Gastrulation occurs when a blastula, made up of one layer, folds inward and enlarges to create a gastrula. This diagram is color-coded: ectoderm, blue; endoderm, green; blastocoel (the yolk sac), yellow; and archenteron (the primary gut), purple.
Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals, the blastocyst, is reorganized into a two-layered or three-layered embryo known as the gastrula. Before gastrulation, the embryo is a continuous epithelial sheet of cells; by the end of gastrulation, the embryo has begun differentiation to establish distinct cell lineages, set up the basic axes of the body (e.g. dorsal–ventral, anterior–posterior), and internalized one or more cell types, including the prospective gut.
Gastrula layers
In triploblastic organisms, the gastrula is trilaminar (three-layered). These three germ layers are the ectoderm (outer layer), mesoderm (middle layer), and endoderm (inner layer). In diploblastic organisms, such as Cnidaria and Ctenophora, the gastrula has only ectoderm and endoderm. The two layers are also sometimes referred to as the hypoblast and epiblast. Sponges do not go through the gastrula stage.
Gastrulation takes place after cleavage and the formation of the blastula, or blastocyst. Gastrulation is followed by organogenesis, when individual organs develop within the newly formed germ layers. Each layer gives rise to specific tissues and organs in the developing embryo.
Following gastrulation, cells in the body are either organized into sheets of connected cells (as in epithelia), or as a mesh of isolated cells, such as mesenchyme.
Basic cell movements
Although
gastrulation patterns exhibit enormous variation throughout the animal
kingdom, they are unified by the five basic types of cell movements that
occur during gastrulation:
The terms "gastrula" and "gastrulation" were coined by Ernst Haeckel, in his 1872 work "Biology of Calcareous Sponges". Gastrula (literally, "little belly") is a neo-Latin diminutive based on the Ancient Greek γαστήρgastḗr ("a belly").
Importance
Lewis Wolpert,
pioneering developmental biologist in the field, has been credited for
noting that "It is not birth, marriage, or death, but gastrulation which
is truly the most important time in your life."
Model systems
Gastrulation
is highly variable across the animal kingdom but has underlying
similarities. Gastrulation has been studied in many animals, but some
models have been used for longer than others. Furthermore, it is easier
to study development in animals that develop outside the mother. Model organisms whose gastrulation is understood in the greatest detail include the mollusc, sea urchin, frog, and chicken. A human model system is the gastruloid.
Protostomes versus deuterostomes
The distinction betweenprotostomes and deuterostomes is based on the direction in which the mouth (stoma) develops in relation to the blastopore.
Protostome derives from the Greek word protostoma meaning "first mouth"
(πρῶτος + στόμα) whereas Deuterostome's etymology is "second mouth"
from the words second and mouth (δεύτερος + στόμα).
The major distinctions between deuterostomes and protostomes are found in embryonic development:
Mouth/anus
In protostome development, the first opening in development, the blastopore, becomes the animal's mouth.
In deuterostome development, the blastopore becomes the animal's anus.
Sea urchins exhibit highly stereotyped cleavage patterns and cell fates. Maternally deposited mRNAs establish the organizing center of the sea urchin embryo. Canonical Wnt and Delta-Notch signaling progressively segregate progressive endoderm and mesoderm.
The first cells to internalize are the primary mesenchyme cells (PMCs), which have a skeletogenic fate, which ingress during the blastula stage. Gastrulation – internalization of the prospective endoderm and non-skeletogenic mesoderm – begins shortly thereafter with invagination and other cell rearrangements the vegetal pole, which contribute approximately 30% to the final archenteron length. The gut's final length depends on cell rearrangements within the archenteron.
The sperm contributes one of the two mitotic asters needed to complete first cleavage. The sperm can enter anywhere in the animal half of the egg but its exact point of entry will break the egg's radial symmetry by organizing the cytoskeleton. Prior to first cleavage, the egg's cortex rotates relative to the internal cytoplasm by the coordinated action of microtubules,
in a process known as cortical rotation. This displacement brings
maternally loaded determinants of cell fate from the equatorial
cytoplasm and vegetal cortex into contact, and together these
determinants set up the organizer. Thus, the area on the vegetal side opposite the sperm entry point will become the organizer. Hilde Mangold, working in the lab of Hans Spemann, demonstrated that this special "organizer" of the embryo is necessary and sufficient to induce gastrulation.
The dorsal lip of the blastopore is the mechanical driver of gastrulation, and the first sign of invagination seen in the frog.
Germ layer differentiation
Specification of endoderm depends on rearrangement of maternally deposited determinants, leading to nuclearization of Beta-catenin. Mesoderm is induced by signaling from the presumptive endoderm to cells that would otherwise become ectoderm.
Cell signaling
In the frog, Xenopus, one of the signals is retinoic acid (RA). RA signaling in this organism can affect the formation of the endoderm
and depending on the timing of the signaling, it can determine the fate
whether its pancreatic, intestinal, or respiratory. Other signals such
as Wnt and BMP also play a role in respiratory fate of the Xenopus by activating cell lineage tracers.
In preparation for gastrulation, the embryo must become asymmetric along both the proximal-distal axis and the anteroposterior axis.
The proximal-distal axis is formed when the cells of the embryo form
the "egg cylinder", which consists of the extraembryonic tissues, which
give rise to structures like the placenta, at the proximal end and the epiblast at the distal end. Many signaling pathways contribute to this reorganization, including BMP, FGF, nodal, and Wnt. Visceral endoderm surrounds the epiblast. The distal visceral endoderm (DVE) migrates to the anterior portion of the embryo, forming the anterior visceral endoderm (AVE). This breaks anterior-posterior symmetry and is regulated by nodal signaling.
The primitive streak is formed at the beginning of gastrulation and is found at the junction between the extraembryonic tissue and the epiblast on the posterior side of the embryo and the site of ingression. Formation of the primitive streak is reliant upon nodal signaling in the Koller's sickle within the cells contributing to the primitive streak and BMP4 signaling from the extraembryonic tissue.Furthermore, Cer1 and Lefty1 restrict the primitive streak to the appropriate location by antagonizing nodal signaling. The region defined as the primitive streak continues to grow towards the distal tip.
