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Birth Tissue Products for Non-opioid Treatment of Post-surgical Pain

用于非阿片类药物治疗术后疼痛的出生纸巾产品

基本信息

批准号：
10653711
负责人：
Yun Guan
金额：
--
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653711
关键词：
Acceleration Accidents Acute Adverse effects Afferent Neurons Anti-Inflammatory Agents Antiinflammatory Effect Attenuated Birth Bullous Keratopathy Cells Cessation of life Cicatrix Clinical Complex Cornea Cytoskeleton Development Diameter Eye diseases Flow Cytometry Goals Human Hyaluronic Acid Immune Immune Targeting Inflammation Inflammatory Injections Injury Interleukin-10 Ion Channel Laws Macrophage Mediating Membrane Mus Muscle Neurons Nociception Opioid Opioid Analgesics Overdose PTX3 protein Pain Pain management Particulate Patients Persistent pain Pharmaceutical Preparations Pharmacotherapy Phenotype Physicians Postoperative Pain Principal Investigator Radiation Rattus Research Personnel Risk Rodent Model Safety Skin Spinal Ganglia Surgical incisions TRPV1 gene Testing Therapeutic Effect Thick Tissues Traction Umbilical cord structure Universities allodynia cytokine drug action healing in vivo indium arsenide manufacture mast cell medical schools mouse model neuronal excitability non-opioid analgesic novel overdose death pain inhibition pain reduction pain relief pre-clinical programs public health emergency receptor recruit regenerative response side effect skin wound voltage wound wound environment wound healing

项目摘要

PROJECT SUMMARY Post-surgical pain causes significant suffering to patients and an over-reliance on opioids for pain reduction. However, opioid analgesics cause severe side effects and a risk of accidental death from overdose. Unfortunately, effective non-opioid pain therapy remains lacking. We aim to determine if human cell and tissue product (HCT/P), such as amniotic membrane and umbilical cord, can be developed for use as a novel and safe treatment of post-surgical pain. In Aim 1, we will first prove the concept by demonstrating the efficacy, receptor mechanisms, and safety of HCT/P for inhibiting post-surgical pain in murine models. Our preliminary studies showed that intraoperative treatment with HCT/P reduced the development of post-surgical pain in rats. In Aim 2, we will demonstrate that HCT/P targets immune cells as an indirect mode of anti-pain action. We hypothesize that HCT/P promotes regenerative wound healing by suppressing immune cell recruitment and inducing anti-inflammatory effects. Our recent studies suggested that the heavy chain-hyaluronic acid-pentraxin 3 complex (HC-HA/PTX3) is a biologically active component uniquely present in HCT/P. We will further explore how HC-HA/PTX3 polarizes macrophages differentiated from human THP-1 cells to an M2 phenotype and whether HC-HA/PTX3 inhibits the activation of human LAD2 mast cell and release of pro-inflammatory cytokines. In Aim 3, we will examine the targeting of primary sensory neurons as the direct mode of anti-pain action by HCT/P and HC-HA/PTX3. We will test whether HC-HA/PTX3 reduces intrinsic membrane excitability and inhibits membrane ion channels in dorsal root ganglion neurons. Furthermore, we will investigate whether the neuronal inhibition by HC-HA/PTX3 involves a novel mechanism that depends on CD44-mediated cytoskeletal rearrangement. To achieve these goals, we will combine the expertise of preclinical and translational pain researchers from Johns Hopkins University School of Medicine and the GMP manufacturing of HCT/P at TissueTech, Inc. This study will provide important rationales for developing HCT/P-based bioceuticals as a viable non-opioid treatment of post-surgical pain. Such drugs will act not only directly, by dampening neuronal excitation, but also indirectly, by changing the wound environment and orchestrating regenerative healing. Through the complementary dual mode of action, we envision that birth HCT/P may lead to an optimal therapeutic effect with lasting pain relief and a potential “cure” of post-surgical pain.

