PROSPECTS FOR DEVELOPMENT OF TECHNOLOGIES FOR RESTORATION OF EXTENDED NERVE DEFECTS WITH USE OF CONDUITS

PROSPECTS FOR DEVELOPMENT OF TECHNOLOGIES FOR RESTORATION OF EXTENDED NERVE DEFECTS WITH USE OF CONDUITS

Tuturov A.O., Sergeev S.M.

Samara State Medical University,  Pirogov Samara City Clinical Hospital No.1, Samara, Russia

Despite of success in microsurgical technique and studies of pathophysiological mechanisms, recovery of peripheral nerves is one of the main problems in traumatology and neurosurgery. Such diseases as Guillain-Barre syndrome and malignant tumors cause the nerve trunk injuries. Mechanic injuries take the first place in etiology [1-6].
Peripheral nerves demonstrate some regenerative properties, which promote the spontaneous growth and development of favorable conditions for recovery [7]. Despite of this, a degree of innervations depends on multiple factors: sizes of diastasis between crossed ends, presence of a nerve laceration, delay in the presurgical period and selection between required surgical manipulations during treatment [8].
Previously, the gold standard of recovery of extensive defects of peripheral nerve trunks was transplantation of autological part of the nerve. Now this technique is criticized because of long term results. The common complications are neuromas in regions of diastasis replaced by the graft, partial or full recovery of sensitivity, a high probability of rotation of nervous fiber bundles in different planes. At the same time, the significant disadvantages of autografting are requirement for additional surgery and limited selection of tissues for grafting [9].
The results of analysis of the above-mentioned disadvantages promoted the search for alternative treatment methods. Currently, the special attention is given to replacement of posttraumatic diastasis with the conduit. Initially such techniques were presented by the region of the humeral artery [O. Bunger 1891], then – with autoveins [Wrede 1909]. At the same time, they were accompanied by some disadvantages: limitation in selection of a required diameter, absence of appropriate donor vessels, decline in venous wall during regeneration and others [10]. The search for ways of correction of these problems caused the creation of artificial conduits [11].
During the last two years, the researchers have directed to the new goal: recovery of extensive defects of nerve trunks with serious injuries with disordered integrity of the nerve and posttraumatic diastasis more than 3 cm. Previously, it was considered that recovery of such injuries is the unreal task because of impossibility of accurate apposition of nerve fibers. It can cause the ingrowth of sensitive axons into motional pathways with subsequent loss of function of the whole nerve trunk [13].
This review analyzes the features of technologies and results of their use for determination of the key directions and for identification of perspectives for future studies. 

Key directions OF the studies

There is a classification of nerve plasty methods with use of various grafts. It includes three groups:
1. Nerve autografting.
2. Tissue autografting for creation of direction for nerve regeneration.
3. Creation of artificial conduits and (or) xenografts for direction of nerve regeneration [14].

The presented classification also demonstrates the stages of development of the technology for recovery of extensive nerve defects with use of conduits. Actually, to replace the autografting, some variants of direction of regenerative processes in nervous tissue through bone-muscle channels, arteries and veins were developed. Only after the second stage of development of technologies for nerve recovery, the researchers gave their attention to development of artificial conduits. The modern conduits appeared only in the end of 20th century.
Analyzing the modern techniques for nerve recovery with use of conduits, we have concluded that all techniques for conduit improvements have four main directions:
1. Studying of external factors influencing on regeneration in nerve conduit and on processes of vitality.
2. Development of the ideal conduit with the following properties: nerve impulse conduction, biodegradability, biocompatibility with nerve tissue, mechanic strength, diffusion of nutrients, directed growth of each nerve fiber.
3. Creation of optimal conditions for regeneration of nerve trunk by means of internal media with fluid or other structures stimulating the growth of nerve fibers, trophy and prevention of neuroma.
4. Recovery of posttraumatic defects of cranial nerves and research of regeneration potential by means of use of technologies stimulating the reinnervation of spinal nerves.

Such classification is optimal for goal-oriented initiation of studies since it allows the direct concentration on researching of the definite field of this method for nerve recovery. This technique can be reviewed according to the above-mentioned points. It simplifies the task of identification of disadvantages in techniques and facilitates the search for future perspectives.
We believe that such directions as the decrease in possibility of injuries to surrounding tissues during installation and use of the conduit or its proper fixation to the nerve are not so significant. They are quite individual and depend on salvation of issues of the surgical approach, selection of surgical technique and features of posttraumatic state of the nerve trunk.

Influence of external factors on nerve regeneration in the conduit

Some researchers of the previous century [Kosaka M. 1990, Kakinoki R. et al., 1998] made the significant influence on development of a new property of the ideal conduit. Their works indicated the importance of connection between the conduits and vessels. During the surgery, the surgeons separated the artery near the injured nerve and placed it into the crevice of the wall of silicone conduit. Then the canal with artery was closed with the same material, and this item was sutured into the space between the crossed ends of the nerve. This procedure provided both direction of nerve tissue growth and deliver of nutrients to nerve fibers in the conduit cavity.
The result of the study was the following conclusion: the vessels inside the conduit wall allow regeneration of axons over the longer distance, but without increase in number of the diameter. Therefore, this conduit can be used for regeneration of nerve in diastasis, which does not exceed the critical length of recovery with non-vascularized conduits [15]. The objective of the procedure was acceleration of reinnervation, but not the attempts for reparation of the nerve with big diastasis.
The vascularized wall of the conduit is the very efficient property of the ideal conduit, which has been lost at the present time.

