelation can occur through physical interactions (transient intersections caused by physical entanglements and weak forces, e.g., hydrogen bonds) and/or chemical cross-linking. These polymers form gels with differing physical characteristics and are responsive to physical triggers (temperature, pH, enzymes, etc.) for release.

Surfactants can also be included in the formulation and have been shown to affect the rheological properties of the bigel. For example, sucrose esters with differing hydrophilic–lipophilic balance (HLB) values were incorporated into an O/H bigel to modulate its rheological properties ^[20]. The addition of surfactants with lower HLB values resulted in samples with higher solid-like and elastic behavior. This was attributed to the overall smaller size of the dispersed organogel particles in the systems ^[20]. Not only the HLB values but also the type and concentration of surfactants are important. In O/H bigels where mono-diglycerides were added, increasing the surfactant concentrations resulted in a phase inversion to a H/O bigel ^[21]. Additionally, the mono- and diglycerides negatively affected the hardness of the bigel in contrast to the addition of sucrose esters ^[21].

The inclusion of active agents can also impact gel properties. Polyphenols, for example, occasionally cause biopolymer aggregation, which may lead to an increase or decrease in the network strength during hydrogel formation ^[22]. In bigels containing aqueous Quercus resinosa polyphenol extracts, an increase in polyphenol concentration increased the consistency index of the bigel ^[22]. Similarly, the addition of vitamin E had a sigmoidal, dose-dependent positive impact on the gel strength and phase transition temperature of a 12-hydroxystearic acid/candelilla wax organogel ^[23].

Preparation conditions must be tightly controlled during bigel production. The preparation temperature, for example, is important when incorporating thermo-labile active agents into the gels. Yet, temperature may also impact the mechanical and rheological properties and structural characteristics of the final bigel ^[24]. The gels can be mixed together while still molten (>70 °C, Figure 2), which usually results in a more homogenous distribution of phases ^[24]^[25]. The homogeneity could be attributed to the liquid form of both phases at high temperatures. Alternatively, both gels can be formed separately and then mixed together after gelling and storage (Figure 2) ^[12]. The second method may result in a more complete gelling of the individual phases, but could also result in less overall stability and homogeneity. However, if the formulation includes sensitive active agents, or thermally unstable hydrogelators, the second method is deemed more suitable due to the shorter exposure of the active agent to harsh conditions ^[14].

The shear rate during mixing also affects the particle size of the dispersed phase (gel discrete particles within the continuous gel matrix) ^[26]. In H/O bigels with a constant hydrogel volume, a small (~40 µm) particle size of the hydrogel pointed to an active filler effect in the continuous oleogel phase ^[21]. Small hydrogel particle sizes resulted in final H/O bigels with the strongest rheological and textural properties when compared to medium and large particle-sized hydrogel bigels ^[26]. Additionally, small particle sizes enhanced the oil binding capacity of the oleogel. Tailoring the dispersed phase’s particle size is therefore necessary for the thorough design of a bigel with ideal properties for the desired application.

The hydrogel–oleogel ratio can impact the type (i.e., O/H, H/O, or complex), textural, rheological and structural properties of the bigel ^[6]. In general, bigels with increasing O:H ratios are characterized by a decreasing firmness and spreadability and an increasing adhesiveness and cohesiveness ^[27]. It was also observed that the organogel rheological properties dominated the properties of beeswax/alginate O/H bigels ^[27]. In another H/O bigel system, an increase in organogel content resulted in more crystalline systems with enhanced thermal stability, a softer texture, lower viscosity, and good plasticity/spreadability ^[28]. Conversely, increased hydrogel content resulted in higher viscosity and bigel strength ^[28].

Finally, storage time also influenced bigel properties ^[29]. In bigels prepared with monoacylglycerides as the oleogelator, refrigerated storage for 15 days improved the mechanical properties of the bigel due to the slow structuring of monoacylglcerides ^[29]. Prior to the 15-day point, the bigel firmness had not reached the maximum potential value, indicating the potential for storage time as a parameter that should be controlled in bigel manufacture ^[29].

