Thermoreversible Gels Research Articles

Polymer architecture dictates thermoreversible gelation in engineered emulsions stabilised with branched copolymer surfactants

Polymer architecture allows control of thermoreversible gelation in branched copolymer-stabilised emulsions.

Evidence by neutron diffraction of molecular compounds in triarylamine tris-amide organogels and in their hybrid thermoreversible gels with PVC.

We report on neutron diffraction experiments performed on organogels prepared from triarylamine tris-amide (TATA), as well as on their ternary thermoreversible gels made up with poly[vinyl chloride] (PVC). Three different solvents together with their deuterated counterparts have been used; tetrachloroethane, wherein TATA fibrils display ohmic conductivity, bromobenzene and o-dichlorobenzene. The TATA crystal structure differs in the three solvents. Most importantly, the difference in the diffraction patterns whether hydrogenous solvents or deuterated solvents are used demonstrate the occurrence of molecular compounds. Tentative unit cells are presented. These results are also discussed in the light of the current views on the solvent role in the gelation process.

Formulation and Evaluation of Flexible Liposome Embedded In Situ Thermoreversible Intranasal Gel of Rizatriptan Benzoate

The present study deals with formulation and evaluation of flexible liposome embedded thermoreversible in situ intranasal gel of rizatriptan benzoate. The flexible liposomes were formulated (F1-F9) and optimized with respect to percentage of ethanol and phospholipid to get optimum vesicle size and entrapment efficiency. The vesicles were characterized for their size, shape and zeta potential. The optimized stable vesicles were incorporated into in situ thermoreversible gel. The ex vivo permeation of drug through goat nasal mucosa was studied. The nasal mucosa used for drug permeation experiment was subjected to histopathological study to check for any damages. The in vivo pharmacokinetic study was carried out in Wistar rats. Vesicles size and entrapment efficiency of stable formulations (F2-F6) was varied from 71.2±14.16 to 199.3±26.03 nm and 72.98 % to 77.44 % respectively. The liposomes were nearly spherical in shape with zeta potential varied from -14.2±4.48 to -11.7±5.26 mV. The improved drug permeation and higher flux across nasal mucosa with enhancement ratio of 2.75 was observed for flexible liposomal thermoreversible gel F2 compared to normal thermoreversible hydrogel of drug. The histopathological study of nasal mucosa revealed that there was no damage to epithelial layer and was found to be intact. The area under the curve of optimized formulation (F2) was 3.98 and 1.53 times more than oral drug solution and intranasal gel respectively, confirming improvement in bioavailability. Thus present study concludes that flexible liposome enriched thermoreversible, mucoadhesive in situ intranasal gel of rizatriptan benzoate is a safe and effective drug delivery system for treatment of migraine.

An efficient polymer cocktail-based transportation method for cartilage tissue, yielding chondrocytes with enhanced hyaline cartilage expression during in vitro culturing

BackgroundChondrocytes are used in cell-based therapies such as autologous chondrocyte implantation (ACI) and matrix-associated cartilage implantation (MACI). To transport the cartilage tissue to the laboratory for in vitro culturing, phosphate-buffered saline (PBS), Euro-Collins solution (ECS) and Dulbecco's Modified Eagle's Medium (DMEM) are commonly employed at 4–8 °C. MethodsIn this study, eight samples of human cartilage biopsy tissues from elderly patients with severe osteoarthritis undergoing arthroscopy, which would otherwise have been discarded, were used. The cartilage tissue samples were compared to assess the cell yield between two transportation groups: i) a thermo-reversible gelation polymer (TGP) based method without cool preservation (∼25 °C) and ii) ECS transport at 4 °C. These samples were subjected to in vitro culture in a two-dimensional (2D) monolayer for two weeks and subsequently in a three-dimensional (3D) TGP scaffold for six weeks. ResultsThe cell count obtained from the tissues transported in TGP was higher (0.2 million cells) than those transported in ECS (0.08 million cells) both after initial processing and after in vitro culturing for 2 weeks in 2D (18 million cells compared with 10 million cells). In addition, mRNA quantification demonstrated significantly higher expression of Col2a1 and SOX-9 in 3D-TGP cultured cells and lower expression of COL1a1 in RT-PCR, characteristic of the hyaline cartilage phenotype, than in 2D culture. ConclusionThis study confirms that the TGP cocktail is suitable for both the transport of human cartilage tissue and for in vitro culturing to yield better-quality cells for use in regenerative therapies.

