Hiroki Yokota Grant progress on LSJL

What can we discern about the plans from LSJL from the grants?  Yokota is one of the primary scientists behind the study Lengthening of Mouse Hindlimbs with Joint Loading.  There does not seem to be very much on the LSJL length effects since the expiring of Ping Zhang’s 2010 grant.  We either have to study the lengthening effects on our own or help Ping Zhang get more funding.

Yokota doesn’t mainly study the lengthening effects which are primarily studied by Ping Zhang as shown by this grant.

Here’s Hiroki Yokota’s 2015 grant:

“The long-term objective of the proposed studies is to elucidate the mechanism of mechanotransduction in bone. Our present bioengineering-oriented project developed a high-resolution piezoelectric mechanical loader and evaluated the role of mechanical stimulation in bone using cultured osteoblasts. The results reveal that (a) deformation of 3D collagen matrix can induce strain-induced fluid flow;(b) strain-induced fluid flow, and not strain itself, predominantly activates the stress-responsive genes in osteoblasts;and (c) architecture of 3D collagen matrix establishes a pattern of strain-induced fluid flow and molecular transport{We are not interested so much on the effects on osteoblasts but more on the effects of fluid flow on bone degradation and fluid flow on mesenchymal stem cells to create neo growth plates}. Many lines of evidence in animal studies support enhancement of bone remodeling with strain of 1000 – 2000 microstrains. An unclear linkage between our in vitro studies and these animal studies is the role of strain and fluid flow in bone remodeling. In vitro osteoblast cultures including our current studies use 2D substrates or 3D matrices that hardly mimic the strain-induced fluid flow in vivo. This difference between in vitro and in vivo data makes it difficult to evaluate the role of strain and fluid flow in bone remodeling and anti-inflammation. First, microscopic strain in bone might be higher than the macroscopic strain measured with strain gauges. A local microscopic strain higher than 1000 – 2000 microstrains may therefore drive fluid flow in bone. Second, the lacunocanalicular network in bone could amplify strain-induced fluid flow in a loading-frequency dependent fashion{This we should try to modify the frequency of LSJL to amplify strain}. Lastly, interstitial fluid flow in bone might be induced by in situ strain as well as strain in a distant location, such that deformation of relatively soft epiphyses induces fluid flow in cortical bone in diaphyses{We are more interested in deformation of the epiphysis as that’s where growth plates typically occur but deformation of the epiphysis in one end may induce fluid flow in the epiphysis in the other}. This renewal proposal will use mouse ulnae ex vivo as well as mouse in vivo loading to examine the above possible explanations for the data divergence.
Specific aims i nclude: (1) fabricating a piezoelectric mechanical loader for ex vivo and in vivo use;(2) quantifying ex vivo macroscopic and microscopic strains using electronic speckle pattern interferometry as well as molecular transport using fluorescence recovery after photobleaching;(3) conducting bone histomorphometry to evaluate ex vivo data;and (4) examining load-driven adverse effects with gene expression and enzyme activities (e.g., matrix metalloproteinases). Mechanical loads will be given in the ulna-loading (axial loading) and elbow-loading (lateral loading) modes{he’s planning on doing another LSJL loading study!}. These two modes have been shown to enhance bone remodeling in the diaphysis with different patterns of strain distribution. Successful completion of the proposed renewal proposal will provide basic knowledge about induction of fluid flow in bone and establish a research platform for devising therapeutic strategies for strengthening bone and preventing bone loss.”

