Linear Ordered Collagen Scaffolds Loaded with Collagen-Binding Neurotrophin-3 Promote Axonal Regeneration and Partial Functional Recovery after Complete Spinal Cord Transection

Abstract

Neurotrophin-3 (NT3) is an important neurotrophic factor for spinal cord injury (SCI) repair. However, constant exchange of cerebrospinal fluid often decreases the effective dosage of NT3 at the targeted injury site. In the present study, a recombinant collagen-binding NT3 (CBD-NT3), consisting of a collagen-binding domain (CBD) and native NT3, was constructed. Linear rat-tail collagen (LRTC) was used as a physical carrier for CBD-NT3 to construct a LRTC/C3 system. The collagen-binding ability of CBD-NT3 was verified, and the bioactivity of CBD-NT3 was assayed with neurite outgrowth of dorsal root ganglia (DRG) explants and DRG cells in vitro. After complete spinal cord transection in rats, LRTC/CBD-NT3 or the LRTC/NT3 system was transplanted into the injury site. Hindlimb locomotion recovery was closely observed using the Basso-Beattie-Bresnahan (BBB) locomotor rating scale and the grid walk test. Significant improvement was observed in the LRTC/CBD-NT3 group. The results of regenerating nerve fiber and anterograde tracing of biotinylated dextran amine (BDA)-labeled corticospinal tract (CST) fibers demonstrated axonal regeneration of LRTC/CBD-NT3 in the injured spinal cord. Serotonin fiber regrowth also illustrated the effectiveness of LRTC/CBD-NT3. Thus, collagen-binding NT3 with LRTC may provide an effective method for treating SCI.

One-year clinical study of NeuroRegen scaffold implantation following scar resection in complete chronic spinal cord injury patients

“…In our previous study, the NeuroRegen scaffold was prepared from bovine aponeurosis, which mainly consists of linearly ordered collagen fibers. When the scaffold was transplanted into complete SCI rat and canine models, it successfully guided neurite outgrowth along its fibers and decreased scar formation (Fan et al, 2010;Han et al, 2009;Han et al, 2010;Han et al, 2015;Li et al, 2013;Lin et al, 2006). Based on these preclinical results, the clinical study was approved by the ethics committee and registered on the National Institute of Health database.…”

Biomaterial-based interventions for neuronal regeneration and functional recovery in rodent model of spinal cord injury: A systematic review

“…The BBB scores and respective standard deviations were extrapolated to the nearest decimal point from the published graphs in some studies. 9,12,30 Studies with no published BBB scores 10,16,17,19,22,24,29 or with published graphs which did not allow for extraction of values 20,21,31 were excluded from cumulative meta-analysis. A 'metan' command was utilized for calculation of individual and poole-weighted mean difference between experimental and control groups using the DerSimonian-Laird method.…”

“…Spinal cord transection [9][10][11]14,21,[23][24][25][26]28,31,32 was the most common injury model followed by hemisection. 12,13,[15][16][17][18][19]22,27,29,30 Most studies contained information about the effects of acute intervention after induction of SCI but some studies also contained information about the effects in the sub-acute or chronic phase.…”

“…Biopolymer design Collagen 9,[11][12][13]16,18 and poly (alpha hydroxyacids) 14,23,24,26,27,30 were the most common biopolymers Figure 3 Forrest plot of improvement in mean BBB scores between experimental and control groups among studies investigating biodegradable polymer scaffold, supporting cells, and neurotrophic factors for axonal regeneration in hemisection model. used, followed by fibrin.…”

“…18,25,27,31 Linearlyoriented scaffolds were investigated in 12 studies with a pore size varying from 10 to 660 μm. 9,10,12,14,16,19,22,23,26,[28][29][30] Scaffold-binding domains for neurotrophic factors were employed in two studies 9,12 whereas one study described the effect of controled release of neurotrophic factors from a heparin-based delivery system. 17 In some early publications, the architecture of the biopolymer implant deteriorated over time.…”