Monthly Archives: September 2015

Vosoritide, A Drug To Help Make People Taller Already Developed and Currently Being Tested!

VosoritideI was reading some random study in the field of orthopedics today and someone mentioned the condition SED, or Spondyloepiphyseal dysplasia congenita based Dwarfism, and that made me remember a few things that I had not looked at for a long time.

I remember people telling me about quack-pseudo-scientific ideas on how to treat SED before on other websites, but I wondered whether the Patent databases had anything written about treating it, in a more scientifically legitimate way. So I googled “Spondyloepiphyseal Dysplasia Congenita” into the Google Patent database to see what would come up.

Some of the first few results were obviously crazy, like the following Drug composition for treating spondyloepiphyseal dysplasia – CN 103142900 A”. This patent apparently was only filed in the China based database, and it is based on a combination of strange vegetables, minerals, and plants. The idea from this ancient formulation I would guess is to reduce the curvature of the spinal or straighten it out, which would obviously give the person a little bit of height increase. However, I would not be willing to put money on an idea based on Traditional Chinese Medicine practices.

It would be the next search result, which really caught my eye. Refer to the patent Variants of C-Type Natriuretic Peptide – US 20100297021 A1″. This was a patent which I don’t believe I have talked about before, and the name of it would not be an indication to most people searching the Patent Database that it is anything of importance, but this patent is basically a patent for a way to help people become taller.

Tyler and I have in our research throughout the years have seen multiple similar patents working on the similar idea which was also for increasing stature. 

Refer to the Abstract below….

The present disclosure provides variants of C-type natriuretic peptide (CNP), pharmaceutical compositions comprising CNP variants, and methods of making CNP variants. The CNP variants are useful as therapeutic agents for the treatment of diseases responsive to CNP, including but not limited to bone-related disorders, such as skeletal dysplasias (e.g., achondroplasia), and vascular smooth muscle disorders (e.g., restenosis and arteriosclerosis).

The Inventor is a Daniel Wendt from Biomarin Pharmaceutical. If we need to remember, Biomarin was the company which made the BMN 111 compound, which is used to treat childhood achondroplasia. I remember reading about this drug maybe a year ago on a website that focused specifically on how to help cope with a child who has the condition.

As one can see, this patent was filed back in 2010 and it has been filed in the USA, Canada, Europe, China, and the World Patent Database System. If I was to guess, I probably had linked to this patent multiple times before, but never really read the patent thoroughly..

Refer to the sections in the patent which I will highlight below…

“….In contrast, mice engineered to produce elevated levels of CNP display elongated long bones and vertebrae.”

I would learn further that in the growth plate, the proliferative zone expresses a compound called NPR-B while the hypertrophy zone expresses NPR-C. CNP (which stands for C-Type Natriuretic Peptide) is an agonist for the NPR-B. Agonist just means some type of chemical or protein that assists or increases a biochemical process. Further down the chain of chemical processes (which in the chemical/medical industry call downstream), the CNP and NPR-B pathway causes the FGFR3 pathway to be blocked. Remember that Achondroplasia is most often caused by a mutation of the FGFR3 causing it to be overstimulated or extra-sensitive. In the FGFR3 pathway, there is a step in the MAPK section. It seems that the CNP/NPR-B disrupts the pathway at MAPK, causing the FGFR3 to become inhibited, thus removing the stunted height morphology.

Refer to the section below from the patent….

“In humans activating mutations of FGFR-3 are the primary cause of genetic dwarfism. Mice having activated FGFR-3 serve as a model of achondroplasia, the most common form of the skeletal dysplasias, and overexpression of CNP rescues these animals from dwarfism. Accordingly, CNP and functional variants of CNP are potential therapeutics for treatment of the various skeletal dysplasias.”

Something that I would further learn is that the plasma-half life of CNP in the human blood stream is very short, only 2.6 minutes (in-vivo). This means to get this biomedical technique to work out, the CNP would need to be continuously pumped into the subject’s body. Apparently the basic level of CNP in the human body is around 5 picoMolar (5*10^(-9) Molar). The level of CNP must be higher than this concentration.

Refer also to more sections from the patent…

“…In a further embodiment, the CNP variants are useful for increasing the size of the growth plate of a bone (e.g., a limb bone). In another embodiment, the CNP variants are useful for elongating a bone or increasing long bone growth. In still another embodiment, the CNP variants are useful for enhancing matrix production, proliferation and differentiation of chondrocytes.”

Apparently to make the femur longer at the highest rate, you want to use a variant of CNP known as N-terminal PEGylated CNP variant.