During the early stages of development, the primitive streak is the structure that will establish bilateral symmetry, determine the site of gastrulation and initiate germ layer formation. To form the streak, reptiles, birds and mammals arrange mesenchymal
cells along the prospective midline, establishing the first embryonic
axis, as well as the place where cells will ingress and migrate during
the process of gastrulation and germ layer formation. The primitive streak extends through this midline and creates the antero-posterior body axis, becoming the first symmetry-breaking event in the embryo, and marks the beginning of gastrulation. This process involves the ingression of mesoderm and endoderm progenitors and their migration to their ultimate position, where they will differentiate into the three germ layers. The localization of the cell adhesion and signaling molecule beta-catenin is critical to the proper formation of the organizer region that is responsible for initiating gastrulation.
Cell internalization
In order for the cells to move from the epithelium of the epiblast through the primitive streak to form a new layer, the cells must undergo an epithelial to mesenchymal transition (EMT) to lose their epithelial characteristics, such as cell–cell adhesion. FGF signaling is necessary for proper EMT. FGFR1 is needed for the up regulation of SNAI1, which down regulates E-cadherin, causing a loss of cell adhesion. Following the EMT, the cells ingress through the primitive streak and spread out to form a new layer of cells or join existing layers. FGF8 is implicated in the process of this dispersal from the primitive streak.
Cell signaling driving gastrulation
During gastrulation, the cells are differentiated into the ectoderm or mesendoderm, which then separates into the mesoderm and endoderm. The endoderm and mesoderm form due to the nodal signaling. Nodal signaling uses ligands that are part of TGFβ family. These ligands will signal transmembrane serine/threonine kinase receptors, and this will then phosphorylate Smad2 and Smad3. This protein will then attach itself to Smad4 and relocate to the nucleus where the mesendoderm genes will begin to be transcribed. The Wnt pathway along with β-catenin plays a key role in nodal signaling and endoderm formation. Fibroblast growth factors (FGF), canonical Wnt pathway, bone morphogenetic protein (BMP), and retinoic acid (RA) are all important in the formation and development of the endoderm. FGF are important in producing the homeobox
gene which regulates early anatomical development. BMP signaling plays a
role in the liver and promotes hepatic fate. RA signaling also induce
homeobox genes such as Hoxb1 and Hoxa5. In mice, if there is a lack in
RA signaling the mouse will not develop lungs. RA signaling also has multiple uses in organ formation of the pharyngeal arches, the foregut, and hindgut.
Gastrulation in vitro
There have been a number of attempts to understand the processes of gastrulation using in vitro techniques in parallel and complementary to studies in embryos, usually though the use of 2D and 3D cell (Embryonic organoids) culture techniquesusing embryonic stem cells (ESCs) or induced pluripotent stem cells
(iPSCs). These are associated with number of clear advantages in using
tissue-culture based protocols, some of which include reducing the cost
of associated in vivo work (thereby reducing, replacing and refining the use of animals in experiments; the 3Rs), being able to accurately apply agonists/antagonists in spatially and temporally specific manner which may be technically difficult to perform during Gastrulation.
However, it is important to relate the observations in culture to the
processes occurring in the embryo for context.
To illustrate this, the guided differentiation of mouse ESCs has resulted in generating primitive streak–like cells that display many of the characteristics of epiblast cells that traverse through the primitive streak (e.g. transient brachyury up regulation and the cellular changes associated with an epithelial to mesenchymal transition), and human ESCs cultured on micro patterns, treated with BMP4, can generate spatial differentiation pattern similar to the arrangement of the germ layers in the human embryo. Finally, using 3D embryoid body- and organoid-based techniques, small aggregates of mouse ESCs (Embryonic Organoids, or Gastruloids)
are able to show a number of processes of early mammalian embryo
development such as symmetry-breaking, polarisation of gene expression,
gastrulation-like movements, axial elongation and the generation of all
three embryonic axes (anteroposterior, dorsoventral and left-right
axes).
In vitro fertilization occurs in a laboratory. The process of in vitro
fertilization is when mature eggs are removed from the ovaries and are
placed in a cultured medium where they are fertilized by sperm. In the
culture the embryo will form. 14 days after fertilization the primitive streak forms. The formation
of the primitive streak has been known to some countries as "human
individuality". This means that the embryo is now a being itself, it is its own entity.
The countries that believe this have created a 14-day rule in which it
is illegal to study or experiment on a human embryo after the 14-day
period in vitro. Research has been conducted on the first 14 days of an embryo, but no known studies have been done after the 14 days. With the rule in place, mice embryos are used understand the
development after 14 days; however, there are differences in the
development between mice and humans.
A neural, or brain organoid, describes an artificially grown, in vitro, tissue resembling parts of the human brain. Neural organoids are created by culturing pluripotent stem cells into a three-dimensional culture that can be maintained for years. The brain is an extremely complex system of heterogeneous tissues and consists of a diverse array of neurons and glial cells.
This complexity has made studying the brain and understanding how it
works a difficult task in neuroscience, especially when it comes to
neurodevelopmental and neurodegenerative diseases. The purpose of
creating an in vitro neurological model is to study these diseases in a more defined setting. This 3D model is free of many potential in vivo
limitations. The varying physiology between human and other mammalian
models limits the scope of animal studies in neurological disorders.
Neural organoids contain several types of nerve cells and have
anatomical features that recapitulate regions of the nervous system. Some neural organoids are most similar to neurons of the cortex. In some cases, the retina, spinal cord, thalamus and hippocampus. Other neural organoids are unguided and contain a diversity of neural and non-neural cells. Stem cells
have the potential to grow into many different types of tissues, and
their fate is dependent on many factors. Below is an image showing some
of the chemical factors that can lead stem cells to differentiate into
various neural tissues; a more in-depth table of generating specific
organoid identity has been published. Similar techniques are used on stem cells used to grow cerebral organoids.
Instructive growth factors regulating fate decisions in embryonic NCSCs
Model development
Using human pluripotent stem cells to create in vitro
neural organoids allows researchers to analyze current developmental
mechanisms for human neural tissue as well as study the roots of human
neurological diseases. Neural organoids are an investigative tool used
to understand how disease pathology works. These organoids can be used
in experiments that current in vitro methods are too simplistic
for, while also being more applicable to humans than rodent or other
mammalian models might be. Historically, major breakthroughs in how the
brain works have resulted from studying injury or disorder in human
brain function. An in vitro human brain model permits the next wave in our understanding of the human nervous system.
Culturing methods
This
flow chart outlines the basic steps to create a cerebral organoid. The
process takes a span of months and the size of the organoid is limited
to the availability of nutrients.
