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ABSTRACT Peripheral nerve injuries (PNIs) resulting in myelin breakdown and axonal degeneration at both the proximal and distal nerve stumps are major clinical concerns that can induce functional loss and diminished quality of life. In biomaterials science, considerable attention has been given to artificial nerve guidance conduits (NGCs), since the engineered tubular structures have the potential to supply a supportive nerve microenvironment to longitudinally align the regenerating axons for bridging the injured nerve sites. Although NGCs may become promising alternatives to nerve autografts, the fabrication approaches available to incorporate directional cues for dictating neuronal behavior and nerve reconnection have been limited to conventional micro/nano‐fabrication techniques that are complex and time‐consuming due to manual processing steps. Thus, our goal here was to develop a simple manufacturing approach for introducing topographical cues onto NGCs. To achieve this goal, we used an established mechanically actuated silk wrinkling approach to create topographically functionalized surfaces as a potential NGC material platform for guided directional alignment of neurons. We 3D‐printed thermo‐responsive shape‐memory polymer (SMP)‐based NGCs that can produce silk fibroin (SF)‐wrinkled topographies on the micro and nano‐meter length scale. Since SF is a commonly used biomaterial surface coating with excellent neuro‐compatibility, we studied the ability to develop NGCs that can autonomously actuate silk wrinkles upon heat‐induced contraction of the SMP and evaluated the effects of the topographically functionalized construct on neuronal behavior. Using an immortalized dorsal root ganglion neuronal cell line, we found that the silk‐wrinkled conduits displayed high neuronal viability and adhesion compared to uncoated conduits and tissue‐culture polystyrene controls. We also found that the wrinkled conduits enabled the neurons to elongate and align parallel to the direction of the wrinkled topography. Longer neurite extension was also observed on the wrinkled conduits compared to their respective controls. These findings demonstrate the potential for functional wrinkled protein coatings to provide directional cues in the fabrication of artificial NGCs for peripheral nerve repair.
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Advances in Biomimetic Nerve Guidance Conduits for Peripheral Nerve Regeneration
Injuries to the peripheral nervous system are a common clinical issue, causing dysfunctions of the motor and sensory systems. Surgical interventions such as nerve autografting are necessary to repair damaged nerves. Even with autografting, i.e., the gold standard, malfunctioning and mismatches between the injured and donor nerves often lead to unwanted failure. Thus, there is an urgent need for a new intervention in clinical practice to achieve full functional recovery. Nerve guidance conduits (NGCs), providing physicochemical cues to guide neural regeneration, have great potential for the clinical regeneration of peripheral nerves. Typically, NGCs are tubular structures with various configurations to create a microenvironment that induces the oriented and accelerated growth of axons and promotes neuron cell migration and tissue maturation within the injured tissue. Once the native neural environment is better understood, ideal NGCs should maximally recapitulate those key physiological attributes for better neural regeneration. Indeed, NGC design has evolved from solely physical guidance to biochemical stimulation. NGC fabrication requires fundamental considerations of distinct nerve structures, the associated extracellular compositions (extracellular matrices, growth factors, and cytokines), cellular components, and advanced fabrication technologies that can mimic the structure and morphology of native extracellular matrices. Thus, this review mainly summarizes the recent advances in the state-of-the-art NGCs in terms of biomaterial innovations, structural design, and advanced fabrication technologies and provides an in-depth discussion of cellular responses (adhesion, spreading, and alignment) to such biomimetic cues for neural regeneration and repair.
