The nanomechanics revolution in medicine
From antibiotic development to inflammation markers, nanomechanics are
bending and shaping the future of the bio-industry. Nanotechnology is
still uppermost in the imagination of much of the industry, often seen
as something of a Sci-Fi concept. But it is a reality, and it is being
used in labs across the world today. Dr Mike Fisher of
Bio Nano Consulting describes how it is already producing some
remarkable results and innovations.
10 June 2011
A growing problem
Within all areas of medical science, there is a constant need for
new techniques, drugs, and ideas. One crucially urgent area is that
of anti-bacterial drugs. The current international portfolio of
antibiotics is becoming increasingly redundant as healthcare
acquired infections (HAI) are on the up, and an increasing
proportion of these are with Multi-Drug Resistant (MDR) bacterial
strains, which are resistant to normal antibiotics.
For instance, MRSA (methicillin-resistant Staphylococcus aureus)
infection rates almost doubled in the five years from 2000 to 2005
in the USA (1). Another resistant strain proving problematic is
Vancomycin-resistant Enterococcus (VRE). Because these MDR strains
only differ slightly (often by a single mutation) from the common
forms of the bacteria, it is feared that with the current rates of
antibiotic consumption by both humans and animals, more MDR strains
However, a novel technique exploiting nanotechnology used in the
micro-electronics industry presents the opportunity to speed up the
discovery process for antibiotics and other pharmaceutical products,
as well as many other diagnostic and therapeutic processes.
The nanotechnology in question uses microcantilevers, and their
bending properties to evaluate the binding interactions between
small molecules such as drugs or DNA. Microcantilevers are thin
(<10µm) strips of silicon (0.5mm long and 0.1mm wide) which can
detect the binding of molecules, target analytes, to ligands
attached to the cantilever (2).
Each cantilever is ‘functionalised’ with particular surface
coatings: these comprise of a primary layer (a self-assembled
monolayer, SAM) and ligands that bind to specific target analytes.
The ligand is immobilised on one side of the cantilever and the
relevant target analyte is added to the system in solution. Binding
interactions of the ligand and target analytes results in bending of
These highly sensitive biosensors detect minute changes in surface
stress as the drug binds specifically to the ligands tethered on the
cantilever (see Figure 1 below). They can also be operated in a
dynamic mode, when the added mass of bacteria or other biological
substances can be detected.
Figure 1. Illustration of microcantilevers with
molecules binding tothe ligands
The full details of how the binding events lead to the compression
forces that bend the cantilevers is currently the subject of much
debate and interest. In order to exploit the full potential of
microcantilevers, it is essential that we have a fundamental
understanding of the origins of the surface stress.
One idea is based on the repulsive and attractive forces between
positively and negatively charged groups on the molecules that are
bound to the functionalised cantilever (3). This raises questions
about the effect of the pH of the solution on the results.
Observations suggest stress transduction is a collective phenomenon,
since cantilever loading affects the results. Using the Vancomycin
study (4) when the faction of the surface covered with ligand, p, is
between 0 – 0.1 no nanomechanical signal is detected. The
nanomechanical signal increased in an almost linear way between
p=0.1 and p=1.
Further evidence that a critical number of binding events are needed
comes from the identification of critical percolation thresholds in
the system. In the Vancomycin case study, a percolation value of
less than 0.075 did not generate detectable bending.
Important characteristics of the nanomechanical cantilevers are the
reproducibility, sensitivity and clinical relevance of the results.
For the Vancomycin study, reproducibility was high, both within
arrays and between arrays. The Vancomycin study also demonstrates
that the system is sensitive down to clinically relevant
concentrations (3-27µM in this case).
This technology has an obvious application in the race to design a
new generation of antibiotics. As described above, VRE is a serious
problem; attaching the target molecule of this antibiotic to the
cantilevers allows the binding of an antibiotic to the target enzyme
molecule to be detected. This means the binding properties of new
drugs can be quantified.
A possible development on this could involve using bacteria sources
from the patient and infection in question to coat the cantilevers,
to see if antibiotic resistance is present. This would help doctors
decide which drug to use and save valuable time by not administering
ineffective drugs to patients.
These microcantilevers have been used in many other research
situations, with fascinating results.
Microcantilevers have been used to detect IFM-induced 1-8U gene
expression, implicated in the development of melanomas (since it is
involved in the transduction anti-proliferative signals).
Complementary single strand DNA was attached to the SAM on the
cantilever and RNA from the 1-8U gene expression was in the solution
(5). Other RNA was included in the solution to measure the
resolution of the system: down to 4 bases pairs of RNA was achieved.
