Researchers Develop Novel Technique for Separating Target Molecules from Mixed Solutions Using Magnetic Nanoparticles

Published on September 18, 2013 at 7:04 AM

201306047919620Separating target molecules in biological samples is a critical part of diagnosing and detecting diseases. Usually the target and probe molecules are mixed and then separated in batch processes that require multiple pipetting, tube washing and extraction steps that can affect accuracy.


This is an illustration showing a simple new technique that is capable of separating tiny amounts of the target molecules from mixed solutions. Credit: J.Wang/Brown


Now a team of researchers at Brown University has developed a simple new technique that is capable of separating tiny amounts of the target molecules from mixed solutions by single motion of magnet under a microchannel. Their technique may make pipettes and test tubes a thing of the past in some diagnostic applications and increase the accuracy and sensitivity of disease detection.

The new platform developed by Anubhav Tripathi and his team at Brown doesn’t rely on external pumps to mix samples or flow target molecules. Instead, their system is static and handy for researchers to use, according to Ms. Jingjing Wang, a graduate student pursuing her PhD. Bead-like magnetic particles are specifically modified by attaching short pieces of DNA to them that can capture target DNA molecules with specific sequences matching. Those are then separated for detection simply by pulling the magnetic beads along the channel. The process is simple, fast and specific.

This process has great applicability particularly for point-of-care platforms that are used to detect bacterial, viral infections and prion diseases by DNA, RNA or protein identification. Specific disease applications include testing for HIV and influenza, explained Wang.

“It can also be used to evaluate the expression of certain protein markers, such as troponin (an indicator of damage to the heart muscle) or any detection that requires binding and separation of known target biomolecules,” she added.

Optimizing the system and characterizing the chip for biological assays was the biggest challenge for the research team as it required that both engineering as well as biological factors be considered, however the team is already developing assays using this new platform. A new microchip based Simple Method of Amplifying RNA Targets (SMART) assay developed to detect influenza from patient samples is already showing high agreement with Polymerase Chain Reaction (PCR), which is considered the “gold standard” for influenza diagnosis. The team’s next challenge is developing assays using this technique to detect wild type and drug-resistant HIV in areas with limited resources such as Kenya and South Africa.


Solar paint paves the way for low-cost photovoltaics

072613solar(Nanowerk Spotlight) Using quantum dots as the basis  for solar cells is not a new idea, but attempts to make such devices have not  yet achieved sufficiently high efficiency in converting sunlight to power. The  latest advances in  quantum dots photovoltaics have recently resulted in solar  cell power conversion efficiencies exceeding 7% (see for instance: “Graded Doping for Enhanced Colloidal Quantum Dot  Photovoltaics”).


Although these performance levels are promising, all  high-performing device results to date have relied on a multiple-layer-by-layer  strategy for film fabrication rather than employing a single-layer deposition  process.    The attractiveness of using quantum dots for making solar cells  lies in several advantages over other approaches: They can be manufactured in an  energy-saving room-temperature process; they can be made from abundant,  inexpensive materials that do not require extensive purification, as silicon  does; and they can be applied to a variety of inexpensive and even flexible  substrate materials, such as lightweight plastics.


In new work, reported in the August 12, 2013 online edition of  Advanced Materials (“Directly Deposited Quantum Dot Solids Using a  Colloidally Stable Nanoparticle Ink”), a research team from the University  of Toronto and King Abdullah University of Science and Technology (KAUST)  developed a semiconductor ink with the goal of enabling the coating of large  areas of solar cell substrates in a single deposition step and thereby  eliminating tens of deposition steps necessary with the previous layer-by-layer  method.


“We sought an approach that would achieve highly efficient  utilization of CQD materials,” says Professor Ted Sargent from the  University of Toronto, who, together with Osman Bakr, an  assistant professor in the Solar & Photovoltaics Engineering Research Center at KAUST,  led the work. “To achieve this, we made a solar cell ink that can be deposited  in a single step which makes it an excellent material for high-throughput  commercial fabrication.”


The team’s ‘solar paint’ is composed of semiconductor  nanoparticles synthesized in solution – so-called colloidal quantum dots (CQDs).  They can be used to harvest electricity from the entire solar spectrum because  their energy levels can be tuned by simply changing the size of the particle.    Previously, films made from these nanoparticles were built up in  a layer-by-layer fashion where each of the thin CQD film deposition steps is  followed by curing and washing steps to densify the film and form the final  semiconducting material.


These additional steps are required to exchange the  long ligands that keep the CQDs stable in solution for short ligands that allow  efficient charge transport. However, this means that many steps are required to  build a thick enough film to absorb enough sunlight.   “We simplified this process by engineering the CQD surfaces with  short organic molecules in the solution phase to enable a stable colloidal  solution and reduce the film formation to a single step,” Bakr explains to  Nanowerk. “At the same time, the post processing steps are reduced  significantly, since the semiconducting material is formed in solution.  This  means that CQD films can be deposited quickly and at low cost, similar to a  paint or ink.”


       colloidal quantum dot solar cell fabrication methods


a)  Schematic of the standard layer-by-layer spin-coating process with active  materials usage yield and required total material indicated. b) Schematic of the  single-step film process with active materials usage yield and required total  material indicated. (Reprinted with permission from Wiley-VCH Verlag)  



Besides the reduction in processing steps, the new process is  also much more efficient in terms of materials usage. While the layer-by-layer,  solid-state treatment approach provides less than 0.1% yield in its application  of CQD materials from their solution phase onto the substrate, the new approach  achieves almost 100% use of available CQDs.


“This means that for the same amount of CQD material, we could  make a thousand-fold larger area of solar cells compared with conventional  methods,” Bakr points out.  “Our technology paves the way for low-cost  photovoltaics that can be fabricated on flexible substrates using roll-to-roll  manufacturing, similar to a printing press,” adds Lisa Rollny, a PhD candidate  in Sarget’s group and a co-author of the paper. “Our ink is also useful in  biological applications, e.g. in biosensors and tracing agents with an infrared  response.”  


“In previous work, we found new routes of passivating the CQD  surface using a combination of organic and inorganic compounds in a solid state  approach with large improvements in efficiency,” says Rollny. “We intend to  integrate this knowledge with our solar CQD ink to further improve the  performance of this material, especially in terms of how much solar energy is  converted into usable electrical energy.”  


Although the team have developed an effective method for  producing a CQD film in a single step, the electronic properties of the  resulting films are not optimized yet. This is due to the very small  imperfections on the CQD surface that reduce the usable electricity output of a  solar cell. Through careful engineering of CQD surfaces in solution, the  researchers  plan to eliminate these unwanted surface sites in order to make  higher quality, higher efficiency CQD solar cells using their single step  process.


By Michael Berger. Copyright © Nanowerk

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Nano Labs and CIMVA Enter Agreement to Develop Nanotechnologies

Nanotubes imagesNano Labs Corp. is pleased to announce the Company has signed a Non-Disclosure & Confidentiality Agreement with CIMVA (Advanced Materials Research Center) to review, identify, develop and market products based on the industrial application of nanotechnologies and advanced materials.

The Agreement will further Nano Labs’ resources to develop its proprietary nanotechnology and manufacture and produce the Company’s prototypes and products.

