iPPS and the engineering of tissue

ouldn't it be nice if we had some science type evidence that showed us the wonderful effect over and beyond just pain and function improvement? We are attempting to do this in the background with our 008 study but I'm a guy that wants to push the envelope a little, I want to understand where this can go, how it works and WHY it works...I also don't mind knowing the potential.......and the way to do that is to read the research that's already out there, that can give us hints and clues as to why our drug might just be one of the most powerful and amazing ones this planet has ever witnessed.


Now if you think I'm emotional and over enthusiastic, that's quite fine, but why don't YOU read the references (see the very end of this post) and tell me what YOUR interpretation is...if its negative, I am the one that wants to hear about it and I promise I will not fling too much mud...I will listen with open ears and eyes...and I will digest it. While our share price gets crushed and some wonder what they have bought...I bunker down and my resolve is even more tightly held...

In 2018 there was a study that was peer reviewed that involved just this topic. Tissue engineering. Before we get to the conclusion from these researchers, lets explore what they did.


DEFINITIONS

Ok for this one I need to explain a few basic concepts first. I've caught just a couple of flights in the last few months and on two occasions the landing was what I deemed to be fairly rough...I always have at the back of my mind, just how much load those shock absorbers take...mate...but they are designed that way...they put those things through hours and hours of testing at much heavier than normal loads....I love the redundancies that modern day aircraft have to keep us safe...



_{Supreme pressure on the shock absorbers of an aircraft, I'm talking tonnes of weight multiplied by significant forward thrust.}



Great Mozz, love the plane engineering, but what's the relevance between your plane shock absorbers and iPPS???


Good question, glad you asked...

We all know cartilage...but it doesn't just form a docile silky smooth layer for the various bones to work and glide with one another...nahh it also has the impressive and vital role of mechanical distribution of loads....not unlike those shock absorbers I just mentioned on a given aircraft.

So what are Chondrocytes anyway?

I've come across these little beasties¹ a few times in the past research, lets explore what they are...

Its the chondrocytes that actually regulate the extra cellular matrix (ECM) and give a balance (homeostasis) to the tissues. Think of these little guys as the ones responsible for the upkeep of cartilage. Poolboy's mansions and clubs are not maintained by he himself, he merely manages the staff that keep the place tidy, clean and suitably organised and to a standard so that more customers will follow, ie healthy growth. The chondrocytes are the staff for the upkeep and staving off of OA. Look after your staff, they will look after you...empower them!

Chondrocytes are the cells that are active cells that synthesize and turnover a large volume of extra cellular matrix (ECM) components like:

• Collagen
• Glycoproteins
• Proteoglycans
• Hyaluronan

All of the above are vital components for supreme joint health.

It's the imbalance in the functioning of the chondrocytes that lead to OA. OA finally is the cartilage degradation, formation of osteophytes and the eventual stiffening of the joints.

The damage to the ECM is caused by such enzyme expressions as MMPs, and ADAMTS. We already have an excellent look through of what iPPS can do to reduce ADAMTS....new to us? Are you in the lucky position that you have just discovered PAR and are thinking of investing? Mate, read this announcement for a proper Bio Chemical primer....(single left click the link below)


PURE EVIDENCE OF TWO OA BIOMARKERS REDUCED BY iPPS


Can't be bothered reading an entire article (above), here is a snapshot:





It's hard to beat placebo, particularly in pain indications, we not only beat it, placebo went the OPPOSITE WAY!

There is more to come...our 008 synovium study will shed new light on the workings of iPPS and how far it goes in terms of positive effects on reduction of OA biomarkers...

So we have seen how important these chondrocytes are...you disrupt them, and you will develop OA. What can we do to promote them...what can we do to support them?

HOW does iPPS work with these chondrocytes? How does it assist? Good question, lets explore.

The iPPS molecule enters the chondrocytes and actually binds to things called promoter proteins. Think of the promoter proteins as functional proteins.



MORE RESULTS

Taken from the main research:

"Alginate suppresses Sox-9 mRNA expression in CAC; PPS selectively promotes a chondrocyte phenotype while suppressing chondrocyte hypertrophy and dedifferentitation".

"PPS promotes proteoglycan (PG) deposition in alginate beads culture "

"Runx2 colocalizes with PPS"


What we want to see is some progress whereby iPPS can show some efficacy in aiding the specialised cells, chondrocytes, which we know to play an integral role in staving off OA and maintaining healthy joints and surrounding tissues. Again, I can only Mozzify ^© so much...these are the words of the researchers:


"The present study confirmed that PPS can completely restore the phenotype of dedifferentiated monolayer expanded chondrocytes marked by enhanced cartilage-specific genes, type II collagen and aggrecan, with indiscernible type I and X collagen."


Read that line just one more time...COMPLETELY RESTORE THE PHENOTYPE, yeah that kinda did it for me...


