REVIEW
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Tattoo Inks for Optical Biosensing in Interstitial Fluid
Martalu D. Pazos, Yubing Hu,* Yuval Elani, Kathryn L. Browning, Nan Jiang,
and Ali K. Yetisen
The persistence of traditional tattoo inks presents an advantage for
continuous and long-term health monitoring in point of care devices. The
replacement of tattoo pigments with optical biosensors aims a promising
alternative for monitoring blood biomarkers. Tattoo inks functionalization
enables the control of interstitial biomarkers with correlated concentrations in
plasma, to diagnose diseases, evaluate progression, and prevent
complications associated with physio pathological disorders or medication
mismatches. The specific biomarkers in interstitial fluid provide a new source
of information, especially for skin diseases. The study of tattoo inks displays
insufficient regulation in their composition, a lack of reports of the related
complications, and a need for further studies on their degradation kinetics.
This review focuses on tattoo optical biosensors for monitoring dermal
interstitial biomarkers and discusses the clinical advantages and main
challenges for in vivo implantation. Tattoo functionalization provides a
minimally invasive, reversible, biocompatible, real-time sensing with
long-term permanence and multiplexing capabilities for the control,
diagnosis, and prevention of illness; it enables self-controlling management
by the patient, but also the possibility of sending the records to the doctor.
1. Introduction
Tattoos are a ubiquitous mode of self-expression, with a preva-
lence in European and American population around 12% and
24%, respectively.[1] Optical biosensors in the last decade have
M. D. Pazos, Y. Hu, Y. Elani, A. K. Yetisen
Department of Chemical Engineering
South Kensington Campus
Imperial College London
London SW7 2AZ, UK
E-mail: yubing.hu@imperial.ac.uk
M. D. Pazos, K. L. Browning
Leo Foundation Center for Cutaneous Drug Delivery
Department of Pharmacy
Copenhagen University
Copenhagen 2100, Denmark
N. Jiang
West China School of Basic Medical Sciences & Forensic Medicine
Sichuan University
Chengdu 610041, China
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/adhm.202101238
© 2021 The Authors. Advanced Healthcare Materials published by
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution License, which permits use, distribution
and reproduction in any medium, provided the original work is properly
cited.
DOI: 10.1002/adhm.202101238
Adv. Healthcare Mater. 2021, 2101238 2101238 (1 of 21) © 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH
developed extensively in different fields,
including therapeutics, environment, and
security.[2] Placing a sensor inside the der-
mis as a tattoo to be in contact with in-
terstitial fluid (ISF) represents a power-
ful platform for continuous monitoring of
biomarkers reducing environmental inter-
ferences and the use of optical biosensors
avoid the necessity of electrical power nor
recharging.
Among the applications of function-
alized tattoos are the monitoring of dif-
ferent physiological biomarkers such as,
glucose,[3] sodium,[4] albumin,[5] oxygen,[6]
cortisol,[7] lactate,[8] pH,[9] nucleic acids[10]
but also external ones such as environ-
mental contaminants[11] or toxic food
additives.[12] Functionalized tattoos are pos-
sible to release drugs,[13] vaccinate,[14] and
also monitor levels of alcohol ingested,[15]
body temperature,[16] electrocardiogram
measurements,[17] prevention of sun
overexposure,[18] and even incorporate
identity documents or credit card details
into our skin.[19] Functionalized tattoos for ISFs sensing provide
effective solutions to monitor and record the evolution of a pa-
tient’s disease with the capability of multiplexing, a considerable
advantage in metabolic diseases such as diabetes where more
than one parameter is normally unbalanced, like pH and glucose.
Preventing future complications means an improvement in per-
sonal quality of life and economic savings for society.
1.1. Tattoos and Ink Composition
Tattoos can be classified as either i) temporary (e.g., transfer tat-
toos, henna, or Genipa Americana), ii) semi-permanent (e.g.,
make-up); and iii) permanent tattoos. The first electric tattoo ma-
chine was designed by Thomas Edison in 1877 (Figure 1A) who
was trying to design an electric pen,[20] there were no significant
advances to modern machines. Tattoo machines can be classi-
fied into three types: Coil, rotary, and pneumatic.[21] The tattoo
needle is an aggrupation of individual needles, and they can be
classified into two groups: Lines or shadows. The needles have
their nomenclature according to the needle diameter, number of
needles grouped, and their configuration (Figure 1A).[20–22] The
location, depth, and inclination of the sensor injection are man-
aged with the tattoo needle. The sensor is dispensed on the skin’s
surface, the needle creates a hole in the skin and, when the nee-
dle is removed, the vacuum generated forces the ink into the
hole. Tattoo pigments are injected into the dermis between 0.4
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Figure 1. Tattoo machines, needles, and inks. A) Types of tattoo machines and tattoo needles 1. Tomas Edison’s patent No.196747 for his electric pen
from 1877. Reproduced with permission.[23] Copyright 1877, United States Patent Office 2. Dual-coil tattoo machine 3. Rotative machine 4. Pneumatic
machine A-Tip, B-Needle, C-Tube, D-Grip, E-Energy system: Coil/rotative motor/air piston, F-Armature bar, G-Contact screw 5. Needle types RL-Round
liner, RS-Round shader, F-Flat, and M-Magnum M1 weaved, M2 double-stacked, MR curved. B) Composition of tattoo inks.

and 2.2 mm in depth; the ideal penetration depth is 2.0 mm as
shallower injection rapidly fades while deeper penetration dam-
ages the subcutaneous tissue.[9]
Tattoo inks are a dispersion of insoluble pigments in a liquid
composed of solvents and additives (Figure 1B). Dyes are un-
suitable for tattoo inks as they are soluble and degradable. Pig-
ments are insoluble and widely used in tattoo ink dispersions,
they can be classified as organic, inorganic, and carbon black.
All pigments are impure; inorganic pigments tend to contain
heavy metals; organic contain primary aromatic amines (PAAs)
and carbon black pigments have polycyclic aromatic hydrocar-
bons (PAHs). Other impurities include formaldehyde, parabens,
and isothiazolinones.[24] Dispersions are thermodynamically un-
stable systems leading to separation of the phases and sedimen-
tation of the solid phase. Suitable inks must contain particles
that do not sediment too quickly and the solvent, usually water,
must not be too volatile as to dry before administration. Exam-
ples of other solvents that can be added to water to modify the
drying properties, to mask odors, and to increase the ink’s wet-
ting, viscosity, and dispersibility include glycerin, propylene gly-
col, and simple and polyvalent alcohols. They are use in low con-
centrations to avoid skin irritation. Additives correct unwanted
features; their concentration must not be higher than 5% of the
ink.[25] The binders keep pigment particles together after drying,
making the injection of the ink into the skin easier; an example
is the polyvinylpyrrolidone.[25] Surfactants are added to decrease
surface tension between the particles and the fluid phase, an ex-
ample is nonylphenol. Inks are usually stored for a long time,
causing sedimentation of the pigment. To minimize settling, ad-
ditives to increase the viscosity and thixotropy are also needed,[26]
an example of a thickening agent is hydroxyethylcellulose. Fillers
like barium sulphate are inorganic substances that add volume
to the tattoo ink, creating a re-dispersible porous structure which
improves storage properties. It is preferable to form flocculated
systems rather than agglomerates for long-term storage of inks;
the flocculated particles are porous and easy to redisperse since
they are weakly bound.[25] As the ink is mostly water, the probabil-
ity of microorganism contamination is high and it is reduced by
using preservatives, like parabens. Ink producers offer the same
colorant for more than one field (plastics, prints, clothes), there-
fore, tattoos inks use pigments that have not been produced to
be introduced into the dermis.[27] Tattoo pigments do not con-
sistently respect the purity and heavy metal maximums set out
in the European Union Resolution ResAP (2008) 1 developed
by the Council of Europe, the document that currently guides
the security of tattoo inks and permanent make-up (PMU) in
Europe.[28] This resolution should be translated into national leg-
islation, however, only ten EU countries have adopted it.[24,27,28]
Most European countries forbid to use of ingredients listed in An-
nexes II and IV of the European Commission (EC) No. 1223/2009
on Cosmetic Products[29] because they are carcinogenic, muta-
genic, reprotoxic, or sensitizing. Manufactures use the preserva-
tives included in Annex V of EU-Regulation 1223/2009 for cos-
metic products, however, there are preservatives allowed in the
list that should be avoided in tattoos, like mercury-containing
preservatives or formaldehyde-releasing substances.[30] Although
some countries do not have national legislation, the producers
have to demonstrate the safety of their components, controlled

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Figure 2. Chemical components of tattoo pigments. A) Percentage of Ti, Al, Si, Cu, Cr, Fe, Cl, S, C, O, and Mg of 10 different colors from the tattoo
ink suppliers: Huck Spaulding Enterprises Inc., Voorheesville, NY and Eberhard Faber Inc., Lewisburg, Tenn. Quantitative electron X-ray microanalysis
by energy-dispersive spectrometry. Reproduced with permission.[31] Copyright 2001, American Medical Association. B) Composition in μg g−1 of the
metals Cd, Co, Cr, Hg, Mn, Ni, Pb, Sr, V, and in mg g−1 of the metals Al, Ba, Cu, Fe, Sb of 7 different colors from the tattoo ink suppliers: Starbrite-
Colors, Millennium Colorworks Inc., Intenze Prod. and Diabolo by Deep Colors. Sector Field Inductively coupled plasma mass spectrometry. Limits of
quantification from 0.07 to 10 ng mL−1 , Hg was in traces. Reproduced with permission.[34] Copyright 2009, Elsevier.