The Agreement allows both organizations to cooperatively identify specific joint research and commercial product projects, which will be subject to Specific Agreements outlining the purpose, activities, ownership, and the general rights and obligations of each party.

Each party will retain the copyrights and their respective industrial property rights for any future partnerships, and will outline any new ownership of copyright or industrial property rights generated, produced or resulting from the activities covered in the Specific Agreement(s).

“We are very excited to be working with this esteemed institution. CIMAV has a long history of success. Invention, innovation and commercialization are the heart and soul of this agreement. So much of science today is developed and commercialized on collaboration. Their resources – in terms of technology research infrastructure, human capital and client base – will allow us all to accomplish great things together,” explains Mr. Bernardo Chavarria, President of Nano Labs.


The CIMAV (Advanced Materials Research Center), participates greatly on three important activities for Mexico. 1. To generate or come up with original basic knowledge and spread it to the national and international scientific community; through worldwide known magazines in the materials, energy, and environmental sectors. 2. To generate human resources for a Master’s Degree and PhD. Level in the materials, energy, and environmental sectors. 3. To transfer the generated knowledge in the organization to the different society sectors.

Since its foundation in October 1994, CIMAV as a CONACYT (National Council of Science and Technology) Public Center, has searched the incorporation of science and technology to society through different ways, just as it has searched for ways to raise the educational level of the human resources. CIMAV, which headquarters is located in Chihuahua, Chihuahua and in Monterrey Unit in Nuevo León state, represents an important effort in decentralizing the scientific and technological activities that are taking place in Mexico, and to spread its benefits to the entire nation.

For more information, please visit


Thin Films Solar Cells on Flexible Substrates

Carbon Nanotube


Thin film silicon solar cells are classified into p-i-n and n-i-p configurations which refer to their deposition sequence; n-i-p processing starts with the n-layer which is normally grown on a metallic back contact. Historically this configuration is connected to flexible substrates because it was used on opaque substrates or poorly transparent substrates like steel foils or high temperature polymers. However, the configuration is not limited to this choice, it is in fact compatible with any kind of substrates, such as rigid or flexible, transparent or opaque. Nevertheless, flexible substrates have remained the main application of n-i-p cells because roll-to-roll processing makes them very interesting to reduce the production costs as well as the energy payback time, particularly when low cost substrates like poly-ethylene are used.

The activities of the n-i-p group combine general aspects of thin film silicon solar cells with special requirements that are imposed by the deposition sequence and the desired compatibility with low temperature substrates. Two main lines of work can be distinguished: .    Substrate texturing .    Light scattering and absorption enhancement

These two combined lines result in, for example, high efficiency triple junctions cell on innovative flat light scattering substrate presented in the last section.

Towards a more fundamental understanding of absorption enhancement in solar cells, we fabricate cells on periodic gratings that permit the study of coupling into guided modes [1].

We obtained fully flexible solar cells on a low cost poly-ethylene substrate with a stabilized efficiency of 9.8% for 0.25cm2 laboratory cells [2].

Research highlights

Substrate texturing

Amorphous and microcrystalline silicon are poor absorbers, particularly for light with energies just above their respective band gaps. Some means of absorption enhancement is required which is commonly called light trapping. It can be achieved by texturing of the interfaces. A common approach for n-i-p cells are back contacts made from so called “hot silver”, which is the texture that silver develops by partial recrystallization during growth on a heated substrate. Unfortunately this is too hot for poly-ethylene, we have to devise other ways. We investigate the incorporation of texture into the substrate itself, during cell fabrication this texture is carried into the other interfaces because of conformal coverage.

Periodic substrate textures

We obtained promising results on low cost poly-ethylene substrates like the one shown below. The substrate texture has been manufactured by a commercial manufacturer.


The used texture is periodic with a simple sinusoidal wave pattern, thus the incoming light is diffracted into the rainbow colours. For use in solar cells the substrate is coated with back reflector consisting of silver and zinc-oxide. The right figure shows that the back reflector reproduces the substrate texture, but silicon with a thickness comparable to the period already modifies significantly the sinusoidal wave into something that resembles an inverse cycloid.
More information


In addition to the substrate shown above, we also investigate embossing processes in order to manufacture novel substrates textures.


The figure above illustrates the embossing process; starting from a master substrate, a negative mold is formed in a polymer (PDMS), then the mold is brought into contact with a UV-sensible lacquer on a substrate. After curing by UV expose it is demolded and the initial texture is reproduced on the substrate.


The process permits, among other options, to reproduce textures that require high temperature processes like hot silver on any other substrate, for example poly-ethylene substrate.     This process reproduces the initial texture with high fidelity. The image above compares AFM surface morphologies of a ZnO master (left) and a replica (right). Features with size below 100 nm are well reproduced.
More information: articles K. Söderström and J. Escarré

Light scattering and absorption enhancement

Absorption enhancement in silicon by light scattering at textured interfaces has been proposed as early as 1982 by E. Yablonovitch. The idea is the following; take a slab of silicon with textured surface and shine weakly absorbed light on it. The transmitted light will be scattered at the surface roughness, some of it into angles above the Brewster angle. This part will bounce back and forth within the slab by total internal reflection. It would thus be trapped until its complete absorption, except that each bounce scatters a certain part out of the slab. The amount of light trapping thus depends on the angular width of this so-called escape cone. This can be related to an average light path enhancement of 4 times the square of the refractive index which is about 60 for silicon. There are a few underlying assumptions that are quite difficult to realize. Despite a significant amount of research over the years, the path enhancement in current cells is more likely to be between 20 and 30, and it is still an open question how Yablonovitch’s limit can be reached. Part of the work in the n-i-p group is devoted to the investigation of such fundamental questions, but always keeping in mind the application in real devices.

Plasmons and guided modes

A light beam that bounces back and forth within a slab by total internal reflection is not an unknown concept in optics, in fact this a simplified description of waveguides. An alternate view on light trapping is thus simply the question of how efficient we can couple an incoming plane wave to guided modes in the silicon layer. So far there appears little relation with plasmons, but remember that plasmon polaritons (as they should be called in this context) are just waves that propagate parallel to the interface in a multilayer structure; therefore the title of this section.


Waveguides are often discussed in terms of dispersion diagrams where the photon energy is plotted against the momentum p (or the wave vector k). For photons these two quantities are related by the speed of light, thus they are represented by straight lines in such a diagram. Note that perpendicular incidence would mean a line that falls on the energy axis. The indicated light lines represent grazing propagation parallel to the interfaces; there is a slight curvature because the refractive index depends on energy.
The diagram to the left shows the modal structure of a 200 nm thick a-Si “waveguide” between air and a zinc-oxide substrate. Such an asymmetric structure is known to have a cut-off, i.e. no guided wave can propagate at energies below 0.25 eV. Between 0.25 and 0.75 eV, only the fundamental mode of s-polarization (s0) can be guided, between 0.75 and 1.25 it can guide two modes (s0 and p0), and for higher energies more and more modes appear. All of these modes are confined between the light lines of silicon and zinc-oxide.
The diagram to the right shows a yet more unusual configuration consisting of a 200 nm thick silicon “waveguide” between a silver “cladding” and air. Most of the modes resemble the waveguide modes of the left image, only that they extend a little further to the left, going as far as the light line of air. Only the lowest energy mode behaves a little strange; it is p-polarized, it has no cut-off, and it runs below the light line of silicon. This particular p0 mode is called plasmon polariton. As mentioned above, it does not propagate in a guiding medium but on the interface between two media.
More information

Light trapping and guided modes

More evidence for the correspondence between light trapping and guided modes was produced in the following experiment: Solar cells were fabricated on a substrate textured with a 1D sinusoidal grating with known period. Such a periodicity folds the above diagrams into Brillouin zones and perpendicular incidence can be represented by vertical lines emerging from the centre of each Brillouin zone. Whenever the characteristics of guided modes and such a vertical line intersects, coupling becomes possible. The excitation of guided modes should thus be visible for specific energies in the form of sharp resonance phenomena. For the 1D grating there should be an additional dependence on the polarization of the incident light.


