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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5976_Библиотеки_им_академика_М_И_Перельмана
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system. In another study, Li et al. developed a microfluidic biochip with a V-shape structure
to investigate the early cytotoxic events that occur in single leukemia cells upon exposure to
chemotherapeutic drugs such as daunorubicin and herbal licoric e compounds [27].
Each microfluidic chip was composed of three channels, three reservoirs, and one chamber
FIGURE 14.1 Schematic representing of the steps of immobilization of liposomes and detection of the toxins.
Cell-mimicking nanoreactors (NMN) immobilized on the surface of the microfluidic channel by surface modification
and anchorage of liposomes to particular positions on the surface. Botulinum neurotoxin is run through the channel
and bound to the receptors on the liposomal membrane. The laminar flow regime gave rise to an enrichment of the
toxin on the liposomes. Low pH buffer in the channel induces conformational changes in the receptor-bound toxin
molecules and resulted in HC-mediated translocation of the LC into the liposome lumen. The LC proteolytically
cleaves FRET peptide reporter molecules inside the liposome lumen that caused unquenching of the FRET pair enable
fluorescent readout. Enhancing fluorescence intensity is directly influenced by the number of active toxin molecules
present in the original test solution and gives an estimate of their potency. Reproduced from Weingart OG, et al. In vitro
quantification of botulinum neurotoxin type A1 using immobilized nerve cell-mimicking nanoreactors in a microfluidic platform.
Analyst. 2019;144(19):5755e5765, with permission from the Royal Society of Chemistry.
14. Use of microfluidic organ-on-a-chip systems for the screening and development of phytopharmaceuticals and herbal drugs328
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consisting of a V-shaped cell retention structure with a central stretch (Fig. 14.3). The V cham-
ber is better because it has three reservoirs, the cell inlet, waste outlet, and the reagent reser-
voir, which is used for drug delivery. Using this microfluidic [Ca
2þ
]i measurement method,
an antiproliferative effect on leukemia cells by isoliquiritigenin, which is a herbal ingredient
isolated from licorice, was demonstrated [27]. Microfluidics-based approach of single-cell
analysis demonstrates that this method can be a promising tool for rapid drug screening, us-
ing a small amount of reagents with reduced costs [27].
3.4 Detection of the pharmacokinetics and separation of herbal drug using
multi-organ-on-a-chip
There are many challenges in drug research and development and their ultimate success in
clinical trials. Drug pharmacokinetics studies, including absorption, distribution, metabolism,
excretion, and toxicity, are critical determinants in the successful outcome in clinical trials
FIGURE 14.2 Photomask microfabrication and on-chip etching step. W: width of the channel (in micrometer).
The cell retention chamber is composed of a short leading channel, shown by the inset. The wet etch channel depth is
shown to be 20 mm. Reproduced from Li X, et al. Real-time monitoring of intracellular calcium dynamic mobilization of a
single cardiomyocyte in a microfluidic chip pertaining to drug discovery. Electrophoresis. 2007;28(24):4723e4733, with
permission from John Wiley and Sons.