by the General Product Safety Directive (Directive 2001/95/EC);
to follow the labelling demands and registration of chemi-
cals via CLP (Classification, labelling, and packaging) (EC No
1272/2008); and to respect the requirements of registration for
the REACH regulation (Regulation, evaluation, authorization
and restriction of chemicals) (EC No 1907/2006).[24] A study of
the Joint Research Center (JRC) of the EC in 2016 proved the vio-
lation of safety limits set by the ResAP(2008)1 by different tattoo
brands in Europe. After JRC results, in 2019 the European Chem-
ical Agency (ECHA) proposed a new annex of restrictions on tat-
too inks and PMU compositions, evaluated by the Committees
for Risk Assessment (RAC) and Socio-Economic Analysis,[24] it
constitutes a common European advance toward a European leg-
islative framework. The absence of coordinated analytical proce-
dures, guidelines for risk assessment, and good manufacturing
practice requirements, causes that banned components such as
aromatic amines, formaldehyde, or benzothiazolinone can be de-
tected in tattoo inks.[29]
The most common elements in tattoo ink composition are oxy-
gen, titanium, and carbon, contained in 73%, 67%, and 67% of
pigments, respectively.[31] However, the quantitative electron X-
ray microanalysis by energy-dispersive spectrometry does not re-
liably identify the presence of elements with an atomic number
lower than 11, like oxygen. Inorganic titanium dioxide (TiO2 ) pig-
ments have a high refractive index, so they scatter light very ef-
fectively; they are used for lightening colors or as white ink (Fig-
ure 2A). Organic pigments are sorted into two main classes: 1)
Azo compounds which contain the group R–N = N–R” and 2.

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Figure 3. Transmission electron microscopy images of the tattoo inks in the dry state. A) Red: Azocompound, B) Blue: TiO2 and Cu-phthalocyanine,
C) Green: TiO2 , carbon black, Cu-phthalocyanine and azocompound, D) Orange: Azocompounds, E) Violet: TiO2 and azocompound, F) Black: Carbon
black, G) Intense green: TiO2 , Cu-phthalocyanine, and azocompound, H) Dark brown: Carbon black and iron oxides, I) Pure black: Carbon black. Solvents
used: Water and glycerin (A–C,G,H,I) and water, isopropyl alcohol, and glycerin (D–F). Magnification scales: A,F) 100 μm, G) 200 μm, and B–D,E,H,I)
500 μm. Ink suppliers: Millennium, Starbrite, and Intenze. Reproduced with permission.[32] Copyright 2017, The Royal Society of Chemistry.

polycyclic compounds which are composed of linked aromatic
rings (except for triphenylmethane) possessing a chromophore
through conjugated pi-bonding systems.[25,32] Carbon black pig-
ments result from the partial burning of heavy petroleum com-
pounds, they usually contains PAHs impurities.[25] Inorganic
pigments often contain heavy metals impurities (Ni, Cr, Cu, and
Co) from iron oxides while organic pigments contain less impu-
rities being the mercury salts, cadmium salts, chromium oxide,
and cobalt oxides the main sensitizing components. Modern inks
reduced their content on these substances but still maintaining
other impurities.[33] The primary metals found in tattoo inks were
Al, Cu, Fe, and Ti.[28,33,34] In a sample of 56 inks, allergenic metals
like Cr and Ni surpassed the maximum of 1 ppm in 62.5% and
16.1% of the inks, respectively (Figure 2B),[34] as well as, other
toxic elements like Cd, Mn, Pb, Sb, and V. Trace amounts of Hg
were also detected.[34] Analyzing or comparing inks” composition
is complicated by the massive variation between brands, includ-
ing inks with equal base color.[27,32,34] Inks also contain carcino-
genic impurities, it is necessary to develop methods that mimic
the effects of ink persistence in the tissue.[27]
The size of tattoo particles ranges from 5 nm to more than
1 μm;[32] therefore, inks contain nanoparticles (NPs) and micro-
particles. NPs are often highly reactive as they possess a high sur-
face to volume ratio and can pass membranes, be transported in
the blood, and enter tissue cells causing oxidative stress, inflam-
mation, and apoptosis.[35] Carbon black particles start in the man-
ufacturing process with a size of 15–300 nm, but quickly form ir-
reversible agglomerates of 1–100 μm.[25,32] The tattoo particles ob-
served with transmission electron microscopy (TEM) (Figure 3)
were irregular with different shapes, forming agglomerates, ag-
gregates, and precipitates of organic pigments, as shown in Fig-
ure 3A for a precipitate of a red azocompound. The lowest pres-
ence of metallic NPs was found in white pigments, mainly com-
posed of TiO2 forming clusters as shown in Figure 3B,C,E,G.[32]
Characterizing the size of tattoo particles is essential to deter-
mine the size of optical sensors in tattoo functionalization. The
persistence of tattoos in the dermis is determined by the size of
the pigment. The sensors should mimic the commercial tattoo
pigments,[18] being small enough to avoid surgical procedures
but large enough to avoid diffusion from the implantation site.
Combining different techniques provides a complete measure-
ment of the ink particles’ size (Table 1). TEM provides the median
diameter ± median absolute deviation, DLS the mean hydrody-
namic diameter (Dh ) and range, however, it cannot differentiate

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Table 1. Size, size distribution and percentage of ink particles <100 nm; Transmission electron microscopy (TEM), dynamic light scattering (DLS),
asymmetrical flow field-flow fractionation with quantification by multiangle light scattering (AF4-MALS), and single-particle inductively coupled plasma
mass spectrometry (SP-ICP-MS); Ink suppliers: Millennium, Starbrite, and Intenze; Reproduced with permission.[32] Copyright 2017, Journal of Analytical
Atomic Spectrometry.

Ink Diameter median Hydrodynamic Diameter of SP-ICP-MS

TEM nm diameter (Dh ) gyration (Dg )
DLS nm AF4-MALS nm
Diameter mean nm Particles <100nm%

B. Blue 170 ± 64 421 (110–980) 84 (32–130) CuH2 Pc 109 ± 17 65

538 (120–980) Al2 O3 183 ± 11 Undetectable
TiO2 441 ± 161 0
E. Violet 39 ± 10 31 (19–52) 112 (22–200) TiO2 427 ± 97 0
And larger particles 137 (60–281) 542 (200–980)
(100–450)
F. Black 19 ± 11 152 (49–450) 274 (42–660) CuO 109 ± 19 67
G. Intense 162 ± 51 277 (81–1350) 92 (26–112) CuH2 Pc 110 ± 17 63
green 810 (100–2400) Al2 O3 466 ± 179 Undetectable
TiO2 109 ± 17 0

small particles if there are aggregates in the sample, explaining Table 2. Differences in thickness, turnover cell time and in vitro model
the lack of concordance between the average diameter provided similarity between human, pig, rat, and mouse; Similarity indicates the
percentage of agreement of each animal model with the human studies.
by TEM and DLS (Table 1). The polydispersity index of tattoo inks Reproduced with permission.[38,39] Copyright 2012, 2001, Beilstein Journal
ranges from 0.15 to 0.43; therefore, inks are not uniform in their of Nanotechnology, Wound Repair Regen.
composition.
AF4 fractionation separates samples into different sizes and Feature Human Pig Rat and mouse
MALS provides the mean gyration diameter (Dg ) and range, the
Epidermis thickness (mm) 50–120 30–140 10–45
combination AF4-MALS detected a new group of NPs in the blue
and green inks. Blue, violet, and green inks had a bimodal parti- Epidermis turnover (days) 27 30 9

cle distribution (Table 1).[32] Spheres have a Dg and Dh (Dg /Dh )
ratio of 0.775, black inks are not spherical as 274/152 = 1.80, TEM
images Figure 3F,I further support this structure.[32] SP-ICP-MS
provides the percentage of particles <100 nm, 67% of the NPs in
the black ink were CuO whereas Figure 3 showed the composi-
tion of black inks was mainly carbon black pigment, this can be
explained because SP-ICP-MS only measures metal-based NPs,
like CuO, and the TEM image in Figure 3F presents unidentified
particles that could be CuO.
1.2. Tattoo Skin Model and Biokinetics
Skin is a barrier for environmental conditions, provides sensory
information and maintains homeostasis. It is formed by three
layers: the epidermis, the dermis, and the hypodermis. The tat-
too sensor is inserted in the dermis layer which consists of a layer
of collagen, elastane filaments and glycosaminoglycans with fi-
broblasts, which have a structural and healing function, defen-
sive macrophages, and storage adipocytes.[36] Skin can be used
as a sensing platform for stimulus from muscles, blood vessels,
free nerve endings, stratum corneum, sweat glands, and ISF. The
location on the body’s anatomy, ethnicity, age, sexual hormonal
influence, climate, and diet leads to varying skin features.[36,37]
Porcine skin is usually used for ex vivo experiments due to its
similarities (Table 2) with human skin, however, the vasculariza-
tion of the human dermis is more complex, and pigs lack eccrine
sweat glands. The porcine model agrees with human studies in
Stratum corneum thickness (cell layers) 15–25 10–25 5
Stratum corneum turnover (days) 17 16 1
Model similarity (%) 100 78 53–57
78%, while the rodents and in vitro studies agrees in 53% and
57%, respectively.[38] Ex vivo experiments use lateral injections to
imitate the post-healing tattoos and vertical injections to imitate
the tattooing mechanism itself, showing the effect of injection
depth on the sensor visibility.
Due to the close contact between ISFs, blood and lymph flu-
ids during the invasive tattoo process, tattoo inks are regarded
to be 100% bioavailable.[25,40,41] The small and/or soluble par-
ticles in the ink formulation are absorbed into the blood or
lymph vessels and are distributed into different organs where
they can be stored or eliminated. The large and/or insoluble
particles that cannot be absorbed and distributed are stored in
the vacuoles called melanosomes from the cytoplasm of dermal
macrophages.[42] Not all ink components are inert, some can be
metabolized by the cytochrome P450-dependent monooxygenase
enzymes CYP or nitro-reductases;[28] tattoo inks only undergo
first phase metabolism.[40] Sun exposure of the tattoo causes pho-
tolysis of the pigments and lightening of the tattoo.[43] Pigments
can be removed by four mechanisms: 1) by bleeding during the
tattoo or healing processes, 2) by the lymphatic or blood vessel
system, 3) by enzymes, 4) by light sources.[40]