Effect of solvent isomers on the gelation properties of tri-aryl amine organogels and their hybrid thermoreversible gels with poly[vinyl chloride

The gelation properties of tri-aryl amine (TATA) in two isomers of dichlorobenzene, namely ortho-dichlorobenzene (o-DCB) and meta-dichlorobenzene (m-DCB), have been studied by calorimetry for mapping out the temperature-concentration phase diagram. It is shown that both systems behave differently, yet both form molecular compounds. The occurrence of these compounds is further demonstrated by neutron diffraction in o-DCB. Depending on the isomer used, X-ray investigations highlight a difference in the position of the diffraction peaks. The morphology observed by scanning electron microscopy reveals fibrillar systems in both cases, yet the fibrils' cross-sections are far larger in m-DCB with respect to o-DCB. The body of these results is discussed in light of current opinions on the role of the solvent. Ternary gels obtained with PVC have also been investigated by means of the same experimental approach. Calorimetry investigations and X-ray diffraction data show no significant difference for the behavior of the TATA moiety. The morphology studied by scanning electron microscopy allows one to distinguish clearly the TATA fibrils and the PVC network. This again confirms the possibility of preparing functional materials with an organogelator and a polymer through the making of hybrid gels.

Ordered hydrocolloids networks as delivery vehicles of nutraceuticals: Optimal encapsulation of curcumin and resveratrol

Nutraceutical compounds such as curcumin and resveratrol are effective for preventing and treating diabetes, cardiovascular disease, obesity and cancer. However, their unstable properties and water insolubility curtail the wholesome application as well as developing food supplements, functional foods and medicinal foods. Highly efficient and economical delivery systems are helpful to overcome this quandary. Among the several available carrier materials, hydrocolloids stand out tall due to their inbred non-toxic traits, cost-effectiveness and compatibility to humans. Herein, iota-carrageenan (IC), from the marine algae, has been chosen as the model hydrocolloid, which forms thermo-reversible gels and oriented fibers with ordered networks, and curcumin and resveratrol, as model nutraceuticals, have been encapsulated in the IC fibers for different time periods, namely for 1, 2, 3, 4 and 5 weeks to determine the optimal encapsulation time. The results demonstrate that encapsulation time dictates the overall entrapped amount in the IC network with an optimal duration of 3 weeks. The two nutraceuticals are readily protected from heat by the IC network and released in a sustained manner. The outcome offers an elegant opportunity to develop value-added delivery systems of nutraceuticals, in particular, and health promoting and disease preventing compounds, in general, based on the ordered hydrocolloid networks.

In Vitro Culture Expansion and Characterization of Buccal Mucosal Epithelial Cells for Tissue Engineering Applications in Urethral Stricture After Transportation Using a Thermoreversible Gelation Polymer.

Introduction: The transportation of tissues from hospitals to clinical laboratories for cell therapy is an essential component of regenerative medicine. Previously, we used laboratory-cultured mucosal cells from buccal epithelium expanded and encapsulated using a scaffold-hybrid approach to the urethral stricture (BEES-HAUS) procedure. In this study, to improve the outcomes, we compared the thermoreversible gelation polymer (TGP) transportation procedure with conventional culture methods, and reported its advantages. Methods: Human buccal mucosal tissues in Phase I of the study were transported in Euro-Collins solution (ECS) and the cells obtained were cultured in two-dimensional (2D) Dulbecco's modified Eagle's medium (DMEM), CnT-Prime epithelial 2D differentiation medium (CnT-PR), and a three-dimensional (3D)-TGP scaffold. In Phase II, tissues were transported in a TGP cocktail and the ECS. The cells were cultured in 2D-DMEM and 3D-TGP, quantified, and characterized by immunohistochemistry. Results: The cells in 3D-TGP culture maintained epithelial morphology in a better manner compared with 2D-DMEM, in which they developed fibroblast-like morphology. The TGP-transported cells grew rapidly. Immunohistochemical analysis results for AE1/AE3, EGFR, integrin-β1, p63, and p75 were intensely positive in 3D-TGP. Conclusion: The TGP-based cocktail used in human buccal tissue transportation yielded cells with better morphology maintenance. The TGP scaffold provides an optimal in vitro environment wherein epithelial cells better maintain their native phenotype compared to those cultured through conventional methods. These results suggest using TGP for the transportation and culture of human buccal tissues for clinical applications. In addition, the use of a TGP-based cocktail for the transport of other tissues for regenerative medicine applications is worth further analysis.

