Poly-caprolactone Nanofiber Nerve Wrap Improves Nerve Regeneration and Rodent Functional Outcomes after Delayed Nerve Repair
Joseph Lopez, MD MBA, Kevin Xin, BS, Amy Quan, MD MPH, Kimberly Xinan, BS, Angelo A. Leto, MD, Joshua Budihardjo, BS, Zuhaib Ibrahim, MD, Hai-Quan Mao, MD, WP A. Lee, MD, Gerald Brandacher, MD.
Johns Hopkins Hospital, Baltimore, MD, USA.
Background: Proper nerve repair plays a critical role in facilitating a neuron's ability to regenerate an axon after nerve injury. Unfortunately, nerve repairs can be compromised by scar proliferation and inter-fascicular connective tissue formation. These factors can have a deleterious impact on patient recovery. As a result, there has been a long-standing clinical interest in developing neuroprotective agents that can reduce the scar burden and improve peripheral nerve regeneration after nerve transection. The purpose of this study was to assess the efficacy of biodegradable, electrospun poly-caprolactone (PCL) nanofiber nerve conduits in improving nerve regeneration. We hypothesized that PCL nerve conduits would improve nerve regeneration and rodent extremity function by decreasing scar deposition at nerve co-aptation sites.
Methods: We utilized a novel, rat forelimb chronic denervation (CD) model to assess the effects of PCL conduits on: a) improving nerve regeneration; and b) improving upper extremity function. Three groups of rats were examined: (1) Group-1 (n = 5) underwent 8 weeks of median nerve CD injury followed by repair with no conduit; (2) Group-2 (experimental, n = 5) underwent 8 weeks of median nerve CD followed by repair and PCL nerve conduit wrapping of the nerve co-aptation site; (3) Group-3 animals (n = 5) were na´ve controls. All animals underwent nerve conduction studies on weeks 12 post-repair. All animals also underwent weekly muscle functional testing. At weeks 14 post-repair, the median nerve and flexor muscles were harvested for nerve histomorphometry and muscle weight. To enable the assessment of scarring at the nerve repair site, nerve samples were stained for collagen using direct red 80 sirius red stain. A student t-test was used to evaluate for statistical significance.
Results: Histomorphometric analysis of regenerating nerve fibers in the median nerve demonstrated relatively robust axonal regeneration in Group 2, with higher total axon count, myelin thickness, axon diameter when compared to the Group 1. The difference in total axon count between Group 2 and 1 was statistically significant (Group 2 = 1769 ▒ 672 axons, Group 1 = 1072 ▒ 123.80 axons, p = 0.0468). Furthermore, the difference in flexor muscle mass weight between the group 2 and group 1 was statistically significant (Group 2 = 0.629 ▒ 0.054, Group 1 = 0.511 ▒ 0.07, p < 0.05). With regard to functional recovery, at 14 weeks post-repair, Group 2 had regained 34.9 % of na´ve baseline hand grip strength. In comparison, Group 1 regained only 25.4% of baseline hand grip strength. Between group 2 and 1, the difference in grip strength was statistically significant (Group 2 = 1.67 ▒ 0.04, Group 1 = 0.97 ▒ 0.39, p = 0.036). Sirius red staining revealed less collagen deposition at the nerve co-aptation site of Group 2 animals when compared to group 1 animals (p < 0.05).
Conclusion: Biodegradable, PCL nanofiber nerve conduits can improve nerve regeneration and subsequent physiological extremity function in the setting of delayed nerve repair by decreasing the scar burden at nerve co-aptation sites.
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