Here’s the Hiroki Yokota 2014 grant:

Mechanical Loading and Bone

“The long-term objective of this study is to elucidate the mechanisms underlying loading-induced bone remodeling and develop unique loading-based therapies for preventing bone loss. The specific goal of this study, based on our most recent observations, is to determine how mechanical loading to the knee (knee loading – application of mild lateral loads to the knee) may exert global suppression of osteoclast development not only in the loaded (on-site) bone but also in the non-loaded (remote) bone{This is unfortunately not very promising for height growth as osteoclast driven remodeling is pretty significant for growth plate formation}. As a potential regulatory mechanism, we will focus on secretory factors (e.g., Wnt3a, NGF?, TNF?, etc.) and low-density lipoprotein receptor-related protein 5 (Lrp5) mediated signaling. In the parent project, we have shown that knee loading enhances bone formation in the tibia and the femur through the oscillatory modulation of intramedullary pressure. However, its effects on bone resorption have not been well understood. Preliminary studies using a mouse ovariectomized model, which mimics post-menopausal osteoporosis, indicate that knee loading can suppress development of multi-nucleated osteoclasts from bone marrow cells, and the loading effects are observed not only in the loaded femur but also in the non-loaded contralateral femur. In this competitive renewal project, we will test the hypothesis that joint loading (knee/elbow loading) can suppress an OVX-induced osteoclastogenesis in a systemic manner through Lrp5-mediated Wnt signaling with Wnt3a as a secretory factor, as well as interactions with other secretory factors. To examine this hypothesis, we propose two specific aims using a mouse loading model (knee loading, elbow loading, ulna bending, and tibia loading), and assays for bone remodeling and primary bone marrow cells.
Aim 1 : Determine the local and global effects of joint loading on osteoclastogenesis Aim 2: Evaluate the role of load-modulated secretory factors in osteoclastogenesis In response to mechanical loading, we will conduct X-ray imaging and colony forming unit assays{The x-rays will be highly useful in determining whether LSJL can induce neo-growth plate formation although the effects would have to be large to show up on the xray}. We will also examine expression of critical secretory factors such as Wnt3a, NGF?, TNF?, OPG, RANKL, etc. in the serum. Primary bone marrow cells will be cultured, and the mechanisms underlying loading-driven regulation of osteoclastogenesis will be investigated. We will examine expression of regulatory factors, including NFATc1 (master transcription factor for osteoclastogenesis) and osteoclast markers such as OSCAR, cathepsin K, etc. We will employ Lrp5 KO mice (global, and conditionally selective to osteocytes), as well as neutralizing antibodies and RNA interference (loss of a function), and plasmids (gain of a function). We expect that this project will contribute to our basic understanding of load-driven regulation of bone resorption and development of loading regimens useful for global prevention of bone loss. ”

Let’s look at Hiroki Yokota’s 2013 Grant:

“The long-term objective of the proposed studies is to elucidate the mechanism of mechanotransduction in bone. Our present bioengineering-oriented project developed a high-resolution piezoelectric mechanical loader and evaluated the role of mechanical stimulation in bone using cultured osteoblasts. The results reveal that (a) deformation of 3D collagen matrix can induce strain-induced fluid flow{If it is fluid flow that can induce neo-growth plate formation via stem cell simulation then we need to make sure that LSJL deforms the 3D collagen matrix};(b) strain-induced fluid flow, and not strain itself, predominantly activates the stress-responsive genes in osteoblasts;and (c) architecture of 3D collagen matrix establishes a pattern of strain-induced fluid flow and molecular transport. Many lines of evidence in animal studies support enhancement of bone remodeling with strain of 1000 – 2000 microstrains{2000 microstrain is about a 0.2% change in bone length.  LSJL laterally compresses the bone so the compression has to be by at least .1 or .2% to work}. An unclear linkage between our in vitro studies and these animal studies is the role of strain and fluid flow in bone remodeling. In vitro osteoblast cultures including our current studies use 2D substrates or 3D matrices that hardly mimic the strain-induced fluid flow in vivo. This difference between in vitro and in vivo data makes it difficult to evaluate the role of strain and fluid flow in bone remodeling and anti-inflammation. First, microscopic strain in bone might be higher than the macroscopic strain measured with strain gauges. A local microscopic strain higher than 1000 – 2000 microstrains may therefore drive fluid flow in bone. Second, the lacunocanalicular network in bone could amplify strain-induced fluid flow in a loading-frequency dependent fashion. Lastly, interstitial fluid flow in bone might be induced by in situ strain as well as strain in a distant location, such that deformation of relatively soft epiphyses induces fluid flow in cortical bone in diaphyses{of course our goal is to create new growth plates in the epiphysis but the fluid flow from compressing the ends of the epiphysis may flow deeper helping to induce mesenchymal condensation to induce neo growth plates closer to where the epiphysis meets the diaphysis}. This renewal proposal will use mouse ulnae ex vivo as well as mouse in vivo loading to examine the above possible explanations for the data divergence.
Specific aims include: (1) fabricating a piezoelectric mechanical loader for ex vivo and in vivo use;(2) quantifying ex vivo macroscopic and microscopic strains using electronic speckle pattern interferometry as well as molecular transport using fluorescence recovery after photobleaching;(3) conducting bone histomorphometry to evaluate ex vivo data;and (4) examining load-driven adverse effects with gene expression and enzyme activities (e.g., matrix metalloproteinases). Mechanical loads will be given in the ulna-loading (axial loading) and elbow-loading (lateral loading) modes. These two modes have been shown to enhance bone remodeling in the diaphysis with different patterns of strain distribution. Successful completion of the proposed renewal proposal will provide basic knowledge about induction of fluid flow in bone and establish a research platform for devising therapeutic strategies for strengthening bone and preventing bone loss. ”

