An engineered biocompatible drug delivery system enhances nerve regeneration after delayed repair

Tajdaran, Kasra; Gordon, Tessa; Wood, Matthew D.; Shoichet, Molly S.; Borschel, Gregory H.

doi:10.1002/jbm.a.35572

Cited by 31 publications

(20 citation statements)

References 50 publications

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“…Overexpression of a single NTF alone, including GDNF, NGF, or BDNF, is usually not sufficient for optimal nerve regeneration and functional recovery (45,46). This might be ascribed to the findings that different kinds and subtypes of neurons show distinctive responses to different NTFs and that the injured peripheral nerve often contains both motor and sensory neurons as well as different subtypes of each (13,14,47).…”

Section: Discussionmentioning

confidence: 99%

Time‐restricted release of multiple neurotrophic factors promotes axonal regeneration and functional recovery after peripheral nerve injury

et al. 2019

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Delivery of multiple neurotrophic factors (NTFs), especially with time‐restricted release kinetics, holds great potential for nerve repair. In this study, we utilized the tetracycline‐regulatable Tet‐On 3G system to control the expression of c‐Jun, which is a common regulator of multiple NTFs in Schwann cells (SCs). In vitro, Tet‐On/c‐Jun‐modified SCs showed a tightly controllable secretion of multiple NTFs, including glial cell line‐derived NTF, nerve growth factor, brain‐derived NTF, and artemin, by the addition or removal of doxycycline (Dox). When Tet‐On/c‐Jun‐transduced SCs were grafted in vivo, the expression of NTFs could also be regulated by oral administration or removal of Dox. Fluoro‐Gold retrograde tracing results indicated that a biphasic NTF expression scheme (Dox+3/−9, NTFs were up‐regulated for 3 wk and declined to physiologic levels for another 9 wk) achieved more axonal regeneration than continuous up‐regulation of NTFs (Dox+12) or no NTF induction (Dox−12). More importantly, the Dox+3/−9–group animals showed much better functional recovery than the animals in the Dox+12 and Dox−12 groups. Our findings, for the first time, demonstrated drug‐controllable expression of multiple NTFs in nerve repair cells both in vitro and in vivo. These findings provide new hope for developing an optimal therapeutic alternative for nerve repair through the time‐restricted release of multiple NTFs using Tet‐On/c‐Jun‐modified SCs.—Huang, L., Xia, B., Shi, X., Gao, J., Yang, Y., Xu, F., Qi, F., Liang, C., Huang, J., Luo, Z. Time‐restricted release of multiple neurotrophic factors promotes axonal regeneration and functional recovery after peripheral nerve injury. FASEB J. 33, 8600–8613 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Time‐restricted release of multiple neurotrophic factors promotes axonal regeneration and functional recovery after peripheral nerve injury

et al. 2019

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“…Simultaneously, there is a period in which the levels of neurotrophic factors receptors in Schwann cells and neurons are increased before returning to normal values. In addition, regional and constant application of exogenous GDNF greatly promotes local axon regeneration and recovery after delayed nerve repair 42 . In the present study, the dorsal horn on the similar side of injury showed the highest expression of CGRP at 5 weeks post-implantation, which subsequently decreased from weeks 5 to 8.…”

Section: Discussionmentioning

confidence: 99%

Biodegradable Bisvinyl Sulfonemethyl-crosslinked Gelatin Conduit Promotes Regeneration after Peripheral Nerve Injury in Adult Rats

Shie

Lin

et al. 2017

Sci Rep

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In our previous study, we found that gelatin-based materials exhibit good conductivity and are non-cytotoxic. In this study, gelatin was cross-linked with bisvinyl sulfonemethyl (BVSM) to fabricate a biodegradable conduit for peripheral nerve repair. First, BVSM on the prepared conduit was characterized to determine its mechanical properties and contact angle. The maximum tensile strength and water contact angle of the gelatin-BVSM conduits were 23 ± 4.8 MPa and 74.7 ± 9°, which provided sufficient mechanical strength to resist muscular contraction; additionally, the surface was hydrophilic. Cytotoxicity and apoptosis assays using Schwann cells demonstrated that the gelatin-BVSM conduits are non-cytotoxic. Next, we examined the neuronal electrophysiology, animal behavior, neuronal connectivity, macrophage infiltration, calcitonin gene-related peptide localization and expression, as well as the expression levels of nerve regeneration-related proteins. The number of fluorogold-labelled cells and histological analysis of the gelatin-BVSM nerve conduits was similar to that observed with the clinical use of silicone rubber conduits after 8 weeks of repair. Therefore, our results demonstrate that gelatin-BVSM conduits are promising substrates for application as bioengineered grafts for nerve tissue regeneration.

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“…FG has also been used as a conduit material [32–36]. In addition, FG has been used as a filler within the lumen of non-porous conduits [37, 38], and as scaffolds to deliver growth factors for nerve regeneration [39, 40]. To the best of our knowledge, all the studies that used Fibrin Glue were done with non-porous conduits up till now.…”

Section: Introductionmentioning

confidence: 99%

Fibrin glue as a stabilization strategy in peripheral nerve repair when using porous nerve guidance conduits

Bhatnagar

Bushman

Murthy

et al. 2017

J Mater Sci: Mater Med

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Porous conduits provide a protected pathway for nerve regeneration, while still allowing exchange of nutrients and wastes. However, pore sizes >30 µm may permit fibrous tissue infiltration into the conduit, which may impede axonal regeneration. Coating the conduit with Fibrin Glue (FG) is one option for controlling the conduit’s porosity. FG is extensively used in clinical peripheral nerve repair, as a tissue sealant, filler and drug-delivery matrix. Here, we compared the performance of FG to an alternative, hyaluronic acid (HA) as a coating for porous conduits, using uncoated porous conduits and reverse autografts as control groups. The uncoated conduit walls had pores with a diameter of 60 to 70 µm that were uniformly covered by either FG or HA coatings. In vitro, FG coatings degraded twice as fast as HA coatings. In vivo studies in a 1 cm rat sciatic nerve model showed FG coating resulted in poor axonal density (993 ± 854 #/mm2), negligible fascicular area (0.03 ± 0.04 mm2), minimal percent wet muscle mass recovery (16 ± 1 in gastrocnemius and 15 ± 5 in tibialis anterior) and G-ratio (0.73 ± 0.01). Histology of FG-coated conduits showed excessive fibrous tissue infiltration inside the lumen, and fibrin capsule formation around the conduit. Although FG has been shown to promote nerve regeneration in non-porous conduits, we found that as a coating for porous conduits in vivo, FG encourages scar tissue infiltration that impedes nerve regeneration. This is a significant finding considering the widespread use of FG in peripheral nerve repair.Graphical Abstract

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An engineered biocompatible drug delivery system enhances nerve regeneration after delayed repair

Cited by 31 publications

References 50 publications

Time‐restricted release of multiple neurotrophic factors promotes axonal regeneration and functional recovery after peripheral nerve injury

Time‐restricted release of multiple neurotrophic factors promotes axonal regeneration and functional recovery after peripheral nerve injury

Biodegradable Bisvinyl Sulfonemethyl-crosslinked Gelatin Conduit Promotes Regeneration after Peripheral Nerve Injury in Adult Rats

Fibrin glue as a stabilization strategy in peripheral nerve repair when using porous nerve guidance conduits

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