Conduits harnessing spatially controlled cell-secreted neurotrophic factors improve peripheral nerve regeneration

Sun, Aaron X.; Prest, Travis A.; Fowler, John R.; Brick, Rachel M.; Gloss, Kelsey M.; Li, Xinyu; Dehart, Michael; Shen, He; Yang, Guang; Brown, Bryan N.; Alexander, Peter G.; Tuan, Rocky S.

doi:10.1016/j.biomaterials.2019.01.038

Cited by 40 publications

(29 citation statements)

References 54 publications

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“…This therapy introduces supportive cells, a biological cue, to nerve conduits, providing an appropriate microenvironment for the regenerating nerves [ 2 ]. Current cell-based protocols typically involve either cell seeding or injection into the lumen of the fabricated nerve conduits [ 17 ]. These methods generally result in cell detachment or leakage after the implantation of nerve conduits.…”

Section: Discussionmentioning

confidence: 99%

“…Bone marrow mesenchymal stem cells (BMSCs), multipotent cells with the ability to differentiate into many lineages including neural-like lineages, were repeatedly found to support nerve regeneration [ 10 , [14] , [15] , [16] ]. However, cell seeding protocols typically involve either cell attachment in culture after fabrication, which potentially results in cell detachment in vivo , or cell lumen injection, which is susceptible to leakage [ 17 ]. Furthermore, these cell seeding methods do not allow for precise control of cell number or cellular distribution within the nerve conduits [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Additive-lathe 3D bioprinting of bilayered nerve conduits incorporated with supportive cells

Liu

Zhang

et al. 2021

Bioactive Materials

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Nerve conduits have been identified as one of the most promising treatments for peripheral nerve injuries, yet it remains unsolved how to develop ideal nerve conduits with both appropriate biological and mechanical properties. Existing nerve conduits must make trade-offs between mechanical strength and biocompatibility. Here, we propose a multi-nozzle additive-lathe 3D bioprinting technology to fabricate a bilayered nerve conduit. The materials for printing consisted of gelatin methacrylate (GelMA)-based inner layer, which was cellularized with bone marrow mesenchymal stem cells (BMSCs) and GelMA/poly(ethylene glycol) diacrylate (PEGDA)-based outer layer. The high viability and extensive morphological spreading of BMSCs encapsulated in the inner layer was achieved by adjusting the degree of methacryloyl substitution and the concentration of GelMA. Strong mechanical performance of the outer layer was obtained by the addition of PEGDA. The performance of the bilayered nerve conduits was assessed using in vitro culture of PC12 cells. The cell density of PC12 cells attached to cellularized bilayered nerve conduits was more than 4 times of that on acellular bilayered nerve conduits. The proliferation rate of PC12 cells attached to cellularized bilayered nerve conduits was over 9 times higher than that on acellular bilayered nerve conduits. These results demonstrate the additive-lathe 3D bioprinting of BMSCs embedded bilayered nerve conduits holds great potential in facilitating peripheral nerve repair.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Additive-lathe 3D bioprinting of bilayered nerve conduits incorporated with supportive cells

Liu

Zhang

et al. 2021

Bioactive Materials

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“…With this double strategy, the authors could control the concurrent precise release of neurotrophic factors as well as the directional neurite outgrowth in PC12 cells. In another study (Sun et al, 2019), Sun et al introduced exogenous cells secreting GFs capable of spatial distribution along the conduit. Instead of using a normal cellular density and distribution along the conduit, the authors used encapsulated bone marrow MSCs (BMSCs) capable of producing high levels of BDNF.…”

Section: Growth Factors (Gfs) As Molecular Therapiesmentioning

confidence: 99%

Modern Trends for Peripheral Nerve Repair and Regeneration: Beyond the Hollow Nerve Guidance Conduit

Carvalho

Oliveira

Reis

2019

Front. Bioeng. Biotechnol.

224

210

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Peripheral nerve repair and regeneration remains among the greatest challenges in tissue engineering and regenerative medicine. Even though peripheral nerve injuries (PNIs) are capable of some degree of regeneration, frail recovery is seen even when the best microsurgical technique is applied. PNIs are known to be very incapacitating for the patient, due to the deprivation of motor and sensory abilities. Since there is no optimal solution for tackling this problem up to this day, the evolution in the field is constant, with innovative designs of advanced nerve guidance conduits (NGCs) being reported every day. As a basic concept, a NGC should act as a physical barrier from the external environment, concomitantly acting as physical guidance for the regenerative axons across the gap lesion. NGCs should also be able to retain the naturally released nerve growth factors secreted by the damaged nerve stumps, as well as reducing the invasion of scar tissue-forming fibroblasts to the injury site. Based on the neurobiological knowledge related to the events that succeed after a nerve injury, neuronal subsistence is subjected to the existence of an ideal environment of growth factors, hormones, cytokines, and extracellular matrix (ECM) factors. Therefore, it is known that multifunctional NGCs fabricated through combinatorial approaches are needed to improve the functional and clinical outcomes after PNIs. The present work overviews the current reports dealing with the several features that can be used to improve peripheral nerve regeneration (PNR), ranging from the simple use of hollow NGCs to tissue engineered intraluminal fillers, or to even more advanced strategies, comprising the molecular and gene therapies as well as cell-based therapies.

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“…NTFs use pathfinding gradients to stimulate or inhibit axonal outgrowth, [ 52 , 53 ] direct axonal elongation [ 54 ], promote stem cell differentiation [ 55 ] and recruitment [ 56 ], and program Schwann cells [ 57 ]. Several design strategies have been employed by directly conjugating NTFs to conduit walls [ 58 ] or stimulating neural cells to secrete NTFs within the lumen [ 59 , 60 ]. Another GF strategy arranges NTFs, extracellular matrix (ECM) proteins, and stem cells in a longitudinal gradient to orient regenerating axons towards the distal stump.…”

Section: Background—critical Challenges In (Re)innervationmentioning

confidence: 99%

Machine intelligence for nerve conduit design and production

et al. 2020

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Nerve guidance conduits (NGCs) have emerged from recent advances within tissue engineering as a promising alternative to autografts for peripheral nerve repair. NGCs are tubular structures with engineered biomaterials, which guide axonal regeneration from the injured proximal nerve to the distal stump. NGC design can synergistically combine multiple properties to enhance proliferation of stem and neuronal cells, improve nerve migration, attenuate inflammation and reduce scar tissue formation. The aim of most laboratories fabricating NGCs is the development of an automated process that incorporates patient-specific features and complex tissue blueprints (e.g. neurovascular conduit) that serve as the basis for more complicated muscular and skin grafts. One of the major limitations for tissue engineering is lack of guidance for generating tissue blueprints and the absence of streamlined manufacturing processes. With the rapid expansion of machine intelligence, high dimensional image analysis, and computational scaffold design, optimized tissue templates for 3D bioprinting (3DBP) are feasible. In this review, we examine the translational challenges to peripheral nerve regeneration and where machine intelligence can innovate bottlenecks in neural tissue engineering.

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Conduits harnessing spatially controlled cell-secreted neurotrophic factors improve peripheral nerve regeneration

Cited by 40 publications

References 54 publications

Additive-lathe 3D bioprinting of bilayered nerve conduits incorporated with supportive cells

Additive-lathe 3D bioprinting of bilayered nerve conduits incorporated with supportive cells

Modern Trends for Peripheral Nerve Repair and Regeneration: Beyond the Hollow Nerve Guidance Conduit

Machine intelligence for nerve conduit design and production

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