Zixin(Sybil) Sha, Beiyu(Beryl) Li
Student of Stanford Pre-collegiate Studies 2017 Investigations in Bioscience and Biotechnology – Nanobiomaterials; Class of 2018 in the International Department of the Affiliated High School of SCNU (HFI); Interested in neurology and the interdisciplinary possibilities between neurology and nanobiomaterials.
Student of Stanford Pre-collegiate Studies 2017 Investigations in Bioscience and Biotechnology – Nanobiomaterials. Class of 2018, Dulwich International High School Suzhou.
“You’re walking across an alien landscape where nothing is familiar. You spot no landmarks; see no recognizable faces — even the sounds you hear are completely foreign. Alone, confused and frustrated, you sink to the ground and stare at the confusing panorama, unsure of what to do next.7”
This is what people with Alzheimer’s experience every day. Alzheimer’s is the most prevalent and severe neurodegenerative disease faced by five million elderly Americans at present. Another estimated one million Americans are suffering from Parkinson’s disease, another devastating neurodegenerative disease. These statistics are estimated to have a striking two-fold increase in the following generation.33 Therefore, developing novel and more effective methods to combat these nervous-system-related diseases has become the highlight in neurological research. One of these novel approaches is to introduce nanobiomaterials, the “nanoscale workers,” to the human body to treat neurological diseases.
What is neurology?
The study of neurology encompasses various pathological disorders of the human central nervous system (CNS), which consists of the brain and spinal cord. Treating the human body is already a difficult task, but dealing with the brain, one of the most sophisticated structures found on earth, is even more challenging for neurologists and researchers. Several important focuses in neurology are epilepsy, amnesia, Alzheimer’s disease and Parkinson’s disease, the symptoms of which could be alleviated with medications such as botulinum toxin injections, but the biggest predicament is that existing medications are unable to restore lost functions or cure the disease completely.
What are nanobiomaterials?
The science of nanobiomaterials studies the intersection between biology and nanomaterial science. Nanobiomaterials can be classified into various categories, including nanoparticles, nanoporous scaffolds, carbon nanotubes, nanopatterned scaffolds, and nanowires.27 Among these, carbon nanotubes (CNT) and nanoparticles are perhaps the most promising in terms of application and potential treatments in neurology. There is growing evidence suggests enormous potentials of CNT and nanoparticles in fields including drug delivery, neuroregeneration, and neural stimulation.
As biochemical substances, drugs can do both good and harm to our body. To prevent drugs from disrupting the physiological environment of the human body while performing its function, targeted delivery of drugs is currently the more desirable form of treatment. However, the situation is always complicated when involving the brain. The blood-brain barrier (BBB) is one major obstacle faced by neurologists who seek to deliver drugs to the brain. The BBB is a highly selective layer of endothelial cells in the brain that separates circulating blood and brain tissues, with tight junctions between endothelial cells making the passage of polar substances extremely difficult. Since most drugs reach their destinations through blood transport, a delivered drug must permeate through the BBB to reach the medulla or the midbrain, the common function site of neurological drugs,13, 32 but the BBB normally does not allow aqueous neuroactive drugs to pass through. Previously, researchers have adopted methods including convection-enhanced delivery (CED) and viral vectors to disrupt or circumvent the BBB.4, 6 While these are either risky due to toxicity or rather ineffective in actual trials, nanobiomaterials provide a safer and more efficient solution. Liposomes and micelles both possess an inner compartment and an outer shell, which allows these nanoparticles to safely diffuse across the BBB. When engineered and packaged with an antioxidant, transmitter or other chemotherapeutic agents in their inner core, these nanoparticles could act as carrier agents and deliver treatments to targeted positions.2, 11, 28
For those suffering from neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, the most ideal treatment cannot be accomplished by simply delivering medicine to the brain. Neurodegeneration is the process that takes place in the aging or severely damaged brain, which means a loss or dysfunction of neurons and synapses. The pathological results of neurodegeneration include slow movements (bradykinesia), tremor, rigidity, and dementia. One cure would be neuroregeneration, meaing the restoration of deteriorated nervous tissues and cells, which counteracts neurodegeneration by regrowing and repairing lost or damaged neurons. However, existing methods for neuroregeneration have low efficiency and high possibility of rejection.
