Nanophotonic

Biosensors
Driving Personalized
Medicine

Maria Soler, Olalla Calvo-Lozano,

M.-Carmen Estevez and
Laura M. Lechuga

24 OPTICS & PHOTONICS NEWS APRIL 2020

Sed min cullor si deresequi rempos magnis eum explabo. Ut et
hicimporecum sapedis di aut eum quiae nonem et adi.

Point-of-care photonic
biosensors could promote
more integrated, informative,
timely and precise diagnoses
of human diseases—and
better-targeted health care.

Nanophotonic interferometric biosensor for multiplexed

analysis of protein and nucleic acid biomarkers.
Dámaso Torres/ICN2

APRIL 2020 OPTICS & PHOTONICS NEWS 25

 Evanescent field

Antigen antibody

Nanophotonic sensor

Evanescent-field sensing
In a typical nanophotonic biosensor, nanostructures on the sensor
strongly enhance the incident light field; changes in refractive index at
the interface due to biorecognition events (for example, antibody–antigen
interactions) are read from the enhanced evanescent field.

Courtesy of the authors

W
e live amid the rise of precision medi- target molecule, or analyte, present in a sample. This
cine. Every day seems to bring news interaction produces a variation in an electrical, opti-
of the discovery and implementation cal or mechanical property of the transducer that can
of novel treatments to eradicate dis- be read and directly related to the amount of analyte.
eases, and personalized therapies to Photonic biosensors exploit light’s unique proper-
attack malignancies with impressive results. Scientists ties to realize some of the more sensitive, robust and
around the world are on a quest for the key remedies reliable sensing platforms currently available. The
to reduce the burdens of cancer and of cardiac, degen- paramount example is the surface plasmon resonance
erative or autoimmune disorders. But first things first: (SPR) biosensor. This system, based on an optical
To fight a disease, first we need to find it. phenomenon discovered between 1902 and 1912, was
Early, accurate and informative diagnosis is essential first sold as an analytical technology in 1990. After
for selecting the most appropriate therapy and admin- 30 years, SPR biosensors have emerged as routine
istering it in time. Rapid identification of an infectious analysis platforms in many research and pharma-
outbreak is crucial to stem an epidemic; early-stage detec- ceutical laboratories, commercialized worldwide.
tion of cancer holds extreme importance for treatment Importantly, they have served as a solid foundation
response and patient survival. Clinical diagnosis thus for the investigation and development of new nano-
must evolve even more to incorporate new methods and photonic technologies that move beyond existing
technologies that enable rapid, simple screening of the biosensors and expand their capabilities.
population, to detect diseases before their physical onset. Yet, despite the impressive ability for nanoscale
These new diagnostic techniques will need to identify control and the vast knowledge and expertise in bio-
remote biological disorders that might carry pathologi- analysis that have arisen in recent years, the optimum
cal consequences—providing information about the nanophotonic biosensor for point-of-care clinical diag-
disease stage and severity, and the most promising nosis has remained elusive. Where do the limitations
drug or treatment candidates. And, ideally, diagnostic lie—and why have optical biosensors been slow to make
systems should be small, portable devices that can be their way into the clinic?
employed directly by those who need it: physicians, In this feature, we overview some of the latest
pharmacists or the patients themselves. advances in nanophotonic technologies for biosensing,
the main challenges and limitations, and current pros-
Photonic biosensors: SPR and beyond pects. We will also look at some promising applications
One of biomedicine’s best assets in this endeavor is of nanophotonic sensors in biomedicine, highlighting
biosensors. These are self-integrated devices that use their unique capabilities and their potential to revo-
specific biorecognition elements—such as antibodies, lutionize clinical diagnosis and general healthcare in
DNA strands or enzymes—to capture and detect a the near future.

26 OPTICS & PHOTONICS NEWS APRIL 2020

1047-6938/20/04/24/8-$15.00 ©OSA
 Photonic biosensors exploit light’s unique properties to
realize some of the more sensitive, robust and reliable sensing
platforms currently available.

