Caffeine-catalyzed gels

Abstract

Covalently cross-linked gels are utilized in a broad range of biomedical applications though their synthesis often compromises easy implementation. Cross-linking reactions commonly utilize catalysts or conditions that can damage biologics and sensitive compounds, producing materials that require extensive post processing to achieve acceptable biocompatibility. As an alternative, we report a batch synthesis platform to produce covalently cross-linked materials appropriate for direct biomedical application enabled by green chemistry and commonly available food grade ingredients. Using caffeine, a mild base, to catalyze anhydrous carboxylate ring-opening of diglycidyl-ether functionalized monomers with citric acid as a tri-functional crosslinking agent we introduce a novel poly(ester-ether) gel synthesis platform. We demonstrate that biocompatible Caffeine Catalyzed Gels (CCGs) exhibit dynamic physical, chemical, and mechanical properties, which can be tailored in shape, surface texture, solvent response, cargo release, shear and tensile strength, among other potential attributes. The demonstrated versatility, low cost and facile synthesis of these CCGs renders them appropriate for a broad range of customized engineering applications including drug delivery constructs, tissue engineering scaffolds, and medical devices.

Keywords: Biocompatible materials; Green-chemistry; Shape-changing thermosets.

Scheme 1

Three variations of CCGs synthesized via caffeine catalyzed crosslinking of citric acid with different diglycidyl functionalized oligomers. Caffeine is used to catalyze CCG formation via deprotonation of citric acid and epoxide ring opening of diglycidyl ether functionalized oligomers of PEG and PPO.

Fig. 1

Overview of gel synthesis and processing. a) General one-pot synthesis of caffeine catalyzed poly(ester-ether) gels. b) Different gels shaped by casting the viscous material at its gel point into 3D silicon molds. Scale bar, 10 mm. c) Demonstration of time in hours required to fully reshape a linear rectangle into a curled object by applying external stress and incubating at 90 °C. d) SEM of a CCG surface texturized using a lotus leaf mold to mimic the micro-post structures with high resolution. Micro-posts were analyzed for 3 different classes of CCGs in 3 different sections of the molded structure. Scale bar, 10 μm. Stacked e) FT-IR of the direct polymerization mixture in liquid form and f) ¹H NMR spectra in CDCl₃ showing gel formation for PEG.CA via the appearance of the signature ester peak at 1755 cm⁻¹ (#) and disappearance of the carboxylic acid peak at 12.5 ppm (*), respectively from t = 0–600 min of the reaction. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Hydration dynamics of three chemically different CCGs. Static contact angles (mean ± s.d., n = 8) using dH₂O on the surface of silicon molded CCGs with a) no specific texturing or b) lotus textured surfaces. c) Scanning electron microscopy (SEM) images of CCGs molded on a lotus leaf textured mold. Scale bar, 50 μm. d) Mass change of CCGs incubated in simulated biological fluids (simulated gastric fluid (SGF), simulated intestinal fluid (SIF), phosphate buffered saline (PBS)) and organic solvents (EtOH, EtOAc, hexanes) for 24 h e) Hydration kinetics of CCGs in simulated biological fluids at 37 °C as measured by % mass change. In both d) and e) error bars correspond to the standard deviation of 3 samples per condition. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Tensile, compressive, and shear mechanical properties. a) Tensile test, b) compression test, and c) shear test indicating the range of mechanical properties of the CCGs and represent average values of three structures per testing condition. d) Summary of mechanical properties. Mean values are provided in bold and standard deviations are in brackets. e) Change in the tensile strength of the specimen before and after rupture test. Error bars correspond to the standard deviation of 10 samples per condition. f) SEM image of ruptured (left) and self-healed (right) specimen. Scale bar, 500 μm.

Fig. 4

In vitro and in vivo toxicity. a)In vitro cytotoxicity on HeLa, HEK293, HT29-MTX-E12, and C2BBe1 cell lines. LC₅₀ values are noted in the graph. Error bars correspond to the standard deviation of n = 8 biological replicates per condition. b) Histology of extracted organs post oral administration of CCGs to n = 3 rats per condition. Scale bar, 1 mm.

Fig. 5

In vitro drug release. Release kinetics of a) 4 kDa and b) 40 kDa FITC-dextran as well as c) piperaquine from CCGs into simulated gastrointestinal fluids. e) Release kinetics of artesunate measured in pH adjusted isopropanol/acetone/water mixture (IAW). f) Molecular description of proposed drug loading reaction showing potential for retention of artesunate to be covalently incorporated into the CCG network directly through a labile ester bond. Error bars correspond to the standard deviation of 3 samples per condition.