Cell Biology

-Rounding up of cells
-karyorrhexis
-pyknosis
-retraction of pseudopodes
-minor modifications of cytoplasmic organells
-engulfment of residing phagocytes (in vivo)
-plasma membrane blebbing

is a response to stress and results in the digestion of cellular substrates by lysosomes

-lack of chromatin condensation
-massive vacuolisation of the cytoplasma
-accumulation of autophagic vacuoles
-little to no uptake by phagocytic cells (in vivo)

-rupture of cell membrane
-swelling of cytoplasmic organells
-moderate chromatin condensation
-oncosis leads to necrosis with karyolysis

autophagy associated cell death. Excessive autophagic activity leads to cell death.

cell canibalism, which is often observed in tumour cells upon glucose starvation. One cell engulfs another live cell by invading into the cells cytoplasma leading to degradation

dependend on iron, ROS/lipid peroxidation and GPX4 inhibition. Accumulation of iron leads to excessive lipid peroxidation. The dysfunction of gluthathione peroxidase 4 (GPX4) prevents detoxification of ROS (reactive oxygen species).
-neuro-degeneration

Based on lysosomal membrane permeabilisation. Is caused by a release of lysosomal enzymes (proteases) into cytoplasma due to disruption of lysosomal membrane.
-neuro-degeneration

cell growth and cell doubling/cell division

-development of tissues and organs
-homeostasis of tissue and organs in adult organisms (replacement of dead cells by proliferation)
-intestinal epithelia (all cells are renewed in about 1 week; fat cells about 10% per year)
-regeneration of damaged tissue and organs e.g. wound healing, liver regeneration
-enlargement of tissue and organs (fatty tissue)
-strong amolification of certain cell types like immune cells
-growth of tumours, cancer by deregulated cell proliferation

cells often require physical contact with a substrate to be able to divide (inside a culture flask or extracellular matrix of a tissue)

cells form a single layer and dont proliferate anymore. If there is a gap in the monolayer, the cells divide to fill the gap and then stop again.

Integrins

Integrins are cell surface proteins and are expressed on cells of the body. Integrins bind ECM proteins and therefore mediate adhesion of cells to the sorrounding ECM.
They can activate the signaling pathways that can promote cell proliferation and supress apoptotic cell death upon binding to their ECM ligands (in combination with growth factors).

when the cells are stimulated with growth factors without anchorage to the ECM.

Through integrins cell with anchorage to the ECM can activate the MEK/MAPK pathway for cell proliferation. The PI3K/Akt pathway for cell survival. And promotes cytoskeletal reorganization through activation of Rho family small GTPases.

-interstitial matrix that surrounds cells in the connective tissue
-basement membrane that is a sheet-like ECM underlying epithelial cells

basement membrane

Parenchymal cells in many organs including kidney, lungs, pancreas, liver, heart and blood vessels use the basement membrane as their adhesive substrate and recieve the signals that secure their function, prevent apoptosis and regulate their cell cycle progression through integrins on their cell surface.

CEMM are cholesteral-enriched membrane microdomains at the plasmamembrane.

In adherent cells CEMM at the plasmamembrane allow correct activation and coupling of signaling molecules to their effectors such as Rac-PAK and PI3K-Akt), which results in cell survival and growth.

Loss of adhesion leads to the shutdown of signaling pathways. After cell detachment from the ECM, integrin signaling is shutdown and CEMMs are internalized in a caveolin-1 (Cav1) - dependend manner, resulting in cell cycle arrest anf anoikis.

-transformed cells
-transformed cells employ different strategies to compensate for or circumvent, the anoikis signals and thus become anchorage independend
-there are three strategies/patterns:
1. adapting to the new surroundings, either by epidermal-to mesenchymal transition (EMT) or by integrin switching, to avoid anoikis
2. counteracting negative signaling by hyperactivation of survival or mitogenic pathways
3. hiding and waiting by entering into a dormant state through either autophagy or entosis and then reactivating the cell cycle when conditions are favorable.

the proliferation of adherent cells is dependend on growth factors and attachment to the appropriate ECM.