The evanescent field and its sensitivity

Most common optical biosensors are based on the
so-called evanescent-field principle, generally using
nanoplasmonics and silicon-photonics nanotechnology.
Evanescent-field biosensors can detect biomolecular inter-
actions occurring at the sensor surface, in real time and
without labels or dyes, thereby offering a rapid, simple
and noninvasive technique for studying biochemical
processes or quantifying analytes.
Plasmonic biosensors employ nanometer-sized metal-
lic films or nanostructures (mainly gold), which absorb
incident electromagnetic radiation and excite coherent
electron resonances (surface plasmon polaritons) at
the surface. This resonance can either propagate along
the thin film (propagating SPR) or be confined to the
vicinity of the nanoparticle (localized SPR, or LSPR). A nanoplasmonic sensor
Either way, it generates a strong near-field enhance- Example of a nanoplasmonic biosensor that uses a surface
ment that penetrates a few nanometers (10–500 nm) dotted with gold nanodisks. Courtesy of the authors
into the surroundings.
This evanescent field is highly sensitive to refrac-
tive-index variations in the medium. Thus, a change event (for example, an antibody–antigen interaction)
of composition or mass at the metal–dielectric inter- provides quantitative information about both the
face translates directly to a variation of the intensity, molecule’s concentration and the affinity and kinetic
wavelength, angle or phase of the light. The real-time parameters of the biomolecular interaction.
interrogation of such variations during a biorecognition The detection limit for nanoplasmonic biosensors
ranges from 10 –5 to 10 –7 refractive-index units (RIU),
equivalent to detection at the nanomolar (nM) level for
biomolecular analysis. Demonstrations in recent years
Comparison of state-of-the-art
have highlighted the great analytical performance
nanophotonic biosensors
of these biosensors, with an exponential increase of
RI detection Mass detection publications and patents of new sensing systems for
Biosensor limit (RIU) limit (pg/mm2) disease diagnostics. These systems can detect proteins,
Nanoplasmonics 10 –5–10 –7 0.1–1 nucleic acids and pathogens in a few minutes, without
Grating couplers 2×10 –6 0.3 the need of fluorescent or colorimetric tags—and with
high accuracy.
Micro-ring resonators 10 –5–7×10 –7 1.5–3
Photonic crystals 10 –5 0.4–7.5 From plasmonics to silicon photonics
Mach-Zehnder interferometer 10 –7–2×10 –8 0.01–0.06 For detecting very low amounts of biomarkers, how-
Young interferometer 6×10 –9×10
–8 –9
0.01–0.75 ever, the sensitivity of nanoplasmonic biosensors can
Bimodal waveguide interferometer 10 –8 0.01 be limited—or they can require light-coupling schemes
that complicate their integration and miniaturiza-
Silicon wires 2×10 –6 0.25
tion. In these cases, silicon-nanophotonics technology
Slot waveguides 10 –6 0.9–16
may offer a powerful alternative. Biosensors based on

APRIL 2020 OPTICS & PHOTONICS NEWS 27

 The bimodal waveguide (BiMW) technology devel-
oped by the Nanobiosensors and Bioanalytical
Applications Group in Barcelona is one example
of an interferometric biosensor.
Olalla Calvo-Lozano