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Figure 4. Tattoo persistence. A) Cycle of capture–release–recapture of the tattoo ink by the macrophages in the skin. 1) Photo of a macrophage with
ink inside. 2) Photo of a new macrophage entering the cycle. Reproduced with permission.[44,45] Copyright 2018, Rockefeller University Press. Scale bar,
10 μm. B) 1) Macrophage with the tattoo pigment inside ready for diphtheria toxin (DT) treatment. 2) Pigment free in the extracellular matrix after 2 days
of DT treatment. 3) Recapture of the pigment by a new macrophage after 90 days of DT treatment. Reproduced with permission.[44] Copyright 2018,
Rockefeller University Press. Macrophages from the tail of CD64dtr mice. Bar = 10 μm.

1.3. Tattoo Persistence and Removal
Each time the needle penetrates, it makes a wound that activates
the inflammatory process and recruits immune cells to repair the
skin and clear the foreign material. The persistence of tattoos can
be explained by macrophages” physiological ability to ingest and
store melanin pigment. The ink particles do not have a homo-
geneous size; macrophages ingest the small particles and elim-
inate them through the lymphatic system while larger particles
remain suspended in the extracellular dermis matrix or are col-
lected by macrophages that cannot break them down due to their
size and remain stored in macrophages” cytoplasmic vacuoles.[44]
When the macrophage dies, the pigment is released and recap-
tured by the new generation of macrophages (Figure 4A). Tattoo
pigments can go through consecutive cycles of capture–release–
recapture without any tattoo elimination.[45] It is possible to iden-
tify the location of the pigments using flow cytometry, as un-
tattooed skin scatters less light.[44] Other theories suggest that
tattoo persistence depends on macrophage longevity more than
macrophage renewal[42] since the skin’s melanophages have the
slowest turnover timescales.[45]
Diphtheria toxin (DT) selectively kills cells with the marker
CD64, which includes all dermal monocyte-derived and
macrophage cells.[45] Two days after toxin exposure, the
macrophages with stored tattoo ink die and release the pig-
ment, which can be observed free in the extracellular dermis
matrix (Figure 4B). 90 days after toxin exposure, the bone marrow
creates monocytes to replace the dead macrophages; these cells
have the same phenotype as those of green macrophages pre-DT
intoxication and they recapture the ink, supporting the pigment
capture–release–recapture theory. The macroscopic appearance
of the tattoo does not change during this process. This model
explains the difficulty of tattoo removal. Lasers heat the particle
and before the particle distributes the heat around its surface,
the laser repeats the pulse, and the particle deforms and breaks
into smaller particles. Lasers also lyse the macrophages.[44,46]
The pulse duration must be briefly than the thermal calm time
of the ink particles, for example, nanoseconds. The smaller
pigment particles are removed by dermal macrophage cells and
lymphocytes through the lymph nodes in the weeks following
each laser procedure, therefore, it is important to space laser
sessions at least six weeks apart.[47] When tattoos inks are a

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Figure 5. Tattoo inflammations patterns and example of pyogenic infection. A) i) Papule-nodular reaction caused by an excess of black ink with appre-
ciable particle agglomeration, which once were nano-sized. ii) Excessive hyperkeratotic pattern. iii) Plaque-like pattern. iv) Ulcero-necrotic pattern in the
red part of a tattoo. v) Lymphatic pattern, black tattoo particles located inside a lymph node, hematoxylin-eosin staining, tenfold optical magnification.
Reproduced with permission.[41,51,54] Copyright 2015, 2018, 2014, Karger Publishers, Asociación Española de Pediatría, PLOS ONE. B) Evolution of a
pyogenic infection in the green ink of a tattoo. Reproduced with permission.[41] Copyright 2015, Karger Publishers.

mixture of different colors, it causes a broad absorption spec-
trum making them more challenging for removal.[46,47] Dark
pigments are easier to remove as black absorbs all wavelengths
of light. The variables to consider in a laser are wavelength, spot
size, and pulse duration. Lasers used for tattoo removal are most
commonly Nd: YAG, Ruby, and Alexandrite. Currently, lasers
still cannot achieve the complete elimination of the tattoo.[47] The
combination of picosecond lasers with different wavelengths,
reduces the number of sessions and provides better results,
known as the rapid tattoo removal technique.[46] The purification
of traditional ink compositions to obtain specific wavelengths
improve QS laser performance.[47] Formulations composed of
microsphere-encapsulated bioresorbable dyes, which can be
removed with only one laser session, are being designed (e.g.,
Freedom-2 solution).[47,48]
1.4. Tattoo Toxicology
Pigments are considered safe because they are inert and insolu-
ble; nevertheless[27] the lack of data on inks composition and the
high variability between brands make necessary the development
of risks assessments to ensure safety. The legislation just con-
siders the pigment instead of the whole formulation.[24] When
products are considered dangerous, it is communicated between
the Member States and the European Commission by the Euro-
pean RAPEX system, the Rapid Exchange of Information System
for Non-Food Product.[28] When a patient gets a tattoo, ≈2.5 mg
cm−2 of pigment is introduced into the skin, possibly causing
mild redness symptoms, swelling, or clear exudate in the first
days after getting the tattoo.[27,49] Ultraviolet (UV) radiation from
the sun affects causes a 20% of tattoo complaints.[41] UV type B
does not penetrate the epidermis, but type A penetrates and ox-
ides the pigments increasing tattoo lightening and elimination.
Cadmium and the PAAs created by exposure of azo pigments to
the sun, cause the majority of the complications.[28,50]
The composition of tattoo inks has been improved to reduce
inflammation, for example, removing the mercury sulfide. Red
inks still causing 80% of inflammatory reactions,[27,51] blue and
green inks also show high incidence,[41] and black inks can pro-
duce non-allergic inflammation via aggregation of nanoparticles
of carbon black. Tattoo allergies are identified by intense itching
and swelling of the area, sneezing, and runny nose and eyes[49]
with an increase in lymphocyte T infiltration.[28,52] There is no
diagnostic reference test for tattoo allergies, the reaction has fre-
quently a retard of weeks, months, or years after the tattoo was
made.[49] When the allergic reaction manifests, it also affects old
tattoos with the same color in another area of the body. The symp-
toms are constant, chronic and it do not respond to topical cor-
ticoid therapy.[41] Allergies cannot be prevented by patch testing,
Buehler test, guinea pig maximization test, or the lymph node as-
say because the allergen is formed over months or years within
the skin, probably through metabolism, in vivo haptenisation or
both, with sunlight an important precipitant factor. A specific al-
lergy test for tattoos is urgently needed as they can also cause
sensitization to other inks such as textile pigments.[28,53]
Local inflammation reaction patterns include, papule-nodular,
plaque-like, excessive hyperkeratotic pattern, ulcero-necrotic,
lymphatic, neuro-sensory, and scar pattern types (Figure 5A)
and present different clinical and histological structures.[41] Most
papule-nodular inflammations are non-allergic reactions caused
by an excess of ink (Figure 5A-i) by sarcoidosis, or by other causes
such as needle trauma. Excessive hyperkeratotic inflammation,
Figure 5A-ii, is indicated by heightening and thickening of the

