title: Collagen nerve conduits releasing the neurotrophic factors GDNF and NGF.
abstract: Artificial nerve conduits (NC) can clinically be instrumental for facilitating the surgery of damaged peripheral nerves. To improve axonal regeneration of injured peripheral nerves, we have developed collagen nerve conduits (NC) releasing glial cell line-derived neurotrophic factor (GDNF) alone or in combination with nerve growth factor (NGF), which exert synergistic action on axonal growth. Degradation of the NC and their mechanical and drug release properties were controlled by two means: (i) cross-linking the collagen tubes by physical means, through a dehydro-thermal treatment (DHT), before loading with the neurotrophic factors (NTFs) GDNF or GDNF/NGF; and (ii) coating the drug-loaded collagen tubes with layers of poly(lactide-co-glycolide) (PLGA). Non-cross-linked collagen NC (C-NC) released high amounts of NTFs during the initial 2-3 days of incubation, whereas the DHT-treated collagen NC (C(dht)-NC) did not show a prominent burst effect. The release kinetics was similar for GDNF alone and GDNF co-delivered with NGF. Within 30 days, the C-NC released 78% and 83% of the total doses of GDNF and NGF, respectively, whereas the C(dht)-NC released only 68% of GDNF and 56% of NGF. The bioactivity of the NTFs released up to 30 days was confirmed by an in vitro bioassay using chicken embryonic dorsal root ganglion (DRG) explants. The C(dht)-NC also possessed adequate mechanical resistance against radial compression, the pull-out of a suture thread, and loss of patency upon bending. Modulus and pull-out strength increased in the order of C-NC, C(dht)-NC approximately Neuragen, and Neurolac, with the latter two products being commercially available collagen and polyester NC, respectively. In vitro degradation time upon incubation with collagenase increased in the same order for the collagen-based NC. In conclusion, co-delivery of synergistically acting GDNF and NGF from structurally improved NC may be a promising tool for the successful repair of peripheral nerve defects.
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Madduri
authors.forename: Kirill
authors.initials: K
authors.lastname: Feldman
authors.forename: Theo
authors.initials: T
authors.lastname: Tervoort
authors.forename: Michaël
authors.initials: M
authors.lastname: Papaloïzos
authors.forename: Bruno
authors.initials: B
authors.lastname: Gander
mesh_terms: D000818:Animals; D002642:Chick Embryo; D003094:Collagen / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000737:chemistry*; D005727:Ganglia, Spinal / Q000254:growth & development; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage* / Q000378:metabolism; D008422:Materials Testing; D020932:Nerve Growth Factor / Q000008:administration & dosage* / Q000378:metabolism; D013314:Stress, Mechanical
chemical_list: D003692:Delayed-Action Preparations; D051100:Glial Cell Line-Derived Neurotrophic Factor; D003094:Collagen; D020932:Nerve Growth Factor