materials
Article
Plasmonic Nanocomposite Implants for Interstitial
Thermotherapy: Experimental and Computational Analysis
Yvonne Kafui Konku-Asase and Kwabena Kan-Dapaah *
Department of Biomedical Engineering, School of Engineering Sciences, University of Ghana,
Legon Accra P.O. Box LG 77, Ghana; yvonnekafui@gmail.com
* Correspondence: kkan-dapaah@ug.edu.gh; Tel.: +233-23-536-4134
Abstract: The ferromagnetic implant (thermoseeds) technique offers desirable features for interstitial
thermotherapy. However, its efficacy has been reported to be limited by issues that are related to the
properties of the metal alloys that are used to fabricate them and the high number of thermoseeds
needed to achieve therapeutic temperature levels. Here, we present the results of a combination of
experimental and computational analysis of plasmonic nanocomposite implants (photoseeds)—a
combination of Au nanoparticles (NPs) and poly-dimethylsiloxane (PDMS)—as a model material.
We performed structural and optical characterization of the Au NPs and repared Au-PDMS nanocom-
posites, followed by an elucidation of the heat generation capabilities of the Au-PDMS photoseeds
in aqueous solution and in-vitro cancer cell suspension. Based on the experimental results, we
developed a three-dimensional (3D) finite element method (FEM) model to predict in-vivo thermal
damage profiles in breast tissue. The optical absorbance of the Au-PDMS photoseeds were increasing
with the concentration of Au NPs. The photothermal measurements and the in-vivo predictions
showed that the photothermal properties of the photoseeds, characteristics of the laser sources,
and the duration of heating can be tuned to achieve therapeutic temperature levels under in-vitro





 and in-vivo conditions. Collectively, the results demonstrate the feasibility of using photoseeds for
Citation: Konku-Asase, Y.K.; interstitial thermotherapy.
Kan-Dapaah, K. Plasmonic
Nanocomposite Implants for Keywords: plasmonic nanocomposite implants; interstitial thermotherapy; photothermal heating;
Interstitial Thermotherapy: breast cancer; finite element method
Experimental and Computational
Analysis. Materials 2021, 14, 841.
https://doi.org/10.3390/ma14040841
1. Introduction
Academic Editor: Eun-Kyung Lim Interstitial thermotherapy (IT) involves the elevation of tumor temperature to hy-
Received: 8 January 2021 perthermic (41–45 ◦C) or ablative (>50 ◦C) levels while using implantable devices. The
Accepted: 7 February 2021 ferromagnetic seeds (thermoseeds) technique is an IT modality that has been described in
Published: 10 February 2021 the literature as safe and effective [1] due to characteristics, such as the limited collateral
damage to surrounding healthy tissue due to the localization of treatment, short heating
Publisher’s Note: MDPI stays neu- time, and uniform heat distribution [2]. First, it involves the implantation of an array of
tral with regard to jurisdictional clai-
the thermoseeds—small rods with diameter and length of 1 mm and a millimeter or a few
ms in published maps and institutio-
centimeters, respectively [3]—into the tissue using either open surgery or percutaneous
nal affiliations.
insertion under the guidance of several imaging techniques, such as ultrasonography,
fluoroscopy, magnetic resonance imaging, and computed tomography [4]. This is followed
by exposure to an extracorporeal AC magnetic field that causes the thermoseeds to generate
Copyright: © 2021 by the authors. Li- heat that is transferred to the tumor by conduction [4,5]. Their temperature self-regulating
censee MDPI, Basel, Switzerland. mechanism, which ensures that the temperature does not exceed a critical point—Curie
This article is an open access article transition temperature (CTT)—is a desirable property for thermotherapy. The feasibility
distributed under the terms and con- and effectiveness of the technique have been demonstrated in single or multimodal studies
ditions of the Creative Commons At- that range from fundamental research through to clinical [2,6].
tribution (CC BY) license (https:// Conventionally, thermoseeds have been fabricated with metal alloys that are based
creativecommons.org/licenses/by/ on Fe, Cu, Ni, and Co. Although alloys made from these metals have been made to have
4.0/).
Materials 2021, 14, 841. https://doi.org/10.3390/ma14040841 https://www.mdpi.com/journal/materials
Materials 2021, 14, 841 2 of 16
CTTs in the therapeutic range (40–100 ◦C) [3–5], a major drawback that affects the efficacy
of the treatment and precludes their clinical use is related to the composition of the alloys.
