Synergistic anti-inflammatory and osteogenic n-HA/resveratrol/chitosan composite microspheres for osteoporotic bone regeneration

Abstract

The development of functional materials for osteoporosis is ultimately required for bone remodeling. However, grafts were accompanied by increasing pro-inflammatory cytokines that impaired bone formation. In this work, nano-hydroxyapatite (n-HA)/resveratrol (Res)/chitosan (CS) composite microspheres were designed to create a beneficial microenvironment and help improve the osteogenesis by local sustained release of Res. Study of in vitro release confirmed the feasibility of n-HA/Res/CS microspheres for controlled Res release. Notably, microspheres had anti-inflammatory activity evidenced by the decreased expression of pro-inflammatory cytokines TNF-α, IL-1β and iNOS in RAW264.7 cells in a dose dependent manner. Further, enhanced adhesion and proliferation of BMSCs seeded onto microspheres demonstrated that composite microspheres were conducive to cell growth. The ability to enhance osteo-differentiation was supported by up-regulation of Runx2, ALP, Col-1 and OCN, and substantial mineralization in osteogenic medium. When implanted into bone defects in the osteoporotic rat femoral condyles, enhanced entochondrostosis and bone regeneration suggested that the n-HA/Res/CS composite microspheres were more favorable for impaired fracture healing. The results indicated that optimized n-HA/Res/CS composite microspheres could serve as promising multifunctional fillers for osteoporotic bone defect/fracture treatment.

Advances in Osteoporotic Bone Tissue Engineering

“…Monocytes, neutrophils, and natural killer cells are also present in the affected site [ 19 ]. Inflammatory markers are the following cytokines: TNF-α, IL-1β and iNOS [ 20 ]. Osteogenesis, osteoclastogenesis, and angiogenesis are greatly regulated by immune cells and their signaling molecules [ 21 ].…”

“…Initial inflammatory action is necessary to start the bone healing process but persistent inflammatory action against the implant usually leads to granulation (formation of connective tissue) and formation of a fibrotic capsule around the implant with undesirable results [ 20 ] or increased healing time [ 22 ].…”

“…To counteract chronic inflammatory action against implants, anti-inflammatory factors such as corticosteroids and prostaglandins were investigated but adverse effects such as hepatotoxicity, cardiotoxicity, and immunological impairment in long-term use were reported. Extended inflammation may cause fibrosis, granuloma formation and further encapsulation and failure of the implant [ 20 ].…”

“…Surgery is the main treatment strategy, but poor results are obtained because of various biological and surgical factors, which makes it hard to achieve a stable fixation and the failure risk (refracturation) following surgery is significant [ 5 , 20 ]. Treating osteoporotic fractures is difficult because of the reduced healing capacity, which correlates for osteoporotic patients with a far higher (~50%) failure rate of implant fixation than against non-osteoporotic patients [ 67 ], making their implants prone to pull out and failure [ 7 ], as osseointegration is inhibited by osteoporosis [ 71 ].…”

“…Treating osteoporotic fractures is difficult because of the reduced healing capacity, which correlates for osteoporotic patients with a far higher (~50%) failure rate of implant fixation than against non-osteoporotic patients [ 67 ], making their implants prone to pull out and failure [ 7 ], as osseointegration is inhibited by osteoporosis [ 71 ]. Decreased bone mass [ 69 ], porous structure and low strength are linked to a reduced supporting ability of an implant [ 20 ].…”