Local induction of inflammation affects bone formation

Abstract

To explore the influence of inflammatory processes on bone formation, we applied a new in vivo screening model. Confined biological pockets were first created in rabbits as a response to implanted bone cement discs. These biomembrane pockets were subsequently used to study the effects of inflammatory stimuli on ectopic bone formation within biphasic calcium phosphate (BCP) constructs loaded with TNF-α, lipopolysaccharide (LPS) or lipoteichoic acid (LTA), all with or without bone morphogenetic protein (BMP)-2. Analysis of bone formation after 12 weeks demonstrated that the inflammatory mediators were not bone-inductive in combination with the BCP alone, but inhibited or enhanced BMP-induced bone formation. LPS was associated with a strong inhibition of bone formation by BMP-2, while LTA and TNF-α showed a positive interaction with BMP-2. Since the biomembrane pockets did not interfere with bone formation and prevented the leakage of pro-inflammatory compounds to the surrounding tissue, the biomembrane model can be used for in vivo approaches to study local inflammation in conjunction with new bone formation. Using this model, it was shown that the modulation of the inflammatory response could be beneficial or detrimental to the subsequent bone formation process. The co-delivery of inflammatory factors and bone-related growth factors should be further explored as a strategy to enhance the bone-forming efficacy of bone substitutes.

Releasing Behavior of Lipopolysaccharide from Gelatin Modulates Inflammation, Cellular Senescence, and Bone Formation in Critical-Sized Bone Defects in Rat Calvaria

“…This dose is far less than the LD50 (3 mg/kg) [36]. Previous studies utilized 345 to 17,253 times more LPS compared to our doses in vivo [17,18,46], which apparently hampered bone formation [18,46]. As with these studies, in our study, although LR-G rereleased LPS immediately, bone formation was still delayed for 1 week, which might due to the temporal burst effect (inducing high dose of LPS).…”

Impact of Bacterial Infections on Osteogenesis: Evidence From In Vivo Studies

“…Only under mild inflammatory conditions may pro‐inflammatory cytokines or bacteria‐derived antigens promote osteoblast differentiation in resident bone‐lining or recruited osteoprogenitor cells. In line with this hypothesis, it has been shown that a transient inflammatory reaction to a low‐dose of bacterial stimuli promotes periosteal or ectopic bone formation, but that the sustained inflammation caused by a high‐dose of bacterial stimuli leads to predominantly osteolysis or impaired ectopic bone formation …”

“…95 To illustrate, the proinflammatory cytokines TNF-α and interleukin (IL)-17 are upregulated during bacterial infection, 22 and their transient expression is known to have pro-osteogenic effects on osteoprogenitor cells. 50,100,102,103 On the other hand, increased cell death, comprised vascularization, and uncontrolled osteoclast activity will be most profound in the vicinity of the bacterial burden. 1,7,14,15,17 Moreover, the increased influx of immune cells can lead to the production of soluble factors hampering osteogenesis.…”

“…In line with this hypothesis, it has been shown that a transient inflammatory reaction to a low-dose of bacterial stimuli promotes periosteal or ectopic bone formation, but that the sustained inflammation caused by a high-dose of bacterial stimuli leads to predominantly osteolysis or impaired ectopic bone formation. 39,49,50,115 Of final note, the current review shows that most of the in vivo bone infection studies have used rodent models. On the one hand, different forms of osteosynthesis can be applied in rodents, 91 with many research tools available for rodents to study the cellular and molecular aspects of bone healing.…”

Combating Implant Infections: Shifting Focus from Bacteria to Host

“…[324][325][326] From a different perspective, there is evidence to support that the heightened inflammatory response resulting from immune training could exacerbate biomaterial-related inflammation and fibrosis, whereas LPS could act prophylactically to inflammatory fibrosis. [325] In the same line of reasoning, PRR ligands can differently impact the osteogenic response, [327][328][329][330][331] and it should be elucidated whether proosteogenic adjuvants also render implants with anti-infective properties. As a potential caveat, the innate immune training concept takes its advantage form the metabolic programming of host cells.…”