“…Ex vivo studies of cultures of mouse bones indicated that CNP37 was delivered to the growth plate and was able to increase chondrocyte cellularity and hypertrophy, which are associated with growth plate expansion and longitudinal bone growth.”

“…These results demonstrate that CNP variants of the disclosure penetrate into the growth plate of wild-type and achondroplastic animals, increase the number and size of chondrocytes, increase the thickness of the proliferating zone and the hypertrophic zone of the growth plate, and increase longitudinal bone growth in treated wild-type and achondroplasic animals. Therefore, the CNP variants are useful for stimulating bone growth in achondroplastic subjects.”

There apparently was even news stories published in the Major Online News Websites talking about this drug/invention. (Note: Yes, I am fully aware that I am assuming that the patent I found is referring to the Vosoritide/BMN 111 chemical compound)

Drug Accelerated Growth in Children With Dwarfism, Pharmaceutical Firm Says – 6/17/2015 – The news reported that children would be growing around 6 cm/year than 4/cm by taking the drug. The other name for BMN 111 is vosoritide. There has been questions about the efficacy of this chemical after the first year of use, and whether after the first year the drug would still be as effective as the first year. In addition, it seems that people who did not suffer from Achondroplasia did not get any type of increased bone longitudinal growth benefit from using it. Since the article was written back in June of just this year, the drug is now in Phase 3 Trials, where around 50-150 children will be subjects for this new treatment.

BioMarin drug boosts growth in children with dwarfism – the source here seems to make a correction on something the previous source said, which is that the 6 cm of increased height is actually from just 6 months of tabulated data, not a full year.

BMN 111 (vosoritide) Improves Growth Velocity in Children With Achondroplasia in Phase 2 Study – This source suggest that the efficacy of BMN 111 will continue past the 6 month range in Phase 2 –

  • There was a dose-related increase in urinary excretion of cGMP measured over the 6 month duration of the study. cGMP is a biochemical marker that may indicate that BMN 111’s  biological effect will continue beyond 6 months.

Refer to the chart from the source below….

BMN 111

It would seem that National Health Industries and Organizations will not fund for a condition unless it has been diagnosed as a real medical condition or a disability. Short stature is not technically a disability, but having achondroplasia or dwarfism does qualify as a medical condition. This is where biomedical research will go and the funding will flow towards.

If you guys are interested in learning more about this compound, just type in the common name for it, Vosoritide or BMN 111. Biomarin even has itself listed on the Nasdaq under the acronym BMRN.

Video Of A 7 Feet Tall Chinese Yeren, A Human Bigfoot Hybrid?

Note: If you really want to see the video of this unique creature, just scroll down this post to the very bottom. I found quite a few videos of this creature off of the Chinese website and, and the Chinese documentaries and expeditions to find more information about it.

I was made aware today of a very interesting viral video that has been on the Youtube universe for a few years now. So far, it has already gained over 10 Mil views. Apparently there is even more old videos of what appears to be a very tall chinese/asian looking ape-like creature from the Chinese internet sources, which I found.

Just like the North American Bigfoot, the Chinese media also like to bring up this case on occasion to have “experts” discuss this person. Apparently very little information is known about him except maybe 1-2 minutes of reel on him, walking around and squatting in a very primitive fashion.

What I do know for a fact, from a lifetime of being fascinated with the paranormal and supernatural is that maybe half of the cultures in the world have some story about giant primate type animals that lived close to humans.

Bigfoot, Sasquatch, Alma, Yeren, Yeti, Abominable Snowman, etc. these are all labels we have given these animals.

In the video below, we see a human that is clearly very tall. His head size compared to his torso and his arms, legs, limbs is just incredible. The average length ratio of most human’s heads to overall body length is supposed to be 1/8.5, but the head/body ratio seems to be much greater here. Personally, I estimate the size of him to be around 7 feet tall, which is tremendously unusual, similar to the case of Siah Khan, the 8 feet tall Iranian farmer. However, if you look at the way this Chinese giant is walking, he seems to be just fine with no ailments. His ability to cognitively function is obviously not at the level of most humans.

If this person only had that shaped head without his great size, then most people would have written his mother’s story about being raped by a Yeren as fake. However, it is his great height and size that is most striking. We realize that the most likely medical explanation is that this human just suffers from microcephaly similar to the Pinhead from the old Freaks movie. Wikipedia says the name was Schlitzie. However, Schlitzie only stood 4 feet tall. This chinese version of a microcephaly seems to be 7 feet tall, if not more.