Detachment induced cell death. It is a self defense mechanism that prevents cell from leaving their natural niche and growing dysplastically and gas a determining role in preventing tumor cell dissemination and metastatic growth.

-tumor cells
-loss of anchorage dependency
- tumors release vast amounts of cells into vessels, but only achorage independend cells can grow and metastasie and therefore the cells want to avoid the mechanism.

Proliferation in multicellular organisms is primarily controlled by signaling molecules (cell communication) and nutritiens (which are controlled by the mTor pathway.

It is significantly stimulated by nutrients. They divide as quickl as possible when sufficient nutrients are present.

in a paracrine, endocrine, autocrine manner and bind to specific receptors.

occurs only when specifically needed or when regulated by mitogens, growth factors and hormones.

through a wide variety of signal transduction pathways. Signaling transduction regulates a vatiety of coordinated biochemical processes like cell cycle, cell death, migration, differentation and growth(protein biosynthesis, cell metabolism)

-until they come in contact with other cells and the signaling molecules are bound to one of the cells surfaces (juxtacrine)
-or receive signals from neighbouring cells, which indicate that they should stop dividing. The signaling molecule is in this case released into the extracellular space (paracrine)

S, G2, M, G1/G0

The synthesis of a cell. The cell replicates its DNA.

gap phase 2; Its the periode after DNA synthesis, but priot to the start if prophase. In this phase the cells continue to increase in size (growth) and the production of proteins and organells happens. The DNA gets checked for errors. The cells get prepared for the cell division.

Mitosis/ cell division; Chromosomes in the nucleus are evenly divided between two cells. When the cell division process is completed, there are two identical daughter cells.
Mitosis consists of Pro, meta, ana and telo-phase.

gap phase 1; The peroid prior to sythesis of DNA. In this phase the cell increases in mass (growth), its preparing for DNA replication and produces proteins and organells. It checks for errors; cells, which are not intended to divide get to the G0 phase.

cells, which are not intended to divide get to the G0 phase. This cells exit the cell cycle and are in a resting state. (dont divide). This can be temporary or terminal (differntiated cells).

a network of enzymes called cyclin-dependent kinases (cdks).
cdk must associate with a cyclin to be active. cyclin-cdk complexes trigger the expression of the next set of cyclins.
S and M phase are controlled by reversible cdk phosophorylation.
The activation of a checkpoint (e.g when there is DNA damage) inhibits the activity of cyclin-CDK complexes and prevents them from iniating next phase of cell cycle.

-G1 checkpoint: is the environment favorable? reqires sufficient size and nutrients and without a g0-ahead- signal, cells may enter G0. Also require growth factors to inactivate repressors and signals from neighbouring cells. If this checkpoint can be passed the cells enter the cell cycle and proceed the S-Phase.

G1(start checkpoint), S (DNA damage checkpoint), G2 checkpoint, M (metaphase to anaphase transition checkpoint)

DNA damage checkpoint; requires DNA to be undamaged/repaired. When passing this checkpoint it goes to G2 phase.

Is all DNA replicated? is the environment favorable? Requires replication to be completed to enter the M-phase/mitosis.

Metaphase to anaphase transition check. Requires all chromosomes to be attached to spindle proteins. If passed it can trigger anaphase and proceed to cytokineses.

After the start in G1, when any checkpoint cant be passed the cell undergoes apoptosis

The start is triggered by the activation of Cyclin D-cdk 4. Its levels imcrease theoughout G1 phase and when the concentration reaches a certain level, the activation of Cyclin E-cdk2 is triggered. It activates S-phase Cyclin A-cdk2, which initiates DNA replication.