A cerebral organoid can be formed by inducing ectoderm cells to differentiate into a cerebral organoids. The general procedure can be broken down into 5 steps. First human pluripotent stem cells are cultured. They are then cultivated into an embryoid body. Next the cell culture is induced to form a neuroectoderm. The neuroectoderm is then grown in a matrigel
droplet. The matrigel provides nutrients and the neuroectoderm starts
to proliferate and grow. Replication of specific brain regions in
cerebral organoid counterparts is achieved by the addition of
extracellular signals to the organoid environment during different
stages of development; these signals were found to create change in cell
differentiation patterns, thus leading to recapitulation of the desired
brain region. SMAD inhibition may be used in usual cerebral organoid culturing processes to generate microglia in cerebral organoids. The lack of vasculature limits the size the organoid can grow. This has
been the major limitation in organoid development. The use of a
spinning bioreactor may improve the availability of nutrients to cells inside the organoid to improve organoid development. Spinning bioreactors have been used increasingly in cell culture and
tissue growth applications. The reactor is able to deliver faster cell doubling times, increased cell expansion and increased extra-cellular matrix components when compared to statically cultured cells.
Components
Differentiation
It
has been shown that cerebral organoids grown using the spinning
bioreactor 3D culture method differentiate into various neural tissue
types, such as the optic cup, hippocampus, ventral parts of the
teleencephelon and dorsal cortex. Furthermore, it was shown that human brain organoids could intrinsically develop integrated light-sensitive optic cups.
The neural stem/progenitor cells are unique because they are able
to self-renew and are multipotent. This means they can generate neurons
and glial cells which are the two main components of neural systems.
The fate of these cells is controlled by several factors that affect the
differentiation process. The spatial location and temporal attributes
of neural progenitor cells can influence if the cells form neurons or
glial cells. Further differentiation is then controlled by extracellular
conditions and cell signaling. The exact conditions and stimuli necessary to differentiate neural
progenitor cells into specific neural tissues such as hippocampal
tissue, optic nerve, cerebral cortex, etc. are unknown. It is believed
that cerebral organoids can be used to study the developmental
mechanisms of these processes.
Gene expression
To
test if the neural progenitor cells and stem cells are differentiating
into specific neural tissues, several gene markers can be tested. Two
markers that are present during pluripotent stages are OCT4 and NANOG.
These two markers are diminished during the course of development for
the organoid. Neural identity markers that note successful neural
induction, SOX1 and PAX6,
are upregulated during organoid development. These changes in
expression support the case for self-guided differentiation of cerebral
organoids. Markers for forebrain and hindbrain can also be tested. Forebrain markers FOXG1 and SIX3 are highly expressed throughout organoid development. However, hindbrain markers EGR2 and ISL1
show early presence but a decrease in the later stages. This imbalance
towards forebrain development is similar to the developmental expansion
of forebrain tissue in human brain development. To test if organoids develop even further into regional specification, gene markers for cerebral cortex and occipital lobe have been tested. Many regions that have forebrain marker FOXG1,
labeling them as regions with cerebral cortical morphology, were also
positive for marker EMX1 which indicates dorsal cortical identity. These
specific regions can be even further specified by markers AUTS2, TSHZ2, and LMO4 with the first representing cerebral cortex and the two after representing the occipital lobe. Genetic markers
for the hippocampus, ventral forebrain, and choroid plexus are also
present in cerebral organoids, however, the overall structures of these
regions have not yet been formed.
Organization
Cerebral
organoids also possess functional cerebral cortical neurons. These
neurons must form on the radially organized cortical plate. The marker TBR1 is present in the preplate, the precursor to the cortical plate, and is present, along with MAP2,
a neuronal marker, in 30-day-old cerebral organoids. These markers are
indicative of a basal neural layer similar to a preplate. These cells
are also apically adjacent to a neutral zone and are reelin+ positive, which indicates the presence of Cajal-Retzius cells. The Cajal-Retzius cells are important to the generation of cortical plate architecture. The cortical plate is usually generated inside-out such that
later-born neurons migrate to the top superficial layers. This
organization is also present in cerebral organoids based on genetic
marker testing. Neurons that are early born have marker CTIP2 and are located adjacent to the TBR1 exhibiting preplate cells. Late-born neurons with markers SATB2 and BRN2
are located in a superficial layer, further away from the preplate than
the early born neurons suggesting cortical plate layer formation.
Additionally, after 75 days of formation, cerebral organoids show a
rudimentary marginal zone, a cell-poor region. The formation of layered
cortical plate is very basic in cerebral organoids and suggests the
organoid lacks the cues and factors to induce formation of layer II-VI
organization. The cerebral organoid neurons can, however, form axons as shown by GFP
staining. GFP labeled axons have been shown to have complex branching
and growth cone formation. Additionally, calcium dye imaging has shown
cerebral organoids to have Ca2+ oscillations and spontaneous calcium surges in individual cells. The calcium signaling can be enhanced through glutamate and inhibited through tetrodotoxin.
Interactions with environment
In DishBrain, grown human brain cells were integrated into digital systems to play a simulated Pong via electrophysiological stimulation and recording. The cells "showed significantly improved performance in Pong" when embodied in a virtual game-world. In the 2020s, significant changes in how these electrophysiological
systems are made and interact with brain organoids could lead to better
stimulation and recording data across the organoind in 3D.
Interactions with surrounding tissues
It is not fully understood how individual localized tissues formed by
stem cells are able to coordinate with surrounding tissues to develop
into a whole organ. It has been shown however that most tissue differentiation requires
interactions with surrounding tissues and depends on diffusible
induction factors to either inhibit or encourage various differentiation
and physical localization. Cerebral organoid differentiation is somewhat localized. The previously
mentioned markers for forebrain and hindbrain are physically localized,
appearing in clusters. This suggests that local stimuli are released
once one or more cells differentiate into a specific type as opposed to a
random pathway throughout the tissue. The markers for subspecification
of cortical lobes, prefrontal cortex and occipital lobe, are also
physically localized. However, the hippocampus and ventral forebrain
cells are not physically localized and are randomly located through the
cerebral organoid. Cerebral organoids lack blood vessels and are limited in size by
nutrient uptake in the innermost cells. Spinning bioreactors and
advanced 3D scaffolding techniques are able to increase organoid size,
though the integration of in vitro nutrient delivery systems is likely
to spark the next major leap in cerebral organoid development.