Of course, we have to realize that this creature/human’s body would look big compared to most Chinese women in the rural area. When we look up the Wikipedia article on Microcephaly, it states that most babies that have shrunken brains develop dwarfed bodies, not giant sized bodies.

This is not the only thing. Pictures from the videos of this Chinese Yeren shows underneath the hair on his head that he had grooves on his skull, similar to the skull of gorillas. I personally don’t understand the Chinese being spoken in the video but I can guess from the pictures that the researchers are analyzing that they are focusing on the head, to see whether this yeren was really human or some type of bigfoot hybrid.

I am not willing to say that this Chinese giant is the missing link, or a human-bigfoot hybrid. His mothers claims of being raped by a Chinese Yeren is also very suspicious. When you look at the video, obviously you know it is not a man in a suit, like people who do hoax for bigfoot sighting. The creature is nearly completely naked. This is video which seems to have been shot decades ago, so there is probably no video editing or graphics design done. The story is probably real, this human did exist, but most likely dead now.

Brent Collins, A Dwarf Suffering From Marfan Syndrome Who Had A Growth Spurt As An Adult

I was informed today of a most interesting case. There was a well known actor who was on the show The Golden Girls back in the 1980s, named Brent Collins, who apparently had the medical conditions of dwarfism and marfan’s syndrome.

The general claim made by the sources I find on google is that this guy had a growth spurt as an adult, maybe around the age of 30 or higher. This is most unusual. The only case which most people had found similar is Adam Rainer. He died in 1988 from a heart attack, which is believed to have been induced by the growth spurt.
brent collins

Some people on the forums say that he started growing at the age of 46, which was just a year before he died.

There are maybe just a few videos on Youtube of him acting, and if you look at his body, his arm limbs are abnormally long. Since we can’t really get a good look at his legs, I will just assume his legs are also disproportionately long compared to his body.

Here are some things that have been guessed by others who tried to analyze his unique case.

Roger – I guess his dwarfism might be caused by an osteodysplasia, due to a genetic mutation, (not sure what kind of dwarfism, maybe SED dwarfism) rather than an endocrine origin, and although radiographic evidences show that development in epiphyseal regions in subjects with SED dwarfism is markedly delayed, when reached the early adulthood the plates shoud be closed, so I do find extraordinary that the epiphyseal plates of Mr.Collins were potentially functional at age 46, unless the ossification centers remained open due to some circumstance. Looks like, as long as he was working, he didn’t show any sign of MFS, as we can see on the 1987 Another World video, so I am surprised that marfan developed so spontaneously, and killed him so fast. (source)

GodsGadfly – I just saw his appearance on _The Golden Girls_–and apparently garnered a few search hits from it. If you know what you’re looking at, you can tell that his arms and fingers were very Marfanoid in proportion to his body, and relative to the normal proportions of a dwarf. I had gotten to wonder if he had Weill-Marchesani Syndrome, but that is not associated with aortic dilation. (source)

It seems that we might be incorrect in assuming that he died at the age of 48, but instead 46.

Can we extrapolate this very unique medical case of this rather good actor to something we can take away?

Brent Collins was said to have started growing around late 1987 and that triggered the heart problem, which is a Marfan’s symptom, to have a problem, causing his death.

It doesn’t make any sense at this point how this man, who would have been in his mid 40s could have still had functional growth plates. I once theorized in an old post that maybe it is possible that a very small minority of females still have functional growth plates even into their 30s, but this case is much more extreme.

Human bones are very hard material that is not malleable using normal magnitudes of force. Maybe, just maybe, because Collins was a dwarf, probably weighing just around 60-80 lbs, the cartilage in his body did not ever experience the amount of gravitational loading needed to ossify the epiphyseal cartilage.

Of course, now I am just completely guessing.

“I Wish I Was Taller”

These are the exact words someone told me today. How often do these words come out of someone’s lips?

Enough times in my life to realize that height is very important for some people.

I decided to try a new gym today and could not get any type of Guest Trial Pass in the local LA Fitness close to my house. Did some searching and found out that while I can’t get a guest pass when I an physically at the facility, I can apply for the pass online, fill out my info, and then take some barcode to be scanned in. So I did that. Went to the gym, and showed it to the trainer/worker at the front desk/guest location, where they check people in. Apparently they don’t get enough people like me so they didn’t really know what to do so I was escorted to be sat down with another worker to put my personal info into the gym database. I mentioned that my name was already in, I didn’t want to take any gym tour, and just wanted to play around the gym to see if I wanted to switch from the YMCA, which had a higher monthly gym fee. The worker asked me what I wanted to do and I replied that I just wanted to play basketball.