PAR peoples, our share price has been emasculated...there is virtually no connect between the potential of our drug and the current sp. This has to be one of the darkest moments for us...and yet we know the sun shines brightly, the drug works, the trials are going on...and the patients still rave. This is the exact moment to stay the course...when the winds are the roughest...when First Officer @Violin1 shouts instructions to us...just follow them....I know it is hard to believe we can survive such share price storms. The naysayers are out in full force....but the science is as true as I have ever come across...

I'm not a blind sailor and I know that it takes more than just science to make a successful investment, I believe we are on the right path though the journey, the ocean, is supremely vast. It is only the fittest, the toughest shareholders that dared to weather the huge storms of Amazon falling several times that could reap the benefits of today's share price, but you had to do one thing...just one thing...hold on!


MORE?

This research points to other research that shows:

"PPS is a proposed disease modifying OA drug (DMOAD) which has also been previously shown to improve synovial and subchondral blood flow, limit cartilage matrix degeneration and stimulate hyaluronic acid (HA) and proteoglycan (PG)/aggrecan synthesis. Recently, our laboratory demonstrated its involvement in the prevention of inflammatory intracellular responses induced by interleukin 1-beta (IL-1β) through inhibition of phosphorylation of certain MAPKs, p38 and ERK."


The good-problem-to-have in terms of research on Pentosan is that it leads to more articles.



_{Where does this research end? So many leads!}


Not unlike discovering a new rabbit's hole (and many of these new such tunnels), exploring just ONE such link from this research² led to these findings from other research papers in regards to just how PPS can assist and work:

1. Reduction in joint swelling
2. Reduction in inflammatory levels
3. Synoviocyte biosynthesis of high-molecular-weight hyaluronan, which is diminished in OA, was normalized when these cells were incubated with NaPPS
4. PPS preserved cartilage integrity
5. PPS resulted in proteoglycan synthesis
6. PPS reduces matrix metalloproteinase activity
7. PPS stimulated the release of tissue plasminogen activator (t-PA)
8. PPS led to the increase of superoxide dismutase,
9. It was found that PPS increases lipases from vascular endothelium
10. PPS results in decreasing plasma levels of the endogenous plasminogen activator inhibitor PAI-1.
11. Blood flow increased via net thrombolytic and lipolytic effects
12. Improved bone cell nutrition was observed as an effect of PPS
13. PPS was responsible for normalisation of thrombolytic status, threshold for platelet activation, and plasma triglyceride levels in a particular canine study

That's a fair bit of new material from just one link. Indeed I have covered a fair few of those points in the past but a few are new to me even after a number of years of research now.In brief, lets take a couple of these newer points to understand what it means...


Superoxide Who? (Point 8)



_{We all love a superhero...}



You guys have heard of antioxidants right? Well this is the superhero in terms of antioxidant defence against oxidative stress! ³ Yes the regulation of this so called oxidative stress is not only important, its vital. Get this balance out of whack and you will be more susceptible to:

• Cancer
• Inflammatory diseases
• Cystic fibrosis
• Ischemia
• Aging
• Rheumatoid arthritis
• Neurodegenerative diseases
• Diabetes

PAI-1 ? (Point 10).

"Unregulated PAI-1 levels inactivate plasma tPA and suppress fibrinolysis in thrombotic or inflammatory conditions".⁴

Talk about a double negative....

I reckon we need Mozz speak here...this is a fanciful way of saying iPPS helps in resolving unnecessarily high levels of clotting, a moderate blood thinner. The best part about the action of iPPS is that it doesn't thin out the blood TOO much unlike our friend Heparin. It's about one fifteenth the thinning capacity which bodes well for us.



CONCLUSION

So we know the vital role chondrocytes play...it is iPPS that aids in the natural production of healthy chondritic cells; "In conclusion, this is the first study to demonstrate that the phenotype of dedifferentiated monolayer CAC is completely restored by combining alginate beads with culture in standard medium supplemented with only PPS. " and further, "...our results confirm that PPS is a suitable alternative novel chondroinductive factor that may offer a solution to the inherent challenges faced in cartilage tissue engineering ".

Certainly we have a potential breakthrough, offering real pain relief (as good if not better than Opioids), improved functioning...doing it safely (unlike the Opioids) but with at least SOME degree of tissue engineering assistance in a number of cases. We are only a couple of quarters away from top line 008 read out and maybe a couple of years away from 002/003 read out. Not saying its a sort period of time, AM saying its going to be a hell of a potential journey.


DYOR applies.






REFERENCES


MAIN REF

https://www.hilarispublisher.com/open-access/pentosan-polysulfate-sodium-restores-the-phenotype-of-dedifferentiatedmonolayer-canine-articular-chondrocytes-cultured-in-alginate-2157-7552-1000218.pdf


OTHER REF's

1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916494/#:~:text=Chondrocytes%20are%20metabolically%20active%20cells,%2C%20and%20hyaluronan%20%5B2%5D.&text=Chondrocytes%20are%20derived%20from%20MSCs,total%20cartilage%20tissue%20%5B7%5D.
2] https://www.addgene.org/mol-bio-reference/promoters/#:~:text=Definition,translated%20into%20a%20functional%20protein.
3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969776/
4] https://www.nature.com/articles/s12276-020-0397-x