3. Organ-on-a-chip systems 329
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[63]. To proceed with drug discovery and reduced cost of new drug development, OoC tech-
nology has increasingly been investigated as potential system to study the pharmacokinetics
of multicomponent extracts [33,64e 66 ]. Moreover, multi-organ-on-chip (MoC) [67] was used
to investigate the pharmacokinetics of medicinal herbal drugs in terms of measuring toxicity
in different cells [68]. Based on the use of MoC chips, the absorption, metabolic function, and
toxicity of ginsenosides compound K (CK) (20-O-b-(
D-glucopyranosyl)-20(S)-protopanaxa-
diol) were successfully measured by culturing HepG2 and HK-2 cells in separate OoCs (in
linked liver-kidney-on chips). The MoC chip has a multilayered structure to enable investi-
gating different aspect of drugs from layer 1 to 5 such as intestinal absorption (layer 1), intra-
vascular transmission (layer 2), liver metabolization and toxicity (layer 3), kidney excretion
and toxicity (layer 4 and 5) (Fig. 14.4). In addition, the absorption of CK was analyzed
with LC-MS/MS. CK administration in the single-OoC or the linked chips of kidney and liver
showed that CK was almost nontoxic to different cells due to absorbing CK through the in-
testinal lumen and reaching to layers of kidney and liver cells via the vascular lumen
(Fig. 14.5)[68]. One important criterion for drug discovery is finding, screening, and purifi-
cation of bioactive components of NPs is a laborious task. Thus, new technology is required
FIGURE 14.3 Microfluidic chip setup. (A) Schematic illustrating the microfluidic device composed of three so-
lution reservoirs and a cell retention structure. (B) Device setup. (C) A single cell was maintained in the cell retention
structure. Reproduced from Li X, Xue X, Li PC. Real-time detection of the early event of cytotoxicity of herbal ingredients on
single leukemia cells studied in a microfluidic biochip. Integrative Biology. 2009;1(1):90e98, with permission from Oxford
University Press.
14. Use of microfluidic organ-on-a-chip systems for the screening and development of phytopharmaceuticals and herbal drugs330
https://t.me/med1917
FIGURE 14.4 Schematic representation of multi-organ-on-a-chip. Reproduced from Liu D, et al. Investigation of
absorption, metabolism and toxicity of ginsenosides compound K based on human organ chips. International Journal of Phar-
maceutics. 2020;587:119669, with permission from Elsevier.
FIGURE 14.5 Schematic illustration of the cytotoxicity of cyclophosphamide and the ginsenosides compound in
the nonlinked and the linked chips of kidney and liver. (A) Representation of the linked chips of liver and kidney,
(B) the liver chip, and (C) the kidney chip. Reproduced from Liu D, et al. Investigation of absorption, metabolism and toxicity
of ginsenosides compound K based on human organ chips. International Journal of Pharmaceutics. 2020;587:119669, with
permission from Elsevier.
3. Organ-on-a-chip systems 331
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for harnessing rapid and high-throughput screening. Cai et al. deve loped a three-phase-
laminar-flow-chip (TPL chip), which could select antitumor ingredients of Macleaya cordata
by screening G-quadruplex ligands. This chip realized the separation and extraction of free
drug from G-quadruplex from the drugs bound to G-quadruplex and showed a higher selec-
tivity [69].
3.5 Chip-based high throughput herbal screening
Although herbs have been widely used for various purposes, many of the bioactive ingre-
dients of CMs are still incomplet ely defined. To perform screening of herbal plants from a
complex mixture, current approaches require highly standardized extraction methods to
identify the active compounds [24]. Traditional approaches such as the disc diffusion method
have been used for manual screening of herbal plant effects against bacteria, fungi, and other
organisms by examining zone of inhibition. These methods are time-consuming and not suit-
able for high-throughput screening. In addition, large amounts of NP samples are required,
thereby imposing major limitations [24]. Therefore, there is a need to develop new high-
throughput screening methodologies. Thus, the integration of microchips to screen complex
mixtures of NP provided by the Herbochip devices establishes an innovative solution for NP-
drug discovery [71].
4. Herbochip
The first Herbochip was developed in 2003 as a microarray-based drug screening technol-
ogy. Herbochip consists of a surface-activated polystyrene slide in which HPLC fractions of
herbal extracts are displayed, allowing the screening of herbal drugs in a reverse fashion in
which a selected protein drug target is used as a probe (Fig. 14.6)[72]. The technical advan-
tage of requiring small amounts of CMs and saving resources are comprehensively applied.
