Tiny technologies, hepatic tissue
engineering and cancer
nanotechnology.
What is hepatic engineering and cancer
nanotechnology? Hepatic tissue
engineering
is a step towards alleviating
the need for donor organs, specifically livers.
Yet many challenges must be overcome.
Some of these challenges.
Include where the.
Cell will attach.
Cell source.
And. Immunological barriers.
Hepatic engineering allows us to mimic the structure of the.
Liver.
And sustain functional and viable hepatocytes, also known.
As liver cells.
Expanding and improving upon this platform, technology will allow advancements to be made
and will continue towards the development of a fully functioning and implantable liver.
Bioreactors have aided in hepatocyte survival and have proven to sustain viable
cells.
For several weeks.
Nanotechnology offers a means to target chemotherapies.
Directly and selectively to cancer cells and neoplasms guided surgical.
Resection of tumors and enhanced.
Therapeutic efficacy.
Of radiation base and other current.
Treatment modalities.
Nanotechnology can also provide rapid detection of cancer related molecules and can
possibly detect.
Cancer earlier, even when they only occur in a small.
Percentage of cells.
Cancer. Nanotechnology has a potential to generate.
Entirely.
Novel and highly.
Effective therapeutic.
Agents.
Why is it important in the.
Health care field? The reason why.
It's so important in the health.
Care field.
Is because there are 500.
Million patients who live.
With liver.
Dysfunctions with 2 million.
Worldwide.
Deaths each year.
This puts a massive strain on the health care system as a.
List of organ donors continues to grow.
And sheds light on.
The disparities in the health care system.
Especially in a time of a pandemic.
The reduction in transplants translated to 48,239 wait listed patient life years lost.
Delaying lifesaving surgeries.
Also affects the lower class, as patients with transplanted livers have less access to
rejection medication due to a lack of.
Insurance.
Causing the individual to have a lower.
Chance of survival even with a new organ.
This important research.
Can help people in these situations.
By reducing the risk of transplanted.
Liver and host.
What is the purpose of.
Studying the two dimensional hepatic microenvironment?
While it allows for the.
Study of the architecture of this organ by creating an artificial microenvironment.
In this organ in 2D.
It does so by patterning.
Surfaces.
With lights and biomolecules that will confer the adhesion of cells.
It can pattern many different cells, such as a single cell, to a bouquet of two cells, to
an asymmetrical to an asymmetric multicellular island.
This uses very generic.
Tools to study a two dimensional system.
This is an example of using 2D hepatic microenvironment to explore.
The importance of the malaria liver stage.
In.
Vivax.
Eradication in the clinical context.
P Vivax has devastating effects with greater than one third of the global population at
risk. 9 million cases globally in 2017 and more than 70% of cases are due to p vivax in
countries with less than 5000 cases per year.
P vivax turns out.
To be a relapsing form of malaria and.
Thus it is difficult to eradicate.
But how does this come to be?
Well, it.
Starts with the spores.
From an infected mosquito, which travels to.
The liver where it infects.
Hepatocytes, and then it multiplies over 7 to 10 days.
Soon it.
Bursts out of the liver and infects young red.
Blood cells known as reticular sites, and then starts the pattern of.
Cyclic fever, which we.
Associate with malaria.
One technique they use in this experiment is known as multi pattern co cultures, also
known as PCC.
What occurs is they pattern human hepatocytes.
From organ donors.
On collagen type one.
They use this technique to manipulate and maintain the human hepatocytes phenotype in a
two dimensional construct at the bottom.
Of the well for 4 to 6.
Weeks, depending on the donor.
As it studies the living stage of pathogens, it allows for miniaturizing these micro
patterned co cultures in a way that they can be put into multi wall plates.
To better understand this technique, think of it as making.
Stamps, where essentially.
Mpc is stamping into multi role plates.
As for how the experiment unfolded.
It starts with the portability.
Of the MPC.
The researcher in this study patterned the plates in Boston, then.
Waited for the.
Rainy season in Thailand, where p vivax is endemic.
Then they flew with the cells.
Frozen.
And the plates to a collaborator lab in.
Thailand, where the researchers there.
Had collected.
Blood from infected.
Vivax patients in the field.
They then fed that to the mosquitoes and then isolated.
Spores.
Whites from the mosquitoes, and put it into the cell culture.
They put it into the MPC, and then the experiment.
Lasted for.
21 days. The place were then brought back to Boston to use machine.
Algorithms to study the parasites.
The other plates were in collaboration.
With another lab at MIT to do single cell sequencing of the infected hepatocytes.
So what were the key findings?
Will they explore the p vivax development in NPCs?
And what they found was that at the beginning.
All the parasites were quite small.
