IEEE TRANSACTIONS ON NANOBIOSCIENCE, VOL. 19, NO.

3, JULY 2020 357

Modeling of Modulated Exosome Release From

Differentiated Induced Neural Stem Cells
for Targeted Drug Delivery
Mladen Veletić , Michael Taynnan Barros , Member, IEEE, Hamidreza Arjmandi ,
Sasitharan Balasubramaniam, Senior Member, IEEE,
and Ilangko Balasingham , Senior Member, IEEE

Abstract — A novel implantable and externally control- exosomal secretion and release via induced stimulation with
lable stem-cell-based platform for the treatment of Glioblas- electromagnetic, optical and/or ultrasonic waves.
toma brain cancer has been proposed to bring hope to Index Terms — Brain, drug delivery systems, exosomes,
patients who suffer from this devastating cancer type. glioblastoma, molecular communication, stem cells.
Induced Neural Stem Cells (iNSCs), known to have potent
therapeutic effects through exosomes-based molecular I. I NTRODUCTION
communication, play a pivotal role in this platform. Trans-
planted iNSCs demonstrate long-term survival and differen-
tiation into neurons and glia which then fully functionally
integrate with the existing neural network. Recent studies
G LIOBLASTOMA Multiforme is the most prevalent and
devastating brain disease whose treatment has the lowest
success rates compared to other therapeutic cancer technolo-
have shown that specific types of calcium channels in dif- gies [1]. The development of brain drug delivery systems
ferentiated neurons and astrocytes are inhibited or activated for this type of cancer is very challenging because of side
upon cell depolarization leading to the increased intracel-
lular calcium concentration levels which, in turn, interact
effects, the complexity of the structures of the brain, and the
with mobilization of multivesicular bodies and exosomal stringent Blood-Brain Barrier (BBB) that protects the brain
release. In order to provide a platform towards treating from damage and potentially toxic blood-borne molecules.
brain cancer with the optimum therapy dosage, we propose Besides, the lack of efficient technologies to deliver drugs
mathematical models to compute the therapeutic exosomal in the located deep and functional brain regions, such as
release rate that is modulated by cell stimulation patterns
applied from the external wearable device. This study serves
the brain parenchyma, and across the BBB hinders the treat-
as an initial and required step in the evaluation of controlled ment of brain pathologies [2]. Hence, novel technologies for
Glioblastoma cancer therapy must emerge to overcome the
BBB blockage while efficiently reaching the brain parenchyma
Manuscript received February 8, 2020; revised April 23, 2020 and
April 27, 2020; accepted April 28, 2020. Date of publication May 6,
within safety guidelines.
2020; date of current version July 1, 2020. This work was supported Molecular communication paradigm has been recently
in part by the EU (EU-H2020-FETOpen GLADIATOR—Next-generation proposed to model particulate drug delivery systems,
Theranostics of Brain Pathologies with Autonomous Externally Control-
lable Nanonetworks: A Trans-disciplinary Approach with Bio-nanodevice
e.g., [3]–[6] and yield analytical expressions that can be of
Interfaces) under Grant #828837 and in part by the Research Council practical use. An externally controllable molecular commu-
of Norway (RCN:WINNOW—Wireless In-body Sensor and Actuator Net- nication platform [7] that consists of stem cells acting as ther-
works) under Grant #270957. (Corresponding author: Mladen Veletić.)
Mladen Veletić is with the Intervention Centre, Oslo University Hospital
apeutic, reporting and diagnostic bio-nanomachines has been
(OUS), 0372 Oslo, Norway, and also with the Faculty of Electrical proposed in the project GLADIATOR: Next-generation Thera-
Engineering, University of Banja Luka, 78000 Banja Luka, Bosnia and nostics of Brain Pathologies with Autonomous Externally Con-
Herzegovina (e-mail: [email protected]).
Michael Taynnan Barros is with the BioMediTech Institute, Tam-
trollable Nanonetworks: a Trans-disciplinary Approach with
pere University, 33520 Tampere, Finland, and also with TSSG, Water- Bio-nanodevice Interfaces (EU-H2020-FET-Open #828837).
ford Institute of Technology, X91 P20H Waterford, Ireland (e-mail: The project is focused on Glioblastoma treatment based
[email protected]).
Hamidreza Arjmandi is with the Electrical Department, Yazd Uni-
on stem-cell-based treatment and external control of
versity, Yazd 89195-741, Iran, and also with the Department of bio-nanomachines communications and comprises of the fol-
Electronics and Telecommunications, Norwegian University of Sci- lowing [8]:
ence and Technology (NTNU), 7491 Trondheim, Norway (e-mail:
[email protected]). • The therapeutic bio-nanomachines – autologous
Sasitharan Balasubramaniam is with the Telecommunication organoids of engineered induced Reprogramming
Software and Systems Group, Waterford Institute of Technology, Neural Stem Cells (iR-NSCs) implanted into the
X91 P20H Waterford, Ireland (e-mail: [email protected]).
Ilangko Balasingham is with the Intervention Center, Oslo Univer- brain parenchyma to synthesize and release rationally
sity Hospital (OUS), 0372 Oslo, Norway, and also with the Depart- designed therapeutic molecules. The iR-NSCs are
ment of Electronics and Telecommunications, Norwegian University of controlled by external miniature wearable devices via
Science and Technology (NTNU), 7491 Trondheim, Norway (e-mail:
[email protected]). in-messaging communication channels. Therapeutic
Digital Object Identifier 10.1109/TNB.2020.2991794 molecules interfere with the target Glioblastoma cells

1536-1241 © 2020 IEEE. Personal use is permitted, but republication/redistribution requires IEEE permission.
See https://www.ieee.org/publications/rights/index.html for more information.