Mitogens like EGF (trigger a signal transduction pathway)
Mitogens bind to receptors that activate a guanine nucleotide exchange factor for the small gtp binding protein ras. Ras-gtp then activates a map kinase pathway that leads to the activation of a set of transcription factors including myc. Myc increases the transcription of cyclin D.

-Mitogens bind to receptors -> signaling pathway that leads to activation of cyclin d-cdk4
- cyclin d-cdk4 triggers activation of cyclin E-cdk2
- cyclin E-cdk2 triggers activation of cyclin A-cdk2
-cyclin A-cdk2 initiates DNA replication

cyclins are expressed in a wave like progression.
cdk levels remain consistent, but cdk is only active when associated with a cyclin.

G1 phase: cyclin E -> triggers start or entry into cell cycle
S phase: cyclin A -> trigger DNA replication
M phase: cyclin B -> initiate spindle assembly and attachment of microtubules to chromosome
M phase: APC (anaphase promoting complex -> destroys all cyclines and initiates seperation of sister chromatids.

3 steps:
-1. cyclin binds to the cyclin box of a cdk and activate cdks by partially opening a kinase pocket.
-2. two phosphorelation processes: First one is mediated by cdk activating kinases (CAK). CAKs phosphorelate cdk leading to a complete opening of the substrate-binding site. The second is a inhibitory phosphrelation mediated by the kinase wee1. Wee1 adds inhibitory phosphates to the ATP binding pocket of cdk. This keeps the cdk in an inactive state.
-3. is the removal of the inhibitory phosphate from cdk. Cdc25 removes the inhibitory phospate from cdk to activate cdk cyclin. This is the step at which checkpoints will often control progression into the next stage of the cell cycle.

The activation is also regulated by a pos. feedback. active cyclin-cdk phosphorylates cdc25 producing more active cdc25 and more active cyclin-cdk. active cyclin-cdk also inhibits wee1 preventing addition of the inhibitory phosphate.

it commits the cell to each stage of the cell cycle.

in the intrinsic pathway, pro-apoptotic factors are released from the mitochondria, activating caspase signaling

the extrinsic pathway requires the binding of extracellular apoptotic death ligands to their specific receptors at the plasma membrane.

The intrinsic and extrinsic pathway can flow independently until the last step of DNA degradation. However, they can also crosstalk at an earlier stage and act simultaneously

Method: cells at two different stages are induced to fuse. In Experiment 1 we have a cell in the S phase and a cell in G1. One of the fused cells jumped to the others cells phase. G1 nucleus immidiately entered S phase and DNA was synthesized. In Experiment 2 we have a cell in M phase and a cell in G1 phase and again one of the fused cells jumped to the others cells phase and G1 nucleus began mitosis without chromosome duplication. Therefore, molecules present in the cytoplasm control the progression to S and M phase.

BrdU incorporation assays to measure DNA synthesis. BrdU assays need the DNA to be denatured in order to allow an anti-BrdU primary antibody access to the BrdU molecule.

EdU assays rely on click chemistry. The fluorescent azide can freely bind to the ethynyl group of the EdU molecule. EdU is a tyhmidine analog that is incorporated into newly synthesized DNA. It labels proliferating and daugther cells and can be used to quantify the percentage of cells in G1, S and G2/M. And the DNA does not need to be denatured and can be uswd in co staining experiments.

Analysis of proliferative capacity using CSFE staining. CSFE is a dys which diffuses into cells and then attaches to the amine group of cytoplasmoc proteins and is metabolized by cellular esterases to a fluorescence dye. When the cells are dividing, the dye is equally distributed to the daughter cells. Therefore, in daugther cells the dye is half as bright as in the mother cells. And so on. This can be analysed as peaks by FACS.

it is a key mechanism during development. Faster growing cells survive and slower growing cells die. Only the "fittest" cell contribuite to the final organ.

population of cells that are similiar, which dont compete with each other and grow

population of cells consisting of different cell types leading to competition. The less fit cells are eliminated and in order to compensate the loss of this cells the sorrounding fitter cells are proliferating.