Assays
Cerebral organoids have the potential to function as a model with which disease and gene expression might be studied. However, diagnostic tools are needed to evaluate cerebral organoid
tissue and create organoids modeling the disease or state of development
in question. Transcriptome analysis has been used as an assay to examine the pathology of cerebral organoids derived from individual patients. Additionally, TUNEL assays have been used in studies as an evaluative marker of apoptosis in cerebral organoids. Other assays used to analyze cerebral organoids include the following:
Genetic modifications
Cerebral organoids can be used to study gene expression via genetic modifications. The degree to which these genetic modifications are present in the
entire organoid depends on what stage of development the cerebral
organoid is in when these genetic modifications are made; the earlier
these modifications are made, such as when the cerebral organoid is in
the single cell stage, the more likely these modifications will affect a
greater portion of the cells in the cerebral organoid. The degree to which these genetic modifications are present within the
cerebral organoid also depends on the process by which these genetic
modifications are made. If the genetic information is administered into
one cerebral organoid cell's genome via machinery, then the genetic
modification will remain present in cells resulting from replication. Crispr/Cas 9 is a method by which this long-lasting genetic modification can be made. A system involving use of transposons has also been suggested as a
means to generate long-lasting genetic modifications; however, the
extent to which transposons might interact with a cell genome might
differs on a cell to cell basis, which would create variable
expressivity between cerebral organoid cells. If, however, the genetic modification is made via “genetic cargo” insertion (such as through Adeno-associated virus/ electroporation
methods) then it has been found that the genetic modification becomes
less present with each round of cell division in cerebral organoids.
Computational methods
Use
of computational methods have been called for as a means to help
improve the cerebral organoid cultivation process; development of
computational methods has also been called for in order to provide
necessary detailed renderings of different components of the cerebral
organoid (such as cell connectivity) that current methods are unable to
provide. Programming designed to model detailed cerebral organoid morphology does not yet exist.
There are many potential applications for cerebral organoid use, such as cell fate potential, cell replacement therapy, and cell-type specific genome assays. Cerebral organoids also provide a unique insight into the timing of
development of neural tissues and can be used as a tool to study the
differences across species. Further potential applications for cerebral organoids include:
Tissue morphogenesis
Tissue morphogenesis with respect to cerebral organoids covers how neural organs form in vertebrates. Cerebral organoids can serve as in vitro tools to study the formation, modulate it, and further understand the mechanisms controlling it.
Migration assays
Cerebral organoids can help to study cell migration. Neural glial cells
cover a wide variety of neural cells, some of which move around the
neurons. The factors that govern their movements, as well as neurons in
general, can be studied using cerebral organoids.
Clonal lineage tracing
Clonal lineage tracing is part of fate mapping,
where the lineage of differentiated tissues is traced to the
pluripotent progenitors. The local stimuli released and the mechanism of
differentiation can be studied using cerebral organoids as a model. Genetic modifications in cerebral organoids could serve as a means to accomplish lineage tracing.
Transplantation
Cerebral organoids can be used to grow specific brain regions and transplant them into regions of neurodegeneration as a therapeutic treatment. They can fuse with host vasculature and be immunologically silent. In some cases, the genomes of these cerebral organoids would first have to be edited. Recent studies have been able to achieve successful transplantation and
integration of cerebral organoids into mouse brains; development of
cell differentiation and vascularity was also observed after
transplantation. Cerebral organoids might serve as the basis for transplantation and
rebuilding in the human brain due to the similarity in structure.
Drug testing
Cerebral
organoids can be used as simple models of complex brain tissues to
study the effects of drugs and to screen them for initial safety and
efficacy. Testing new drugs for neurological diseases could also result
from this method of applying drug high-throughput screening methods to cerebral organoids. After 2015, significant effort has gone into fabricating microscale
devices to generate reproducible cerebral organoids at high-throughput.
Organoids
can be used to study the crucial early stages of brain development,
test drugs and, because they can be made from living cells, study
individual patients. Additionally, the development of vascularized cerebral organoids could be used for investigating stroke therapy in the future.
Zika Virus
Zika virus
has been shown to have teratogenic effects, causing defects in fetal
neurological development. Cerebral organoids have been used in studies
in order to understand the process by which Zika virus affects the fetal
brain and, in some cases, causes microcephaly.Cerebral organoids infected with the Zika virus have been found to be
smaller in size than their uninfected counterparts, which is reflective
of fetal microcephaly. Increased apoptosis was also found in cerebral organoids infected with Zika virus. Another study found that neural progenitor cell (NPC) populations were
greatly reduced in these samples. The two methods by which NPC
populations were reduced were increased cell death and reduced cell
proliferation. TLR3
receptor upregulation was identified in these infected organoids.
Inhibition of this TLR3 receptor was shown to partially halt some of the
Zika induced effects. Additionally, lumen size was found to be increased in organoids infected with Zika virus.The results found from studying cerebral organoids infected with Zika
virus at different stages of maturation suggest that early exposure in
developing fetuses can cause greater likelihood of Zika virus-associated
neurological birth defects.
Cocaine
Cocaine
has also been shown to have teratogenic effects on fetal development.
Cerebral organoids have been used to study which enzyme isoforms are
necessary for fetal neurological defects caused by cocaine use during
pregnancy. One of these enzymes was determined to be cytochrome P450 isoform CYP3A5.
Microcephaly
In one case, a cerebral organoid grown from a patient with microcephaly
demonstrated related symptoms and revealed that apparently, the cause
is overly rapid development, followed by slower brain growth.
Microencephaly is a developmental condition in which the brain remains
undersized, producing an undersized head and debilitation. Microcephaly
is not suitable for mouse models, which do not replicate the condition. The primary form of the disease is thought to be caused by a homozygous mutation in the microcephalin gene. The disease is difficult to reproduce in mouse models because mice lack the developmental stages for an enlarged cerebral cortex
that humans have. Naturally, a disease which affects this development
would be impossible to show in a model which does not have it to begin
with. To use cerebral organoids to model a human's microcephaly, one group of
researchers has taken patient skin fibroblasts and reprogrammed them
using four well known reprogramming factors. These include OCT4, SOX2, MYC and KLF4.
The reprogrammed sample was able to be cloned into induced pluripotent
stem cells. The cells were cultured into a cerebral organoid following a
process described in the cerebral organoid creation section below. The
organoid that resulted had decreased numbers of neural progenitor cells
and smaller tissues. Additionally, the patient-derived tissues displayed
fewer and less frequent neuroepithelial tissues made of progenitors,
decreased radial glial stem cells, and increased neurons. These results
suggest that the underlying mechanism of microcephaly is caused by cells
prematurely differentiating into neurons leaving a deficit of radial
glial cells.