For example, alloys of Fe and Cu are not biocompatible, whereas Ni-based alloys have
been reported to exhibit poor corrosion resistance [7], potentially cause hypersensitiv-
ity [8], and exhibit inconsistent CTTs [9]. To address these issues, alloys with different
compositions have been examined while using in-vitro and in-vivo (animal and human)
studies. Corrosion analysis of NiCu and PdCo alloys using in-vitro experiments by Paulus
et al. [7] concluded that PdCo—compared to NiCu—alloys are more suited for use as a long
term implants due to their excellent corrosion resistance. Furthermore, PdCo thermoseeds
have been shown to provide suitable features [10,11], such as sufficient power output
to treat tumors with high blood flow, consistent CTT, and reduced risk of whole-body
heating due to the Hf factor, which does not exceed a limit—experimentally estimated
to be 5× 109 A m−1s−1 [12]. Vallet-Regı́’s [13] studied glass–glass thermoseeds synthe-
sized from mixtures of a melt-derived glass with composition ratio: 40:40:20 mol.% of
SiO2:CaO:Fe2O3 and a sol–gel glass with composition SiO2(58)–P2O5(6)–CaO(36) (mol.%)
and concluded that, although the thermoseeds exhibited promising bioactive properties,
the presence of glass ceramic grains on the surface hindered the bioactivity process.
Nanotechnology-assisted photothermal therapy (N-PTT) is a minimally invasive can-
cer treatment modalitiy that can potentially address challenges that are associated with
the inductively heated ferromagnetic implant technique [14,15]. It has been receiving a
lot of attention recently due to its potential to reach deep tissue coupled with a reduced
effect of non-selective cell death on the healthy tissue surrounding it [15,16]. Furthermore,
recent technological advances in laser delivery equipment offer the opportunity for the
development of more efficient, safe, and affordable interstitial strategies [14–16]. N-PTT
relies on the ability of nanoparticles (NPs) that are embedded within the target tissue
to absorb and convert extracorporeal near infrared (NIR) light to heat for therapeutic
purposes [14–16] Traditionally, plasmonic NPs, such as Au, Ag, Cu, as well as carbon
nanotubes or graphene, have been exploited for N-PPT, due to the opportunity to ma-
nipulate their localized surface plasmon resonance (LSPR) to enhance their absorption
capabilities [16,17]. This confines heating to the location of the plasmonic nanomaterials
and reduces, but does not eliminate, heating of the surrounding tissue. Recently, several
groups have reported the use of ceramic (iron-oxides) nanostructures, such as Fe3O4 and
γ-Fe3O3, for PTT. Chu et al. [18] showed that various shapes of Fe3O4 NPs were able to
kill cancer cells and tumors in in-vitro and in-vivo models, respectively. In another study,
Espinosa and co-workers [19] demonstrated the ability of Fe3O4 NPs to act simultaneously
as magnetic and photothermal agents, so-called photothermal agents.
Nanocomposites, which are materials that are formed by incorporating nanoparti-
cles as fillers into polymer-based matrices were first reported in the literature in 1961
by Blumstein [20] in order to improve the thermal stability of PMMA. In the last few
decades, their use as stimuli-responsive multifunctional materials has played a major
role in opening up new frontiers in several fields in biomedical engineering such as drug
delivery, tissue engineering, thermotherapy and biosensing [21–23] For example, function-
alized hydrogel nanocomposites have been exploited for several targeted drug delivery
applications for cancer treatment [22]. Furthermore, several investigators have reported
the use of polymethylmethacrylate (PMMA)-based nanocomposites as bone cements for
several application in orhtopaedics and tissue engineering applications [24]. Our group
recently reported a novel nanocomposite probe for killing of cancer cells [23]. The probe
is essentially a cannula with a distal heat generating magnetic nanocomposite tip and
a proximal insulated shaft. Bonyár and co-workers [25] demonstrated the use Au/Ag
Poly-dimethylsiloxane (PDMS) films to enhance the sensitivity of substrates that are used
for surface enhanced Raman spectroscopy based biosensing applications.
Au NPs have been the prime candidates for photothermal therapy, due characteristics,
such as their tunable optical properties and biocompatibility [26]. Several groups have
reported fundamental research studies using in-vitro and in-vivo experiments. Recently,
Materials 2021, 14, 841 3 of 16
Rastinehad et al. [27] reported a pilot clinical trial using Au nanoshell for localized pho-
tothermal ablation of prostate tumor. PDMS is a silicone-based elastomer that possesses an
attractive combination of properties, including inertness, biocompatibility, optical trans-
parency, and high elasticity. Because of these material properties and its ease of fabrication,
it has been widely utilized to prepare different nanocomposites for several biomedical
applications [28]. In this study, we explored the feasibility of Au-PDMS nanocomposite
implants (photoseeds) for IT. First, we studied the optical and structural properties of the
Au NPs and Au-PDMS. Second, the heating performance of the fabricated cubic photoseeds
was investigated in aqueous solutions and in-vitro cancer cell suspensions. Finally, the
in-vivo performance of the cylindrical photoseeds was studied by simulating the heating
of breast tissue with a three-dimensional finite element method (3D FEM) model, which
was validated with experimental temperature measurements in aqueous solution.