So he mentions that he loves basketball and used to play a lot. Then he had to take the job at LA Fitness and couldn’t play much anymore. So I make the off-handed remark (which was also a joke) that all all he needed was to “be a little taller and have a little more skill to become a professional basketball player”. Then he says “I wish I was taller”.

A 2nd look at him tells me that he is already 5′ 11″, maybe even 6′ 0″. White, in his 20s, bearded, seems to be bored of his job, but goes through the motions and decently polite.

Apparently being even 5′ 11″ (or even 6′ 0″) is not enough anymore. He is still wishing he is taller. At what point does a normal guy stop wishing that he is taller? 

I think back in my life to the number of people who I have met who desperately wished that they could just grow taller.

The most extreme case was a Southeast Asian girl I dated for a short time. She would mention her short stature and tell me in confidence that becoming taller was her main wish in life. Not making more money, not getting married, not becoming successful. I would ask her whether she would choose ten million dollars or 9 inches in height. She choose to be taller. That relationship did not last.

Do these people, become bitter and resentful at some point at people who are taller than them after they reach a certain age and realize that there is almost nothing that they can do to change something about themselves which they don’t like?

Readers: I plan to do a short series of posts on topics related to medicine and biohacking in the next few weeks, sort of as a short guide on how to improve other areas of one’s body.




Taking Iron Supplements Increases A Person’s Adult Height – Can It Really Be This Easy?

A few recent articles that was reported to me has had me go back to the link between increased levels of Iron in a person’s blood and a very noticeable increase in a person’s adult height, compared to a person with iron levels that are closer to average levels. Let me refer the readers to the following links below…

The idea that oral ingestion of such a common, easy to obtain supplement to help one grow taller is shocking, but it does seem, based on the backing of the medical professionals, that taking Iron supplements when a person is still developing has a very noticeable effect on their final adult height.

Originally, the article was brought up by someone from the reddit/r/tall subreddit group and it lead me back to a very short, blurb of a post I wrote last year on the link between Iron and people being taller. Back then, I did absolutely no work or analysis on what is really going on. – (

Here is my new, much more detailed analysis on the link.

First, we have to realize that almost any type of vitamin/mineral/nutritional deficiency that one suffers when one is younger, particularly when one is still a baby, infant, or child, has the effect of stunting the growth of the person. While the human body is said to be almost all Carbon, Oxygen, Nitrogen, and Hydrogen, there is a small percentage of the human that operates based on the unique characteristics of other elements. Calcium, Pottasium, Phosphorous, Magnesium, Copper, Sulfur, Chlorine, off of the top of my head.

I am not a nutritionist, but I would assume that to get all of the other minerals/elements into our body, we need to be eating a variety of different types of foods, including fish, meat, nuts, fruits, etc. This is to make an effort to get all of the necessary minerals the body needs to grown to its natural maximum height. What I am talking about is the stunting effect of not having enough of some mineral or vitamin.

However, I have not really heard of the ability of a vitamin or mineral, when in excess can actually help the human body become taller. The common idea with nutritionists is that anything can become a poison to the human body, at a high enough concentration. This old idea would suggest that a higher than average level of iron intake into the human body would have an adverse effects on health, thus decreasing the person’s eventual adult height.

That is not what the medical researchers are saying though. When you have the body oversaturated with iron, the child grows up to be taller than if they just took an average amount of the mineral. Of course I am not stupid and suggest that a mother should be feeding her new born iron infused formula to possibly turn the kid into a basketball player, going that extreme.

Let’s take a look at the studies to see what they are actually saying.

The first study is talking about a iron condition known as HFE associated Hemochromatosis. This unique physiological trait that is genetic derived seemes to cause higher than average levels of iron to be adsorbed and retained in the body. It seems that when a person is growing, the growth rate has some type of effect on the level of iron in the person’s body.

When the human body is going through a rate of higher than average growth, like through a growth spurt or puberty, there is not enough iron that is available in the body to maximum the rate of interstitial growth. This means that for most people who don’t have the HFE Hemochromatosis, they did not maximize their rate of growth to maximum height.

In the study, about 175 participants from Switzerland went in for testing. 93% of the participants were found to have a homozygous C282Y mutation. Their iron levels in the blood were tested and were found to have serum ferritin level of more than 300 μg per liter or a transferrin saturation of more than 45%. There was about 120 men and the rest were female. The men’s heights, when averaged out turned out to be a little over 178 cm, which is around 4 cm higher than the average height taken from Swiss Military records. The female subjects’ average height was around 167 cm, or 3.3 cm higher than the average height of females.