Alzheimer's disease
Alzheimer's disease pathology has also been modeled with cerebral organoids. Affected individual's pluripotent stem cells were used to generate
brain organoids and then compared to control models, synthesised from
healthy individuals. It was found that in the affected models,
structures similar to that of plaques caused by amyloid beta proteins and neurofibrillary tangles, that cause the disease's symptoms were observed. Previous attempts to model this so accurately have been unsuccessful,
with drugs being developed on the basis of efficacy in pre-clinical
murine models demonstrating no effect in human trials.
Autism spectrum disorders
Cerebral organoids can also be used to study autism spectrum disorders. In one study, cerebral organoids were cultured from cells derived from macrocephaly ASD patients. These cerebral organoids were found to reflect characteristics typical
of the ASD-related macrocephaly phenotype found in the patients. By cultivating cerebral organoids from ASD patients with macrocephaly,
connections could be made between certain gene mutations and phenotypic
expression. Autism has also been studied through the comparison of healthy versus affected synthesised brain organoids. Observation of the two models showed the overexpression of a transcription factor FOXG1 that produced a larger amount of GABAergic
inhibitory neurons in the affected models. The significance of this use
of brain organoids is that it has added great support for the
excitatory/inhibitory imbalance hypothesis which if proven true could help identify targets for drugs so that the condition could be treated.
The field of epigenetics and how DNA methylation
might influence development of ASD has also been of interest in recent
years. The traditional method of studying post-mortem neural samples
from individuals with ASD poses many challenges, so cerebral organoids
have been proposed as an alternate method of studying the potential
effect that epigenetic mechanisms may have on the development of autism.
This use of the cerebral organoid model to examine ASD and epigenetic
patterns might provide insight in regards to epigenetic developmental
timelines. However, it is important to note that the conditions in which
cerebral organoids are cultured in might affect gene expression, and
consequentially affect observations made using this model. Additionally,
there is concern over the variability in cerebral organoids cultured
from the same sample. Further research into the extent and accuracy by which cerebral
organoids recapitulate epigenetic patterns found in primary samples is
also needed.
Preterm hypoxia/ischemia
Preterm
hypoxic injury remain difficult to study because of limited
availability of human fetal brain tissues and inadequate animal models
to study human corticogenesis. Cerebral organoid can be used to model
prenatal pathophysiology and to compare the susceptibility of the
different neural cell types to hypoxia during corticogenesis.
Intermediate progenitors seem to be particularly affected, due to the
unfolded protein response pathway. It has also been observed that hypoxia resulted in apoptosis in
cerebral organoids, with outer radial glia and neuroblasts/immature
neurons being particularly affected.
Glioblastomas
Traditional means of studying glioblastomas
come with limitations. One example of such limitations would be the
limited sample availability. Because of these challenges that come with
using a more traditional approach, cerebral organoids have been used as
an alternative means to model the development of brain cancer. In one
study, cerebral organoids were simulated to reflect tumor-like qualities
using CRISPR CAS-9. Increased cell division was observed in these
genetically altered models. Cerebral organoids were also used in mice
models to study tumorigenesis
and invasiveness. At the same time, the growth of brain cancers is
influenced by environmental factors which are not yet replicable in
cerebral organoid models. Cerebral organoids have been shown to provide
insight into dysregulation of genes responsible for tumor development.
Multiple Sclerosis
Multiple
sclerosis is an auto-immune inflammatory disorder affecting the central
nervous system. Environmental and genetic factors contribute to the
development of multiple sclerosis, however the etiology of this
condition is unknown. Induced pluripotent stem cells from healthy human
controls, as well as from patients with multiple sclerosis were grown
into cerebral organoids creating an innovative human model of this
disease.
Limitations
Cerebral
organoids are preferred over their 3D cell culture counterparts because
they can better reflect the structure of the human brain, and because,
to a certain extent, they can reflect fetal neocortex development over
an extended period of time. While cerebral organoids have a lot of
potential, their culturing and development comes with limitations and
areas for improvement. For example, it takes several months to create one cerebral organoid,
and the methods used to analyze them are also time-consuming. Additionally, cerebral organoids do not have structures typical of a human brain, such as a blood brain barrier. This limits the types of diseases that can be studied. Other limitations include:
Necrotic centers
Until recently, the central part of organoids have been found to be necrotic due to oxygen as well as nutrients being unable to reach that innermost area. This imposes limitations to cerebral organoids' physiological applicability. Because of this lack of oxygen and nutrients, neural progenitor cells are limited in their growth. However, recent findings suggest that, in the process of culturing a
cerebral organoid, a necrotic center could be avoided by using fluidic
devices to increase the organoid's exposure to media.
Reliability in generation
The
structure of cerebral organoids across different cultures has been
found to be variable; a standardization procedure to ensure uniformity
has yet to become common practice. Future steps in revising cerebral organoid production would include
creating methods to ensure standardization of cerebral organoid
generation. One such step proposed involves regulating the composition and
thickness of the gel in which cerebral organoids are cultured in; this
might contribute to greater reliability in cerebral organoid production. Additionally, variability in generation of cerebral organoids is introduced due to differences in stem cells used. These differences can arise from different manufacturing methods or host differences. Increased metabolic stress has also been found within organoids. This
metabolic stress has been found to restrict organoid specificity. Future steps to streamline organoid culturing include analyzing more than one sample at a time.
Maturity
At the moment, the development of mature synapses in cerebral organoids is limited because of the media used. Additionally, while some electrophysiological properties have been
shown to develop in cerebral organoids, cultivation of separate and
distinct organoid regions has been shown to limit the maturation of
these electrophysiological properties. Modeling of electrophysiological
neurodevelopmental processes typical of development later in the
neurodevelopmental timeline, such as synaptogenesis, is not yet suggested in cerebral organoid models. Since cerebral organoids are reflective of what happens during fetal
neurodevelopment, there has been concern over how late onset diseases
manifest in them. Future improvements include developing a way to
recapitulate neurodegenerative diseases in cerebral organoids.
Ethical
concerns have been raised with using cerebral organoids as a model for
disease due to the potential of them experiencing sensations such as
pain or having the ability to develop a consciousness. Currently it is unlikely given the simplicity of synthesised models
compared to the complexity of a human brain; however, models have been
shown to respond to light-based stimulation, so present models do have some scope of responding to some stimuli.