The figure shows the external quantum efficiencies of cells on the grating and a flat reference substrate. Note that there are sharp resonances between 600 and 750 nm. The observed polarization dependence and their variation with changes of the angle of incidence further support the idea of guided mode excitation.
More information

High efficiency triple junctions cell on innovative flat light scattering substrate

To reconcile the opposing requirements of layer growth and light scattering which need flat and rough interfaces, respectively, the separation of the light-scattering interface from the growth interface would be of high interest. With this new approach, light scattering is promoted by a textured layer with a low index of refraction filled with a material with a higher refractive index. This stack is then polished to obtain a flat substrate onto which the cell is grown.

We first fabricated this type of substrate as shown in the figure above and experimentally studied them in single-junction, thick µc-Si:H solar cells [Söderström Solmat 2012]. In second we have been able to fully exploit the potential of these substrates to lead to high efficiency solar cells by growing triple-junctions a-Si:H/µc-Si:H/µc-Si:H in nip configuration. This solar cell exhibits efficiencies of 13.7% in the initial state and 12.5% after degradation as shown in the below. The efficiency after degradation is among the highest reported to this date for purely silicon based n-i-p thin film solar cells [Söderström accepted for publication in JAP].


Key publications

[1] K. Söderström, G. Bugnon, F.-J. Haug, S. Nicolay and C. Ballif, Experimental study of flat light-scattering substrates in thin-film silicon solar cells, Solar Energy Materials and Solar Cells, vol. 101, p. 193-199, Elsevier, 2012
[2] K. Söderström, F.-J. Haug, J. Escarré, O. Cubero, C. Ballif, Photocurrent increase in n-i-p thin film silicon solar cells by guided mode excitation via grating coupler, Applied Physics Letters 96, 213508, 2010
[3] T. Söderström, F.-J. Haug, X. Niquille, V. Terrazzoni, and C. Ballif, Asymmetric intermediate reflector for tandem micromorph thin film silicon solar cells, Appl. Phys. Lett., Vol 94 , pp. -063501, 2009
[4] F.-J. Haug, T. Söderström, O. Cubero, V. Terrazzoni-Daudrix, X. Niquille, S. Perregeaux, and C. Ballif, Periodic textures for enhanced current in thin film silicon solar cells, Presented at the MRS Spring Meeting, San Francisco, 2008
[5] T. Söderström, F.-J. Haug, V. Terrazzoni-Daudrix, X. Niquille, M. Python and C. Ballif, N/I buffer layer for substrate microcrystalline thin film silicon solar cell, Journal of Applied Physics, Vol 104, pp. -104505, 2008


New Research: Nanotechnology in Oil and Natural Gas Production

QDOTS imagesCAKXSY1K 8(Nanowerk News) Flotek Industries, Inc. announced today  sponsorship of applied research at Texas A&M University to investigate the  impact of nanotechnology on oil and natural gas production in emerging,  unconventional resource plays.
“With the acceleration of activity in oil and gas producing  shales, a better understanding of the impact of various completion chemistries  on tight formations with low porosity and permeability will be key to developing  optimal completion techniques in the future,” said John Chisholm, Flotek’s  Chairman, President and Chief Executive Officer. “While we know Flotek’s Complex  nano-Fluid chemistries have been successful in enhancing production in tight  resource formations, we believe a more complete understanding of the interaction  between our chemistries and geologic formations as well as a more precise  comprehension of the physical properties and impact of our nanofluids in the  completion process will significantly enhance the efficacy of the unconventional  hydrocarbon completion process. This research continues our relationship with  Texas A&M where we also are conducting research into acidizing applications  in Enhanced Oil Recovery.”
Specifically, the research will focus its investigation on the  oil recovery potential of complex nanofluids and select surfactants under  subsurface pressure and temperature conditions of liquids-rich shales.
Dr. I. Yucel Akkutlu, Associate Professor of Petroleum  Engineering in the Harold Vance Department of Petroleum Engineering at Texas  A&M University will serve as the principal investigator for the project. Dr.  Akkutlu received his Masters and PhD in Petroleum Engineering from the  University of Southern California. He has over a decade of postgraduate  theoretical and experimental research experience in unconventional oil and gas  recovery, enhanced oil recovery and reactive flow and transport in heterogeneous  porous media. He has recently participated in industry-sponsored research on  resource shales including analysis of microscopic data to better understand  fluid storage and transport properties of organic-rich shales.
“As unconventional resource opportunities continue to grow in  importance to hydrocarbon production, understanding ways to maximize recovery  will be key to improving the efficacy of these projects,” said Dr. Akkutlu. “The  key to enhancing recovery will be to best understand robust, new technologies  and their impact on the completion process. Research into complex nanofluid  chemistries to understand the physical properties and formation interactions  will play an integral role in the future of completion design to optimize  recovery from unconventional hydrocarbon resources.”
Source: Flotek Industries

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Peripheral Nerve Repair: Use of Nanotechnology and Tissue engineering

Author: Tilda Barliya PhD

QDOTS imagesCAKXSY1K 8Peripheral nerve lacerations are common injuries and often cause long lasting disability (1a) due to pain, paralyzed muscles and loss of adequate sensory feedback from the nerve receptors in the target organs such as skin, joints and muscles (1b).


Nerve injuries are common and typically affect young adults with the majority of injuries occur from trauma or complication of surgery. Traumatic injuries can occur due to stretch, crush, laceration (sharps or bone fragments), and ischemia, and are more frequent in wartime, i.e., blast exposure. Domestic or occupational accidents with glass, knifes of machinery may also occur.

Statistics show that peripheral nervous system (PNS) injuries were 87% from trauma and 12% due to surgery (one-third tumor related, two-thirds non– tumor related). Nerve injuries occurred 81% of the  time in the upper extremities and 11% in the lower extremities, with the balance in other locations (4).

Injury to the PNS can range from severe, leading to major loss of function or intractable neuropathic pain, to mild, with some sensory and/or motor deficits affecting quality of life.

Functional recovery after nerve injury involves a complex series of steps, each of which may delay or impair the regenerative process. In cases involving any degree of nerve injury, it is useful initially to categorize these regenerative steps anatomically on a gross level. The sequence of regeneration may be divided into anatomical zones (4):

  1. the neuronal cell body
  2. the segment between the cell body and the injury site
  3. the injury site itself
  4. the distal segment between the injury site and the end organ
  5. the end organ itself

A delay in regeneration or unsuccessful regeneration may be attributed to pathological changes that impede normal reparative processes at one or more of these zones.


