Joint Pain on a Chip: Mechanistic Analysis Therapeutic Targets and an Empirical Strategy for Personalized Pain Management

芯片上的关节疼痛：机制分析治疗目标和个性化疼痛管理的经验策略

基本信息

批准号：
10387104
负责人：
MICHAEL S GOLD
金额：
$ 228.74万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-26 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10387104
关键词：
3D Print Adipose tissue Administrative Supplement Adult Affect Afferent Neurons Ally Applications Grants Arthralgia Biological Markers Bioreactors Cells Clinical Management Complex Degenerative polyarthritis Development Devices Drug usage Electrophysiology (science)Elements Engineering Ensure Etiology Gene Expression Gene Proteins Generations Goals Health Human Hypersensitivity Image In Vitro Injury Interleukin-1 beta Joints Laboratories Life Liquid substance Mechanical Stress Mechanics Mediating Mediator of activation protein Methods Microelectrodes Microfluidics Modeling Modification National Institute of Arthritis and Musculoskeletal and Skin Diseases Neurites Neurons Nociception Nociceptors Non-Steroidal Anti-Inflammatory Agents Operative Surgical Procedures Opioid Optics Pain Pain Measurement Pain management Pathology Patients Peripheral Nervous System Pharmaceutical Preparations Process Production Replacement Arthroplasty Resort Risk Sensory Speed Stimulus Synovial Fluid Synovial Membrane System Testing Therapeutic Intervention Time Tissues Treatment Efficacy Treatment-related toxicity arthropathies base cell type cost design disability disabling symptom effective therapy induced pluripotent stem cell joint destruction joint injury joint stress macrophage mechanical load mechanical properties microphysiology system multi-electrode arrays nerve stem cell nerve supply neural initiation new therapeutic target novel opioid epidemic opioid exposure osteoarthritis pain osteochondral tissue pain model personalized strategies personalized therapeutic protein metabolite relating to nervous system release factor response screening specific biomarkers targeted treatment therapeutic target tissue repair

项目摘要

Life’s wear and tear can leave joints damaged. All too often, the result is the pain and disability of osteoarthritis (OA). Because pain is the most debilitating symptom of OA, it remains the primary target for therapeutic interventions that typically progress from non-steroidal anti-inflammatory drugs (NSAIDs) to weak opioids, and then to stronger opioids. If pain can’t be controlled, total joint replacement surgery remains the only viable long- term treatment option. However, the associated risks and costs will necessarily keep surgery an option of last resort. Thus, there is a critical need for the development of safe and effective methods for the treatment of OA- associated pain. Recently, our team successfully developed an in vitro multi-component joint on a chip (microJoint), in which engineered osteochondral complexes, synovium and adipose tissues were integrated. OA-like pathology has also been successfully modeled in the microJoint. In this new grant application, we propose to introduce sensory innervation into the microJoint. The result will be a more “complete” joint that enables the dynamic interplay between the peripheral nervous system and joint tissues. We hypothesize that a distinct combination of factors released from different cellular/tissue compartments within the joint mediate pain, hypersensitivity, and hyper- innervation of OA. Furthermore, we hypothesize that opioids not only increase the rate of joint degeneration but potentiate the release of pain producing mediators. In aim 1, a neuron-containing microfluidic ally will be developed to innervate the current microJoint (Neu-microJoint). This new bioreactor will be 3D printed and allow for the non-invasive assessment of neural activity via multi electrode arrays embedded in the tissue chamber, and high-speed optical recording. Human sensory neurons or induced pluripotent stem cell (iPSC)-derived sensory neuron progenitors, will be cultured in the new bioreactor chamber. In aim 2, our previsouly establised OA-model will be created in the Neu-microJoint system. We will assess the activation and/or sensitization of nociceptive afferents with electrophysiology, as well as neurite outgrowth. In aim 3, we will mechanically insult the Neu- microJoint and assess the emergence of “pain” in response to prolonged mechanical stress of the joint with the goal of creating a more natural OA-model. In aim 4, we will assess the impact of drugs used clinically for the management of OA on our OA models in the Neu-microJoint as a means of validating this platform for the assessment of therapeutic efficacy and toxicity of novel compounds. We will then use “omic” approaches to identify new biomarkers and therapeutic targets. Results from this unbiased screen may not only reveal an injury specific pain signature, but suggest medications approved for use in people that could be re-purposed for the treatment of OA pain. In aim 5, we will assess the impact of opioids on neural activity in the presence and absence of joint injury triggered with different stimuli, as well as the integrity of all joint elements. Our Neu-microJoint will enable identification of mechanisms responsible for pain associated with joint injury and therefore novel therapeutic targets, screening of therapeutic interventions, and the implementation of personalized therapeutic strategies.

生活中的磨损常常会导致关节受损，从而导致骨关节炎的疼痛和残疾。 (OA) 由于疼痛是 OA 最令人衰弱的症状，因此它仍然是治疗的主要目标。通常从非甾体抗炎药 (NSAID) 发展为弱阿片类药物的干预措施，以及如果无法控制疼痛，全关节置换手术仍然是唯一可行的长期疗法。然而，相关的风险和费用必然会使手术成为最后的选择。因此，迫切需要开发安全有效的治疗 OA-的方法。最近，我们的团队成功开发了一种体外多组件芯片关节（microJoint），其中整合了工程化的骨软骨复合体、滑膜和脂肪组织，类似于 OA 的病理学。在 microJoint 中也已成功建模。在这个新的资助申请中，我们建议引入。感觉神经支配到微关节中，其结果将是一个更“完整”的关节，从而实现动态相互作用。我们认为这是多种因素的独特组合。从关节内的不同细胞/组织室释放的物质会介导疼痛、过敏和过度敏感。此外，我们发现阿片类药物不仅会增加关节退化的速度，而且还会增加关节退化的发生率。增强疼痛产生介质的释放在目标 1 中，将使用含有神经元的微流体盟友。这种新的生物反应器将通过 3D 打印来驱动当前的微关节 (Neu-microJoint)。通过嵌入组织室中的多电极阵列对神经活动进行非侵入性评估，以及高速光学记录人类感觉神经元或诱导多能干细胞（iPSC）衍生的感觉。神经元祖细胞将在新的生物反应器室中培养，目标 2 是我们之前建立的 OA 模型。将在 Neu-microJoint 系统中创建。我们将评估伤害感受的激活和/或敏化。在目标 3 中，我们将机械地侮辱神经元。 microJoint 并评估因关节长期机械应力而出现的“疼痛” 创建更自然的 OA 模型的目标在目标 4 中，我们将评估临床使用的药物对 OA 模型的影响。在 Neu-microJoint 中的 OA 模型上进行 OA 管理，作为验证该平台的一种手段然后我们将使用“组学”方法来评估新化合物的治疗功效和毒性。新的生物标志物和治疗靶标的公正筛选结果可能不仅揭示了特定的损伤。疼痛特征，但建议批准用于人群的药物可以重新用于治疗在目标 5 中，我们将评估阿片类药物在存在和不存在关节的情况下对神经活动的影响。不同刺激引发的损伤以及所有关节元件的完整性将能够实现。确定与关节损伤相关的疼痛机制，并因此开发新的治疗方法目标、治疗干预措施的筛选以及个性化治疗策略的实施。