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Figure 6. Implantable optical biosensors and light processes. A) Architecture of an optical biosensor composed of three elements: Biological recognition
area, transducer, and processing system. Reproduced with permission.[2,59] Copyright 2016, 2011, Portland Press, Hindawi. B) Optical processes of light
when interacting with a molecule 1. Absorption and heat emission 2. Transmission, 3.a. Fluorescence emission, 3.b. Phosphorescence emission, 4.a.
Elastic scattering and 4.b Inelastic scattering. Reproduced with permission.[62] Copyright 2013, Annual Reviews.
tattoo by vast hyperkeratosis and cornification of the surface that
can end in necrosis and ulceration. Plaque-like inflammation,
Figure 5A-iii, can be a result of allergy and is seen as thickness
and elevation along the edge containing the problematic tattoo
color. Ulcero-necrotic inflammation, Figure 5A-iv, is an intense
inflammation caused by a strong allergy that develops necrosis
and ulceration, and it can reach down the subcutaneous fat, mus-
cle, or lymph nodes. Lymphatic inflammation, Figure 5A-v, is
caused by an overload of ink, causing the particles to be trans-
ported to the lymph nodes, visibly coloring them. The particles
block the flow of lymph, causing edema and inflammation. The
pigment can also color the dermis in areas that do not belong to
the tattoo design.
The tattooing process causes a release of histamine from cells
due to the tattoo needle piercing the skin.[41] People with chronic
autoimmune skin problems like psoriasis, lupus erythematosus,
and vitiligo, having a higher chance of response when getting a
tattoo being at risk for developing the Köbner phenomenon, char-
acterized by the manifestation of the patient’s chronic illness as
a response to the local lesion caused by the tattoo process.[41,53,55]
The tattooing process allows microorganisms to enter the body
through the needle’s penetration or healing phase[28] and can
cause bacterial infections, which represent the 5% of total tattoo
complications (Figure 5B).[28,41,53] Local discomfort, erythema,
edema, fever, and purulence are all signs of bacterial infection
in a tattoo.[53] 20% of the inks investigated in a study, includ-
ing those labelled as sterile, were contaminated.[28] UV radiation
produce cytotoxic reactive oxygen species in inks with genotoxic
PAHs,[29,40,56] and produce carcinogenic metabolites like primary
amines in yellow pigments and 3,3”-dichloro-4-aminobiphenyl or
3,3”-dichlorobenzidine in orange pigments.[28,43] Furthermore,
tattoos hide skin areas that could be developing a neoplasm, de-
laying the diagnosis.[53] There is a lack of record in the epidemi-
ological data linking tattoos and cancer; however, skin cancers
in tattoos are considered coincidental. The discrepancy between
the epidemiological data and the carcinogenic composition of tat-
toos can be explained by the ink’s single-dose exposure.[28,50,53]
Studying the toxicity, bioavailability and physicochemical char-
acteristics of traditional tattoo inks allows the design of sensors
that mimic the desired features and avoid the undesired ones to
maintain the advantage of a timelessness platform but also the
advantage of the continuous monitoring of health biomarkers by
substituting pigments with optical sensors.
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2. Technologicals for Tattoo Optical Biosensors
2.1. Tattoo Optical Biosensors
A biosensor is a bioanalytical platform able to change bio-
logical signals into quantitatively or qualitatively interpretable
parameters.[57] They are composed of 3 elements (Figure 6A):
First, a biological recognition area, which communicates with the
molecule of interest, second, a transducer, which converts the bi-
ological response into a measurable signal. Finally, a processing
system, which interprets the signal.[57] Sensors in medicine are
used to diagnose, treat, or continuously monitor diseases. A per-
fect biosensor will have excellent sensitivity and selectivity for
the analyte of interest, as well as sufficient temporal and con-
centration resolution and multiplexing capabilities.[58] Depend-
ing on the transduction method, biosensors can be optical, elec-
trochemical, thermal, magnetic, and piezoelectric.[2,59] For exam-
ple, the transducer of optical colorimetric sensors detects color
changes when the analyte is present, and the color change can be
correlated with the analyte concentration. Biosensing is a broad
field, therefore, this article will focus on optical tattoo biosensors,
where the information is obtained by modifications in the opti-
cal characteristics of the target molecule recognized by a sensor
tattooed on the dermis. Photons of light interact with the sample
changing its properties and modifying the initial incident light
wave; a photodetector converts the changes into an electrical sig-
nal proportional to the measured analyte concentration.[57] When
the light passes through the analyte (Figure 6B), it is affected by
absorption, transmission, emission, elastic, or inelastic scatter-
ing from the analyte. In absorption, the light is captured and con-
verted into heat whereas in transmission the light passes through
the object changing its amplitude or intensity. Luminescent ma-
terials, like fluorescent and phosphorescent molecules, can ab-
sorb electromagnetic radiation and re-emit it in the form of visi-
ble light. In the scattering phenomena the light changes through
the object. It is elastic scattering, also called Rayleigh scattering
in particles <5 nm and Mie scattering in particles >5 nm, if the
light modifies its trajectory, but the energy and wavelength of the
incident light does not change and the electron, after being ex-
cited, returns to its initial energy level.[60] It is inelastic scatter-
ing, also called Raman scattering, if the energy and wavelength
of the incident light change and the electron, after being ex-
cited, returns to a higher or lower energy level. The energy of the
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Figure 7. Example of tattoo inks’ label-based functionalization. The tattoo ink is functionalized with microparticles which produce fluorescence when
the concentration of a biomarker in the interstitial fluid increases.
liberated photon differs from the energy of the incident photon
and is higher in Stokes Raman scattering or lower in anti-Stokes
Raman scattering.[61] The optical sensing measurement can be
carried out in a solution (with particles distributed randomly)
or on a planar surface (particles bound to specific locations). A
greater surface-to-volume ratio is one of the benefits of sensors
in suspension which allows a higher analyte binding and a better
accessibility of the analyte. Simultaneously, the disadvantages are
a decreased sensitivity, lower stability and reusability of the sen-
sor, fewer multiplexing abilities, and more cytotoxic effects.[62]
Recent biosensor advancements have centered on non-
invasive wearable electronic sensors placing the sensor in acces-
sories which can be in close contact with the body for monitoring
physiological parameters, like body temperature or electrophys-
iological signals.[63,64] A perfect wearable device would combine
electrochemical performance with mechanical stress resistance
while causing the least amount of disruption to the wearer’s ev-
eryday activities.[65] Wearable health technologies have the poten-
tial to early identify asymptomatic and pre-symptomatic COVID-
19 infection.[66,67] However, wearable sensors require electrical
power or recharging to operate and the sensing data contains en-
vironmental interferences.[9] Placing the biosensor inside the hu-
man body represents a powerful platform for continuous mon-
itoring of biomarkers thereby providing extensive and detailed
knowledge of the disease’s evolution. Tattooing the sensor into
the body should be minimally invasive to allow Point-of-care
(POC) use, providing high quality real-time diagnostic results
within minutes. To avoid surgical procedures and reduce tissue
damage or patient discomfort, it is necessary to minimize the
sensor size. The sensor is injected with a tattoo needle in the
dermis to be able to access the ISF, as soon as the biosensor
is inserted in the skin, an unfavorable response to the foreign
substance is initiated, resulting in device malfunction, poor bio-
compatibility, and tissue injury. This negative response can de-
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pend on the biosensor’s various properties: Form, dimension,
pattern, roughness, porosity, structure, interface material/device,
sterilization, time of insertion, wrapping, and metabolization.[57]
Optical biosensors are sorted into two groups based on the la-
bel’s need to generate the signal or if the analyte’s contact with
the transducer produces the signal directly.[2] Besides, biosen-
sors can be divided depending on their mechanism into, catalytic
biosensors, which the biological recognition element from the
sensor transforms the analyte into a metabolite (e.g., enzymes,
cells, tissues) and affinity biosensors, where the analyte binds to
the biological recognition element without being altered (e.g., an-
tibodies, nucleic acids, aptamers) (Figure 6A).[57,68]
Label-based biosensing relies on direct interaction between the
analyte and labelled particle through different physicochemical
processes to produce a detectable signal (Figure 7). Fluorophores
and phosphorescent molecules are some of the most widely used
labels. Fluorescence occurs when an electron absorbs a photon
from an energy source and migrates to a higher electronic state,
energy is then emitted in the form of a photon when the elec-
tron falls back to the initial state thereby generating light that
can be measured externally. A processing system interprets the
signal providing qualitative and quantitative information about
the target molecule.[62] Phosphorescent labels continue to re-
lease photons after the incident light source stops, while fluo-
rophores need a constant energy source to glow. Fluorophores
and phosphorescent labels can be proteins, peptides, small or-
ganic and inorganic compounds, synthetic oligomers, and poly-
mers. Fluorescent proteins, such as, the yellow fluorescent pro-
tein, exhibit autofluorescence and are frequently used in biolog-
ical imaging. Fluorophores and phosphorescent molecules are
defined by a wavelength of maximum absorption and emission.
Typically, the excitation energies are in the UV or visible spec-
trum while emission energies range from visible light to near-
infrared. Some nanostructured semiconductor particles such as
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quantum dots (Qdots) have a very long fluorescence lifetime and
a high quantum yield producing high fluorescent brightness lev-
els. The quantum yield is the difference between the emitted and
absorbed photons: the higher the quantum yield, the more sub-
stantial brightness. QDots exhibit different emission colors de-
pending on size and allow imaging of deep tissues using the
Near-Infrared-II region. Using this spectrum, the scattering or
absorption by biomolecules and autofluorescence is minimized,
thereby increasing the resolution,[62,69,70] Quantum dots have a
high dark fraction as 20% to 90% of all particles never emit flu-
orescence. By combing QDots with other fluorophore molecules
the dark fraction is reduced or even eliminated improves the pho-
ton emission’s efficiency, increasing the fluorescence lifetime.
The combination of fluorophores are non-radioactive, however,
to improve the biocompatibility, biomimetic materials must be
used.[62]
Photoinduced electron-transfer sensors are triggered by ana-
lyte binding to an acceptor causing or cancelling electron trans-
fer to a donor.[62] When fluorophores are involved, these sensors
are called fluorescence resonance electron transfer (FRET) sen-
sors or Förster resonance energy transfer. An external excitation
source provides energy to the fluorophore donor which transfers
energy to the fluorophore acceptor that emits light. Due to the
electron transfer, the fluorophores must be in proximity. It is ad-
vantageous to study, for example, protein interactions. Marking
each protein with either the donor or acceptor fluorophore probe
allows observation of whether the proteins are close enough to
interact and produce fluorescence. Unlike FRET, some sensors
do not require an external excitation source such as chemilumi-
nescent resonance electron transfer (CRET) sensors and biolu-
minescent resonance electron transfer (BRET) sensors, reducing
the unwanted absorbance of light by biological materials and the
scattering of the incident light from nanomaterials, increasing
their sensitivity. In CRET, the analyte binds to the chemilumi-
nescent donor which is usually an enzyme that catalyzes a reac-
tion exciting the acceptor fluorophore and produces a signal. In
BRET, the donor is a natural bioluminescent protein. The fluo-
rophores must be in proximity. However, since BRET uses large
proteins, allows higher distances between the acceptor and the
donor than CRET and it is perfect for detecting in vivo protein-
protein interactions. The most significant disadvantage of these
biosensors is that their emission wavelengths are in the same
wavelength range that biological molecules absorb light, mak-
ing them not suitable for implantable biosensors now. However,
recent attempts have reduced the absorption and increased the
sign-to-noise ratio.[62,71]
Label-free biosensors are ideal for molecules which are com-
plicated to label or have no adequate label identified. More-
over, they have a reduced analysis time, consumption of organic
solvents, size, low cost, high sensitivity and they can quantify
molecules in real-time.[72] The interaction between the analyte