2. Methods
2.1. Experimental Analysis
Materials Characterization. The morphologies of the Au NPs (99.97+%, 28 nm, US
Research Nanomaterials Inc., Houston, TX, USA) were studied with a transmission elec-
tron microscope (TEM, Philips CM10, Philips Electron Optics, Eindhoven, The Nether-
lands). The absorption spectra of molten Au-PDMS nanocomposites were acquired with a
Xenon lamp-based UV-vis-NIR spectrophotometer (Evolution 300, Thermo Fisher Scientific,
Waltham, MA, USA). A Fourier transform infrared spectroscopy (FTIR, Tensor 27, Bruker
Inc, Madison, WI, USA) was used to investigate the functional groups of the nanocomposite
samples. The scan wave number was in the range of 600 to 3000 cm−1.
Nanocomposite preparation and Implant Fabrication.We prepared the Au-PDMS
nanocomposites by varying the weight fraction of the Au NPs (φAu) within pristine PDMS
(Sylgard 184 silicone elastomer kit, Dow Corning Corp., Auburn, MI, USA) matrix using
the conventional blend mixing method according to the manufacturer’s specifications,
as follows: we (a) mixed the base and curing agent in a 10:1 ratio by weight, (b) stirred
with spatula for about 20 min. to produce a uniform mixture with adequate cross-linking,
(c) degassed for 15 min in a glass beaker that was connected to a vacuum pump to remove
bubbles, (d) added NPs to the mixture, stirred for another 10 min, and then degassed again
for 15 min, (e) poured mixture into cubic acrylic moulds with a side length of 0.5 cm, and
(f) cured at 100 ◦C in an oven for 35 min. The two types of nanocomposites that were
fabricated in the study were designated as AuNP-5 and AuNP-10, according to the φau of
5%, and 10%, respectively. AuNP-0, pristine PDMS, was studied as a control.
Photothermal Measurements. Figure 1 shows the experimental setup used for pho-
tothermal measurements. The sample (photoseed in 0.5 mL of deionized water or suspen-
sion of cells) contained in a 1.5 mL Eppendorf tube was irradiated by an NIR continuous
laser at a wavelength, λ, of 810 nm (Photon Soft Tissue Diode Laser, Zolar Technology &
MFG, Canada) with an external adjustable power, P0 (0–3 W). The distance between the
sample and laser was 4–5 cm and the laser spot diameter was 1 mm. The laser power
range was between 0.5–1.0 W. Each sample was identically exposed for 5 min. The surface
temperatures were also continuously captured with an infrared camera (E5 Thermal Imager,
FLIR Systems Inc., Wilsonville, OR, USA). Additionally, the measurements were obtained
in triplicates, except stated otherwise.
Materials 2021, 14, 841 4 of 16
Figure 1. Experimental setup used for the photothermal measurments. The sample (a photoseed
and 0.5 mL of deionized water or suspension of cells) contained in a 1.5 mL Eppendorf tube was
irradiated by a near-infrared continuous laser at a wavelength of 810 nm.
In order to evaluate the heat generation capabilities, the photothermal conversion
efficiency, η was calculated based on the formulation that was developed by Roper et al. [29],
which is expressed as
Q mwcp ∆T
η =
P0(1− 10−A
= (1)
810) P0(1− 10−A810) ∆t
where Q represents the heat that is dissipated by electron-phonon relaxation of plasmons
on the Au surface induced by the laser irradiation of Au NPs at λ = 810 nm assuming that
heat dissipated from light absorbed by the Eppendorf tube, conduction, and radiation were
negligible. m −1 ◦ −1w (g) and (cp = 4.185 J g C ) are the mass and constant pressure specific
heat capacity of water, respectively. T (◦C) represents temperature and t (s) time. A810 is
the absorbance at λ = 810 nm.
Cell Culture and Viability. 20 µL of 1× 105 MDA-MB-231 cells (American Type Culture
Collection, Manassas, VA, USA) were cultured each in 75 cm2 CELLTREAT tissue culture
flask (T75 flask), (Pepperell, MA, USA) at 37 ◦C. This was done under normal atmospheric
pressure levels in a Leibovitz’s L-15 medium (Thermo Fisher Scientific, Inc., Waltham, MA,
USA), which was supplemented with 100 I.U. mL−1 penicillin/100 µg mL−1 streptomycin
and 10% FBS to form a “L15+" medium (Sigma-Aldrich, St. Louis, MO, USA). The cells
were incubated for 72 h to obtain about 70% confluent cells in the tissue culture flask.