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358 IEEE TRANSACTIONS ON NANOBIOSCIENCE, VOL. 19, NO. 3, JULY 2020

Fig. 1. Block diagram of the brain tumor management platform as a fully

autonomous externally controllable molecular communication network.
The controlled release of therapeutic molecules by the autologous
organoid has been considered in the presented paper.
Fig. 2. Exosome biogenesis and release from the late endosomes known
whose location is known. Therapeutic molecules also as the multivesicular bodies. Extracellular stimuli can enhance exosome
formation and trigger exosome release.
interfere with another type of bio-nanomachines, that we
call reporting bio-nanomachines.
• The reporting bio-nanomachines – engineered Glioblas- The therapeutic bio-nanomachines, i.e., the iR-NSCs which
toma Stem Cells (GSCs) that serve as the gateway for synthetize and release exosomes, can be obtained from human
communicating the efficacy of the treatment. The GSCs somatic cells through direct lineage conversion of differ-
synthesize and release reporting molecules. entiated cells [14]. The iR-NSCs implanted into the brain
• The diagnostic bio-nanomachines – engineered induced differentiate into neurons and glia. In the adult mouse brain
Monitoring Neural Stem Cells (iM-NSCs) that collect though, they have demonstrated long-term survival and dif-
and analyze reporting molecules. The iM-NSCs serve ferentiation into neurons (cortex: 3.26% ± 2.14%; hilus:
as ‘sensors’ of the hybrid implantable diagnostic system 2.51% ± 1.11%, observed in 6 mice), astrocytes (cortex:
which provides feedback to external miniature wearable 74.46% ± 5.38%; hilus: 68.87% ± 4.48%, observed in more
devices via out-messaging communication channels. than 5 mice), and oligodendrocytes (cortex: 4.34% ± 2.20%;
External wearable devices with enabling communication inter- hilus: 4.24% ± 2.03%, observed in more than 3 mice) within
faces, iR-NSCs, GSCs, and iM-NSCs form a radically new six months [15]. Differentiated iR-NSCs migrate, functionally
closed-loop platform for the management of brain malignan- integrate, and interact with the existing neuronal circuitry.
cies shown in Fig. 1, and provide a breakthrough theranostic The therapeutic exosomes are produced through intracellu-
(therapeutic + diagnostic) intervention. lar machinery and released from cells upon fusion of an
A promising strategy in stem-cell based platforms is to intermediate endocytic compartment, called the multivesicular
use extracellular vesicles, specifically exosomes, as cargos body, with the plasma membrane through the process called
to deliver, respectively, therapeutic and reporting molecules exocytosis [16], as shown in Fig. 2.
to their recipients [9]–[11]. Exosomes are 40 − 100 nm There is the experimental evidence in the literature that
cell-derived extracellular vesicles that play an important role exosome release from neurons and glia within the cen-
in cell-to-cell signaling by keeping and transporting trans- tral nervous system does exist in-vitro [17] and in-vivo
membrane proteins in their lipid bilayer and the cytosol [18]–[23]. Besides, the experimental evidence shows that 1) in
molecular components from their progenitor cell including neurons, glutamatergic activity is enhanced by depolarization
functional proteins, genetic lipids, genetic materials like mes- and an increase in the intracellular calcium which is further
senger RNA (mRNA), microRNA (miRNA), short interfering associated with enhanced exosomal secretion and release from
RNA (siRNA), and genomic DNA (gDNA) [9]. Upon arrival somato-dendritic compartments [24], [25], and 2) in astrocytes,
to the target cell, exosomes fuse to the cell’s membrane and vesicular secretion and release are regulated by intracellu-
deliver the transmembrane proteins and biologically active lar calcium levels [26], [27]. Although the exact molecular
molecules. Due to their biological tolerability, natural target- mechanisms underlying regulated exocytosis in neurons and
ing, and phagocytosis-inhibition factors, exosomes have been astrocytes have yet to be fully resolved, we form a hypothesis
recently regarded as one of the most promising opportunities to based on the cited works that stimulation patterns, e.g., radio-
deliver chemical packages to the target cell, while protecting frequency, ultrasonic, or optical waves [28]–[30], applied
the packages from enzymes circulating in body fluids [12]. from the external wearable device to neurons and astrocytes,
Hence, exosomes are envisioned to pose as the main carrier to depolarize their membranes and change intracellular calcium
deliver reactive drug molecules to Glioblastoma cells within a dynamics which can be further associated with alteration in
potential therapeutic solution termed as an exosome-mediated exosomal release. Here we aim to theoretically investigate
drug delivery system [13]. Of note, a therapeutic combi- the aspects of controlled therapeutic exosomal release by
nation of proteins, lipids and genetic materials assembled in computing the modulated release rate and the concentration of
exosomes for the treatment of Glioblastoma is unknown at released exosomes from a proposed mathematical model that
present and represents an open research question. combines the i) cell depolarization, ii) intracellular calcium