Repairing nerve defects with large gaps remains one of the most operative challenges for surgeons. Incomplete recovery from peripheral nerve injuries can produce a diversity of negative outcomes, including numbness, impairment of sensory or motor function, possibility of developing chronic pain, and devastating permanent disability.

In the past few years several techniques have been used to try and repair nerve defects and include:

  • Coaptation
  • Nerve autograph
  • Biological or polymeric nerve conduits (hollow nerve guidance conduits)

For example, When a direct repair of the two nerve ends is not possible, synthetic or biological nerve conduits are typically used for small nerve gaps of 1 cm or less. For extensive nerve damage over a few centimeters in length, the nerve autograft is the “gold standard” technique. The biggest challenges, however, are the limited number and length of available donor nerves, the additional surgery associated with donor site morbidity, and the few effective nerve graft alternatives.

Degeneration of the axonal segment in the distal nerve is an inevitable consequence of disconnection, yet the distal nerve support structure as well as the final target must maintain efficacy to guide and facilitate appropriate axonal regeneration. There is currently no clinical practice targeted at maintaining fidelity of the distal pathway/target, and only a small number of researchers are investigating ways to preserve the distal nerve segment, such as the use of electrical stimulation or localized drug delivery. Thus development of tissue-engineered nerve graft may be a better matched alternative (6,7).

The guidance conduit serves several important roles for nerve regeneration such as: a) directing axonal sprouting from the regenerating nerve b) protecting the regenerating nerve by restricting the infiltration of fibrous tissue c) providing a pathway for diffusion of neurotropic and neurotophic factors

Early guidance conduits were primarily made of silicone due to its stability under physiological conditions, biocompatibility, flexibility as well as ease of processing into tubular structures. Although silicone  conduits have proven reasonably successful as conduits for small gap lengths in animal models (<5 mm). The non-biodegradability of silicone conduits has limited its application as a strategy for long-term repair and recovery. Tubes also eventually become encapsulated with fibrous tissue, which leads to nerve compression, requiring additional surgical intervention to remove the tube.Another limiting factor with inert guidance conduits is that they provide little or no nerve regeneration for gap lengths over 10 mm in the PNS unless exogenous growth factors are used (6,7).

In animal studies, biodegradable nerve guidance conduits have provided a feasible alternative, preventing neuroma formation and infiltration of fibrous tissue. Biodegradable conduits have been fabricated from natural or synthetic materials such as collagen, chitosan and poly-L-lactic acid.

Nanostructured Scaffolds for Neural Tissue Engineering: Fabrication and Design

At the micro- and nanoscale, cells of the CNS/PNS reside within functional microenvironments consisting of physical structures including pores, ridges, and fibers that make up the extracellular matrix (ECM) and plasma membrane cell surfaces of closely apposed neighboring cells. Cell-cell and cell-matrix interactions contribute to the formation and function of this architecture, dictating signaling and maintenance roles in the adult tissue, based on a complex synergy between biophysical (e.g. contact-mediated signaling, synapse control), and biochemical factors (e.g. nutrient support and inflammatory protection). Neural tissue engineering scaffolds are aimed toward recapitulating some of the 3D biological signaling that is known to be involved in the maintenance of the PNS and CNS and to facilitate proliferation, migration and potentially differentiation during tissue repair.

Nanotechnology and tissue engineering are based on two main approaches:

  • Electrospinning (top-down) – involves the production of a polymer filament using an electrostatic force. Electrospinning is a versatile technique that enables production of polymer fibers with diameters ranging from a few microns to tens of nanometers.
  • Molecular self-assembly of peptides (bottom-up) – Molecular self-assembly is mediated by weak, non-covalent bonds, such as van der Waals forces, hydrogen bonds, ionic bonds, and hydrophobic interactions. Although these bonds are relatively weak, collectively they play a major role in the conformation of biological molecules found in nature.

Pfister et al (6) very nicely summarized the various polymeric fibers been used to achieve the goal of nerve regeneration, even in humans. These material include a wide array of polymers from silica to PLGA/PEG and Diblock copolypeptides.

Many of these approaches also enlist many trophic factors that have been investigated in nerve conduits

Currently there are three general biomaterial approaches for local factor delivery:

  1. Incorporation of factors into a conduit filler such as a hydrogel
  2. Designing a drug release system from the conduit biomaterial such as microspheres
  3. Immobilizing factors on the scaffold that are sensed in place or liberated upon matrix degradation.

Maeda et al had a  creative approach to bridge larger gaps by using the combination of nerve grafts and open conduits in an alternating “stepping stone” assembly, which may perform better than an empty conduit alone (8).


Peripheral nerve repair is a growing field with substantial progress being made in more effective repairs. Nanotechnology and biomedical engineering have made significant contributions; from surgical instrumentation to the development of tissue engineered grafting substitutes.  However, to date the field of neural tissue engineering has not progressed much past the conduit bridging of small gaps and has not come close to matching the autograf. Much more studies are needed to understand the cell behaviour that can promote cell survival, neurite outgrowth, appropriate re-innervation and consequently the functional recovery post PNS/CNS injuries. This is since understanding of the cellular response to the combination of these external cues within 3D architectures is limited at this stage.



1a. Jaquet JB, Luijsterburg AJ, Kalmijn S, Kuypers PD, Hofman A, Hovius SE.  Median, ulnar, and combined median-ulnar nerve injuries:functional outcome and return to productivity. J Trauma 2001 51: 687-692.

1b. Lundborg G, Rosen B. Hand function after nerve repair. Acta Physiol (Oxf) 2007 189: 207-217.

1. Chang WC., Kliot M and Stretavan DW. Microtechnology and Nanotechnology in Nerve Repair. Neurological Research 2008; vol 30: 1053-1062.

2. Biazar E., Khorasani MT and Zaeifi D. Nanotechnology for peripheral nerve regeneration. Int. J. Nano. Dim. 2010 1(1): 1-23.

3. Albert Aguayo. Nerve regeneration revisited. Nature Reviews Neuroscience 7, 601 (August 2006).

4. Burnett MG and  Zager EL. Pathophysiology of Peripheral Nerve Injury: A Brief Review. Neurosurg Focus. 2004;16(5) .

5. Dag Welin. Neuroprotection and axonal regeneration after peripheral nerve injury. MEDICAL DISSERTATIONS

Welin, D., Novikova, L.N., Wiberg, M., Kellerth, J-O. and Novikov, L.N. Survival and regeneration of cutaneous and muscular afferent neurons after peripheral nerve injury in adult rats. Experimental Brain Research, 186, 315-323, 2008.

6. Pfister BJ., Gordon T., Loverde JR., Kochar AS., Mackinnon SE and Cullen Dk. Biomedical Engineering Strategies for Peripheral Nerve Repair: Surgical Applications, State of the Art, and Future Challenges. Critical Reviews™ in Biomedical Engineering 2011, 39(2):81–124.

7. Zhou K, Nisbet D, Thouas G,  Bernard C and Forsythe J. Bio-nanotechnology Approaches to Neural Tissue Engineering. Intechopen. Com.

8. Maeda T, Mackinnon SE, Best TJ, Evans PJ, Hunter DA, Midha RT. Regeneration across ’stepping-stone’ nerve grafts. Brain Res. 1993;618(2):196–202.

