Combining Gene and Stem Cell Therapy for Peripheral Nerve Tissue Engineering

Busuttil, Francesca; Rahim, Afidah Abdul; Phillips, James B.

doi:10.1089/scd.2016.0188

Cited by 23 publications

(14 citation statements)

References 87 publications

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“…In regenerative medicine and tissue engineering, the use of Stem Cells and their secretome is fast expanding with the aim to develop innovative therapeutic strategies for the treatment of peripheral nerve injuries (Caplan, 2015; Caseiro et al, 2016; Busuttil et al, 2017; Sayad-Fathi et al, 2019). In particular, Mesenchymal Stem Cells (MSCs) present relevant key features: they can be easily expanded, they can differentiate into different cell types, they are immune-privileged and immune-modulatory, they show preferential homing to injured sites (Frausin et al, 2015; Sullivan et al, 2016; Jiang et al, 2017).…”

Section: Methodological Considerations – Approaches For the Treatmentmentioning

confidence: 99%

The Median Nerve Injury Model in Pre-clinical Research – A Critical Review on Benefits and Limitations

Ronchi

Morano

Fregnan

et al. 2019

Front. Cell. Neurosci.

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The successful introduction of innovative treatment strategies into clinical practise strongly depends on the availability of effective experimental models and their reliable pre-clinical assessment. Considering pre-clinical research for peripheral nerve repair and reconstruction, the far most used nerve regeneration model in the last decades is the sciatic nerve injury and repair model. More recently, the use of the median nerve injury and repair model has gained increasing attention due to some significant advantages it provides compared to sciatic nerve injury. Outstanding advantages are the availability of reliable behavioural tests for assessing posttraumatic voluntary motor recovery and a much lower impact on the animal wellbeing. In this article, the potential application of the median nerve injury and repair model in pre-clinical research is reviewed. In addition, we provide a synthetic overview of a variety of methods that can be applied in this model for nerve regeneration assessment. This article is aimed at helping researchers in adequately adopting this in vivo model for pre-clinical evaluation of peripheral nerve reconstruction as well as for interpreting the results in a translational perspective.

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Section: Methodological Considerations – Approaches For the Treatmentmentioning

confidence: 99%

The Median Nerve Injury Model in Pre-clinical Research – A Critical Review on Benefits and Limitations

Ronchi

Morano

Fregnan

et al. 2019

Front. Cell. Neurosci.

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“…Similarly, GDNF has been shown to enhance motor and sensory recovery after nerve injury, but overdosage of GDNF has shown some serious effects on Schwann cell proliferation, termed as the "candy-store effect." Overexpression of GDNF across a nerve injury can result in the induction of a neuroma of coiled motoneuron axons and Schwann cells, hence, hindering nerve growth across a gap (Busuttil et al, 2017;Eggers et al, 2013). to be biologically advantageous, as high amounts of FK506 cause toxicity and reduce neurite growth.…”

Section: Nerve Histomorphometrymentioning

confidence: 99%

“…Despite the ability of FK506 to assist in nerve regeneration, systemic delivery has numerous potentially serious side effects such as central nervous system toxicity, infection, nephrotoxicity, and hyperglycemia(Dumont et al, 1992;Felldin et al, F I G U R E 9 % EMG activity at (a) 10 week for FK506 and GDNF vs. no drug (n = 4) and at (b) 18 weeks for FK506 and GDNF vs. no drug (n = 6 for GDNF; n = 8 for FK506). Overexpression of GDNF across a nerve injury can result in the induction of a neuroma of coiled motoneuron axons and Schwann cells, hence, hindering nerve growth across a gap(Busuttil et al, 2017;Eggers et al, 2013).Prior studies have shown that the presence of neurotrophic factors such as GDNF or FK506 provides beneficial effects in the repair of nerve injuries, but these effects are dependent on the consistency of drug release and control over the released drug concentration over the treatment period. EMG: electromyography [Color figure can be viewed at wileyonlinelibrary.com] F I G U R E 1 0 (a) Nerve histomorphometry (number of myelinated fibers at the distal end) at 10 weeks for FK506 and GDNF group vs. no-drug group (n = 4).…”

