Special Issue
Published as part of the ACS Chemical Neuroscience special issue “Monitoring Molecules in Neuroscience 2023”.
Analytical
chemical monitoring devices are an important way of studying diseased
and injured tissue. They typically involve a sampling element, often a
commercial microdialysis probe, coupled to a microfluidic manifold that
incorporates relevant chemical sensors. Devices of this nature are
finding increasing utility due to improvements in real-time, continuous,
chemical monitoring and advancements in sampling tissue and organs,
such as the brain, by less invasive means. This paper describes the
design and development, using the aid of computational modeling, of a
new class of sampling device that incorporates tissue sampling directly
into the sensor-containing manifold.
The successful sampling and monitoring of tissue extracellular fluid (ECF) can provide vital information for clinicians.
(1)
Chemical levels that deviate from typical values in the blood and ECF
can be useful indicators of the proliferation of disease, degeneration,
and damage.
(2)
The accepted standard for chemical monitoring is the sampling of blood,
which requires the repeated removal of small samples for offline
analysis using high performance liquid chromatography (HPLC) or mass
spectrometry (MS). This analysis can be time-consuming and often misses
dynamic changes that occur at faster time scales, for example during the
acute progression of diseases.
(3)Accurate
detection of patient deterioration by quickly elucidating patterns in
disease and injury progression can be achieved by online, real-time
measurement facilitated by integrated microfluidic channels within
analytical chemical devices.
(4)
Three main approaches can be employed to achieve continuous monitoring:
(1) Implanted electrodes with modified surfaces for chemical
transduction through biosensing;
(5) (2) optical devices that sense in close proximity to the media in question─using light sources;
(6,7) and (3) sampling devices such as microdialysis probes which deliver samples representative of ECF for ex-vivo analysis.
(5)
Of these methods, implanted electrodes often suffer from disturbances
of the electrode surface that lead to drift, ultimately reducing the
measurement accuracy and precision over time.
(8)Conversely,
optical methods, although noninvasive and thus the most desirable,
often lack sufficient sensitivity to provide reliable reporting of
dynamic changes in chemical concentrations.
(9)
Therefore, implantable microdialysis probes that act as delivery
devices for analytical equipment outside of the body provide a middle
ground between the aforementioned methods.
(10)
When microdialysis is coupled with microfluidics and linked to ex-vivo
biosensors, continuous monitoring of dialysate can be achieved.
(11)
A distinct advantage here is all sensing apparatus is found outside of
the body and thus readily accessible and can be easily replaced when
performance issues are observed.
(12) This has been shown with the development of continuous online microdialysis (coMD)
(13,14) which displays data at 200 samples per second, with a slight offset delay.
However,
the probes that afford this analysis are concentric in nature and
penetrate tissue directly to establish a diffusional concentration
gradient. On the order of a few 100 μm, such diameters create
penetration injuries, which lead to inflammation and the development of
barriers of tissue that can surround and hamper the sampling probe.
(15,16)
The retrodialysis of dexamethasone, a glucocorticoid anti-inflammatory,
has been employed by Varner et al, to alleviate such barriers by
reducing the proliferation of abnormal tissue and thus enhancing the
level of detection at the sampling zone.
(17,18)
However, such pharmacological interventions can be completely avoided
by designing surface probes that do not have to be inserted into the
cortex and as such do not create penetrative injuries upon placement. It
is worth noting that such devices can only currently be utilized when a
craniectomy or craniotomy has occurred but the “softness” of these
prospective technologies means that surface probes could be folded and
introduced in minimally invasive ways, such as through a burr hole,
before being unraveled.
(19,20)Surface
microdialysis (s-μD) is not a new concept. Foundational work from
Abrahamsson, Akesson, and colleagues led to the development of a probe
that can be sutured to the heart, bowel, liver, and other tissue.
(21−23)
This device is now commercially available and is known as the OnZurf
probe. The devices that follow the general principles described here
build on this work but incorporate soft, flat, and flexible materials
and a different form factor. Such materials allow for the incorporation
of flexible electronics using soft lithography and the possibility of
developing new surgical protocols to reduce the risk of surgery on a
very fragile region of the body.