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VELETIĆ et al.: MODELING OF MODULATED EXOSOME RELEASE FROM DIFFERENTIATED iNSCs FOR TARGETED DRUG DELIVERY 359

signaling, and iii) vesicular exocytosis. The proposed model neurons is of particular interest,1 leading to the therapeutic
is first-of-a-kind and distant from the existing scarce computa- exosomal release in the brain extracellular matrix where,
tional models regarding exosomes mostly developed to study among other particles, the therapeutic exosomes propagate
the role of exosome communication in the cancer-immunity following the law of diffusion and ideally bind to targeted
interplay [31], [32]. Of note, mechanisms associated with bio- receptors in Glioblastoma cells and GSCs.
genesis of therapeutic exosomes with Glioblastoma targeting The experimental evidence reveals that exocytosis is reg-
ligands and modification of the cell membranes with promot- ulated by intracellular calcium signaling in many different
ers sensitive to specific wavelengths in the electromagnetic cell types [39], [40]. Neuron depolarization triggers electrical
spectrum are beyond the scope of this paper. activity that involves voltage-gated Ca2+ channels. The result-
The presented paper contributes by enabling computation ing opening of voltage-gated Ca2+ channels and an increase
of the modulated exosomal release rates that are required in the cytosolic calcium concentration evoke exocytosis and
within the proposed exosome-mediated drug delivery system the release of exosomes among other secretory vesicles like
to treat the cancer in a precise way by dosing the therapy synaptic-like microvesicles, lysosomes and ectosomes [25],
depending on the stage of the illness, the desired intensity of [41], [42]. In somato-dendritic exocytosis, the release is mostly
the treatment, and the genomics that affects the binding of the restricted to active zones that contain L-type Ca2+ chan-
exosomes. nels [43].
The rest of the paper is organized as follows. In Section II, We use the well-known Hodgkin-Huxley neuron model to
we present the mathematical model of modulated exosomal describe the electrical activity of a depolarized neuron via
release for iR-NSCs differentiated into neurons and astro- membrane potential (v m ) that is dependent on voltage-gated
cytes. As of neurons, the model is developed combining the potassium (K+ ) channels, voltage-gated sodium (Na+ ) chan-
Hodgkin-Huxley model [33] for initiation and propagation nels, a leak current, and an induced control current (i ind )
of action potentials with the Watts and Sherman [34] and as [33]:
Montefusco-Pedersen model [35] for local calcium and regu- dv m 1 
lated exocytosis. As of electrically silent astrocytes, the model =− gK (v m − VK ) + gNa (v m − VNa )
dt cm
is developed combining the Hodgkin-Huxley like formalism 
+g L (v m − VL ) − i ind , (1)
for inositol 1,4,5-triphosphate (IP3 ) receptor-mediated oscil- 
lations of local calcium [36] with the Watts-Sherman- and control
Montefusco-Pedersen model. In Section III, we briefly dis- where cm is specific membrane capacitance, VK , VNa and
cuss the stochastic properties of modulated exosomal release VL are Nernst potentials for K+ ions, Na+ ions and other
addressing the deviation from the averaged values derived ions lumped together as “leak” channel, respectively, and
in Section II. In Section IV and Section V, we present gK , gNa and g L are the corresponding membrane conduc-
the numerical results and provide the concluding remarks, tances. Voltage-gated conductances gK = ḡKm K 4 and gNa =
respectively. ḡNa m 3Na h Na change with time during an action potential/spike
– an elementary stereotyped impulse generated and exchanged
II. M ATHEMATICAL M ODEL OF M ODULATED by neurons. m K 4 and m 3Na h Na represent the opening prob-
E XOSOMAL R ELEASE ability for K+ and Na+ channels, respectively. The gating
In what follows, we opt to characterize the modulated (sim- variables m K , m Na and h Na and the relevant parameters are
plified) release of exosomes by the iR-NSCs differentiated defined in Appendix A-A.
into neurons and astrocytes [15]. Note that differentiation of Aiming to couple neuronal electrical activity and
iR-NSCs can also lead to a loss of the engineered properties in Ca2+ -mediated exocytosis, we first describe intracellular
the therapeutic exosomes. However, in the considered scenario, Ca2+ dynamics with particular attention to microdomain
we assume that the structure of the therapeutic exosomes Ca2+ concentrations surrounding high-voltage activated
remains intact after differentiation. L-type Ca2+ channels ([Ca] L ) and low-voltage-activated
T-type Ca2+ channels [43], linked to a description of Ca2+
below the plasma membrane ([Ca]m ), in the bulk cytosol
A. Modulated Exosomal Release in Neurons ([Ca]c ), and in the endoplasmic reticulum ([Ca] E R ). According
In the nervous system, synaptic exocytosis is well-studied to the evidence that somato-dendritic exocytosis by neurons
where calcium ions (Ca2+ ) and SNAREs (soluble shares common mechanisms with Ca2+ -mediated exocytosis
N-ethylmaleimide-sensitive fusion protein attachment by excitable endocrine cells (where Ca2+ threshold of
protein receptors) play a critical role in synaptic vesicle exocytosis depends on the electrical activity pattern) [44], [45],
docking, fusion and neurotransmitter release [37]. The release we adapt the Montefusco-Pedersen computational model
is restricted to electron-dense regions called active zones initially developed for the fine-tune control of glucagon
which contain voltage-gated Ca2+ channels – P-, Q- and secretion in pancreatic alpha cells [35]. Glucagon secretion
N-type Ca2+ channels – that control Ca2+ influx from the occurs as exocytosis of stored peptide vesicles initiated
extracellular domain, and mediate and regulate exocytosis.
1 Conversely, synaptic exocytosis leads to particle release in the extracellular
Nonetheless, vesicular exocytosis has been also observed
matrix inside synaptic clefts. This imposes particle binding to receptors
from somato-dendritic neuronal compartments [38]. For the located in post-synaptic terminals, preventing released particles from reaching
presented study, the vesicular somato-dendritic exocytosis by receptors in Glioblastoma cells and GSCs.