Liposomes Disguise Chemotherapy Drug Packed into Trojan Horse Nanobins

QDOTS imagesCAKXSY1K 8A new gentler chemotherapy drug in the form of nanoparticles has been designed by Northwestern Medicine® scientists to be less toxic to a young woman’s fertility but extra tough on cancer. This is the first cancer drug tested while in development for its effect on fertility using a novel in vitro test.

The scientists designed a quick new in vitro test that predicts the toxicity of a chemotherapy drug to fertility and can be easily used to test other cancer drugs in development as well as existing ones. Currently the testing of cancer drugs for fertility toxicity is a time and resource intensive process.

“Our overall goal is to create smart drugs that kill the cancer but don’t cause sterility in young women,” said Teresa Woodruff, a co-principal investigator of the study and chief of fertility preservation at Northwestern University Feinberg School of Medicine. The paper was published March 20 in in the journal PLOS ONE.

The scientists hope their integration of drug development and reproductive toxicity testing is the beginning of a new era in which chemotherapy drugs are developed with an eye on their fertotoxity (fertility toxicity). As cancer survival rates increase, the effect of cancer treatments on fertility is critically important to many young patients.

Woodruff and Thomas O’Halloran, also a co-principal investigator and director of the Chemistry of Life Processes Institute at Northwestern, are a wife and husband team who developed and tested the drug. Their intersecting interests — hers in fertility preservation, his in cancer drug development — percolated over dinner conversations and sparked the collaboration.

O’Halloran also is the associate director for basic sciences research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and Woodruff is the Thomas J. Watkins Memorial Professor of Obstetrics and Gynecology at Feinberg. Richard Ahn, now a fourth-year medical student at Feinberg in the M.D.-PhD program and the study’s lead author, coordinated the preclinical testing of the nanobins as a graduate student in O’Halloran’s lab.

A Tiny Trojan Horse

The chemotherapy drug, arsenic trioxide, is packed into a very tiny Trojan horse called a nanobin. The nanobin consists of nano-size crystalline arsenic particles densely packed and encapsulated in a fat bubble. The fat bubble, a liposome, disguises the deadly cargo — half a million drug molecules.

“You have to wallop the tumor with a significant dose of arsenic but at the same time prevent exposure to normal tissue from the drug,” said O’Halloran. The fat bubble is hundreds of times smaller than the average human cell. It is the perfect size to stealthily slip through holes in the leaky blood vessels that rapidly grow to feed tumors. The local environment of the tumor is often slightly acid; it is this acid that causes the nanobin to release its drug cargo and deliver a highly effective dose of arsenic where it is needed.

The scientists show this approach to packaging and delivering the active drug has the desired effect on the tumor cells but prevents damage to ovarian tissue, follicles or eggs.

While the drug is gentle on fertility, it is ferocious on cancer. When tested against lymphoma, it was more potent than the drug in its traditional free form.

“The drug was designed to maximize its effectiveness but reduce fertotoxicity,” said O’Halloran, also the Morrison Professor of Chemistry in the Weinberg College of Arts and Sciences at Northwestern. “Many cancer drugs cause sterilization, that’s why the reproductive tract is really important to focus on in the new stages of drug design. Other body systems get better when people stop taking the drug, but fertility you can’t recover.”

Arsenic trioxide was approved a few years ago for treating some types of blood cancers such as leukemia in humans, but O’Halloran thinks the arsenic trioxide nanobins can be used against breast cancer and other solid tumors. In his previously published preclinical research, nanobins were effective in reducing tumor growth in triple-negative breast cancer, which often doesn’t respond well to traditional chemotherapy and has a poor survival rate.

Quick Test For Fertility Toxicity

Woodruff was able to show early effects of the drug on fertility by using an in vitro follicle culture and a quick, simple new test she developed. She compared the fertotoxicity of the nanobin and free drug and found the nanobin was much less toxic to female fertility than the free drug in the experimental model.

“The system can be adapted very easily for any cancer drug under development to get an early peek under the tent,”said Woodruff, also the Thomas J. Watkins Memorial Professor of Obstetrics and Gynecology at Feinberg. “As this new drug goes forward in development, we can say this is a good drug for young female cancer patients who are concerned about fertility.”

The information gained from the toxicity test will help inform the treatment decisions of oncologists and their young female cancer patients to improve their chances of creating a future family.

“They may prescribe less toxic drug regimens or refer them to specialists in fertility preservation,” Woodruff said.


Nanotechnology Key to New Desalination System

Nanowerk News) The scarcity of fresh water is an  increasingly serious problem around the world due to growing populations and  diminishing supplies of fresh water. Desalination could help alleviate these  shortages, but it has traditionally been an extremely expensive process. The demand for water is so great that the worldwide desalination  market is expected to reach an astonishing $87.8 billion by 2016, even though  only about 1 percent of the world’s drinking water is produced by desalination.  There is a huge need for technologies that could reduce this cost. To help meet this need, the Innovation Fund, the University of  Chicago’s venture philanthropic proof-of-concept fund, awarded Heinrich Jaeger, the William J. Friedman and Alicia Townsend  Professor of Physics at the University of Chicago, $65,000 in its third round of  funding at the end of 2011 to establish the commercial feasibility of a  nanoparticle desalination system that Jaeger invented.

Dr. Jaegger

A grant from the University of Chicago’s Innovation Fund will help Heinrich  Jaeger, PhD, establish the commercial feasibility of a nanoparticle desalination  system.

“In order for desalination to become a real solution to the  growing water scarcity problem, new technologies will be required to reduce the  major cost components of the process,” says Sean Sheridan, an assistant director  at UChicagoTech, which administers the Innovation Fund. “Professor Jaeger’s  nanofiltration technology represents a promising step towards achieving this  goal.”
The high cost of traditional desalination is driven by the price  of energy for high-pressure systems and the capital cost of high-pressure pumps  and seals. Today, recovery of capital and electric power add up to as much as  73% of the cost of desalinated water.
“Our system has the potential to cut these costs by using an  ultrathin self-assembled nanoparticle membrane,” Jaeger says. “Due to its  extreme thinness and excellent permeability characteristics, this nanofiltration  membrane can be used for a wide range of nanofiltration processes at low  pressures, including desalination.”
The nanofiltration membrane was developed by Jaeger and Xiao-Min  Lin, scientist at Argonne’s Center for Nanoscale Materials, together with  University of Chicago postdocs Jinbo He, Edward Barry and Sean McBride. At about  30 nanometers, it is the world’s thinnest and has unique features that may turn  out to make the crucial difference with this technology. The size, shape and  chemical structure of the membrane’s pores can be systematically tuned to  optimize its filtration properties. As a result, it allows 100 times more flow  at the same pressure. In addition, the self-assembly process used to fabricate  it reduces costs.
UChicagoTech’s role
Jaeger has a close working relationship with UChicagoTech, which  is committed to supporting University faculty as they work to translate bench  science to commercial applications. He regularly updates the office on his new  ideas and research results. After he approached UChicagoTech with his initial  data about the nanofiltration system, UChicagoTech helped him to develop a  business proposal and present the opportunity to the Innovation Fund.  UChicagoTech also filed an international patent application at the end of 2012  to protect the technology.
“The Innovation Fund award has been extremely helpful by giving  us not only financial support to further develop this technology in a timely  manner but also by connecting us with a highly supportive group of industry  experts and entrepreneurs,” Jaeger says.
The award is helping to optimize the low-pressure ion  rejection/permeation characteristics for the product; develop and test a system  that is environmentally friendly, compatible with drinking water standards, and  scalable for the production of large volumes of water; and design an assembly  process that is compatible with existing commercial filtration systems.
Initially, Jaeger intends to target small, distributed or mobile  water treatment systems. After being proven on a small scale, the technology  could attract additional funding and be developed for larger systems.
“The potential of this technology to establish a new class of  nanofiltration devices is an exciting prospect,” Jaeger says. “Many purification  processes in a wide range of industries depend on nanofiltration and could  benefit greatly from highly specialized and tunable parameters in a low-pressure  technology. UChicagoTech’s help has been indispensible.”
Source: By Greg Borzo, University of  Chicago