biomolecular markers in the picomolar to attomolar

(pM–aM) range without any labelling or amplification
steps. Moreover, the use of silicon technology implies
an intrinsic potential for producing photonic integrated
circuits (PICs) for possible incorporation into miniatur-
ized lab-on-a-chip (LOC) sensing systems.
silicon resonators or waveguides also work through At the level of the lab, evanescent-field-based bio-
an evanescent-field principle, and in some cases their sensors have shown the analytical and technological
sensitivity can outperform that of their nanoplasmonic capabilities to become the next-generation diagnostic
counterparts by more than two orders of magnitude. systems—they have demonstrated excellent performance
In particular, interferometric sensors today constitute and versatility, achieved outstanding detection limits,
the most sensitive technology available, with detec- and shown promise for label-free, real-time analysis
tion limits of up to 10–8 RIU. These sensors consist of a of all types of clinical biomarkers. Clinical settings,
waveguide that is partly exposed to a sensing area and though, demand “black box” devices that can operate
partly used as reference. The evanescent field generated in point-of-care settings with the same accuracy and
along the waveguide probes the refractive-index changes reliability as in the lab. It’s a significant challenge—how
occurring at the sensing area, producing a difference do we get there?
in the phase of the light. When recombined, the inter-
ferometric signal obtained can be correlated with the Engineering compact,
analyte concentration, as with nanoplasmonic sensors. ready-to-use biosensors
Interferometric biosensors have also been applied In one sense, the answer is simple: Miniaturize every-
in clinical diagnostics, showing sensitivities for thing—but also automate it, simplify it and make it
clinically reliable. But, as always, the devil is in the details.
The objective of point-of-care diagnostic biosen-
sors is fully operational, portable devices that can be
readily employed by end-users. Biosensors in clinical
settings must analyze human samples like blood or
urine directly, without pretreatment, providing unam-
biguous responses about the levels of specific molecules
with an exquisite accuracy, selectivity and reproduc-
ibility. Multiplexed assays—the simultaneous detection
of different markers from the same sample—are also a
requirement for rapid, truly informative diagnostics.
To meet these demands, research in
nanophotonic biosensors has expanded
to include integration with aspects
of the systems that contain them.

Advanced microfluidic systems

Pumping
Examples of nanophotonic system Microfluidics engineering has
biosensors integrated in evolved tremendously over the last
microfluidic systems. Nanophotonic
sensor decade, in part thanks to progress in
Top: Courtesy of the authors / Right: Waste
Courtesy of Microfluidic ChipShop GmBH reservoir micro- and nanofabrication techniques

28 OPTICS & PHOTONICS NEWS APRIL 2020

The objective of point-of-care diagnostic biosensors is fully
operational, portable devices that can be readily employed
by end-users.

that enable production of miniaturized polymer car-

tridges providing full and automated control of fluid
transport. The latest microfluidic systems include Toward personalized therapies

T
hydraulic or pneumatic valves that can control multiple he design of novel diagnostics based on
channels; microreactors; integrated pumps and waste nanophotonic sensing technology is open-
reservoirs; and other elements. ing new avenues for personalized medicine.
Optical label-free biosensors for direct, real-
These LOC devices can be automated and remotely
time analysis of biomolecular interactions can
controlled by software, which dramatically mini-
be further exploited in biomedical research to
mizes sample handling and manipulation by the boost the development of precise and individual-
user and scales down the biosensor system’s overall ized therapies for serious diseases, like cancer
footprint. Other strategies for on-chip fluid manipula- or autoimmune disorders, and to facilitate the
tion take advantage of capillary action and material’s widespread administration of such personalized
approaches.
hydrophilicity; centrifugal forces (as in the case of
Recent efforts have started to address this
compact-disc microfluidics); or even electrochemistry complex but far-reaching goal. Nanophotonic
(in digital microfluidic systems). The latter is espe- biosensors have been already described for the
cially interesting, since it enables fluid transportation label-free analysis of cell regulation pathways,
and mixing using nanoliter-volume droplets, which as well as for so-called epigenetic alterations,
such as DNA methylation or alternative splic-
dramatically reduces the sample volume required
ing events. Such events have been suggested as
for the analysis.
potential targets for the earliest possible detec-
tion of tumor-initiating processes as well as for
Integration in handheld devices
precision therapeutics. Direct, label-free analysis
Current research also focuses on the integration of of such genomic disorders in pre-tumor cells
all optical components into miniaturized platforms, affords an opportunity for developing population-
and their transfer from laboratory optical tables to screening techniques with diagnostic, prognostic
small, portable devices. Replacing lasers, microscopes and therapeutic information outputs that could
substantially reduce the cancer burden.
and spectrometers by LEDs and CMOS detectors can
Likewise, optical label-free biosensors
allow compact devices with reasonable performance have been reported as potential alternatives
to be realized. for live-cell analysis, which could facilitate
Here, optical-biosensor development has exploited implementation of novel personalized can-
the breakthrough of extremely powerful smartphones. cer treatments. Recently discovered cell-based
immunotherapies, like the CAR-T cell therapy,
Nanoplasmonic sensors have been adapted to employ
might greatly benefit from devices able to achieve
the flash LED lights and the high-quality cameras of
single-cell sensitivities and to monitor, in real
commercial smartphones for operation as simple external time, the activity of bioengineered immune cells
accessories. Although these devices can’t boast the ana- without labelling or staining. Such
lytical sensitivity of conventional laboratory platforms, nanophotonic biosensors,
they offer the promise of truly portable point-of-care if realized, could help
bring down currently
diagnostic systems.
exorbitant treatment
Solving and simplifying in-coupling of light for costs and speed up
these compact platforms, and providing high-through- the administration of
put readouts from them, remain ongoing challenges. powerful immuno-
Imaging 2D microarrays at relatively large scales often therapies to cancer
patients worldwide.
results in crosstalk issues or low signal-to-noise ratios.
In waveguide-based biosensors, for example, coupling