and the transducer produces the signal directly. Surface plas-
mon resonance (SPR) is measured by direct stimulation of low
molecular weight molecules incident light that is polarized at a
certain angle, known as the resonance angle. The interaction of
the light with the sample generates surface plasmons on the sur-
face of a conducting material, like a metal, sandwiched between
two media, like glass and liquid. The transducer can recognize
a change in the wavelength and the resonance angle when the
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plasmons are generated. This change is found to be proportional
to the mass of analyte at the surface and therefore the concen-
tration of the analyte in solution.[2,62] SPR biosensors are able
to detect, monitor, and quantify biomarkers, detect molecular
interactions, and time-dependent binding interactions.[73] Local-
ized surface plasmon resonance (LSPR) is the resulting effect of
limit SPR in a metal nanoparticle enhancing the electric field
close to the surface of the particle. The LSP is concentrated in
a tiny area at the nanoparticle surface, and the resonance may
be altered by modifying the physicochemical properties of the
nanoparticle. Using nanostructured materials instead of films
enhance the SPR signal and enable the detection of hard-to-find
biomarkers; because of their chemical stability, gold nanoparti-
cles are widely employed even though silver ones provide bet-
ter LSPR bands. SPR and LSPR methods have the possibility
to be employed in a variety of biosensing applications, however,
many and important challenges remain before they can be ef-
ficiently used in practice including their sensitivity, specificity,
and reproducibility.[74–77] Surface-enhanced Raman spectroscopy
(SERS) allows ultrasensitive imaging and sensing to detect in-
elastic Raman scattering.[62] The Raman spectrum is character-
istic for each molecule and allows a qualitative and quantitative
analysis of a mixed sample.[2,61] An example of functionalization
of tattoos with label free sensing techniques is developed by the
group of Wang et al., with a SERS tattoo for sensing of food
toxins.[12] The sensor comprises of a gold coated tattoo that can
transmit an efficient plasmonic pattern to various surfaces for tar-
get sensing, for example for the detection of a fungicide (thiaben-
dazole) used in orange preservation and packaging. The results
provide a limit of analyte detection at 0. 1 μM, below the EU spec-
ified maximum value, however, the sensitivity of these tattoos is
lower than other alternatives. Monitoring biomarkers in the ISF
by surface-enhanced Raman scattering is also possible, SERS tat-
toos were in vivo tested in pigs and the results showed the capa-
bilities of these tattoos for the continuous monitoring of nucleic
acids.[10] SPR and SERS are the most common optical biosen-
sor transducers for viral detection.[78] The ultrasensitive and spe-
cific potential for biomarker detection with Raman spectroscopy
has piqued interest for the detection of SARS-CoV-2.[79,80] SERS
can distinguish between viruses, viral strains, and viruses with
gene deletions in biological medium based on their spectral
differences,[81] it is a potent advantage and opportunity for tattoo
functionalization.
2.2. Interstitial Fluid as a Substitute for Blood Biosensing
Traditional tattoo inks can be replaced with biosensors that can
inform about different biomarkers in the dermal ISF, the sensor
is injected with a needle in the dermis to be able to access the der-
mal ISF.[9] Extravasation of plasma from capillaries results in the
formation of the ISF, it is composed of composed of water with
polysaccharides, lipids, proteins, and electrolytes, such as sodium
(Na+ ), chloride (Cl– ), bicarbonate (HCO3 – ), potassium (K+ ), cal-
cium (Ca+2 ), and magnesium (Mg+2 )[9] and it is a medium via
which nutrients and undesirable substances are exchanged be-
tween blood arteries and cells.[82]
The flow between the blood capillaries, the interstitial space,
and the lymphatic capillaries is regulated by the hydrostatic and
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www.advancedsciencenews.com
Table 3. Electrolytes, glucose, proteins, and pH values in blood and ISF.
Parameter Plasma
Sodium mmol L−1 140.36 ± 0.80
Potassium mmol L−1 4.33 ± 0.21
Magnesium mmol L−1 0.93 ± 0.08
Total calcium mmol L−1 2.22 ± 0.55
Chloride mmol L−1 103.33 ± 1.15
Bicarbonate mmol L−1 24.50 ± 0.47
Total protein g L−1 74.35 ± 0.92
pH 7.35–7.43
glucose mmol L−1
Fasting plasma 5.05 (4.37–5.73)
Notes: The mean value and standard deviation are shown in units according to the International System of Units.
oncotic Starling forces.[29] The filtration forces are hydrostatic
pressure (PH ) and interstitial fluid pressure (PISF ). PH is higher
in capillaries than in veins, while PISF is constant and ≈0 mmHg.
The absorption forces are the plasma and the ISF oncotic pres-
sures, 𝜋, and they are mainly created by proteins. In the capillar-
ies, filtration occurs in the arteriolar end and absorption in the
venous end. The lymphatic circulation drains the excess fluid
and/or proteins that were filtered. Net pressure is the differ-
ence between the four Starling forces.[83,84] Lipophilic uncharged
biomarkers and glucose molecules are transported from blood to
ISF by simple diffusion, other interstitial biomarkers are trans-
ported by structural proteins, enzymes, receptors, and trans-
port proteins or by vesicles through exocytosis, endocytosis, or
phagocytosis.[84–86]
The best method to monitor blood biomarkers is measuring
blood directly; however, this practice is limited by the require-
ment of a specialist, the impossibility of continuous monitor-
ing, and discomfort associated with drawing blood. Urine and
saliva are easier to measure compared to ISF, although they have
limited biomarkers and unstable concentrations.[87] There are
biosensors in the market to monitor ISF that correlate well with
blood. The analysis of the electrochemical composition of both
blood and ISF shows considerable variations in some parame-
ters (Table 3). However, there is no agreement in the literature of
the average value for the parameters indicated in Table 3. There
is a necessity to perform studies in this field; many of the arti-
cles are out of date, presented as ratios or percentages, and do
not use International System of Units (SI), making comparison
arduous.
The composition in blood and ISF is comparable except for
a reduction of calcium concentration by half and protein con-
centration by one third in ISF compared to plasma.[105] Proteins,
due to their high molecular weight, barely diffuse into the ISF.
The oncotic pressure of the ISF must always be lower than in the
capillary blood to allow passive diffusion of the biomarkers into
the tissue.[83,106] Calcium can be found in plasma as free calcium
ions, as inorganic complexes or as calcium bound to proteins,
explaining why calcium concentrations are lower in ISF.[92] Al-
though the pH range differences are not very significant (7.35–
7.4 for plasma and 7.1 and 7.4 for ISF), the average value is more
unstable in the ISF as proteins such as hemoglobin or albumin
are potent and powerful pH buffers maintaining a constant blood
pH.[95]
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ISF References
140.60 ± 4.09 N=5 [ 88–91]
4.25 ± 0.33 N=5 [ 88–91]
0.77 ± 0.23 N=4 [ 88,89,91]
1.73 ± 0.74 N=5 [88,89,91,92]
110.90 ± 5.09 N=3 [88,91]
28.00 ± 1.00 N=3 [ 88,91,93]
25.30 ± 6.65 N=4 [ 89,90,94]
7.1–7.4 N=4 [89,95,96] [95,96]
5.42 (4.76–6.01)Time lag 8–10 min N=8 [97–104]
Glucose in ISF is a widely studied biomarker. As shown in
Table 3, plasma and ISF concentrations are comparable, 5.05
and 5.42 mmol L−1 , respectively. Average fasting plasma glucose
levels continue to increase by 0.07 mmol L−1 in women and
0.09 mmol L−1 in men per decade since 1980,[99] it is essential
to have reliable and safe devices that continuously control blood
sugar levels in real-time and tattooed biosensors are promising
candidates. Continuous glucose monitoring (CGM) devices meet
this need, however, the average error percentage for CGM devices
runs at around 15%. The calibration of the measuring device is
the primary source of sensor error as it can be performed dur-
ing rapid plasma glucose changes.[107] The blood and ISF glucose
concentrations have been to follow that same variations through-
out the day.[87,107] However, there is a time lag (Table 3) for the
equilibrium of concentrations between the two fluids responsible
for the ISF biosensing errors.[108,109] On average, ISF and plasma
sugar levels take 8 to 10 min to equilibrate, including the physi-
ological delay as well as the lag induced by the glucose measure-
ment system. A further 5–10 min delay is expected in periods of
rapid glucose variability, like after physical exercise, meals, or dur-
ing hypoglycemic events.[107] The physiological delay can be algo-
rithmically corrected.[110] Despite the difficulties described, it is
reasonable to switch to interstitial glucose biosensing instead of
blood glucose due to the advantage of continuous measurement
devices and the similarity in glucose values obtained in stable
situations.[111] In addition to the electrolytes, glucose, proteins,
and pH discussed above, a comparative study of 65 biomarkers
showed that half of the analytes had similar concentrations in ISF
and plasma with some higher in ISF (Figure 8A–C).
There is a 60–79% similarity in both fluids’ components.[87,112]
ISF also contains specific cell and tissue biomarkers not found
in plasma (resulting from metabolic processes) and exogenous
biomarkers of environmental exposure (Figure 8D).[87] Some of
these markers could be new indicators of skin diseases.[112] It is
expected that amino acids like serine and organic acids like lac-
tic acid have higher concentrations in ISF as they are frequent
components of the skin structure.[87]
2.3. Tattoo Biosensing for Interstitial Fluid Biomarkers
Tattooed sensors for ISF biomarkers monitoring are a promis-
ing approach to improve the patient’s quality of life by offering
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www.advancedsciencenews.com
Figure 8. Biomarker concentrations in ISF (grey) and in plasma (red). A–C) Biomarkers detected in similar concentrations in ISF and plasma expressed
in μM. D) Biomarkers detected uniquely or predominately in ISF expressed in percentages of prevalence of the biomarker in a twenty-patient trial.
Reproduced with permission.[87] Copyright 2020, American Association for the Advancement of Science.
a comfortable alternative to blood sampling that allows contin-
uous monitoring and multiplexing capacities for the control of
more than one biomarker, especially convenient in metabolic dis-
eases such as diabetes where the illness decompensates more
than one physiological parameter, for example glucose and pH.[9]
The "Dermal Abyss" project aims to create a continuous glucose
monitorization platform using an enzymatic biosensor made of
glucose oxidase, peroxidase, and potassium iodide. When in-
terstitial glucose levels increase the biomarker is metabolized
by the enzyme glucose-oxidase creating gluconolactone and hy-
drogen peroxide. The enzyme peroxidase catalyzes the produc-
tion of hydrogen peroxide and reacts with the potassium io-
dide producing iodine. The iodine produces a measurable color
signal at 680 nm which relates the iodine values indirectly to
the glucose concentration. The tattooed biosensors can send
the measured concentrations to a smartphone for interpretate
and store the data.[9] Other enzymatic glucose biosensors use
both enzymes but substitute potassium iodide with 3,3”,5,5”-
tetramethylbenzidine. The hydrogen peroxide formed reacts with
the 3,3”,5,5”-tetramethylbenzidine under peroxide catalysis pro-
ducing a color change from blue to green with an absorbance
peak at 680 nm. This allows to control glucose changes from con-
centrations of 2 mmol L−1 up to 50 mmolL−1 .[5] Despite promis-
ing results, both projects require more permanence, reversibil-
ity, and color range. The dependence on the use of enzymes has
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a negative impact on the reversibility of the sensor; their substi-
tution for diboronic acid provides reversible glucose responsive-
ness. Shibata et al. design a glucose sensor (Figure 9A) which
consist of two diboronic acids groups which act as the recogni-
tion site for the glucose and one anthracene molecule which is
the fluorophore. This component has been tested in injectable
hydrogel microbeads which can be introduced in traditional tat-
too inks for in vivo CGM by fluorescence (Figure 9B)[3] and the
results proved the reversibility of the beads and a successful con-
trol of glucose monitoring (Figure 9C), however, due to their
small size (130 μm), the microbeads dispersed from the implan-
tation site one month after being injected.[114] Increasing the size
(1000 μm), changing the shape to fibers, and adding polyethylene
glycol to the formulation improved the biocompatibility and in-
creased the sensor’s response time to glucose (up to 140 days),
but still maintaining some challenges related with the use of flu-
orophores like the photobleaching, calibration, or the potential
risks of excessive skin irradiation.[114] Sensing the ISF goes be-
yond the glucose biomarker.
The "Dermal Abyss" project also offers sensors capabilities for
other clinical biomarkers, like the monitorization of sodium by
using the fluorophore diaza-15-crown-5 to control dehydration
states caused by loss of electrolytes or hypertension caused by hy-
pernatremia. Other example is the monitorization of pH by the
fluorophore seminaphtorhodafluor or by the anthocyanin which
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www.advancedsciencenews.com www.advhealthmat.de