Lung Cancer (NSCLC), Drug Administration and Nanotechnology

Lung Cancer (NSCLC), drug administration and nanotechnology

November 8, 2012 by tildabarliya

Note to Readers: Great report!  Thanks to Dr. Tilda Barliya, we have a very insightful look into the world of applied nanotechnology in the field of “diagnosis, delivery and treatment”. Thank you Tilda.  Cheers!  – BWH

Author: Tilda Barliya PhD

Dr. Saxena has greatly introduced us to lung cancer , the associated drug treatments and their market share in the post titled ” NSCLC and where the future lie?”. Since lung cancer is the most leading cause of death in both man and women, and have gained lots of attention I am interested in elaborating on NSCLC and explore the potential use of nanotechnology in this matter.

As previously mentioned, there are 3 common types of lung cancer:

  • Adenocarcinomas are often found in an outer area of the lung. (Most common)
  • Squamous cell carcinomas are usually found in the center of the lung next to an air tube (bronchus).
  • Large cell carcinomas can occur in any part of the lung. They tend to grow and spread faster than the other two types. (Least common).

Figure 1. The Signs and symptoms of lung cancer anatomy.


Since each type develops in different areas/part of the lung, it is hypothesized that they might need different routs of administration. The possible routes of administration are:

  • IV (systemic)————->through the blood
  • Inhaled aerosols (more localized)———–>through the airways

In order to understand what does “different routs of administration” refers to, we need to dig into the anatomy of the lung, i.e, airways and blood circulation as well as understand the lung-blood barriers components that may affect drug absorption.

The Blood Circulation

Two different circulatory systems, the bronchial and the pulmonary, supply the lungs with blood (Staub, 1991). The bronchial circulation is a part of the systemic circulation and is under high pressure. It receives about 1% of the cardiac output and supplies the airways (from the trachea to the terminal bronchioles), pulmonary blood vessels and lymph nodes with oxygenated blood and nutrients and conditions the inspired air (Staub, 1991). In addition, it may be important to the distribution of systemically administered drugs to the airways and to the absorption of inhaled drugs from the airways (Chediak et al., 1990). The pulmonary circulation comprise an extensive low pressure vascular bed, which receives the entire cardiac output. It perfuses the alveolar capillaries to secure efficient gas exchange and supplies nutrients to the alveolar walls. Anastomoses between bronchial and pulmonary arterial circulations have been found in the walls of medium-sized bronchi and bronchioles (Chediak et al., 1990; Kröll et al.,1987)



  • Fast: 15–30 seconds to 1-2 hours
  • suitable for drugs not absorbed by the digestive system
  • IV can deliver continuous medication


  • Patients are not typically able to self-administer
  • It is the most dangerous route of administration because it bypasses most of the body’s natural defenses, exposing the user to health problems, known as chemo side affects.
  • Finally dose at the organ site is much lower than the administrated dose

Most of the conventional chemotherapy are mainly administrated IV (Docetaxel, Paxlitaxel, Gemcitiabine, Avastin etc).

The Airways

The human respiratory system can be divided in two functional regions: the conducting airways and the respiratory region. The conducting airways, which are composed of the nasal cavity and associated sinuses, the pharynx, larynx, trachea, bronchi, and bronchioles, filter and condition the inspired air. From trachea to the periphery of the airway tree, the airways repeatedly branch dichotomously into two daughter branches with smaller diameters and shorter length than the parent branch (Weibel, 1991). For each new generation of airways, the number of branches is doubled and the crosssectional area is exponentially increased. The conducting region of the airways generally constitutes generation 0 (trachea) to 16 (terminal bronchioles). The respiratory region, where gas exchange takes place, generally constitutes generation 17-23 and is composed of respiratory bronchioles, the alveolar ducts, and the alveolar sacs.

The air-blood barrier of the gas exchange area is composed of the alveolar epithelial cells (surface area 140 m2) on one side and the capillary bed (surface area 130 m2) on the other side of a thin basement membrane (Simionescu, 1991; Stone et al., 1992). The extensive surface area of the air-blood barrier in combination with its extreme thinness (0.1-0.5 μm) permit rapid gas exchange by passive diffusion (Plopper, 1996).


The lung is a very attractive target for drug delivery. It provides direct access to disease in the treatment of respiratory diseases, while providing an enormous surface area and a relatively low enzymatic, controlled environment for systemic absorption of medications. (


  • Can be self medicated
  • Easy to use
  • Reduced side effects associated with systemic delivery


  • Slower route of action
  • Potential problem of deposition to the deeper alveolar (higher generations, like G 8-10)
  • Immuno-defense system
  • Difficulty in measuring the exact dose inside the lung
  • inhaled aerosol is entrapped in the mucus in the conducting airways

Need to be reminded that in addition, a drug’s efficacy may be affected by where in the respiratory tract it is deposited, its delivered dose and the disease it may be trying to treat.

Major components of the lung – barriers to drug absorption
As one of the primary interfaces between the organism and the environment, the respiratory system is constantly exposed to airborne particles, potential pathogens, and toxic gases in the inspired air (Plopper, 1996). As a result a sophisticated respiratory host defense system, present from the nostrils to the alveoli, has evolved to clear offending agents (Twigg, 1998).

The system comprises of:

  • mechanical (i.e. air filtration,cough, sneezing, andmucociliary clearance),
  • chemical (antioxidants, antiproteases and surfactant lipids),
  • immunological defense mechanisms and is tightly regulated to minimize inflammatory reactions that could impair the vital gas-exchange

**Intratracheal inhalation is another  administration option but will be left out of the discussion for now

From a drug delivery perspective, the components of the host defense system comprise barriers that must be overcome to ensure efficient drug deposition and absorption from the respiratory tract.

Generally, lung physiological investigations show that the airway and alveolar epithelia, not the interstitium and the endothelium, constitute the main barrier that restricts the movement of drugs and solutes from the airway lumen into the cells or the blood circulation.

Aerosols are defined as An aerosol is a suspensions of fine solid particles or liquid droplets in a gas.The major aspect affect the efficacy of aerosols as a drug delivery system is Drug Deposition.

Aerosol Drug deposition is affected by:

  • particle properties (e.g. size, shape, density, and charge),
  • respiratory tract morphology,
  • the breathing pattern (e.g. airflow rate and tidal volume)

These parameters determine not only the quantity of particles that are deposited but also in what region of the respiratory tract the particles are deposited.

