Nanotechnology employed in medicine gives rise to an ability of direct communication with biomolecules. The manipulation of chemicals in order to stimulate a natural self-assembly potentiates therapeutics to promote reinnervation of nerves and reperfusion of the vasculature with minimal invasiveness. Whether the fabrication of nanomedicine is facilitated by a "top down" or "bottom up" approach, research is being conducted to increase therapeutic efficacy with constructions that interact on the same level of the cellular matrix. Neurosurgery with nanomedicine is becoming improved with enhanced diagnostics with FeO2 particles, carboxyfullerenes as neuroprotectants, RADA 16-I with hemostasis and axonal regeneration, and laminin coating for electrodes. Neurological diseases previously thought incurable may in the future find the answer through nanomedicine.
Nanomedicine in Neurosurgery
Neurological disorders and traumas can incapacitate and leave individuals debilitated for the rest of their lives with only palliation as treatment. In some neurodegenerative diseases even symptomatic treatment and therapies wane in patients with long standing illnesses. From the beginning of life children can be affected by autism, cerebral palsy, and Tourette syndrome; the elderly may have predispositions to develop Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Other neurologic ailments such as epilepsy, multiple sclerosis, stroke, and traumatic brain injury can occur at any age without warning. A meta-analysis conducted by Chaudhuri et al. (2007) reviewed the prevalence rates in developed countries of twelve common neurologic disorders from the beginning of 1990 to 2005. In the United States alone the annual incidence of Alzheimer's disease is 468,000 with a prevalence of almost two and a half million. There exists an annual incidence of 541,000 individuals affected by strokes with a prevalence of almost three million. The number of strokes recorded in the study was exclusive, leaving out asymptomatic injuries, transient ischemic attacks, and any diagnosis found on imaging. Nothing at the present can be done to halt some of these neurological disorders, but there is still research being conducted to reshape therapies and refine them into cures. A more accurate interaction with biomolecular processes in the human body requires applications derived on a similar scale that can speak the cellular language. Medical research has already begun to synthesize technology on the nanoscale.
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Nanomedicine is one of many words used to describe the implementation of technology being utilized on a 1x10-9 metric level in medicine. Already a wide variety of products have research and applications utilizing nano-sized particles such as sunscreen, microprocessors in computers, and water filters. The real challenge comes from working with these extremely small particles. The physical forces that are involved at the nanometer level do not obey the classical laws such as heat transfer, nor do they fall into the quantum sizes of molecules and their atomic interactions. The forces that compel these small structures are influenced by a combination of covalent and noncovalent bonds, size, charge, and density to name a few. The term mesoscale is used to define this "gray area" where they are caught in the middle, therefore the difficulties are found in the undefined, new properties at this small scale (Apuzzo et al., 2007).
Two basic concepts of approach are being utilized to assemble and mold nanotechnology, referred to as the "top down" and "bottom up" approach. The "top down" concept references the use of larger tools to manipulate the nano-sized particles. An atomic force microscope is used to view a method known as dip-pen nanolithography, a technique that has been utilized in reorganizing a section of collagen (Cronin-Golomb et al., 2001) as well as maneuvering proteins and deoxyribonucleic acid (DNA) strands into specific sizes and reaction sites (Amro, 2002). The significance of the studies lies in the potential to mediate and influence naturally occurring self-assembling molecules; the concept and relevance of self-assembly will be addressed in the next section since the mesoscale forces pertain more to a "bottom up" construction.
The "bottom up" approach is slightly more involved, taking into consideration the intricate molecular forces that exist on this scale. The concept behind this approach is to emulate natural, biologic structures with synthesized materials. One method (Schafmeister, 2007) uses chemically produced bis-peptides that possess an array of different shapes. The different shapes of bis-peptides are linked together with carboxyl and amine groups that are initially "masked" on the outside. A series of different acid washes are used to peel away the masked groups in a specific sequence in order to form a new structured ring known as a diketopiperazine. This process is repeated with a specific order of bis-peptides until the desired structure is fabricated. These new shapes are to mimic specific proteins and enzymes that work in a "lock and key" like fashion just as in the human body.