One very promising candidate for promoting neurogenesis is the CNTs, cylindrical nanostructures wrapped up with single or multilayered graphite sheet.5 CNTs possess outstanding mechanical and electrical properties such as conductivity, mechanical strength, and easiness of surface-modification. Numerous experiments were conducted to investigate how these properties could aid in applying CNTs in neurogenesis. As early as ten years ago, the research of Hu et al and Matsumoto et al shows that both chemically modified single-walled CNT (SWNT) and multi-walled CNT (MWNT) significantly promotes neuronal outgrowth and branching when synthesized as a substrates for cultured neurons or bonded with neurotrophin proteins that promote the development and differentiation of neurons.12, 20 Chao et al also found the stable conductivity and large surface-area-to-volume ratio of CNT-scaffolds beneficial for human embryonic stem cells’ differentiation into neurons.9 Singh et al, on the other hand, reported that combining chitin and CNTs enhances the mechanical and electrical properties of CNTs, making them both highly conductive and biocompatible.31 But the surprises brought by CNTs are more than just that. Later experiments discovered more exciting properties of CNTs, such as their ability to direct the differentiation of neural stem cells and decrease macrophage activation, which leads to less inflammation and thus a longer lifetime for the implant.15, 26 These inimitable qualities make CNT perfect scaffolds for neural regeneration and promoting neural cells differentiation.
Neural stimulation is a frequently used technique in treating neurological disorders by restoring lost neural circuits and functions, based on the fact that neurons pass on electrical signals to each other. Traditional methods use electrodes, ultrasound or light to create intervening electric fields and stimulate neurons, but these approaches are either too invasive or lacking in spatial resolution.24 For these reasons, scientists have been looking at nanobiomaterials for noninvasive, precise mediators for neural stimulation.
Nanobiomaterial surfaces are easily modified for targeting with structures and scales resembling neuronal membranes and ion channels,18, 35 making them particularly suitable as mediators to “convert a wirelessly transmitted primary stimulus to a localized secondary stimulus at the nanomaterial-neuron interface”.34 In artificial in vitro environments, CNTs proved effective in performing neural stimulation and transmitting electrical signals.19, 34 According to Mazzatenta et al, who performed electrophysiological recordings of hippocampal neurons grown on nanotubes, neurons grown on single-walled carbon nanotube substrates “displayed spontaneous electrical activity.” Electrical signals carrying information are induced through applying currents to the single-walled carbon nanotube, indicating effective neuron-neuron signaling as well as neural stimulation through CNTs.21
Besides CNTs, gold nanoparticles (GNP) have also been proved effective in neural stimulation. When conjugated with ligands and targeted to ion channels on neuronal membranes, GNPs could generate heat upon illumination, depolarize neurons, and fire action potentials.8, 10 The above studies together show that CNTs and GNPs might provide novel means for neural stimulation and help deliver electrical signals between damaged neuronal circuits — an exciting prospect for those dealing with Alzheimer’s and other neurodegenerative diseases.
Other things considered…
Nanobiomaterials appear to be the panacea for current predicaments in neurology, but there are reasons why they are still not in clinical trial or medical applications despite having been discovered more than a decade ago. The biggest barrier for applying nanobiomaterials to the human body, whether as carrier implants or biosensors, is the automatic rejection by the body called the Foreign Body Reaction. Any foreign material placed in the body will trigger inflammatory response that forms a collagen capsule wrapping around the material, rendering efforts futile as the material does not have access to the blood or other tissues to perform its due function.3 Another obstruction is the immediate toxicity of nanobiomaterials: for instance, carbon nanotubes’ length, surface chemistry, composition and tendency to aggregate are all factors that could contribute to its toxicity upon exposure in physiological environments.14 Clinical trials or in vivo experiments of carbon nanotubes to treat neurological diseases are also significantly lacking; ex vivo experiments have obtained different, even contradictory results regarding the biodistribution and long-term effect on the implanted nanobiomaterial, causing confusions that are yet to be clarified before attempting application in human body.1