Moreover, Herbochip enables many-fold screening of active components from herbal ex-
tracts. The Herbochip system has been used to screen herbal fractions based on binding to
protein targets such as cytochrome P450 3A4 (CYP450 3A4) and tumor necrosis factor-
alpha (TNF-a). Results led to defining drugs with CYP450 3A4 and TNF-a inhibitory activ-
ities [73,74]. The extraction of herbal medicines can be performed using water or ethanol,
depending on the herbal medicine and probe targets that it binds. The water extract fraction
of Andrographis Herbal, for instance, can bind TNF-a in Herbochip [71]. In fact, Herbochip is
relatively simple and can be used for screening various functional activities of herbal medi-
cines by using different targets [72]. More than 300 types of herbal extracts can be separately
blotted on Herbochip and screened simultaneously through visualization using Cy5-
conjugated streptavidin within a week [75]. Therefore, with the use of biotinylated protein
target coupled with streptavidin-cy5 visualization system, it is possible to identify whether
herbal species interact positively with targets or inhibit targets. Therefore, their use for the
treatment of certain conditions can be determined [74]. In fact, the success with using Herbo-
chip relies on direct interaction between herbal extracts and disease-related target proteins,
which increases the potential application of these extracts [72].
14. Use of microfluidic organ-on-a-chip systems for the screening and development of phytopharmaceuticals and herbal drugs332
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An Herbochip for the screening of antiinflammatory fractions of the Geranium wilfordii
extract (GWE) has been developed (Fig. 14.7)[71,73] by employing the inflammatory cytokine
TNF-a as a drug target based on a reverse screening method. Findings from these experi-
ments suggested that the antirheumatoid activity observed with the ethanolic fraction of
GWE could be associated with its inhibitory effect on TNF-a [71]. Similarly, nerve growth fac-
tor (NGF) was used as a drug target to identify the NGF-binding Rhizoma (CPRR), Ecliptae
herba (EH), Fritillariae thunbergii Bulbus (FTB), Gastrodiae Rhizoma (GR), Kaki Calyx (KC), and
Polygoni multiflori Radix (PMR) [75]. A similar approach characterized the NGF binding
compounds obtained from the water fraction of Ginkgo folium extracts using Herbochip.
With the application of Herbochip, it was found that the bioactive component of G. folium
is quercetin and that it could be used as a potential antidepression drug [76]. Besides, human
FIGURE 14.6 Schematic illustration of Herbochip screening process. Herbal extracts are separated by high-
performance liquid chromatography (HPLC) and then dotted and fixed on a chip. The chip is hybridized with
biotinylated protein target (nerve growth factor, NGF) and binding to streptavidin with a fluorescence Cy5 dye for
detection. Reproduced from Lee PSC, Zhang LM, Yan AL, Lam KYC, Dong TT, Lin H, Chan GKL, Tsim KWK. Indication of
nerve growth factor binding components from herbal extracts by HerboChip: a platform for drug screening on a chip. Chinese
Medicine. 2016;11(1):1e7, with permission from Chinese Springer Nature under Creative Commons Attribution License 4.0.
4. Herbochip 333
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Glucose-Regulated Protein 78 (hGRP781-508) has been recommended to be used as a target
protein for antihepatitis B virus (HBV) drug discovery in the Herbochip screening platform.
In this regard, Lam et al. prepared a Paeonia suffruticosa extract (PSE)-Herbochip, which was
arrayed with ethanoic extract of PSE [77] and used GRP78 as a molecular target in Herbochip
to screen antiviral/HBV activities in the extract of PSE for the treatment of hepatitis B.
Screening of PSE against GRP78 confirmed its anti-HBV activity, and it led to suggesting it
as a potential antiviral drug [72].
FIGURE 14.7 Schematic illustration depicting a Herbochip. Two caves are molded in each plastic slide
(25 75 1.4 mm) for the control and testing samples. high-performance liquid chromatography (HPLC) fractions in
duplicate are spotted in each cave. The 96 fractions from HPLC represent spots 1e96, and 6 controls spots as C1eC6.