The grants from 2013-2006 are virtually the same.  It’s only 2014 which is different however it’s unfortunate that it’s not focusing on the lengthening effects.

Unfortunately Ping Zhang’s grant Load-Driven Bone Lengthening only ran from 2008-2010.

How Much Will It Cost To Fund This Biomedical Project?

There were a few people in recent days who wanted to start a KickStarter project to fund this type of project. The project is the idea of using regenerative medicine, stem cell therapy, tissue engineering, and 3D Bioprinting to get an alternative to limb lengthening surgery into market.

What they were discussing was a recent post I wrote entitled – “How Close Are We Towards Growth Plate Regeneration To Grow Taller?”

In response, I have to show these people just how crazy it is to get something new in medicine to the public. Refer to Forbes.com post written back in 2014 entitled – “The Truly Staggering Cost Of Inventing New Drugs”

Eli Lilly, states that it would cost on average about $1.3 Billion USD to get just one drug approved and into the market. $1 Billion Dollars!

If you then take into consideration just how easy it is to have drugs fail trials and testing, then the real cost could be around $4 Billion. The high range is $11 Billion for just one drug to be approved.

I did a quick search on Google to find out what is the project in Kickstarter’s history which got the most funding. It seems that based on this article in Entrepreneur.com it would be the Pebble Time based Watch, with a grand total of $20 Mil. $20 Mil is indeed a lot of money to fund such a project. Of course I have been to trade shows for the latest electronic gear in Hong Kong and China before so I have seen at least 4-5 companies who have also come out with similar type products, aka a smart watch which looks suspiciously similar in design to the Apple Watch.

What we would need to get this project started would be something at least 50X that amount. How many people would even believe us that this idea we have is even possible?

I have emailed someone named Harald from the beginning of this website back in 2012 and he has still not been able to raise even $100 K  to get people to fund what he says is research. He claims he is part of a biomedical team of researchers. It has been 10 years and so far no one has been willing to step up. The honest truth is that no one will step up. The first $50 Mil will be just wasted money, since it will just be used as initial startup cost, which will be sunk cost which would take maybe 20 years to get back, if the project is successful.

This idea I have shown to be quite valid would require a truly herculean amount of will, effort, and money to get it done. There is probably less than 10 people in the entire world who would have the financial ability and incentive to fund us. Of course, for any type of potential investor to invest in us, (since no one wants to loose money on a bad investment), we would have to first show very clearly that the science and the technical details are completely valid and it will work.

