Porous composite hydrogels with improved MSC survival for robust epithelial sealing around implants and M2 macrophage...

The application of mesenchymal stem cell (MSC)-based therapy is expected to make a significant contribution to the improvement of epithelial sealing around implants. However, there is currently no optimal MSC delivery biomaterial for clinical application in peri-implant epithelium (PIE) integration. In this study, we show that injectable photo-cross-linkable porous gelatin methacryloyl (GelMA)/silk fibroin glycidyl methacrylate (SilMA) hydrogels encapsulating gingival tissue-derived MSCs (GMSCs) are a simple and practical approach for re-epithelization applications. The hydrogels played a prominent role in supporting the proliferation, survival, and spread of GMSCs. Moreover, it was found that GMSCs-laden Porous GelMA/SilMA hydrogels could significantly upregulate the hemidesmosomes (HDs)-related genes and proteins expression and promote M2 polarization while inhibiting M1 polarization in vitro. Based on a rat model of early implant placement, application of the MSC-loaded hydrogels could enhance the protein expression of LAMA3 and BP180 (COL17A1) at the implant-PIE interface and reduce horseradish peroxidase (HRP) penetration between the implants and PIE. Noticeably, hydrogel-based MSC therapy contributed to augmenting M2 macrophage infiltration at two time points in the gingival connective tissue around implants. These findings demonstrated that GMSCs-laden Porous GelMA/SilMA hydrogels could facilitate epithelial sealing around implants and M2-polarized macrophages and may be a novel and facile therapeutic strategy for implant-PIE integration. STATEMENT OF SIGNIFICANCE: In the case of poor integration between the implant and gingival epithelium, peri-implantitis can develop, which is one of the main causes of implant failure. While stem cell therapy has tremendous potential for addressing this issue, poor cell survival and engraftment compromise the effectiveness of the therapy. Due to the excellent modifiable and tunable properties of gelatin and silk fibroin, injectable photo-cross-linkable porous hydrogels were developed using gelatin methacryloyl (GelMA) and silk fibroin glycidyl methacrylate (SilMA) as delivery vehicles for gingiva-derived MSCs (GMSCs). Porous GelMA/SilMA not only enhanced the proliferation and viability of GMSCs but also promoted their immunomodulatory capability for favorable epithelial sealing around implants. Overall, GMSCs-seeded porous hydrogels could be promising strategies for re-epithelization treatment.