To scale the data correctly to a reference/scale, data from a reference population in Ireland was used, which has the highest percentage of people having the C282Y mutation of all European nations. This is to remove the possibility that there is a large percentage of people with Northern European ethnicity in the 175 subject group. The data is statistically relevant, with P<0.001

The researchers suggested that it is possible that the increased levels of iron helped in the growth process in the first 2 decades of a person’s life.

The 2nd study’s main point is that it would make sense for a person to take iron supplements intermittently than on a regular basis, at least to prevent the onset of anemia in developing countries.

The following factors were tested from doing two tests, giving ferrous sulfate daily and weekly (as well as Albendazol to help treat intestinal worms).

The results showed that the hemoglobin levels were the same for the daily and weekly. The level of serum ferritin (SF) was higher in the daily dosage group. It was the group that was given the ferrous sulfate on a weekly rate that had a slightly higher amount of vertical growth, at about just 3 mm more. The total number of children who participated in the program was about 400.

Iron deficiency derived Anemia was gone though.

Based on the two studies, and the dozens of other studies that is referenced, I would like to make a few guesses on what this all means.

Most developing nations, where the children don’t get regular access to meat and sources of high protein, have stunted growth. One of the main ways the growth is stunted is not getting enough iron in the blood. Parents who believe that they should only be feeding their children vegetarian diets are depriving their children of certain minerals, like iron, which is hard to get from vegetables and fruit.

If we remember, the traditional idea is that the East Asians, specifically the Japanese, are below average in stature. The Japanese have always had a diet high on seafood and fish, which is high in iodine, but low in iron. After hundreds of years, the Japanese, along with other East Asian females developed higher rates of Anemia (due to Iron Deficiency), Short stature, and Osteoporosis.

Obviously women have smaller appetites. Based on a study in Canada (British Columbia), the adult male is supposed to get 8 mg of iron, while women are supposed to get 18 mg of iron. In addition, when the female is pregnant, she should be getting 27 grams of iron, to account for the fact that the developing fetus in her uterus is sucking away the calcium and iron levels from her body to form itself. East Asian females in particular are notorious for not eating enough, and trying to loss weight through dieting.

There are just too many stories of women who develop osteoporosis from pregnancy.

I personally suspect that this condition that pregnant human females develop, known as Pica, (the unusual desire or craving for strange food like dirt), is the body telling the female that she needs a source of calcium, or iron fast.

Eating strange things, like dirt, paint, soil, clay, ash, etc. is a common practice in some countries in Africa, like Kenya. There is even a store in Georgia selling clay for pregnant expectant mother under the name Kaolin (aka Geophagic Earth). Further research on the internet validated the idea that the medical condition known as Pica seems to be related to Iron Deficiency. Clay itself has a high level of calcium, iron, magnesium, and copper.

This might tangentially explain why a small minority of females have reported (only anecdotally) growing taller after pregnancy, sometimes by as much as 2.5 inches. It might not just be the relaxin effect, or the loss of calcium from their bones. It might also be the increased levels of consumption of iron in their diet, through very strange cravings.

What this post is suggesting is that it might be a good idea to make sure that the developing child and the pregnant female is getting a lot of iron, calcium, and minerals through her system to maximize health and final adult height.

I am willing to make a bet that as much as 3-5% of all females can gain around 1 Inch of extra height through their first pregnancy, if they can get their stimulated relaxin, calcium, PTHrP, and Iron levels just right, so they all operate at exactly the right step (in this multistep process) to remodel the tensile strength of the bones (by reducing Calcium Hydroxyapatite crystals embedded in the Organic ECM), turning them almost collagenous in nature (using increased PTHrP level), relaxing the surrounding soft tissue like tendons using relaxin, and then re-hardening the bones up through increased Iron and Calcium levels.

Breakthrough-New LSJL method with me performing it in full

Below is a demonstration of me performing LSJL on the femoral epiphysis.  The key to chondroinduction as is expanded on below(need to get the studies from UCSD, does anyone have access to them?) is to achieve between 0.1 – 10(or more) MPa in the epiphyseal bone marrow.    A blood pressure cuff can achieve 120mmHg during a heart beat which is about 0.015MPa an order of magnitude below what we need.  The highest recorded blood pressure is 300mmHg which is still below what we need.  Systolic blood pressure is “specifically the maximum arterial pressure during contraction of the left ventricle of the heart.”  We’re not specifically looking for the arterial pressure we’re looking for the bone marrow hydrostatic pressure.