Super competition means that super competitor cells eliminate their wild type neighbours and the super competitor cells are proliferating

to identify the cells, which need to be eliminated after interacting with their neighbors.

drosophila: apoptosis
vertebrates: cell extrusion (cells are "pushed or expelled oit of a tissue)

elimination of tumor cells, response to varoius environmental cues

1. less fit get eliminated and the wild type replaces
2. wild type gets elimanted and super competitor cells replace (myc overexoression?

1. recognition of winner/loser cells with cell cell interaction. Genes that are involved in the early stages are: flower, azot, xrp1
2. removal of loser cells
apoptosis (upregulation of jnk pathway, ros production) or cell extrusion

apoptotic induction of loser cell by winner cells, necroptosis, senescence, differentiation, mechanical extrusion, entosis, phagocytosis

-proliferation (in proliferation epithelial)
-cell hypertrophy (in postmitotic tissue)

adult tissues are mainzainef by asymmetric stem cell division. Loser lineages are eliminated by forced stem cell differentiation leading to cell lineage replacement. e.g mouse esophagus epithelium

In mouse embryonic epiblast at E6.5 constitute of heterotypic cell population with different levels of c-myc expression. The relatively lower myc expressing cells are outcompeted by neighboring cells with higher myc expression and are gradually removed as embryonic development progresses.

Cells with a growth advantage to wild type cells induce the expression of a pro apoptotic gene and eventually their death. Due to the elimination of cells through apoptosis normal and uniform organ size is reached at the end lf development.
when apoptosis is blocked by genetic elimination of pro apoptotic gene function or ubiquitous expression of p53, wild type cells populate portions of the organ. But a wide variation of final organ sizes is observed.

when rapidly proliferating cells are transplanted into the damaged adult liver, these cells contribute to the regenerative response by their increased proliferation and inducing the apoptosis of the wilde type host liver cells.

during tissue repair after an injury, damaged cells die immediately. But damaged viable cells are eliminated by cell competition with healthier cells. Without cell competition from repairing cells, tissue repair is incomplete

tumor supression, aging, regeneration, tissue homeostasis, size control, development, stem cells

cell competition can help removing cells with mutations that are potentially oncogenic. therefore, cell comp. behaves as a tumor supressing mechanism when alterations in apico basal polarity appear in isolated cells. wild type vells eliminate mutant cells in a process termned EDAC

-ethical
-cost
-time
-poor predictors of human response (11% of drugs came out as approved products; 50 drugs save for animals, only 1 approves safe in humans
better are: in vitro models using human cells/tissues

goal: integration of organs on a chip to form a body on a chip
why: predict in pre clinical studies hoe humans will respond to drugs or chemicals
how: experimental device guided by physiologically based pharmacokinetic model

physiologically based pharmacokinetic. computer models treat the human body as a series of interconnected compartments. Such compartments are reactors, absorbers or holding tanks.

-compex in nature, develops over longer time
-often displays species dependency
-involves multitude of factors and different cell types
-difficult to address in vitro

1. target selection and hit identification
2. lead identification and optimisation. run early safety tests to allow candidate selection
3. preclinical development. de-risk preclinical in vivo findings, address human relevance
4. clinical development. support mode of action identification of clinical flags

-apply molecular tools to in vitro tests (pattern approach: capture multiple/ all genes, proteins,..) -> omics, high content imaging
-combine existing in vitro assays (targeted approach: combination of specific assay data) -> integrated safety score
-improve cell models (holistic approach: models displaying in vivo like functionality over prolonged time) -> mps

