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Over the course of this blog, I have delved into many concepts involving nano and microparticles and their potential applications in the field of nanorobotics. Despite the vast range of particulate systems that I have previously mentioned, all come from one of four fundamental structural material types: metals, ceramics, glasses, and polymers. In my final blog post, I will discuss how these materials can be combined to form composite nanoparticulate systems, where the constituent materials retain their identities, each adding to the overall properties of the “composite nanoparticle.”

Composites can be broadly sorted into two categories: Fiber Reinforced Composites and Aggregate Composites. A composite nanoparticle is generally defined as a nanoparticle of composite structure characterized by a core-shell structure, onion-like structure of multiple materials.

In a paper titled Multifunctional Composite Nanoparticles: Magnetic, Luminescent, and Mesoporous, Lin et al. suggest that nanocomposite materials with unique magnetic and luminescence properties have great potential in biological applications such as MRI contrast, drug delivery, cell sorting, and labeling. They focus on the synthesis of mesoporous silica nanoparticles, characterized by their uniquely high surface area, large pore volume, uniform pore size, and low cytotoxicity, combined with gadolinium. Such a composite nanoparticle, they demonstrated, was quite useful as an MRI contrast. They theorize that further modifications with polymer constituents and other metals would give the mesoporous silica nanoparticles even more unique characteristics suited to other biomedical applications.

Researchers agree that leveraging the properties of metals, ceramics, glasses, and polymers at the nanoscale lends nanoparticulate systems a wide variety of applications as catalysts (with huge activity and specificity), metal-semiconductor junctions, drug carriers, optical sensors, and modifiers of polymeric films for packaging.

Composite nanoparticles present a great opportunity to leverage all that we know about nanoparticles of the four fundamental structural material types – metals, ceramics, glasses, and polymers – to create novel nanomaterials and robots to carry out ever more complex and useful tasks.

 

References:

https://link.springer.com/referenceworkentry/10.1007%2F978-0-387-48998-8_243

https://www.hindawi.com/journals/jchem/2013/536341/

https://pubs.acs.org/doi/pdf/10.1021/cm061976z

https://link.springer.com/article/10.1007/s11051-016-3374-5

Metals, Stents, and Nanobots

Atherosclerosis – caused by the deposition of fat, cholesterol, calcium and other substances on the inner walls of the arteries – is the process by which blood vessels harden and narrow. It is a major medical issue that limits the ability of oxygen-rich blood to reach vital organs, thereby increasing an individual’s risk of heart attack or stroke.

In the past, physicians have used angioplasty or bypass surgery to either break up or circumvent the occluding plaque, but these methods have not always effective and are far from ideal. Currently, drug-eluting stents, self-expanding stents, and stents of various novel components (like magnesium for example) represent the cutting edge in atherosclerosis treatment (and as such are being heavily researched by scientists hoping to make a leap forward in the treatment of this disease).

Interestingly, “nanobots” have also been deployed to deal with serious medical threat. In 2015, a research team based in Drexel University demonstrated that they had created a micro-robotic technology capable of drilling through plaque buildup in clogged arteries. The micro-robots they discuss take the form of small microbeads with the ability to join together and form a corkscrew-like structure. These robots are made up of tiny iron oxide beads, with an average diameter of 400 nanometers, joined together in a long chain. Importantly, the Drexel researchers have reported that these beads are “composed of inorganic, biocompatible materials that will not trigger an immunological response.”

The exciting capability of these micro-robots is revealed when the beads are exposed to a magnetic field. When a bead chain is exposed to a finely tuned external magnetic field, they can be induced to move through the bloodstream. The rotation of a finely tuned magnetic field causes the bead chain to form a spinning helical structure that propels itself through the bloodstream. The properties of the aforementioned magnetic field control the speed, direction, and size of the chain, thus affecting the force with which it moves. After being injected into the body via catheter and manipulated by the magnetic field, these drill-like micro-robots can be directed to the site of an arterial occlusion. Upon deployment, the bead chains will drill into plaque buildups, loosening them. The plaques can then be finished off by a small surgical drill delivered via catheter to the site of the occlusion. After the surgery, the biodegradable beads release anticoagulant drugs into the bloodstream to help prevent future plaque buildup at the site.

The use of magnetic fields to transform metal micro-bead chains into small spinning drills is an incredibly novel idea. It represents the creativity necessary to develop nano- and micro-robots into effective therapeutic tools capable of making a difference in patient’s lives.