Formulation development and evaluation of carbopol-incorporated mucoadhesive thermoreversible gels of sucralfate for rectal drug delivery

Objective : The present study describes the preparation and evaluation of a Poloxamer 188 (P188)-based thermoreversible gel using Carbopol 934P (C934P) as a mucoadhesive polymer of Sucralfate for enhancing the bioavailability and to avoid the first-pass metabolism. Methods: Eight formulations (F1-F8) were prepared using cold method. The prepared gels were characterized by pH, drug content, spreadability, mucoadhesive force, gelation temperature, and drug release profile. Thermoreversibility of P188/C934P gel was demonstrated by rheological studies. The drug-polymer compatibility was studied using Fourier transform infrared (FTIR). The incorporation of carbopol into P188 gel also reduced the amounts of drug released from the gel formulations. Results: FT-IR studies revealed that there are no interactions between the drug and polymers. Drug content of gels was estimated and the results were found to be satisfactory. In vitro dissolution studies revealed a good drug release from the gels. The drug release was higher in formulations F5 and F6 and lower in F4, F7, and F8 formulations. These findings suggested that developed thermoreversible gels could be used as promising dosage forms to rectal drug delivery for prolonged periods in the management of hemorrhoids.

Polymer Architecture Effects on Poly(N,N-Diethyl Acrylamide)-b-Poly(Ethylene Glycol)-b-Poly(N,N-Diethyl Acrylamide) Thermoreversible Gels and Their Evaluation as a Healthcare Material.

Thermoreversible gels which transition between liquid-like and solid-like states when warmed have enabled significant novel healthcare technologies. Poly(N,N-diethyl acrylamide) (PDEA) is a thermoresponsive polymer which can be used as a trigger to form thermoreversible gels, however its use in these materials is limited and crucial design principles are unknown. Herein ABA copolymers with the structure PDEA-b-poly(ethylene glycol) (PEG)-b-PDEA are synthesized to give four block copolymers with varied molecular weight of PDEA and PEG blocks. Rheometry on solutions of the block copolymers reveals that high molecular weight PEG blocks are required to form thermoreversible gels with predominantly solid-like behavior. Furthermore, small-angle X-ray scattering elucidates clear differences in the nanostructure of the copolymer library which can be linked to distinct rheological behaviors. A thermoreversible gel formulation based on PDEA (20kDa)-b-PEG (10kDa)-b-PDEA (20kDa) is designed by optimizing the polymer concentration and ionic strength. It is found that the gel is mucoadhesive, stable, and non-toxic, as well as giving controlled release of a hydrophobic drug. Overall, this study provides insight into the effect of polymer architecture on the nanostructure and rheology of PDEA-b-PEG-b-PDEA and presents the development of a highly functional thermoreversible gel with high promise for healthcare applications.

Thermoresponsive Triblock‐Copolymers of Polyethylene Oxide and Polymethacrylates: Linking Chemistry, Nanoscale Morphology, and Rheological Properties

AbstractThermoreversible gels switch from a free‐flowing liquid state to an elastic gel mesophase upon warming, displaying the reverse transition upon cooling. While this phenomenon makes these advanced materials highly attractive in numerous fields, the generation of optimal materials of tailored rheology and transition temperatures is stifled by the lack of design principles. To address this need, a library of ABA copolymers has been prepared with “A” blocks exhibiting thermoresponsive behavior and “B” blocks of poly(ethylene glycol). This library evaluates the effect of “A” chemistry, probing three polymer classes, and A/B block molecular weight on thermally‐induced phase changes in solutions of the polymers. An exploration by rheometry coupled to Small‐Angle Neutron Scattering (SANS) elucidates temperature‐dependent hierarchical self‐assembly processes occurring on the nanoscale as well as bulk rheology. This process deciphered links between rheology and supracolloidal assemblies (sphere, ellipses, and cylinders) within the gel state with interactions probed further via structure factors. Several design principles are identified to inform the genesis of next‐generation thermoreversible gels, alongside novel materials exhibited thermoresponsive behavior in the solution state for use in applied healthcare technologies.

