Hierarchical Delivery of Anti-Inflammatory Compound and Stem Cells for Chronic Wounds

Background: Chronic wounds, especially in diabetic patients, pose a significant clinical challenge due to current treatment limitations and an increasingly affected population. A major issue is the stalled inflammatory phase, which prevents proper healing. This study developed a novel co-delivery system to address the deficiency of growth factors and persistent inflammation in chronic wounds. Methods: Gelatin nanoparticles (NPs) were synthesized to carry curcumin, an anti-inflammatory compound. These curcumin-loaded NPs (NP/Curc) were then incorporated into gelatin methacrylate (GelMA) hydrogels to form a hierarchical delivery construct, nanoparticles encased within a hydrogel. These hydrogels were then cryogenically milled into microparticles (MPs) to carry human mesenchymal stem cells (hMSCs). The viability and growth of hMSCs on the surface of curcumin-loaded MPs were evaluated. The release of curcumin from various MP configurations was analyzed. The anti-inflammatory effects of the MPs were assessed by measuring pro-inflammatory cytokine expression in human monocyte THP-1 cells. Results: Curcumin directly loaded into hydrogels showed a rapid burst release within three days. In contrast, NP/Curc had a more sustained release profile. Curcumin incorporation did not adversely affect the cell-carrier functions of MPs. Conditioned media from hMSCs cultured on the plain MPs demonstrated anti-inflammatory effects in THP-1 cells. Low doses of curcumin released from the MPs also showed anti-inflammatory activity. The combination of hMSCs and curcumin exhibited an additive effect in reducing IL-8 expression by 4× in THP-1 cells. Conclusions: This study demonstrates the feasibility of co-delivering cells and curcumin without compromising the cell viability of hMSCs. Using gelatin nanoparticles as a carrier prolongs curcumin release, offering a sustained therapeutic effect. This strategy of hierarchical delivery of curcumin and co-delivery of cells represents a promising approach for treating chronic wounds by simultaneously providing growth factors and reducing inflammation.