Guidelines and legislation
Steps
are being taken towards resolving the grey area such as a 2018
symposium at Oxford University where experts in the field, philosophers
and lawyers met to try to clear up the ethical concerns with the new
technology. Similarly, projects such as Brainstorm from Case Western University aim
to observe the progress of the field by monitoring labs working with
brain organoids to try to begin the ‘building of a philosophical
framework’ that future guidelines and legislation could be built upon.
Additionally, the "humanization" of animal models has been raised as a
topic of concern in transplantation of human stem cell derived
organoids into other animal models. For example, potential future concerns of this type were described when human brain tissue organoids were transplanted into baby rats, appearing to be highly functional, to mature and to integrate with the rat brain. Such models can be used to model human brain development and, as demonstrated, to investigate diseases (and their potential therapies) but could be controversial.
Scope–severity grid from Bostrom's paper "Existential Risk Prevention as Global Priority"
Risks of astronomical suffering, also called suffering risks or s-risks, are risks involving much more suffering than all that has occurred on Earth so far. They are sometimes categorized as a subclass of existential risks.
According to some scholars, s-risks warrant serious consideration
as they are not extremely unlikely and can arise from unforeseen
scenarios. Although they may appear speculative, factors such as
technological advancement, power dynamics, and historical precedents
indicate that advanced technology could inadvertently result in
substantial suffering. Thus, s-risks are considered to be a morally
urgent matter, despite the possibility of technological benefits.
Sources of possible s-risks include embodied artificial intelligence and superintelligence, as well as space colonization, which could potentially lead to "constant and catastrophic wars" and an immense increase in wild animal suffering
by introducing wild animals, who "generally lead short, miserable lives
full of sometimes the most brutal suffering", to other planets, either
intentionally or inadvertently.
Types of S-risk
Artificial intelligence
Artificial intelligence
is central to s-risk discussions because it may eventually enable
powerful actors to control vast technological systems. In a worst-case
scenario, AI could be used to create systems of perpetual suffering,
such as a totalitarian regime expanding across space. Additionally, s-risks might arise incidentally, such as through
AI-driven simulations of conscious beings experiencing suffering, or
from economic activities that disregard the well-being of nonhuman or
digital minds. Steven Umbrello, an AI ethics researcher, has warned that biological computing may make system design more prone to s-risks.
Space colonization
Space colonization
could increase suffering by introducing wild animals to new
environments, leading to ecological imbalances. In unfamiliar habitats,
animals may struggle to survive, facing hunger, disease, and predation.
These challenges, combined with unstable ecosystems, could cause
population crashes or explosions, resulting in widespread suffering.
Additionally, the lack of natural predators or proper biodiversity on
colonized planets could worsen the situation, mirroring Earth’s
ecological problems on a larger scale. This raises ethical concerns
about the unintended consequences of space colonization, as it could
propagate immense animal suffering in new, unstable ecosystems. Phil
Torres argues that space colonization poses significant "suffering
risks", where expansion into space will lead to the creation of diverse
species and civilizations with conflicting interests. These differences,
combined with advanced weaponry and the vast distances between
civilizations, would result in catastrophic and unresolvable conflicts.
Strategies like a "cosmic Leviathan" to impose order or deterrence
policies are unlikely to succeed due to physical limitations in space
and the destructive power of future technologies. Thus, Torres concludes
that space colonization could create immense suffering and should be
delayed or avoided altogether.
Magnus Vinding's "astronomical atrocity problem" questions
whether vast amounts of happiness can justify extreme suffering from
space colonization. He highlights moral concerns such as diminishing
returns on positive goods, the potentially incomparable weight of severe
suffering, and the priority of preventing misery. He argues that if
colonization is inevitable, it should be led by agents deeply committed
to minimizing harm.
Genetic engineering
David Pearce has argued that genetic engineering is a potential s-risk. Pearce argues that while technological mastery over the pleasure-pain axis and solving the hard problem of consciousness could lead to the potential eradication of suffering,
it could also potentially increase the level of contrast in the hedonic
range that sentient beings could experience. He argues that these
technologies might make it feasible to create "hyperpain" or "dolorium"
that experience levels of suffering beyond the human range.
Excessive criminal punishment
S-risk
scenarios may arise from excessive criminal punishment, with precedents
in both historical and in modern penal systems. These risks escalate in
situations such as warfare or terrorism, especially when advanced
technology is involved, as conflicts can amplify destructive tendencies
like sadism, tribalism, and retributivism.
War often intensifies these dynamics, with the possibility of
catastrophic threats being used to force concessions. Agential s-risks
are further aggravated by malevolent traits in powerful individuals,
such as narcissism or psychopathy. This is exemplified by totalitarian
dictators like Hitler and Stalin, whose actions in the 20th century inflicted widespread suffering.
Exotic risks
According to David Pearce, there are other potential s-risks that are more exotic, such as those posed by the many-worlds interpretation of quantum mechanics.
Mitigation strategies
To
mitigate s-risks, efforts focus on researching and understanding the
factors that exacerbate them, particularly in emerging technologies and
social structures. Targeted strategies include promoting safe AI design,
ensuring cooperation among AI developers, and modeling future
civilizations to anticipate risks. Broad strategies may advocate for
moral norms against large-scale suffering and stable political
institutions. According to Anthony DiGiovanni, prioritizing s-risk
reduction is essential, as it may be more manageable than other
long-term challenges, while avoiding catastrophic outcomes could be
easier than achieving an entirely utopian future.
Induced amnesia
Induced amnesia has been proposed as a way to mitigate s-risks in locked-in conscious AI and certain AI-adjacent biological systems like brain organoids.
Cosmic rescue missions
David
Pearce's concept of "cosmic rescue missions" proposes the idea of
sending probes to alleviate potential suffering in extraterrestrial
environments. These missions aim to identify and mitigate suffering
among hypothetical extraterrestrial life forms, ensuring that if life
exists elsewhere, it is treated ethically. However, challenges include the lack of confirmed extraterrestrial
life, uncertainty about their consciousness, and public support
concerns, with environmentalists advocating for non-interference and
others focusing on resource extraction.
In 2023, the use of molten salts as electrolytes for high-energy rechargeable lithium metal batteries was demonstrated.
