Modern Trends for Peripheral Nerve Repair and Regeneration: Beyond the Hollow Nerve Guidance Conduit

Abstract

Peripheral nerve repair and regeneration remains among the greatest challenges in tissue engineering and regenerative medicine. Even though peripheral nerve injuries (PNIs) are capable of some degree of regeneration, frail recovery is seen even when the best microsurgical technique is applied. PNIs are known to be very incapacitating for the patient, due to the deprivation of motor and sensory abilities. Since there is no optimal solution for tackling this problem up to this day, the evolution in the field is constant, with innovative designs of advanced nerve guidance conduits (NGCs) being reported every day. As a basic concept, a NGC should act as a physical barrier from the external environment, concomitantly acting as physical guidance for the regenerative axons across the gap lesion. NGCs should also be able to retain the naturally released nerve growth factors secreted by the damaged nerve stumps, as well as reducing the invasion of scar tissue-forming fibroblasts to the injury site. Based on the neurobiological knowledge related to the events that succeed after a nerve injury, neuronal subsistence is subjected to the existence of an ideal environment of growth factors, hormones, cytokines, and extracellular matrix (ECM) factors. Therefore, it is known that multifunctional NGCs fabricated through combinatorial approaches are needed to improve the functional and clinical outcomes after PNIs. The present work overviews the current reports dealing with the several features that can be used to improve peripheral nerve regeneration (PNR), ranging from the simple use of hollow NGCs to tissue engineered intraluminal fillers, or to even more advanced strategies, comprising the molecular and gene therapies as well as cell-based therapies.

Fibroblasts Colonizing Nerve Conduits Express High Levels of Soluble Neuregulin1, a Factor Promoting Schwann Cell Dedifferentiation

“…For short nerve gap repair in human, up to 3 cm [8,9], tubulization is successfully used as a good alternative to autograft, especially in small diameter, noncritical sensory nerves [44], while short nerve gaps are successfully repaired in rat up to 1 cm [10,25,45]. Because several research groups [29], including ours [30], are making efforts to functionalize and enrich tubular conduits to further promote nerve regeneration in more complex situations, such as longer nerve gap or delayed repair, we focused our attention on investigating what occurs inside a hollow conduit after nerve gap repair.…”

3D Printing and Bioprinting Nerve Conduits for Neural Tissue Engineering

“…After implanting the 3D printed conduit between the transected sciatic nerves of the rat, it was observed that the regenerated nerve branched into four branches at the proximal end and merged into a nerve at the distal end, and the injured nerves showed promising recovery. This suggests that the guiding fascicular structure can simulate the direction and track of nerve growth [29,30]. In the actual situation, the structure of the scaffold should be designed according to the injury of the native nerve, so as to prevent the nerve incorrect connection and play a correct guiding role on the nerve stump.…”

Biomimetic Approaches for Separated Regeneration of Sensory and Motor Fibers in Amputee People: Necessary Conditions for Functional Integration of Sensory–Motor Prostheses With the Peripheral Nerves

“…These scaffolds can be made by different biomaterials, such as porcine submucosa ECM, Axoguard R Nerve Connector (Axogen, Inc., FL, United States); collagen I, NeuraGen R (Integra LifeSciences Corporation, United States); polyglycolic acid, Neurotube R (Synovis Micro Companies Alliance, Inc., AL, United States); and poly-DL-lactide-co-caprolactone and polyvinyl alcohol, Neurolac R (Polyganics, Netherlands) (Tian et al, 2015;Costa Serrão de Araújo et al, 2017). Several improvements have been tested in animal models, including (i) fillings with hydrogels that favor axons regeneration; (ii) inclusion of topographic cues, like microfilaments/nanofilaments or groove patterns, to favor guidance and directionality by interacting with the growth cone; or (iii) incorporation of growth factors and supporting cells (Carvalho et al, 2019;Wang and Sakiyama-Elbert, 2019).…”

“…The use of biomaterials allowed higher precision and greater control in the administration of the neurotrophic factors: osmotic pumps, hydrogels, polymeric microspheres, and the inclusion of the different molecules at the level of the tubular conduct implanted (Tajdaran et al, 2019). Factors are included within the lumen (hydrogels, nanofibers, and through the presence of cells that produce neurotrophic factors), in the conduit wall (included in the polymer or in microspheres), and at the surface (adsorbed or conjugated with other type of molecules) (Carvalho et al, 2019).…”