1. Lecture 3: Design and Fabrication of Medical Nanodevices
Contents:
Design of Medical Nanodevices
Methods of Nanomaterials Fabrication
Top-Down Approach
Bottom-Up Approach
Synthesis of Metallic Nanoparticles and Applications
Synthesis of Semiconductor Nanoparticles and Applications
Synthesis of Oxide Nanoparticles and Applications
Vapor Phase Reactions
Solid-State Phase Segregation
Heterogeneous Nucleation
Kinetically Confined Synthesis
Synthesis of Carbon Nanotubes and Applications
Conclusions

2. Design of Medical Nanodevices
The design of nanorobots requires the culmination of various scientific fields ranging from quantum mechanics to kinematics analysis.
Materials used for the construction could be carbon, hydrogen, silicon, fluorine, sulfur, polimer, lipids, etc. depending on the interaction with the environment.
Nanorobots must be able to perform their task or job without being too much influenced by their surroundings, i.e. pH.
At the same time, when used in medicine, these nanorobots must be undetected by the immune system and operate like any other normal structures composing the human body.

3. Roadmap in Developing Nanomachines
Step 1. Developing the nanocomponents which include power supplies, fuel buffer tanks, sensors, motors, manipulators, on-board computers, pumps, pressure tanks and structural support.
Step 2. Assembling of nanorobots which includes making complex assemblies from the nanocomponents with nanoscale precision. Ideally the assembling would be performed by bionanorobots which have ability to build the nanomachines from available reserves or supplies, to repair damaged parts, to sense environment and respond appropriately, and so forth.

4. Roadmap in Developing Nanomachines (continued)
Step 3. Artificial intelligence, This would require development in basic computational capabilities, and rules would have to be established so that bionanomachines can make quick and sharp decisions at the nanoscale level. Nanocomputers, communicational and navigational equipment will have to be developed in order to establish communication between the nanorobots and outside world. This will allow us to program swarm behavior. All these capabilities will form the basic principle of a nanorobot with artificial intelligence.
Step 4. Self-assembling and self-evolution. Bioswarms will have ability to self-assemble and self-evolve, and would manage energy efficiently.

5. Examples of Design at Nanoscale
The vast numbers of natural molecular machines are protein-based.
Naturally, proteins are used to perform various cellular tasks.
Biocomponents are a rational choice for designing nanorobots.
Molecular manufacturing is the process of building machines at the atomic or molecular level.
One example of a realistic approach in manufacturing to nanorobots for medical purposes is biochips, which are a collection of nanoarrays arranged on a solid substrate.
The advantage of using biochip is that they allow numerous tests at the same time. Biochips are able to identify biological components and perform thousands of biological reactions in only several seconds.

6. Methods of Nanomaterials Fabrication
Two techniques are used for the synthesis of nanomaterials.
The first is the top down approach which uses nanoscale imprinting and milling techniques to create nanostructures out of bulk materials.
The second is the bottom-up approach which uses basic chemistry techniques to build atom-by-atom and assemble nanostructures.
For synthesizing nanoparticles in particular, the top-down approach employs milling and repeated thermal cycling as primary techniques.
Bottom-up techniques allow a variety of different approaches to be used, making this for nanoparticle synthesis far more common. These techniques include heterogeneous nucleation on substrates, phase segregation through annealing solids at high temperatures, confining particles in a small space using chemical reactions, and other thermodynamic and kinetic approaches.

7. Top-Down Approach and Applications
Milling produces nanoparticles from bulk materials at sizes larger than 20 nm. Limitations include that the particles have a broad size distribution and varied shape, may contain impurities from the milling medium, and may have defects resulting from milling.
Applications of nanoparticles produced from this process are the fabrication of nanocomposites and nanograined bulk materials. One example uses a high-energy ball milling process for synthesis of nanocrystalline hydroxyapatite particles that can be used as bone filler for coating metallic prosthesis, in dental implants, and for making matrices for controlled drug release applications.
Repeated thermal cycling produces very fine particles by repeated quenching of the bulk material. As a result of heating, the material with low thermal conductivity can be broken into small pieces. This process has limitations:It can be difficult to design and control, and it is not applicable to all materials.
Applications. Metal nanopowders, consisting of 25 nm nanosilver or 80 nm nanoaluminum particles, are produced by heating the metals of interest using repetitive pulsed electrical arc discharge and plasma in a reactor. Nanosilver powders can be used in inkjet applications and for their antimicrobial properties as well. Nanoaluminum powders can be used in making primers, advanced propellants and explosives.