-2D micropatterned Co cultures (longterm incubation increases predictivity for dili)
-3D transwell co cultures (different cell types contributing to toxic effect)
-3D spheroids (high complexity in semi ht format)
-3D bioprinted (large tissue allows assessment of morphological changes)

reproducability and co culture ability (spheroids, scaffolds), in vivo like complexity and architecture (organoids), in vivo like architecture (organ on a chip), high throughput production (3d bioprinting)

simplified architecture (spheroids, scaffolds), lack vascularity and difficult to adapt to hts (organoids, organ on a chip, 3d bioprinting)

amount of cdk is consistent throughout the cell cycle, but the amount of a specific cyclin increases before most stages of the cell cycle. In the absence of a pos. feedback, this increase of cyclin would lead to a linear increase in the amount of active cyclin cdk. This is unfavorable because events in one stage of the cell cycle would start at different times due to some event need more active cyclin cdks. And because, the activity of cyclin cdk is reversible. If the signal for the expression is removed, the amount of cyclin cdk would decrease leading to less active cyclin cdk.

the expression of cyclin starts before the next stage of the cell cycle. The cell build up a large concentration of inactive cyclin cdk before the next stage. When its ready for the next stage, it activates cdc25. Due to the pos. feedback the inital signal is not needed, because it can maintain its own activity through pos. feedback. Therefore it avoids the limitations by producing a switch like activation of cyclin cdk.

cyclin cdk cant be turned off by simply removing the signal thag triggered the expression

to inactivate cyclin cdk cells target cyclins for destruction by ubiquitylation and then digestion via the proteosome.

Because the receptor, myc and ras regulate the expression of cyclin D, mutation can lead to uncontrolled cell division. Therfore, receptor, ras and myc are oncogenes.

cyclin D cdk 4 increases the transcirption of cyclin E with the transcription factors E2F1, E2F2 and E2F3. These are activators. But there are also inhibitors for the cyclin E transcription. E2F4 and E2F5.

Cyclin D-cdk4 phosphorylate pRb. This leads to transcription of cyclin E and formation formation of cyclin E-cdk2. cyclin E-cdk2 also phosphorylates pRb leading to more transcription of cyclin E. Once activated cyclin E-cdk2 can maintain its own activity and becomes independent of the mitogen.

Retinoblastoma protein is a tumor supressor gene. It controls the interacton of E2F proteins and cyclin E (g1-s). It can control E2Fs activity by binding to it and preventing transcription.

When pRb is bound to E2F1-3, the transcription factors are inactive. cyclin d-cdk2 triggers cyclin E transcription by phosphorylating pRb. When phosphorylated, pRb releases E2F1-3. When E2F1-3 are free from pRb, they bind to the enhancer of cyclin E to increase its transcription. This promotes expression of cycl E, which activates CDK2 driving the cell into the s-phase.

However, when E2F4-5 are bound to pRb, they help repress cyclin E transcription. When phosphorylated, pRb releases E2F4-5, but they dont bind the repressor of cyclin E. Therefore, they cant supress its transcription anymore.

pRb is in its active form when bound to E2Fs and prevents the transcription, which means that it inhibits cell division. (tumor supressor)

anti mitogens antagonize mitogens by targeting the same cell cycle regulators. (e.g TGF-b)

TGF-b inhibits cell cycle progression by induction of the cdk p15ink4B and also p21cip1 in g1 phase

cyclin dependent kinases inhibitors. The cell cycle progression is neg. controlled by CDKIs. They are mostly involved in cell cycle arrest in G1.

p27 is a CDKI protein, which inhibits cyclin dependent kinases.

two classes.
1. includes ink4 proteins (inhibitors of cdk4)
2. Cip/Kip

p16 Ink4a (CDKI2A/ CDKN2A), p15 Ink4b (CDKN2B), p18 Ink4c (CDKN2C) and p19 Ink4d (CDKN2D). Ink4 proteins specifically bind to and inhibit monomeric cdk4 and cdk6 proteins.

