Stem cell-loaded microgels to treat discogenic low back pain

装载干细胞的微凝胶可治疗椎间盘源性腰痛

• 批准号: 10398627
• 负责人: Dmitriy Sheyn
• 金额: $ 165.57万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-27 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398627
• 关键词: Adult; Affect; Aftercare; Animal Model; Attenuated; Autopsy; Biocompatible Materials; Biological Assay; Biomanufacturing; Cell Differentiation process; Cell Survival; Cells; Chronic low back pain; Clinic; Complete Blood Count; Cyclic GMP; Data; Deposition; Development; Disease; Encapsulated; Ensure; Ethnic Origin; Evaluation; Fibrinogen; Gender; Goals; Health; Healthcare Systems; Helping to End Addiction Long-term; Hour; Human; Hydrogels; Hypersensitivity skin testing; Immunocompromised Host; In Vitro; Inflammation; Injectable; Injections; Injury; Intervertebral disc structure; Letters; Low Back Pain; Magnetic Resonance Imaging; Mechanics; Methods; Microencapsulations; Microfluidics; Minnesota; Modeling; Molds; Monitor; Morbidity - disease rate; Motor; Natural regeneration; Needles; Operating Rooms; Operative Surgical Procedures; Outcome; Outcome Measure; Outcome Study; Pain; Pain management; Patients; Phenotype; Population; Preparation; Procedures; Property; Protocols documentation; Puncture procedure; Race; Rattus; Readiness; Reproducibility; Reproducibility of Results; Research; Safety; Saline; Ships; Specialist; Spinal; Spinal Puncture; Sprague-Dawley Rats; Sterility; Stimulus; Surgeon; Symptoms; System; Technical Expertise; Techniques; Temperature; Testing; Time; Treatment Efficacy; Underserved Population; United States National Institutes of Health; Universities; Validation; Vertebral column; Videoconferencing; Xenograft procedure; biobehavior; cell bank; chronic back pain; conditioned place preference; cost; disability; discogenic pain; immunoreaction; in vivo; induced pluripotent stem cell; innovation; intervertebral disk degeneration; meetings; member; multidisciplinary; novel therapeutics; nucleus pulposus; preconditioning; prescription opioid; progenitor; reduce symptoms; regeneration potential; single-cell RNA sequencing; stability testing; stem cell therapy; stem cells; sterility testing; targeted treatment; therapeutic candidate; underserved community

PROJECT SUMMARY Low back pain (LBP) is a leading cause of disability and morbidity in the adult population, affecting approximately 80% of adults within their lifetime. Up to 40% of all low back pain is attributed to discogenic pain from IVD degeneration. While people of different races, ethnicity and gender suffer from chronic back pain, this disease has been shown to affect often people from underserved communities. IVD degeneration is known to affect the NP, the central part of the IVD. Despite decades of research, robust therapies targeting underlying causes rather than symptoms of IVD degeneration are still in the earliest stages of development. Conservative treatments alleviate symptoms rather than targeting the underlying disease. Stem cell therapy has been shown a great promise to regenerate IVD in animal models. Specifically, we have shown that induced pluripotent stem cells can be differentiated to notochordal cells (iNC), the original progenitors of NP cells. Different cell delivery and microencapsulation techniques will be explored to generate, iNC-microgel, preconditioned iNC-microgels and iNCs in bulk hydrogel. Cell purity, identity, viability and sterility data will be obtained. Furthermore, the material composition and properties will be investigated, and the stability of microencapsulated iNCs after preparation evaluated. Safety and efficacy of the therapeutic candidates will be evaluated in a rat model of IVD degeneration and discogenic low back pain, induced by disc puncture of the lumbar spine. After confirming successful induction of IVD degeneration, different therapeutic candidates and controls will be injected. The candidate’s regenerative potential and reproducibility of results will be evaluated by biobehavioral testing, MRI and immunohistochemical analyses. For mechanism of action studies, single cell RNA sequencing of the treated IVDs will be employed. The outcome of the study will be defined therapeutic candidate for low back pain stem cell therapy and multidisciplinary team including biologist, clinicians, translational experts and statisticians that will be set up for biomanufacturing and IND- enabling studies via U19 mechanism of the NIH HEAL initiative.

项目总结 腰背痛(LBP)是成年人残疾和发病的主要原因，影响到大约80%的 在他们的有生之年。高达40%的下腰痛可归因于IVD变性所致的间盘源性疼痛。而当 不同种族、民族和性别的人患有慢性背痛，这种疾病被证明经常影响 来自服务不足社区的人。众所周知，IVD退行性病变会影响到IVD的中枢部分--NP。尽管 几十年的研究，针对IVD变性的根本原因而不是症状的强有力的治疗仍在进行中 发展的最早阶段。保守治疗缓解了症状，而不是针对潜在的疾病。 干细胞治疗在动物模型中再生IVD有很大的前景。具体地说，我们已经证明了 诱导的多能干细胞可以分化为脊索细胞(INC)，即NP细胞的原始祖细胞。不同 将探索细胞递送和微囊化技术以产生Inc.微凝胶、预处理Inc微凝胶 和块状水凝胶中的INCS。将获得细胞纯度、身份、活力和无菌数据。此外，这些材料 将研究其组成和性能，并对制备后的微囊INCS的稳定性进行评价。 候选治疗药物的安全性和有效性将在IVD变性和椎弓根性低的大鼠模型中进行评估。 腰椎腰椎穿刺术引起的背部疼痛。在确认成功诱导IVD变性后， 将注射不同的治疗候选药物和对照药物。候选人的再生潜力和重现性 结果将通过生物行为测试、MRI和免疫组织化学分析进行评估。对于行动机制 研究中，将对治疗后的静脉畸形进行单细胞RNA测序。 这项研究的结果将被确定为下腰痛干细胞治疗和多学科治疗的候选药物。 包括生物学家、临床医生、翻译专家和统计学家在内的团队将为生物制造和工业- 通过NIH Hear倡议的U19机制进行研究。