CONCEPT OF IDEAL CONDUIT

Mentioning the artificial conduit for nerve trunk regeneration, it is necessary to indicate the advantages and possibilities, which are not common for the autograft. Firstly, the structure of the conduit is characterized by selectivity, which prevents entry of scar tissue into the cavity, and allows delivery of oxygen and nutrients. Secondly, flexibility and elasticity of the conduit prevent the nerve compression, which often causes some postsurgical complications [16, 17]. Thirdly, biocompatibility and biodegradability of the materials of the conduit make the positive influence on the condition of the nerve after surgery and promote the faster regeneration [18].
Multiple experimental studies [Lundborg et al.] showed that nerve regeneration over 3-5 mm is possible only with appropriate recovery of nerve tissue structure and its functional elements. This result can be compared with nerve trunk regeneration after standard microsurgical manipulations. But if such type of conduits is used for bigger diastasis, it can be harmful due to toxicity and/or rends to decrease [19, 20]. If the wall of the conduit is too thick, its degradation is too slow, resulting in increasing probability of possible pathologic influence as a foreign body. Small intestinal wall is more prone to early degradation and decreasing influence of abnormal processes in the nerve. The ideal proportions of the conduit were selected solving this problem: the diameter – 1.5 mm, the wall thickness – about 0.3 mm [21].
As mentioned, the ideal conduit should include the ability to conduct the nerve impulse for single-moment restoration of structure and functions of the nerve trunk [22]. The alternative property is stimulation of nerve regeneration inside the conduit with use of direct current going through the polymer composites. Three experimental groups were compared. The first group was presented by the conduit with microwires for sessions of electric stimulation (ES). The second group was presented by the conduit without contact with electrodes. The third group was presented by autological insert of the nerve part. ES demonstrated the potential of 100 mV through microwires going through the skin into the conduit. The sessions of stimulation were carried out under narcosis during one hour, 1, 3, 5 and 7 days after grafting. Then ES program was completed.
As result, the researchers proved that their technique with direct current was similar with nerve recovery with autografting technique according to most parameters. When comparing the results with the standard conduit, the significant advantage of the ES tube was found. The thickness of myelin sheath was significantly higher (0.51 ± 0.08 µm vs. 0.36 ± 0.11 µm). Also the total amount of myelin sheaths and their diameters were higher in the ES group [23].
The structure of the conduit wall is quite variable unit. Analyzing the materials for production of cylindric conduits, one should note that they have the rigid structure, for example, polyethyleneglycol. Using its physical properties and microstereolithography, the researchers were able to add multiple longitudinal hatches to the internal wall which promote the partial growth of nervous fibers [24]. Ryan A. Koppes et al. offered their technique for making the hatches on the internal surface of the conduit. The study included the making of “thermal pictures” on the wall of the conduit which influence on increasing quality of growth of nerve fibers in the conduit [25]. As result, 92.3 % of the cells in microchannels were positively stained for S-100 protein, meaning the migration of Schwann's cells in crevices of the conduit. The rate of growth of the neurite inside the conduit with hatches is 1.8-1.9 times higher, and the length is 2.4-3.4 times higher than inside the conduit with the smooth wall.
The main result of the study was the confirmation of the property of the ideal conduit: the conduit must contain the microchannels for precise apposition of nerve fibers [26].
Each artificial conduit has at least one significant disadvantage: need for production. In some studies, only the material synthesis takes several weeks. For solution of this problem, the conduit made of extracellular matrix of swine urine bladder was tested. The size of the diastasis was 10 mm. The comparison with the autograft gave some results, which had showed that the swine conduit was at least similar to the effect of the autological nerve insert. The foot movements were more active after 4 weeks in the group of extracellular matrix. After 6 weeks, the higher amount of sensitive axons was observed in the conduit (455 ± 31 vs. 140 ± 34) and in more distal region (253 ± 27 vs. 77 ± 14) as compared to the autograft group.
Therefore, it was found that the presented matrix stimulated the growth of sensory fibers. According to some authors, it is promoted by structural proteins (laminin, fibronectin, collagen) in the extracellular matrix of swine urine bladder [27].
From one side, the technique reduces the presurgical preparation as some authors found [L. Nguyen et al.], but from other side, the technology of the extracellular matrix protein requires for constant availability of this material in the hospital and specific conditions of storing.
Certainly, a lot of studies show the bordering position from the perspective of the above-mentioned classification. It has some additional criteria. An example of such bidirectional work is the technology for nerve recovery with use of macromesh electrodes. During surgery, the microwires were positioned under the proximal muscles and were placed into the subdermal pocket on the animal’s back. As result, the electrodes penetrating the wall of the conduit with radial branching from the center to the circumference stimulated the growth of nerve fibers and directed the fibers in the interval manner [28]. One should note that the animal showed the better walking habits during 3 months after surgery. The representative parts of follow-up of the lower extremities showed the progressing increase in spreading of toes and the decrease in the length of prints in comparison of early postsurgical period with the late one.
The last studies demonstrated one of the possible ways for use of RGD. This peptide can be used as the internal covering of the conduit for stimulation of regeneration processes. The use of RGD-covering at the early stage of regeneration of peripheral nerves provides the activation of Schwann's cells, leading to improvement in adherence to the conduit and development. From this point of view, beta tricalcium phosphate (β-TCP) is interesting. It is non-toxic and provides the high porosity [29].
The covering made of these substances can be reviewed as the alternative for internal medium of the conduit.