History
Thermal batteries originated during World War II
when German scientist Georg Otto Erb developed the first practical
cells using a salt mixture as an electrolyte. Erb developed batteries
for military applications, including the V-1 flying bomb and the V-2
rocket, and artillery fuzing systems. None of these batteries entered
field use during the war. Afterwards, Erb was interrogated by British
intelligence. His work was reported in "The Theory and Practice of
Thermal Cells". This information was subsequently passed on to the
United States Ordnance Development Division of the National Bureau of Standards. When the technology reached the United States
in 1946, it was immediately applied to replacing the troublesome
liquid-based systems that had previously been used to power artillery proximity fuzes. They were used for ordnance applications (e.g., proximity fuzes) since WWII and later in nuclear weapons. The same technology was studied by Argonne National Laboratories and other researchers in the 1980s for use in electric vehicles.
Rechargeable configurations
Since the mid-1960s much development work has been undertaken on rechargeable batteries using sodium (Na) for the negative electrodes. Sodium is attractive because of its high reduction potential
of −2.71 volts, low weight, relative abundance, and low cost. In order
to construct practical batteries, the sodium must be in liquid form. The
melting point
of sodium is 98 °C (208 °F). This means that sodium-based batteries
operate at temperatures between 245 and 350 °C (470 and 660 °F). Research has investigated metal combinations with operating temperatures at 200 °C (390 °F) and room temperature.
The sodium–sulfur battery (NaS battery), along with the related lithium–sulfur battery employs cheap and abundant electrode materials. It was the first alkali-metal commercial battery. It used liquid sulfur for the positive electrode and a ceramic tube of beta-alumina solid electrolyte (BASE). Insulator corrosion was a problem because they gradually became conductive, and the self-discharge rate increased.
Because of their high specific power, NaS batteries have been proposed for space applications. An NaS battery for space use was successfully tested on the Space Shuttle mission STS-87 in 1997, but the batteries have not been used operationally in space. NaS
batteries have been proposed for use in the high-temperature environment
of Venus.
A consortium formed by Tokyo Electric Power Co.
(TEPCO) and NGK Insulators Ltd. declared their interest in researching
the NaS battery in 1983, and became the primary drivers behind the
development of this type ever since. TEPCO chose the NaS battery because
its component elements (sodium, sulfur and ceramics) are abundant in
Japan. The first large-scale field testing took place at TEPCO's
Tsunashima substation between 1993 and 1996, using 3 × 2
MW, 6.6 kV battery banks. Based on the findings from this trial,
improved battery modules were developed and were made commercially
available in 2000. The commercial NaS battery bank offers:
Capacity : 25–250 kWh per bank
Efficiency of 87%
Lifetime of 2,500 cycles at 100% depth of discharge (DOD), or 4,500 cycles at 80% DOD
The Citroën Berlingo First Electric "Powered by Venturi" used a ZEBRA storage battery; a specially-prepared version was driven from Shanghai to Paris in 2010.
A lower-temperature variant of molten-salt batteries was the development of the ZEBRA
(originally, "Zeolite Battery Research Africa"; later, the "Zero
Emissions Batteries Research Activity") battery in 1985, originally
developed for electric vehicle applications. The battery uses NaNiCl 2 with Na+-beta-alumina ceramic electrolyte.
The NaNiCl 2 battery operates at 245 °C (473 °F) and uses molten sodium tetrachloroaluminate (NaAlCl 4),
which has a melting point of 157 °C (315 °F), as the electrolyte. The
negative electrode is molten sodium. The positive electrode is nickel in the discharged state and nickel chloride in the charged state. Because nickel and nickel chloride are nearly insoluble in neutral and basic melts, contact is allowed, providing little resistance to charge transfer. Since both NaAlCl 4 and Na are liquid at the operating temperature, a sodium-conducting β-alumina ceramic is used to separate the liquid sodium from the molten NaAlCl 4.
The primary elements used in the manufacture of these batteries have
much higher worldwide reserves and annual production than lithium.
It was invented in 1985 by the Zeolite Battery Research Africa Project (ZEBRA) group at the Council for Scientific and Industrial Research (CSIR) in Pretoria, South Africa.
It can be assembled in the discharged state, using NaCl, Al, nickel and
iron powder. The positive electrode is composed mostly of materials in
the solid state, which reduces the likelihood of corrosion, improving
safety. Its specific energy
is 100 Wh/kg; specific power is 150 W/kg. The β-alumina solid ceramic
is unreactive to sodium metal and sodium aluminum chloride. Lifetimes of
over 2,000 cycles and twenty years have been demonstrated with
full-sized batteries, and over 4,500 cycles and fifteen years with 10-
and 20-cell modules. For comparison, LiFePO4lithium iron phosphate batteries store 90–110 Wh/kg, and the more common LiCoO2 lithium-ion batteries store 150–200 Wh/kg. A nano lithium-titanate battery stores 72 Wh/kg and can provide power of 760 W/kg.
The ZEBRA's liquid electrolyte freezes at 157 °C (315 °F), and
the normal operating temperature range is 270–350 °C (520–660 °F).
Adding iron to the cell increases its power response. ZEBRA batteries are currently manufactured by FZSoNick and used as a power backup in the telecommunication industries,
Oil&Gas and Railways. It is also used in special electric vehicles
used in mining. In the past it was adopted in the Modec Electric Van, the Iveco Daily 3.5-ton delivery vehicle, the prototype Smart ED, and the Th!nk City. In 2011 the US Postal Service began testing all-electric delivery vans, one powered by a ZEBRA battery.
In 2010 General Electric announced a Na-NiCl 2
battery that it called a sodium–metal halide battery, with a 20-year
lifetime. Its cathode structure consists of a conductive nickel network,
molten salt electrolyte, metal current collector, carbon felt
electrolyte reservoir and the active sodium–metal halide salts. In 2015, as a result of a global restructuring, the company abandoned the project. In 2017 Chinese battery maker Chilwee Group (also known as Chaowei)
created a new company with General Electric (GE) to bring to market a
Na-NiCl battery for industrial and energy storage applications.
When not in use, Na-NiCl 2
batteries are typically kept molten and ready for use because if
allowed to solidify they typically take twelve hours to reheat and
charge. This reheating time varies depending on the battery-pack temperature,
and power available for reheating. After shutdown a fully charged
battery pack loses enough energy to cool and solidify in five-to-seven
days depending on the amount of insulation.
Sodium metal chloride batteries are very safe; a thermal runaway
can be activated only by piercing the battery and also, in this
unlikely event, no fire or explosion will be generated. For this reason
and also for the possibility to be installed outdoor without cooling
systems, make the sodium metal chloride batteries very suitable for the
industrial and commercial energy storage installations.
