„Pathway protection“ – Verbesserte Motoneuron-Regeneration durch additive End-zu-Seit-Koaptation sensorischer Axone

Zusammenfassung

Die neuronale Regeneration nach proximaler Nervenverletzung und nach zeitlich verzögerter Nervenrekonstruktion ist eingeschränkt, was klinisch eine große Herausforderung darstellt. Experimentelle Studien haben gezeigt, dass die periphere Nervenregeneration einerseits durch die „chronische Axotomie“ der neuronalen Zellkörper und der proximalen Axone, welche von ihren Zielstrukturen getrennt sind und andererseits durch die „chronische Denervation“ des distalen Nervens beeinträchtigt wird. Der denervierte distale Nerv durchläuft Veränderungen, die mit der Waller´schen Degeneration assoziiert sind. Es kommt zu einer Aktivierung der Schwann-Zellen, die mit einwachsenden Axonen interagieren und deren Regeneration fördern, sowie zu einer Erhöhung der Konzentration von Wachstumsfaktoren. Diese Veränderungen führen zu der Entwicklung eines regenerationsfördernden Milieus im distalen Nerven, welches allerdings zeitlich begrenzt ist und bei lange andauernder Denervation abnimmt. Dies führt zu einer deutlichen Reduktion der neuronalen Regeneration. In der klinischen Situation führen proximale Nervenverletzungen, Rekonstruktionen mit langen Regenerationsdistanzen und verzögerte Nervenrekonstruktionen zu eingeschränkten funktionellen Ergebnissen. Um die neuronale Regeneration zu verbessern, wurden verschiedene Techniken der „pathway protection“ entwickelt, welche die chronische Denervation des distalen Nervens und der Zielorgane reduzieren sollen. Der Großteil dieser „Babysitter-Techniken“ verwendet motorische Spendernerven, die meist End-zu-Seit an den denervierten distalen Nerven koaptiert werden. In experimentellen Studien wurde gezeigt, dass es durch die einwachsenden Spenderaxone zu einer Erhöhung der Konzentration von Wachstumsfaktoren kommt und dass die distalen Zielorgane früher reinnerviert werden können. Durch motorische „Babysitter-Operationen“ wird allerdings ein motorisches Spendernervdefizit geschaffen. Um dieses zu umgehen wurde in den letzten Jahren die Möglichkeit der „pathway protection“ mit sensiblen Spendernerven untersucht. In experimentellen Studien konnte die motorische Regeneration durch End-zu-Seit-Koaptation sensibler Spendernerven an den distalen denervierten Nerven, beziehungsweise an lange Nerventransplantate, die Veränderungen der „chronischen Denervation“ durchlaufen, verbessert werden. Die sensible „pathway protection“ wurde bereits klinisch eingesetzt, es liegen allerdings noch keine funktionellen Langzeitergebnisse vor.

Abstract

Proximal nerve injuries and delayed nerve repair lead to reduced peripheral nerve regeneration. Poor functional results after nerve injury are clinically a very challenging problem. Experimental studies defined “chronic axotomy” of the neuron and the proximal part of a dissected nerve that are separated from their distal target, as well as “chronic denervation” of the distal nerve stump as an independent factors that reduce regenerative capacity of injured nerves. The denervated distal nerve undergoes changes associated with Wallerian degeneration. Denervated Schwann cells change their phenotype to interact with in-growing axons and increase the expression of growth factors. These changes lead to a pro-regenerative environment in the distal nerve stump. This growth-permissive environment deteriorates with time leading to significantly reduced nerve regeneration. Clinically, delayed nerve repair and long regeneration distances often result in inadequate functional outcomes. Different “pathway protection” techniques were developed to improve nerve regeneration and reduce the chronic denervation of the distal nerve. Most of these “babysitter” procedures used a motor donor nerve which was coapted usually end-to-side to the denervated distal nerve stump. Experimental studies showed that in-growing donor axons increase neurotrophic factor levels and improved reinnervation of distal targets. Motor “babysitter” procedures are, however, associated with a motor donor nerve deficit. In recent years, sensory “pathway protection” was investigated to avoid such motor deficit. Motoneuron regeneration of its axons can, in experimental animal models, be improved by end-to-side coaptation of sensory donor axons to either a denervated distal nerve stump or to a long autologous nerve graft, both of which undergo changes associated with chronic denervation. Sensory “pathway protection” has already been successfully clinically applied, however long-term functional analysis awaits.

Schlüsselwörter

Denervation - Chirurgie der peripheren Nerven - Nervenregeneration - Experimentelle Chirurgie - Wachstumsfaktoren - Schwann Zellen

Key words

Nerve reconstruction - peripheral nerve injury - Schwann cells - growth factors - babysitter technique

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