Nanotechnology in Neurosurgery

Nanotechnology is a broad term used to describe the research and development of technology involving materials and devices at size scale less than 100 nm. Its application to medicine, “nanomedicine,” is an interdisciplinary field of sciences for the diagnosis, treatment and monitoring of medical conditions. In the realm of neurosurgery, nanotechnological advances are rapidly evolving in many domains, including functional, head trauma, neurodegeneration, neuro-oncology, spine, peripheral nerve and vascular subspecialties.

Neuro-oncology

To date, most studies investigating nanotechnology in neurosurgery involve neuro-oncology. Nanoparticles such as liposomes, polymeric nanoparticles, dendrimers, gene therapy and immunotherapy delivered by nanosystems have been tested as therapeutic interventions against brain tumors. The following are a few notable examples:

o

• A Phase 1 trial assessing the safety and pharmacokinetics of intravenous administration of liposomal irinotecan did not demonstrate signs of toxicity.¹
• Doxorubicin-conjugated with polyethylene glycol and a biodegradable non-immunogenic platform PMLA demonstrated efficacy in in vitro glioma cell lines and several breast carcinoma cell lines.²
• Liposomes and polymeric nanoparticles trialed in animal models as drug-delivery vehicles for temozolomide, paclitaxel, cisplatin and oxaliplatin.^3,4
• Polymeric nanoparticles demonstrated strong efficacy in transporting non-viral gene therapy.⁵
• Intranasal administration of plasmid DNA nanoparticles led to long-term genetic changes in rodent models.⁶
• Iron oxide magnetic nanoparticles conjugated to monoclonal antibodies demonstrated an antitumor effect and enhancing radiosensitivity of glioblastoma.^7,8
• Gold-coated iron oxide magnetic nanoparticles have been utilized for intramedullary spinal cord tumors in a rodent model as a proof of concept.⁹

Neurodegeneration

Neurodegenerative diseases, such as Parkinson’s, Alzheimer’s and Huntington’s disease, lack definitive treatments, despite ongoing intensive research. Nanotechnology may offer an opportunity for therapeutic advances in these conditions:

• Alzheimer’s disease (AD): It has allowed for new drug development, improvement of older drugs due to nanocarriers, increased drug bioavailability and increased levels of the active pharmacologic agent. It is also being harnessed to target the formulation and breakdown of Aβ amyloid.¹⁰ Lastly, biosensors with nanosheets have shown great promise in the early diagnosis of AD.¹¹
• Parkinson’s disease (PD): Nanomedicine may improve drug delivery systems by increasing the bioavailability of existing drugs but may also be used in the delivery of gene therapy. Nanotechnology has offered promising results in detecting PD using biosensors based on gold nanoparticles, quantum dots or carbon nanotubes.^12-14 In addition, the technology has allowed for the creation of newer carbon monofilament electrodes to produce better results during an electrophysiology study during deep brain stimulation.¹⁵
• Huntington’s disease (HD): Nanomedicine has similarly offered better delivery systems for gene therapy to address the pathophysiological CAG trinucleotide repeat expansion within the Huntington gene. It has also contributed to the construction of better research mechanistic models to investigate this molecular pathophysiology via nanofibrils of polyglutamine peptides.¹⁶

Neurotrauma

Neurotraumatic events such as traumatic brain injury usually induces a secondary inflammatory cascade that is detrimental to patients. The following nanotechnology is currently being assessed:

• Traumatic Brain Injury (TBI): Immune-modifying nanoParticles (IMPs) are highly negatively-charged and bind macrophage receptors on monocytes, thereby sequestering them to the spleen. This in turn reduces the inflammatory cascade. This may provide benefit in clinical trials.¹⁷

Spine

In spine, nanotechnology has allowed for the engineering of implants, scaffolds, membranes and balloons with spectacular physicochemical properties, including:

• Nano-roughened surface modifications of existing titanium interbody implants promoting stem cell differentiation into the osteoblastic lineage with better results than the well-established polyetheretherketone (PEEK) cages.¹⁸
• Bioabsorbable self-retaining fusion cages carry the promise of improved stability and fusion rates compared to PEEK.¹⁹
• Gel scaffolds of bone morphogenetic protein-2-binding peptide nanofibers have been shown to promote osteogenesis and achieve both endogenous and exogenous fusion for spinal arthrodesis.²⁰
• Biodegradable electrospun nanofibrous poly(D,L-lactide) balloons [ENPBs] that can be filled with calcium phosphate cement (CPC) have been demonstrated to prevent water-induced collapsibility of CPC and eliminate cement leakage, while maintaining enough load-bearing ability to restore height in vertebral body fractures.²¹
• Nanofibrous membranes created for preventing excessive scar formation.²²

Nerve Regeneration

Nanotechnology holds promise in bridging the neural gap over 2 cm. A few examples include:

• Highly aligned nanocomposite scaffolds for promoting and guiding neuronal regeneration and tissue growth.²³
• An immunomodulator, the CX3CR1 ligand, has been used to stimulate nerve repair in a nerve-guidance carbon nanotube scaffold based on the principle that an infiltrating immune cellular milieu after nerve injury propagates regeneration.²⁴

Neurovascular

In the neursvascular domain, nanomedicine offers promise mainly in stroke management and vascular malformation imaging.

• Many liposome-based nanosystems have incorporated molecules, such as melanin, VEGF with transferrin and even hemoglobin, to provide a neuroprotective effect on the ischemic brain.^25,26
• Nanomedicine has allowed for the development of new masking techniques from the immune system so that existing drugs (e.g., tPA) can be administered with greater bioavailability, decreased systemic toxicity and better targeting.²⁷
• Regarding imaging, quantum dots and nanoparticles can be utilized to image macrophages, thus allowing for early identification of endothelial damage in aneurysms or other vascular malformations.²⁸

Conclusion

Nanotechnological research and development are underway in all facets of neurosurgery.²⁹ The application of these technologies in clinical practice is imminent, as they will allow neurosurgeons to diagnose and treat neurosurgical conditions more effectively and efficiently with a higher degree of precision and accuracy. The big future of neurosurgery, ironically, may be nanometers in size.

References