# Natural Powerhouse Duo: Hierarchical Levan Hydrogels with Nanoencapsulated Cannabidiol as Local Delivery Systems

## TL;DR

Researchers created a new hydrogel system to deliver cannabidiol (CBD) for wound healing, showing it can release CBD effectively and support cell viability.

## Contribution

A novel hierarchical levan hydrogel system with nanoencapsulated CBD is developed for sustained local drug delivery.

## Key findings

- CBD-loaded hydrogels showed a burst release followed by sustained release over 72 hours.
- CBD-loaded hydrogels supported >70% viability of gingival mesenchymal stem cells over 28 days.
- CBD-loaded hydrogels promoted adipogenic differentiation, while non-loaded ones supported osteogenic differentiation transiently.

## Abstract

The nonpsychoactive cannabinoid cannabidiol (CBD) has shown a wide range of pharmacological effects that are beneficial for wound healing. However, its local delivery is challenged by a very low aqueous solubility.

In this work, we synthesized hierarchical hydrogels made of the fructan hydrolyzed levan crosslinked with glycerol diglycidyl ether and loaded them with CBD nanoencapsulated within Pluronic® F127 polymeric micelles (25% w/w payload).

Hydrogels showed the typical porous structure (high resolution-scanning electron microscopy) and water uptake capacity up to ~ 1700%. The CBD release kinetics was studied in water (pH 6.8) and phosphate buffered saline (pH 7.4) under sink conditions, at 37°C. An initial burst release stage within the first 2 h of the assay was followed by a more sustained release stage over 72 h. As expected, hydrogels with a lower crosslinking density exhibited faster CBD release in both media. Release data fit the Korsmeyer-Peppas model with a combined mechanism involving diffusion and polymer chain relaxation together with the release of CBD-loaded polymeric micelles. The good compatibility of the hydrogels was initially confirmed in the monocyte-derived human macrophage cell line THP-1 over 72 h. Then, we showed > 70% viability of primary patient-derived gingival mesenchymal stem cells (GMSCs) exposed to hydrolyzed levan solutions, CBD-loaded polymeric micelle suspensions, and the CBD-loaded hydrogels for 28 days. Finally, we conducted preliminary differentiation studies of GMSCs cultured on non-loaded and CBD-loaded hydrolyzed levan hydrogels. Non-loaded hydrogels promote a transient increase in the secretion of the osteogenic marker alkaline phosphatase secretion that peaked at day 7 and declined thereafter, while CBD-loaded ones promote adipogenic differentiation.

Overall, results demonstrate the potential of levan hydrogels as platforms for local drug delivery applications.