mentioning

confidence: 99%

“…Despite the ability of FK506 to enhance nerve regeneration, systemic delivery has numerous potentially serious side effects, such as central nervous system toxicity, infection, nephrotoxicity, and hyperglycemia (Dumont et al, 1992;Felldin et al, 1997;Nielsen, Leyssac, Kemp, Starklint, & Dieperink, 1995). Likewise, GDNF has been shown to enhance motor recovery following nerve injury, but overexpression of GDNF has been shown to induce coil-like neuroma formation of motor axons and hinder Schwann cell migration (Busuttil, Rahim, & Phillips, 2017;Eggers et al, 2013). Local controlled delivery of drugs like FK506 or GDNF from a nerve guide could provide their neurotrophic benefits on nerve regeneration but prevent the negative consequence of systemic delivery or overdosage.…”

mentioning

confidence: 99%

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Drug‐delivering nerve conduit improves regeneration in a critical‐sized gap

Labroo

Hilgart

Davis

et al. 2018

Biotech & Bioengineering

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Autologous nerve grafts are the current "gold standard" for repairing large nerve gaps. However, they cause morbidity at the donor nerve site and only a limited amount of nerve can be harvested. Nerve conduits are a promising alternative to autografts and can act as guidance cues for the regenerating axons, without the need to harvest donor nerve. Separately, it has been shown that localized delivery of GDNF can enhance axon growth and motor recovery. FK506, an FDA approved small molecule, has also been shown to enhance peripheral nerve regeneration. This paper describes the design of a novel hole-based drug delivery apparatus integrated with a polytetrafluoroethylene (PTFE) nerve conduit for controlled local delivery of a protein such as GDNF or a small molecule such as FK506. The PTFE devices were tested in a diffusion chamber, and the bioactivity of the released media was evaluated by measuring neurite growth of dorsal root ganglions (DRGs) exposed to the released drugs. The drug delivering nerve guide was able to release bioactive concentrations of FK506 or GDNF. Following these tests, optimized drug releasing nerve conduits were implanted across 10 mm sciatic nerve gaps in a BL6 yellow fluorescent protein (YFP) mouse model, where they demonstrated significant improvement in muscle mass, compound muscle action potential, and axon myelination in vivo as compared with nerve conduits without the drug. The drug delivery nerve guide could release drug for extended periods of time and enhance axon growth in vitro and in vivo.

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“…Current approaches for nerve repair after traumatic injury commonly utilize scaffolds carrying/enriched in cells, extracellular matrix molecules, growth factors, and other signaling molecules in order to encourage nerve growth (Busuttil et al, 2017;Sensharma et al, 2017). Neural tissue engineering has identified a number of biomolecules, including proteins and their related peptides, capable of promoting nerve regeneration both in vitro and in vivo (Tian et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Ten‐eleven translocation methylcytosine dioxygenase 3‐loaded microspheres penetrate neurons in vitro causing active demethylation and neurite outgrowth

Nawrotek

Rudnicka

Gatkowska

et al. 2021

J Tissue Eng Regen Med

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Epigenetic processes, such as DNA methylation and other chromatin modifications, are believed to be largely responsible for establishing a reduced capacity for growth in the mature nervous system. Ten-eleven translocation methylcytosine dioxygenase 3 (Tet3)-, a member of the Tet gene family, plays a crucial role in promoting injuryinduced DNA demethylation and expression of regeneration-associated genes in the peripheral nervous system. Here, we encapsulate Tet3 protein within a clinically tolerated poly(lactide-co-glycolide) microsphere system. Next, we show that Tet3loaded microspheres are internalized into mHippoE-18 embryonic hippocampal cells. We compare the outgrowth potential of Tet3 microspheres with that of commonly used nerve growth factor (NGF)-loaded microspheres in an in vitro injury model.Tet3-containing microspheres increased levels of nuclear 5-hydroxymethylcytosine indicating active demethylation and outperformed NGFcontaining microspheres in measures of neurite outgrowth. Our results suggest that encapsulated demethylases may represent a novel avenue to treat nerve injuries.

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Combining Gene and Stem Cell Therapy for Peripheral Nerve Tissue Engineering

Cited by 23 publications

References 87 publications

The Median Nerve Injury Model in Pre-clinical Research – A Critical Review on Benefits and Limitations

The Median Nerve Injury Model in Pre-clinical Research – A Critical Review on Benefits and Limitations

Drug‐delivering nerve conduit improves regeneration in a critical‐sized gap

Ten‐eleven translocation methylcytosine dioxygenase 3‐loaded microspheres penetrate neurons in vitro causing active demethylation and neurite outgrowth

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