Ligament Healing: Role of Neuropeptides

韧带愈合：神经肽的作用

• 批准号: 7225879
• 负责人: RAY VANDERBY
• 金额: $ 2.59万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7225879
• 关键词: blood circulation; cell differentiation; cell proliferation; extracellular matrix; immunocytochemistry; immunofluorescence technique; immunoprecipitation; injury /disease stressor; laboratory rat; ligaments; musculoskeletal circulation; musculoskeletal regeneration; musculoskeletal transplantation; neuroimmunomodulation; neuropeptides; pathologic process; peripheral nervous system; protein structure function; radioimmunoassay; skeletal pharmacology; tissue engineering; wound healing

DESCRIPTION (provided by applicant): The peripheral nervous system (PNS) is a key affecter of proliferative and inflammatory processes after injury. Neuropeptides (NPs) from the PNS modulate cytokine responses and control local blood flow. Our preliminary studies show NPs has a prominent role in ligament healing. We show peripheral neuropathies significantly degrade mechanical strength of healing tissues. We also show local delivery of NPs to a transected ligament dramatically improves functional recovery (i.e. strength and stiffness). After only two weeks of healing with adjuvant NPs, healing ligaments exceed the strength of even their sham-operated (but not transected) controls. This level of healing dramatically exceeds any published study of normal healing or augmented healing in ligaments or tendons (better than stem cell augmentation, better than growth factors, and better than increased hemorrhage). Because NPs profoundly influence cellular repopulation during healing, they may establish an entirely new paradigm for tissue engineering. However, before NPs can be effectively used, we must elucidate their specific and combinatorial roles on healing tissues and grafts. Therefore, our objectives are: 1) In a healing ligament model, define the influence of sympathetic and sensory NPs on functional recovery (i.e. ligament strength, stiffness, and laxity). 2) Study the biological mechanisms by which NPs have this remarkable effect on ligament healing (i.e. collagen microstructure, cell proliferation, blood flow, as well as anabolic and catabolic agents in the extra-cellular matrix). 3) Demonstrate the role of NPs to augment healing in a ligament graft model (quantified as above). 4) Study the biological mechanisms by which NPs affect ligament graft healing (quantified as above). Ligaments are chosen as our experimental model due to their simplicity and well-defined healing behavior. Rat medial collateral ligament (MCL), anterior cruciate ligament (ACL), and ACL graft tissue (hamstring tendon) will be used. No PNS neuropathies will be created other than those induced by MCL transection and ACL graft harvest and reconstruction. This study will be the first to optimize NP concentrations relative to ECM healing and the first to define the combinatorial effect of NPs on tissue and tissue graft healing. We expect this study to significantly impact the scientific basis and the treatment of: ligament and tendon healing, ligament and tendon grafting, as well as many, associated tissue engineering applications.

描述（由申请人提供）：周围神经系统（PNS）是损伤后增殖和炎症过程的关键影响者。 PNS 中的神经肽 (NP) 调节细胞因子反应并控制局部血流。我们的初步研究表明纳米粒子在韧带愈合中具有显着的作用。我们发现周围神经病变会显着降低愈合组织的机械强度。我们还表明，将纳米粒子局部递送至横断韧带可显着改善功能恢复（即强度和刚度）。使用纳米粒子辅助治疗仅两周后，愈合韧带的强度甚至超过了假手术（但未横断）对照的强度。这种愈合水平大大超过了任何已发表的关于韧带或肌腱正常愈合或增强愈合的研究（优于干细胞增强，优于生长因子，优于出血增加）。由于纳米粒子在愈合过程中深刻影响细胞再生，因此它们可能为组织工程建立一个全新的范例。然而，在纳米颗粒能够有效使用之前，我们必须阐明它们在愈合组织和移植物中的特定和组合作用。因此，我们的目标是：1）在愈合韧带模型中，定义交感神经和感觉神经元对功能恢复（即韧带强度、刚度和松弛）的影响。 2) 研究纳米颗粒对韧带愈合产生显着影响的生物学机制（即胶原微结构、细胞增殖、血流以及细胞外基质中的合成代谢和分解代谢剂）。 3) 展示纳米粒子在韧带移植模型中增强愈合的作用（如上量化）。 4) 研究纳米粒子影响韧带移植物愈合的生物学机制（量化如上）。由于韧带简单且具有明确的愈合行为，因此选择韧带作为我们的实验模型。将使用大鼠内侧副韧带（MCL）、前十字韧带（ACL）和ACL移植组织（腿筋腱）。除了 MCL 横断和 ACL 移植物收获和重建引起的神经病变之外，不会产生 PNS 神经病变。这项研究将是第一个优化与 ECM 愈合相关的 NP 浓度的研究，也是第一个定义 NP 对组织和组织移植物愈合的组合效应的研究。我们预计这项研究将显着影响以下方面的科学基础和治疗：韧带和肌腱愈合、韧带和肌腱移植以及许多相关的组织工程应用。