 

References

https://www.smithsonianmag.com/innovation/tiny-robots-can-clear-clogged-arteries-180955774/

https://www.sciencealert.com/graphene-based-nanobots-could-clean-up-the-metal-from-our-oceans

Continuing in the vein of analyzing the potential applications of non-polymeric and non-organic materials in the field of nanorobotics, it is time for us to investigate a relatively new class of material, bulk metallic glass, which shows extraordinary promise in an array of biomedical applications.

Bulk metallic glasses (BMGs) are amorphous metallic alloys that combine the high strength of metallic materials with the flexibility and processability of polymeric materials. Due to their unique, glassy properties, they can be pressure molded or blow molded into various shapes. This allows engineers to create structures considered impossible to form with conventional metallic materials. They can be patterned on multiple length scales to carry out various functions. Such nanopatterning allows the material to better resist the classical foreign body response and fibrous encapsulation. BMGs, specifically Pt-based BMGs, are notable for their high strength, elasticity, corrosion resistance, and unique processability, all of which indicate they are a promising alternative to conventional metallic implants.

 

Thermoplastic forming of micropatterned BMGs

 

The ease of manufacturing nanoarchitectures with BMGs makes them an area of increasing interest for biomedical and structural engineering researchers. Aside from established methods of pressure (thermoplastic) and blow molding, BMGs could be fabricated via other methods to create unique 3D nanostructures. These structures could have potentially limitless uses in medicine and structural engineering. One such method of creating novel 3D nanostructures is known as two-photon lithography: A laser is used to “write” a three-dimensional pattern in a polymer by crosslinking and hardening the polymer wherever the two meet. Once patterned, the non-crosslinked portions of the polymer are dissolved away, revealing a three-dimensional scaffold. Next, the polymer is coated with a continuous layer of a material (in this case, bulk metallic glass). Finally, the polymer is etched from within the structure, leaving a hollow architecture behind. There is a great degree of freedom in designing the polymer structure onto which the BMGs are coated. These nanoarchitectures even have the potential to form scaffolds or bodies for the “real-deal” Nanorobots I mentioned in my first post.

 

 

The metallic nature of BMGs means that these nanoarchitectures could be outfitted with simple circuits. Like metals, BMGs have high conductivity and magnetic properties. Taking advantage of these properties, one could fabricate a BMG nanostructure with built-in logic circuits relying on magnetic and electrical interactions that would enable it to carry out basic commands given certain environmental stimuli.

 

In a recent review of BMGs, researchers from Cambridge looked at the potential uses of BMGs in biological applications. They theorized that the development of nanometeraccurate linear actuators using BMGs is highly possible and quite desirable. Such devices could be used for accurate positioning of cell-operation manipulators in the biomedical industry. They assert that soft-magnetic BMGs are appropriate materials for the magnetic yokes of such linear actuators. (1)

 

BMGs can also be used in more convention nanotechnologies. The easy manipulation of their structure allows them to be engineered as porous drug-eluting stents or nanoparticles. However, unlike polymeric nanoparticles, they would have unique electrical and magnetic features, be relatively bioinert, very strong, and would not break down.

As you can see BMGs are a very interesting material with unique properties that can be leveraged to do things at the nano-level that no other current materials are capable of.

 

(1) https://www.cambridge.org/core/services/aop-cambridge-core/content/view/A31027E7DF42614D95A8A2EDA5BB4D73/S0883769400007922a.pdf/new_bulk_metallic_glasses_for_applications_as_magneticsensing_chemical_and_structural_materials.pdf

Until now, the majority of this blog has been focused on the nanoparticulate applications of various polymers and some metals. There are, however, many other unique material types that can be used to great effect in nano-bioapplications. Ceramics and bioglasses are particularly useful in the areas of joint and bone repair.

Ceramic materials are inorganic, nonmetallic, and characterized by ionic bonds and crystalline structures with long-range order. Bioglass materials are also comprised of ionic bonds but are structurally amorphous and exhibit short-range order.

Because they can be made of the same components in bone (calcium phosphates), ceramics have unique osteoinductive, osteoconductive, and osteointegrative properties which lend themselves well to bone repair. Osteoinductive materials promote new bone growth by recruiting stem cells and causing their specialization into bone-related cells such as osteoclasts, osteoblasts, or osteocytes. Osteoconductive materials promote the growth of existing bone while osteointegrative materials provide scaffolds in which new or existing bone can grow.

Common ceramic materials used in bioapplications include Alumina (AlO₃), zirconium, hydroxyapatite, calcium phosphates, and various composite materials. Bioglasses are commonly made from different combinations of silica (SiO₂), calcium oxide (CaO), and sodium oxide (Na₂O). Ceramics and bioglasses are characteristically bioinert.