3. Characterization

Analytical methods can be applied to properly characterize the produced bigel, and to ascertain its functionality. Several techniques are commonly used to assess bigel properties, but the initial step performed is an inversion test, to determine the formation of a “correct” bigel (that can stand under its own weight, or behave as a solid under gravitational pull). The most common analytical techniques are further described in the following sections (Figure 3).

Figure 3. Schematic overview of analytical techniques commonly applied during bigel characterization. Illustration created with biorender.com.

3.1. Microstructural Analysis

Microstructural analyses are frequently carried out to study the morphology of bigels. Microscopy is a simple characterization technique encompassing several modes with distinct suitability for analyzing different bigel types. Confocal laser scanning ^[15]^[24]^[26]^[30]^[31]^[32]^[33], phase contrast ^[14], optical ^[15]^[22]^[30]^[34] (including fluorescence ^[27]^[35] and polarized light ^[26]^[28]^[29]^[34]^[36]), transmission electron ^[37], and scanning electron ^[38]^[39] microscopy have been used for this purpose. All microscopy techniques provide insights into the microstructure of the bigel and, more specifically, the arrangement of the phases. However, unique microscopy techniques could be selected to gain additional information about the materials. For example, micro-spectroscopy techniques such as Raman microscopy could provide spatial chemical mapping of the material without staining the samples, potentially lending insights into the distribution of active agents in the bigel ^[40]. Microscopes with heated stages could allow for the visualization of the melting behavior of bigels for saturated fat-replacer applications and controlled release strategies relying on thermal triggers.

3.2. Rheological and Mechanical Testing

The rheological and mechanical properties of bigels are commonly used to evaluate the quality and utility of the produced bigels, since these parameters directly impact the commercial applicability of the products.

The flow behavior and viscosity of the gels are significantly affected by the organo/hydrogelator molecular weight, concentration, and structure (e.g., branched vs. linear polysaccharide gelators) ^[13]. Small-Amplitude Oscillatory Shear (SAOS) tests are typically used to study the viscoelastic properties of gels under small deformations. They allow people to gain insights into the (type, strength and number of) interactions and molecular/aggregate/microstructures underlying the overall gel structure ^[13]. Prior to SAOS testing, a strain sweep test would be utilized to determine the linear viscoelastic region, which allows for the identification of the extent of deformation the gel structure can experience before structural breakdown or yielding becomes apparent. A stress sweep test would allow for the determination of the yield stress associated with the gel structure. Larger deformations may be applied with a creep test. In this test, the response of the gel to a constant stress provides information on the viscoelastic behavior of the gel under moderate deformations. After stress removal, the percent recovery of the gel is related to the elastic behavior or the storage of the deformation energy in the gel structure. As with SAOS measurements, these tests give indirect information about the interactions and molecular conformations underlying the overall gel structure.

The bigel textural properties, such as firmness, cohesiveness, adhesiveness, and spreadability, have been derived from compression–decompression tests like texture profile analysis (TPA) ^[1]^[11]^[13]. These parameters are important in both pharmaceutical and food applications. In drug delivery applications, e.g., a topical cream, the texture of the gel is central to patient use and compliance. In food applications, e.g., solid fat replacers, the bigel must replicate the rheological and textural properties of the replaced fat. Pastry shortening, for example, is a key ingredient in puff pastries with a significant role in the formation of the final product’s structure through the lamination process ^[24]. The bigel, therefore, needs to be able to form a continuous layer on the dough, withstand high shear rates and extensional deformation, and mimic the flow behavior, firmness, and melting profile of the replaced solid fat ^[24]. Therefore, rheological and textural testing are of great importance in screening potential bigel formulations for fat replacers and other uses.

Although the organogel and hydrogel properties impact the final rheological properties, bigels are ultimately multiphasic materials whose overall rheological behaviour depends on many factors, such as each separate phase properties, the particle size distribution and the volumetric fraction of the dispersed phase ^[13]. The exact relationship and interplay between any or all these factors and bigel rheological behavior have not been fully elucidated yet. However, empirical modifications to established theoretical rheological models for complex gelled systems have been developed ^[41]^[42]. They can eventually be used to better understand the contributions of hydrogels and organogels to bigel rheology ^[43].

