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Electrical Stimulation and Tacrolimus (FK506) Enhance Recovery After Nerve Surgery and the Dual Use of Both Therapeutics Reduces Variance in Functional Outcomes.
Evan B Marsh, BS1; Lauren Schellhardt, BS2; Dan A. Hunter, RA3; Mackinnon Susan, MD, FRCS(C), FACS4; Snyder-Warwick K Alison, MD5; Matthew D Wood, PhD2
1Washington University in Saint louis, Saint Louis, MO; 2Washington University School of Medicine, St Louis, MO; 3Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St Louis, MO; 4Biomedical Engineering, Washington University in Saint Louis, Saint Louis, MO; 5Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, Saint Louis, MO

Electrical stimulation and tacrolimus (FK506) enhance recovery after nerve surgery and the dual use of both therapeutics reduces variance in functional outcomes.

Introduction: Repaired nerve injuries can fail to achieve functional recovery. Therapeutic options in addition to surgery, such as systemic tacrolimus (FK506) and electrical stimulation (E-stim), can improve recovery. We tested whether dual administration of FK506 and E-stim further enhance regeneration and recovery than either therapeutic alone using rat models.

Methods: Rats were randomized to four groups: E-stim, FK506, FK506 + E-stim, and Repair Alone. All groups underwent tibial nerve transection-and-repair. Two sets of animals were utilized to measure outcomes of early nerve regeneration using nerve histology and functional recovery (21- and 42-day endpoint respectively). Functional recovery was measured by behavioral analyses (walking track and grid-walk) and at the endpoint, muscle mass and force.

Results: Dual E-stim and FK506 administration produced histomorphometric measurements of early nerve regeneration no different than either therapeutic alone. All treatments were superior to Repair Alone (Figure 1A). E-stim and FK506 + E-stim groups had generally improved behavioral recovery based on both analyses compared to Repair alone (Figure 1B,C). The FK506 group had improved recovery only based on walking track analysis and muscle force and mass.

Discussion: Dual administration of FK506 and E-stim showed minimal additive effects to further improve regeneration or recovery compared to either therapy alone. However, the concurrent use of both therapies ensured earlier functional recovery and decreased variability in functional outcomes compared to either therapy alone, suggesting a moderate benefit. Given the high variability generally observed in clinical outcomes, this benefit of reduced variance could be advantageous for clinical translation.
Figure 1: A, Histomorphometric outcomes of total number of fibers 21 days after nerve transection and repair. B, Recovery at 42 days after tibial nerve injury and repair measured by walking track analysis. All experimental groups had better TFI values compared to repair alone. FK506 had the greatest mean TFI and FK506 + E-stim had the lowest variance of any group. C, Recovery after tibial nerve injury and repair measured by grid-walk assessment. FK506 + E-stim animals showed the greatest improvement compared to repair alone and had the lowest variance of any group. All data presented as mean SD. *P<0.05. **P<0.01. ***P<0.001. ****P<0.0001.

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