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- Award ID(s):
- 2219014
- PAR ID:
- 10463966
- Date Published:
- Journal Name:
- Nanomaterials
- Volume:
- 13
- Issue:
- 18
- ISSN:
- 2079-4991
- Page Range / eLocation ID:
- 2528
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Nanomaterial advancements have driven progress in central and peripheral nervous system applications such as tissue regeneration and brain–machine interfacing. Ideally, neural interfaces with native tissue shall seamlessly integrate, a process that is often mediated by the interfacial material properties. Surface topography and material chemistry are significant extracellular stimuli that can influence neural cell behavior to facilitate tissue integration and augment therapeutic outcomes. This review characterizes topographical modifications, including micropillars, microchannels, surface roughness, and porosity, implemented on regenerative scaffolding and brain–machine interfaces. Their impact on neural cell response is summarized through neurogenic outcome and mechanistic analysis. The effects of surface chemistry on neural cell signaling with common interfacing compounds like carbon‐based nanomaterials, conductive polymers, and biologically inspired matrices are also reviewed. Finally, the impact of these extracellular mediated neural cues on intracellular signaling cascades is discussed to provide perspective on the manipulation of neuron and neuroglia cell microenvironments to drive therapeutic outcomes.more » « less
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Abstract Injured peripheral nerves typically exhibit unsatisfactory and incomplete functional outcomes, and there are no clinically approved therapies for improving regeneration. Post‐operative electrical stimulation (ES) increases axon regrowth, but practical challenges, from the cost of extended operating room time to the risks and pitfalls associated with transcutaneous wire placement, have prevented broad clinical adoption. This study presents a possible solution in the form of advanced bioresorbable materials for a type of thin, flexible, wireless implant that provides precisely controlled ES of the injured nerve for a brief time in the immediate post‐operative period. Afterward, rapid, complete, and safe modes of bioresorption naturally and quickly eliminate all of the constituent materials in their entirety, without the need for surgical extraction. The unusually high rate of bioresorption follows from the use of a unique, bilayer enclosure that combines two distinct formulations of a biocompatible form of polyanhydride as an encapsulating structure, to accelerate the resorption of active components and confine fragments until complete resorption. Results from mouse models of tibial nerve transection with re‐anastomosis indicate that this system offers levels of performance and efficacy that match those of conventional wired stimulators, but without the need to extend the operative period or to extract the device hardware.more » « less
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ABSTRACT The ability to interface electronic materials with the peripheral nervous system is required for stimulation and monitoring of neural signals. Thus, the design and engineering of robust neural interfaces that maintain material-tissue contact in the presence of material or tissue micromotion offer the potential to conduct novel measurements and develop future therapies that require chronic interface with the peripheral nervous system. However, such remains an open challenge given the constraints of existing materials sets and manufacturing approaches for design and fabrication of neural interfaces. Here, we investigated the potential to leverage a rapid prototyping approach for the design and fabrication of nerve cuffs that contain supporting features to mechanically stabilize the interaction between cuff electrodes and peripheral nerve. A hybrid 3D printing and robotic-embedding (i.e., pick-and-place) system was used to design and fabricate silicone nerve cuffs (800 µm diameter) containing conforming platinum (Pt) electrodes. We demonstrate that the electrical impedance of the cuff electrodes can be reduced by deposition of the conducting polymer poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) on cuff electrodes via a post-processing electropolymerization technique. The computer-aided design and manufacturing approach was also used to design and integrate supporting features to the cuff that mechanically stabilize the interface between the cuff electrodes and the peripheral nerve. Both ‘self-locking’ and suture-assisted locking mechanisms are demonstrated based on the principle of making geometric alterations to the cuff opening via 3D printing. Ultimately, this work shows 3D printing offers considerable opportunity to integrate supporting features, and potentially even novel electronic materials, into nerve cuffs that can support the design and engineering of next generation neural interfaces.more » « less
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Abstract Background Characterizing the biomechanical failure responses of neonatal peripheral nerves is critical in understanding stretch-related peripheral nerve injury mechanisms in neonates. Objective This in vitro study investigated the effects of prestretch magnitude and duration on the biomechanical failure behavior of neonatal piglet brachial plexus (BP) and tibial nerves. Methods BP and tibial nerves from 32 neonatal piglets were harvested and prestretched to 0, 10, or 20% strain for 90 or 300 seconds. These prestretched samples were then subjected to tensile loading until failure. Failure stress and strain were calculated from the obtained load-displacement data. Results Prestretch magnitude significantly affected failure stress but not the failure strain. BP nerves prestretched to 10 or 20% strain, exhibiting significantly lower failure stress than those prestretched to 0% strain for both prestretch durations (90 and 300 seconds). Likewise, tibial nerves prestretched to 10 or 20% strain for 300 seconds, exhibiting significantly lower failure stress than the 0% prestretch group. An effect of prestretch duration on failure stress was also observed in the BP nerves when subjected to 20% prestretch strain such that the failure stress was significantly lower for 300 seconds group than 90 seconds group. No significant differences in the failure strains were observed. When comparing BP and tibial nerve failure responses, significantly higher failure stress was reported in tibial nerve prestretched to 20% strain for 300 seconds than BP nerve. Conclusion These data suggest that neonatal peripheral nerves exhibit lower injury thresholds with increasing prestretch magnitude and duration while exhibiting regional differences.more » « less
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/nano13182528
