An Investigation for Skin Tissue Regeneration Enhancement/Augmentation by Curcumin-Loaded Self-Emulsifying Drug Delivery System (SEDDS)

Abstract

Diabetes, one of the global metabolic disorders, is often associated with delayed wound healing due to the elevated level of free radicals at the wound site, which hampers skin regeneration. This study aimed at developing a curcumin-loaded self-emulsifying drug delivery system (SEDDS) for diabetic wound healing and skin tissue regeneration. For this purpose, various curcumin-loaded SEDDS formulations were prepared and optimized. Then, the SEDDS formulations were characterized by the emulsion droplet size, surface charge, drug content/entrapment efficiency, drug release, and stability. In vitro, the formulations were assessed for the cellular uptake, cytotoxicity, cell migration, and inhibition of the intracellular ROS production in the NIH3T3 fibroblasts. In vivo, the formulations' wound healing and skin regeneration potential were evaluated on the induced diabetic rats. The results indicated that, after being dispersed in the aqueous medium, the optimized SEDDS formulation was readily emulsified and formed a homogenous dispersion with a droplet size of 37.29 ± 3.47 nm, surface charge of -20.75 ± 0.07 mV, and PDI value of less than 0.3. The drug content in the optimized formulation was found to be 70.51% ± 2.31%, with an encapsulation efficiency of 87.36% ± 0.61%. The SEDDS showed a delayed drug release pattern compared to the pure drug solution, and the drug release rate followed the Fickian diffusion kinetically. In the cell culture, the formulations showed lower cytotoxicity, higher cellular uptake, and increased ROS production inhibition, and promoted the cell migration in the scratch assay compared to the pure drug. The in vivo data indicated that the curcumin-loaded SEDDS-treated diabetic rats had significantly faster-wound healing and re-epithelialization compared with the untreated and pure drug-treated groups. Our findings in this work suggest that the curcumin-loaded SEDDS might have great potential in facilitating diabetic wound healing and skin tissue regeneration.

Keywords: curcumin; diabetic wound; nanomedicine; self-emulsifying drug delivery system (SEDDS); skin regeneration; wound healing.

Figure 1

Droplet size (A), PDI (B), and zeta potential, and (C) results of the optimized SEDDS.

Figure 2

The in vitro drug release profile of curcumin-loaded SEDDS formulations.

Figure 3

Effects of the dilution and buffer pH on the droplet size of SEDDS (A) pH 5.5, (B) pH 6.5, (C) pH 7.4, and (D) pH 8.5.

Figure 4

Effects of the dilution and buffer pH on the PDI of SEDDS (A) pH 5.5, (B) pH 6.5, (C) pH 7.4, and (D) pH 8.5.

Figure 5

Drug contents of the curcumin-loaded SEDDS over the long-term storage (*** p < 0.001, and ** p < 0.05) compared to F1, F2, and F3 on day 0.

Figure 6

The cell viability results of the curcumin-loaded SEDDS in NIH3T3 cells.

Figure 7

Cell migration upon the curcumin-loaded SEDDS treatment.

Figure 8

The intracellular ROS level determined by H₂DCFDA in NIH3T3 cells. (FI = fluorescence intensity).

Figure 9

Cellular uptake of the curcumin-loaded SEDDS (F3 formulation) in NIH3T3 fibroblasts, determined by FACS. (A) one-hour cell incubation at different doses of F3 SEDDS; (B) four-hour cell incubation at different doses of F3 SEDDS; (C) time-dependent uptake of F3 SEDDS at 100 µg/mL curcumin dose; (D) F3 SEDDS vs. pure drug at 10 µg/mL curcumin after 1 h cell incubation; (E), F3 SEDDS vs. pure drug at 100 µg/mL after 4 h cell incubation; and (F) fluorescence microscopy images. F10: F3 SEDDS at 10 µg/mL curcumin. F100: F3 SEDDS at 100 µg/mL curcumin.

Figure 10

Photos of skin wounds upon treatment in the diabetic rats.

Figure 11

(A) Wound sizes (mm²) and (B) percentage re-epithelialization in the diabetic rats upon treatment.