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

项目总结 术后疼痛给患者带来了巨大的痛苦，并过度依赖阿片类药物来减轻疼痛。 然而，阿片类镇痛剂会引起严重的副作用，并有因过量服药而意外死亡的风险。 不幸的是，有效的非阿片类疼痛治疗仍然缺乏。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，可以开发为一种新型的 手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抑制小鼠术后疼痛的有效性、受体机制和安全性。我们的 初步研究表明，术中应用HCT/P治疗可减少 大鼠手术后疼痛。在目标2中，我们将演示HCT/P作为一种间接模式针对免疫细胞 止痛作用。我们假设Hct/P通过抑制Hct/P促进创面再生愈合 免疫细胞募集和诱导抗炎作用。我们最近的研究表明，重物 链-透明质酸-五肽3复合体(HC-HA/PTX3)是一种独特的生物活性成分 存在于HCT/P中。我们将进一步探讨HC-HA/PTX3是如何分化巨噬细胞的 人THP-1细胞向M2表型转化及HC-HA/PTX3是否抑制人LAD2的激活 肥大细胞和促炎细胞因子的释放。在目标3中，我们将研究初级 感觉神经元作为HCT/P和HC-HA/PTX3的直接止痛作用方式。我们将测试一下 HC-HA/PTX3降低背根固有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/PTX3对神经元的抑制是否涉及 一种依赖CD44介导的细胞骨架重排的新机制。为了实现这些目标， 我们将结合来自约翰霍普金斯大学的临床前和转化性疼痛研究人员的专业知识 TIseTech，Inc.医学院和HCT/P的GMP制造。这项研究将提供 开发以HCT/P为基础的生物制剂作为可行的非阿片类药物治疗的重要理由 手术后疼痛。这些药物不仅会直接起作用，通过抑制神经元兴奋，而且还会间接起作用， 通过改变伤口环境和安排再生愈合。通过互补性 双重作用模式，我们设想，分娩HCT/P可能会导致持续疼痛的最佳治疗效果 缓解和潜在的手术后疼痛的“治愈”。

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.