Trying to get people to open their wallets is one of the hardest things one learns to do as an adult. Selling is truly the most important skill to learn.

Instead of going on Kickstarter, me and Tyler would have to go on Shark Tank and ask Mark Cuban, who actually has a billion, and the other less rich sharks to give us at least $100 Mil to get started on this project. Of course, then once we reach the first goal, we would have to go back and ask for another $300 Mil. At $300 Mil, not even someone like Kevin O’Leary would have the money to fund our endeavor.

I can see Mark Cuban, who loves basketball and owns a basketball team being very interested in funding a company or project like this, as well as the other sharks. Unlike Cuban, who is 6′ 3″, the others are of short stature. Daymond John, Kevin O’Leary, Robert Herjavek, Barbara Corcoran, they are all on the shorter side. I can see a trip on Shark Tank being most likely to work out. It would at least give our project the big exposure we need, and the short statured “sharks” would definitely be interested in getting something in life which even they can’t buy with their millions. Money can buy limb lengthening surgery for these guys but they probably will never be willing to put up with the pain, loss of time, and helpless feeling.

The other options is to find a rich Arab/Saudi Sheik or Prince who might have a height complex and is willing to give us maybe $50-$100 Mil to get the project started. Before when I used to work in the alternative energy sector in a former life, the CEO at the time said that the company I was at was in talks with a Saudi Family in getting investments (as well as the billionaire T Boone Pickens). My CEO told in passing that apparently the real net worth of the Saudi Family was a total of $1 Trillion!! (True Story).

The third option is to look for a crazy billionaire who was a scientist or biologist in a former life. Off of the top of my head, I am thinking Patrick Soon-Shiong. Patrick is supposed to be the richest person in all of Los Angeles. He is the type of person who is willing to take moon-shots, similar in style to Google. At the current moment Soon-Shiong is willing to put his own billions in looking for a cure for different types of cancers. If he is willing to put billions down to search for a cure for cancer, he just might be willing to also put a billion down to get this stem cell therapy to work out. I honestly believe that if this form of limb lengthening surgery alternative reaches the public market, it will become a multi-billion dollar industry within 10 years.

The last option is just a crazy billionaire who is willing to believe in our idea. Richard Branson. From Necker Island. Is someone like Branson willing to talk to a person like me? Personally, I have met Branson before when I was in Las Vegas in an audience where he was giving a speech and Q&A. He was very inspirational but he is also a very smart, shrewd, calculated business man who is always willing to get a good deal on a business.

If we are going to present our idea to any of these billionaires, I suggest that first we actually really dig deep into the science, learn everything we can, write out a 1000+ page book out to explain all of the technical details, and find someone who knows these types of investors in maybe 5 years.

This is assuming that the researchers at EpiBone don’t come along and get further into the research and development than us.

A Viable, Real Method To Stop Growth Plates From Closing By Inhibiting Chondrocyte Mineralization and Epiphyseal Cartilage Neovascularization – Breakthrough!

Recent searching through the Google Patent Database revealed a few patents which have been filed which pertains to our goals.

The most important patent is a couple of researchers from Columbia University, Jie Jiang and Helen Lu entitled Methods for inhibiting cartilage mineralization – WO 2008156725 A2″.

What makes this patent so unique and special is that the chemical that is proposed for injection to the locallized area is a chemical which I have written before multiple times and theorized was the key to possible bone interstitial growth even after bone maturity. – “Parathyroid Hormone And Parathyroid Hormone-Related Protein May Lead To Non-Invasive Epiphyseal Growth Plate Regeneration (Big Breakthrough)”.

Of course that post was written in late 2012, which was only the very start of my research. It seems that this patent which was filed back in 2008 seems to validate this idea that using Parathyroid Hormone-Related Protein (PTHrP) would have inhibitory effects on the mineralization process on chondrocytes in hyaline cartilage.