8. Bottom-Up Approach
Homogeneous nucleation is a one method of the bottom-up approach.
It can be used to synthesize nanoparticles in all the three states: liquid, solid and gaseous.
Homogeneous nucleation is initiated in a saturated medium by disturbing the equilibrium of saturation throught decreasing the temperature of the solution/medium.
This will lead to supersaturation, nucleation and growth of the centers of nucleation in the medium. For example, when the temperature of a glass matrix is slowly reduced, quantum dots will be formed due to supersaturation in the matrix.

9. Bottom-Up Approach (continued)
The process of supersaturation of the growth species is governed by two processes.
First, the growth species have been generated, diffused in the mixture and adsorbed on the surface of the growth surface.
Secondly, there will be surface growth due to irreversible incorporation of growth species onto the solid surface.
There are several ways of controlling the nanoparticle growth process, which can help control the size distribution. The growth control can be achieved by surface processes such as mononuclear growth, polynuclear growth or by diffusion-limited growth.
Mononuclear growth is layer-by-layer growth where one layer of growth is completed before the formation of another layer starts on the surface.
In polynuclear growth, the surface process is very fast because of high surface concentration, which causes the growth of the second layer to start before the layer is completed. Polynuclear growth is favored over mononuclear growth for formation of the same-sized nanoparticles, because as particles grow bigger, the radius difference gets smaller.
Diffusion-limited growth is the most preferable process for formation of monosized nanoparticle (i.e., particles of the same size); it can be simply controlled through “drop-by-drop” addition of the reactant or a variation of the technique.

10. Synthesis of Metallic Nanoparticles and Application
For synthesis of metallic nanoparticles using homogeneous nucleation methods, metal complexes are reduced using reducing agents in dilute solutions. Precursors may include metals, inorganic salts and complexes.
Some of the common reducing agents used are NaOH, H2O2, CO, P and H2. And polymer stabilizers like PVA (polyvinyl alcohol) and sodium polyacrylate are used as well.
A combination of a diluted low concentration of the reactants in the solution and polymer stabilizers forming a layer around the nanoparticles results in diffusion-limited growth and steric stabilization to produce monosized nanoparticles.
The kind of reducing agent used can be a factor in deciding the size of nanoparticle produced, as well as the size distribution.
Application. The electrochemical deposition method is common for synthesizing metallic nanoparticles and reflects the same process described above. This process can produce palladium, nickel and cobalt nanoparticles in the size range of 1.4 to 4.8 nm. Palladium nanoparticles have applications as quantum dots and catalysts, and in making filters to remove groundwater contamination, nanofibers and textiles. Nickel nanoparticles have applications in making alloys, batteries, magnetic materials and solid oxide fuel cells. Cobalt nanoparticles have applications as sealants, shock absorption materials, in manufacturing medical equipment, and in manufacturing radioactive shielding.

11. Synthesis of Semiconductor Nanoparticles and Applications
This process uses pyrolysis of organometallic precursors to synthesize “non-oxide” semiconductor nanoparticles.
Pyrolysis is a process of overcoming the activation energy by increasing the energy of the material using heat.
Organometallic materials are organic compounds that have at least one metal-to-carbon bond and are used as catalysts in many applications.
Application. Cadmium selenide (CdSe) quantum dots are synthesized using trioctylphosphine selenide as a precursor. CdSe quantum dots can be used in manufacturing polymer-based photovoltaic cells, chemical sensors, optical temperature probes and emitters for color displays.

12. Synthesis of Oxide Nanoparticles and Applications
This process uses sol-gel processing to synthesize metal oxides and organic-inorganic hybrid materials.
Sol-gel preparation uses metal salts as precursors. Catalysts are then used to promote hydrolysis of these salts.
This results in a rapid reaction leading to supersaturation of the growth species. It basically uses temporal nucleation followed by diffusion-controlled growth principles.
The size of the nanoparticles produced depends on the concentration of the reactants and the aging time and can range from 1 to 100 nm.
Application. IFC-305 (a novel drug for liver diseases) encapsulated silica oxide nanoparticles are synthesized using sol-gel processing for controlled drug delivery.

13. Vapor Phase Reactions
Synthesis in the vapor phase usually happens in vacuum conditions at high temperatures. As a result, low concentrations of growth species are available as reactants in the diffusion-controlled growth process.
The nanoparticles generated are then collected on a low-temperature non-stick substrate.
The challenge with this process is that not all nanoparticles will settle on the substrate. Stabilization to prevent these nanoparticles from agglomeration is also difficult.
Application. Gallium arsenide (GaAs) nanoparticles can be synthesized using this approach. The size range of the particles is 10 to 20 nm. GaAs nanoparticles can be used in quantum dot applications and a wide variety of electronic and optoelectronic applications.