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Natural biological processes that occur in nature organize their structures through self-assembly. Through noncovalent forces nanomolecules are naturally pulled together depending on the charges that exist around them (Belcher & Seeman, 2002). Size and density of the molecules as well as the attractive forces that initially bonded them will dictate whether or not the structure will be stable enough to sustain the mesoscale forces holding it together. These intricate events occur at all points in time naturally, yet it can be difficult to manipulate in a laboratory setting. Even after multiple observations of self-assembly the exact mechanics and play of the interacting forces are still not entirely understood.
The ultimate goal of nanomedicine is to increase the efficacy of therapeutics and refine diagnostics, imaging, and interventions. Medical therapies have become more advanced and less invasive as technology continues to improve current methods. Research concerning biological processes on the nanoscale is becoming more involved with the pathophysiologic interactions of chemicals inside the body to better target specific lesions as well as mitigate potential hazards and risk factors prior to becoming problematic. The advancements are significant in regards to approaching neurological conditions and preserving neural functions without the necessity of subjecting patients to open procedures.
New applications in diagnostics are already being implemented in laboratories as well as research. An array of individual biomolecules can be tagged and viewed simultaneously through the use of quantum dots. Unlike fluorescent dyes in which either only a single color or single wavelength of light can be utilized, quantum dots have a unique characteristic that is size dependent. On the nanoscale, different size dots emit differing wavelengths of light simultaneously with only a single source of light (Alivisatos, 2001). Multiple biomolecules that are tagged with these quantum dots can be easily managed and tracked while observing their activities and interactions in the body. The quantum dots are extremely useful in research in regards to tracking nanoparticles in experiments involving minimally invasive techniques to ensure the therapeutics reach the targeted areas.
Another method that has shown improvement in diagnostics is the use of iron oxide. Previously, gadolinium was the preferred contrast agent in specific neural imaging and surgery because in certain central nervous system diseases it revealed leaky, deteriorated areas of the blood brain barrier; however it only shows contrast for a few hours before it begins to blur and depending on the length of surgery, may require additional injections which can be extremely toxic resulting in nephrogenic systemic fibrosis. In contrast, nanoparticles of iron oxide have shown to keep a sharper contrast image that peaks at twenty four to forty eight hours with a single administration. Iron oxide has also revealed malformations and lesions that were previously undetectable with a gadolinium contrast (Apuzzo et al., 2008a, 2008b). Patients afflicted by strokes showed an improved uptake of the iron oxide nanoparticles compared to the gadolinium contrast.
Once a particular lesion can be identified by diagnostic studies a proper regiment of surgical or medical treatment can begin. A very recent study conducted by Chan et al. (2010) has shown promise in regards to damaged vasculature. An engineered nanoparticle labeled the nanoburr is capable of seeking out damaged basement membranes of the endothelial system. The nanoburr was designed with specific peptide ligands which act as hooks that have an affinity for specific peptide sequences which are representative of vascular damage. The core is surrounded by a lipid monolayer that has the potential to cross the blood brain barrier and locate areas that are ischemic or have an aneurysm. Once the injured site has been located, the peptide ligands hook onto the basement membrane and initiate the release of the therapeutics inside. The significance lies not only in the ability to escort medications that do not possess the profile that allows passage across the blood brain barrier, but the technique to deliver those medications less invasively since the nanoburr can be administered intra-arterially as well as intravenously. Biodegradable nanoparticles that can assist with the proliferation of damaged endothelial tissue could be a potential payload of the nanoburr. The research of Anderson et al. (2010) has incorporated the aid of adult human stem cells to induce angiogenesis in injured vasculature. The adult stem cell's genetic coding was modified to amplify vascular endothelial growth factor in ischemic areas. The research showed that scaffold nanoparticles impregnated with these engineered stem cells increased the density of the vasculature four fold.