APRIL 2020 OPTICS & PHOTONICS NEWS 29

 M. Cruz Cardenosa-Rubio (left) and Olalla Calvo-Lozano
(right) working with a small benchtop SPR system
developed in the laboratory.
Maria Soler

macromolecules, synthetic polymers and 2D materi-

als could offer interesting alternatives to serve as the
interface for bioreceptor immobilization.
Finally, the “nightmare scenario” of evanescent-
field biosensors working in label-free format—and, yet,
a key ultimate goal of such sensors—is direct analysis
of human samples, like blood or urine. The large con-
the light from macrometric sources to multiple submi- centration of non-relevant molecules present in these
cron waveguides in parallel is an arduous task. fluids, together with the huge variability of samples
To get past these problems, new nanophotonic from different patients, generally results in false-positive
designs incorporating gratings, photonic crystals or or false-negative analytical results. The solution to this
integrated tapers, which may offer an efficient and challenge may lie in combining efficient anti-fouling
cost-effective solution, should be investigated and imple- surface coatings with integrated on-chip sample pro-
mented in the sensor fabrication process. Also worth cessing (for example, filtration membranes) that could
researching could be data processing and machine be automated to ensure a rapid, reliable analysis.
learning, to enhance the acquisition and use of opti-
cal signals by boosting the signal-to-noise ratios and Toward accurate, informative
minimizing crosstalk for multiplexed assays, thereby and early diagnosis
providing fast, clear and precise information for the The vast majority of the clinical diagnosis applications
clinical diagnosis. developed for optical biosensors target the quantifica-
tion of disease-specific circulating biomarkers. Classic
Surface chemistry and sample treatment
examples are the detection of C-reactive protein (CRP)
Surface biofunctionalization is crucial in biosensor and cytokines, like interleukins or interferons, for inflam-
development. To achieve high detection sensitivity, matory disorders, or of the carcinoembryonic antigen
selectivity and reproducibility, the target bioreceptor (CEA), the prostate specific antigen (PSA) and the p53
must be appropriately anchored to the sensor trans- protein (among others) for cancer diagnosis. Also, DNA
ducer. Parameters such as the receptors’ density and mutations of specific genes, like BRCA1 and BRCA2,
orientation and the anti-fouling properties of the sens- have been extensively targeted for the detection of
ing surface must be carefully controlled to enhance breast cancer. Still other optical biosensors, developed
the biosensor’s analytical performance and ensure its for infectious diseases, often target direct detection
operational reliability. and identification of the pathogen, such as the bacteria
Numerous surface-chemistry strategies—such as Escherichia coli or Staphylococcus aureus.
covalent binding to functional monolayers of alkane- Recently developed photonic biosensors aim at still
thiols or silanes, or employing affinity-ligands such as more advanced and improved diagnosis, targeting
the biotin–streptavidin pair—are widely used to accom- novel biomarkers for accurate, early disease detection
plish these goals. However, these procedures need to and providing specific information related to prognosis
be optimized for each specific application, depending and optimum therapy. We close this feature by looking
on the nature, size and properties of the bioreceptor at a number of areas where nanophotonic biosensors
and the target analyte. Some new research perspectives could help change the game.
envision overcoming those pitfalls through a universal-
surface chemistry strategy, suitable for the detection of MicroRNAs. MicroRNAs are small, non-coding nucleic
different types of biomarkers, like proteins, nucleic acids acids that circulate in body fluids in very low con-
and pathogens. The development of multifunctional centration, but whose specific levels are strongly