Develop and characterize thermally reversible transparent gels from pea protein isolate and study the gel formation mechanisms

Gels with thermo-reversibility and transparency like gelatin have been applied in various products in food and pharmaceutical industry. The replacement of gelatin by ingredients of plant origin has attracted attentions owing to the emerging markets of vegan, Halal and Kosher products. This work reports a thermo-reversible protein gel prepared with pea protein isolate extracted using ammonium sulfate precipitation method. The protein concentration and pH were discovered to be critical, and within a window of pH 2.4–4.2 and protein concentration of 10–15%, thermo-reversible gels were obtained, many of which possessing good mechanical properties with compressive stress up to 6.32 ± 1.40 kPa. Dynamic rheological measurement disclosed the thermo-reversibility of the gel being stable upon repeated heating and cooling process from 80 °C to 4 °C. Lower pH favored the formation of transparent gels with fine-stranded network as observed by scanning electron microscopy (SEM), whereas with the increase of pH up to 4.2, the gel gradually became opaque when the gel network changed to particulate aggregates while gel thermo-reversibility retained. Hydrogen bonds were shown to be dominant in forming the gel network structure during the cooling process while hydrophobic interactions and disulfide bonds were not significantly involved. The pea protein gel has the characteristics of being transparent and thermo-reversible with good mechanical property, which has provided opportunities of replacing gelatin in food applications such as fruits, beverage and fermented food products with mild acidic pH environment.

Thermoreversible Gelation of Associating Polymers in Hydrogen-Bonding Mixed Solvents.

The thermoreversible gelation of associating polymers in hydogen-bonding mixed solvents is studied theoretically on the basis of the model ternary solution in which polymers carrying functional group A are dissolved in a primary solvent SB (mainly water) and cosolvent SC. Functional group A forms intermolecular cross-links (A-A) leading to gelation. It can also form hydrogen bonds with either solvent molecule SB or SC (A-SB, A-SC). If bound to a solvent molecule, A becomes inert. Solvent molecules form complexes with variable association numbers (SB-SC). Ternary phase diagrams for sol-gel transition lines and their cross sections on the temperature-solvent composition plane are constructed. It is shown that a minimum in the polymer concentration along the sol-gel transition line appears at a special solvent composition which depends upon the structure of the complexes. At such an optimal gel point, the sol-gel transition temperature becomes the highest, thus leading to stable, strong gels. The degree of adsorption, preferential adsorption coefficient, average molecular weight of the complexes, and cross-link probability are calculated as functions of the solvent composition. At the optimal gel point, the preferential adsorption coefficient changes its sign and the average molecular weight of the complexes reaches a maximum. Results are compared with the experimental data on poly(vinyl alcohol) in a mixed solvent of water/dimethyl sulfoxide, dimethyl sulfoxide/urea, or water/methanol.

Super aggregated amphotericin B with a thermoreversible in situ gelling ophthalmic system for amoebic keratitis treatment

Acanthamoeba spp. are the causative agents of a sight-threatening infection of the cornea known as Acanthamoeba keratitis (AK). Amphotericin B - deoxycholate (AB) is used in the treatment of infectious keratitis, however, its topical administration has side effects as blepharitis, iritis, and painful instillation. In this context, the preheating of AB can decrease its toxicity by the formation of super aggregates (hAB). hAB associated with a thermoreversible in situ gelling ophthalmic system is a promising option due to the latter biocompatibility, low toxicity, and high residence time on the ocular surface. Our objective was to develop a topical ocular formulation of hAB for the treatment of AK. After heating at 70°C for 20 min, hAB was incorporated into a thermoreversible gelling system. The amebicidal activity of AB and hAB was evaluated against trophozoites and cysts of A. castellanii (ATCC 50492) and a regional clinical isolate (IC01). The results showed that the preheating of AB did not change the pharmacological action of the drug, with the amebicidal effect of AB and hAB under trophozoites and cysts of Acanthamoeba spp. The thermoreversible system remained stable, allowing the increase of drug retention time. For assessment of cytotoxicity, HUVEC (ATCC® CRL-1730) cells were challenged with AB and hAB for 48h. Cell viability was assessed, and hAB did not show cytotoxicity for HUVEC cells. As far as we know this was the first study that showed the preheated AB associated with a thermoreversible in situ gelling ophthalmic system as a promising system for topical ocular topical administration of hAB for AK therapy.

Amylomaltases in Extremophilic Microorganisms.