Here is what is important to realize. This patent technically talks about using PTHrP on articular cartilage. The fact that two researchers from a leading research university is willing to put 5,000K USD to file a patent for this idea shows that the science is real. They thought the idea was viable enough to get a patent on it. So I would say it is reasonable to assume that using PTHrP on the articular cartilage will prevent the chondrocytes from mineralization.

Scientifically speaking, when you do the research on looking at how IHH (Indian Hedgehog) controls the rate of stimulation of PTHrP in the profeliferation and hypertrophic layers of the growth plate, it might cause the more discriminatory researcher to suggest that maybe IHH, not PTHrP should be the chemical we should focus on. Technically, it is true that IHH is the chemical that will cause PThrP to be stimulated. There is a negative feedback look in the layer of the growth plate. If the PTHrP chemical is stimulated, it tells the levels of IHH to drop, like a sort of check system to make sure the chemical process doesn’t turn into a run-away chemical reaction chain. However, from what I remember, it is PTHrP that is what actually causes the type of chondrocyte actions that we wants, specifically increased proliferation and then increased hypertrophy. In addition, I seem to remember vaguely at least 1 study which says that increased PTHrP seems to prevent the hypertrophic chondrocytes from undergoing apoptosis too quickly.

This is why I believe that this patent (or method/technique) can be translated to the application of inhibiting chondrocyte mineralization also in the epiphyseal cartilage layers.

If you read the patent and dig into the details, the inventors mention that there is at least half a dozen ways to get the PTHrP to be administered to the deep zone layer of articular cartilage. if there is a half different way to get the chemical to reach the end of the bones/ epiphysis, then there is probably the same number of ways to reach a growth plate that is still not fully closed.

To further validate this idea, there was also another patent filed by a completely different research team based in China on the same idea. You inject PTHrP to stop early onset osteoarthritis.  Refer to the patent # Treatment of early-stage osteoarthritis
US 8586533 B2″. For this particular 2nd patent, they prefer the intra-articular injection method. Also, for the exact amount of PTHrP used, they suggest within the range of from about 0.1 nM to about 200 nM in the synovial fluid of the synovial joint. 

What is even more amazing is that fact that we don’t even need to use this organic protein alone to inhibit chondrocyte mineralization.

Refer to the studies below.

Here are the other chemicals to stimulate. – TFG-Beta1, Glutamate, and Vitamin C Sulfate.

Here are the chemicals to decrease – Annexin V

So theoretically, would injection of a TGF-Beta1 and PTHrP combination into the layer of growth plates work in stopping the growth plates from completely closing up?

Of course, no chemical is good enough to completely inhibit the process of epiphyseal fusion. I forget which study I read (involving Sox9) which explained in extremely fine detail what was the exact chronological steps for the chondrocytes to die and have the remaining area turned into osteoblastic tissue.

The first step I believe was that the hypertrophic chondrocytes had something activated to cause them to secrete the chemical alkaline phosphatase (ALP). The waste that is expelled by the chondrocyte which had expression levels of ALP in it caused the area to become vascularized. Once the area becomes vascularized, then it become mineralized. Certainly mineralization is one of the key steps in this multi-step process. Then there are maybe 4-5 other steps after this, but we are not going to focus on those steps. In any series of chemical reactions, the easiest way to stop the series of reactions is to stop the first reaction from happening, thereby nipping the entire thing at the bud.

The idea that if we can just inhibit this one step, the mineralization step, means that the overall ECM still stay elastic and not bone hard. It may still go through the step of neo-vascularization become vascularized, and it may cause a run-away reaction of all the chondrocytes going through apoptosis but the matrix should stay in a cartilage-type tissue form for a much longer time. This would give the overall structure to possibly more time to expand longitudinally, thus making the bones longer than if they went their normal rate.

In conclusion we might consider the idea of also using Chondromodulin Type I or Type II, as well as GDF-5 in combination ,to possibly stop the vascularization as well.

