At first, material scientists may not always be appropriately introduced by their collaboration partners to the specific needs of the biological system they are asked to develop biomaterials for. This can lead to discrepancies, and although the most modern fabrication techniques are used, the developed material compositions may become inappropriate. One example we have experienced in our own group is the properties of an electrospun polycaprolactone nerve guide that, although the qualification of this synthetic polymer has been proven before [23], did in our hands induce a massive and deleterious foreign body reaction upon suture between separated nerve ends [12]. Another example is the natural polysaccharide chitosan, which was already in the 1990s used as biomaterial for nerve guide fabrication but demonstrated insufficient stability to be further processed into a clinical product [16]. Anyhow chitosan was further investigated for its use as a biomaterial for neural repair [20], and finally, about 20 years later, an optimized nerve guide was developed [24] and registered for clinical use (nerve gap repair <3 cm) in Europe and the USA (see Chap. 5). A third example, again from our own laboratory, is the use of a hyaluronic acid-based laminin containing hydrogel, originally developed to support regeneration of vascular and neural tissue and with favorable properties for organotypic in vitro cultures of sensory dorsal root ganglia [43, 58]. Surprisingly, this specific hydrogel did, instead of supporting the regeneration process, impair peripheral nerve regeneration [38]. In general, hydrogels are used to provide a matrix in which invading or transplanted cells feel as confident as in their physiological destinations. In the context of peripheral nerve regeneration, the hydrogel should support the migration of Schwann cells and other support cells, like, e.g., the pro-regenerative macrophages mentioned before. But when it comes to the questions of how cell-friendly the hydrogel filler and how porous the wall of the NGC should be, specific interactions have to be considered. A recent study demonstrated that when the porous properties of the NGC wall allow uncontrolled infiltration of the cell-friendly hydrogel filler with fibroblasts, this will negatively interfere with the nerve regeneration process [13]. Interestingly, a much simpler modification of a hollow single lumen chitosan nerve guide, namely, the longitudinal introduction of a central chitosan film, was much more successful in increasing the regeneration outcome across a critical defect length of 15 mm in the rat sciatic nerve after immediate [37] and after delayed nerve reconstruction [52]. It can be expected that translation of this two-chambered chitosan nerve guide design into a medical product will be done in a reasonable period. As another example for fruitful collaboration between material scientists and clinical scientists, a more complex, microstructured collagen nerve guide has been developed recently. This specific nerve implant allowed successful nerve repair across a 20 mm sciatic nerve gap in the rat [4] and can also be filled with mesenchymal stem cells for cellular regeneration support [3]. For the latter nerve guide, first results from a clinical study are expected in not later than 1–2 years’ time.

Another obstacle for the translation of all the recent innovations into a promising new medical product, likely, is the fact that many attempts are not adequately evaluated. Simple biocompatibility studies may convince material scientists in the first step, but the novel biomaterials may reveal non-appropriate properties when tested in a more comprehensive way in challenging preclinical models. The highest potential for a propagation of a novel nerve guide into a medical product for clinical use have those approaches that have proven their regeneration-supporting properties in comprehensive in vitro and in vivo studies. Reports that conclude only from biocompatibility studies with glial cell lines, for example, that a biomaterial is very promising for the fabrication of a NGC, are of minimal value for clinical scientists. In vitro studies utilizing cell lines can indeed reveal important information, but the cell lines need to be appropriate for the specific field of neural regeneration addressed. And for a more substantial indication of the biomaterial properties, those studies need regularly to be followed by evaluation of the behavior of primary nerve cells [19]. Also from an ethical point of view, in vitro studies are warranted to reduce the number of animals devoted to in vivo experiments, but a final comprehensive preclinical in vivo evaluation, probably also in different animal models, is unavoidable [19]. A meaningful result from in vivo studies, again, will only be obtainable when the different levels of peripheral nerve regeneration that range from proven regeneration of axons across a substantial distance over evidenced reinnervation of distal targets (including indicated specificity of this reinnervation) to, most important, functional recovery [6, 44] are appropriately evaluated. Qualified preclinical animal models should recapitulate the specific nerve regeneration processes, which also take place during peripheral nerve regeneration in human patients. The rat sciatic nerve transection and reconstruction model is the far most used in vivo system [1, 18]. Therefore, studies using this model have a higher value with regard to comparability among each other. The rat sciatic nerve model allows evaluation of the reconstruction of defect lengths up to 15–20 mm in a large variety of functional assessments [6, 44]. Although already accepted as a critical defect length model, the critical defect length in human patients is considerably longer (> 10 cm), but the rat sciatic nerve model is still the most appropriate and at best standardized model [1]. The rat median nerve model is considered to be appropriate for extrapolation toward human upper limb or digital nerve injuries and provides from an ethical point of view the high advantage of only minimal impairment for the animal well-being [28]. Rat models have further been developed to additionally address different health conditions and their impact on peripheral nerve regeneration. Studies performed in the Goto-Kakizaki rat that presents with moderately increased and clinically relevant blood glucose levels, thus resembling diabetes type 2 conditions [50, 51], deliver information important for an increasing amount of patients. The mean life expectancy of the laboratory rat additionally allows consideration of delayed nerve reconstruction approaches, a condition that is also highly relevant for a significant number of patients in which primary nerve reconstruction cannot be performed due to a seriously affected general health condition [9]. Finally, after comprehensive preclinical investigation, first inhuman experiences are eventually achievable by repairing the sural nerve after its harvest as an autologous nerve graft with the novel nerve guide that is about to be established for clinical use [5].

For the clinical scientists and clinicians interested into the latest developments and novel medical products that may become available in the nearer future, it is of outmost importance to know about the predictability of the results published from experimental work. Only with this knowledge, the curious reader will be able to conclude that an experimental approach to develop a novel nerve guide is indeed promising and deserves the enterprise to be processed toward a clinical product.

In vitro studies demonstrating the biocompatibility with primary peripheral nerve cells, primary neurons, or organotypic cultures from dorsal root ganglia or spinal cord preparations and also providing evidence for a stimulated neurite outgrowth from primary sensory or motor neurons by the tested biomaterial provide a legitimization for in vivo studies [19]. For this legitimation, it is not obligatory to demonstrate optimal biomaterial properties by complex peripheral nerve regeneration in vitro models, which evaluate neurite outgrowth from spinal cord slices to peripheral nerve segments or nerve guide material [17, 56]. The latter in vitro systems are the most refined and sophisticated ones, but on the opposite, they are difficult to establish and to propagate.