# Total Flavonoids of Rhizoma drynariae Enhance Bone Marrow Mesenchymal Stem Cell-Mediated Tendon–Bone Healing by Promoting Tissue Regeneration, Angiogenesis, and Modulation of Cytokine Expression

## TL;DR

This study shows that a natural extract from Rhizoma drynariae, when combined with bone marrow stem cells, can improve healing of tendon-bone injuries by boosting tissue repair and blood vessel growth.

## Contribution

The study demonstrates a novel therapeutic strategy using TFRD and BMSCs to enhance tendon–bone healing and functional recovery.

## Key findings

- TFRD promotes BMSC proliferation, migration, and differentiation, and enhances blood vessel formation.
- Combining TFRD with BMSCs improves collagen alignment, cartilage formation, and mechanical strength at the healing site.
- TFRD modulates cytokine expression, reducing inflammation and improving the local healing environment.

## Abstract

Tendon–bone injuries are common in sports and often lead to poor recovery due to insufficient healing at the tendon–bone interface. Current surgical treatments can restore structure but rarely achieve full functional recovery. In this study, we explored how total flavonoids of Rhizoma drynariae (TFRD), a natural extract widely used in traditional Chinese medicine, can enhance the regenerative capacity of bone marrow mesenchymal stem cells (BMSCs) for tendon–bone repair. Through both cell experiments and a rat Achilles tendon injury model, we found that TFRD significantly promoted BMSC proliferation, migration, and differentiation, while also stimulating blood vessel formation and reducing local inflammation. When combined with BMSCs, TFRD improved collagen alignment, cartilage formation, and mechanical strength at the healing site. These findings provide experimental evidence that combining TFRD with BMSCs may represent an effective and safe therapeutic strategy for promoting tendon–bone interface regeneration and accelerating functional recovery after sports injuries.

(1) Objective: This study aimed to investigate the synergistic effect and underlying mechanisms of Total Flavonoids of Rhizoma drynariae (TFRD) in combination with Bone Marrow Mesenchymal Stem Cells (BMSCs) in the repair of tendon–bone injuries. (2) Methods: The effects of TFRD on the proliferation and migration of BMSCs were assessed using CCK-8 and scratch assays, and its potential to promote osteogenic and chondrogenic differentiation was evaluated. Concurrently, the pro-angiogenic effect of TFRD on Human Umbilical Vein Endothelial Cells (HUVECs) was observed. In vivo, a rat model of Achilles tendon–bone injury was established and animals were divided into four groups: SHAM, Model, BMSCs, and BMSCs + TFRD. After an 8-week intervention, the level of functional recovery was evaluated through histological analysis, immunohistochemistry, serum biochemical analysis, and biomechanical testing. (3) Results: A concentration of 5.0 μg/mL TFRD significantly promoted the proliferation, migration, and differentiation of BMSCs and enhanced the tube formation capacity of HUVECs. In the BMSCs + TFRD group, histological analysis revealed well-organized collagen fibers, increased cartilage deposition, and an optimized tendon–bone interface (TBI) structure. Immunohistochemistry showed upregulated expression of COL I, COL II, and SOX-9, alongside downregulated VEGFA. Furthermore, serum IL-6 levels were decreased, while IL-10 and TGF-β levels were elevated. The biomechanical properties were also significantly improved in this group. (4) Conclusions: TFRD promotes tendon–bone healing and functional recovery by enhancing BMSC functions, promoting angiogenesis, and improving the local microenvironment.