Around day.
Eight, after.
Letting them grow, we can.
See that some of the.
Parasites are.
Small and some have replicated.
There was also a remarkable cellular rearrangement where.
In the culture you can see they're.
Up to 130 microns.
So they take up the whole hepatocyte cytoplasm and squish up against the nucleus
around day ten. This was.
The first time anyone saw these results in vitro.
Where the structure was bursting out and there are mirrors.
Streaming out of the hepatocytes.
And then they entered into the blood stage.
After 21 days.
Small, persistent forms.
Known as hipness.
Whites were seen. However, there are no known biomarkers for.
Hepatocytes, so researchers.
Use the for clinical hallmarks to.
Describe and determine if those forms are hypnotic whites.
All of the four clinical.
Hallmarks were.
Seen, such as the forms were small, inactive.
Mononuclear and.
Persisting. They did not.
Express mature markers like mirrors, white.
Surface protein.
They were differentially drug sensitive.
And last but not least.
Dormant.
Forms are capable of reactivating.
Dr. Brodie and her team also conducted an experiment that was done within a three rd
hepatic microenvironment.
This experiment was conducted to study in.
Vitro.
How human hepatocyte endothelial.
Interactions relate to regeneration using 3D.
Tools. Dr.
Bharti and her team took human hepatocytes and made.
Spheroids.
Using micro fabricated molds.
They created.
A microchip that has a channel in the middle containing human endothelial cells.
And spheroids around.
Them. They noticed that hepatocytes enter the cell cycle in the.
Presence of prostaglandin.
E two. The cells no longer.
Cycle as they are dependent on prostaglandin.
E two. And the endothelial cells.
They found that in the presence of il one beta but.
Absence of prostaglandin.
E two the cells do not cycle.
I01 Beta induced cycling is dependent on prostaglandin.
E two from endothelial cells and endothelial cells.
Human liver regeneration are.
Making prostaglandin e two and contributing to hepatocyte cell cycle entry.
Dr. Bharti and her team conducted a similar experiment in vivo.
They made an implantable version of the chip, put it inside the entire peritoneal
space of the mouse where they can manipulate the liver.
A partial hepatitis C was done and the hepatocytes enter into cell cycle and.
The liver regrows.
Once the mouse.
Liver regrew, the.
Regenerative stimulus went away.
They redid the experiment in a different type of mouse to have a more lasting effect.
What were the key findings?
About 5% of the hepatocytes enter into cell cycle.
This experiment had a transient effect because when the mouse liver.
Regrew the regenerative.
Stimulus went away.
They also found that hepatocytes expand and reorganize after injury.
Another application of nanotechnology is.
For the purpose.
Of cancer detection.
The tumor.
Microenvironment refers to the environment surrounding a tumor cell.
Including the blood vessels, extracellular matrix and immune cells in the.
Local region.
Early detection of tumors is important.
As this leads to better patient outcomes.
Some detection methods.
That are currently.
Used include.
Mammograms, which screen for breast.
Cancer. Colonoscopies which can detect colon.
Cancers.
And liquid biopsies which can detect cancer.
Products in.
The blood. However, it is difficult to determine.
If a person has a tumor very early.
On using these methods because the signals that indicate.
Cancer are very.
Limited. Nanotechnology can be used to detect.
Cancers early on.
And this new technique makes use.
Of proteases.
Proteases are enzymes which are active in tumor microenvironment, and this activity can
be used to detect.
The presence of tumors.
Tiny nanoparticles.
Carry peptides which.
Are small proteins.
And can be.
Delivered to the tumor microenvironment through the.
Blood.
The nanoparticles.
Leak out of the blood vessels once.
They reach the tumor, and here they can be.
Activated by the local proteases.
The protease is cleaved off of the peptides that are carried by the nanoparticles, and
these peptides can be eliminated from the body through the bloodstream.
One protease interacts with.
One nanoparticle.
And cleaves many peptides from the surface of the.
Nanoparticle. Thus, one protease.
Results in many peptides.
Being returned to the bloodstream, resulting.
In amplification of the signal.
The peptides in the blood are then filtered through the kidneys, and these peptides can
be detected in their urine.
This method of detecting.
Tumors can.
Have many different applications.
Rapid tests similar to the ones used to detect COVID 19 can be developed.
This can be adapted for lung cancers as well, resulting in the development of
breathalyzers that can detect exhaled particles that are indicative of lung cancer.
Finally, once the presence of the tumor is detected, it can be then located using
imaging techniques such as pet.
Once tumors are detected and located, patients can then be treated, resulting in
better outcomes and even remission of cancer.
If you are interested in learning more.
Check out the.
Following sources for more.
Information.