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360 IEEE TRANSACTIONS ON NANOBIOSCIENCE, VOL. 19, NO. 3, JULY 2020

TABLE I
G OVERNING E QUATIONS OF M ICRODOMAIN C ALCIUM C ONCENTRATIONS IN N EURONS

by secretory stimuli. The ultrastructural analysis indicates as follows:

that the glucagon-containing vesicles have a diameter 
RCa L = m 2Ca L h Ca L FH [Ca] L|opened, K L , n L +
of ∼ 250 nm [46], which is similar to the size of the

exosome-containing endocytic compartments (∼300 nm [16]). + 1 − m 2Ca L h Ca L FH [Ca] L|closed, K L , n L , (4)
Table I provides equations that describe the Ca2+ con-
RCam = FH ([Ca]m , K m , n m ) , (5)
centrations in single microdomains surrounding high-voltage
activated L-type Ca2+ channels when the channels are opened where
and closed, sub-membrane Ca2+ concentration, Ca2+ con- xn
centration in the bulk cytosol, and Ca2+ concentration in FH (x, K , n) = φ , (6)
xn + K n
the endoplasmic reticulum [35]. i Ca L and i CaT represent the
Ca2+ current entering the single domain through L-type Ca2+ is the Hill function where φ is a fusion constant given in s−1 .
channels and the sub-membrane compartment through T-type K L , n L , K m and n m are given in Appendix A-A, Table IV.
Ca2+ channels, respectively, and are defined as: Note that (4) contains two terms that stem from the two states
of L-type Ca2+ channels, opened and closed, respectively.
gCaL (v m − VCa )
i Ca L = , (2) Considering normalized constant exosome concentrations in
NL the considered microdomains, we define the collective exocy-
i CaT = gCaT m 3CaT h CaT (v m − VCa ). (3) tosis rate
where gCa L and gCaT are the membrane conductances of the R(neuron) (t) = RCa L (t) + RCam (t). (7)
L-type and T-type Ca2+ channels, respectively, m 2Ca L h Ca L and
m 3CaT h CaT represent the opening probability for the L-type in terms of the amount of exosomes per second per liter.
Ultimately, the relative (normalized) concentration of
and T-type Ca2+ channels, respectively, VCa is the Nernst
released therapeutic neuronal exosomes depending on L-type
potential for Ca2+ ions, and N L is the number of L-type Ca2+
Ca2+ microdomain concentrations and sub-membrane Ca2+
channels. The gating variables m Cax and h Cax , x ∈ {T, L} are
concentrations, respectively, is defined as:
defined in Appendix A-A, eqs. (32) and (33), respectively.
(neuron)
As of the parameters used in the equations, f is the the ratio cTx (t) = cCa L (t) + cCam (t), (8)
of free-to-total Ca2+ , α is the constant that converts current
to flux, Bμd is the constant that describes the flux from the where
t
microdomains to the sub-membrane, Bm is the constant that
cCax (t) = RCax (t)dτ, x ∈ {L, m}. (9)
describes the flux from the sub-membrane compartment to 0
the bulk cytosol, Vμd , Vm , Vc and V E R are the volumes of a Therefore, the whole amount of exosomes released during
single microdomain, the sub-membrane compartment, the bulk [0, t] is given by multiplying (8) by the concentration of the
cytosol, and the endoplasmic reticulum, respectively, kPMCA exosomes around the microdomain and microdomain volume.
is the rate of Ca2+ -ATPases through the plasma membrane,
pleak is the rate of the leak from endoplasmic reticulum
to the cytosol, and kSERCA is the rate of sarco/endoplasmic B. Modulated Exosomal Release in Astrocytes
Ca2+ -ATPase pump-dependent sequestration of Ca2+ into the Most of the existing models that describe mechanisms of
endoplasmic reticulum. The values of parameters given in astrocytic signaling that regulate release of a wide range of
Table I which are used to obtain the numerical results are neurotransmitters, neuromodulators, hormones, and metabolic,
provided in Appendix A-A, Table IV. trophic and plastic factors within secretory vesicles from
Following the work of Watts and Sherman for glucagon astrocytes, also including this work, use phenomenological
secretion in pancreatic alpha cells [34], we consider the descriptions of gliotransmitters in which increased cytosolic
relative exosomal release rate functions for microdomains Ca2+ concentration plays the most important role [47], [48].
(equivalent to the fusion rates obtained by Watts and Sherman) The predominant sources of Ca2+ for exocytosis by astrocytes
in neurons depending on L-type Ca2+ microdomain concen- reside within the endoplasmic reticulum and Ca2+ influx
trations and sub-membrane Ca2+ concentrations, respectively, through voltage-gated Ca2+ channels.

