Introduction: Man-machine interfacing remains the main challenge for accurate and reliable control of bionic prostheses. Implantable electrodes in nerves and muscles may overcome some of the limitations by significantly increasing the interface's reliability and bandwidth. Before human application, experimental preclinical testing is essential to assess chronic in-vivo biocompatibility and functionality. Here, we analyze available animal models, their costs and ethical challenges in special regards to simulating a potentially life-long application in a short period of time and in non-biped animals. Methods:We performed a literature analysis following the PRISMA guidelines including all animal models used to record neural or muscular activity via implantable electrodes, evaluating animal models, group size, duration, origin of publication as well as type of interface. Furthermore, behavioral, ethical, and economic considerations of these models were analyzed. Additionally, we discuss experience and surgical approaches with rat, sheep, and primate models and an approach for international standardized testing. Results:Overall, 343 studies matched the search terms, dominantly originating from the US (55%) and Europe (34%), using mainly small animal models (rat: 40%). Electrode placement was dominantly neural (77%) compared to muscular (23%). Large animal models had a mean duration of 135 ± 87.2 days, with a mean of 5.3 ± 3.4 animals per trial. Small animal models had a mean duration of 85 ± 11.2 days, with a mean of 12.4 ± 1.7 animals.Discussion: Only 37% animal models were by definition chronic tests (>3 months) and thus potentially provide information on long-term performance. Costs for large animals were up to 45 times higher than small animals. However, costs are relatively small compared to complication costs in human long-term applications. Overall, we believe a combination of small animals for preliminary primary electrode testing and large animals to investigate long-term biocompatibility, impedance, and tissue regeneration parameters provides sufficient data to ensure long-term human applications.

Background Currently used prosthetic solutions in upper extremity amputation have limited functionality, owing to low information transfer rates of neuromuscular interfacing. Although surgical innovations have expanded the functional potential of the residual limb, available interfaces are inefficacious in translating this potential intoThe institution of one or more of the authors (CLH, DM) has received, during the study period, funding from the Defense Advanced Research Projects Agency. One or more of the authors (DF, OCA) have received, during the study period, funding from the H2020 European Research Council (grant number 810346). One of the authors (DM) is a co-owner and employee of Ripple Neuro LLC. One of the authors (CLH) is a former employee of Ripple Neuro LLC. Two authors (CH, MFR) are employees of Otto Bock Healthcare Products GmbH. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request. Clinical Orthopaedics and Related Research® neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDA approval status, of any drug or device before clinical use.

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Surgical nerve transfers are used to efficiently treat peripheral nerve injuries, neuromas, phantom limb pain or improve bionic prosthetic control. Commonly, one donor nerve is transferred to one target muscle. However, the transfer of multiple nerves onto a single target muscle may increase the number of muscle signals for myoelectric prosthetic control and facilitate the treatment of multiple neuromas. Currently, no experimental models are available for multiple nerve transfers to a common target muscle in the upper extremity. This study describes a novel experimental model to investigate the neurophysiological effects of peripheral double nerve transfers. For this purpose, we developed a forelimb model to enable tension-free transfer of one or two donor nerves in the upper extremity. Anatomic dissections were performed to design the double nerve transfer model (n=8). In 62 male Sprague-Dawley rats the ulnar nerve of the antebrachium alone (n=30) or together with the anterior interosseus nerve (n=32) was transferred to reinnervate the long head of the biceps brachii. Before neurotization, the motor branch to the biceps’ long head was transected at the motor entry point and resected up to its original branch to prevent auto-reinnervation. In all animals, coaptation of both nerves to the motor entry point could be performed tension-free. Mean duration of the procedure was 49 ± 13 min for the single nerve transfer and 78 ± 20 min for the double nerve transfer. Twelve weeks after surgery, muscle response to neurotomy, behavioral testing, retrograde labeling and structural analyses were performed to assess reinnervation. These analyses indicated that all nerves successfully reinnervated the target muscle. No aberrant reinnervation was observed by the originally innervating nerve. Our observations suggest a minimal burden for the animal with no signs of functional deficit in daily activities or auto-mutilation in both procedures. Furthermore, standard neurophysiological analyses for nerve and muscle regeneration were applicable. This newly developed nerve transfer model allows for the reliable and standardized investigation of neural and functional changes following the transfer of multiple donor nerves to one target muscle.

The facial dermato-muscular system consists of highly specialized muscles tightly adhering to the overlaying skin and thus form a complex morphological conglomerate. This is the anatomical and functional basis for versatile facial expressions, which are essential for human social interaction. The neural innervation of the facial skin and muscles occurs via branches of the trigeminal and facial nerves. These are also the most commonly pathologically affected cranial nerves, often requiring surgical treatment. Hence, experimental models for researching these nerves and their pathologies are highly relevant to study pathophysiology and nerve regeneration. Experimental models for the distinctive investigation of the complex afferent and efferent interplay within facial structures are scarce. In this study, we established a robust surgical model for distinctive exploration of facial structures after complete elimination of afferent or efferent innervation in the rat. Animals were allocated into two groups according to the surgical procedure. In the first group, the facial nerve and in the second all distal cutaneous branches of the trigeminal nerve were transected unilaterally. All animals survived and no higher burden was caused by the procedures. Whisker pad movements were documented with video recordings 4 weeks after surgery and showed successful denervation. Whole-mount immunofluorescent staining of facial muscles was performed to visualize the innervation pattern of the neuromuscular junctions. Comprehensive quantitative analysis revealed large differences in afferent axon counts in the cutaneous branches of the trigeminal nerve. Axon number was the highest in the infraorbital nerve (28,625 ± 2,519), followed by the supraorbital nerve (2,131 ± 413), the mental nerve (3,062 ± 341), and the cutaneous branch of the mylohyoid nerve (343 ± 78). Overall, this surgical model is robust and reliable for distinctive surgical deafferentation or deefferentation of the face. It may be used for investigating cortical plasticity, the neurobiological mechanisms behind various clinically relevant conditions like facial paralysis or trigeminal neuralgia as well as local anesthesia in the face and oral cavity.