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The role of aligned polymer fiber-based constructs in the bridging of long peripheral nerve gaps.

ABSTRACT: Peripheral nerve regeneration across long nerve gaps is clinically challenging. Autografts, the standard of therapy, are limited by availability and other complications. Here, using rigorous anatomical and functional measures, we report that aligned polymer fiber-based constructs present topographical cues that facilitate the regeneration of peripheral nerves across long nerve gaps. Significantly, aligned but not randomly oriented fibers elicit regeneration, establishing that topographical cues can influence endogenous nerve repair mechanisms in the absence of exogenous growth promoting proteins. Axons regenerated across a 17 mm nerve gap, reinnervated muscles, and reformed neuromuscular junctions. Electrophysiological and behavioral analyses revealed that aligned but not randomly oriented constructs facilitated both sensory and motor nerve regeneration, significantly improved functional outcomes. Additionally, a quantitative comparison of DRG outgrowth in vitro and nerve regeneration in vivo on aligned and randomly oriented fiber films clearly demonstrated the significant role of sub-micron scale topographical cues in stimulating endogenous nerve repair mechanisms.

SUBMITTER: Kim YT

PROVIDER: S-EPMC2483242 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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The role of aligned polymer fiber-based constructs in the bridging of long peripheral nerve gaps.

Kim Young-Tae YT Haftel Valerie K VK Kumar Satish S Bellamkonda Ravi V RV

Biomaterials 20080429 21

Peripheral nerve regeneration across long nerve gaps is clinically challenging. Autografts, the standard of therapy, are limited by availability and other complications. Here, using rigorous anatomical and functional measures, we report that aligned polymer fiber-based constructs present topographical cues that facilitate the regeneration of peripheral nerves across long nerve gaps. Significantly, aligned but not randomly oriented fibers elicit regeneration, establishing that topographical cues ...[more]

PMID: 18448163

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Project description:Nerve conduits enhance nerve regeneration in the repair of long-distance peripheral nerve defects. To help optimize the effectiveness of nerve conduits for nerve repair, we developed a multi-step electrospinning process for constructing nerve guide conduits with aligned nanofibers. The alignment of the nerve guide conduits was characterized by scanning electron microscopy and fast Fourier transform. The mechanical performance of the nerve guide conduits was assessed by testing for tensile strength and compression resistance. The biological performance of the aligned fibers was examined using Schwann cells, PC12 cells and dorsal root ganglia in vitro. Immunohistochemistry was performed for the Schwann cell marker S100 and for the neurofilament protein NF200 in PC12 cells and dorsal root ganglia. In the in vivo experiment, a 1.5-cm defect model of the right sciatic nerve in adult female Sprague-Dawley rats was produced and bridged with an aligned nerve guide conduit. Hematoxylin-eosin staining and immunohistochemistry were used to observe the expression of ATF3 and cleaved caspase-3 in the regenerating matrix. The recovery of motor function was evaluated using the static sciatic nerve index. The number of myelinated fibers, axon diameter, fiber diameter, and myelin thickness in the distal nerve were observed by electron microscopy. Gastrocnemius muscle mass ratio was also determined. The analyses revealed that aligned nanofiber nerve guide conduits have good mechanical properties and can induce Schwann cells, PC12 cells and dorsal root ganglia to aggregate along the length of the nanofibers, and promote the growth of longer axons in the latter two (neuronal) cell types. The aligned fiber nerve conduits increased the expression of ATF3 and cleaved caspase-3 at the middle of the regenerative matrix and at the distal nerve segment, improved sciatic nerve function, increased muscle mass of the gastrocnemius muscle, and enhanced recovery of distal nerve ultrastructure. Collectively, the results show that highly aligned nanofibers improve the performance of the nerve conduit bridge, and enhance its effectiveness in repairing peripheral nerve defects.

Project description:Peripheral nerve injury accounts for roughly 2.8% of all trauma patients with an annual cost of 7 billion USD in the U.S. alone. Current treatment options rely on surgical intervention with the use of an autograft, despite associated shortcomings. Engineered nerve guidance conduits, stem cell therapies, and transient electrical stimulation have reported to increase speeds of functional recovery. As an alternative to the conduction effects of electrical stimulation, we have designed and optimized a nerve guidance conduit with aligned microchannels for the sustained release of a small molecule drug that promotes nerve impulse conduction. A biodegradable chitosan structure reinforced with drug-loaded halloysite nanotubes (HNT) was formed into a foam-like conduit with interconnected, longitudinally-aligned pores with an average pore size of 59.3?±?14.2??m. The aligned composite with HNTs produced anisotropic mechanical behavior with a Young's modulus of 0.33?±?0.1?MPa, very similar to that of native peripheral nerve. This manuscript reports on the sustained delivery of 4-Aminopyridine (4AP, molecular weight 94.1146?g/mol), a potassium-channel blocker as a growth factor alternative to enhance the rate of nerve regeneration. The conduit formulation released a total of 30?±?2% of the encapsulated 4AP in the first 7?days. Human Schwann cells showed elevated expression of key proteins such as nerve growth factor, myelin protein zero, and brain derived neurotrophic factor in a 4AP dose dependent manner. Preliminary in vivo studies in a critical-sized sciatic nerve defect in Wistar rats confirmed conduit suturability and strength to withstand ambulatory forces over 4?weeks of their implantation. Histological evaluations suggest conduit biocompatibility and Schwann cell infiltration and organization within the conduit and lumen. These nerve guidance conduits and 4AP sustained delivery may serve as an attractive strategy for nerve repair and regeneration.

Project description:Peripheral nerve injuries can result in lifelong disability. Primary coaptation is the treatment of choice when the gap between transected nerve ends is short. Long nerve gaps seen in more complex injuries often require autologous nerve grafts or nerve conduits implemented into the repair. Nerve grafts, however, cause morbidity and functional loss at donor sites, which are limited in number. Nerve conduits, in turn, lack an internal scaffold to support and guide axonal regeneration, resulting in decreased efficacy over longer nerve gap lengths. By comparison, peptide amphiphiles (PAs) are molecules that can self-assemble into nanofibers, which can be aligned to mimic the native architecture of peripheral nerve. As such, they represent a potential substrate for use in a bioengineered nerve graft substitute. To examine this, we cultured Schwann cells with bioactive PAs (RGDS-PA, IKVAV-PA) to determine their ability to attach to and proliferate within the biomaterial. Next, we devised a PA construct for use in a peripheral nerve critical sized defect model. Rat sciatic nerve defects were created and reconstructed with autologous nerve, PLGA conduits filled with various forms of aligned PAs, or left unrepaired. Motor and sensory recovery were determined and compared among groups. Our results demonstrate that Schwann cells are able to adhere to and proliferate in aligned PA gels, with greater efficacy in bioactive PAs compared to the backbone-PA alone. In vivo testing revealed recovery of motor and sensory function in animals treated with conduit/PA constructs comparable to animals treated with autologous nerve grafts. Functional recovery in conduit/PA and autologous graft groups was significantly faster than in animals treated with empty PLGA conduits. Histological examinations also demonstrated increased axonal and Schwann cell regeneration within the reconstructed nerve gap in animals treated with conduit/PA constructs. These results indicate that PA nanofibers may represent a promising biomaterial for use in bioengineered peripheral nerve repair.

Dataset Information

The role of aligned polymer fiber-based constructs in the bridging of long peripheral nerve gaps.

Publications

The role of aligned polymer fiber-based constructs in the bridging of long peripheral nerve gaps.

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