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VELETIĆ et al.: MODELING OF MODULATED EXOSOME RELEASE FROM DIFFERENTIATED iNSCs FOR TARGETED DRUG DELIVERY 361

Similar to neurons, astrocytes have on their plasma We presume the same properties of L-type Ca2+ channels
membrane glutamate-sensitive receptors – groups I and II in neurons and astrocytes [52]. Hence, Ca2+ concentration
metabotropic glutamate receptors (mGluRs). Once activated by [Ca] L in single astrocytic microdomains is described as in
nearby glutamate, mGluRs trigger the intracellular release of neuronal microdomains (Table I) by setting v m = Vm + v ind
Ca2+ from the endoplasmic reticulum. This process is carried in all corresponding equations, where Vm denotes the resting
out through chemical processes involving IP3 – a secondary astrocytic membrane potential.2 Table II shows equations that
messenger molecule with a pivotal role in mobilizing Ca2+ describe the Ca2+ concentrations in single microdomains sur-
into the cytosol. In tripartite synapses (a concept introduced rounding high-voltage activated N-type Ca2+ channels when
to underline the presence of the astrocyte in the vicinity of two the channels are opened and closed,3 and the sub-membrane
neurons), the IP3 synthesis has been described simply under Ca2+ concentration [35]. i CaN represents the Ca2+ current
the hypothesis that a quantized amount of IP3 molecules is entering the single domain through N-type Ca2+ channels, and
released after the increase of glutamate due to pre-synaptic is defined as:
spiking activity. Thus, the lifetime process of IP3 leads to the
gCaN (Vm + v ind − VCa )
following equation [49], [50]: i Ca N = , (14)
NN
d[IP3 ] [IP30 ] − [IP3 ]
= + rIP3 u (v m − Vt h ) , (10)
dt τIP3 where gCaN is the membrane conductance of the N-type Ca2+
where channels and N N is the number of N-type Ca2+ channels.
m Ca N h Ca N represents the opening probability for the N-type
1
τh IP3 = , (11) Ca2+ channels. The gating variables m Ca N and h Ca N are
a2 (Q + [Ca]c ) defined in Appendix A-A, eqs. (32) and (33), respectively,
[IP3 ] + d1 by replacing v m with Vm + v ind . Other used parameters are
Q = d2 . (12)
[IP3 ] + d3 defined in Section II-A.
The first term on the right side of (10) refers to the IP3 Once produced in-situ (or received from other cells through
degradation, where [IP30 ] is the concentration at equilibrium gap junction), IP3 molecules bind to receptors located on
and τIP3 is the degradation time constant. The second term the surface of endoplasmic reticulum enabling the release of
refers to the production of IP3 , where rIP3 is the production Ca2+ . Since internal stores are also sensitive to Ca2+ , the rise
rate. The coefficients shown in (10)-(12) are given in Appen- of Ca2+ concentration mobilizes further release of Ca2+ .
dix A-B, Table V. In (10), the IP3 production is enabled when This process is called Calcium-Induced Calcium Release
the pre-synaptic potential v m is above a given threshold Vt h (CICR) [50]. Additional Ca2+ flow occurs spontaneously from
(u(·) is the Heaviside function). This is an approximation of the endoplasmic reticulum into the cytosol (leakage flow)
what actually happens at the molecular level, which relates while Ca2+ dependent ATPase pumps (SERCA) operate in
the production of IP3 with the presence of glutamate in the the opposite direction to uptake Ca2+ back into the stores
synapse. In our scenario, where the astrocyte differentiated for future use (pump flow). During rest conditions, Ca2+
from iR-NSC acts as a neuron-independent unit, we are concentration is regulated by the balance between passive
interested in regulating the [IP3 ] with a given stimulation leakage from the endoplasmic reticulum and SERCA uptake.
pattern, as envisioned in Fig. 1. Thus, considering that the Ca2+ dynamics and the release/uptake processes triggered by
[IP3 ] production rate is a function of a generic control signal IP3 have been described analytically by Sneyd et al. [54] and
v ind applied to depolarize the astrocyte, we modify (10) as Li and Rinzel [36]. In this work, we use the Nadkarni-Jung
model based on the Li-Rinzel model [49], [55], where the
d[IP3 ] [IP30 ] − [IP3 ]
= + rIP3 ( v ind ). (13) equations given in Table II define Ca2+ concentrations in
dt τIP3 
control the bulk cytosol and the endoplasmic reticulum. The gating
variables h IP3 and m IP3 ,∞ are defined in Appendix A-B,
Of note, a practical solution to provide v ind is beyond the
eqs. (38) and (39), respectively. The values of used parame-
scope of this paper and is left as future work.
ters in Table II are given in Appendix A-A, Table IV and
We now couple (13) with Ca2+ dynamics to propose a
Appendix A-B, Table V.
model for IP3 production and Ca2+ -microdomain-dependent
Following the work of Watts and Sherman for glucagon
exocytosis by electrically silent astrocytes. As with neu-
secretion in pancreatic alpha cells [34], we now define the
rons, we describe Ca2+ dynamics with particular attention
relative exosomal release rate function in astrocytes depending
to microdomain Ca2+ concentrations, linked to a description
on N-type Ca2+ microdomain concentrations:
of Ca2+ below the plasma membrane ([Ca]m ), in the bulk
cytosol ([Ca]c ), and in the endoplasmic reticulum ([Ca] E R ). 
RCa N = m Ca N h Ca N FH [Ca] N|opened , K N , n N
Electrophysiological recordings detected high-voltage acti-  
vated L-type, N-type and R-type Ca2+ channels (in addition + 1 − m Ca N h Ca N FH [Ca] N|closed , K N , n N . (15)
to low-voltage-activated T-type Ca2+ channels) in rat cortical
2 The resting membrane potentials in astrocyte range from −25 to −85
astrocytes [51]. However, we describe microdomain Ca2+
mV [53]. Here, we select Vm = −70 mV.
concentrations surrounding L-type and N-type Ca2+ channels 3 Note that Montefusco and Pedersen [35] use similar expresions for the
([Ca] L and [Ca] N ), since the role of R-type Ca2+ channels in P/Q-type Ca2+ channels used by Watts and Sherman [34] for the N-type
astrocytic exocytosis is largely unknown. Ca2+ channels.