Subsequently, the cell samples were rinsed with sterile DPBS (Fisher Scientific, Pittsburg,
PA, USA), followed by Trypsin-EDTA solution (Fisher Scientific, Pittsburg, PA, USA) in
order to reduce the concentration of divalent cations and proteins that inhibit trypsin action.
The solutions in the flask were kept in the incubator for 2 min. This was done to detach the
cells from the flask surface. L15+ medium was added and the combination of cells in these
solutions were centrifuged to count and determine the number of live cells present. The
resulting pellet from the centrifugation was resuspended in 1 mL of the L15+ medium. For
photothermally heated cells, their viability was evaluated with the Trypan Blue Exclusion
(TBE) assay that is described in the next section.
Materials 2021, 14, 841 5 of 16
Trypan Blue Exclusion (TBE) Assay. Cytotoxicity was measured using the TBE assay
method. Trypan blue is a molecule that is able to enter cells with damage to their mem-
branes. Trypan blue stock solution was added to cell suspensions. After that, the resulting
solutions were loaded in a hemacytometer and then examined under an optical microscope
at low magnification. Cell viability (CV) was determined with the following expression
% CV = [1.0− (viable cell÷ total cells)]× 100 (2)
where viable cells are cells that were taken up by the trypan blue dye, which causes
them to turn blue. Total cells, which represents the total number of cells counted before
application of the laser. The relative CV was measured by comparison with a control,
which corresponds to a condition without a photoseed (cells only).
2.2. Computational Analysis
The COMSOL Multiphysics 4.3a Software package (Comsol, Burlington, MA, USA)
was used in order to develop a finite element method (FEM) model of biological tissue
that were embedded with photoseeds and irradiated with a continuous wave Gaussian
NIR laser beam. The model, which combined optical and thermal effects, was then used to
predict photothermal profiles and cell death.
Geometry. The geometry that was used in the FEM model, as shown schematically in
Figure 2, consisted of tissue embedded with cylindrical photoseeds. According to Ref. [30],
such models give a better illustration of the main thermal phenomena. The tissue was
configured as a multi-layered block of tissue with proportions being assigned according
to the Breast Imaging Reporting and Data System (BIRADS) developed by American
Cancer Research [31]. 4 cylindrical photoseeds were centrally arranged in a 2× 2 array
within the tissue block. The space (s) between the photoseed array was 0.5 cm. The
diameter (ds) and length (L) of the photoseed were 1 mm and 1.5 cm, respectively. P1 is
the control point where temperatures were recorded. The assigned optical, thermal, and
physical properties of different tissue layers were approximate values that were obtained
from the literature. The material properties of the photoseeds were assumed to represent
AuNP-10. Its absorption coefficient, µa, was calculated from the UV-vis-NIR absorbance at
λ = 810 nm (A810) while using the expression [32]:
µa = 2.303A810/l (3)
where l = 30 µm is the thickness of the sample.
Figure 2. FEM geometry. Schematic of the model used to predict the in-vivo photothermal heating. d is the distance
between adjacent photoseeds and L is the length of the photoseed.
Materials 2021, 14, 841 6 of 16
Light Distribution. The optical diffusion approximation of the transport theory [33]
was used to describe light distribution due to the dominance of scattering over absorption
in biological tissues. Assuming that the light source was a continuous wave Gaussian NIR
laser beam that was incident onto the breast model, the ϕ can be defined by
P0 exp(−µeff~r · n̂)φ(~r) = (4)
4πDr
where P0 is the laser power and n̂ is the direction of the beam. Table 1 presents a summary
of the values of the optical properties of the tissues, which were obtained from Ref. [34].
Table 1. The optical properties of the biological domains that were used in the simulations. The
values were obtained from Ref. [34].
Coefficients, (m−1)
Tissue
Absorption, µa Reduced Scattering, µ′s
Fat 3 950
Gland 6 1100
Temperature Distribution. The Pennes bio-heat transfer equation [35] was used to
estimate the temperature distribution. The resulting equation is given by:
∂T
ρcp = λ(T)∇2T + ρbcbωb(Ω)(Tb − T) + Qmet + Q (5)∂t
where ρ (kg m−3) is the density, c (J kg−1 K−1p ) is the specific heat capacity at constant
pressure. λ(T) (W m−1 K−1) is the temperature dependent thermal conductivity, which is
assumed to be a linear function that is defined by [36]:
λ(T) = λ(37 ◦C)[1 + 0.0028(T − 293.15K)] (6)
where T (K) and Tb (K) are the normal body and arbitrary temperatures, respectively. ρb is
the density of blood, cb, the specific heat capacity of blood, and ωb(Ω) is the coefficient
of blood perfusion that is assumed to be dependent on the cell damage, Ω, and is defined
by [37,38]:
 ω0b if Ω = 0
 (1 + 25Ω− 260Ω
2)ω0b , if 0 < Ω ≤ 0.1ωb(Ω) =  (7)(1−Ω)ω0b , if 0.1 < Ω ≤ 1
0, if Ω > 1
ω0b (s
−1) is the baseline coefficient of blood perfusion. Q −3met (W m ) is the metabolic
heat. Q accounts for external heat sources, which varies for the different domains of
geometry. The heat that is generated after the absorption of NIR light is defined as µa ϕ(r)
(W m−3) and Nσa ϕ(r) (W m−3) for all domains. Table 2 presents a summary of the values
of the thermo-physical properties that were used in the simulation were obtained from the
literature [38,39].