Ceramic nanoparticles, or Nanoceramics, have unique properties due to their structure and small size. Unlike conventional bulk ceramics, nanoceramics can exhibit superplasticity and bioactivity due to their fine grain size and controllable crystallinity. They are typically manufactured by a process called chemical solution deposition, also known as sol-gel. They can manifest certain electrical or magnetic properties, being dielectric, ferroelectric, ferromagnetic, and even superconductive. Mesoporous bioactive glasses have shown excellent characteristics as drug-carrying bone regeneration materials and as nanoparticles.

Nanoceramics have been used to make a material called nanotruss, which is more than 85% air extremely light, strong, and flexible. The fractal nanotruss is a nanostructure architecture made of alumina or aluminum oxide. Its unique property is that it can compress to a small fraction of its original volume and recover its shape without any structural damage after applied forces are removed.

Micro-bioglasses have found applications in dental care and can be found in common products such as Sensodyne. In the presence of saliva and water, a calcium phosphate layer can crystallize to form hydroxyapatite in tiny holes in teeth that allow hot or cold sensations to reach nerves and cause pain. The treatment of sensitive teeth with microparticulate bioglasses is called NovaMin and is an example of the bioregenerative properties of bioglasses.

The study of micro and nanoceramics and bioglasses is a growing field and promises to reveal ever more creative and useful applications to better human health. The interesting magnetic and electrical properties of nanoceramics are particularly noteworthy for their potential use in the electronic industry and applications in room temperature superconductors, a revolutionary theoretical technology.

Metallic Nanoparticles are a focus of intense interest in the field of drug delivery and disease imaging. In fact, various imaging modalities have been developed to utilize metallic compounds or magnetic nanoparticles, such as Fe₃O₄ and silver particles, as contrast agents. In this blog post, we go in depth on the methods of manufacture and applications of metallic nanoparticles, specifically iron oxide nanoparticles, gold nanoparticles, and silver nanoparticles.

 

Iron Oxide Nanoparticles

Fe₃O₄ is an ultrafine, biocompatible, superparamagnetic iron oxide. Superparamagnetic iron oxide nanoparticles (SPIONs), show great promise in the field of enhanced resolution contrast agents (for MRI), in targeted drug delivery (as ligands can be easily conjugated to iron oxide particles), in cell tracking, and in the early detection of cancer, diabetes, and atherosclerosis. The magnetic abilities of SPIONs make them ideal imaging probes for use in magnetic resonance imaging modalities. Their small size allows them to permeate tissue more easily, allowing for visualization not previously possible with older contrast agents. SPIONs are produced via a coprecipitation process, in which iron oxide crystals of various sizes are formed.

Carboxylation is used to attach useful moieties to SPIONs in order to increase the agent’s half-life in circulation or target the NPs to specific tissues. They can easily be conjugated to drugs, proteins, antibodies, or nucleotides. The ability of SPIONs to combine contrast agents with ligands capable of targeting specific tissue types is a big advantage over traditional, nonspecific contrast agents.

 

Gold Nanoparticles

Colloidal gold, also known as gold nanoparticles, have unique optical properties, modulated by their size and lattice structure, that arise from their interaction with light. The free electrons existing around the positive ion cores in gold NPs can absorb photons (light energy) and undergo oscillations with respect to their underlying lattice structure. This activity has been dubbed localized surface plasmon resonance (LSPR). Absorbed energy is released as light. The absorption and emission spectra of a gold NP is determined by its size as well as its shape.

These physical properties have myriad potential uses in biological imaging and material science, and as such, are currently an area of intense research. The main method of gold NP synthesis involves the reduction of gold salts using citrate to produce monodisperse nanoparticles in the range of 10-20 nm in diameter. The strong affinity of gold allows for easy conjugation of a variety of ligands, such as oligonucleotides, phosphines, and amines, further increasing the potential for development of unique ligands capable of targeting cancer cells more specifically.

 

Silver Nanoparticles

Silver Nanoparticles typically range between 1 and 100 nm in diameter. Mostly composed of silver oxide compounds, silver NPs have proved to be an effective agent for the treatment of wounds. The LSPR characteristics of silver NPs lend them towards use in molecular labeling. Silver nanoparticles are synthesized by the reduction of silver slats with reducing agents in the presence of a colloidal stabilizer, such as polyvinyl alcohol. The size of silver NPs greatly affects their capabilities, as small 1-10 nm sized particles have been shown in a recent study to attach to and block certain parts of the HIV virus while larger particles did not.

