椎间盘退变实验动物模型的研究进展

腰痛的病因很复杂,其中椎间盘退变被认为是主要病因.近年来,对椎间盘退变发生机制的研究成为脊柱外科的热点：而椎间盘退变实验动物模型的构建与制备是从事此类研究的关键步骤.通过实验干预或自发过程,在实验动物活体内模拟并观察分析椎间盘退变的过程,从而为椎间盘退变的病因学研究提供参考依据,进而对椎间盘退变的可能治疗方法或药物进行评估.笔者就椎间盘退变实验动物模型的构建与制备方法作一综述.     

椎间盘退变机制研究现状及生物治疗展望

椎间盘退变性疾病的发病率与复发率较高,严重影响患者的工作及日常生活。目前的治疗方法主要是缓解疼痛症状或神经受压症状,却无法阻止退变进程,这也是导致高复发的主要原因之一。目前的研究认为,椎间盘退变是一个与细胞外基质数量减少、细胞老化凋亡、炎性介质刺激和血管增生等相关的复杂程序。大量实验研究提示,椎间盘再生活性物质、干细胞移植、自体软骨细胞移植、基因治疗等方法可以不同程度地增加椎间盘细胞和基质数量,促进椎间盘再生或修复,从而逆转退变进程。     

骨髓间充质干细胞移植治疗腰椎间盘退变的研究进展

腰痛是骨科的常见症状,给患者和社会带来了沉重的负担。研究表明大多数腰痛和椎间盘退变有关，而目前的治疗都只能缓解症状，不能逆转椎间盘退变。随着对椎间盘退变病理认识的深入,采用生物学方法逆转椎间盘退变成为可能。细胞治疗和组织工程就是其中方法之一。笔者对骨髓间充质干细胞（BMSC）作为种子细胞治疗椎间盘退变的研究进展做一综述。     

椎间盘退变的发生机制及其修复的生物学进展

椎间盘退变常导致髓核突出、椎管狭窄、小关节退变和脊柱节段不稳而引起腰腿痛。近年来报道因椎间盘退变而引起的腰腿痛患病率高达60％～80％。目前国内外治疗椎间盘退变的措施主要有药物、激素、物理疗法、开放手术及内窥镜和经皮椎间盘镜等微创手术，这些方法虽然能缓解临床症状，但并非是针对椎间盘退变本身的治疗。手术治疗中不可避免地会改变椎间盘的正常结构，进而继发脊柱不稳，不但难以预防椎间盘退变，而且还存在促进椎间盘退变的可能。     

椎间盘退变的基础研究进展

椎间盘退变是机体退变的一部分,此进程可以引起一些轻微或自限性症状。目前认为脊柱疼痛多与椎间盘退变有关。治疗方法包括保守治疗和手术治疗两类,保守治疗即口服消炎镇痛药物或者物理治疗等;手术治疗的方法包括脊柱椎间融合术和椎间盘置换髓核成形术等。但目前几乎所有的治疗     

椎间盘退变基因治疗的研究动态

椎间盘退变疾病(disc degeneration diease,DDD)是一种发病率及致残率很高的疾病,目前常规的治疗方法包括：药物治疗、类固醇注射封闭、理疗以及手术治疗等。近来微创手术方面取得长足进步,出现了如椎间盘镜(endoscopic discectomy)和经皮椎间盘切除术(percutaneous discectomy)等方法。但是,这些治疗措施仅着眼于改善疾病的临床症状,而不是从根本上减缓或中止退变进程。基因治疗作为近年来兴起的一种治疗方法,可在分子水平进行调控,从而为延缓或逆转疾病进程提供了可能。本文就目前椎间盘退变基因治疗的研究现状及进展进行综述。     

椎间盘退行性变的生物学治疗研究进展

椎间盘退行性变是椎间盘突出的前提和病理基础。椎间盘组织再生能力有限，一旦发生退变，很难阻止或逆转。椎间盘突出症常用的治疗方法是保守治疗和手术治疗，前者常出现复发，而手术治疗为有创治疗，会破坏脊柱的稳定性和完整性，伴有许多并发症。理想的治疗方法是针对退变的原因，通过人工干预，早期阻止或逆转椎间盘的退变，恢复其生物学功能，即椎间盘退变的生物学治疗。     