Thermal Damage. The Arrhenius injury model was used to estimate tissue destruction.
The model, which relates temporal temp∫erature(to cell d)eath, is defined by [40]:τ −E
Ω a(τ) = A exp dt (8)
0 RT(t)
Materials 2021, 14, 841 7 of 16
where Ea (J mol−1) is the activation energy, A (s−1) is a scaling factor, and R = 8.3 (J mol−1K−1)
is the gas constant. The values for Ea and A were obtained from Ref. [38] as 302 kJ mol−1 and
1.18 × 1044 s−1, respectively. Ω = 1 corresponds to the 100% irreversible cell damage.
Table 2. Thermo-physical properties of the biological domains that were used in the simulation.
The values were obtained from Refs. [38,39].
Tissue c [J (kg K)−1] λ [W (mK)−1] ρ [kg m−3] Qmet [W m−3] ωb [s−1]
Fat 2348 0.21 911 400 0.0002
Gland 2960 0.48 1041 700 0.0005
Blood 3617 - 1050 - -
Model Validation. Finally, experimental measurements were made using a water
model in order to validate the numerical model. A single cubic AuNP-10 photoseed
(volume = 0.125 cm3) was inserted into 0.5 mL distilled water in a 1.5 mL Eppendorf
tube. The samples were allowed to equilibrate at room temperature (≈25 ◦C) prior to
their exposure to irradiation by a 1 W (810 nm) continuous near-infrared laser for 5 min.
Three water samples were heated with the same photoseed. Temperature measurement
was made at the bottom surface of the photoseed. The computational model calculations
were made following the same experimental protocol. The baseline temperature for the
calculations was 25 ◦C, instead of the 37 ◦C used in the main simulations. The calculated
temperatures were directly compared with the experimental measurements.
Implementation. All of the properties and dimensions were explicitly added to
the FEM model as parameters and variable under the “Global Definition” and “Model”
nodes, respectively. The geometry was drawn with the “ellipsoid”, “block”, “sphere”, and
“cylindrical” shapes, as well as the “difference” and “union” transform functions.
The temperature distribution was achieved using the bio-heat heat transfer application
mode. Additionally, 37 ◦C was taken as the initial temperature of the model, and all of the
boundary conditions were specified as those outlined above. The heat source was added to
the bio-heat transfer application mode as a user-defined heat source.
We resolved the model with successively smaller element sizes and compared the
results, until an asymptotic behavior of the solution emerged, in order to enhance the
accuracy of results. The comparison was done by analyzing the temperature at the interface
between photoseed and the tissue. The mesh size for all calculations was defined as a
physics-controlled mesh with the element size specified as “extra fine” (element sizes:
maximum = 0.42 cm and minimum = 0.018 cm) and “extremely fine” (element sizes:
maximum = 0.24 cm and minimum = 0.0024 cm) for the tissue and photoseed domains,
respectively. This resulted in 91,557 tetrahedral; 4952 triangular; 236 edge; and, 11 vertex
elements. The degrees of freedom were 126,430. The numerical solutions were obtained
using the time-dependent solver “GMRES” with its default settings. The simulations were
run on a mid-range workstation with Intel(R) Xeon(R) E5-1620 CPU and 8GB of RAM.
The numerical solution was broken down into three steps: (i) The volumetric power
output was calculated using Equation (4), (ii) the temperature distribution was determined
as a function of time, using the output from step (i) as heat generation term in Equation (5),
and (iii) the thermal dose was calculated as a function of time, using the temperature
history, and it was used as the input to Equation (8). Time-dependent studies were carried
out in all of the finite element analyses.