The future applications of nanobiomaterials in neurology sounds promising, yet beware–the above discussions are confined to possibilities based on existing primary literature. A future in which neurologists gain successful control over the extent of foreign body reaction and in which the full potential and detriments of nano-implants are realized may be more distant than near. As MIT professor Polina Anikeeva said in an interview on applying nanoparticles in brain stimulation, “It’s literally the first microscopic step…We basically just took a tiny step outside the dish.25”
- Ahn, H., Hwang, J., Kim, M. S., Lee, J., Kim, J., Kim, H., . . . Hyun, J. K. (2015). Carbon-nanotube-interfaced glass fiber scaffold for regeneration of transected sciatic nerve. Acta Biomaterialia, 13, 324-334. doi:10.1016/j.actbio.2014.11.026
- Alyautdin, R., Khalin, I., Nafeeza, M. I., Haron, M. H., & Kuznetsov, D. (2014). Nanoscale drug delivery systems and the blood–brain barrier. International Journal of Nanomedicine, 9, 795–811.doi:10.2147/IJN.S52236
- Anderson, J. M., Rodriguez, A., & Chang, D. T. (2008). FOREIGN BODY REACTION TO BIOMATERIALS. Seminars in Immunology, 20(2), 86–100.doi:10.1016/j.smim.2007.11.004
- Azad, T. D., Pan, J., Connolly, I. D., Remington, A., Wilson, C. M., & Grant, G. A. (2015). Therapeutic strategies to improve drug delivery across the blood-brain barrier. Neurosurgical Focus, 38(3), E9. doi:10.3171/2014.12.FOCUS14758
- Baughman, R. H. (2002). Carbon Nanotubes–the Route Toward Applications. Science, 297(5582), 787-792. doi:10.1126/science.1060928
- Bobo, R. H., Laske, D. W., Akbasak, A., Morrison, P. F., Dedrick, R. L., & Oldfield, E. H. (1994). Convection-enhanced delivery of macromolecules in the brain. Proceedings of the National Academy of Sciences of the United States of America, 91(6), 2076–2080.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC43312/
- Botek, A., S., B., & M. (2012, October 10). Another World: People With Alzheimer’s Share Their Perspectives. Retrieved July 10, 2017, from https://www.agingcare.com/articles/alzheimers-patients-share-their-experiences-153702.htm
- Carvalho-De-Souza, J., Treger, J., Dang, B., Kent, S., Pepperberg, D., & Bezanilla, F. (2015). Photosensitivity of Neurons Enabled by Cell-Targeted Gold Nanoparticles. Neuron, 86(1), 207-217. doi:10.1016/j.neuron.2015.02.033
- Chao, T.., Xiang, S., Chen, C., Chin, W., Nelson, A. J., Wang, C., & Lu, J. (2009). Carbon nanotubes promote neuron differentiation from human embryonic stem cells. Biochemical and Biophysical Research Communications, 384, 426-430. doi:10.1016/j.bbrc.2009.04.157
- Chapman, C. A., Wang, L., Chen, H., Garrison, J., Lein, P. J., & Seker, E. (2017). Nanoporous Gold Biointerfaces: Modifying Nanostructure to Control Neural Cell Coverage and Enhance Electrophysiological Recording Performance (Adv. Funct. Mater. 3/2017). Advanced Functional Materials, 27(3). doi:10.1002/adfm.201770015
- Dinda, S., & Pattnaik, G. (2014). Nanobiotechnology-based Drug Delivery in Brain Targeting. Current Pharmaceutical Biotechnology, 14(15), 1264-1274. doi:10.2174/1389201015666140608143719
- Hu, H., Ni, Y., Mandal, S. K., Montana, V., Zhao, B., Haddon, R. C., & Parpura, V. (2005). Polyethyleneimine Functionalized Single-Walled Carbon Nanotubes as a Substrate for Neuronal Growth. The Journal of Physical Chemistry B, 109(10), 4285-4289. doi:10.1021/jp0441137
- Jain, K. (2007). Nanobiotechnology-Based Drug Delivery to the Central Nervous System. Neurodegenerative Diseases, 4(4), 287-291. doi:10.1159/000101884
- Johnston, H. J., Hutchison, G. R., Christensen, F. M., Peters, S., Hankin, S., Aschberger, K., & Stone, V. (2010). A critical review of the biological mechanisms underlying the in vivo and in vitro toxicity of carbon nanotubes: The contribution of physico- chemical characteristics. Nanotoxicology, 4(2), 207-246. doi:10.3109/17435390903569639