CDK interacting proteins. Bind to cyclin cdk complexes. Inhibit cdk activity by forming inactive trimeric complexes (cyclin E-cdk2, cyclin A cdk2, cyclin A cdc2, cyclin B cdc2). There are 3 members: p21 Clip1 (CDKN1A), p27 Kip1 (CDKN1B), p57 Kip 2 (CDKN1C)

anti-mitogens like TGF-b inhibit the cell cycle by preventing cyclin D from binding Cdk4. anti-mitogens bind to the receptor that phosphorylates a protein called Smad.Smad dissociates from the receptor and binds Smad4. The complex then enters the nucleus and increases the expression of a protein called ink4. ink4 binds cdk4 and physically prevents it from binding cyclin d. Therefore, cyclin E is not expressed the the cell doeas not enter start.

dna damage triggers arrest of cell cycle by reducing the amount of cdc25. dna damage kinases phosphorylate cdc25 that exposes a degradation motif and then cdc25 is ubiquitylated and digested by the proteosome.

p52 is a specific transcription factor for cells that inhibit cell cycle and promote apoptosis. It is also a tumor supressor gene because it prevents cells from becoming cancerous.

dna damage leads to activation of p53. Most p53 is associated with another protein called mdm2. mdm2 prevents p53 from entering the nucleus to activate gene expression and it leads to uniquitylation of p53 and digestion of p53 by the proteosome. dna damage is recognised by kinases ATM/ATR and Chk1/Chk2. these kinaaes phosphorylate mdm2, which causes it to dissociate from p53. released from mdmd, p53 can enter the nucleus where it activates the transcription of genes which encode proteins that arrest the cell cycle. one of those proteins is p21, which binds cyclincdk complexes such as e-cdk2.

strong mitogenic signals (oncogenic stress) inhibit entering the cell cycle/ cycling of normal cells or induce apoptosis

Tumorigenisis, developmental diseases like down syndrome

growth factors (cell growth), mitogens (cell division) and survival factors (cell survival)

specific to a cell type. Often/usually required for progress past g1 for inactivating repressors of cdks. e.g NGF, EGF, MGF

receptor tyrosine kinases. Many mitogen and growth factors are RTKs. Activation of RTKs by dimerization and autophosphorylation.

the centrosome gets doubled in s phase and migrates during prophase to the spindle poles.

To segregate the chromosomes accurately (in anaphase). it is build during metaphase and contains 3 types of microtubules.

1. astral MT (from centrosome to cell membrane)
2. interpolar MT (towards the center of the cell and overlapp with:)
3.interloper/ kinetochore MT (coming from the opposite centrosome; attach to the chromosome and generate the force to seperate the chromosomes)

by wrapping them in a protein complex that contains cohesins. cohesins prevent chromosome seperation even if the chromosome is attacht to MT. Allow cell to only seperate until all chromosomes are attached.

by activating APC (anaphase promoting complex). APC is the equivalent of E2 and E3 ligases and target specific proteins for degradation including cyclin B and securin through ubiquitylation. The loss if cyclin B reduced cdk2 activity and the destruction of securin triggers seperation of the chromosomes. Securin is a complex wirh seperase and when it is released from securin, seperase becomes active. It digest the cohesin complex and once freed from cohesin, the mitotic spindle generates force to pull the chromosomes to the opposite side.

Apc is inactive until all chromosomes are attached to the MT. Active APC requires cdc20. cdc20 interacts with proteins in the kinetochore of unattached chromosomes and is kept inactive. when all chromosomes are attached cdc20 can no longer interact and is now able to bind APC and trigger APC activation.

contractile ring (actin and myosin ring) underneath the plasma membrane. Rho signaling is activated triggering the initiation, contraction and membrane incorporation.

abnormal growth of cells. They divide rapidly, dont adhere to normal cell cycle regulation and often break through tissue boundaries to invade distant tissue(metastasis).
unusual nr of chromosomes, dna methylation and histine modifications are abnormal. Unusual miRna activity, metabolism is altered, stimulate angiogenesis

genes involved in stimulating normal cell cycle

proto oncogene that has mutations that make the protein either hyperactive or independently active. contribute to the development of cancer.

