CAREER: Alternative Non-Opioid Therapies for Low Back Pain

虽然大多数人在一生中都会经历腰痛，但其中超过25%的人将继续遭受慢性未解决的腰痛。疼痛药物是慢性腰痛患者的常见治疗方法，通常会导致成瘾，这在美国是一个巨大的问题。这个问题可以通过创造直接针对疼痛根源的治疗方法来减少，从而减少对全身疼痛药物的需求。 慢性下背痛可以从脊柱中的椎间盘引起。神经可以长入这些椎间盘，并成为疼痛的来源。该项目的假设是，局部治疗可以通过使现有神经缩回和防止新神经的再生长来减轻腰痛。因此，该项目的研究目标是了解不希望的神经生长，并设计局部递送治疗方法以防止和逆转神经生长。该项目将识别和测试导致神经纤维收缩和防止神经纤维再生的化合物。在研究目标的同时，主要的教育目标是向科学和公众展示这种新的背痛研究，并培养学生与不同的受众进行沟通。因此，该项目将培训学生和同行教师进行科学交流，并教育50岁以上的当地社区了解腰痛。总的来说，该项目的完成将为首席研究员在腰痛研究领域的职业生涯奠定基础，同时为下一批工程师做好准备，并增加公众对腰痛和治疗的了解。首席研究员的长期职业研究目标是开发新的基于生物材料的肌肉骨骼疼痛治疗方法。 为了实现这一目标，该项目将设计有针对性的生物材料，以防止和逆转疼痛（伤害性）感觉神经纤维发芽到以前无神经的椎间盘（IVD）髓核（NP）核心，这是慢性腰痛（LBP）的主要原因之一。该项目的总体假设是，治疗性生物材料和化合物的局部递送可以通过引起现有神经缩回或死亡并防止疼痛神经纤维的再生长来减轻疼痛并防止慢性病。 研究计划有三个目标。 第一个目标是鉴定和测试引起不期望的感觉神经纤维的枯死的化合物，并表征枯死的机制。 研究将在3D细胞培养物中进行，其中神经突延伸物已从大鼠幼仔的修剪背根神经节（DRG）中生长。 将髓磷脂相关糖蛋白（MAG）和树脂毒素（RTX）（两种与脊髓损伤后和细胞培养研究中的死亡有关的化合物）添加到培养基中，并评估神经突延伸的死亡。 设计研究以确定MAG和RTX的理想浓度以在体外引起感觉神经元的死亡，评估具有死亡化合物的DRG和NP细胞的细胞健康，并差异性地评估MAG和/或RTX如何影响感觉神经突亚群中疼痛相关离子通道的基因表达，并因此影响下游疼痛。 第二个目标是开发新的材料，以防止不必要的神经生长。 研究将在3D凝胶共培养物中进行，该共培养物由人源NP核心组成，周围环绕含有大鼠源DRG的凝胶和NP核心的基质支持物。 将已知具有神经抑制性的含有甲基丙烯酸化硫酸软骨素A和C（MA-CS-A和MA-CS-C）的微粒的各种组合物掺入NP核心中，并评估它们防止神经向内生长的能力。 研究旨在开发具有可调组成的NP的神经学3D体外模拟物用于NP细胞和DRG的长期培养，以确定CS浓度和体外对DRG生长的类型效应，以验证抑制机制并制造用于神经抑制剂的可注射递送的微粒，从而实现体内递送。 第三个目的是在动物模型中测试鉴定的材料和化合物预防和逆转LBP的功效。 将在大鼠腰椎间盘穿刺模型中进行研究，该模型已被广泛用作椎间盘退变模型。 穿刺后10周，根据目标1和2中获得的结果将动物分为5个处理组：MAG或RTX顶枯化合物、MA-CS-A或MA-CS-C微粒、顶枯化合物和微粒、I型胶原对照或假手术对照。 将使用新型啮齿动物步态分析评估疼痛的程度和缓解情况。 研究的目的是确定新的生物材料和化合物的组合，减轻疼痛和稳定的椎间盘在LBP的动物模型，并增加了解生物材料/化合物对神经突起的NP的影响。 确定这些疗法的有效性，直接治疗LBP，而不使用成瘾性止痛药，有可能导致新的治疗方法，这将大大有利于患者和社会。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

While the majority of the population will experience low back pain during their lifetime, over 25% of these people will go on to suffer from chronic unresolved low back pain. Pain medicine is a common treatment for chronic low back pain patients and often results in addiction, which is a huge problem in the United States. This problem can be reduced by creating treatments that target pain directly at its source and thus reduce the need for the systemic pain medicines. Chronic low back pain can arise from the discs in the spine. Nerves can grow into these discs and be a source of pain. The hypothesis of this project is that local delivery of treatments can reduce low back pain by causing existing nerves to retract and by preventing re-growth of new nerves. As such, the research goal of this project is to understand undesired nerve growth and to engineer treatments for local delivery to prevent and reverse nerve growth. The project will identify and test compounds that cause retraction of and prevent regrowth of nerve fibers. In parallel with the research goal, the major education goal is to present this new back pain research to both scientific and public audiences and to train students to communicate with varied audiences. Therefore, this project will train students and peer faculty in the communication of science and educate the local community over the age of 50 about low back pain. Taken together, the completion of this project will provide the foundation for the principal investigator's career in low back pain research while preparing the next group of engineers and increasing knowledge among the general public about low back pain and treatments.The principal investigator's long-term career research goal is to develop novel biomaterial-based treatments for musculoskeletal pain. Toward this goal, this project