The axonal fluid within the peripheral nerve is rich in neurotrophic factors and neuropoietic cytokines [5]. In an experimental model of primary nerve repair, we collected axoplasmic fluid from the proximal nerve stump and injected it underneath the epineurium after the performance of primary repair [6]. Our results showed that the number of myelinated axons were increased and the functional recovery was enhanced when axoplasmic fluid was supplied within the repair sites.

VEGF is a signaling protein that is normally involved in vasculogenesis and angiogenesis, yet it is known that peripheral nerves are also sensitive to VEGF. It has been stated that VEGF has a neurotrophic and mitogenic activity on cells in the peripheral nervous system, and in an avascular nerve graft model local application of VEGF promoted invasion of the graft with Schwann cells and neovascularization [7, 8]. Based on our unpublished data, we have found that, in the diabetic rat model, the VEGF treated nerves regenerated better after crush injury [1]. Recent literature further suggests that overexpression of VEGF via local gene transfer attenuates denervation atrophy following peripheral nerve injury [9].

DHEA is the most abundant circulating steroid in humans. Although it is mostly regarded as a metabolic intermediate in sex steroid biosynthesis, it also possesses certain biological effects on different types of tissues and acts as a neurosteroid [10]. All steroids are capable of reducing ischemia/reperfusion injury via blocking the formation of free oxygen radicals [11]. As the peripheral nervous system is rich in myelin and polyunsaturated lipid content, it is very sensitive to lipid peroxidation which may occur by the formation of free radicals after any given ischemia/reperfusion injury. In 1989, Schmelzer et al. was the first to report the effects of ischemia and reperfusion on peripheral nerves [12]. Since then, various therapy regimens directed against the formation of free radicals have found their places in the literature.

In two different studies we investigated the efficacy of DHEA on the regeneration of peripheral nerves in a crush injury model and a nerve transection model respectively [13, 14]. We noticed that, the subepineural injection of DHEA enhanced the recovery of crushed sciatic nerves in terms of the recorded sciatic functional indexes and the calculated myelinated fiber numbers [13]. We believe this effect was due to the anti-inflammatory and antioxidative properties of DHEA which further led to better restoration of endoneural microcirculation.

In our second study we wanted to see the effects of DHEA on nerve regeneration after nerve transection and epineural sleeve neurorraphy [14]. We supplied DHEA to the repair sites via intraoperative injections into the created epineural chambers and observed that DHEA proved to promote a faster axonal regeneration, and prevention of denervation atrophy.

In order to achieve an ideal regeneration environment, and avoid the interference of overt fibrosis, epineurium was used to cover primary nerve repair sites in previous studies [15, 16]. We have reported our own experience with the epineural sleeve neurorraphy technique in an experimental model in the rat sciatic nerve. Our technique was a modification of the original, with the use of 10-0 sutures to fix the overlapping epineural sheaths and avoiding the use of neural core sutures [17, 18]. We found the epineural sleeve neurorraphy technique to be superior to the conventional primary nerve repair techniques in terms of improved nerve regeneration and better functional recovery. The basic benefits of epineural sleeve neurorraphy technique were the decreased tension at the nerve repair site and the creation of a closed environment rich in neural factors to enhance axonal regeneration.

In another study, we bridged the sciatic nerve defects of rats with autogenous nerve grafts, and used the epineural sleeve technique for proximal and distal coaptation of the grafts. Our results proved that with the use of epineural sleeve technique a significantly better nerve recovery was recorded in terms of clinical, electrophysiological and histological parameters [19].

The most trusted and common method of bridging nerve defects is the use of autogenous sensory nerve grafts. Although one can find a rich spectrum of other reconstruction options in the literature, there is still no better method of reconstructing a nerve defect than bridging the gap with autogenous sensory nerve cables. Although autogenous nerve grafting was claimed as the gold standard method of reconstructing peripheral nerve defects, the procedure does not stand exempt from its possible complications and limitations. The limited source of available donor sensory nerves stands as the major limitation and the remaining sensory deficit in the sensory dermatome of the harvested peripheral nerve is just another drawback.

The sural, the lateral cutaneous forearm, and the medial cutaneous forearm nerves are the most commonly used donors due to the tolerable sensational losses occurring after their harvest. When a lower extremity donor nerve is selected another drawback is the less-favorable neural-to-connective tissue ratio as compared to upper extremity donor nerves [20]. Most of the time more than one sensory nerve cable is needed to reconstruct a motor nerve in order to achieve proper continuity and alignment of the nerve and this fact only increases the demand on a limited supply of donor nerves.

To overcome the shortage of sensory donor nerves within the body we wanted to investigate the efficacy of single fascicle nerve grafts for the reconstruction of peripheral nerve gaps. In an experimental study in the rat model we bridged sciatic nerve defects of 15 mm with whole trunk nerve grafts or single fascicular nerve grafts (large or small fascicular) and compared their regeneration potentials [21]. Single-fascicle grafting procedures resulted in faster functional recovery and better morphometric outcomes when compared with conventional nerve repairs as the grafts with smaller diameters suffered less ischemic injury during graft take as compared to their large diameter counterparts [21].

In 2004, Okuyama et al. stated that single and multiple fascicle nerve grafts revealed similar functional and histomorphological outcomes when used to bridge tibial nerve defects of 20 mm, and concluded that single fascicle grafts can be promising alternatives to large cable grafts clinically [22]. In 2011, Tzou et al. investigated bridging sciatic nerve defects of 25 mm with the use of whole trunk sciatic, single-cable sural and three-cable sural nerve grafts and concluded that although single fascicle nerve grafts had a potential in bridging nerve defects they were not as effective as the three cable and whole trunk nerve grafts [23].

From our previous studies we knew that the epineurium acted as a path for the regenerating nerve fibers [17–19]. We wanted to take its use one step further and created closed chambers of epineural tubes and filled them with supportive cells to obtain favorable microenvironments for enhanced nerve regeneration across nerve defects. For this purpose we put bone marrow stromal cells (BMSC) of isogenic origin within the epineural tubes that were created to bridge sciatic nerve defects of 20 mm in a rat model [24

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