The key to distraction osteogenesis may be the blood clot that’s formed during the fracture.  This creates a chondrogenic environment.  And this fracture does not pose a large risk to health.  So the goal is to mimic the hydrostatic pressure creation in the bone marrow without inducing fracture.  Note in the video that my knee is bent to increase the pressure.

Nothing much in the video.  Just me performing the new LSJL method on my left knee epiphysis.  This is exactly the way I do it except I’m usually lying down on my back so it’s easier to perform.

Pressure and shear stress in trabecular bone marrow during whole bone loading.

“Skeletal adaptation to mechanical loading is controlled by mechanobiological signaling. Osteocytes are highly responsive to applied strains, and are the key mechanosensory cells in bone. However, many cells residing in the marrow also respond to mechanical cues such as hydrostatic pressure and shear stress, and hence could play a role in skeletal adaptation. Trabecular bone encapsulates marrow, forming a poroelastic solid. According to the mechanical theory, deformation of the pores induces motion in the fluid-like marrow, resulting in pressure and velocity gradients. The latter results in shear stress acting between the components of the marrow. To characterize the mechanical environment of trabecular bone marrow in situ, pore pressure within the trabecular compartment of whole porcine femurs was measured with miniature pressure transducers during stress-relaxation and cyclic loading. Pressure gradients ranging from 0.013 to 0.46kPa/mm were measured during loading. This range was consistent with calculated pressure gradients from continuum scale poroelastic models with the same permeability. Micro-scale computational fluid dynamics models created from computed tomography images were used to calculate the micromechanical stress in the marrow using the measured pressure differentials as boundary conditions. The volume averaged shear stress in the marrow ranged from 1.67 to 24.55Pa during cyclic loading, which exceeds the mechanostimulatory threshold for mesenchymal lineage cells{but we have to be in the range to stimulate chondrodifferentiation}. Thus, the loading of bone through activities of daily living may be an essential component of bone marrow health and mechanobiology. Additional studies of cell-level interactions during loading in healthy and disease conditions will provide further incite into marrow mechanobiology.”

Intermittent hydrostatic pressure can induce chondrostimulation.  0.1 to 10 MPa tend to be the levels to induce chondrogenic differentiation.  There are 1 million Pascals in a MegaPascal so the average shear stress in the bone marrow from cyclic loading is below the levels needed to induce chondroinduction.  0.1MPa is needed to induce proteoglycan production and above 10MPa induces more chondrogenic markers.

The in situ mechanics of trabecular bone marrow: the potential for mechanobiological response.

“Bone adapts to habitual loading through mechanobiological signaling. Osteocytes are the primary mechanical sensors in bone, upregulating osteogenic factors and downregulating osteoinhibitors, and recruiting osteoclasts to resorb bone in response to microdamage accumulation. However, most of the cell populations of the bone marrow niche,which are intimately involved with bone remodeling as the source of bone osteoblast and osteoclast progenitors, are also mechanosensitive. We hypothesized that the deformation of trabecular bone would impart mechanical stress within the entrapped bone marrow consistent with mechanostimulation of the constituent cells. Detailed fluid-structure interaction models of porcine femoral trabecular bone and bone marrow were created using tetrahedral finite element meshes. The marrow was allowed to flow freely within the bone pores, while the bone was compressed to 2000 or 3000 microstrain at the apparent level.Marrow properties were parametrically varied from a constant 400 mPas to a power law rule exceeding 85 Pas. Deformation generated almost no shear stress or pressure in the marrow for the low viscosity fluid, but exceeded 5 Pa when the higher viscosity models were used{high viscosity is high internal friction?. The shear stress was higher when the strain rate increased and in higher volume fraction bone. The results demonstrate that cells within the trabecular bone marrow could be mechanically stimulated by bone deformation, depending on deformation rate, bone porosity, and bone marrow properties{we need to alter this with LSJL}. Since the marrow contains many mechanosensitive cells, changes in the stimulatory levels may explain the alterations in bone marrow morphology with aging and disease, which may in turn affect the trabecular bone mechanobiology and adaptation.”

The higher the temperature is, the lower a substance’s viscosity is. Consequently, decreasing temperature causes an increase in viscosity.

Bone is considered to have laminar flow in that the bones move in separate layers.  Bone is a viscous tissue meaning “having a thick, sticky consistency between solid and liquid; having a high viscosity”<-Salt, cornstarch, and flour are ways to increase bone marrow viscosity.