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362 IEEE TRANSACTIONS ON NANOBIOSCIENCE, VOL. 19, NO. 3, JULY 2020

TABLE II
G OVERNING E QUATIONS OF M ICRODOMAIN C ALCIUM C ONCENTRATIONS IN A STROCYTES

FH is defined in (6). K N and n N are given in Appendix A-B, Rv (t) = R(cell) (t)/E[Ne ], in which R(cell) (t) is the exosomal
Table V. The relative exosomal release rate functions release rate for neurons or astrocytes proportional to the rates
depending on L-type Ca2+ microdomain concentrations and in (7) and (16), respectively, and E[Ne ] is the average number
sub-membrane Ca2+ concentrations, RCa L and RCam , fol- of the exosomes contained in a fused intermediate endocytic
low (4) and (5), respectively. Considering normalized con- compartment (multivesicular body). The total number of the
stant exosome concentrations in the considered microdomains, released exosomes (N ) can thus be estimated as a compound
Nv (t ) i
we define the collective exocytosis rate Poisson process N = i=1 Ne , in which Nv (t) is the total
number of release events that follows the inhomogeneous
R(astro) (t) = RCa L (t) + RCa N (t) + RCam (t). (16)
Poisson process with the rate Rv (t), and Nei s are the inde-
Ultimately, the relative (normalized) concentration of pendent identically distributed random variables that represent
released therapeutic astrocytic exosomes depending on the number of exosomes in the i th release event.
L-type and N-type Ca2+ microdomain concentrations and
sub-membrane Ca2+ concentrations, respectively, is defined
IV. N UMERICAL R ESULTS
as:
(astro) The numerical results provided in this section are obtained
cTx (t) = cCa L (t) + cCa N (t) + cCam (t), (17)
using the parameter values collected from [33] and [49], and
where from [35] (for pancreatic cells). Some of the presented results
t are thus unrealistic (e.g., the negative Ca2+ concentrations
cCax (t) = RCax (t)dτ, x ∈ {L, N, m}. (18) for astrocytic microdomains), but are presented to primarily
0 illustrate the application of the proposed methodology. The
simulation framework has been implemented in M ATLAB.
III. S TOCHASTIC P ROPERTIES OF M ODULATED The effects of the controlled exocytosis by neurons differen-
E XOSOMAL R ELEASE tiated from iR-NSCs are depicted in Fig. 3 using the induced
current pulses of 500 ms duration and amplitudes ranging from
In the previous section, we implicitly assumed that the 5−20 μA/cm2 (Fig. 3(a), upper plot). Neurons are electrically
release events of the exosomes from different domains of the excitable and respond to the provided stimuli by creating
membrane were statistically independent. This assumption is sequences of action potentials with the rate proportional to the
justified by considering the following: stimuli (Fig. 3(a), lower plot). The spiking sequences further
• We assume that the cells can regenerate and replenish control the dynamics of voltage-gated calcium channels in
the exosomes whenever the exosomes are released. This the membrane, which, in turn, control the intracellular Ca2+
is a more reasonable and realistic assumption for neurons concentration near open or closed Ca2+ channels (of L-type),
in which the refractory period between the spikes enables below the plasma membrane, in the bulk cytosol and the
the time to replenish the storage of the exosomes, in addi- endoplasmic reticulum. The concentrations are evaluated by
tion to the re-polarization process. equations provided in Table I and shown in Fig. 3(b). The
• We assume that the exosomes are distributed through rates of released exosomes with relative contributions of the
different domains of the cell membrane whose release Ca2+ compartments are evaluated by (4), (5) and (7) and
permeabilities are modulated through independent ion shown in Fig. 3(c) where we observe action-potential driven
channels in different microdomains. oscillations around the baseline values that increase with
Nonetheless, due to the many stochastic phenomena, the mod- the stimuli intensity. When the stimulation is interrupted at
ulated exosomal release deviates from the average values t = 750 ms, the release fades after ∼ 50 ms. The corre-
evaluated in the previous section. We thus model the exo- sponding concentrations of released exosomes are evaluated
somal release process as a Poisson process whose rate is by (8) and (9). Under the assumption of having non-depleted