 

The medley of metal nanoparticles in development today demonstrates the ways in which the physical properties of nanomaterials can be exploited to control and combat disease. Lattice structure, bonding nature, and the characteristics of metal atoms account for a wide range of intersting phenomena that require futher reserach. The unique properties of metals, especially on the nanoscale, have allowed for increased targeting specificity, better imagining of tissues and organs, and many other therapeutic advances.

 

 

Refrence:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2996072/#!po=54.2453

 

Nanoparticles (NPs) come in many different varieties: Gold NPs, Liposomes, Polymeric NPs, dendrimers, and Micelles to name a few. The differences between these microscopic particles lie in the materials used to make them.

Polymeric nanoparticles are made of natural or synthetic polymers – repeating units of covalently attached small molecules (monomers) – that are often hydrophobic in character and necessarily biocompatible. Synthetic polymers, PLGA, PLA, and PGA, are commonly used in drug delivery due to their special characteristics.

Due to their unique degradation profiles, these materials, when used in drug delivery, allow small molecule medicines to be gradually released into the bloodstream over periods of weeks, months or years. The ability to continually release medication into the bloodstream for weeks or months on end eliminates the need to constantly take pills or endure daily injection in order to deliver therapy. Polymers breakdown in one of two ways – Bulk degradation –   whereby the entire polymer diminishes over time or – Surface erosion – in which the surface of the polymer is gradually eroded to release the encapsulated medicines.

Polymeric NPs are made using oil and water emulsion techniques, similar to the one pictured below. Polymers are dissolved in organic solvents and combined with a drug and other chemicals in water such that the hydrophobicity of the polymer and drug together cause the formation of spheres of drug encapsulated by polymer. The shape of a polymeric NP is directly influenced by the way in which it is made. More interesting shapes, like rods, cubes or discs, can be made using microfluidic techniques.

Once a polymeric NP is made, its surface can be modified to increase its survivability in the bloodstream. Surface charge and PEGylation (addition of Polyethylene glycol to the NP surface) can make the NP last longer in circulation. PEG specifically makes NPs more water-soluble, more stable, and less susceptible to attack by immune cells or clearance by the liver or kidney.

Polymeric nanoparticles are fast becoming the standard for drug delivery systems throughout the world due to their ability to deliver medication over long periods of time and to stay in circulation by evading capture or excretion. The next step in improving their effectiveness would be to increase their ability to target diseased tissue. Attempts to do this have been made many times over the past decade, mainly by attaching specific antibodies to NP surfaces so that they will bind to specific epitopes characteristic of diseased tissue. This approach, however, has not produced significant increases in targeting specificity and as such is an area of NP drug delivery in need of further improvement and study.

Nanobots. Microscopic robots capable of remodeling tissue, repairing individual cells, eliminating pathogens, rooting out disease, even restoring entire organs; a cure-all promised by the Sci-Fi books and movies I devoured growing up. Since I was young, I’ve been fascinated by the potential of nanobots to heal and alter the human body.

But the tiny metal machines I envisioned as a child, ones with robotic spider legs and glowing red eyes, can’t be built at the micro and nanoscopic level. The robots you and I think of today can’t be miniaturized to the extent necessary to interact with or alter individual cells.

But robots don’t have to be metal and neither do machines.

A robot is simply a machine capable of carrying out a complex series of actions automatically or in response to a certain stimulus. In that sense, our very cells are like organic robots.
In fact, there are many things that can act intelligently, or at least predictably, at the micro and nanoscales. With these materials and a little biological know-how, one can build molecular machines capable of interacting with cells.

Nanoparticles (NPs) are a great example. NPs come in many different flavors and can be altered to suit a variety of purposes. Commonly made of organic polymers like PLGA (poly(lactic-co-glycolic acid)) and n-BCA (poly(butyl cyanoacrylate)), they have been utilized extensively in the field of drug delivery to allow insoluble compounds passage through the blood, to target specific cell types, and to hide drugs from macrophages that would remove them from circulation.

I want to dedicate this blog to investigating the ways in which biomaterials can be used to build molecular machines at the nanoscale as well as how these machines can be further developed, improved and applied to the treatment of human disease.

I’ll start off with recent publication in Nature Biotechnology. Researchers from Arizona State University and the National Center for Nanoscience and Technology of the Chinese Academy of Sciences have succeeded in creating molecular machines using DNA origami. They’ve programmed folded DNA to target tumors and shut off their nutrient supply by clotting the surrounding blood vessels. Here’s a cool graphic that explains the basic approach.

Here’s a link to the paper.