Thermosensitive, fast gelling, photoluminescent, highly flexible, and degradable hydrogels for stem cell delivery

Abstract

Stem cell therapy is a promising approach to regenerate ischemic cardiovascular tissues yet experiences low efficacy. One of the major causes is inferior cell retention in tissues. Injectable cell carriers that can quickly solidify upon injection into tissues so as to immediately increase viscosity have potential to largely improve cell retention. A family of injectable, fast gelling, and thermosensitive hydrogels were developed for delivering stem cells into heart and skeletal muscle tissues. The hydrogels were also photoluminescent with low photobleaching, allowing for non-invasively tracking hydrogel biodistribution and retention by fluorescent imaging. The hydrogels were polymerized by N-isopropylacrylamide (NIPAAm), 2-hydroxyethyl methacrylate (HEMA), 1-vinyl-2-pyrrolidinone (VP), and acrylate-oligolactide (AOLA), followed by conjugation with hypericin (HYP). The hydrogel solutions had thermal transition temperatures around room temperature, and were readily injectable at 4 °C. The solutions were able to quickly solidify within 7 s at 37 °C. The formed gels were highly flexible possessing similar moduli as the heart and skeletal muscle tissues. In vitro, hydrogel fluorescence intensity decreased proportionally to weight loss. After being injected into thigh muscles, the hydrogel can be detected by an in vivo imaging system for 4 weeks. The hydrogels showed excellent biocompatibility in vitro and in vivo, and can stimulate mesenchymal stem cell (MSC) proliferation and paracrine effects. The fast gelling hydrogel remarkably increased MSC retention in thigh muscles compared to slow gelling collagen, and non-gelling PBS. These hydrogels have potential to efficiently deliver stem cells into tissues. Hydrogel degradation can be non-invasively and real-time tracked. STATEMENT OF SIGNIFICANCE: Low cell retention in tissues represents one of the major causes for limited therapeutic efficacy in stem cell therapy. A family of injectable, fast gelling, and thermosensitive hydrogels that can quickly solidify upon injection into tissues were developed to improve cell retention. The hydrogels were also photoluminescent, allowing for non-invasively and real-time tracking hydrogel biodistribution and retention by fluorescent imaging.

Keywords: Cell retention; Fast gelling hydrogels; Photoluminescent hydrogels; Real-time cell tracking; Stem cell therapy.