If we stop both the mineralization and the vascularization, then we would stop the growth plate from ever closing, if we can figure out how to stop the hypertrophic chondrocytes from expression ALP through their waste.

{Tyler-Note that just because mineralization of the growth plates ceases does not mean that height will increase.  Stopping growth mineralization does not stop growth plate senescence see mice and rats.  Also, slowing down mineralization has been shown to decrease height in some instances.  It’s possible that it could increase height but experiments would be needed to test.  The better strategy is to stop growth plate senescence._

Scientists Have Gotten Cartilage To Grow In The Lab From Explanted Seed Chondrocyte Cells And Reimplanted Back Into Patient

This is just some extra news that is worth showing the readers that the idea of taking a small piece of tissue from a patient, and then growing the cell into tissue in a lab culture in small microbiology petri dish, is very straight forward. This is something i already has been done at least once before by some other teams. Not only does the full tissue become synthesized in a culture dish, that tissue is reimplanted back into the cartilage defect areas of the patient. The entire process from the earliest step to the final step has been taken.

The last step now is to get the explanted tissue of chondrocytes to be grown into a columnar structure (via Thyroxine, refer to insanely critical study on power of Thyroxine to form growth plate organization ie columnar fashion back in 1994 by Dr. Ballock and Reddi Here) and have the released waste of proteoglycan and GAG (Glycoaminoglycan) into the ECM (Extracellular Matrix) to expand so that the tissue can expand, turning it into a “synthetic growth plate”. <– This step should not be that hard, and I believe it has already been accomplished in a research grant from 2012-2014.

Refer to the article “Doctors Have Discovered A Revolutionary Treatment For Knee Injuries” on Business Insider.

At Ohio State University, in the Wexner Medical Center, a  Dr. David C  Flanigan (His website is at www.flaniganmd.com) and his research team have been testing human cartilage grown in the lab. A patient named Taylor Landgraf, who was locally trying to get to the local gym and using a skateboard fell and tore the cartilage in his knee, as well as tearing his meniscus.

Taylor decided to look into getting some type of more modern type of treatment to repair his cartilage, since cartilage is probably one of the only tissue types which do not regenerate and heal itself, due to its unique structure. I would assume that he would get in contact with the Wexner Medical Center and somehow learn about the possibility of having lab grown tissue transplanted into his body.

So the researchers take a little bit of chondrocyte tissue as a type of tissue seed material from Taylor’s body. It is placed in a medium (agragose/hyaluronic acid/etc.) and grown in a cell line. The cartilage cells are replicated over and over again (I do have some issues here since it is well known that all cells have a limit to how many times they can replicated, similar to the idea of the Hayflick Limit).

Based on my own personal experience of listening to the speaker/CEO of RoosterBio, a company that sells mesenchymal stem cells, it was told to me that to have enough quantities of cells to form a reasonably large sized tissue, say even 2 cm by 2 cm, you would need around 60-200 Million cells. This suggests that if we assume cell mitosis, then to divide 10 times reveals a 2^10, or approximately 1000X magnification of cell numbers. What I am trying to say is that the amount of tissue you have to carve out of the patient may be quite sizable to have at least around 100,000 cells to start with (10^6). Assuming the Hayflick Limit of around 30 mitotic divisions (from the age of 20-30) , then we can start with much less. If we are assuming from the fetal stage, Wikipedia says instead that the limit of division is around 40-60 times.

Anyway, the result from starting with a cell line, and replicating it over and over again is a piece of living cartilage, about the size of a quarter (diameter of an inch, or 2.5 cm). You take that quarter sized cartilage, and carve it into the shape of the cartilage defect in the patient’s knee (or any other joint or location where cartilage has been scratched off). and pop it into the area where cartilage is missing.

So why is this worth mentioning? Is this big news or old news?

