Lemke Angela, Penzenstadler Carina, Ferguson James, Lidinsky Dominika, Hopf Rudolf, Bradl Monika, Redl Heinz, Wolbank Susanne, Hausner Thomas
Ludwig Boltzmann Institute for Experimental and Clinical Traumatology/AUVA Research Center, Donaueschingenstraße 13, Vienna 1200, Austria
Austrian Cluster for Tissue Regeneration, Austria.
Dis Model Mech. 2017 Aug 1;10(8):1015-1025. doi: 10.1242/dmm.028852. Epub 2017 May 26.
Inflammation, fibrosis and perineural adhesions with the surrounding tissue are common pathological processes following nerve injury and surgical interventions on peripheral nerves in human patients. These features can reoccur following external neurolysis, currently the most common surgical treatment for peripheral nerve scarring, thus leading to renewed nerve function impairment and chronic pain. To enable a successful evaluation of new therapeutic approaches, it is crucial to use a reproducible animal model that mimics the main clinical symptoms occurring in human patients. However, a clinically relevant model combining both histological and functional alterations has not been published to date. We therefore developed a reliable rat model that exhibits the essential pathological processes of peripheral nerve scarring. In our study, we present a novel method for the induction of nerve scarring by applying glutaraldehyde-containing glue that is known to cause nerve injury in humans. After a 3-week contact period with the sciatic nerve in female Sprague Dawley rats, we could demonstrate severe intra- and perineural scarring that resulted in grade 3 adhesions and major impairments in the electrophysiological peak amplitude compared with sham control (=0.0478). Immunohistochemical analysis of the nerve structure revealed vigorous nerve inflammation and recruitment of T cells and macrophages. Also, distinct nerve degeneration was determined by immunostaining. These pathological alterations were further reflected in significant functional deficiencies, as determined by the analysis of relevant gait parameters as well as the quantification of the sciatic functional index starting at week 1 post-operation (<0.01). Moreover, with this model we could, for the first time, demonstrate not only the primary formation, but also the recurrence, of severe adhesions 1 week after glue removal, imitating a major clinical challenge. As a comparison, we tested a published model for generating perineural fibrotic adhesions, which did not result in significant pathological changes. Taken together, we established an easily reproducible and reliable rat model for peripheral nerve scarring that allows for the effective testing of new therapeutic strategies.
炎症、纤维化以及与周围组织的神经周粘连是人类患者神经损伤和外周神经外科手术后常见的病理过程。这些特征在外周神经松解术后可能再次出现，外周神经松解术是目前治疗外周神经瘢痕形成最常用的外科治疗方法，从而导致神经功能再次受损和慢性疼痛。为了成功评估新的治疗方法，使用一种可重复的动物模型来模拟人类患者出现的主要临床症状至关重要。然而，迄今为止尚未发表一种结合组织学和功能改变的临床相关模型。因此，我们开发了一种可靠的大鼠模型，该模型展现了外周神经瘢痕形成的基本病理过程。在我们的研究中，我们提出了一种通过应用含戊二醛的胶水诱导神经瘢痕形成的新方法，已知这种胶水会导致人类神经损伤。在雌性斯普拉格 - 道利大鼠中，让胶水与坐骨神经接触3周后，我们能够证明存在严重的神经内和神经周瘢痕形成，导致3级粘连，并且与假手术对照组相比，电生理峰值幅度出现重大损伤（假手术对照组=0.0478）。对神经结构的免疫组织化学分析显示神经有强烈炎症以及T细胞和巨噬细胞的募集。此外，通过免疫染色确定了明显的神经变性。这些病理改变在显著的功能缺陷中进一步体现出来，这是通过分析相关步态参数以及从术后第1周开始对坐骨神经功能指数进行量化确定的（<0.01）。此外，利用这个模型我们首次不仅证明了严重粘连的初次形成，还证明了在去除胶水1周后粘连的复发，这模拟了一个主要的临床挑战。作为比较，我们测试了一种已发表的用于产生神经周纤维化粘连的模型，该模型未导致显著的病理变化。综上所述，我们建立了一种易于重复且可靠的外周神经瘢痕形成大鼠模型，可用于有效测试新的治疗策略。