Materials 2021, 14, 841 8 of 16
3. Results
3.1. Experimental Analysis
Materials Characterization. TEM revealed the spherical morphology of the AuNPs
(Figure 3a) and NP size distribution with an average diameter of 28 nm. UV-vis-NIR spectra
(Figure 3b) show extended profiles that were independent of the [Au] and an A810 that
increased with the [Au] (Figure 3c). For instance, A810 increased from ≈1.28 to 1.54 when
φAu was increased from 5 to 10 wt.%. Here, it is important to note that the photothermal
efficiency of any type of NIR photothermal heating depends on the optical absorption in
the NIR regime and these results suggest that increasing the [Au] will increase absorbance,
leading to high heat generation. Photographs of the photoseeds—AuNP-0 (Figure 3d)
and AuNP-10 (Figure 3e)—that was used in our photothermal experiments. FTIR spec-
troscopy (Figure 3f) revealed the characteristic bands of AuNP-0 at V (7.56–8.64 m−1), W
(10.10–10.57 m−1), X & Y (12.57 & 14.11 m−1), and Z (29.50–29.62 m−1) corresponding to
-CH3 rocking and Si-C stretching in Si-CH3, Si-O-Si stretching, -CH3 deformation in Si-CH3
and asymmetric -CH3 stretching in Si-CH3, respectively. These bands were not affected by
the addition of NPs. This suggests that no primary chemical bonds were formed during
the nanocomposite preparation process.
Photothermal heating in aqueous solution. The photothermal heat generation perfor-
mance of the photoseeds in aqueous solution was evaluated based on initial (after t = 30 s)
heating rate, dT/dt, temperature rise, ∆T, and the corresponding η, following 5 min of
irradiation at two different P0 : 0.5 and 1.0 W). Table 3 and Figure 4 summarize the results.
As expected, dT/dt and ∆T increased with P0 and [Au] (Figure 4a,b). For instance, dT/dt
increased from 0.03 to 0.08 ◦C/s (∆T: 8.32 to 17.84 ◦C) when the P0 used to irradiated
AuNP-5 was increased from 0.5 to 1.0 W (Table 3). Additionally, the heating rate increased
from 0.03 to 0.06 ◦C/s (∆T: 8.32 to 15.20 ◦C) for AuNP-5 and AuNP-10, respectively when
they were irradiated at P0 = 0.5 W (Table 3). Furthermore, it can seen from Figure 4c that η
increased with P0 but decreased with [Au].
Table 3. A summary of the results from photothermal measurements expressed as the mean values of initial (t = 30 s)
heating rate, dT/dt, temperature change, ∆T, calculated as the difference between the initial (t = 0 min) and final (t = 5 min)
temperatures and η, photothermal conversion efficiency, calculated while using Equation (1).
P0 = 0.5 W P0 = 1.0 W
Sample [Au] (wt.%)
dT/dt (◦C/s) ∆T (◦C) η (%) dT/dt (◦C/s) ∆T (◦C) η (%)
In Aqueous Solution
AuNP-5 5 0.03 8.32 29.61 0.08 17.84 63.47
AuNP-10 10 0.06 15.20 26.38 0.09 27.46 47.66
No photoseed - - 1.30 - - 2.70 -
In-vitro Suspension
AuNP-10 + Cells 10 - 5.40 - - 11.5 -
Cells only - - 1.80 - - 2.70 -
Materials 2021, 14, 841 9 of 16
Figure 3. Materials characterization results. (a) Transmission electron microscopy (TEM) of the Au nanoparticles (AuNPs),
Scale bar: 30 nm, (b) UV-vis-near infrared (NIR) absorbance spectra of the Gold and Poly dimethylsiloxane (Au-PDMS)
nanocomposites at different [Au]: 5 and 10%. Absorbance as a function of (c) wavelength (λ) and (d) [Au] at λ = 810 nm.
Photographs of fabricated samples (Scale bar: 4.5 mm): (d) AuNP-0 and (e) AuNP-10. (f) Fourier transform infra-red of all
three samples.
Photothermal Heating of Cells Suspension. Based on the results of photothermal
heating in aqueous solution, we used a AuNP-10 sample (due to its capability to produce
desired temperature levels at low P0) to evaluate the ability of a photoseed to kill in-
vitro MDA-MB-231 breast cancer cells that are suspended in aqueous solutions during
irradiation at two different P0-0.5 and 1.0 W. Cells suspensions containing no photoseed
were used as the control. Calculated cell viabilities (Figure 5a) showed a clear dependence
on temperature levels (Figure 5b). The maximum T varied as a function of the presence or
absence of AuNP as well as P0. For instance, CV reduced from ≈91% (no. of cells: total—113,
viable: 59, ∆T = 42 ◦C) to≈48.8% (no. of cells: total—113, viable: 59, ∆T = 49 ◦C) when P0
used to irradiate the cells suspension in the presence of AuNP-10 was increased from 0.5 to
1.0 W. Without the photoseed, CV remained relatively high, ≈97% (no. of cells: total—113,
viable: 59, ∆T = 42 ◦C) and ≈94% (no. of cells: total—113, viable: 59, ∆T = 42 ◦C) for
P0 of 0.5 and 1.0 W, respectively. The time dependence of the cell death due to elevated
temperature levels has been previously reported [41,42].
