Biopolymer-nanotube nerve guidance conduit drug delivery for peripheral nerve regeneration: In vivo structural and functional assessment

Manoukian, Ohan S.; Rudraiah, Swetha; Arul, Michael R.; Bartley, Jenna M.; Baker, Jiana T.; Yu, Xiaojun; Kumbar, Sangamesh G.

doi:10.1016/j.bioactmat.2021.02.016

Cited by 24 publications

(28 citation statements)

References 62 publications

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“…Our results extend in a surprising new direction our earlier discoveries that 4-AP exhibits unexpected pro-regenerative properties when used to treat acute traumatic injury in the peripheral nervous system 20,27,28 . We previously found that treatment with 4-AP promotes durable functional recovery and remyelination in crush injuries of sciatic nerves.…”

Section: Discussionsupporting

confidence: 82%

“…4-AP is a potassium channel blocker, and a potential activator of high voltage-activated calcium channels (HVACCs) 22 , with a long history of clinical use for transiently improving neuromuscular function in patients with diverse chronic neurological syndromes 23,24 . In contrast with the effects of 4-AP in chronic syndromes, in which there is no evidence for alterations in tissue structure and where benefits disappear in concurrence with clearance of 4-AP from the body 25,26 , effects in acute injuries include restoration of normal tissue structure and durable functional improvement 20,21,[27][28][29][30] . However, it is plausible that 4-AP could actually worsen skin wound healing, as several studies have reported that calcium channel blockers enhance repair of such injuries [31][32][33] , and 4-AP is predicted to increase calcium release.…”

Section: Introductionmentioning

confidence: 99%

“…These outcomes raise the question of whether a pharmacological approach to enhancing Schwann cell recovery might have similar benefits. 4-AP is an interesting candidate for such studies, due to its ability to enhance recovery of both Schwann cells and neurons after peripheral nerve crush injuries (17)(18)(19)(20)(21)(22). What 4-AP would do in skin injuries, however, is unknown and not predictable.…”

Section: Introductionmentioning

confidence: 99%

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4-aminopyridine promotes accelerated skin wound healing via neurogenic-mediator expression

Guddadarangaiah

Govindappa

Nelson

et al. 2021

Preprint

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The discovery of ways to enhance skin wound healing is of great importance due to the frequency of these lesions. We discovered that 4-aminopyridine (4-AP), a potassium channel blocker, greatly enhances skin wound healing. Benefits include faster wound closure, restoration of normal-appearing skin architecture and epidermal thickness, increased vascularization and increases in K14+ keratinocytes. Hair follicle number was increased, both histologically and by analysis of K15 and K17 expression. Levels of vimentin (which marks fibroblasts) and α-smooth muscle actin (α-SMA, which marks collagen-producing myofibroblasts) increased, as did α-SMA+ cell numbers. 4-AP also increased numbers of axons and S-100+ Schwann cells, and increased expression of p75-NTR and SOX10. Treatment also increased levels of nerve growth factor, transforming growth factor-β, Substance P and PGP9.5, important modulators of wound healing. As 4-AP is already used for treatment of multiple sclerosis and other chronic neurological syndromes, it has strong potential for rapid translational development.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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4-aminopyridine promotes accelerated skin wound healing via neurogenic-mediator expression

Guddadarangaiah

Govindappa

Nelson

et al. 2021

Preprint

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“…While additional aligned nanofibers within the microchannels contributed only slightly to regeneration, adding an additional neurotrophic factor gradient, yielded an effect comparable to autograft. Similarly, the combination of a multichannel design with controlled release of 4-aminopyridine, a potassium channel blocker thought to improve nerve conduction in neurological disorders such as multiple sclerosis, was comparable to autograft in a 15 mm sciatic nerve gap rat model ( Manoukian et al, 2021 ). Here the multichannels were fabricated by unidirectional freeze drying.…”

Section: Biological Functionalization Beyond the Hollow Tubementioning

confidence: 99%

Implantable Biomaterials for Peripheral Nerve Regeneration–Technology Trends and Translational Tribulations

Rezza

Külahçi

Gorantla

et al. 2022

Front. Bioeng. Biotechnol.

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The use of autografted nerve in surgical repair of peripheral nerve injuries (PNI) is severely limited due to donor site morbidity and restricted tissue availability. As an alternative, synthetic nerve guidance channels (NGCs) are available on the market for surgical nerve repair, but they fail to promote nerve regeneration across larger critical gap nerve injuries. Therefore, such injuries remain unaddressed, result in poor healing outcomes and are a limiting factor in limb reconstruction and transplantation. On the other hand, a myriad of advanced biomaterial strategies to address critical nerve injuries are proposed in preclinical literature but only few of those have found their way into clinical practice. The design of synthetic nerve grafts should follow rational criteria and make use of a combination of bioinstructive cues to actively promote nerve regeneration. To identify the most promising NGC designs for translation into applicable products, thorough mode of action studies, standardized readouts and validation in large animals are needed. We identify design criteria for NGC fabrication according to the current state of research, give a broad overview of bioactive and functionalized biomaterials and highlight emerging composite implant strategies using therapeutic cells, soluble factors, structural features and intrinsically conductive substrates. Finally, we discuss translational progress in bioartificial conduits for nerve repair from the surgeon’s perspective and give an outlook toward future challenges in the field.

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“…However, it also has limitations such as a secondary operation, limited availability and the risk of neuroma formation [ 61 , 62 ]. Researchers believe that nerve conduits have emerged as promising substitutes for autografts [ 46 , 63 ]. Zhu et al created an extracellular matrix scaffold with instructive niches for oriented nerve regeneration [ 45 ].…”

Section: Macro-/micro-channels In Porous Scaffoldsmentioning

confidence: 99%

Effects of Macro-/Micro-Channels on Vascularization and Immune Response of Tissue Engineering Scaffolds

Wen

Qian

Kang

2021

Cells

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Although the use of porous scaffolds in tissue engineering has been relatively successful, there are still many limitations that need to be addressed, such as low vascularization, low oxygen and nutrient levels, and immune-induced inflammation. As a result, the current porous scaffolds are insufficient when treating large defects. This paper analyzed scientific research pertaining to the effects of macro-/micro-channels on the cell recruitment, vascularization, and immune response of tissue engineering scaffolds. Most of the studies contained either cell culturing experimentation or experimentation on small animals such as rats and mice. The sacrificial template method, template casting method, and 3D printing method were the most common methods in the fabrication of channeled scaffolds. Some studies combine the sacrificial and 3D printing methods to design and create their scaffold with channels. The overall results from these studies showed that the incorporation of channels within scaffolds greatly increased vascularization, reduced immune response, and was much more beneficial for cell and growth factor recruitment compared with control groups that contained no channels. More research on the effect of micro-/macro-channels on vascularization or immune response in animal models is necessary in the future in order to achieve clinical translation.

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Biopolymer-nanotube nerve guidance conduit drug delivery for peripheral nerve regeneration: In vivo structural and functional assessment

Cited by 24 publications

References 62 publications

4-aminopyridine promotes accelerated skin wound healing via neurogenic-mediator expression

4-aminopyridine promotes accelerated skin wound healing via neurogenic-mediator expression

Implantable Biomaterials for Peripheral Nerve Regeneration–Technology Trends and Translational Tribulations

Effects of Macro-/Micro-Channels on Vascularization and Immune Response of Tissue Engineering Scaffolds

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