Figure 9. Insertable fluorescent microspheres for in vivo continuous interstitial glucose monitoring. A) Schematic design of the injectable fluorescent
microbeads, the intensity of the microbeads’ fluorescence increases as the glucose content rises. B) In vivo interstitial glucose monitoring in the dermis
of a mouse ear, pseudocoloured photos for glucose levels within the normal (left) and hyperglycemic ranges (right). C) The fluorescence intensity (a.u.,
arbitrary units) traces blood glucose concentrations. The time lag is mostly caused by the time it takes for interstitial fluid glucose concentration to
equalize with blood glucose concentration. Reproduced with permission.[3] Copyright 2010, Proceedings of the National Academy of Sciences.

Figure 10. Dermal tattoo biosensors for colorimetric metabolite detection. A) Tattooed biosensors for the detection of pH, glucose, and albumin. Scale
bar = 1.0 mm. B) Multiplexing capacities of tattoo functionalization. Colorimetric readouts in i) alkalosis, ii) metabolic acidosis, iii) hyperglycemia, iv)
hypoglycemia, v) hypoalbuminemia, and vi) co-developed hypoglycemia and respiratory alkalosis. Scale bars = 1.0 cm. Ex vivo porcine skin tissues.
Reproduced with permission.[5] Copyright 2019, Wiley-VCH GmbH.

changes color from red in acidosis to blue in alkalosis staying vi- sulated in alginate microsphere.[117] This epidermal tattoo-patch
olet at neutral pH.[9] Other popular targets for tattoo interstitial enhances skin penetration of the drug avoiding the use of nee-
biosensing include potassium, oxygen, cortisol, lactate, and albu- dles.
min concentrations (Figure 10A,B).[5–8,17,115,116]
An important advantage in optical biosensing is the simplicity
in data collection. The dermal sensors quantitative records can be 3. Future Perspectives and Challenges
collected by a smartphone camera (Figure 11A).[5] In the case of
There is a potential future use of tattoos for DNA vaccina-
multiplex tattoos, each sensor must be photographed separately
tion since tattoos provide higher peptide-specific immune re-
(Figure 11B). A mobile application allows the interpretation and
sponses than intramuscular needle injections. The dermis con-
storage of the measured data, improving the communication be-
tains plenty of antigen-presenting cells, which create an efficient
tween doctor and patient to enable individualized medicine as
antigen-specific immune response.[14] Moreover, tattoos are use-
the data could be sent to the health center (Figure 11C). Portable
ful for vaccination with peptides who aggregates easily, and it al-
compatible optical readout devices may be connected to the der-
lows to remove adjuvants on the vaccine composition reducing
mal tattoo sensor to improve the accuracy and stability of the
size effects.[118] The tattoo biosensing functionalization might
electrolyte levels.[] Wearable devices with optical capabilities can
play a major role in combating viral pandemics with ongoing
also be employed in combination with optical functionalized tat-
research and improvement.[119] Other different projects demon-
toos for sensing.[9] Since alcohol abuse leads to accidents and
strating the future capabilities of tattoo functionalization beyond
health problems, temporary-tattoo sensors can also monitor al-
ISF biosensing have been initiated to create an interactive plat-
cohol concentration (Kim et al., 2016) and raise awareness of
form with our skin where biosensors are no longer an external
responsible consumption. The functionalization of tattoos goes
device, they are an extension of our body providing new capabil-
beyond the sensing biomolecules, an example is the use of tat-
ities. Butterfield et al. demonstrate the use of UV-sensitive pho-
toos for microballistic transdermal doxorubicin drug delivery by
tochromic nano-capsule tattoo ink to indicate overexposure of UV
ultrasound,[13] or the release of anti-inflammatory drug encap-
light (Figure 12A–E), and the need for sun protection, known as

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Figure 11. Reading process of a multiplexed tattooed optical sensor. A) Quantitative readouts using a smartphone camera at 5.0 mm normal incidence
to the detection area. Reproduced with permission.[5] Copyright 2018, Wiley-VCH GmbH. B) Multiplexing capacities of tattoo functionalization with
fluorescent sensors: seminaphtorhodafluor pH-sensor, diaza-15-crown-5 sodium-sensor, and benzofuran isophthalate tetraammonium salt potassium-
sensor. Tattoo under normal light and LED excitation. Scale bar = 5 mm. C) Screenshots of the smartphone apps used for rapid detection and point-of-
care diagnosis. The smartphone app. shows the selection of the sensor type (left), imaging of the test samples (middle), the quantitative and diagnostic
results are displayed to the user (right). Reproduced with permission.[4] Copyright 2020, Sensors and Actuators B: Chemical.

