Project

Peripheral nerve repair; Axonal regeneration; Schwann cells; Neurotrophic factors; Nanofibres; Collagen; Silk fibroin; Drug delivery system; Nanostructured medicinal products; Peripheral nerve repair; Axonal regeneration; Nerve conduits; Schwann cells; Neurotrophic factors; Nanofibres; Collagen; Silk fibroin; Drug delivery system; Gene therapy; Nanostructured medicinal products.

Lead
Accidents can cause injuries to peripheral nerves, generating important health care costs due to prolonged work leave and chronic disabling. In this project, we develop nerve conduits endowed with biological information to repair injured nerves, accelerating and improving the recovery of tactile sense and muscle control.
Lay summary
Lead Accidents can cause injuries to peripheral nerves, generating important health care costs due to prolonged work leave and chronic disabling. In this project, we develop nerve conduits endowed with biological information to repair injured nerves, accelerating and improving the recovery of tactile sense and muscle control. Background Accidents at work and sports can cause injuries to peripheral nerves, which are steadily increasing and affecting mostly the population of working age. Thus, treatment and convalescence generate important health care costs due to long term work leave and often chronic disabling. The clinical standard for bridging the affected part of the injured nerve is the implantation of a donor nerve from the same patient. However, the availability of patients’ own nerves is limited and their use associated with significant morbidity at the donor site.  As alternative, artificial nerve conduits (NCs) are increasingly used for short nerve gaps (<20 mm), although recovery of sense of touch and muscle control remains often unsatisfactory. One way to improve NCs performance is to endow them with functionally active biological components such as growth factors, Schwann cells, extracellular matrix material and directional nanostructures for guided axonal growth. Aim The project aims at developing nerve conduits endowed with Schwann cells and guiding nanostructures. The Schwann cells will be seeded inside the tubes and release growth-promoting substances such as adhesion molecules and neurotrophic factors. The nanostructures will guide and enhance unidirectional growth of the axons (basic components of a nerve). This will eventually lead to faster and better nerve regeneration and recovery of sense of touch and muscle control. Relevance The proposed nerve conduits with integrated structural and biological functions are believed to improve regeneration of severed peripheral nerves to recover clinically relevant sense of touch and muscle function. The expected findings should also shed some more light onto the basic molecular and structural requirements of successful axonal re-growth. The project builds on recent key discoveries at cellular and molecular levels and on advances in bioengineering.

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Last update: 06.05.2013

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Peripheral nerve injuries (PNIs) are steadily increasing in number, with axonal regeneration re-maining impaired and resulting in the failure of function. Approx. 300,000 people are affected annually in Europe, causing substantial work leave, chronic disabling and health care expenses. The clinical “gold standard” for the repair of PNIs is use of autologous nerve grafting, although it is associated with morbidity and increased scar formation at the donor site. Limited availabil-ity of donor nerves and morbidity associated with nerve graft harvesting elicited the develop-ment of artificial nerve conduits (NC). For improving peripheral nerve regeneration, artificial NC have attracted considerable interest. Synthetic and biopolymer-based NC have been shown to facilitate nerve regeneration over small nerve gaps. Strategies to improve efficacy of nerve repair treatment included the use of neurotrophic factors (NTFs). NC delivering neurotrophic factors promote nerve regeneration, although the clinical outcome generally remains unsatisfactory, because of aberrant axonal growth resulting in mismatched connections between the nerve cells and their peripheral targets. Aberrant axonal growth may be associated with inadequate localized drug delivery. Cell-based treatments resulted in enhanced axonal growth, although functional recovery also remained sub-optimal. Recently, neuroma formation occurred in the human median nerve (2 cm gap) repaired by FDA-approved Neuragen nerve guide, indicating their failure to facilitate nerve regeneration over critical size gaps. So far, no artificial NC, with or without embedded growth factors or cells, provided equal therapeutic benefits to autologous nerve grafting, showing the immediate need for bioartificial NC, which may complement the autologous nerve grafting. The aim of the project is to enhance axonal regeneration and path finding to achieve im-proved efficacy and specificity of reinnervation by developing biologically functionalized biode-gradable and bioartificial NC. The bioartificial NC will be made from collagen and silk fibroin. Longitudinally aligned nanofibers will be engineered into the NC lumen along with genetically modified Schwann cells delivering glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) in a combined fashion mediated by recombinant adenovirus. The major advantage of the proposed NC is the biomimicking of the internal organization of intact nerve, which is expected to enhance functional nerve regeneration. Own recent experiments, in vitro and in vivo, demonstrated the synergistic effect of GDNF and NGF on axonal outgrowth and migration of Schwann cells, which were closely associated with regenerating axons. Longitudinally aligned nanofibers guided the direction of the axonal growth from dorsal root ganglions isolated from 9-day old chicken embryos in the presence of exogenously added GDNF and NGF in vitro. Integration of the physical, chemical, cellular and molecular cues within the 3D bioartificial NC holds great promise to enhance functional nerve regeneration in peripheral nervous system.