will engineer targeted biomaterials that will prevent and reverse the sprouting of painful (nociceptive) sensory nerve fibers into the previously nerve-free nucleus pulposus (NP) core of intervertebral discs (IVD), which is one of the major causes of chronic low back pain (LBP). The project's overarching hypothesis is that local delivery of therapeutic biomaterials and compounds can alleviate pain and prevent chronicity by causing existing nerves to retract or dieback and prevent re-growth of painful nerve fibers. The Research Plan is organized under three objectives. The FIRST OBJECTIVE is to identify and test compounds that cause dieback of undesired sensory nerve fibers and characterize mechanisms of dieback. Studies will be performed in 3D cell cultures in which neurite extensions have been grown from trimmed dorsal root ganglion (DRG) harvested from rat pups. Myelin associated glycoprotein (MAG) and Resiniferatoxin (RTX), two compounds associated with dieback after spinal cord injury and in cell culture studies, will be added to the culture medium and dieback of neurite extensions will be assessed. Studies are designed to determine ideal concentrations of MAG and RTX to cause dieback of sensory neurons in vitro, to assess cell health of DRGs and NP cells with dieback compounds and to differentially assess how MAG and/or RTX impact gene expression of pain-associated ion channels in sensory neurite subsets, and therefore downstream pain. The SECOND OBJECTIVE is to develop novel materials to prevent undesired nerve growth. Studies will be performed in 3D gel cocultures consisting of a human derived NP core surrounded by a gel containing rat derived DRGs and matrix support for the NP core. Various compositions of microparticles containing methacrylated chondroitin sulfate A and C (MA-CS-A and MA-CS-C), which are known to be neuro-inhibitory, will be incorporated into the NP core and their ability to prevent nerve ingrowth will be assessed. Studies are designed to develop a neurological 3D in vitro mimic of NP with tunable composition for long term culture of NP cells and DRGs, to determine CS concentration and type effects on DRG growth in vitro, to verify mechanism of inhibition and to fabricate microparticles for injectable delivery of neuro-inhibitors, enabling in vivo delivery. The THIRD OBJECTIVE is to test efficacy of identified materials and compounds to prevent and reverse LBP in an animal model. Studies will be performed in a rat lumber disc puncture model that has been used extensively as a model of disc degeneration. Ten weeks after puncture, animals will be divided into 5 treatment groups depending on results obtained in objectives 1 and 2: MAG or RTX dieback compounds, MA-CS-A or MA-CS-C microparticles, dieback compound and microparticles, type I collagen control or sham surgical control. The degree and resolution of pain will be assessed using a novel rodent gait analysis. Studies are designed to identify novel biomaterial and compound combinations that alleviate pain and stabilize the disc in an animal model of LBP and to increase understanding of the effects of biomaterials/compounds on neurites in the NP. Determining the effectiveness of these therapeutics to directly treat LBP without the use of addictive pain medications has the potential to lead to new treatments that will greatly benefit patients and society.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.