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ICE Krakow

ICE Krakow

ul. Marii Konopnickiej 17 30-302 Kraków


Rossi, Arianna (1. Institute of Science and Technology for Ceramics (Istec- Research National Council) 2. University of Messina )


Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) play an important role in cell physiology, cell-cell communication, and immunomodulation. EVs are promising for regenerative medicine1, but their therapeutic effect in vivo is reduced due to their rapid clearance and short half-life2.
Injectable hydrogels emerged as great bioactive compound carriers due to their ability to mimic the extracellular matrix (ECM) and provide an accurate control on release3. These systems can be made of different polymers, including gellan gum (GG), a biocompatible bacteria-derived polysaccharide4.
In the present work, we develop a novel delivery system consisting of a gellan gum-based hydrogel to achieve a controlled release of EVs derived from human adipose mesenchymal stem cells (hA-MSC). We then evaluated the cross-talk between the EVs, hA-MSC, rat hippocampal neural stem cells (rH-NSC), and human skin fibroblasts (WS1).

Gellan gum-based hydrogels were fabricated by using bivalent ions, including magnesium and calcium ions. The resulting system was also implemented with hyaluronic acid (HA) (weight ratio between GG and HA from 1:4 to 1:1) and spermidine (ratio between polymers and spermidine equal to 1:5), a biocompatible crosslinking agent able to enhance the hydrogel stability and endowed with anti-inflammatory properties5. The resulting samples were characterized using rheology to evaluate the gelation time and mechanical properties, the stability and the swelling ability of hydrogels were investigated up to 21 days after the incubation in physiological-like conditions.
EVs were isolated from hA-MSC by an ultracentrifugation protocol6 and loaded within the hydrogels7. To evaluate hydrogel biocompatibility a preliminary screening on rH-NSC, WS1, and hA-MSC was performed analyzing cell viability and cell morphology up to 7 days. In addition, MSCs-derived EVs release from the hydrogel, and the resulting cross-talk effect was tested by real-time PCR.

The hydrogels showed a dependence of gelation time, stability, mechanical properties, and swelling degree on their composition. Hydrogels exhibited good biocompatibility without affecting cell viability and morphology of all the screened cell cultures. MSCs-derived EVs were homogenously embedded into the hydrogel without negatively affecting the gelation kinetic and they were released in a sustained and controlled way, additionally, they maintained their structure and bioactivity enhancing the cell viability.

In the current work, we developed a fully bioresorbable and biocompatible controlled delivery system for EVs. This system is able to overcome issues that normally are faced in vivo. In fact, it might prolong the retention of EVs and maximize the localized benefit in situ. The resulting system displayed good biocompatibility on human fibroblasts, hA-MSC, and rH-NSC and is a promising system for several regenerative medicine applications.

  1. Elsharkasy, O. M. et al., Adv. Drug Deliv. Rev. 159,332-343 (2020).

  2. Imai, T. at al., J. Extracell. Vesicles. 4,26238 (2015).

  3. Grimaudo, M. A. et al., Acta Biomater. 28,S1742-7061(21)00787-X (2021).

  4. Das, M. et al., J. of Drug Deliv. Sci. and Tech. 56,A101586 (2020).

  5. Liu. R. et al., Free Radic. Biol. Med. 161,339-350 (2020).

  6. Momen-Heravi, F., Methods Mol. Biol. 1660,25-32 (2017).

  7. Holkar, K. et al., ACS Biomater. Sci. Eng. 7(6),2687-2700 (2021).


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