项目摘要术后疼痛给患者带来了巨大的痛苦，并且过度依赖阿片类药物来减轻疼痛。然而，阿片类镇痛药会引起严重的副作用，并有因过量而意外死亡的风险。不幸的是，仍然缺乏有效的非阿片类药物疼痛治疗。我们的目标是确定人类细胞和组织产品（HCT/P），如羊膜和脐带，可被开发用作新的以及术后疼痛的安全治疗。在目标1中，我们将首先通过演示 HCT/P在小鼠模型中抑制术后疼痛的疗效、受体机制和安全性。我们初步研究表明，术中HCT/P治疗可减少大鼠术后疼痛。在目标2中，我们将证明HCT/P作为间接模式靶向免疫细胞抗疼痛的作用。我们假设HCT/P通过抑制免疫细胞募集和诱导抗炎作用。我们最近的研究表明，链-透明质酸-正五聚蛋白3复合物（HC-HA/PTX 3）是一种独特的生物活性成分，存在于HCT/P中。我们将进一步探索HC-HA/PTX 3如何使巨噬细胞分化为人THP-1细胞转化为M2表型以及HC-HA/PTX 3是否抑制人LAD 2的活化肥大细胞和促炎细胞因子的释放。在目标3中，我们将研究主要目标感觉神经元作为HCT/P和HC-HA/PTX 3抗疼痛作用的直接模式。我们将测试 HC-HA/PTX 3降低背根细胞膜兴奋性并抑制膜离子通道神经节神经元此外，我们将研究HC-HA/PTX 3的神经元抑制是否涉及依赖于CD 44介导的细胞骨架重排的新机制。为了实现这些目标，我们将联合收割机结合来自约翰霍普金斯大学的临床前和转化疼痛研究人员的专业知识 TissueTech，Inc.医学院和HCT/P GMP生产本研究将提供开发基于HCT/P的生物制品作为一种可行的非阿片类药物治疗的重要依据术后疼痛这些药物不仅通过抑制神经元兴奋直接起作用，而且还间接起作用，通过改变伤口环境和协调再生愈合。通过互补双重作用模式，我们设想，出生HCT/P可能导致持久疼痛的最佳治疗效果缓解和潜在的“治愈”术后疼痛。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain.

DOI：
10.1126/sciadv.ade9931
发表时间：
2023-03-29
期刊：
SCIENCE ADVANCES
影响因子：
13.6
作者：
Chu, Jiachen;Yang, Junhua;Zhou, Yuan;Chen, Jianan;Chen, Kevin Hong;Zhang, Chi;Cheng, Henry Yi;Koylass, Nicholas;Liu, Jun O.;Guan, Yun;Qiu, Zhaozhu
通讯作者：
Qiu, Zhaozhu

Astrocytes contribute to pain gating in the spinal cord.

星形胶质细胞有助于脊髓疼痛门控。

DOI：
10.1126/sciadv.abi6287
发表时间：
2021-11-05
期刊：
Science advances
影响因子：
13.6
作者：
Xu Q;Ford NC;He S;Huang Q;Anderson M;Chen Z;Yang F;Crawford LK;Caterina MJ;Guan Y;Dong X
通讯作者：
Dong X

BzATP Activates Satellite Glial Cells and Increases the Excitability of Dorsal Root Ganglia Neurons In Vivo.

DOI：
10.3390/cells11152280
发表时间：
2022-07-23
期刊：
CELLS
影响因子：
6
作者：
Chen, Zhiyong;Zhang, Chi;Song, Xiaodan;Cui, Xiang;Liu, Jing;Ford, Neil C.;He, Shaoqiu;Zhu, Guangwu;Dong, Xinzhong;Hanani, Menachem;Guan, Yun
通讯作者：
Guan, Yun

Predicting Wide-Dynamic Range Neuron Activity from Peripheral Nerve Stimulation using Linear Parameter Varying Models.

使用线性参数变化模型，从周围神经刺激中预测宽动力范围的神经元活性。