A blood pressure cuff generates 120mmHg ish which is about 0.015MPa.  You need about 75000mmHg to generate 10MPa.    Specifically we want to increase the intraosseous pressure.

According to a study on the relationship between intraosseous pressure and intra-articular pressure selective compression of veins can increase intraosseous pressure.

According to Intraosseous Pressure in the Patella in Relation to Simulated Joint Effusion and Knee Position: An Experimental Study in Puppies,  the intraosseous pressure of the patella is about 12mmHg.  “During extension of the knee joint, a significant rise in intraosseous pressure of the tibial epiphysis and patella was observed, whereas during flexion femoral epiphyseal pressure and patellar pressure increased significantly.”

Pressure increased with degree of knee flexion.  This is like doing a hamstring curl.

A method of measuring bone marrow blood pressure is mentioned here:

Bone marrow pressure in osteonecrosis of the femoral condyle (Ahlbäck’s disease)

Bone-Marrow Pressure and Bone Strength

“During rapid dynamic loading, however, a slight rise in intra-medullary pressure was observed. Contraction of the femoral muscles also resulted in a greater bone-marrow pressure increase. A correlation of 0.98 between stimulus strength and intra-medullary pressure was obtained. The rise in intra-medullary pressure with femoral muscle contraction is suggested to have a possible role under extreme stresses in living conditions.”

“The normal resting range of bone-marrow pressure in all the rats studied in the present
series varied from 1.07 to 2.40 kPa (8 to 18 mmHg) [mean resting pressure 1.65 kPa (12.4
mmHg), standard error of the mean 0.08 kPa (0.6 mmHg)]. The most frequently observed
values were between 1.6 kPa to 1.87 kPa (12 to 14 mmHg). The marrow pressure tended
to vary within the range of 0.267 kPa under resting conditions. “<-This is about 3 orders of magnitude of the pressure we need.

“The bone-marrow pressure did not alter [during slow loading] either during the period of loading or on completion of the process and maintenance of the load. ”

“In slow loading experiments the compression was applied over a period of 1 minute to gaps of
1.36 kg from 0 to 12.25 kg by slow rotation of the central loading screw. Each applied load was
maintained for 2 minutes to allow for any gradual pressure build-up. Any rise in the marrow
pressure following loading was permitted to settle before the next incremental load was applied.  During fast loading similar loads were applied but the process of each loading was completed within 2 seconds. After each step of loading there was an observational pause of 2 minutes. A sudden loading omitting two and more of the intermediate steps was also tried. ”

“During fast loading, bone-marrow pressure variations were normal within the range of 0
to 2.7 kg. Beyond this level as the loads were swiftly applied, sudden pressure changes were
observed, these being more pronounced if the loading omitted two of the intermediate
steps. A rise of 2 kPa (15 mmHg) was observed when the compression was raised
from 4 kg to 12.25 kg. Generally, a higher magnitude of compression engendered greater increases in the intra-medullary pressure. ”

“Stimulation of the femoral nerve, causing contraction of the quadriceps muscles
resulted in a considerable rise in bone marrow pressure. There was a progressive increase in bone-marrow pressure with each increment in stimulus strength. A maximum pressure rise of 8 kPa (60 mmHg) was recorded with 5 V stimulation.”

“In life, excessive compression stress tends to cause bone fracture which can be resisted by
the sudden and significant rise of marrow pressure caused by simultaneous contraction of the overlying muscles”

This next study found that pressure increased by approximately 3X in response to load which still doesn’t get us up three orders of magnitude:

Microfluidic Enhancement of Intramedullary Pressure Increases Interstitial Fluid Flow and Inhibits Bone Loss in Hindlimb Suspended Mice

“Increases in ImP may be induced by deformations in the matrix that result in volumetric decreases in the intramedullary cavity”

“dynamic IFF rather than pressure was the primary factor driving skeletal adaptation in our studies.”<-Perhaps it is the same for inducing chondroinduction?

” in vitro in sheep tibia (up to 300 mmHg in response to a load of 2000 N over 0.15 second) and excised human femurs (93.5 mmHg in response to a load of 980 N over 0.03 second)”

According to the LSJL study

Knee loading dynamically alters intramedullary pressure in mouse femora

“sinusoidal forces of 0.5 Hz and 10 Hz, pressure amplitude increased up to 4-N loads and reached a plateau at 130 Pa.”<-which is 3 orders of magnitude below where we need to be but maybe it is interstitial fluid flow that can induce chondrogenesis and not hydrostatic pressure.

