Systemically administered omeprazole impairs bone healing and implant osseointegration.
Hydrogels composed of two-dimensional (2D) nanomaterials have become an important alternative to replace traditional inorganic scaffolds for tissue engineering. Here, we describe a novel nanocrystalline material with 2D morphology that was synthesized by tuning the crystallization of the sodium-magnesium-phosphate system. We discovered that the sodium ion can regulate the precipitation of magnesium phosphate by interacting with the crystal's surface causing a preferential crystal growth that results in 2D morphology. The 2D nanomaterial gave rise to a physical hydrogel that presented extreme thixotropy, injectability, biocompatibility, bioresorption, and long-term stability. The nanocrystalline material was characterized in vitro and in vivo and we discovered that it presented unique biological properties. Magnesium phosphate nanosheets accelerated bone healing and osseointegration by enhancing collagen formation, osteoblasts differentiation, and osteoclasts proliferation through up-regulation of COL1A1, RunX2, ALP, OCN, and OPN. In summary, the 2D magnesium phosphate nanosheets could bring a paradigm shift in the field of minimally invasive orthopedic and craniofacial interventions because it is the only material available that can be injected through high gauge needles into bone defects in order to accelerate bone healing and osseointegration.
Postoperative pain relief is crucial for full recovery. With the ongoing opioid epidemic and the insufficient effect of acetaminophen on severe pain; non-steroidal anti-inflammatory drugs (NSAIDs) are heavily used to alleviate this pain. However, NSAIDs are known to inhibit postoperative healing of connective tissues by inhibiting prostaglandin signaling. Pain intensity, inflammatory mediators associated with wound healing and the pharmacological action of NSAIDs vary throughout the day due to the circadian rhythm regulated by the clock genes. According to this rhythm, most of wound healing mediators and connective tissue formation occurs during the resting phase, while pain, inflammation and tissue resorption occur during the active period of the day. Here we show, in a murine tibia fracture surgical model, that NSAIDs are most effective in managing postoperative pain, healing and recovery when drug administration is limited to the active phase of the circadian rhythm. Limiting NSAID treatment to the active phase of the circadian rhythm resulted in overexpression of circadian clock genes, such as Period 2 (Per2) at the healing callus, and increased serum levels of anti-inflammatory cytokines interleukin-13 (IL-13), interleukin-4 (IL-4) and vascular endothelial growth factor. By contrast, NSAID administration during the resting phase resulted in severe bone healing impairment. open Scientific RepoRtS | (2020) 10:468 | https://doi.org/10.1038/s41598-019-57215-y www.nature.com/scientificreports www.nature.com/scientificreports/ and Table S2). For instance, macrophage activity, leukocyte recruitment, and pro-inflammatory mediators such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-12 (IL-12) increase at the beginning of daily activity. During this phase, the levels of Tol-Like Receptors TLR9 and TLR4 also increase, leading to the upregulation of CCL2, CXCL1, CCL5, and subsequent leukocyte recruitment and potential tissue damage in injured sites 12-15 ( Fig. 1). By contrast, anti-inflammatory mediators and other growth or angiogenesis factors, such as the vascular endothelial growth factor (VEGF), peak during the resting phase 13,16,17 ( Fig. 1 and Table S2).The circadian rhythm affects many aspects of connective tissue metabolism 18 . A 24-hour oscillation occurs in bone tissue during growth 19 , formation, resorption 20,21 , and in the endochondral ossification during bone fracture healing 21 . Bone formation occurs during the resting period, and resorption occurs mostly during the active period 21 . Experimental studies in rodents and humans reveal that the disruption of sleep and circadian rhythm impairs bone formation 22 . All bone cells such as osteoblasts, osteoclasts, and chondrocytes express clock genes, such as Per or Cry, that influence bone volume regulation 23,24 . Cry2 influences the osteoclastic activity and Per2 regulates osteoblast activity 25 . The circadian clock also affects pain, with sensitivity peaking during the active phase 26 . Part of the pain response oscillation could b...
Donepezil is an acetylcholinesterase inhibitor commonly used to treat mild to moderate Alzheimer’s disease. Its use has been associated with increased bone mass in humans and animals. However, the effect of postoperative administration of donepezil on bone healing remains unknown. Therefore, this study aimed to assess the impact of postoperative injection of donepezil on bone healing, titanium-implant osseointegration, and soft tissue healing. Twenty-two Sprague-Dawley rats were randomly assigned to receive a daily dose of either donepezil (0.6 mg/kg) or saline as a control. In each rat, a uni-cortical defect was created in the right tibia metaphysis and a custom-made titanium implant was placed in the left tibiae. After two weeks, rats were euthanized, and their bones were analysed by Micro-CT and histology. The healing of bone defect and implant osseointegration in the rats treated with donepezil were significantly reduced compared to the saline-treated rats. Histomorphometric analysis showed lower immune cell infiltration in bone defects treated with donepezil compared to the saline-treated defects. On the other hand, the healing time of soft tissue wounds was significantly shorter in donepezil-treated rats compared to the controls. In conclusion, short-term administration of donepezil hinders bone healing whereas enhancing soft tissue healing.
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