Progress in Composite Hydrogels and Scaffolds Enriched with Icariin for Osteochondral Defect Healing

Abstract

Osteochondral structure reconstruction by tissue engineering, a challenge in regenerative medicine, requires a scaffold that ensures both articular cartilage and subchondral bone remodeling. Functional hydrogels and scaffolds present a strategy for the controlled delivery of signaling molecules (growth factors and therapeutic drugs) and are considered a promising therapeutic approach. Icariin is a pharmacologically-active small molecule of prenylated flavonol glycoside and the main bioactive flavonoid isolated from Epimedium spp. The in vitro and in vivo testing of icariin showed chondrogenic and ostseoinductive effects, comparable to bone morphogenetic proteins, and suggested its use as an alternative to growth factors, representing a low-cost, promising approach for osteochondral regeneration. This paper reviews the complex structure of the osteochondral tissue, underlining the main aspects of osteochondral defects and those specifically occurring in osteoarthritis. The significance of icariin's structure and the extraction methods were emphasized. Studies revealing the valuable chondrogenic and osteogenic effects of icariin for osteochondral restoration were also reviewed. The review highlighted th recent state-of-the-art related to hydrogels and scaffolds enriched with icariin developed as biocompatible materials for osteochondral regeneration strategies.

Keywords: bone morphogenetic proteins; cartilage; flavonoids; hydrogel; osteoarthritis; osteochondral defect.

Figure 1

Types of cartilage defects. Partial thickness defect develops only in the articular cartilage. In full-thickness defect, the subchondral bone plate is exposed, but not disturbed. The osteochondral defect develops in the cartilage and subchondral bone.

Figure 2

Chemical structure of icariin.

Figure 3

Icariin’s effect on bone marrow stem cells (BMSCs) as a promoter of bone formation and a potential accelerator of chondrogenesis via different signaling pathways. Icariin exerts an osteogenic effect by promoting the expression of osteoblastic specific genes, bone morphogenetic proteins (BMP-2, BMP-4), SMAD4, RUNX2, osteoprotegerin (OPG), alkaline phosphatase (ALP), collagen type I (COL I), osteocalcin (OCN) and the downregulation of the receptor activator of nuclear factor kappa-B ligand (RANKL). Icariin also upregulates calcium deposition and bone nodule formation. Its chondrogenic effect is due to the upregulated expression of SRY-Box transcription factor 9 (SOX9), collagen type II (COL II), aggrecan (AGG), and the downregulation of COL I. It also serves as an activator of hypoxia-inducible factors (HIF-1α and HIF-2α) and several metalloproteinases (MMP) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) in chondrocytes.

Figure 4

Types of functional composite biomaterials conditioned as hydrogel, containing bioceramics or bioglasses for controlled delivery of icariin are a promising therapeutic approach in osteochondral defect reconstruction.