Establishment of a Sheep Model for Hind Limb Peripheral Nerve Injury: Common Peroneal Nerve

Abstract

Thousands of people worldwide suffer from peripheral nerve injuries and must deal daily with the resulting physiological and functional deficits. Recent advances in this field are still insufficient to guarantee adequate outcomes, and the development of new and compelling therapeutic options require the use of valid preclinical models that effectively replicate the characteristics and challenges associated with these injuries in humans. In this study, we established a sheep model for common peroneal nerve injuries that can be applied in preclinical research with the advantages associated with the use of large animal models. The anatomy of the common peroneal nerve and topographically related nerves, the functional consequences of its injury and a neurological examination directed at this nerve have been described. Furthermore, the surgical protocol for accessing the common peroneal nerve, the induction of different types of nerve damage and the application of possible therapeutic options were described. Finally, a preliminary morphological and stereological study was carried out to establish control values for the healthy common peroneal nerves regarding this animal model and to identify preliminary differences between therapeutic methods. This study allowed to define the described lateral incision as the best to access the common peroneal nerve, besides establishing 12 and 24 weeks as the minimum periods to study lesions of axonotmesis and neurotmesis, respectively, in this specie. The post-mortem evaluation of the harvested nerves allowed to register stereological values for healthy common peroneal nerves to be used as controls in future studies, and to establish preliminary values associated with the therapeutic performance of the different applied options, although limited by a small sample size, thus requiring further validation studies. Finally, this study demonstrated that the sheep is a valid model of peripheral nerve injury to be used in pre-clinical and translational works and to evaluate the efficacy and safety of nerve injury therapeutic options before its clinical application in humans and veterinary patients.

Recognising the potential of large animals for modelling neuromuscular junction physiology and disease

“…Therefore, the first advantage of using large mammals is a better recapitulation of the length of affected nerve. For example pigs and sheep have recently successfully been used as preclinical models to study nerve regeneration following peripheral nerve injury (Alvites et al, 2021 ; Burrell et al, 2020 ), suggesting potential for future translational clinical applications to humans and other veterinary species.…”

Repair of Long Nerve Defects with a New Decellularized Nerve Graft in Rats and in Sheep

“…Hence, standardized models of long nerve gap injury in large animals are necessary to evaluate tolerability and efficacy of new treatment strategies for severe nerve injuries [ 6 ]. In this sense, sheep are proposed as an optimal large animal model, since they have similarities in general body and neural structures to humans [ 37 , 38 ], and particularly peripheral nerve dimensions and structure similar to humans [ 20 , 39 , 40 , 41 ]. Moreover, their calm nature, compared to other large animals used as experimental models, such as pigs, enables easier postoperative management and clinical testing [ 18 , 42 ].…”

“…In the present study, the regenerative potential of a novel decellularized nerve allograft was evaluated and compared to autograft repair of a 70 mm long resection of the peroneal nerve in sheep. This nerve is the most commonly affected in injuries involving the lower limb in humans [ 41 , 43 ]. Moreover, it is adequate because it is similar in size and plurifasciular, as is the human peroneal nerve, and induces a limited motor deficit that still allows the animals to stand and walk [ 20 , 44 ].…”

Effects of Olfactory Mucosa Stem/Stromal Cell and Olfactory Ensheating Cells Secretome on Peripheral Nerve Regeneration

“…Despite the promising results observed after the application of CM in vivo, the fact that a limited number of animals were used in each therapeutic group does not allow to amplify and generalize the conclusions discussed here, requiring their validation in subsequent assays. In addition, the already repeatedly identified limited equivalence of results obtained in the rat model for clinical application in human or veterinary medicine [ 71 ] also requires further testing of these therapeutic applications in more complex animal models that better mimic real clinical scenarios and function as intermediate bridges in a translational perspective [ 72 ]. Furthermore, although different important dimensions in the functional assessment of nerve regeneration have been explored in this work, new functional tests may be used to further determine the ability of the studied therapeutic options to promote peripheral nerve regeneration after injury, namely kinematic analysis, nerve conductivity tests, or tracing methods that were not considered here [ 30 ].…”