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VELETIĆ et al.: MODELING OF MODULATED EXOSOME RELEASE FROM DIFFERENTIATED iNSCs FOR TARGETED DRUG DELIVERY 363

Fig. 3. Modulated exocytosis by neurons differentiated from iR-NSCs. The quantities are evaluated using the parameter sets given in Table III and
Table IV, Appendix A-A.

readily releasable exosomes in the cytosol throughout the stim- the membrane potential intensity Fig. 4(a), lower plot). IP3
ulation period, we observe an approximately linear increase mobilizes Ca2+ into the cytosol. The Ca2+ concentrations
in the concentration of released exosomes for all stimuli near open or closed Ca2+ channels (of L- and N-type),
intensities. We also observe that for the considered scenario, below the plasma membrane, in the bulk cytosol and the
∼ 70% of the concentration of released exosomes stems endoplasmic reticulum are evaluated by equations provided
from the concentration dependent on sub-membrane Ca2+ in Table II and shown in Fig. 4(b). The corresponding rates
concentrations. of released exosomes with relative contributions of the Ca2+
As of astrocytes, the [IP3 ] production rate function compartments are evaluated by (4), (15) and (16) and shown
rIP3 (v ind ) given in (13) has not been characterized in the in Fig. 4(c) where one can approximate them as constant
literature to the best of our knowledge. Therefore, to obtain during the controlling phase. When the control signal is
the numerical results, we simply assume that [IP3 ] produc- interrupted at t = 37.5 s, the release slows down to zero.
tion is linearly proportional to the intensity of depolarization The corresponding concentrations of released exosomes are
v ind . The effects of the controlled exocytosis by astrocytes evaluated by (17) and (18). Under the assumption of hav-
differentiated from iR-NSCs are depicted in Fig. 4 using the ing non-depleted readily releasable exosomes in the cytosol,
generic control signals of 25.0 s duration and amplitudes we observe the increase in the concentration of released
ranging from 10 − 40 mV Fig. 4(a), upper plot). Astrocytes exosomes for all tested stimuli intensities. We also observe
respond to depolarization by triggering the production of IP3 that for the considered parameter set, the total concentration
molecules whose concentration is an exponential function of of released exosomes mostly stems from the concentration

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364 IEEE TRANSACTIONS ON NANOBIOSCIENCE, VOL. 19, NO. 3, JULY 2020

Fig. 4. Modulated exocytosis by astrocytes differentiated from iR-NSCs. The quantities are evaluated using the parameter set given in Table V,
Appendix A-B.

dependent on N-type Ca2+ concentrations and sub-membrane however, higher release rates and exosome concentrations do
Ca2+ concentrations for weak depolarization (the first two not necessarily mean better therapy. This rather depends on
scenarios), and the concentration dependent on N-type Ca2+ each individual and clinical setup.
concentrations for strong depolarization (the third and fourth
scenario). V. C ONCLUSION
Unlike neurons, astrocytes are electrically silent and unable The overarching goal of our research is to deliver a
to generate action potentials. This implies different mecha- multi-functional and multi-modal brain tumor reprogramming
nisms that trigger the elevation of astrocyte intracellular Ca2+ and monitoring platform based on autonomous, externally con-
levels, including chemical processes involving IP3 . These trollable molecular communication technology for the man-
mechanisms have significantly slower dynamics compared to agement of malignant brain tumors. The platform will integrate
neural spiking, thus imposing the significantly slower dynam- hybrid (electronic + biological) nanosensors, multi-functional
ics of exocytosis by astrocytes compared to exocytosis by autologous organoids and enabling brain molecule-machine
neurons, as shown in Fig. 3 and Fig. 4. interfaces. Autologous organoids consist of engineered iNSCs
Finally, as of the cellular performance, higher release rate to synthesize and release rationally designed therapeutic exo-
and exosome concentrations from neurons and astrocytes mean somes. The iNSCs are envisioned to be equipped by promot-
better response to depolarization. Although neurons and astro- ers sensitive to specific wavelengths in the electromagnetic
cyte both react positively in that context, the later demonstrate spectrum, which enables the modulation of exosomal release
a more prominent increase in release rates in response to by providing stimulation patterns via in-messaging interfaces.
the applied signals. As of the drug delivery performance, Thereby, it is required to model the exosomal release from the

