A human 3D bone-sensory nerve co-culture model to investigate bone-derived pain

用于研究骨源性疼痛的人体 3D 骨感觉神经共培养模型

• 批准号: NC/Y000951/1
• 负责人: Deborah Mason
• 金额: $ 64.59万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FY000951%2F1
• 关键词: human; 3D; bone; sensory; nerve

Background Bone-derived pain from conditions such as cancer metastasis, non-healing fracture, osteoporotic fracture, or osteoarthritis (OA) are notoriously hard to manage and prevalent, with an estimated 1.5 million bone cancer metastases, 22 million non-union factures, 8.9 million osteoporotic fractures and 530 million OA sufferers currently worldwide. Complex signalling exists between bone and nerves which couple pathology and pain in health and disease. Sensory nerve invasion and sensitisation are associated with bone diseases, and intrinsic to pain responses in animal models and human patients with osteoarthritis, fracture and bone metastasis. This project aims to (i) develop a humanised 3D bone-sensory nerve co-culture model, (ii) use the model to investigate mechanisms linking changes in bone structure to local pain sensation and (iii) test whether the model can screen 2 drugs known to prevent pain and influence bone structure.Investigating bone-nerve interactions is challenging due to the position of these nerves within mineralised bone. Currently, no human derived models of the sensory nerve-bone interface exist. Some models of bone pain have been produced that use nerves from the spine, called dorsal root ganglia (DRG) from animals and humans, but are technically challenging and not commonly adopted. Animal models are extensively used for the investigation of bone derived pain. In 2019, over 650 original research papers were published investigating bone derived pain in pathology using animal models, 4% of which were large animals including canines, with an average of 23 animals typically used per study, totalling over 14000 animals. A pharmaceutical company testing drugs for bone pain may use more than 1000 animals p.a. In a recent review on orthopaedic animal testing15, it was revealed that over a 9-year period, 40% of academic orthopaedic animal studies were never published and almost half of those published were never cited totalling nearly 10,000 animal lives with no justifiable impact on orthopaedic knowledge. Animal models of osteoarthritis use >10 animals per group to reveal effects on bone structure and pain. For example, in osteoarthritis research 132-198 mice or 360 rats would be used to test 1 drug. Our new bone-sensory nerve model will facilitate low-cost research to identify new molecular targets and pre-screening of drugs for pain. It will reduce early-stage preclinical research animal usage, and replace models currently used to identify and test new treatments to ease bone derived pain. We will promote the use of this model over animal testing through dissemination at national and International conferences and workshops (e.g. Orthopaedic Research Society Preclinical Models Section, British Orthopaedic Research Society, Osteoarthritis Research Society International), and by validation with drugs from our current collaborators in the pharmaceutical industry.

背景 众所周知，癌症转移、不愈合骨折、骨质疏松性骨折或骨关节炎 (OA) 等疾病引起的骨源性疼痛难以控制且普遍存在，目前全球估计有 150 万骨癌转移、2200 万骨不连、890 万骨质疏松性骨折和 5.3 亿 OA 患者。骨骼和神经之间存在复杂的信号传导，将健康和疾病中的病理和疼痛联系起来。感觉神经侵袭和敏化与骨疾病相关，并且是患有骨关节炎、骨折和骨转移的动物模型和人类患者的疼痛反应所固有的。该项目旨在 (i) 开发人性化 3D 骨感觉神经共培养模型，(ii) 使用该模型研究骨结构变化与局部疼痛感觉之间的联系机制，以及 (iii) 测试该模型是否可以筛选 2 种已知可预防疼痛和影响骨结构的药物。由于这些神经在矿化骨内的位置，研究骨与神经的相互作用具有挑战性。目前，不存在感觉神经-骨界面的人类衍生模型。一些骨痛模型使用来自动物和人类的脊柱神经，称为背根神经节（DRG），但在技术上具有挑战性并且不被普遍采用。动物模型广泛用于骨源性疼痛的研究。 2019 年，发表了超过 650 篇原始研究论文，使用动物模型研究病理学中的骨源性疼痛，其中 4% 是包括犬科动物在内的大型动物，平均每项研究通常使用 23 只动物，总计超过 14000 只动物。一家制药公司每年可能使用 1000 多只动物来测试骨痛药物。最近一篇关于骨科动物测试的综述15显示，在 9 年的时间里，40% 的学术骨科动物研究从未发表，其中近一半的发表研究从未被引用过，总计近 10,000 条动物的生命，对骨科知识没有产生合理的影响。骨关节炎动物模型每组使用超过 10 只动物来揭示对骨骼结构和疼痛的影响。例如，在骨关节炎研究中，将使用 132-198 只小鼠或 360 只大鼠来测试 1 种药物。我们的新骨感觉神经模型将促进低成本研究，以确定新的分子靶标和预筛选疼痛药物。它将减少早期临床前研究动物的使用，并取代目前用于识别和测试新疗法以缓解骨源性疼痛的模型。我们将通过在国家和国际会议和研讨会（例如骨科研究协会临床前模型部分、英国骨科研究协会、国际骨关节炎研究协会）上传播，并通过我们目前在制药行业的合作者的药物进行验证，来推广该模型在动物试验中的使用。