I wrote this post as a proof of concept. The type of cartilage that you get is most likely not going to be of the epiphyseal type, hyaline in nature. It will be fibrocartilage. The cartilage has an unorganized cartilage organization structure (ie. non-lamellar). Articular cartilage is hyaline in nature. Would the two different types of cartilage which now are next to each other bind at the boundaries and have something that will function overall at a reasonably good level? The reseatchers at this lab at OSU seem to think that this type of therapy is good enough for Taylor, at least semi-permanently for maybe 10-20 years. When that fibro-articular cartilage composite type starts to break down in 15 years, the researchers will have gone further on the tissue regenerative science and have something much better for him down the line in the future.

In fact, there is probably a much better technique for this Taylor patient which he should have tried, called Microfracture Surgery. Microfracture Surgery involves the surgeon just stabbing  the subchondral bone layer underneath the now grinded out articular layer of the knee epiphysis to make a hole. The stem cell type medium that exists in the cavity of the bones will leak out, and form as a type of blood clot turning into fibrocartilage tissue.

This way of doing it by the team with Flanigan seems a little too invasive, and not that necessary. However, it shows that researchers can grown cartilage in the lab from a patients own chondrocyte (or maybe even MSCs) and grown the cells into tissue, and reimplanted back into the body, and have that transplant to work just fine.

This is another step in the long process for what we ultimately want. It is a proof of concept for one of the most critical ideas and steps.

My Calling Is Helping The Most Lonely

Sometimes I don’t pay enough attention to this project or the research. I leave for a while to live my life and focus on other areas of it. Then I find something, read something, that makes me remember the real reason why I ever first started this quest. My girlfriend left me, I was devastated, and I believed that one of the reasons she left me was because I felt I was not tall enough. She left me for a guy who was much taller than me. It hurt me at a level which I have never felt before, and I swore on my life that I would find a way to change the situation, not just for me, but for other guys in the world.

I remember once reading this controversial article from some internet website where the author wrote that men in today’s world are no longer needed by women, since women can do almost everything better than men. The way the school system is setup reveals that academics rewards the students based on following orders and being disciplined, which has never been a strong point of young men. While men still need women for the act of reproduction, companionship, intimacy, and sex, women no longer need the skills and qualities within men for survival. They no longer as the males of their family to go out and hunt down a sabretooth tiger for the even meal. As a heterosexual male who have somewhat old-fashion conservative views, the article seemed to push at a pressure point within my psyche that made me feel insecure, sad, and a little bit angry.

It turns out that when the modern young adult female talks about the income inequality among the sexes today, the women are not comparing themselves to the bottom 80% of men in their society, but the top 20% of men. In every society, there is always a heriarchy of men, with some being of higher class, and most men being of the lower class. Throughout the history of the human race, within almost all tribes and groups, it would turn out that the majority of males would never get a chance to have sex, and find a sexual partner or mate in life. Historically, it was the top minority of men in society who get sexual access to the majority of females. Think of the harems of the Emperor of China or the Caliphate of the Ottoman Empire or the Persian Empire, which had up to thousands of young girls who were carefully protected from other men by the army of the male rulers. Being a human guy in this world, in any time frame, has always been hard. It is just that hundreds of years ago, being born as a female was also very hard, with the constant threat of kidnapping, assault, rape, and forced marriages. Now that the world has become more peaceful and most men in the developed world no longer view females as property, the females of our species don’t feel that type of threat from male strangers that they were taught hundreds of years ago. The main point is, in this modern age, it is much harder to be a guy than a girl. When we really, objectively look at the overall condition of the human race, it has been the males who have suffered the most throughout history.

I refer to the readers this amazing book “Is there anything good about men? How Cultures Flourish by Exploiting Men” by the professor Roy F. Baumeister. This book will shake the very core belief system of most young men who were born and/or raised in one of the developed western nations. 

Of all the types of men who would most likely fail with females, I believe that it is men who are short who have it worst. The only exception may be being disabled, and that can be up for debate. The fact that short men are so disrespected and treated badly by society, and looked down upon by girls as unworthy of companionship shows that this type of discrimination is too pervasive in the minds of females. Being short is often the kiss of death.