3.3. Other Characterization Methods

In addition to the microstructural, rheological and textural properties, other characteristics dictate the usability of bigel formulations for specific applications. Thermal analysis, for example, allows for determining the thermal stability/melting temperature of the bigel formulation. The temperature-dependent transformation from solid-like to liquid-like behavior is critical for practical applications in both the pharmaceutical and food realms. This transformation impacts the release profile of enclosed components, and the structural characteristics of the bigel (e.g., baking pastry with a saturated fat replacer). A temperature sweep test utilizing a rheometer, as described above, will allow the “visualization” of the phase transitions as a function of temperature through studying the viscoelastic parameters ^[44]. The actual phase transition between solid and liquid structures can also be studied by differential scanning calorimetry. For this test, a weighed amount of the bigel is heated or cooled over a temperature range, and the heat flow is recorded for the bigel and compared to the heat flow to a reference material undergoing the same heating or cooling profile. Endo- and exothermic peaks indicate melting or crystallization processes. Specifically, the temperatures at which these transitions occur will be of interest to the applicability of the bigel ^[25]. Thermogravimetric analyses can also be performed, providing information about thermal events such as melting and water evaporation ^[45].

Fourier transform infrared (FTIR) spectroscopy has been applied to identify functional groups on polymers, and chemical interactions between bigel components themselves and with enclosed molecules of interest. For example, in a Carbopol^® 934/sorbitan monostearate and sesame oil bigel, the characteristic peaks of the raw materials closely reseembled those of the separate systems, indicating the absence of chemical interactions between the two polymers ^[35]. X-ray diffraction is another useful tool used to elucidate whether the bigel structures are amorphous or contain crystalline substructures ^[46]. Electrical impedance has also been used to assess changes in microstructure caused by, for example, different O:H ratios of the material based on the conductivity of the phases and their interconnectivity ^[36]. Impedance values depend on the diffusion of solutes within the gel matrices. Higher impedance is associated with low diffusion coefficients for solutes, provided that interconnected channels are present ^[36].

Analysis can also be performed to determine the release characteristics and related properties of the bigel. In pharmaceutical applications, this testing is typically performed under both in vivo and in vitro conditions. Mucoadhesion ^[47]^[48]^[49], in vivo and ex vivo skin permeation ^[45]^[50]^[51], in vitro cytocompatibility ^[49]^[51], and in vivo drug release ^[35]^[37] are all useful tests to assess the behavior and efficacy of bigels as delivery systems. Modified Franz cells are common apparatuses used to measure drug release, penetration and diffusion. They can measure mucoadhesion, depending on the barrier material used ^[1]^[35]. The bioaccessibility and bioavailability of active agents in the gastrointestinal tract can also be measured using in vitro digestion models ^[52]. Drug release via diffusion can be effectively estimated based on Fick’s law ^[1]. The swelling of the gel structure will widen the channels and pores in a gel and aid in diffusion ^[25]. The hydrogel portion of the bigel dictates the swelling behavior. Factors affecting the swelling include temperature, pH, and ionic strength. Moreover, the presence, proportion, and distribution of organogels in the bigel tend to control the swelling and thus the release of the encapsulated molecules, especially due to the lack of swelling of the organogel structure ^[1]^[47].

Although bigels exhibit greater physical stability than similar colloids, biphasic systems can still undergo destabilization over time. Therefore, their stability should be assessed. Storage studies are used to evaluate changes in microstructural, thermal, and rheological properties over a predetermined time at a preset temperature profile ^[1]. Accelerated photostability tests have also been performed, where the quantity of a photo-labile active agent (e.g., ketoprofen) was measured after exposure to daylight ^[37]. The amount of the encapsulated compound remaining in the bigels after storage under selected scenarios has seldom been reported, but it is important for establishing bigels as effective materials for diverse applications.

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Subjects: Polymer Science

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Alyssa Francavilla

Maria G. Corradini

Iris J. Joye

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Update Date: 13 Nov 2023

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