Reproduced from Huang M, et al. Identification of anti-inflammatory fractions of Geranium wilfordii using tumor necrosis
factor-alpha as a drug target on HerbochipÒean array-based high throughput screening platform. BMC Complementary and
Alternative Medicine. 2015;15(1):1e11, with permission from Springer Nature.
14. Use of microfluidic organ-on-a-chip systems for the screening and development of phytopharmaceuticals and herbal drugs334
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Although Herbochips consume small amounts of reagents, the hybridization and signal
detection may take several hours [71]. Moreover, Herbochips with higher sensitivity wherein
the HPLC condition will be optimized specifically for each herb to ensure good separation,
are required. Before dotting on a chip, it is essential to examine the content of each pixel in
the array [76].
5. Current challenges and future directions
Herbal remedies and NPs offer an immense opportunity for therapeutics, which is so far
poorly untapped [78]. Despite the advances in the field, there are still challenges to the clinical
translation of NPs for patient use. A major roadblock in drug discovery, is defining drug
properties, including absorption, distribution, metabolism, excretion, and toxicity, which
are critical determinants at all levels of the discovery process [63]. Due to complex structure
of natural products, it is essential to pinpoint bioactive com pounds and their functional struc-
ture. Specifically, most of the activity of an herbal medicine relies on the collective function of
different phytochemicals it contains [78]. Thus, each active phytochemical plays a central role
in herbal product function and the correlation between its active components [76]. In view of
drug discovery from natural sources, a multidisciplinary approach is required to implement a
high-throughput screening of complex natural mixtures, investigating an effective dose appli-
cation, toxicity, and elucidating the molecular mechanism underlying their efficacy [68,71].
In recent years, OoC technology has become a promising platform for the drug discovery
and development [26]. An MoC system based on a pharmacokinetic model that can mimic
multiple organ functionality in a dynamic environmen t can be advantageous. In particular,
it can help to overcome uncertainty issue related to complex metabolism of the body, which
is challenging to figure out by using conventional pharmacokinetic studies [79,80]. The
advantage of using MoC is the ability to evaluate the distribution and toxicity of potentially
bioactive compounds in two-linked organs such as the liver and kidney [68]. In addition,
organ-based drug screening platforms need to recapitulate time-dependent dynamics of mul-
tiple organ interactions to reveal underlying mechanisms of drug action, toxicity, and disease.
Thus, with the application of MoC and better simulation of in vivo-like conditions, the
screening process and predicting drug efficacy and toxicity can be speeded up [65].
A grea t deal of effort has been made to perform high-throughput and rapid screening of
bioactive compounds from natural product extracts based on ligand-binding natural com-
pounds. In this context, microfluidic systems have a unique capability to integrate multistep
extraction, separation, and purification [69,81]. However, the MoC needs to be improved in
terms of functionality of each organ that MoC represents, fully integrating different organs to
ensure more accurate mimicking of the entire body [65]. The need for using advanced artifi-
cial intellige nce (AI) algorithms is obvious to aid real-time screening and interpretation of
large data collected from high-throughput drug screening studies. Deep learning algorithms
can predict the validity of the bioactive herbal compounds and their potential therapeutic ef-
fects in disease treatment [64,82].
5. Current challenges and future directions 335
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6. Conclusion
Natural products (NPs) and their derivatives constitute a major and growing source of
bioactive pharmaceutical compounds. The development of new approaches for rapid
screening of no vel NP chemistries and evaluating their potential toxicity are of paramount
significance. Organ-on-chip is a promising platform to gain a better insight into the use
and effect of NPs. Therefore, it is essential to make the chip device more reliable by using
stem cells or patient-derived cells to investigate the effectiveness and pharmacokinetics of
natural components for precision medicine.
Acknowledgments
The authors acknowledge that they have no competing interests. The authors also acknowledge funding from the
National Institutes of Health (1UG3TR003148-01) and the American Heart Association (18TPA34230036). AE and
NA acknowledge the Islamic Development Bank (IsDB) grant (Grant No. 2020-276278).
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