- Kim, J. Y., Khang, D., Lee, J. E., & Webster, T. J. (2009). Decreased macrophage density on carbon nanotube patterns on polycarbonate urethane. Journal of Biomedical Materials Research Part A, 88A(2), 419-426. doi:10.1002/jbm.a.31799
- Lam, C., James, J. T., McCluskey, R., Arepalli, S., & Hunter, R. L. (2006). A Review of Carbon Nanotube Toxicity and Assessment of Potential Occupational and Environmental Health Risks. Critical Reviews in Toxicology, 36, 189-217. doi:10.1080/10408440600570233
- Liu, Z., Tabakman, S., Welsher, K., & Dai, H. (2009). Carbon nanotubes in biology and medicine: In vitro and in vivo detection, imaging and drug delivery. Nano Research, 2(2), 85-120. doi:10.1007/s12274-009-9009-8
- Lugo, K., Miao, X., Rieke, F., & Lin, L. Y. (2012). Remote switching of cellular activity and cell signaling using light in conjunction with quantum dots. Biomedical Optics Express, 3(3), 447. doi:10.1364/boe.3.000447
- Malarkey, E. B., & Parpura, V. (2010). Carbon Nanotubes in Neuroscience. Acta Neurochirurgica. Supplement, 106, 337–341.doi:10.1007/978-3-211-98811-4_62
- Matsumoto, K., Sato, C., Naka, Y., Kitazawa, A., Whitby, R. L., & Shimizu, N. (2007). Neurite outgrowths of neurons with neurotrophin-coated carbon nanotubes. Journal of Bioscience and Bioengineering, 103(3), 216-220. doi:10.1263/jbb.103.216
- Mazzatenta, A., Giugliano, M., Campidelli, S., Gambazzi, L., Businaro, L., Markram, H., . . . Ballerini, L. (2007). Interfacing Neurons with Carbon Nanotubes: Electrical Signal Transfer and Synaptic Stimulation in Cultured Brain Circuits. Journal of Neuroscience, 27(26), 6931-6936. doi:10.1523/jneurosci.1051-07.2007
- Mckenzie, J. L., Waid, M. C., Shi, R., & Webster, T. J. (2004). Decreased functions of astrocytes on carbon nanofiber materials. Biomaterials, 25(7-8), 1309-1317. doi:10.1016/j.biomaterials.2003.08.006
- Melita, E. D., Purcel, G., & Grumezescu, A. M. (2015). Carbon nanotubes for cancer therapy and neurodegenerative diseases. Romanian Journal of Morphology & Embryology, 56(2)., 349-356. Retrieved July 9, 2017, from http://www.rjme.ro/RJME/resources/files/560215349356.pdf
- Menz, M. D., Oralkan, O., Khuri-Yakub, P. T., & Baccus, S. A. (2013). Precise Neural Stimulation in the Retina Using Focused Ultrasound. Journal of Neuroscience, 33(10), 4550-4560. doi:10.1523/jneurosci.3521-12.2013
- Nanoparticle Brain Stimulation. (n.d.). Retrieved July 10, 2017, from https://www.asme.org/engineering-topics/articles/bioengineering/nanoparticle-brain-stimulation
- Nho, Y., Kim, J. Y., Khang, D., Webster, T. J., & Lee, J. E. (2010). Adsorption of mesenchymal stem cells and cortical neural stem cells on carbon nanotube/polycarbonate urethane. Nanomedicine, 5(3), 409-417. doi:10.2217/nnm.10.16
- Padmanabhan, J. and Kyriakides, T. R. (2015), Nanomaterials, Inflammation, and Tissue Engineering. WIREs Nanomed Nanobiotechnol, 7 355–370. doi:10.1002/wnan.1320
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- Radad, K. S., Moldzio, R., Al-Shraim, M., Kranner, B., Krewenka, C., & Rausch, W. D. (2017). Recent advances on the role of neurogenesis in the adult brain: therapeutic potential in Parkinson’s and Alzheimer’s diseases. CNS Neurol Disord Drug Targets. doi:10.2174/1871527316666170623094728
- Rubinsztein, D. C. (2006). The roles of intracellular protein-degradation pathways in neurodegeneration. Nature, 443(7113), 780-786. doi:10.1038/nature05291
- Singh, N., Chen, J., Koziol, K. K., Hallam, K. R., Janas, D., Patil, A. J., . . . Rahatekar, S. S. (2016). Chitin and carbon nanotube composites as biocompatible scaffolds for neuron growth. Nanoscale, 8(15), 8288-8299. doi:10.1039/c5nr06595j
- Subirats, X., Muñoz-Pascual, L., Abraham, M. H., & Rosés, M. (2017). Revisiting blood-brain barrier: A chromatographic approach. Journal of Pharmaceutical and Biomedical Analysis, 145, 98-109. doi:10.1016/j.jpba.2017.06.027
- The Challenge of Neurodegenerative Diseases. (n.d.). Retrieved July 10, 2017, from https://neurodiscovery.harvard.edu/challenge
- Wang, Y., & Guo, L. (2016). Nanomaterial-Enabled Neural Stimulation. Frontiers in Neuroscience, 10. doi:10.3389/fnins.2016.00069
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