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VELETIĆ et al.: MODELING OF MODULATED EXOSOME RELEASE FROM DIFFERENTIATED iNSCs FOR TARGETED DRUG DELIVERY 365

TABLE III TABLE IV

PARAMETER S ET (E LECTRICAL ACTIVITY OF N EURONS ) [33] PARAMETER S ET (C ALCIUM DYNAMICS AND
E XOCYTOSIS BY N EURONS ) [35]

iNSCs to study the feasibility and potential of the envisioned

system. Moreover, new models could be used in designing and
optimizing the target platform.
In this paper, we proposed an integrated mathematical model
for the therapeutic exosomal release modulated by the stimulus
externally applied to the neurons and astrocytes differentiated
from iNSCs within safety guidelines. The proposed models
integrate cell stimulation, intercellular signaling, and exocy-
tosis, and provide insights into the relative contributions of
the various subcellular Ca2+ compartments in the control of
exosomal release. According to the results presented in Fig. 3
and Fig. 4, we infer the positive effect of cell depolarization
in both neurons and astrocytes on the exosomal release,
where the intensity of the exosomal release is proportional to
the intensity of applied stimulation. We considered noiseless
stimulation which is very unlikely to occur in-vivo. The
set of control interfering noise sources will depend on the
future selected technology to deliver depolarizing signals to
therapeutic bio-nanomachines for the envisioned treatment of
Glioblastoma. A number of technologies have been developed
to target specific cell types for stimulation, such as opto-
genetics, where the cells are engineered to respond to light
at a specific wavelength. Therefore, through this technique,
minimization of noise can be achieved when only selected
cells are targeted for stimulation.
Based on the models, we will develop the controlled trans-
mission of exosomes in the brain in a closed-loop manner
and provide an avenue for developing new tools that can be
used to deliver drugs and treat cancerous cells leading to
advanced engineering technologies. We will further use the
computed exosomal release rates as input to the end-to-end
communication model that we plan to develop in the next step.
The information capacity will be used to evaluate the system
performance and as an objective function encompassing all
relevant system parameters to optimize its design. In this
way, we believe that optimized drug delivery systems based Gating variables in the steady state:
on exosomes would redefine the current medical treatment αm K/Na
strategies. m K/Na,∞ = (21)
αm K/Na + βm K/Na
αh Na
A PPENDIX A h Na,∞ = (22)
S UPPLEMENTARY E QUATIONS AND PARAMETERS αh Na + βh Na
OF THE M ODEL Time constants and gating functions:
A. Neurons 1
Gating variables (m K , m Na and h Na ): τm K/Na = (23)
αm K/Na + βm K/Na
dm K/Na m K/Na,∞ (v m ) − m K/Na 1
= (19) τh Na = (24)
dt τm K/Na (v m ) αh Na + βh Na
dh Na h Na,∞ (v m ) − h Na 0.01(v m + 55)
= (20) αm K = (25)
dt τh Na (v m ) 1 − FE (v m , 55, 10)

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366 IEEE TRANSACTIONS ON NANOBIOSCIENCE, VOL. 19, NO. 3, JULY 2020

TABLE V Time constants:

PARAMETER S ET (IP3 - AND C ALCIUM DYNAMICS AND τm VCa
E XOCYTOSIS BY ASTROCYTES ) [35], [49] τm Cax =   x  
v m −Vτm Ca v m −Vτm Ca
exp − Sτ x
+ exp Sτ
x
m Cax m Cax

+τm0VCa (36)
x
τh VCa
τh Cax =   x  
v m −Vτh v m −Vτh
exp − Sτ Cax
+ exp Sτ
Cax
h Cax h Cax

+τh0VCa (37)
x

The parameters shown in (34)-(37) are given in Table IV.

B. Astrocytes
Gating variable (h IP3 ):
dh IP3 h IP3 ,∞ − h IP3
= (38)
dt τh IP3
Gating variables in the steady state (m IP3 ,∞ and h IP3 ,∞ ):
  
[IP3 ] [Ca]c
m IP3 ,∞ = (39)
[IP3 ] + d1 [Ca]c + d5
Q
h IP3 ,∞ = (40)
Q + [Ca]c
The parameter shown in (38) and (39) are given in Table V.
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