Particle properties

As the cross-sectional area of the airways increases, the airflow rate rapidly decreases, and consequently the residence time of the particles in the lung increases from the large conducting airways towards the lung periphery. The most important mechanisms of particle deposition in the respiratory tract are (1) inertial impaction, (2) sedimentation, and (3) diffusion.

  • Inertial impaction – Inertial impaction occurs predominantly in the extrathoracic airways and in the tracheobronchial tree, where the airflow velocity is high and rapid changes in airflow direction occurs. Generally, particles with a diameter larger than 10 μm are most likely deposited in the extrathoracic region, whereas 2- to 10-μm particles are deposited in the tracheobronchial tree by inertial impaction. A long residence time of the inspired air favors particle deposition by sedimentation and diffusion.
  • Sedimentation – Sedimentation is of greatest importance in the small airways and alveoli and is most pronounced for particles with a diameter of 0.5-2 μm, Ultrafine particles (<0.5 μm in diameter) are deposited mainly by diffusional transport in the small airways and lung parenchyma where there is a maximal residence time of the inspired air.

Most therapeutic aerosols are almost always heterodisperse, consisting of a wide range of particle sizes and described by the log-normal distribution with the log of the particle diameters plotted against particle number, surface area or volume (mass) on a linear or probability scale and expressed as absolute values or cumulative percentage (

Optimal drug delivery to the lungs depends on an interaction between;

  • the inhaler device,
  • the drug formulation properties,
  • the inhalation maneuver

The devices currently available for pulmonary drug administration of pharmaceutical aerosols in clinical therapy include nebulizers, pressurized metered dose inhalers (pMDIs), and dry powder inhalers (DPIs).

However, much effort is put into the development of new inhaler devices and formulations to optimize the pulmonary delivery system for local or systemic drug targeting.

One of the major problems in aerosol delivery is

One disadvantage of the aerosol inhalation is, however, that a substantial portion of the aerosolized drug is not delivered to the lungs (i.e. delivered to the nose, mouth, skin, exhaled). only 10–15% of the emitted dose in the lungs.

In general the aerosol exposure techniques have a low dosing effectiveness, which often requires longer exposure times to administer the target dose and renders investigations of rapid kinetic events difficult. In addition, aerosol exposure requires an advanced equipment for exposure and ml-quantities of test formulation to fill up the device.

Airway geometry and humidity

Progressive branching and narrowing of the airways encourage impaction of particles. The larger the particle size, the greater the velocity of incoming air, the greater the bend angle of bifurcations and the smaller the airway radius, the greater the probability of deposition by impaction. The lung has a relative humidity of approximately 99.5%. The addition and removal of water can significantly affect the particle size of a hygroscopic aerosol and thus deposition. Drug particles are known to be hygroscopic and grow or shrink in size in high humidity, such as in the lung. A hygroscopic aerosol that is delivered at relatively low temperature and humidity into one of high humidity and temperature would be expected to increase in size when inhaled into the lung. The rate of growth is a function of the initial diameter of the particle, with the potential for the diameter of fine particles <1 µm to increase five-fold compared with two-to-three-fold for particles >2 µm. he increase in particle size above the initial size should affect the amount of drug deposited and particularly, the distribution of the aerosolized drug within the lung,

Lung Clearance Mechanism

Once deposited in the lungs, inhaled drugs are either cleared from the lungs, absorbed into the systemic circulation or degraded via drug metabolism. Drug particles deposited in the conducting airways are primarily removed through mucociliary clearance and, to a lesser extent, are absorbed through the airway . epithelium into the blood or lymphatic system. a low-viscosity periciliary or sol layer covered by a high-viscosity gel layer. Insoluble particles are trapped in the gel layer and are moved toward the pharynx (and ultimately to the gastrointestinal tract) by the upward movement of mucus generated by the metachronous beating of cilia. In the normal lung, the rate of mucus movement varies with the airway region and is determined by the number of ciliated cells and their beat frequency. Movement is faster in the trachea than in the small airways and is affected by factors influencing ciliary functioning and the quantity and quality of mucus.

Drugs deposited in the alveolar region may be phagocytosed and cleared by alveolar macrophages or absorbed into the pulmonary circulation. Alveolar macrophages are the predominant phagocytic cell for the lung defence against inhaled microorganisms, particles and other toxic agents. There are approximately five to seven alveolar macrophages per alveolus in the lungs of healthy nonsmokers. Macrophages phagocytose insoluble particles that are deposited in the alveolar region and are either cleared by the lymphatic system or moved into the ciliated airways along currents in alveolar fluid and then cleared via the mucociliary escalator.

Very little is known about how the drug-metabolizing activities of the lung affect the concentration and therapeutic efficacy of inhaled drugs. All metabolizing enzymes found in the liver are found to a lesser extent in the lung. Therefore assuming, drug deposition could have been calculated it would be hard to impossible to evaluate it’s metabolism.

In summary:

As the end organ for the treatment of local diseases or as the route of administration for systemic therapies, the lung is a very attractive target for drug delivery. It provides direct access the site of disease for the treatment of respiratory diseases without the inefficiencies and unwanted effects of systemic drug delivery. It provides an enormous surface area and a relatively low enzymatic, controlled environment for systemic absorption of medications. But it is not without barriers. Airway geometry, humidity, clearance mechanisms and presence of lung disease influence the deposition of aerosols and therefore influence the therapeutic effectiveness of inhaled medications. A drug’s efficacy may be affected by the site of deposition in the respiratory tract and the delivered dose to that site. To provide an efficient and effective inhalant therapy, these factors must be considered. Aerosol particle size characteristics can play an important role in avoiding the physiological barriers of the lung, as well as targeting the drug to the appropriate lung region.

Drug formulations and chemo drug delivery will be further discussed in a another post.


1. N R Labiris and M B Dolovich. “Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications”. Br J Clin Pharmacol. 2003 December; 56(6): 588–599.

2. Tronde A. “Pulmonary drug absorption”. Acta Universities Upsalninesis Uppsala 2002.

3. Naushad Khan Ghilzai. Pulmonary drug delivery.


Nanotechnology and MRI imaging

October 17, 2012 by tildabarliya

Author: Tilda Barliya PhD via Pharmaceutical Intelligence:

The recent advances of “molecular and medical imaging” as an integrated discipline in academic medical centers has set the stage for an evolutionary leap in diagnostic imaging and therapy. Molecular imaging is not a substitute for the traditional process of image formation and interpretation, but is intended to improve diagnostic accuracy and sensitivity.

Medical imaging technologies allow for the rapid diagnosis and evaluation of a wide range of pathologies. In order to increase their sensitivity and utility, many imaging technologies such as CT and MRI rely on intravenously administered contrast agents. While the current generation of contrast agents has enabled rapid diagnosis, they still suffer from many undesirable drawbacks including a lack of tissue specificity and systemic toxicity issues. Through advances made in nanotechnology and materials science, researchers are now creating a new generation of contrast agents that overcome many of these challenges, and are capable of providing more sensitive and specific information (1)

Magnetic resonance imaging (MRI) contrast enhancement for molecular imaging takes advantage of superb and tunable magnetic properties of engineered magnetic nanoparticles, while a range of surface chemistry offered by nanoparticles provides multifunctional capabilities for image-directed drug delivery. In parallel with the fast growing research in nanotechnology and nanomedicine, the continuous advance of MRI technology and the rapid expansion of MRI applications in the clinical environment further promote the research in this area.