Amylomaltases (4-α-glucanotransferases, E.C. 2.4.1.25) are enzymes which can perform a double-step catalytic process, resulting in a transglycosylation reaction. They hydrolyse glucosidic bonds of α-1,4′-d-glucans and transfer the glucan portion with the newly available anomeric carbon to the 4′-position of an α-1,4′-d-glucan acceptor. The intramolecular reaction produces a cyclic α-1,4′-glucan. Amylomaltases can be found only in prokaryotes, where they are involved in glycogen degradation and maltose metabolism. These enzymes are being studied for possible biotechnological applications, such as the production of (i) sugar substitutes; (ii) cycloamyloses (molecules larger than cyclodextrins), which could potentially be useful as carriers and encapsulating agents for hydrophobic molecules and also as effective protein chaperons; and (iii) thermoreversible starch gels, which could be used as non-animal gelatin substitutes. Extremophilic prokaryotes have been investigated for the identification of amylomaltases to be used in the starch modifying processes, which require high temperatures or extreme conditions. The aim of this article is to present an updated overview of studies on amylomaltases from extremophilic Bacteria and Archaea, including data about their distribution, activity, potential industrial application and structure.

Hyaluronic Acid Hydrogels Crosslinked in Physiological Conditions: Synthesis and Biomedical Applications.

Hyaluronic acid (HA) hydrogels display a wide variety of biomedical applications ranging from tissue engineering to drug vehiculization and controlled release. To date, most of the commercially available hyaluronic acid hydrogel formulations are produced under conditions that are not compatible with physiological ones. This review compiles the currently used approaches for the development of hyaluronic acid hydrogels under physiological/mild conditions. These methods include dynamic covalent processes such as boronic ester and Schiff-base formation and click chemistry mediated reactions such as thiol chemistry processes, azide-alkyne, or Diels Alder cycloaddition. Thermoreversible gelation of HA hydrogels at physiological temperature is also discussed. Finally, the most outstanding biomedical applications are indicated for each of the HA hydrogel generation approaches.

Modulation of the Molecular Structure of Tri-aryl Amine Fibrils in Hybrid Poly[vinyl chloride] Gel/Organogel Systems

This paper reports on the thermodynamics through mapping out temperature–concentration phase diagrams and the molecular structure and the morphology of binary organogels prepared with trisamide triarylamine (TATA) in tetrachloroethane and on their ternary thermoreversible hybrid gels formed with polyvinyl chloride (PVC). For low PVC contents, the TATA organogel moiety behaves as in the binary systems, while for higher PVC contents, the thermal behavior is significantly altered with the appearance of a nonvariant event. The molecular structure of the TATA assemblies is compared with that observed in the bulk solid state. Three molecular packings are observed in the bulk, whose crystalline lattices are tentatively derived. Structure I obtained after the crystallization–purification process is seen to transform at higher temperature into structure II. By cooling, structure III is obtained, which transforms reversibly into structure II on heating. The metastability of structure I leads one to contemplate the possible formation of molecular compounds during the crystallization–purification process in the presence of chlorinated solvents, the more so as the crystalline structures in the gels turn out to exhibit high similarities. Finally, the morphology observation reveals that the TATA fibrils and the PVC matrix can be well identified for low PVC contents, while for higher PVC contents, one essentially observes the TATA fibrils

Organoid culture of mouse fallopian tube epithelial stem cells with a thermo-reversible gelation polymer

In this study, a three-dimensional (3D) thermo-reversible gelation polymer (TGP) culture system was established for organoid culture of mouse fallopian tube (FT) epithelial stem cells (FTESCs) without cell isolation. FT tissues from 6- to 8-week-old ICR mice were digested with collagenase, and whole FT cells (FTCs) were inoculated into the TGP. After 6 days of culture, many spheres in the TGP formed. Some cells in the spheres were positive for 5-ethynyl-2′-deoxyuridine (EdU), a marker of cell proliferation. Furthermore, all the spheres that formed in the TGP were also labelled for EpCAM and LGR5. Some cells in the spheres were stained for PAX8, a secretory cell marker, and fewer cells were labelled with TUBB4, a ciliated cell marker. These results indicate that the 3D TGP culture system is a useful tool for organoid culture of FTESCs in vitro.

Development of In-Situ Spray for Local Delivery of Antibacterial Drug for Hidradenitis Suppurativa: Investigation of Alternative Formulation.