Materials 2021, 14, 841 10 of 16
Figure 4. Photothermal heating in aqueous solution results. Temporal response curves for the
different samples when (a) P0 = 0.5 W and (b) P0 = 1.0 W. (c) Conversion efficiency (η) as a function
of P0 for different P0 W. Exposure time: t = 5 min.
Figure 5. Photothermal heating in cell suspensions results. (a) In vitro cell viability assessed with
Trypan blue dye and (b) the corresponding temperature change as a function of laser power after
5 min of irradiation.
Materials 2021, 14, 841 11 of 16
3.2. Computational Analysis
In order to assess the in-vivo performance of the photoseeds, we conducted a para-
metric study based on P0-(0.5–2.0 W; 0.5 W step). Each simulation was run for 15 min.
A comparison of the three cross-sectional (xy, zy, zx planes) views of the predicted
temperature profiles for the case when P0 = 1 W (Figure 6a) showed to be a nonuniform
distribution with the maximum occurring around the photoseeds and within the boundary
that formed by the simple 2× 2 photoseeds configuration (see Figure 6a). It can also be
observed that the geometry of the lesion was different for each cross-sectional view. This
suggests a dependence of the geometry on the configuration of the photoseeds within
the tissue. Furthermore, the temperature at the center of the boundary formed by the
photoseeds (P1, cf. Figure 2) rose sharply and then approached a plateau ≈3 min after the
laser beam was turned on (Figure 6b). As expected, the heat spread radially outward into
the tissue surrounding the photoseeds boundary (Figure 6c). This is consistent with heat
transfer by conduction.
Figure 6. FEM simulation results. (a) Predicted temperature distributions for different cross-sectional views of the geometry.
Temperature change as a function of (b) time at and (c) distance away from point P1. Study parameters: P0 = 1.0 W, t = 15 min.
It can be seen from the comparison of the cross-sectional (zx plane) views of the
predicted thermal dose profiles (Figure 7) for the four different laser powers that the
size of the area where complete thermal damage (Ω = 1) occurred increased with P0. It
moved from virtually no damage when P0 = 0.5 W to just around the photoseeds when
P0 = 1.0 W to covering the entire area enclosed by the photoseeds and a little bit beyond
when P0 = 1, 5 W to a perimeter that surrounds the photoseeds with a bigger interval when
P0 = 2.0 W than for the case when P0 = 2.0 W. Here, it is important to note that using the
laser beam power increases to enlarge the lesion size must be done cautiously to mitigate
the deleterious effects of the laser beam on adjacent tissue as shown for the case when
P0 = 2.0 W (see Figure 6a). Additionally, it can be observed from Figure 7b,c that the time
required to attain Ω = 1 decreased and the size of lesion increased, respectively, with
increasing P0.
Materials 2021, 14, 841 12 of 16
Model Validation. The FEM predictions were consistent with the experiments, where
the temperature (measured around the photoseed) increased with time. The duration
of prediction temperatures were also in good agreement with the experimental results
(Figure 8).
Figure 7. FEM Simulation results. (a) Comparison of the cross-sectional views (zx-plane) thermal distributions for different
P0. Thermal damage as a function of (b) time at and (c) distance away from point P1. Study parameters: P0 = 0.5–2.0 W,
t = 15 min.
Figure 8. FEM model validation results. Comparison of the temporal response curves for the FEM
predictions and experimental data for a 5 min irradiation of a cubic photoseed (φau = 10% wt.) in
0.5 mL of distilled water contained in a 1.5 mL Eppendorf tube.
4. Discussion
Recent efforts to develop mulitfunctional nanocomposite materials have presented
engineers with devise opportunities to design novel strategies that are opening up new
Materials 2021, 14, 841 13 of 16
frontiers in cancer treatment. Furthermore, laser-based technologies provide desirable
benefits over other conventional modalities, such as radiation, microwave, radiofrequency,
and ultrasound. They offer precise selectivity in heating with more control over blood
perfusion and shorter treatment duration. Additionally, they are easier to setup and
can be easily coupled with when imaging devices with minimal image artefacts [43].
The combination of these two technologies in the manner present here and previously
reported elsewhere can potentially overcome the challenges associated with the thermoseed
technique.
N-PTT strategies depend on an interplay between several factors, such as the pho-
tothermal (optical) capabilities of the nanocomposites, the configuration of the implants
within the target tissue, and the irradiation protocols (e.g., power, shape, duration cross-
section, and direction of the laser source) [18]. Here, we performed several experiments to
explore key aspects of these factors. We showed the feasibility of fabricating the photoseeds
and their ability to generate heat when irradiated with NIR (810 nm) laser in aqueous
solutions and in-vitro cell suspensions. Generally, the trend of T that is observed in these
experiments is in agreement with measured absorbance properties and also consistent with
previously reported studies [44]. For the case of the anomalous reciprocal relationship
between η and [Au], according to Qin et al. [45] a combination of small size (<30 nm) and
low concentration leads to high η. However, increasing [Au] may lead to the formation of
clusters, due to the high surface area to volume ratio of the NPs. Therefore, it is reasonable
to state here that the η of AuNP-10, which had a higher NP concentration, was lower than
AuNP-5, because clusters in AuNP-10 acted as large particles to increase scattering at the
expense of absorption.