INTERNAL MEDIUM OF THE CONDUIT

Another variant of optimization of nerve fiber growth is the use of grouped matrices/particles of neurotrophic factors in biodegradable microspheres. At the present time, there are some projects, which include the nanotechnologies, slow release of growth factors [30] and inoculation of Schwann's cells or stem cells. However the efficiency of these studies is unclear due to potential danger. Some research groups reported that stem cells can be similar with cancer cells and express markers in multiple human and murine oncogenic models [31, 32].
A perspective direction is the use of various growth factors of the nerve [33, 34, 35], for example, gelatin microspheres with BDNF in gelatin-methacrylamide hydrogel in two-layer conduit made of collagen [36]. Estimating this system, one can note multiple positive properties: the biodegradable conduit, potential use of autological tissues, well calculated internal medium, which does not require for external nutrition. The single moment, which makes the negative influence on complete structural and functional nerve recovery, is absence of tissue relatedness between nerve tissue and the conduit. Certainly, it plays the role of the directing channel and does not make any negative influence on the nerve after degradation, but the regeneration is to be realized in maximally identical conditions. The search for appropriate materials is required since not all ways for recovery of extensive defects of nerve trunks were used at the present time.
A study of the web of Nephila spiders resulted in development of a new type of the conduit. The silk with intrachannel system for direction of nerve fibers along big intervals (up to 15 cm) could be a quite adequate technology for nerve reconstruction [37]. Many conduits lose their positive properties in recovery of total nerve injuries. Certainly, there were many conduits with good values of restoration of lost integrity over short intervals (2-3 cm), but none of them could make any significant influence on a bigger nerve defect [38, 39, 40]. Moreover, the silk conduit can restore the total nerve injury. It is biodegradable and almost biocompatible with nerve tissue. But the time required for conduit production and selection of required diameter for the injured nerve trunk changes the further tasks and methods of solution.

CRANIAL NERVE INJURIES

Studies of recovery of cranial nerves are common at the present time. Mainly, the seventh pair is studied. It is affected by multiple factors. A serious injury to this nerve causes its peripheral paralysis. In 2009, the researchers [Tan et al.] could perform the recovery of the facial nerve with 100 mm diastasis over 8 weeks. Other results testified some improvements or real facts influencing on success of reinnervation of the seventh pair [11, 41, 42].
Currently, the special interest is given to the system for anastomosing of the facial nerve and the hypoglossal nerve by the end-to-side type [Yamamoto Y. et al., 2007]. Trying to prevent the common complications of neurography, the researchers used the technology of tabulated nerve trunk for its regeneration. They used the conduit for cooperative effect of regeneration processes of the perpendicular-oriented nerves. In this case, the silicone conduit was sutured to the end of the facial nerve on one side and to the hole in epineural sheath of the hypoglossal nerve on other side. Electric stimulation of reinnervated nerves was performed at the final stage of the tests. For estimation of the results, this technique was compared with nerve recovery after use of the autograft of end-to-side type. There were some mild differences in duration of muscular response in the group of the autological insert and the silicone conduit (0.89 ± 0.63 ms and 1.08 ± 0.30 ms correspondingly).
The results show the successful testing of the end-to-side conduit system, as well as possible use of this technology for other cranial nerves [43].

CONCLUSION

It is important to research the development of the most perspective field of restorative medicine. Most research groups give their attention to acceleration of regeneration processes and increasing distance of the restored diastasis, although these tasks have been solved mostly.
Currently, more attention should be given to formation of the conduit and its internal medium with maximal similarity to morphology and physiology of the nerve by means of development of close analogues of nerve tissue, but not by means of attempts of replacement. Now the conduit should combine the maximal amount of the following properties: fast production, preserved vascularization, biodegradability or homology to nerve tissue, presence of directing hatches on the internal wall or microchannels in the cavity, an ability to diffuse the nutrients and to conduct the nerve impulse. The internal medium should be homological to the nervous one and should combine the necessary substances promoting the regeneration ad growth of neuritis in normal conditions. They are natural media and elements of the body, for example, genuine cerebrospinal fluid, Schwann's cells, neurotrophic factors and others.

Information on financing and conflict of interests

The study was conducted without sponsorship.
The authors declare the absence of any clear and potential conflicts of interests relating to publication of this article.

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