Implantable microsystem for spinal cord adaptation to treat paraplegia - Project Part B: Neurobiological validation

Status:

completed 12/2011

Aims:

The aim of this project was the establishment of a mechanical micro system (mMS) to reconnect severed spinal cord tissue. In addition to the mechanical stabilization of the injury area the device offers the possibility of suction of the spinal cord stumps and a targeted delivery of pharmacological substances into the center of the lesion. A prototype had been designed in a preliminary design study (Innovationswettbewerb Medizintechnik, BMBF) and its principle function had been demonstrated using the spinal cord hemisection injury model in rat.

Activities/Methods:

The micro system's geometry was adapted to a complete transection injury and its design was optimized. Another casting method for micro system technical processing of bio- absorbable synthetic materials was developed. This process allowed the first fabrication of a bio-absorbable device. In a time series (5, 12 and 16 weeks post lesion and mMS implantation) to investigate the regenerative axon growth into the lumen of the device immunohistochemical staining and anterograde axon tracing showed a highly increased in-growth of nerve fibers. Axons of all analyzed fibre populations involved in motor function (corticospinal tract [CST], serotonergic [5-HT+], catecholaminergic [TH+]) and sensory function (posterior column [CGRP+]) could be detected in the mMS lumen (see preliminary report). Furthermore, regenerating axons of descending nerve fibers after lesion and mMS implantation also extended through the device into caudal spinal cord areas. In an additional behavioral experiment (20 weeks) more animals from the mMS group were able to reach or even exceed the mBBB threshold values of 5, 10 and 15 compared with transection-only controls. Furthermore, only mMS animals were able to reach the highest threshold value of mBBB 20.

Results:

A protocol was established to infuse pharmaceutically active substances directly into the lesion center via the device's internal channel system. The effect of iron chelator (DFO) infusion on functional improvement was investigated in a behavioral study. This study showed that the chelator infusion via mMS and osmotic minipump reduced collagen scar formation in the lesion area while it increases the positive effect of angiogenesis. Compared with control animals locomotor behavior of treated (mMS+DFO) rats was improved. This functional improvement in the mBBB open field test occurred on a lower level than in the previously performed studies. Therefore, pilot experiments to uncover the causes for these observations are planned in the context of future experiments. Finally, pilot experiments regarding future studies using the intended combination of mMS together with the transplantation of somatic umbilical cord blood-derived stem cells free of ethical issues were performed. The results of these pilot experiments in the complete transection lesion model indicate that the cell transplantation approach can also be applied to the mMS implantation model. According to the above-mentioned results the mechanical microconnector system is a suitable bridging device for the severed spinal cord. Not only does it lead to a markedly improved integrity of the spinal cord tissue but it further allows an increased regenerative axon growth of motor and sensory nerve fibers. Such positive events after its implantation into the acutely injured spinal cord bring about a considerable improvement in motor function.

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