30 OPTICS & PHOTONICS NEWS APRIL 2020

Nanophotonic biosensors are fast becoming a versatile,
powerful technology with exceptional potential for upgrading
diagnostics—and improving global health care and well-being.

associated with pathological disorders. Direct detec- resistance, giving clues for the correct treatment. Here,
tion and quantification of microRNA panels with ongoing research has already achieved significant
multiplexed optical biosensors could become a highly results. Nanophotonic biosensors have been reported
precise screening technique for the early diagnosis for bacterial analysis (for example, for S. aureus) with
of several cancers. limits of detection between 4 and 10 colony-forming
Some first steps have already been made toward that units (cfu) per milliliter. These sensors can even
goal. A bimodal waveguide (BiMW) interferometric sen- accurately differentiate methicillin-resistant (MRSA),
sor has achieved ultrasensitive detection of such small methicillin-susceptible (MSSA) and borderline oxa-
nucleic-acid chains, identifying microRNA-181 in urine cillin-resistant (BORSA) S. aureus strains in less than
of bladder cancer patients, with a limit of detection of 20 minutes. Other reported nanoplasmonic sensors
only 23 aM in less than 20 minutes in a direct assay. can work in multiplex format, identifying two or more
Micro-ring resonator arrays have also been employed different bacteria species.
for the multiplexed analysis of eight microRNAs from
surgical glioma cells. Routine monitoring. Finally, portable, user-friendly point-
of-care biosensors might be very interesting for routine
Autoantibodies. Likewise, new protein biomarkers therapy monitoring and follow-up. Nanoplasmonic
have been described for early cancer diagnosis. Solid biosensors have been developed for monitoring of the
tumors in particular, like lung, breast or colorectal drug acenocoumarol, an anticoagulant employed for
cancer, can trigger immune reactions in the patient, thromboembolic disorders, and for adalimumab, pre-
releasing specific antibodies into the bloodstream. scribed for Crohn’s disease, as well as for follow-up on
These so-called autoantibodies appear and increase gluten-free diets for patients with celiac disease.
their levels at the initial stages of tumor development, As these examples suggest, nanophotonic label-
even before the physiological onset of the illness. free biosensors are fast becoming a versatile, powerful
Nanoplasmonic biosensors have recently been devel- technology with exceptional potential for upgrading
oped to target different cancer-related autoantibodies, diagnostics—and thereby improving global health care
achieving adequate limits of detection in serum and and well-being. OPN
plasma samples.
Maria Soler, Olalla Calvo-Lozano, M.-Carmen Estevez, and
Bacterial detection. Infectious-disease diagnosis could OSA Fellow Laura M. Lechuga (laura.lechuga@icn2.cat) are
with the Nanobiosensors and Bioanalytical Applications
present still another opportunity for optical label-free
Group, Catalan Institute of Nanoscience and Nanotech-
biosensors. Bacterial infections, if not promptly identi- nology, Barcelona, Spain.
fied and suitably treated, can be extremely dangerous,
in some cases even ending with a sepsis shock, in which
the infection rapidly spreads to the whole body, a fatal References and Resources
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