The mechanical damage to neurons and their processes induced by spinal cord injury (SCI) causes a progressive cascade of pathophysiological events beginning with the derangement of ionic equilibrium and collapse of membrane permeability. This leads to a cumulative deterioration of neurons, axons, and the tissue architecture of the cord. We have previously shown that the application of the hydrophilic polymer polyethylene glycol (PEG) following spinal cord or brain injury can rapidly restore membrane integrity, reduce oxidative stress, restore impaired axonal conductivity, and mediate functional recovery in rats, guinea pigs, and dogs. However there are limits to both the concentration and the molecular weight of the application that do not permit the broadest recovery across an injured animal population. In this study, PEG-decorated silica nanoparticles (PSiNPs) sealed cells, as shown by the significantly reduced leakage of lactate dehydrogenase from damaged cells compared with uncoated particles or PEG alone. Further in vivo tests showed that PSiNPs also significantly reduced the formation of reactive oxygen species and the process of lipid peroxidation of the membrane. Fabrication of PSiNPs containing embedded dyes also revealed targeting of the particles to damaged, but not undamaged, spinal cord tissues. In an in vivo crush/contusion model of guinea pig SCI, every animal but one injected with PSiNPs recovered conduction through the cord lesion, whereas none of the control animals did. These findings suggest that the use of multifunctional nanoparticles may offer a novel treatment approach for spinal cord injury, traumatic brain injury, and possibly neurodegenerative disorders.
"All chemicals were purchased from Sigma-Aldrich unless otherwise specified. TMR-doped, PEG-modified silica nanoparticles were synthesized according to the previously described procedure
. In brief, the mixture composed of 1.77 mL of Triton X-100, 1.8 mL of n-hexanol, 7.5 mL of cyclohexane, and 0.5 mL of 1% aqueous tetramethyl rhodamine-dextran (TMR-dextran, Invitrogen) solution was prepared to form water-in-oil (W/O) reverse microemulsion by adjusting solution pH to 2.0. "
[Show abstract][Hide abstract] ABSTRACT: Background
Traumatic spinal cord injury (SCI) leads to serious neurological and functional deficits through a chain of pathophysiological events. At the molecular level, progressive damage is initially revealed by collapse of plasma membrane organization and integrity produced by breaches. Consequently, the loss of its role as a semi-permeable barrier that generally mediates the regulation and transport of ions and molecules eventually results in cell death. In previous studies, we have demonstrated the functional recovery of compromised plasma membranes can be induced by the application of the hydrophilic polymer polyethylene glycol (PEG) after both spinal and brain trauma in adult rats and guinea pigs. Additionally, efforts have been directed towards a nanoparticle-based PEG application.
The in vivo and ex vivo applications of PEG-decorated silica nanoparticles following CNS injury were able to effectively and efficiently enhance resealing of damaged cell membranes.
The possibility for selectivity of tetramethyl rhodamine-dextran (TMR) dye-doped, PEG-functionalized silica nanoparticles (TMR-PSiNPs) to damaged spinal cord was evaluated using an ex vivo model of guinea pig SCI. Crushed and nearby undamaged spinal cord tissues exhibited an obvious difference in both the imbibement and accumulation of the TMR-PSiNPs, revealing selective labeling of compression-injured tissues.
These data show that appropriately functionalized nanoparticles can be an efficient means to both 1.) carry drugs, and 2.) apply membrane repair agents where they are needed in focally damaged nervous tissue.
"Chitosan is bio-compatible, biodegradable, non-toxic and can easily be prepared from the exoskeletons of crustaceans. Chitosan has widely been used as a drug carrier and wound healer and first indications are that this natural polymer after topical application is capable of inducing the sealing of neuronal membranes and restores the conduction of nerve impulses through the length of the spinal cord preferentially targeting the region of damage (Cho et al. 2010a, b). In addition, chitosan can easily participate in the preparation of microcapsules or micro/nano-spheres serving as a carrier, which is particularly suitable for controlled drug release (for review, see Cho and Borgens 2012) "
[Show abstract][Hide abstract] ABSTRACT: Important advances in the development of smart biodegradable implants for axonal regeneration after spinal cord injury have recently been reported. These advances are evaluated in this review with special emphasis on the regeneration of the corticospinal tract. The corticospinal tract is often considered the ultimate challenge in demonstrating whether a repair strategy has been successful in the regeneration of the injured mammalian spinal cord. The extensive know-how of factors and cells involved in the development of the corticospinal tract, and the advances made in material science and tissue engineering technology, have provided the foundations for the optimization of the biomatrices needed for repair. Based on the findings summarized in this review, the future development of smart biodegradable bridges for CST regrowth and regeneration in the injured spinal cord is discussed.
Cell and Tissue Research 03/2012; 349(1):375-95. DOI:10.1007/s00441-012-1352-5 · 3.57 Impact Factor
"The hydrophilic polymer polyethylene glycol (PEG) has similar chemical properties with regard to membrane sealing (Shi and Borgens 2000). The application of PEG-decorated silica nanoparticles in a spinal cord lesion model in vivo results in an accumulation of the particles at the lesion site and the recovery of electrical conduction through the lesion site (Cho et al. 2010). Whether such approaches will be applied in future clinical treatments will largely depend on the feasibility of rapid application following injury, targeted delivery to the lesion site and their sideeffects profile. "
[Show abstract][Hide abstract] ABSTRACT: Degeneration of the axon is an important step in the pathomechanism of traumatic, inflammatory and degenerative neurological diseases. Increasing evidence suggests that axonal degeneration occurs early in the course of these diseases and therefore represents a promising target for future therapeutic strategies. We review the evidence for axonal destruction from pathological findings and animal models with particular emphasis on neurodegenerative and neurotraumatic disorders. We discuss the basic morphological and temporal modalities of axonal degeneration (acute, chronic and focal axonal degeneration and Wallerian degeneration). Based on the mechanistic concepts, we then delineate in detail the major molecular mechanisms that underlie the degenerative cascade, such as calcium influx, axonal transport, protein aggregation and autophagy. We finally concentrate on putative therapeutic targets based on the mechanistic prerequisites.
Cell and Tissue Research 03/2012; 349(1):289-311. DOI:10.1007/s00441-012-1362-3 · 3.57 Impact Factor
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