Further down the line, this could be used to detect the response of
melanoma patients to anti-interferon therapy. Detecting DTT (an
organochlorine insecticide compound) by cantilevers required
specific monoclonal antibodies in the solution (6). Building on this
achievement, a pesticide contamination detector product could be
Portable instruments capable of analyzing multiple components are
becoming available (7) and based on this, ‘point-of-care’
diagnostics is an attractive commercial market. Since the diagnosis
and management of complex diseases such as cancer requires
quantitative detection of a number of proteins, this is an appealing
field for the development of microcantilevers.
PSA (prostate-specific antigen), marker for prostate cancer, can be
detected over a wide range of concentrations; from 0.2ng/ml to 60
µg/ml in solution with HAS (human serum albumin) and HP (human
plasminogen) at 1mg/ml, making these findings clinically relevant
(8). CRP (C-reactive protein, an indicator of inflammation) has also
been detected with microcantilevers (9).
The questions of specificity and sensitivity need to be addressed
for other disease-related proteins and bio-molecules for the
clinical possibilities of this technology to be fully realised.
Advantages for drug discovery
As the above studies illustrate, these Nanomechanical Cantilever
Biosensors have clear applications in the drug discovery field. The
numerous advantages make it a valuable tool for drug development,
but is also very versatile, as the studies above illustrate. One
necessity in any experiment, reproducibility, is present in these
There is no need to label samples or use external probes, making
this new technique a quick single step process for the detection of
bio-molecules. The cantilevers can be used in arrays, permitting the
screening of multiple drug-target interactions in parallel, saving
valuable time in the drug-development pipe-line.
The quality of information provided is high; ligand-receptor binding
constants can be quantifiably measured, and with sensitivity down to
very low concentrations (100pM), the effects of different
antibiotics can be distinguished with differential bending signals
of -9±2nm. The nanomechanical signal is not limited by mass and the
system can be portable.
Binding can be detected down to very low concentrations, beyond
clinically relevant concentrations, giving the system a broad
dynamic range. Large quantities of prototype drug molecules do not
therefore need to be made to be tested in this system.
The benefit that the microcantilever system offers over standard
systems such as SPR (surface Plasmon resonance) is that, in addition
to measuring binding constants, it can also measure surface stresses
that drugs create when binding to biological surfaces, such as
bacterial membranes. This information can be extremely valuable in
predicting true in vivo drug efficacy.
As the studies and advantages suggest, there is an obvious
application of this technology in the commercial market. It is
available on a commercial basis for the assessment of drug-target
interactions for a broad range of antibiotics and drugs under
development. Bio Nano Consulting have already used it in
collaborative work with Targanta Therapeutics of Cambridge MA (now
part of The Medicines Company) to elucidate the mechanism of action
of its drug orytavancin.
It is hoped that this novel technique can be used in the drug
development pipeline to speed up the process of developing much
needed antibiotics and other pharmaceutical products, as well as
helping bring to clinic and the commercial market a host of new
diagnostic and therapeutic techniques, from insecticide detection to
cancerous cell markers.
Dr Mike Fisher
Business Developmnet Director,
Bio Nano Consulting.
In addition to his role at Bio Nano Consulting, Dr Mike Fisher is
the Theme Manager for Healthcare & Life Sciences within the UK’s
Nanotechnology Knowledge Transfer Network, an advisor to Barrack
Hill Partners, an executive search and HR consulting firm based in
Boston and Florida, and a Producer of TechNation/BioTechNation, a
technology-based radio show on National Public Radio in the USA.
1. Elixhauser, A., Steiner, C. 2007. Infections with
Methicillin-Resistant Staphylococcus Aureus (MRSA) in US Hospitals,
1993-2005, HCUP Statistical Brief #35, Agency for Healthcare
Research andQuality, Rockville, MD.
2. Fritz J, et al. 2000. Translating biomolecular recognition into
nanomechanics. Science, (288):316-318.
3. Watari M, et al. 2007. Investigating the molecular mechanisms of
in-plane mechanochemistry on cantilever arrays, Journal of the
American Chemistry Society, (129):601-609.
4. Ndieyira J. W. et al. 2008. Nanomechanical detection of
antibiotic-mucopeptide binding in a model for superbug drug
resistance. Nature Nanotechnolg, 3:691-696.
5. Zhang et al. 2006. Rapid and label-free nanomechanical detection
of biomarker transcripts in human RNA. Nature Nanotechnology 1:214 -
6. Alvarez et al. 2003. Development of nanomechanical biosensors for
detection of the pesticide DDT. Biosensors and Bioelectronics.
7. Jianrong et al. 2004. Nanotechnology and Biosensors.
Biotechnology Advances, 22(7):505-518.
8. Wu et al. 2001. Bioassay of prostate-specific antigen (PSA) using
microcantilevers. Nature Biotechnology, 19:856-860.
9. Wook Wee et al. Novel electrical detection of label-free disease
marker proteins using piezoresistive self-sensing micro-cantilevers.
Biosensors and Bioelectronics, 20(10):1932-1938.