“solar freckles.”[18] The capsules are reversible since their color
disappears rapidly after application of topical sunscreen. The ma-
jor cause of skin cancer is UV exposure, these tattoos would in-
crease preventative behaviors providing a visual reminder to pro-
tect the skin and would reduce the incidence of this pathology.
These tattoos are semi-permanent and are long lasting, remain-
ing functional for months to years. In addition to being incorpo-
rated into the skin as tattoos, UV-sensitive sensors can be used in
skin patches, contact lenses, textiles, or wearable devices.[120] UV-
fluorescent tattoos can be also used for identifying biopsy sites at
the time of surgery.[121]
Temporary cell-based tattoos have also shown a lot of interest.
One example is provided by Tastanova et al., who developed a
synthetic cellular biomedical tattoo for detecting cancer-related
hypercalcemia. The cells expressed calcium-receptors which re-
acted when calcium increased in blood and produced black pig-
ment melanin. The sensing component was a calcium-sensing
receptor, the visualization component was the development of a
visible tattoo by the accumulation of melanin produced by the oxi-
dation of tyrosine by the enzyme tyrosinase in the melanosome of
melanocytes of a transgenic HEKTattoo (human embryonic kidney)
cell line (Figure 13). The HEKTattoo cells were microencapsulating
in alginate—PLL (poly-L-lysine)—alginate beads. The system was
confirmed in wild-type mice tattooed with the encapsulated engi-
neered cells, there was appearance of tattoos in mice with hyper-
calcemia breast and colon adenocarcinoma cells while there was
no tattoos in ones with normocalcemic tumor cells, validating
the use of cell-based tattoos for detect hypercalcemia associated
with cancer and its potential for future cancer management.[122]
Another example for the possibilities that the combination of
cells and tattoos offers is the "Living Tattoos" project of the Mas-
sachusetts Institute of Technology, which consists of a temporary
skin-patch tattoo, composed of bacterial cells mixed with hydro-
gels and nutrients. The cells can act as a chemical optical biosen-
sor for environmental components, contaminants, as well as, for
changes in pH or temperature by emitting fluorescence. Each cell
in the tattoo would perform a simple computational operation
and different cell types can interact between them in the same tat-
too to achieve complex logic operations. The main challenges are
the precision to incorporate the cells into the hydrogel matrix and

Adv. Healthcare Mater. 2021, 2101238 2101238 (14 of 21) © 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH
www.advancedsciencenews.com
Figure 12. UV-sensitive nano-capsule tattoo ink. A) Structure of the photochromic nanocapsules. B) Optical micrograph of dispersed nanocapsules
before (left) and after (right) UV-exposure. C) Plot of visible color shift quantified in simulated sunlight. Ex vivo porcine skin. D) Photochromic tattoo
behavior immediately after removal UV stimulation. Ex vivo porcine skin. E) Blue photochromic nanocapsules mixed with conventional tattoo inks and
exposed to UV light. Reproduced with permission.[18] Copyright 2020, American Chemical Society.
to maintain the viability and responsiveness of the cells.[11] Many
new high-stretchable functional materials have been proposed as
candidates for use in temporal tattoos, most of them come from
the use of specialized synthetic materials/composites or hetero-
geneous collections of material micro/nanostructures.[63] This
review article is focused on tattoos made with implantable optical
biosensors for monitoring biomarkers in ISF. However, it should
be mentioned that there are other types of tattoo sensors for
plenty different future applications, highlighting electrochemi-
cal sensors in temporary skin-patch tattoos. The use of graphene
in electronic tattoos sensors act as commercially available wear-
able health and fitness trackers; patients’ electrocardiogram, elec-
tromyogram, electroencephalogram, temperature, and hydration
are all effectively controlled by these tattoos. Graphene is an elec-
trically conductive material, optically transparent, robust, electro-
chemically stable, and biocompatible, however, it is too large to be
used as a tattoo ink, so it has to be transferred on human skin like
a temporary tattoo.[16,123,124] Another example of the advantages of
using 2D materials for temporal tattoo biosensing in electronic
tattoos sensors is the use of carbides and nitrides called MXenes
which are nanomaterials that successfully measured pulse, respi-
ration rate, and surface electromyography.[125] The advantages of
these tattoos include excellent mechanical flexibility, small size,
comfort, and high adhesion to the skin. The "Duoskin" project in-
troduces three different types of tattoos functionalized with the
use of gold leaves.[19] The first type is touch sensitive input tat-
toos, allowing the skin itself to act as a control unit, the second
type display data, allowing the monitoring of body parameters,
such as temperature changes. The last type are communicative
tattoos, which convert the skin into an interactive platform which
wirelessly exchanges information with other devices.[19] With this
type of temporary electronic tattoos sensors, information such as
identity documents or credit card details would be incorporated
into our skin. The functionalization of tattoos seems to be a very
promising field for plenty different future applications.
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www.advhealthmat.de
Optical biosensors in the last decade have developed exten-
sively in different fields, including therapeutics, toxicology, en-
vironment, military, and safety, but lot remains to be done before
traditional methods can be fully replaced.[2] The examples above
show how tattoo sensors have progressed over the last decade and
their future applications. However, several challenges arise when
designing a tattoo sensor for ISF biosensing, some related to the
biological sensing platform and others to the optical sensors. The
main biological challenges include the time delay that exists to
reach equilibrium between the concentrations of the biomarker
of interest in blood and ISF.[3] As it has been shown for glucose
(Table 3), the lag time could be up to 8 min. This challenge can be
reduced by using mathematical models that algorithmically cor-
rect the delay by considering all the parameters that influence the
regulation of the specific biomarker;[110] it is crucial to study the
physiological regulation of the biomarker for which the tattoo is
to be designed. An advantage and disadvantage for ISF biosens-
ing is the inherent composition of this fluid, it is a complex ma-
trix with many components which allows multiplexing capacities
for the sensor,[] making it suitable for monitor more than one
biomarker and provide a complete control of the patient’s pathol-
ogy, but at the same time it hinders the specificity of the sen-
sor as there are very similar species in the same medium. Also
other physiological fluids, like sweat can affect to the stability of
the dermal sensor and can be prevented with sensor coatings.[]
Adding blocking agents to minimize non-specific binding can
enhance the signal of interest.[126] Biofouling is the accumula-
tion of proteins, cells and other biological materials on a sur-
face, it is one of the main challenges for in vivo biosensors.[127] It
can be reduced by modifying the sensor surface to prevent non-
specific interactions or by antibiofouling membranes.[17] Physio-
logical components can also produce optical signals that can in-
terfere with the measurement of the biomarker of interest,[72,128]
is extremely important to achieve high signal-to-background ra-
tios by using high-precision devices.[62,71] The influence of the
© 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH
www.advancedsciencenews.com
Figure 13. Synthetic cellular tattoo for the detection of hypercalcemia as-
sociated with cancer. A) Molecular mechanism of pigment production by
HEKTattoo cells inducted by hypercalcemia. The sensing component of the
biomedical tattoo system (I). The visualization component (II). IP3, in-
ositol 1,4,5-trisphosphate; NFAT, nuclear factor of activated T cells; SRF,
serum response factor. B) Photograph of a nude mouse inoculated with
hypercalcemia cells (top) and a negative control nude mouse inoculated
with normocalcemic cancer and implanted with HEKTattoo cells (bottom).
C) Ca+2 blood concentrations of wild-type mice in the normocalcemic
groups (168 cancer cell line) and hypercalcemia groups (410.4 constitu-
tive tyrosine expression and Colon-26 cancer cell lines). 168 versus 410.4
(p = 0.0001) and Colon-26 (p = 0.0001). Horizontal dashed lines represent
hypercalcemia conditions (mild, 5.6–8 mg dl−1 ; moderate, 8.1–10 mg dl−1 ;
severe, >10 mg dl−1 ). The termination point was a tumor size of 10 mm,
last points collected over 18 days at the terminal tumor size. D) In vivo
melanin production by microencapsulated HEKTattoo cells extracted from
the implantation site of mice in the hypercalcemia and normocalcemic
groups after 38 days. 168 versus 410.4 (p = 0.0003) and Colon-26 (p =
0.0001). Data are represented as means ± SEM, and statistical significance
of difference between hypercalcemia and normocalcemic groups was cal-
culated using one-way ANOVA (analysis of variance) with Dunnett’s mul-
tiple comparison test (n ≥ 6 mice) where **p < 0.01, ***p < 0.001, and
****p < 0.0001. Reproduced with permission.[122] Copyright 2018, AAAS.
anatomical location of the tattoo, the tattoo implantation depth
and the skin differences between ethnicity, age, sexual hormonal
impact, climate, and diet should be studied. The skin is subjected
to an almost constant mechanical stress which can affect sensor’s
performance,[65,129] 3D printing allows the creation of temporal
tattoos with highly stretchable sensors in hydrogels.[11]
Diffusion of the sensor from the tattoo site into the ISF is
a challenge that must be controlled by modifying the sensor
size,[114] but is a difficult challenge since they should be small
enough to avoid surgical procedures but should be large enough
to be retained in the desired area, tattoo biosensors should mimic
in size the traditional tattoo pigments.[18] The dimension of the
implanted sensor also affects the degree of tissue damage. An ex-
ample of the importance of size is the miniaturization of a CGM
sensor using microbeads to coat and reduce the sensor’s size.[3]
The microbeads, <1 μm, were inserted into the skin using a nee-
dle, however, they were not suitable for long-term monitoring in
vivo as they dispersed from the implantation site and permeated
the cell-membrane proving challenging to remove. Another at-
tempt to formulate the microbeads as fibers of 1000 μm in diam-
Adv. Healthcare Mater. 2021, 2101238 2101238 (16 of 21)
www.advhealthmat.de
eter for long-term application, however, the fibers needed to be re-
moved after three months and local inflammation reactions were
registered.[114] Biocompatibility encompasses the physiological
reaction to the implanted sensor as well as the technological re-
action in the sensor. To improve biocompatibility, biomimetic
materials are used, for example soft and flexible polymeric hy-
drogels, or porous silicones which are natural components in
our body found in collagen fibers and bones, when the sensor
degrades, the metabolites formed are non-toxic and natural or-
thosilicic acids, which are safely eliminated from the body.[130]
The use of coatings with self-healing properties that actively re-
spond to the in vivo environment enhances the biocompatibility
of the sensor,[131,132] A novel strategy to improve the biocompat-
ibility of tattooed sensors for monitoring glucose in the ISF was
the introduction of anti-inflammatory-drug-loaded alginate mi-
crospheres into the tattoo itself, creating a combined smart tattoo
that releases drug but also monitors biomarkers. The drug was
successfully and completely released microspheres over a period
of 3–4 weeks improving not only the biocompatibility of the sen-
sor, also its in vivo functionality.[117]
Tattooed enzymatic biosensors exhibited excellent capacities
for interstitial biomarker monitorization. However, their main
challenges include a short-duration functionality, a lack in long-
term reversibility, dependence on oxygen levels, low precision,
low stability, or loss of activity because of immobilization;[2,9,114]
the variety of colors and intensities of the contemporary enzy-
matic biosensors should be increased to allow higher-resolution
signals. Other label-based optical sensors based on fluorescence
are affected by photobleaching, light scattering, cyto-toxicity, po-
tential health risks of excessive skin UV irradiation, and weak
fluorescence signal;[126] pulsed excitation system is required to
minimize photobleaching.[114] The accurate of the sensor redouts
can be improved using portable and customizable optical read-
out devices.[] Some sensors, like QDots, contain heavy metals
making their long-term use impossible in in vivo due to the risk
of toxicity from leakage of components. Encapsulation of QDots
in nanoparticles is a powerful solution to ensure patient safety,
also providing beneficial properties to the sensor like enhancing
its half-life.[62] Label-free techniques have not yet been used for
continuous in vivo monitoring as the sensor surface, miniatur-
ization, and multiplexing viability must be improved.[72,133] The
main challenge of label-free optical biosensors is their low sen-
sitivity and specificity for the detection of the biomarker of in-
terest in a complex sample, like ISF.[2,73] Despite the difficulties
described, continuous biomarker monitoring by minimally inva-
sive and long-lasting methods is an advantageous development
toward personalized medicine. Secondary diseases from uncon-
trolled biomarkers cause enormous societal and economic costs;
effective and continuous health monitoring with multiplexing ca-
pacities can prevent them, improve the quality of life of patients
and enables individualized medication. Since the ISF is rich in
biomarkers, the designed dermal tattoo sensors can be employed
to real-time and long-term monitoring of biomarkers for multi-
plexed POC diagnostic devices.
4. Conclusions
In addition to aesthetics, tattoos could be platforms for diagnos-
ing or health monitoring.[134] Their permanence under the skin
© 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH
www.advancedsciencenews.com
provides a useful advantage for substituting pigments with im-
plantable biosensors.[135] The sensor is introduced into the der-
mis with a tattoo needle to monitor biomarkers in the ISF, pro-
viding high-quality, real-time diagnostic results of ISF composi-
tion within minutes, which will be used as POC devices.[9,65] In
this article, an analysis of the functionalization of tattoos for opti-
cal biosensing in ISF has been made discussing the components
and mechanisms involved. From the analysis of several tattoo
brands, it can be concluded that there is a high variability in the
ink composition between different manufacturers due to the lack
of pharmaceutical regulation. Tattoo inks are a thermodynam-
ically unstable dispersions of insoluble pigments in a solvent,
they can contain allergic metals, cytotoxic nanoparticles, or toxic
metals above the safety limit.[24,136] Long-term tattoo persistence
is well understood by macrophage capture–release–recapture re-
newal theory.[137] Pigments are considered safe because they are
inert and insoluble; nevertheless, there is a necessity to develop
risk assessments as part of the injected tattoo ink is also ab-
sorbed into the blood and distributed to other body areas.[138]
Tattoo inflammations are the most reported complications and
allergy inflammations cannot be prevented because they are pro-
duced by in vivo haptenisation;[139] the delay in the onset of symp-
toms also explains the lack of records of tattoo complications.[138]
ISF can substitute blood as a sensing platform since the com-
position is similar except for calcium and proteins, which are
higher in the blood.[140] It also provides new clinically valuable
biomarkers.[87,128] Placing the biosensor inside the human body
represents a powerful platform for continuous monitoring of
biomarkers reducing environmental interferences.[9] Using opti-
cal biosensors avoid the necessity of electrical power nor recharg-
ing. Some examples of tattoo biosensing for ISF biomarkers, the
different types of optical biosensors and their main challenges
and future perspectives are discussed. The potential opportu-
nities offered by the functionalization of tattoos cover different
fields and seems limitless.[57,74] Functionalized tattoos for inter-
stitial biosensing provide effective way to monitor and record the
evolution of a patient’s disease with the capability of measure
more than one biomarker within the same tattoo.[] Preventing
future complications means an improvement in personal quality
of life and economic savings for society. Secondary diseases from
uncontrolled biomarkers cause enormous societal and economic
costs; effective and continuous health monitoring with multiplex-
ing capacities can prevent them, improve the quality of life of pa-
tients,andenablespersonalizedtherapeutic decisions.
Acknowledgements
Acknowledgment to the Imperial College of London and to Leo Founda-
tion Center for Cutaneous Drug Delivery from the University of Copen-
hagen. This work was supported by the Engineering and Physical Sciences
Research Council (EP/T013567/1), the UKRI Future Leaders Fellowship
from the Medical Research Council (MR/S031537/1), the LEO Foundation
Grant (LF15007), the Fundamental Research Funds for the Central Univer-
sities, the SUND Outgoing Mobility Grant from the University of Copen-
hagen, and the Fundamental Research Funds for the Central Universities
of China (YJ202152).
Conflict of Interest
The authors declare no conflict of interest.
Adv. Healthcare Mater. 2021, 2101238 2101238 (17 of 21)
www.advhealthmat.de
Author Contributions
M.D.P.: Conceptualization, writing original draft, review and editing, vi-
sualization, funding acquisition. Y.H.: Project administration, writing—
review and editing. Y.E.: Writing—review and editing, funding acquisi-
tion. K.L.B.: Conceptualization, writing—review and editing, funding ac-
quisition. N.J.: Writing—review and editing. A.K.Y.: Conceptualization, re-
sources, supervision.
Keywords
health monitoring, interstitial fluids, optical biosensors, tattoos
Received: June 23, 2021
Revised: August 20, 2021
Published online:
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Marta Lucía Domínguez Pazos is currently working as a Researcher at the NanoBiosensors and Bio-
analytical Applications Group, Institut Català de Nanociència i Nanotecnologia in Barcelona and she
is a Ph.D. candidate in this institution for the biochemistry, molecular biology and biomedicine pro-
gram from the Universitat Autònoma de Barcelona. She completed her bachelor’s degree in pharmacy
at the University of Santiago de Compostela (2019) and her M.Sc. in pharmaceutical sciences at the
University of Copenhagen. Her master’s thesis focused on the functionalization of tattoos with optical
biosensors for monitoring blood sugar levels at the Yetisen Research Group, Imperial College London
(2021).