髓核移植治疗椎间盘退变的研究进展

椎间盘退变导致的腰腿痛为骨科常见病,目前研究日益深入。纤维环及软骨终板的老化变性、髓核细胞的坏死和凋亡、细胞外基质(Ⅱ型胶原等)的过度降解和纤维化以及加速退变的细胞因子(如IL-1、TNF-α等)的产生被认为是导致椎间盘退变的主要原因[1]。尽管在椎间盘退变晚期症状严重时手术摘除脱出间盘不失为有效治疗方法,但如果在其退变早期能够延缓甚至逆转退变过程,可能更具有积极意义。近十余年来出现了众多治疗早期椎间盘退变的方法和实验研究,如非甾体类解热镇痛消炎药对症治疗、生长因子质粒转染髓核细胞的基因治疗[2~4]、髓核移植治疗等…     

椎间盘退变的基因治疗

下腰痛是一种常见病、多发病,它影响人们的生活质量和精神状态,成为困扰人类的疾病之一［1-3］。很多因素都会导致下腰痛,其中椎间盘退变是最重要的因素之一［4］。目前临床上针对椎间盘退变引起相关疾病的治疗策略是解除椎间盘退变相关的脊髓、神经和血管刺激或压迫,并非针对椎间盘退变的病理过程,因而临床症状可反复发作,而且手术后病变节段的相邻节段椎间盘退变加速［5-6］。随着科学技术的发展,特别是分子生物学技术不断进步,延缓甚至逆转椎间盘退变正成为可能。目前治疗椎间盘退变的分子生物学技术主要包括三大类：细胞治疗、组织工程治疗及基因治疗。本综述主要着重基因治疗。     

椎间盘退变的生物学治疗研究进展

椎间盘退变是导致慢性腰痛最常见的原因, 也是成年人致残的主要原因。由于缺乏有效的治疗手段, 椎间盘退变一般表现为迁延不愈, 造成严重的经济和社会负担。椎间盘退变是多因素共同作用的结果, 随年龄增长发病率逐年增加。机械创伤、遗传因素、生活方式以及代谢障碍等与椎间盘退变的发生密切相关。目前主要的治疗方式包括药物治疗和手术治疗, 均以缓解症状、改善功能为目的, 不能从根本上逆转椎间盘退变的进程, 远期疗效并不理想。生物学疗法理论上不仅能够在一定程度上逆转或延缓椎间盘退变的进程, 而且能够最大限度地保留和恢复椎间盘正常的生理功能, 是近年来的研究热点。抑制炎症反应、促进残存细胞增殖分裂、干细胞移植、细胞支架及新型生物材料的研发都为椎间盘退变的治疗提供了新的思路和方向。本文就椎间盘退变的干细胞疗法、细胞因子疗法、基因疗法以及组织工程和细胞支架治疗进行综述。     

椎间盘退变与细胞死亡的相关研究进展

腰椎间盘退行性变被认为是临床下腰痛的重要原因,其分子机制尚未明确.近年来,椎间盘退变的分子基础研究已经成为热门.椎间盘独特的生理结构和生物力学特性导致了它易于退变的特点.椎间盘退变开始与椎间盘细胞学行为的改变有关,包括细胞死亡的增加和细胞外基质的降解.然而,在退变椎间盘中的细胞死亡机制仍不明确,主要包括细胞凋亡和自噬.对椎间盘退变分子机制的深入研究能够为将来进一步改善和治疗椎闻盘退变打下基础.虽然椎间盘退变的生物学研究方面已经取得了一定的进展,但是椎间盘本身的生物环境对生物学治疗的发展仍具有挑战性.     

Regeneration potential and mechanism of bone marrow mesenchymal stem cell transplantation for treating intervertebral disc degeneration

Intervertebral disc degeneration is a primary cause of low back pain and has a high societal cost. The pathological mechanism by which the intervertebral disc degenerates is largely unknown. Cell-based therapy especially using bone marrow mesenchymal stem cells as seeds for transplantation, although still in its infancy, is proving to be a promising, realistic approach to intervertebral disc regeneration. This article reviews current advances regarding regeneration potential in both the in vivo and vitro studies of bone marrow mesenchymal stem cell-based therapy and discusses the up-to-date regeneration mechanisms of stem cell transplantation for treating intervertebral disc degeneration.     

Future perspectives of cell-based therapy for intervertebral disc disease

Intervertebral disc degeneration is a primary cause of low back pain and has a high societal cost. Research on cell-based therapies for intervertebral disc disease is emerging, along with the interest in biological therapy to treat disc disease without reducing the mobility of the spinal motion segment. Results from animal models have shown promising results under limited conditions; however, future studies are needed to optimise efficacy, methodology, and safety. To advance research on cell-based therapy for intervertebral disc disease, a better understanding of the phenotype and differentiation of disc cells and of their microenvironment is essential. This article reviews current concepts in cell-based therapy for intervertebral disc disease, with updates on potential cell sources tested primarily using animal models, and discusses the hurdles to clinical application. Future perspectives for cell-based therapies for intervertebral disc disease are also discussed.

     

Relevance of in vitro and in vivo models for intervertebral disc degeneration

Models available for the study of intervertebral disc degeneration are designed to answer many important questions. In vitro biologic models employ a variety of cell, tissue, or organ culture techniques with culture conditions that partially mimic the cellular environment of the degenerated human intervertebral disc. In vitro biomechanical models include intervertebral disc or motion-segment loading experiments as well as finite element modeling techniques. The literature describes numerous in vivo animal models for use in the study of intervertebral disc degeneration, each of which has its own advantages and disadvantages. Human-subject studies have included the use of magnetic resonance imaging and other techniques to assess diffusion into the intervertebral disc, to measure intradiscal pressure, to conduct kinematic or stiffness studies of lumbar motion segments, and to evaluate muscular forces on the spine. Although all of these studies are helpful in answering specific questions, their relevance in assessing disc degeneration in patients with symptoms of discogenic pain must be carefully considered.     

Biological repair of the degenerated intervertebral disc by the injection of growth factors

The homeostasis of intervertebral disc (IVD) tissues is accomplished through a complex and precise coordination of a variety of substances, including cytokines, growth factors, enzymes and enzyme inhibitors. Recent biological therapeutic strategies for disc degeneration have included attempts to up-regulate the production of key matrix proteins or to down-regulate the catabolic events induced by pro-inflammatory cytokines. Several approaches to deliver these therapeutic biologic agents have been proposed and tested in a preclinical setting. One of the most advanced biological therapeutic approaches to regenerate or repair a degenerated disc is the injection of a recombinant growth factor. Abundant evidence for the efficacy of growth factor injection therapy for the treatment of IVD degeneration can be found in preclinical animal studies. Recent data obtained from animal studies on changes in cytokine expression following growth factor injection illustrate the great potential for patients with chronic discogenic low back pain. The first clinical trial for growth factor injection has been initiated and the results of that study may prove the usefulness of growth factor injection for treating the symptoms of patients with degenerative disc diseases. The focus of this review article is the effects of an in vivo injection of growth factors on the biological repair of the degenerated intervertebral disc in animal models. The effects of growth factor injection on the symptoms of patients with low back pain, the therapeutic target of growth factor injection and the limitations of the efficacy of growth factor therapy are also reviewed. Further quantitative studies on the effect of growth factor injection on pain generation and the long term effects on the endplate and cell survival after an injection using large animals are needed. An international academic-industrial consortium addressing these aims, such as was achieved for osteoarthritis (The Osteoarthritis Initiative), may further the development of biological therapies for degenerative disc diseases.

     

Biological treatment strategies for disc degeneration: potentials and shortcomings

Recent advances in molecular biology, cell biology and material sciences have opened a new emerging field of techniques for the treatment of musculoskeletal disorders. These new treatment modalities aim for biological repair of the affected tissues by introducing cell-based tissue replacements, genetic modifications of resident cells or a combination thereof. So far, these techniques have been successfully applied to various tissues such as bone and cartilage. However, application of these treatment modalities to cure intervertebral disc degeneration is in its very early stages and mostly limited to experimental studies in vitro or in animal studies. We will discuss the potential and possible shortcomings of current approaches to biologically cure disc degeneration by gene therapy or tissue engineering. Despite the increasing number of studies examining the therapeutic potential of biological treatment strategies, a practicable solution to routinely cure disc degeneration might not be available in the near future. However, knowledge gained from these attempts might be applied in a foreseeable future to cure the low back pain that often accompanies disc degeneration and therefore be beneficial for the patient. This study was supported by a grant from the AO Spine (SRN 02/103).     

Basic science of spinal degeneration

This article summarizes recent advances in our understanding of spinal pathology and pain. Degeneration appears to start in the intervertebral discs, often before age 20 years, and can be distinguished from ‘normal’ ageing by the presence of physical disruption, typically in the form of annulus fissures, prolapse or endplate fracture. Disruption is ultimately mechanical, but frustrated attempts by a small population of disc cells to heal a large avascular matrix give rise to the typical biological features of disc degeneration. Genetic inheritance and ageing are important risk factors for disc degeneration because they can weaken the disc matrix, and hinder repair processes. Discogenic pain appears to arise from the disc periphery as a result of in-growing nerves being sensitized by soluble factors from activated disc and blood cells. A degenerated disc loses pressure in the nucleus and bulges radially outwards, like a flat tyre. This often leads to a transient segmental instability, which can be reversed by the growth of osteophytes around the margins of the vertebral body. Annulus collapse in severe disc degeneration transfers compressive load-bearing to the neural arch, leading to facet joint osteoarthritis, and possibly to degenerative scoliosis. The anterior vertebral body then becomes relatively unloaded, and consequent focal bone loss (exacerbated by systemic osteoporosis) increases the risk of anterior wedge deformities, and senile kyphosis. Future interventions may include physical therapy to aid disc healing, disc prostheses with no moving parts, and injection therapies to block pain pathways.     

Biologic modification of animal models of intervertebral disc degeneration

Intervertebral disc degeneration is a chronic process that can become manifest in clinical disorders such as idiopathic low back pain, sciatica, disc herniation, spinal stenosis, and myelopathy. The limited available treatment options (including discectomy and spinal fusion) for these and other disabling conditions that arise from intervertebral disc degeneration are highly invasive, achieve limited success, and only address acute symptoms while doing nothing to halt the process of degeneration. Although the precise pathophysiology of intervertebral disc degeneration has yet to be clearly delineated, the progressive decline in aggrecan, the primary proteoglycan of the nucleus pulposus, appears to be a final common pathway. Animal models as well as in vitro studies of the process of disc degeneration have yielded many potentially useful targets for the reversal of disc degeneration. One current research trend is the use of established animal models of disc degeneration to study the role of therapeutic modalities in reversing the process of degeneration, often with use of the delivery of genes or gene products that influence the anabolic and catabolic pathways of the disc. This article reviews the ability of gene-product delivery systems and gene therapy to alter biologic processes in animal models of disc degeneration and examines future trends in this field.     

椎间孔镜下髓核摘除术治疗椎间盘退变性腰腿痛

目的探讨椎间孔侧路镜下髓核摘除术治疗腰椎间盘退变性腰腿痛的临床效果。方法2010-08-2011-11,我科对31例经保守治疗无效的腰椎间盘退变性腰腿痛患者实施了椎间孔侧路镜下髓核摘除微创手术。结果 YESS法穿刺15个间盘,TESSYS法穿刺19个间盘。随访3～6个月,平均4.2个月,失访2例。术前术后腰腿痛VAS评分有统计学意义(P<0.01)。术后3个月疗效MacNab评定:优17例,良8例,可3例,差1例,优良率86.2%。结论椎间孔镜技术治疗腰椎间盘退变性腰腿痛具有更微创、效果良好、恢复快优点,掌握好病例选择是关键。     

The effects of dynamic loading on the intervertebral disc

Loading is important to maintain the balance of matrix turnover in the intervertebral disc (IVD). Daily cyclic diurnal assists in the transport of large soluble factors across the IVD and its surrounding circulation and applies direct and indirect stimulus to disc cells. Acute mechanical injury and accumulated overloading, however, could induce disc degeneration. Recently, there is more information available on how cyclic loading, especially axial compression and hydrostatic pressure, affects IVD cell biology. This review summarises recent studies on the response of the IVD and stem cells to applied cyclic compression and hydrostatic pressure. These studies investigate the possible role of loading in the initiation and progression of disc degeneration as well as quantifying a physiological loading condition for the study of disc degeneration biological therapy. Subsequently, a possible physiological/beneficial loading range is proposed. This physiological/beneficial loading could provide insight into how to design loading regimes in specific system for the testing of various biological therapies such as cell therapy, chemical therapy or tissue engineering constructs to achieve a better final outcome. In addition, the parameter space of ‘physiological’ loading may also be an important factor for the differentiation of stem cells towards most ideally ‘discogenic’ cells for tissue engineering purpose.