Hidradenitis suppurativa (HS) has been considered an orphan disease with limited treatments available. The available topical treatment for this condition is clindamycin lotion; however, short retention and frequent application are the main setbacks. Thus, the present study aimed to attain an optimized antibacterial in situ spray formulation for the hidradenitis suppurativa skin condition, which gels once in contact with the skin surface at around 37 °C and possesses bioadhesion as well as sustained-release properties of the incorporated drug. Different concentrations of thermo-reversible gelling polymer, Pluronic F-127, were investigated along with the selected bioadhesive polymers, HPMC and SA. The optimized formulation F3 consisting of 18% Pluronic F-127 with 0.2% HPMC and 0.2% SA was characterized based on various physicochemical properties. The gelation temperature of F3 was found to be 29.0 ± 0.50 °C with a gelation time of 1.35 ± 0.40 min and a pH of 5.8. F3 had the viscosity of 178.50 ± 5.50 cP at 25 °C and 7800 ± 200 cP at 37 °C as the gel set. The optimized formulation was found to be bioadhesive and cytocompatible. Cumulative drug release was 65.05% within the time-frame of 8 h; the release pattern of the drug followed zero-order kinetics with the Higuchi release mechanism. The average zone of inhibition was found to be 43.44 ± 1.34 mm. The properties of F3 formulation reflect to improve residence time at the site of application and can enhance sustained drug release. Therefore, it could be concluded that optimized formulation has better retention and enhanced antimicrobial activity for superior efficacy against HS.

Nanoparticulate ophthalmic drug delivery of norfloxacin to prevent ocular infection after cataract surgery: Evaluation in animal model

Post cataract surgery, patients generally experience bacterial infection called endophthalmitis which is considered as potent blinding complication. This infection arises from the colonization of Staphylococcus epidermidis on the newly implanted lense. To overcome this problem, we developed nanoparticulate ophthalmic drug delivery of Norfloxacin to prevent ocular infection after cataract surgery. Sustained release Norfloxacin loaded polymeric nanoparticles were developed by high pressure homogenization method. The nanoparticles were characterized for particle size, zeta potential, polydispersity index (PDI), encapsulation efficiency (EE), in vitro Norfloxacin release and surface characteristics using scanning electron microscopy (SEM). The optimized nanoparticulate formulation was further used for the development of thermoreversible ophthalmic gel using poloxamer polymer. The formulated ophthalmic gel was evaluated for gelation temperature, pH, bioadhesiveness, and in vitro corneal permeation study. The antibacterial efficacy testing of thermoreversible gel was assessed in animal model (rabbit) infected with Staphylococcus epidermidis. At the end of study period the inhibitory effect of thermoreversible gel was determined on test animals. The antibacterial effects were compared with control group and plain thermoreversible gel (without nanoparticle formulation). The optimized nanoparticulate formulation of Norfloxacin showed slow and gradual sustained release over the period of 72 hours, encapsulation efficiency of between 90.12 to 98.50%, particle size 95–210 nm, PDI 0.18 to 0.212 and zeta potential between 20 to 25 mV. The nanoparticles were found spherical and smooth in nature. The optimized formulation of nanoparticle was used in thermoreversible gel. The results obtained showed that the thermoreversible gel was clear and transparent (prime requirement for ophthalmic product) with high gelling capacity and moderately viscous liquid (1170 cp), highest bioadhesive strength of 2312.90 dyne/cm2. The exvivo corneal study showed excellent permeation through cornea as compare to control sample. Norfloxacin released from thermoreversible gel killed Staphylococcus epidermidis in animal models as compare to control group and showed effect up to 14 days. With these findings, we demonstrate a new and effective system for sustained drug release of Norfloxacin from thermoreversible gel with specific application to prevent ocular infection after cataract surgery.

Thermoreversible Gelation with Two-Component Mixed Cross-Link Junctions of Variable Multiplicity in Ternary Polymer Solutions.

Theoretical scheme is developed to study thermoreversible gelation interfering with liquid–liquid phase separation in mixtures of reactive f-functional molecules R{A} and g-functional ones R{B} dissolved in a common solvent. Formed polymer networks are assumed to include multiple cross-link junctions containing arbitrary numbers and of functional groups A and B of each species. Sol-gel transition lines and spinodal lines are drawn on the ternary phase plane for some important models of multiple cross-link junctions with specified microscopic structure. It is shown that, if the cross-link structure satisfies a certain simple condition, there appears a special molar ratio of the two functional groups at which gelation takes place with a lowest concentration of the solute molecules, as has been often observed in the experiments. This optimal gelation concentration depends on f and g (functionality) of the solute molecules and the numbers and (multiplicity) of the functional groups in a cross-link junction. For cross-links which allow variable multiplicity, special attention is paid on the perfectly immiscible cross-links leading to interpenetrating polymer networks, and also on perfectly miscible cross-links leading to reentrant sol-gel-sol transition. Results are compared with recent observations on ion-binding polymer solutions, polymer solutions forming recognizable biomolecular complexes, polymer/surfactant mixtures, hydrogen-bonding polymers, and hydrophobically-modified amphiphilic water-soluble polymers.