For such remotely controlled interstitial techniques, patient safety should be taken into
consideration during the selection of laser parameters, since high doses can cause collateral
damage to healthy tissue [46]. Computational modeling is an essential part of N-PTT
strategies, because it enables treatment, wplanninghich is usually aimed at customizing
treatment parameters for optimal results [47]. Here, we used the smallest building block
(2× 2 array) of photoseed configuration in the tissue to show that the predicted lesions
spread radially outwards from within the array boundaries, where the highest temperature
occurs. Generally, this result is similar to those that were reported for thermoseeds. For
instance, Chen et al. [30] performed a 3D computational study of ferromagnetic implant
hyperthermia using a fixed 4× 4 array and showed that the higher temperature occurred
within the region containing the thermoseeds and spread radially outwards. Dughiero
et al. [3] found that the geometry of the lession was not affected by configuration when
they compared the results of a uniform 3× 3 array and a nonuniform arrangement of 20
thermoseeds. It is important to note that the lesion size can be altered by material properties,
which, for the case of nanocomposite, can be achieved through the manipulation of the
concentration of NPs and the kind of polymer. The direct heating of the tissue by the laser
beam, as predicted by the FEM model, can be exploited to reduce the number of photoseeds
used.
We acknowledge that the Au-PDMS nanocomposite model system that was used in
our study does not have the desired thermal self-regulating feature of the ferromagnetic
metal alloys. Au NPs were mainly used because they have been the prime candidates
for photothermal therapy [26]; however, several groups have recently shown Fe3O4 NPs
to exhibit photothermal properties [18,19]. In addition to their approval for biomedical
use by the United States Food and Drug Administration, there is an opportunity to ma-
nipulate their composition during synthesis to obtain CTTs that meet the requirements
for thermotherapy [48,49]. This offers the opportunity for thermal self-regulating features
to be to incorporated in the photoseeds. Furthermore, recent studies that have explored
the simultaneous application (DUAL-mode) of both NIR laser and alternating magnetic
field (AMF) to the Fe3O4 NPs have shown promising and interesting results. The studies
found that the amount of heat that was generated with DUAL-mode equaled the sum of
the heating for NIR laser or AMF only [19]. The essence of these results is that the use of
Materials 2021, 14, 841 14 of 16
the DUAL-mode can potentially lead to a reduction in the number of implants needed to
achieve therapeutic temperature levels.
Finally, the results that are presented here provide useful insights that offer a context
within which the feasibility of the photoseeds for IT can be discussed. However, we
acknowledge that extensive experimental work, including in-vivo studies, is needed to
obtain a realistic assessment of the actual performance of this novel approach.
5. Conclusions
In summary, we used a combination of experiments and models to demonstrate the
feasibility of using photothermally heated photoseeds for interstitial therapy. Experimen-
tally, we found that the photoseeds were capable of generating plasmonic heat under NIR
laser irradiation to increase the temperatures in two different media—aqueous solution
and cell suspensions. The maximum T values obtained were shown to be a function of
parameters, such as NP concentration and laser power. Using in-vivo predictions, we
showed how the geometry of the lesion is influenced by the laser power and configuration
of the implants within the target region. Collectively, the implications of the results are
quite significant, since such N-PTT strategies provide several opportunities to overcome
the challenges that are associated with conventional thermoseed technique. For instance,
photoseed will benefit from a plethora of novel nanomaterials and polymers coupled with
facile nanocomposite processing methods and recent advances in laser delivery equipment.
Our long term goal is to develop an interstitial thermotherapy technique that is based on
photoseeds that will be fabricated at the point of care based on patients data.
Author Contributions: Conceptualization, K.K.-D. and Y.K.K.-A.; methodology, K.K.-D. and Y.K.K.-
A.; software, K.K.-D.; validation, K.K.-D.; formal analysis, Y.K.K.-A.; investigation, K.K.-D. and
Y.K.K.-A.; resources, K.K.-D.; writing—original draft preparation, Y.K.K.-A.; writing—review and
editing, K.K.-D.; supervision, K.K.-D.; project administration, K.K.-D.; funding acquisition, K.K.-D.
All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by the University of Ghana Building a New Generation of Aca-
demics in Africa (BANGA-Africa) project with funding from the Carnegie Corporation of New York.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data presented in this study are available in article.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or
in the decision to publish the results’.
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