It is well known that magnetic nanoparticles, distributed in a magnetic field, create extremely large microscopic field gradients. These microscopic field gradients cause substantial diphase and shortening of longitudinal relaxation time (T1) and transverse relaxation time (T2 and T2*) of nearby nuclei, e.g., proton in the case of most MRI applications. The magnitudes of MRI contrast enhancement over clinically approved conventional gadolinium chelate contrast agents combined with functionalities of biomarker specific targeting enable the early detection of diseases at the molecular and cellular levels with engineered magnetic nanoparticles. While the effort in developing new engineered magnetic nanoparticles and constructs with new chemistry, synthesis, and functionalization approaches continues to grow, the importance of specific material designs and proper selection of imaging methods have been increasingly recognized (2)

Earlier investigations have shown that the MRI contrast enhancement by magnetic nanoparticles is highly related to their composition, size, surface properties, and the degree of aggregation in the biological environment.

Therefore, understanding the relationships between these intrinsic parameters and relaxivities of nuclei under influence of magnetic nanoparticles can provide critical information for predicting the properties of engineered magnetic nanoparticles and enhancing their performance in the MRI based theranostic applications. On the other hand, new contrast mechanisms and imaging strategies can be applied based on the novel properties of engineered magnetic nanoparticles. The most common MRI sequences, such as the spin echo (SE) or fast spin echo (FSE) imaging and gradient echo (GRE), have been widely used for imaging of magnetic nanoparticles due to their common availabilities on commercial MRI scanners. In order to minimize the artificial effect of contrast agents and provide a promising tool to quantify the amount of imaging probe and drug delivery vehicles in specific sites, some special MRI methods, such as  have been developed recently to take maximum advantage of engineered magnetic NPs

  • off-resonance saturation (ORS) imaging
  • ultrashort echo time (UTE) imaging

Because one of the major limitations of MRI is its relative low sensitivity, the strategies of combining MRI with other highly sensitive, but less anatomically informative imaging modalities such as positron emission tomography (PET) and NIRF imaging, are extensively investigated. The complementary strengths from different imaging methods can be realized by using engineered magnetic nanoparticles via surface modifications and functionalizations. In order to combine optical or nuclear with MR for multimodal imaging, optical dyes and radio-isotope labeled tracer molecules are conjugated onto the moiety of magnetic nanoparticles

Since most functionalities assembled by magnetic nanoparticles are accomplished by the surface modifications, the chemical and physical properties of nanoparticle surface as well as surface coating materials have considerable effects on the function and ability of MRI contrast enhancement of the nanoparticle core.

The longitudinal and transverse relaxivities, Ri (i=1, 2), defined as the relaxation rate per unit concentration (e.g., millimole per liter) of magnetic ions, reflects the efficiency of contrast enhancement by the magnetic nanoparticles as MRI contrast agents. In general, the relaxivities are determined, but not limited, by three key aspects of the magnetic nanoparticles:

  1. Chemical composition,
  2. Size of the particle or construct and the degree of their aggregation
  3. Surface properties that can be manipulated by the modification and functionalization.

(It is also recognized that the shape of the nanoparticles can affect the relaxivities and contrast enhancement. However these shaped particles typically have increased sizes, which may limit their in vivo applications. Nevertheless, these novel magnetic nanomaterials are increasingly attractive and currently under investigation for their applications in MRI and image-directed drug delivery).

Composition Effect: The composition of magnetic nanoparticles can significantly affect the contrast enhancing capability of nanoparticles because it dominates the magnetic moment at the atomic level. For instance, the magnetic moments of the iron oxide nanoparticles, mostly used nanoparticulate T2 weighted MRI contrast agents, can be changed by incorporating other metal ions into the iron oxide.  The composition of magnetic nanoparticles can significantly affect the contrast enhancing capability of nanoparticles because it dominates the magnetic moment at the atomic level. For instance, the magnetic moments of the iron oxide nanoparticles, mostly used nanoparticulate T2 weighted MRI contrast agents, can be changed by incorporating other metal ions into the iron oxide.

Size Effect: The dependence of relaxation rates on the particle size has been widely studied both theoretically and experimentally. Generally the accelerated diphase, often described by the R2* in magnetically inhomogeneous environment induced by magnetic nanoparticles, is predicted into two different regimes. For the relatively small nanoparticles, proton diffusion between particles is much faster than the resonance frequency shift. This resulted in the relative independence of T2 on echo time. The values for R2 and R2*are predicted to be identical. This process is called “motional averaging regime” (MAR). It has been well demonstrated that the saturation magnetization Ms increases with the particle size. A linear relationship is predicted between Ms1/3 and d-1. Therefore, the capability of MRI signal enhancement by nanoparticles correlates directly with the particle size. 

Surface Effect: MRI contrast comes from the signal difference between water molecules residing in different environments that are under the effect of magnetic nanoparticles. Because the interactions between water and the magnetic nanoparticles occur primarily on the surface of the nanoparticles, surface properties of magnetic nanoparticles play important roles in their magnetic properties and the efficiency of MRI contrast enhancement. As most biocompatible magnetic nanoparticles developed for in vivo applications need to be stabilized and functionalized with coating materials, the coating moieties can affect the relaxation of water molecules in various forms, such as diffusion, hydration and hydrogen binding.

The early investigation carried at by Duan et al suggested that hydrophilic surface coating contributes greatly to the resulted MRI contrast effect. Their study examined the proton relaxivities of iron oxide nanocrystals coated by copolymers with different levels of hydrophilicity including: poly(maleic acid) and octadecene (PMO), poly(ethylene glycol) grated polyethylenimine (PEG-g-PEI), and hyperbranched polyethylenimine (PEI). It was found that proton relaxivities of those IONPs depend on the surface hydrophilicity and coating thickness in addition to the coordination chemistry of inner capping ligands and the particle size.

The thickness of surface coating materials also contributed to the relaxivity and contrast effect of the magnetic nanoparticles. Generally, the measured T2 relaxation time increases as molecular weight of PEG increases.

In Summary

Much progress has taken place in the theranostic applications of engineered magnetic nanoparticles, especially in MR imaging technologies and nanomaterials development. As the feasibilities of magnetic nanoparticles for molecular imaging and drug delivery have been demonstrated by a great number of studies in the past decade, MRI guiding and monitoring techniques are desired to improve the disease specific diagnosis and efficacy of therapeutics. Continuous effort and development are expected to be focused on further improvement of the sensitivity and quantifications of magnetic nanoparticles in vivo for theranostics in future.

The new design and preparation of magnetic nanoparticles need to carefully consider the parameters determining the relaxivities of the nanoconstructs. Sensitive and reliable MRI methods have to be established for the quantitative detection of magnetic nanoparticles. The new generations of magnetic nanoparticles will be made not only based on the new chemistry and biological applications, but also with combined knowledge of contrast mechanisms and MRI technologies and capabilities. As new magnetic nanoparticles are available for theranostic applications, it is anticipated that new contrast mechanism and MR imaging strategies can be developed based on the novel properties of engineered magnetic nanoparticles.