Proinflammatory cytokines are infamous for their catabolic effects on tissues and joints in both inflammatory diseases and following the implantation of biomedical devices. However, recent studies indicate that many of these same molecules are critical for triggering tissue regeneration following injury. This review will discuss the role of inflammatory signals in regulating bone regeneration and the impact of both immunomodulatory and antiinflammatory pharmacologic agents on fracture healing, to demonstrate the importance of incorporating rational control of inflammation into the design of tissue engineering strategies.

The dose effect of dual delivery of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2) on bone regeneration was investigated in a rat cranial critical-size defect (CSD). It was hypothesized that decreasing amounts of BMP-2 would result in a dose-dependent decrease in bone formation, and that this reduction in bone formation could be reversed by adding increasing amounts of VEGF. In vitro release kinetics of VEGF or BMP-2 were examined over 28 days. Next, scaffolds were implanted within a rat cranial CSD containing different combinations of both BMP-2 and VEGF. At 12 weeks, samples were analyzed using microcomputed tomography and histology. In vitro, VEGF and BMP-2 exhibited burst release in the first 24 h followed by a significant decrease in release rate over 27 days. Overall, BMP-2 had a more sustained release versus VEGF. An in vivo dose-dependent decrease in percentage of bone fill (PBF) was observed for BMP-2. The addition of VEGF was unable to reverse this decrease in PBF, although improvements in the number of bridged defects did occur in some groups. This suggests that for this particular model simultaneous release of BMP-2 and VEGF does not increase bone formation over BMP-2 alone at 12 weeks.

No abstract

This study presents a first step in the development of a bone tissue engineering strategy to trigger enhanced osteogenesis by modulating inflammation. This work focused on characterizing the effects of the concentration of a pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α), on osteogenic differentiation of mesenchymal stem cells (MSCs) grown in a 3D culture system. MSC osteogenic differentiation is typically achieved in vitro through a combination of osteogenic supplements that include the anti-inflammatory corticosteroid dexamethasone. Although simple, the use of dexamethasone is not clinically realistic, and also hampers in vitro studies of the role of inflammatory mediators in wound healing. In this study, MSCs were pre-treated with dexamethasone to induce osteogenic differentiation, and then cultured in biodegradable electrospun poly(ε-caprolactone) (PCL) scaffolds, which supported continued MSC osteogenic differentiation in the absence of dexamethasone. Continuous delivery of 0.1 ng/mL of recombinant rat TNF-α suppressed osteogenic differentiation of rat MSCs over 16 days, which was likely the result of residual dexamethasone antagonizing TNF-α signaling. Continuous delivery of a higher dose, 5 ng/mL TNF-α, stimulated osteogenic differentiation for a few days, and 50 ng/mL TNF-α resulted in significant mineralized matrix deposition over the course of the study. These findings suggest that the proinflammatory cytokine TNF-α stimulates osteogenic differentiation of MSCs, an effect that can be blocked by the presence of anti-inflammatory agents like dexamethasone, with significant implications on the interplay between inflammation and tissue regeneration.

Proinflammatory cytokines are infamous for their catabolic effects on tissues and joints in both inflammatory diseases and following the implantation of biomedical devices. However, recent studies indicate that many of these same molecules are critical for triggering tissue regeneration following injury. This review will discuss the role of inflammatory signals in regulating bone regeneration and the impact of both immunomodulatory and antiinflammatory pharmacologic agents on fracture healing, to demonstrate the importance of incorporating rational control of inflammation into the design of tissue engineering strategies.