Sumitomo
studied a battery using a salt that is molten at 61 °C (142 °F), far
lower than sodium based batteries, and operational at 90 °C (194 °F). It
offers energy densities as high as 290 Wh/L and 224 Wh/kg and
charge/discharge rates of 1C with a lifetime of 100–1000 charge cycles.
The battery employs only nonflammable materials and neither ignites on
contact with air nor risks thermal runaway. This eliminates waste-heat
storage or fire- and explosion-proof equipment, and allows closer cell
packing. The company claimed that the battery required half the volume
of lithium-ion batteries and one quarter that of sodium–sulfur
batteries. The cell used a nickel cathode and a glassy carbon anode.
In 2014 researchers identified a liquid sodium–cesium alloy that
operates at 50 °C (122 °F) and produced 420 milliampere-hours per gram.
The new material was able to fully coat, or "wet," the electrolyte.
After 100 charge/discharge cycles, a test battery maintained about 97%
of its initial storage capacity. The lower operating temperature allowed
the use of a less-expensive polymer external casing instead of steel,
offsetting some of the increased cost of cesium.
Innovenergy in Meiringen, Switzerland
has further optimised this technology with the use of domestically
sourced raw materials, except for the nickel powder component. Despite
the reduced capacity compared with lithium-ion batteries, the ZEBRA technology is applicable for stationary energy storage from solar power.
In 2022, the company operated a 540 kWh storage facility for solar
cells on the roof of a shopping center, and currently produces over a
million battery units per year from sustainable, non-toxic materials (table salt).
Professor Donald Sadoway
at the Massachusetts Institute of Technology has pioneered the research
of liquid-metal rechargeable batteries, using both magnesium–antimony
and more recently lead–antimony. The electrode and electrolyte layers are heated until they are liquid and self-segregate due to density and immiscibility.
Such batteries may have longer lifetimes than conventional batteries,
as the electrodes go through a cycle of creation and destruction during
the charge–discharge cycle, which makes them immune to the degradation
that afflicts conventional battery electrodes.
The technology was proposed in 2009 based on magnesium and antimony separated by a molten salt. Magnesium was chosen as the negative electrode for its low cost and low
solubility in the molten-salt electrolyte. Antimony was selected as the
positive electrode due to its low cost and higher anticipated discharge
voltage.
In 2011, the researchers demonstrated a cell with a lithium anode
and a lead–antimony cathode, which had higher ionic conductivity and
lower melting points (350–430 °C). The drawback of the Li chemistry is higher cost. A Li/LiF + LiCl +
LiI/Pb-Sb cell with about 0.9 V open-circuit potential operating at
450 °C had electroactive material costs of US$100/kWh and US$100/kW and a
projected 25-year lifetime. Its discharge power at 1.1 A/cm2 is only 44% (and 88% at 0.14 A/cm2).
Experimental data shows 69% storage efficiency, with good storage capacity (over 1000 mAh/cm2), low leakage (< 1 mA/cm2) and high maximal discharge capacity (over 200 mA/cm2). By October 2014 the MIT team achieved an operational efficiency of approximately 70% at high charge/discharge rates (275 mA/cm2), similar to that of pumped-storage hydroelectricity
and higher efficiencies at lower currents. Tests showed that after 10
years of regular use, the system would retain about 85% of its initial
capacity. In September 2014, a study described an arrangement using a molten
alloy of lead and antimony for the positive electrode, liquid lithium
for the negative electrode; and a molten mixture of lithium salts as the
electrolyte.
A recent innovation is the PbBi alloy which enables lower melting
point lithium-based battery. It uses a molten salt electrolyte based on
LiCl-LiI and operates at 410 °C.
Ionic liquids
have been shown to have prowess for use in rechargeable batteries. The
electrolyte is pure molten salt with no added solvent, which is
accomplished by using a salt having a room temperature liquid phase.
This causes a highly viscous solution, and is typically made with
structurally large salts with malleable lattice structures.
Thermal
batteries use an electrolyte that is solid and inactive at ambient
temperatures. They can be stored indefinitely (over 50 years) yet
provide full power in an instant when required. Once activated, they
provide a burst of high power for a short period (a few tens of seconds
to 60 minutes or more), with output ranging from watts to kilowatts. The high power is due to the high ionic conductivity
of the molten salt (resulting in a low internal resistance), which is
three orders of magnitude (or more) greater than that of the sulfuric acid in a lead–acid car battery.
One design uses a fuze strip (containing barium chromate and powdered zirconium
metal in a ceramic paper) along the edge of the heat pellets to
initiate the electrochemical reaction. The fuze strip is typically fired
by an electrical igniter or squib which is activated with an electric current.
Another design uses a central hole in the middle of the battery
stack, into which the high-energy electrical igniter fires a mixture of
hot gases and incandescent
particles. This allows much shorter activation times (tens of
milliseconds) vs. hundreds of milliseconds for the edge-strip design.
Battery activation can be accomplished by a percussion primer, similar to a shotgun shell. The heat source should be gasless. The standard heat source typically consists of mixtures of iron powder and potassium perchlorate in weight ratios of 88/12, 86/14, or 84/16. The higher the potassium perchlorate level, the higher the heat output (nominally 200, 259, and 297 cal/g
respectively). This property of unactivated storage has the double
benefit of avoiding deterioration of the active materials during storage
and eliminating capacity loss due to self-discharge until the battery is activated.
More recently, other lower-melting, eutectic electrolytes based on lithium bromide, potassium bromide, and lithium chloride or lithium fluoride
have also been used to provide longer operational lifetimes; they are
also better conductors. The so-called "all-lithium" electrolyte based on
lithium chloride, lithium bromide, and lithium fluoride (no potassium salts) is also used for high-power applications, because of its high ionic conductivity. A radioisotope thermal generator, such as in the form of pellets of 90SrTiO4, can be used for long-term delivery of heat for the battery after activation, keeping it in a molten state.
Uses
Thermal batteries are used almost exclusively for military applications, notably for nuclear weapons and guided missiles. They are the primary power source for many missiles such as the AIM-9 Sidewinder, AIM-54 Phoenix, MIM-104 Patriot, BGM-71 TOW, BGM-109 Tomahawk and others. In these batteries the electrolyte is immobilized when molten by a special grade of magnesium oxide that holds it in place by capillary action. This powdered mixture is pressed into pellets to form a separator between the anode and cathode
of each cell in the battery stack. As long as the electrolyte (salt) is
solid, the battery is inert and remains inactive. Each cell also
contains a pyrotechnic heat source, which is used to heat the cell to the typical operating temperature of 400–550 °C.
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