(20)By
extension, such devices can also make for useful environments to
support cell growth, monitoring, and the development of cellular layers
into organs, for organ-on-a-chip (OOAC) and organ-in-a-chip (OIAC)
applications. The use of semipermeable membranes can allow for the
delivery of nutrients to a tissue chamber and the corresponding
microfluidics can be used for rapid chemical stimulation.
(24,25)
Therefore, the development of soft, flexible, near 2-dimensional
sampling microdialysis probes solves many immediate issues with chemical
monitoring of tissues and has a wide applicability that spans multiple
subfields of bioengineering. Such devices open the possibility of
monitoring tissues on different scales:
In-vivo
monitoring could be easily implemented to assess the brain after
trauma, with thin, conformal and biocompatible devices being placed
directly on the surface of the brain under the dura. Less damage would
be sustained to the tissue during implantation, reducing the foreign
body response (FBR) and increasing the viability and longevity of the
implanted device.
Ex-vivo monitoring would
benefit from the use of such devices. For example, the chemical state
of a kidney could be continually monitored for health and function in
transit, without penetrative injuries. (26)
As transplant organs are very sensitive, preserving their integrity
while getting clear updates about their health (with minimal damage)
would be essential to performing successful transplant operations.
OOAC
and OIAC experiments could be developed using these devices where
tissue slices could be placed in close proximity to, or be directly
embedded within, the device. Using the microfluidic characteristics of
the analytical chemical device, the conditions and delivery of nutrients
these tissues would need to survive could be mimicked, in addition to
the simulation of disease states. (27−29)
Skin monitoring using such noninvasive, conformal devices could monitor the composition of sweat on the surface of the skin. (30) Consumer health, such as fitness monitors or continuous glucose monitoring for diabetes, could benefit from such form factors.
Current
fabrication methods offer great freedom of design; therefore,
highlighting the critical parameters and design features for effective
chemical sampling using microfluidics will greatly aid the development
of efficient prototypes. One way of ascertaining these critical
parameters is by constructing possible prototypes using computational
models. Applying modeling to microfluidic geometries to assess the fluid
dynamics and performance of a system is a quick way to home in on
feasible, real-world solutions.
(31)
Such modeling has already been utilized within this field to
investigate drug delivery using retrodialysis and tissue damage from
low-flow perfusion devices.
(32−34)
Computational modeling is therefore becoming an increasingly useful
tool that allows for the iterative evaluation, development, and
optimization of microfluidic and microdialysis systems.
(35)One
such computational modeling environment is COMSOL Multiphysics. This is
an interactive environment that can be used for solving a range of
scientific and engineering questions. COMSOL works on the basis that
partial differential equations form the basis of fundamental scientific
laws. Within the software, models can be built that simulate physics
phenomena by combining these partial differential equations, without the
need for an in-depth knowledge of mathematics. A key differentiator of
COMSOL is the ability to model and investigate multiple phenomena at the
same time, which is more indicative of real-world scenarios, where
multiple variables can impact the performance of your system.
(36)
However, users of such software should be aware that such tools should
only be used as a guide for their experimental counterparts and are,
more often than not, based on assumptions and simplifications. In
addition, although time can be saved by using modeling such as COMSOL,
there is a computational cost, and this increases with the complexity of
the model that is created. With the increase in computational power
available at a low cost, we can also go beyond modeling simple fluidic
components as circuit analogies or numerical solutions and generate
large data sets without conducting physical experiments. For even more
complex systems, where a system cannot be adequately modified from
first-principles, machine learning can be utilized to probe complex
microfluidic behavior.
(37,38)In
this paper, we show how modeling can be implemented, in order to
optimize the prototyping of near-2D sampling devices. We consider the
separation of consecutive signals, multiple sampling points, and
changing the geometry of channels in order to ascertain key
considerations for robust chemical sampling with high resolution and
minimal time delay, with potential applicability to neuromonitoring.
More at link.
No comments:
Post a Comment