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Studies are still being conducted in the possible future use of carboxyfullerenes as neuroprotection in order to prevent and/or delay neuronal damage. A serious problem in stroke patients as well as other nervous system diseases deals with oxygen reduction in mitochondria leading to superoxide radicals that have the potential to damage and destroy cells if not mitigated by antioxidants. One study conducted by Almli et al. (1997) began with mice that had a specific transmutase gene which encodes for amyotrophic lateral sclerosis. The data gathered shows evidence of hindering neuronal cell damage through the utilization of different carboxyfullerene isomers. A more recent study (Ali et al., 2008) involved an approach of studying the activity and structures of different isomers of carboxyfullerenes, superoxide radicals, and naturally occurring antioxidants in order to predict the efficacy of potential therapy. The observations revealed that due to carboxyfullerenes structure they create an s-orbital of electrons around it that yields an electronic property metal-like in nature that has an affinity for oxide anions. This state combined with a predesigned number of carboxylic groups in increased concentrations enhances its efficiency as an antioxidant. Carboxyfullerene isomer C3 was introduced to the water of mice which yielded data consistent with prolonged life, improved memory, and increased spatial learning in standardized tests compared to its peers. The information gathered regarding efficacy in neuroprotection will be applied to future therapies.
Despite improvements of diagnostic imaging and noninvasive procedures to mitigate deteriorating diseases and debilitations, surgical intervention may become inevitable. Much advancement has been made to reduce the invasiveness of some neurosurgical procedures. Precision has been enhanced with the incorporation of instruments manufactured with the aid of nanotechnology as well as fabricated on the nanoscale. Versatile self-assembling compounds possess characteristics ranging from improved hemostasis to facilitating regeneration.
Invasive surgery is still the treatment of choice regarding neurological lesions that have failed or become refractive to the current medical therapy, which is a common occurrence in patients debilitated by Parkinson's disease on long term medications. Surgical blades are becoming more refined and durable with the use of nanotechnology. Surface friction on the blades has been reduced even more with quasi-crystals and plasma sharpening, making a cleaner incision which can heal faster. This technique along with two nanoamorphous coatings of metal is also being applied to suture needles and bone drills which make them more durable and increase the incision accuracy due to their enhanced gripping surfaces (Nokes et al., 2007).
It is necessary in operations that expose the entire field to be constantly irrigated with saline to keep the operating field clear in order that the surgeon maintains visualization with the objective. Apuzzo et al. (2008a) reports that a clear gel of self-assembling nanofiber peptides can be utilized as a biological barrier in neurosurgery that inhibits blood and debris from moving in or out of the surgical field. Procedures can still be conducted within this transparent gel unhindered. This crystal clear gel is extremely useful when accuracy with incisions is paramount, such as in microsurgery. With the aid of a 10 to 20 nanometer edge composed of silicon nitride Chang et al. (2007) demonstrated that individual axons can be severed without damage to any peripheral tissues or nerves. The composition makes it more robust than bulk steel enabling multiple incisions that do not result in dullness, fracture, or irritation to surrounding cells. The precise incision that is made on the nerve axon preserves the cytoplasmic membranes and leaves the severed ends the ability to repair themselves once they are reconnected.
An innovative chemical known as peptide RADA 16 has been incorporated in multiple studies and research due to its versatile nanofiber scaffold (Kinoshita et al., 2005). Composed of amino acids with covalent peptide bonds, RADA 16 reassembles into stable beta sheet structures that form a rigid nanofiber scaffold; one of its most intriguing characteristics is that RADA 16-I is biodegradable into amino acids that can be utilized by adjacent tissue. During a research conducted by Ellis-Behnke et al. (2006) in attempting to utilize RADA 16-I in neuronal tissue regeneration, they discovered that the nanofiber scaffold possessed a hemostatic profile. In order to test versatility in different tissue, experiments were conducted on cortical vessels, the spinal cord, a femoral artery, and the liver. The data revealed that in all areas applied with NHS-1 (ten mg of RADA 16-I powder dissolved in one mL Milli-Q water), bleeding was controlled on average of ten seconds. A promising feature of the solution showed that six months post treatment, the hamster brain revealed no signs of fibril tangles or prion-like substances.
