Ratliff J K, Oldfield E H
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Neurosurg. 2001 Dec;95(6):1001-11. doi: 10.3171/jns.2001.95.6.1001.
Although the use of multiple agents is efficacious in animal models of peripheral nerve injury, translation to clinical applications remains wanting. Previous agents used in trials in humans either engendered severe side effects or were ineffective. Because the blood-central nervous system barrier exists in nerves as it does in the brain, limited drug delivery poses a problem for translation of basic science advances into clinical applications. Convection-enhanced delivery (CED) is a promising adjunct to current therapies for peripheral nerve injury. In the present study the authors assessed the capacity of convection to ferry macromolecules across sites of nerve injury in rat and primate models, examined the functional effects of convection on the intact nerve, and investigated the possibility of delivering a macromolecule to the spinal cord via retrograde convection from a peripherally introduced catheter.
The authors developed a rodent model of convective delivery to lesioned sciatic nerves (injury due to crush or laceration in 76 nerves) and compared the results to a smaller series of five primates with similar injuries. In the intact nerve, convective delivery of vehicle generated only a transient neurapraxic deficit. Early after injury (postinjury Days 1, 3, 7, and 10), infusion failed to cross the site of injury in crushed or lacerated nerves. Fourteen days after crush injury, CED of radioactively-labeled albumin resulted in perfusion through the site of injury to distal growing neurites. In primates, successful convection through the site of crush injury occurred by postinjury Day 28. In contrast, in laceration models there was complete occlusion of the extracellular space to convective distribution at the site of laceration and repair, and convective distribution in the extracellular space crossed the site of injury only after there was histological evidence of completion of nerve regeneration. Finally, in two primates, retrograde infusion into the spinal cord through a peripheral nerve was achieved.
Convection provides a safe and effective means to deliver macromolecules to regenerating neurites in crush-injured peripheral nerves. Convection block in lacerated and suture-repaired nerves indicates a significant intraneural obstruction of the extracellular space. a disruption that suggests an anatomical obstruction to extracellular and, possibly, intraaxonal flow, which may impair nerve regeneration. Through peripheral retrograde infusion, convection can be used for delivery to spinal cord gray matter. Convection-enhanced delivery provides a promising approach to distribute therapeutic agents to targeted sites for treatment of disorders of the nerve and spinal cord.
尽管在周围神经损伤的动物模型中使用多种药物有效，但转化为临床应用仍存在不足。先前在人体试验中使用的药物要么产生严重副作用，要么无效。由于神经中存在血脑屏障，药物递送受限给基础科学进展转化为临床应用带来了问题。对流增强递送（CED）是目前周围神经损伤治疗的一种有前景的辅助方法。在本研究中，作者评估了对流在大鼠和灵长类动物模型中使大分子穿过神经损伤部位的能力，研究了对流对完整神经的功能影响，并探讨了通过从外周插入的导管进行逆行对流将大分子递送至脊髓的可能性。
作者建立了一种向损伤坐骨神经进行对流递送的啮齿动物模型（76条神经因挤压或切割受伤），并将结果与一小系列五只具有类似损伤的灵长类动物进行比较。在完整神经中，载体的对流递送仅产生短暂的神经失用性缺陷。损伤后早期（损伤后第1、3、7和10天），输注未能穿过挤压或切割神经的损伤部位。挤压损伤14天后，放射性标记白蛋白的CED导致其通过损伤部位灌注到远端生长的神经突。在灵长类动物中，损伤后第28天成功实现了通过挤压损伤部位的对流。相比之下，在切割模型中，在切割和修复部位细胞外空间对对流分布完全阻塞，并且仅在有神经再生完成的组织学证据后，细胞外空间中的对流分布才穿过损伤部位。最后，在两只灵长类动物中，实现了通过外周神经向脊髓的逆行输注。
对流提供了一种安全有效的方法，可将大分子递送至挤压损伤的周围神经中再生的神经突。切割和缝合修复神经中的对流阻滞表明细胞外空间存在明显的神经内阻塞。这种破坏提示细胞外以及可能的轴突内流动存在解剖学阻塞，这可能会损害神经再生。通过外周逆行输注，对流可用于递送至脊髓灰质。对流增强递送为将治疗剂分布到靶向部位以治疗神经和脊髓疾病提供了一种有前景的方法。
