Sustained Local Release of NGF from a Chitosan–Sericin Composite Scaffold for Treating Chronic Nerve Compression

Abstract

Chronic nerve compression (CNC), a common form of peripheral nerve injury, always leads to chronic peripheral nerve pain and dysfunction. Current available treatments for CNC are ineffective as they usually aim to alleviate symptoms at the acute phase with limited capability toward restoring injured nerve function. New approaches for effective recovery of CNC injury are highly desired. Here we report for the first time a tissue-engineered approach for the repair of CNC. A genipin cross-linked chitosan-sericin 3D scaffold for delivering nerve growth factor (NGF) was designed and fabricated. This scaffold combines the advantages of both chitosan and sericin, such as high porosity, adjustable mechanical properties and swelling ratios, the ability of supporting Schwann cells growth, and improving nerve regeneration. The degradation products of the composite scaffold upregulate the mRNA levels of the genes important for facilitating nerve function recovery, including glial-derived neurotrophic factor (GDNF), early growth response 2 (EGR2), and neural cell adhesion molecule (NCAM) in Schwann cells, while down-regulating two inflammatory genes' mRNA levels in macrophages, tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β). Importantly, our tissue-engineered strategy achieves significant nerve functional recovery in a preclinical CNC animal model by decreasing neuralgia, improving nerve conduction velocity (NCV), accelerating microstructure restoration, and attenuating gastrocnemius muscles dystrophy. Together, this work suggests a promising clinical alternative for treating chronic peripheral nerve compression injury.

Relevance and Recent Developments of Chitosan in Peripheral Nerve Surgery

“…Chitosan microspheres loaded with NGF has been incorporated to collagen-chitosan scaffolds for a rat’s sciatic nerve and led to promising results in functional outcome in combination with microchannels as inner lining (Zeng et al, 2014) as well as combined with a chitosan nerve guide conduit for reconstruction of facial nerve injuries (Liu et al, 2013). Further developments in tissue engineering enable an additional loading of cores-shell poly(lactide-co-glycolide)-chitosan microparticles as drug delivery system for continuous release of NGF (Zhang et al, 2017).…”

“…The indication of chitosan tubes is not only limited to the treatment of PNI but can also be extended for nerve compression syndromes. Zhang et al (2017) developed a chitosan-sericin scaffold for a continuous delivering of NGF. After application, a better functional recovery, as well as superior histological results has been demonstrated, probably caused by the beneficial effects of degradation products and the corresponding inducement of mRNA levels of GDNF, EGR2, NCAM as well as down-regulation levels of inflammatory genes (Zhang et al, 2017).…”

Application of stem cells and chitosan in the repair of spinal cord injury

“…Importantly, Chitosan (also known as glucosamine (1 ‐ 4) ‐ 2 ‐ amino ‐ b ‐ d glucose) is a natural cationic polysaccharide obtained by the deacetylation of chitin, which could be designed as scaffolds for cell accommodation, growth and differentiation (Gao et al, 2014). Usually, CS has been widely developed as a promising alternative therapeutic strategy in the areas of nerve regeneration(Zhang et al, 2018a,2018b; Yao et al, 2018), bone formation (Yao et al, 2017; Chen et al, 2017) and cartilage tissue injury repair (Sumayya and Muraleedhara Kurup, 2018) in the form of delivery carriers (Zhang et al, 2017a,2017b) and degradable scaffolds (Li et al, 2018a,b,d; Luo et al, 2018). The aforementioned functionalities of CS are due to its unique and appealing properties such as compatibility, biodegradability, nontoxicity, control release of neurotrophic factors or stem cells through scaffolds/nanoparticles.…”

“…Cores‐shell prepared with CS and PLGA encapsulated GDNF, which could maintain the bioactivity of GDNF for a long time, is also able to reduce the initial burst release and neutralize the acidity of PLGA degradation products and promote the PC12 cells to differentiate into neuron‐like cells in vitro (Zeng et al, 2017). In addition, porous CS‐sericin scaffold prepared with genipin for delivery of NGF showed great progress in the functional recovery of SCI in preclinical model by decreasing neuralgia, promoting structural restoration and attenuating inflammation, thereby benefiting the repair of nerve compression (Zhang et al, 2017a,2017b). The cell viability of attached neural stem cell decreased in naked NT‐3 daily addition groups, while the application of CS carrier could stably and constantly support the NSCs survival, proliferation and differentiation for at least 14 weeks(Yang et al, 2010; Yang et al, 2015).…”

Signatures of altered DNA methylation gene expression after central and peripheral nerve injury

“…In addition, the peripheral nerve microenvironment contains a variety of neurotrophic factors or growth factors, which play an irreplaceable role in nerve regeneration. In previous studies, different scaffolds combined with various neurotrophic factors or growth factors, such as glial cell line‐derived neurotrophic factor (GDNF), nerve growth factor (NGF), and neurotrophin‐3 (NT‐3), achieved good nerve repair effects (Ma et al, 2018b; Zeng et al, ; Zhang et al, ).…”