A year later, experiments conducted by Ellis-Behnke et al. (2006) incorporated RADA 16-I into a new solution called self-assembling peptide nanofiber scaffold (SAPNS). The new solution is now conducive to neuronal axon growth which forms a bridge between the severed ends of nerves and provides an "in vivo" domain that promotes migration, cellular differentiation, and growth. Tests were conducted with hamsters of varying age that had iatrogenically induced separations of the optic tract. With the aid of a fluorescently stained cholera-toxin subunit B fragment, the treatment showed reduction in the axonal gap within the first twenty four hours with total reconstruction within thirty days of all test subjects. A series of visual stimulations were provided to test the behavior of the hamsters and the data showed that the treatment was effective in seventy-five percent of the test population; the other twenty-five percent was due to some incisions being too deep. RADA 16 has great potential in medicine by virtue of its versatile self-assembling nanofiber scaffold.
Neurosurgical procedures will have decreased risks in regards to unobstructed operating fields, minimal blood loss, avoidance of damaging peripheral tissue, and reconnection of severed axons. Reduction in surgical complications increases a more positive prognosis in the recovering patient. Post surgical wounding healing and follow up care has been enhanced with nanotechnology applications.
Depending on the neurological lesion that was operated on, electrodes may have been used to facilitate neural mapping of eloquent cortex during surgery. Upon completion of surgery the electrodes may be left in to continue the neural mapping in seizure patients or as neural stimulators. Although therapies can be applied directly through neural electrodes they cannot monitor or give feedback of the efficacy of the treatments. Another enigma with post surgical electrodes is the body's innate inflammatory mechanisms and scaring triggered by a foreign body left at the surgery site, which can potentially attenuate the therapeutic electrical stimulations (Apuzzo et al, 2008a & 2008b). The research of Bellamkonda et al. (2006) has the potential to mitigate the problematic inflammatory process invoked by the neural electrodes. The technique utilizes silicon probes coated with eight bilayers of nanoscale constructed laminin to reduce the astrocytic response to a foreign body and decrease the cytokine mediated astrogliosis. Interception of the inflammatory response is essential to prevent glial scarring which can impede therapeutic signals transmitted by electrodes intended for chronic therapy in the post surgical patient.
Further augmentation of post surgical wound recovery can be facilitated by bandages that have been constructed with nano-sized pores. The nanofibrous polyurethane membrane has the ability to provide proper oxygenation to wounds while still keeping infectious microorganisms away from the wound. An electrospun nanofibrous membrane can be produced with dual-porosity scaffolds with provisions of a selective membrane that still allows the wound to drain properly to prevent festering (Chu et al., 2007). Impregnation of the electrospun nanofibrous membrane with nano-sized silver colloids can further enhance postsurgical recovery. According to Hwang et al. (2005) an ethanol-based silver/sulfur composite colloid possesses an unmatched antimicrobial potency in comparison to other silver colloids. Staphylococcus aureus and Escherichia coli were utilized in the study to test the efficacy of the silver/sulfur composite exhibiting a reduction from over 1.2 x 105 number of bacterial cells down to fewer than ten cells within fifteen minutes with a colloidal concentration of three parts per million. Employment of a colloidal concentration of twelve parts per million reduced the equivocal starting number of bacterial cells down to less than ten cells within five minutes.
A plethora of applications exist and are currently in use now along with tentative applications in the future. All medical fields will benefit from being able to interact with cells and disease processes on the nanometer level. Some research that has been applied in animal test subjects is still under review while other studies are still stuck in an in vitro environment. These pending applications show great potential to be diagnostic and therapeutic at the same time while staying inert in the human body until a specific disease state activates it.