-allow cells to avoid apoptosis
- allow damaged dna to be passes on
-allow cells to divide indefinitly

normal cells have low passaging value, because they lose ability to divide after some time due to cellular ageing.
Transformed cells have high passaging value, because they have the ability to continuously divide.

cultured normal cells have limited capacity to divide and after become senescent.

irreversible cell cycle arrest mechanism that acts to protect against cancer. But also for development, tissue repair and ageing. It is indiced by stress inducing factors like internal damaging events, oxidative stress, autphagy factors,..

telomere shortening. Telomeres are repetetive dna sequences and protect dna by acting as caps. Telomeres are at the end of the chromosome and when cells undergo cell division the telomere length gets shorter. At some point cell no longer divide.

RNA and protein

conversation of normal cells to cancerous cells e.g proto oncogene to oncogene

-loss of tumor supressor genes
-change of cell surface proteins to avoid immune detection
-loss of cell-cell adhesion
-loss of anchorage dependence
-loss of density inhibition
-loss of Dna repair proteins e.g BRCA1 and BRCA2

-chemotherapie
-radiation therapie

uses chemicals to stop the cell cycle. Kills cancer cell bit also normal cells that rapidly divide like hair, intestine or blood cells

affecrs cancer cells mor than normal cells because of cancers loss od dna repair mechanisms.

analytical technique to measure cell size and other quantitative charakteristics. An electrical platform requires no need to label them (label free)

representation of real time biological interactions. Often used in Impedance Spectroscopy.

younger cells have less mutations. suboptimal or damaged cells are detected and eliminated. During aging cells are more prone to mutations. The tissue could be mainly populated by suboptimal cells and de comparison between winner and loser cells becomes less efficient resulting in no elimination OR including AD and transplant of stem cells CC is still efficient in elderly and promotes healthier ageing.

maintenance of stem cell populations by division asymmetry or population asymmetry.
normal: lost and replaced in neutral competition. loss and replacement are balanced to maintain a stable stem cell population and no stem cell has advantage over another.

however, with mutations it leads to non-neutral competition. Stem cells with a advantage over non-mutant stem cells are kept and the other is driven out.

Unspecific drug binding, key functions of organ to be represented in vitro, stability over time, gain in predictability vs prive for complexity

in vitro concentration and clinical exposure, drug related factors vs patient ralted factors, acute effects vs rare clinical events

replacing animal studies, adding even more stringent filters early on for established areas, use mps/organ on a chip

is a microfluid device that mimics the structure and function of a human organ on a small chip.

-combine diseases-pharmacology and safety in vitro
-support internal decision making
-reduce animal testing
-support entry into humans
-more personalized

-in vitro - in vibo translation
-sourcing of animal and human cells
-price vs complexity

liver, cardiac, neuro

kidney, gut, vascular, retina

liver+liver-kidney, liver-gut, endothel-cardiac

advanced microfluid system that integrated multiple organ on a chip models. e.g organ volume rates translate into ratios of microfluidic chamber vomumes.

physiologically based pharmacokinetic modeling is a computational approach used to predict how drugs are absorbed, distributed, metabolized and excreted in the human body.

realistic ratio of cell mass in one organ to another, mimic flow split of blood during recirculation, physiological shear rates

deal with the behavior and the manipulation of fluids (gases and liquids) on small length scales, typically, the submillimeter range.

Almost all of the test wirh uF devices show high non specific binding. Needs to be overcome.

refers to fast fabrication and testing of microfluidic devices, biosensors,.. for biomedical applications.

is a miniaturized controlled environment designed to grow and study cells on a microscale. Often using a microfluidic technology. Mimic natural physiological conditions of tissue and organs. The medium is recirculated to mimic the bodys recirculation.

1. exhaustive testing in test tubes or petri dishes (in vitro)
2. then in organisms (in vivo). Therefore, animals like mice, rabbits or monkeys are experimented on.
3. then tested on humans