Here’s some papers on how hydrostatic pressure and interstitial fluid flow play a role in the initial creation of bone epiphysis and growth plate.

According to Mechanobiology of mandibular distraction osteogenesis: finite element analyses with a rat model., “A 0.25 mm distraction was simulated and the resulting hydrostatic stresses and maximum principal tensile strains were determined within the tissue regenerate. When compared to previous histological findings, finite element analyses showed that tensile strains up to 13% corresponded to regions of new bone formation and regions of periosteal hydrostatic pressure with magnitudes less than 17 kPa corresponded to locations of cartilage formation. Tensile strains within the center of the gap were much higher, leading us to conclude that tissue damage would occur there if the tissue was not compliant enough to withstand such high strains, and that this damage would trigger formation of new mesenchymal tissue. These data were consistent with histological evidence showing mesenchymal tissue present in the center of the gap throughout distraction.”<-So it is possible to form cartilage with less than 0.1MPa.

” In reality, tensile hydrostatic stresses (i.e., negative pressures) greater than 47.07 mmHg (=6.3 kPa), which is the vapor pressure of water at 37 degrees C, would cause the water in the tissue to boil.”

Pressure in a liquid is the force exerted over a given area, a fluid’s pressure pushes on the walls of the surrounding container, as well as on all parts of the fluid itself.

The pressure in the liquid increases with depth because of gravity. The liquid at the bottom has to bear the weight of all the liquid above it, as well as the air above that.

Here’s a study that states that maybe it’s interstitial fluid flow and not necessarily hydrostatic pressure that can induce changes in bone(and therefore chondroinduction):

Fluid pressure gradients, arising from oscillations in intramedullary pressure, is correlated with the formation of bone and inhibition of intracortical porosity

“Fluid flow that arises from the functional loading of bone tissue has been proposed to be a critical regulator of skeletal mass and morphology. To test this hypothesis, the bone adaptive response to a physiological fluid stimulus, driven by low magnitude, high frequency oscillations of intramedullary pressure (ImP), were examined, in which fluid pressures were achieved without deforming the bone tissue. The ulnae of adult turkeys were functionally isolated via transverse epiphyseal osteotomies, and the adaptive response to four weeks of disuse (n=5) was compared to disuse plus 10min per day of a physiological sinusoidal fluid pressure signal (60mmHg, 20Hz). Disuse alone resulted in significant bone loss (5.7±1.9%), achieved by thinning the cortex via endosteal resorption and an increase in intracortical porosity. By also subjecting bone to oscillatory fluid flow, a significant increase in bone mass at the mid-diaphysis (18.3±7.6%), was achieved by both periosteal and endosteal new bone formation. The spatial distribution of the transcortical fluid pressure gradients (∇Pr), a parameter closely related to fluid velocity and fluid shear stress, was quantified in 12 equal sectors across a section at the mid-diaphyses. A strong correlation was found between the ∇Pr and total new bone formation (r=0.75); and an inverse correlation (r=-0.75) observed between ∇Pr and the area of increased intracortical porosity, indicating that fluid flow signals were necessary to maintain bone mass and/or inhibit bone loss against the challenge of disuse. By generating this fluid flow in the absence of matrix strain, these data suggest that anabolic fluid movement plays a regulatory role in the modeling and remodeling process. While ImP increases uniformly in the marrow cavity, the distinct parameters of fluid flow vary substantially due to the geometry and ultrastructure of bone, which ultimately defines the spatial non-uniformity of the adaptive process.”

“one is a highly structured composite material comprised of a collagen-hydroxyapatite matrix and a hierarchical network of lacunae-canaliculi channels. These tunnels permit interstitial flow of fluid through tiny microporosities, and thus ‘‘by-products’’ of load, such as the change in fluid velocities or pressures, represent a means by which a physical signal could be translated to the cell{Mesenchymal Stem Cells are cells so could be affected by fluid pressures as well}”

“intracortical fluid flow is induced not only by bone matrix deformation, but also by the intramedullarypressure (ImP) generated during loading.  Applying anabolic oscillatory ImP alone can induce transcortical fluid flow as measured by streaming potential”<-So there are two alternatives to achieving 0.1 MPa in the epiphyseal bone marow: oscillitary intramedullary pressure and bone matrix deformation to induce fluid flow.

” maximum fluid pressure on the order of 8 kPa will result in approximately 0.8 [microstrain] in the matrix.”

“While the endosteum is permeable, theyhave found that the periosteum is, in essence, impermeable unless the periosteal superficial layer is removed in the adult canine tibial cortex.”