In vitro modelling of bone infection for osteomyelitis and osteoradionecrosis

骨感染，包括骨髓炎和骨放射性坏死，会导致严重的发病率和死亡率，特别是在骨髓炎是第二大肌肉骨骼感染的老年人中。[1]这些情况可能会产生毁灭性的后果，包括剧烈疼痛、骨质破坏、截肢，甚至败血症和死亡。目前的治疗方法往往效果有限，而开发更有效的治疗方法需要更好地了解疾病发展/病因学的潜在机制。目前迫切需要精确复制骨感染病理生理学的模型。利用动物模型研究骨感染为研究这些疾病的病理生理学提供了有价值的见解。[2]然而，动物模型有几个局限性，包括伦理问题、成本高和重复性差。准确复制这些感染的病理生理学的体外模型可以提供一种替代动物试验的方法，使研究人员能够以更可控和更可重复性的方式探索微生物病原体、免疫内皮细胞和骨驻留成骨细胞/骨细胞之间的复杂相互作用。体外模型可以促进探索微生物病原体、内皮细胞和骨驻留细胞之间的复杂相互作用，从而更好地了解这些疾病，并开发更有效的治疗方法。尽管骨的组织工程器官体外模型最近取得了进展，[3，4]仍然严重缺乏模拟受感染的骨的病理生理学[5]的模型，如骨髓炎或感染，与辐射引起的坏死组织的发展相关-统称为骨放射性坏死。在此，我们提出了先进的骨髓炎和骨放射性坏死的体外模型，最终目的是取代造成严重损害的动物模型。我们将推进基于3D IPSCs的细胞培养、3D-流体芯片平台和混合水凝胶来克服这些挑战，并构建血管化的体外骨骼模型。此外，我们还将照射和感染培养物以产生放射性骨坏死模型。

Bone infections, including osteomyelitis and osteoradionecrosis, cause significant morbidity and mortality, especially in elderly people where osteomyelitis is the second most critical musculoskeletal infection.[1] These conditions can have devastating consequences, including severe pain, bone destruction, amputation, and even sepsis and death. Current treatments often have limited success, and the development of more effective therapies requires a better understanding of the underlying mechanisms of disease development/aetiology. There is a critical need for models that accurately replicate the pathophysiology of bone infections.The use of animal models for studying bone infections has provided valuable insights into the pathophysiology of these diseases.[2] However, animal models have several limitations, including ethical concerns, high cost, and poor reproducibility. In vitro models that accurately replicate the pathophysiology of these infections could offer an alternative to animal testing, allowing researchers to explore the complex interactions between microbial pathogens, immune endothelial cells, and bone-resident osteoblasts/osteocytes in a more controlled and reproducible manner.In vitro models could facilitate the exploration of complex interactions between microbial pathogens, endothelial cells, and bone-resident cells, leading to a better understanding of these diseases and the development of more effective treatments. Despite the recent advances tissue engineered organotypic in vitro models of bone,[3,4] there are still a critical lack of models mimicking the pathophysiology[5] of infected bone, such as osteomyelitis or infection, associated with the development of necrotic tissue due to radiation - collectively known as osteoradionecrosis.Here, we propose develop advanced in vitro models of osteomyelitis and osteoradionecrosis, with the ultimate goal of replacing animal models that cause severe harm. We will advance 3D iPSCs-based cell cultures, 3D-fluidic chips platforms, and hybrid hydrogels to overcome these challenges and construct vascularised in vitro models of bone. Furthermore, we will irradiate and infect the cultures to generate models of osteoradionecrosis.