Yubing Hu is a research associate and assistant supervisor in the Department of Chemical Engineer-
ing at Imperial College London. Dr. Hu received a bachelor’s degree from Zhejiang University in 2016
and earned a Ph.D. degree from the Hong Kong University of Science and Technology in 2020. Her
Ph.D. study focused on the development of fluorescent polymer materials for advanced sensing and
imaging applications. Her current research aims to develop a variety of optical biosensors for wear-
able diagnostic devices. Her research works have been published in Advanced Materials, Advanced
Functional Materials, andCCS Chemistry.

Yuval Elani is a UKRI Future Leaders Fellow and Lecturer at the Chemical Engineering Department at
Imperial College London. His group works on biomimetic technologies, microfluidics, and synthetic
biology. Yuval previously held EPSRC and Imperial College Research Fellowships at Imperial Chem-
istry. Prior to joining Imperial, Yuval was at Cambridge University, where he studied natural sciences.
Yuval has been awarded several prizes for academic excellence, including the Royal Society of Chem-
istry Felix Franks Medal for Biotechnology, Rita and John Cornforth Award, Roscoe Medal, and the
Imperial President’s Medal.

Kathryn Browning is an assistant professor in the LEO Foundation Center for Cutaneous Drug Delivery
in the Department of Pharmacy at the University of Copenhagen, Denmark. She received her Ph.D. in
physical chemistry from the University of Cambridge, UK. Following this, she worked as a postdoctoral
researcher in Uppsala University, Sweden, using neutron scattering to study lipid exchange and re-
moval in atherosclerotic lipoproteins. Her current research focuses on drug delivery through the intact
stratum corneum.

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www.advancedsciencenews.com www.advhealthmat.de

Nan Jiang earned her Ph.D. degree from Wuhan University of Technology. After her Ph.D. study, she
worked as a postdoctoral fellow and a research associate at Harvard University and Imperial College
London. She is currently working as a faculty member at Sichuan University. Her research is aimed at
optical biosensors and microfluidic devices. She has 27 peer-reviewed papers as first author (co-first
author) and corresponding author. Some important works have been published on leading journals
such as Advanced Materials, Advanced Functional Materials, Energy & Environmental Science, and ACS
Nano. Some works have been selected as “Cover paper.”

Ali K. Yetisen is a Senior Lecturer and Associate Professor in the Department of Chemical Engineering
at Imperial College London. He was previously a Tosteson fellow at Harvard University. He holds a
Ph.D. degree in Chemical Engineering and Biotechnology from the University of Cambridge. He has
been awarded several international prizes including IChemE Nicklin Medal, Birmingham Fellowship,
MGH ECOR Award, Humboldt Research Fellowship Award, Carl Friedrich von Siemens Fellowship
Award, and a Fellowship of the Royal Society of Chemistry.

Adv. Healthcare Mater. 2021, 2101238 2101238 (21 of 21) © 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH