Encapsulation of MSCs and GDNF in an Injectable Nanoreinforced Supramolecular Hydrogel for Brain Tissue Engineering

Abstract

The co-administration of glial cell line-derived neurotrophic factor (GDNF) and mesenchymal stem cells (MSCs) in hydrogels (HGs) has emerged as a powerful strategy to enhance the efficient integration of transplanted cells in Parkinson's disease (PD). This strategy could be improved by controlling the cellular microenvironment and biomolecule release and better mimicking the complex properties of the brain tissue. Here, we develop and characterize a drug delivery system for brain repair where MSCs and GDNF are included in a nanoparticle-modified supramolecular guest−host HA HG. In this system, the nanoparticles act as both carriers for the GDNF and active physical crosslinkers of the HG. The multifunctional HG is mechanically compatible with brain tissue and easily injectable. It also protects GDNF from degradation and achieves its controlled release over time. The cytocompatibility studies show that the developed biomaterial provides a friendly environment for MSCs and presents good compatibility with PC12 cells. Finally, using RNA-sequencing (RNA-seq), we investigated how the three-dimensional (3D) environment, provided by the nanostructured HG, impacted the encapsulated cells. The transcriptome analysis supports the beneficial effect of including MSCs in the nanoreinforced HG. An enhancement in the anti-inflammatory effect of MSCs was observed, as well as a differentiation of the MSCs toward a neuron-like cell type. In summary, the suitable strength, excellent selfhealing properties, good biocompatibility, and ability to boost MSC regenerative potential make this nanoreinforced HG a good candidate for drug and cell administration to the brain.

Developing hydrogels for gene therapy and tissue engineering

“…The former is like Parkinson’s disease (PD) and involves lesions located in the substantia nigra and nigrostriatal pathways, whereas the latter is like chorea, bradykinesia, and torsion spasticity, and involves lesions located in the striatum [ 233 , 234 ]. Hydrogels combined with MSCs, and glial cell line-derived neurotrophic factor (GDNF) are good materials for the delivery of cellular drugs and the treatment of PD [ 235 ]. RNAi-loaded plasmid nanoparticles achieved effective repair in a PD model (Fig.…”

Enhancing Immunomodulatory Function of Mesenchymal Stromal Cells by Hydrogel Encapsulation

“…The nanoparticles served to reinforce the HA hydrogel and ensure the slow release of GDNF. The encapsulated MSCs showed an elevated expression of genes in immunomodulatory IL-4, IL-13, and IL-10 pathways, as well as the IL-11 gene [122] (Table 1).…”

Hemostatic Tranexamic Acid-Induced Fast Gelation and Mechanical Reinforcement of Polydimethylacrylamide/Carboxymethyl Chitosan Hydrogel for Hemostasis and Wound Healing

“…Injectable hydrogel is a kind of hydrogel material that can be injected in vitro and rapidly gelate in vivo , possessing the unique advantages of filling irregular wounds, enabling minimally invasive transplantation, and encapsulating cells, drugs, and bioactive molecules. − As such, it has broad application prospects in rapid hemostasis, wound dressings, 3D cell culture, and targeted drug delivery . Particularly, many injectable hydrogels have been developed for hemorrhage control and wound healing, , which are essential for traumatic or surgical injuries to reduce life-threatening complications.…”