DNA computers are still currently being developed in research as an algorithm that can interact and communicate with cells (Benenson & Shapiro, 2006; Benenson, 2009). This concept is based on the knowledge that DNA is the biological storage of information. The double-stranded helix can replicate itself, leaving the original strand inside the cell's nucleus and utilizes a messenger ribonucleic acid (mRNA) to shuttle the encoded information known as codons to a ribosome outside the nucleus for decoding. As the ribosome reads the codons on the mRNA and interprets the data, a transfer ribonucleic acid (tRNA) provides the appropriate amino acid according to the codons. Once the tRNA has double checked that the specific amino acid needed was brought, it then releases it to an ever growing chain of amino acids that will eventually comprise some kind of protein. Benenson and Shapiro's proposition is to utilize a synthesized enzyme with a specific profile that reacts with DNA strands like a computer program to sense disease states. The enzyme recognizes particular codons at unique points on DNA strands and, once criteria has been met with the enzyme identifying a state in its genetic program, cleaves the strand and continues until the program has reached the end state like a ribosome reading a termination codon. The significance lies in fabricating single strands of DNA with two programs that combine to attach to the enzyme and initiate cleaving. One of the two programs will be attached to a protector strand that possesses an affinity for a unique mRNA produced only by certain diseases so that once the disease is present, the protector strand binds to the mRNA leaving the two programs to combine and link with the designer enzyme. Unknown to the authors at the time, such designer enzymes and proteins were fabricated a year later (Schafmeister, 2007).
Benenson and Shapiro took their work a step further and devised an enzyme and DNA combination which only reacts with a diagnostic molecule that contains a therapeutic drug at the termination end, mimicking the role of a physician but on a much smaller scale. The codons on the diagnostic molecule senses increased and decreased expression of specific genes inside the organism so that once it links up with the enzyme primed with the DNA software it can provide information about the environment. The enzyme and DNA software run a yes/no query on the diagnostic molecule that cleaves the designer molecule as long as all states say yes. If one of the codons does not show the specific increase/decrease of genetic material sensed and the query state in the program reads no, then computation is paused at that state until the query reads yes. A specific disease state is indicated once the diagnostic molecule has been completely cleaved through and the therapeutic drug for that specific diagnosis is released. A counter-balance has been designed with this concept to act in the event of either diagnostic errors or the disease that was previously targeted was successfully eradicated. A separate combination of designer enzyme, DNA software, and diagnostic molecule possesses a suppressor to the original therapeutic released to neutralize it. These biocomputers have the potential to exist indefinitely due to the fact that no energy is consumed unless cleavage is taking place, and the energy that is released from that reaction is what fuels the next reaction.
As innovative and grand as this technology is, there exist people and groups that oppose nanotechnology and feel it should be banned and all nano research ceased. Even with all the positive discoveries and inventions, these particular people possess fears of nanotechnology destroying everything. The concept known as the "gray goo" is an idealization of nano-sized machines over self-replicating and devouring natural resources to be used as fuel or raw materials for more self-replication (Freitas, 2006). Indefinite programs could be written to facilitate an unending execution of commands. Such disasters can range from laboratory accidents to terrorists utilizing the technology for ill purposes. Any number of technological advances has the potential to be harmful, which is why plans to mitigate such events are always necessary. Fire and explosives can be utilized for positive and negative outcomes, and there exist designs to counter potential disasters.
Ceasing this research would only hinder potential cures for ailments that as of today only have palliation as treatments. There also exist people who thrive outside of laws that the rest of the world abides by and accomplishes their goals through terror; no ban or illegalization would stop them from continuing research to further their means, which would put the rest of the world behind the power curve in regards to reacting to nanotech threats. If bans need to be implemented, they should be targeted at weaponizing the technology and not at medicinal purposes or defense.
Nanotechnology is the next logical step for medicine in order to increase efficiency and decrease invasiveness. Some applications derived on the nanoscale are already being utilized and there are promising research and studies being conducted to restore lost neural functions. Vestibulocochlear implants have existed now for some years to increase hearing and neuronal implants have been used as a brain-machine interface to restore some vision in acquired blindness. Nanomedicine is leading the way through improved diagnostics and therapeutics, precision in surgical techniques, and post surgical wound care and therapies. With all the medical technology that is currently being utilized and developed, nanomedicine is proving that a more accurate interaction with biomolecular processes in the human body requires applications derived on a similar scale that can speak the cellular language.