Invited Discussion

Brachial plexus injury reconstruction is a complex issue fraught with challenges for the reconstructive microsurgeon, and we commend these authors for tackling this important clinical problem.

The authors used the rat model to compare various ways of reinnervating the musculocutaneous nerve with nerve-transfer techniques. They used the ipsilateral anterior, posterior, or anterolateral portion of the anterior division of the C7 nerve root or the ipsilateral phrenic nerve to reinnervate the musculocutaneous nerve. Eight animals in each of these four operative experimental groups were assessed at different time points (1, 2, 3, and 4 months post-surgical intervention). At the earlier time points, they found superior regeneration in the anterior and posterior division groups, compared to that in the anterolateral portion of the anterior division of C7 and phrenic nerve groups. However, at 3 and 4 months, these differences were lost.

In studying nerve regeneration in the rodent model, the timing of outcomes assessment and nerve harvest is indeed crucial. Assessing results at a time too close to the operative intervention precludes evaluation, as regeneration will not yet have occurred. In contrast, evaluating regeneration “too late” will not show any differences between positive and negative controls, because of what we term the “blow-through” effect of regeneration associated with the rodent model. Previous work has found that there is an optimal, but narrow, range of time points at which to assess histomorphometric differences between experimental groups in the rodent model. Given enough time, rodents exhibit extremely robust nerve regeneration, even under significant challenge such as the use of interposed allograft material. Therefore, it is important to assess for inter-experimental group differences early enough to avoid the phenomenon that, later on, the results between groups would blend.

In an experiment[1] that investigated nerve allotransplantation in a rat model and had clear negative (MHC disparate allograft) and positive (isograft) controls, a 2.5-cm sciatic nerve graft was interposed. Subsequent histomorphometric assessment at 6, 8, 10, and 14 weeks post-grafting showed that only at the 10-week endpoint was there a statistically significant difference between the two control groups. The length of nerve graft used will also affect the time at which outcomes should be assessed. For example, if a shorter 2.0-cm graft is used, then an earlier 7-week endpoint will best assess differences between groups in this rat model.[2] In a murine model, a 0.8-cm graft will show differences at 3 weeks, which will be lost by 6 weeks.[3] In another type of rat nerve injury model-nerve transection and repair-21 days is the ideal time to assess for differences between groups.[4]

Further evidence of the robust nature of nerve regeneration in the rat model was provided by early work showing that spontaneous regeneration can occur for up to 2.4 cm in rodents.[5] The paper by Xu and colleagues shows excellent additional evidence of this robust regeneration in that, despite the fewer numbers of fibers present in the anterolateral portion of the anterior division of C7 and in the phrenic nerve, with enough time, regeneration at the level of that seen using the entire anterior or posterior division occurred.

Thus, we differ in the conclusions formed from the presented results. Our conclusion is that this experiment provides evidence that the anterolateral fascicles of the C7 anterior division and the phrenic nerve, with smaller numbers of nerve fibers, would not, in fact, be as useful a source for neurotization as donors with large nerve-fiber populations in the reconstruction of brachial plexus injuries. The concept that use of more motor nerve fibers leads to improved results has been supported previously: Cederna et al.[6] showed that reinnervation with a reduced number of nerve fibers results in diminished force generation by the corresponding skeletal muscle. In our view, the true findings from this study by Xu and colleagues were those revealed at the earlier time point, showing significant differences between the small and large donor-nerve groups, and not at the later time points, when no differences were noted between groups.

REFERENCES

• 1 Calvert G T, Doolabh V B, Grand A G et al.. Rat-strain differences in recovery following peripheral-nerve allotransplantation.  J Reconstr Microsurg. 2001;  17 185-191
• 2 Doolabh V B, Mackinnon S E. FK506 accelerates functional recovery following nerve grafting in a rat model.  Plast Reconstr Surg. 1999;  103 1928-1936
• 3 Grand A G, Myckatyn T M, Mackinnon S E, Hunter D A. Axonal regeneration after cold preservation of nerve allografts and immunosuppression with tacrolimus in mice.  J Neurosurg. 2002;  96 924-932
• 4 Sobol J B, Lowe III J B, Yang R K et al.. Effects of delaying FK506 administration on neuroregeneration in a rodent model.  J Reconstr Microsurg. 2003;  19 113-118
• 5 Mackinnon Se, Hudson A R, Hunter D A. Histologic assessment of nerve regeneration in the rat.  Plast Reconstr Surg. 1985;  75 384-388
• 6 Cederna P S, Youssef M K, Asato H et al.. Skeletal muscle reinnervation by reduced axonal numbers results in whole muscle force deficits.  Plast Reconstr Surg. 2000;  105 2003-2009