14. Solid-State Phase Segregation
Metals and semiconductor nanoparticles are synthesized in a glass matrix using this method.
Precursors are mixed in a liquid glass melt at high temperatures during glass making.
Then the glass is cooled down to the phase transition temperature for a planned period of time. This causes supersaturated precursors to form nanoparticles by nucleation and growth through solid-state diffusion.
Application. This process is used in formation of nanocrystalline cobalt aluminate (CoAl2O4) nanoparticles which can be used as an inorganic ceramic blue pigment for applications in paint, glass, porcelain enamels and fiber. Its optical properties can also be used in manufacturing color filters for automotive lamps or luminescent materials in optical devices.

15. Heterogeneous Nucleation
Heterogeneous nucleation reactions take place on a substrate and for synthesis of quantum dots or nanoparticles. The growth of the nanoparticles on the substrate can take place in the following manner:
If the growth species are more strongly bonded to each other than to the substrate, they will form ‘islands’ on the substrate, with a group of atoms sticking together on the substrate. This process is referred to as island growth.
If the growth species equally favor strongly binding to the substrate just as they do to each other, the falling and distribution of the atoms will be layer by layer, one monosized particle layer at a time before more atoms start to make another layer above it. This is referred to as the layer growth.
Island-layer growth is a combination of the above two processes to make a continuous film. Some atoms will tend stick together and form islands, whereas others will individually directly stick to the substrate. This will give a larger size distribution.

16. Heterogeneous Nucleation
Homogeneous surface defects that act as nucleation centers need to be created.
This can be done using a process like thermal oxidation.
Oxygen is used in thermal oxidation to form oxide layers on the surface of the substrate.
This can be done by heating the substrate such that the oxygen atoms can diffuse through the substrate surface and form defects.
Application. Nickel nanoparticles between in the size range nm with a narrow size distribution can be formed using homogeneous nucleation process. As mentioned above, nickel nanoparticles have applications in making alloys, batteries, magnetic materials and solid oxide fuel cells.

17. Kinetically Confined Synthesis
This process deals with stopping the synthesis when we have achieved our desired products/results.
This can be accomplished by supplying only a limited amount of precursor for the reaction, by physically filling up the reaction space; or by terminating the growth species’ progress by having organic compounds or alien ions occupy the reaction site.
One of these techniques is used in growth termination method. Here, the stop growth method is used for synthesis of monosized nanoparticles, organic compounds or specific ions.
Application. This techniques is used to synthesize cadmium sulfide (CdS) colloidal nanoparticles. The size of the nanoparticles can be controlled by the concentration of organic ligands introduced to the system. CdS nanoparticles have applications is optoelectronics.

18. Synthesis of Carbon Nanotubes and Applications
Carbon nanotubes were discovered in the soot of arc discharge in 1991.
Since then, researchers have successfully developed some manufacturing techniqures for carbon nanotubes, such as arc discharge, laser ablation, plasma torch, and chemical vapor deposition.
Arc discharge is the most traditional manufacturing method, which consists of placing acertain amount of inert gas into a vacuum chamber between the two graphite electrodes. The discharging of electrodes leads to the formation of soot on the cathode containing the carbon nanotubes. This method produces both single- and multiwall nanotubes with lengths of up to 50 micrometers with few structural defects.

19. Synthesis of Carbon Nanotubes and Applications (continued)
In laser ablation, a graphite target is vaporized by pulsed laser radiation in a reactor filled by an inert gas. The carbon vapor condenses on the cooler surfaces of the reactor producing the nanotubes. This technique provides better control of graphite ablation and evaporation, and thus is suitable for manufacturing single-wall carbon nanotubes with a controllable diameter.
Application. Carbon nanotubes have a wide variety of applications. In nanomedicine, the single- and multiwall carbon nanotubes could be used, for example, in cancer diagnostics and treatments. Nanotubes have a very interesting characteristic that could make them incredibly useful in dealing with cancer: the nanotubes naturally penetrate into the cells. This opens up great possibilities in both drug delivery and diagnosis.

20. Conclusions
We have discussed design approaches and methods of fabrication of medical nanodevices with various types of nanoparticles.
There are a wide variety of techniques to choose from for synthesis of nanoparticles.
We have also discussed different applications that these nanoparticles are being used in or are being considered for.
Important points that need to be considered when designing a synthesis process are:
Synthesis of nanoparticles is possible in all three phases: liquid, solid and gaseous.
Stabilization processes to prevent the nanoparticles from agglomeration are very important.
Making a same size distribution of nanoparticles is another important factor, which can be controlled by diffusion-limited growth processes or by confining the growth space