The silent pain and suffering that this certain group of guys go through in life is felt. I am not God, and I am not a savior. I am trying my best to help a minority group of men in this world who are prevented from finding companionship because they did were not lucky at birth and ended up short. Being short and ending up a certain height is something that is almost completely out of our control. However, we should have that type of power and control, if we really wanted it.

This world is really hard for the short men. Maybe we can find some solution to make it so that their problem of short stature can be solved. It might not come about tomorrow, or even a year from now. However, I believe that one day we will find multiple solutions to solve the problem of being short.

Rejection

From Reddit/r/ForeverAlone – Tried to get a female friend to set me up with someone. Her response: “sorry, you’re too short”  – (https://www.reddit.com/r/ForeverAlone/comments/3hu8el/tried_to_get_a_female_friend_to_set_me_up_with/)

 

 

 

 

How Close Are We Towards Growth Plate Regeneration To Grow Taller?

This seems like a reasonable question to ask when a person who is past bone maturity and physeal ossification is interested in learning how they can grow taller.

Well, to answer this question, there are many factors and variables we have to take into consideration. It is really hard to give a definite answer, although I have stated before that we might be as close as 15 years away from some commercial company developing the technology to do that. On the other end, it could be as far away as 50-70 years, assuming that the rate of progress continues for the fields of tissue engineering, regenerative medicine, 3D Bio-printing, and stem cell R&D. Let’s remember that the rate of scientific/technological progress for the biological sciences and biomedical application does not follow the trajectory of Moore’s Law, unlike electronics and Computer Science. To make progress and breakthroughs in BIology is extremely resource/financially intensive, unlike CS, which often just requires a programming wunderkid sitting in his underwear in his dorm room eating Cheetos.

I revealed in a post a month ago about the company EpiBone who is developing osteochondral grafts as implants which has as an advisor Dr. Warren Grayson, who I have said since 2013 is one of maybe 6-7 researchers in the world we should be following. Refer to the post EpiBone Company To Engineer Osteochondral Grafts – Research Breakthrough!. The company reveals that there are definitely plenty of people who realizes that there is a huge financial incentive to get this technological problem to work out. There has already been at least 1 patent filed by the research group at EpiBone on how to use a bioreactor to build bone tissue. Refer to “Methods, Devices and Systems for Bone Tissue Engineering Using a Bioreactor – US20120035742 A1″

Let’s now look at the research of Dr. Robert Tracy Ballock, who I have said is the other main researcher we should be following. His work has been on the Growth Plate for the last 15 years or so. He has been working with Dr. Eben Alsberg, who showed that it was possible to growth a functional growth plate. Refer to his grant on Growth Plate Regeneration available here. Further searching on this grant and his work shows that there was 2 grants, one for the 2012-2013 period, and a 2nd grant for the 2013-2014 time frame. (2012-04-11 – 2014-09-30). If you search around the internet for any new academic papers published under Dr. Ballock’s name, he has not published anything for this year, or even late 2014. I would guess that he is finished with his research from the grant which lasted 2 years and plans to write something up. There might even be a Patent application that is filed from his research soon. Whatever he has found, he is not revealing it yet, at least not to the general public.

3 months ago there was a biomedical conference where a university researcher named Dr. Juan Taboas (Ph. D) presented his work called “Repair and Regeneration of the Physis” at the Houston Methodist Research Institute. Just two months ago, the video of his presentation was available for the general public to watch, but now that video has been set to private and one requires a password to watch the video. I did watch maybe the first 5 minutes of the presentation, which was over 1 hour long. There was a video/audio syncing problem so I was not able to record the presentation back then. The part I watched was not that informative and did not reveal too much about his current research.

The abstract of his talk is below…

Physeal regeneration poses a considerable challenge in orthopaedic regenerative medicine. The physis is the cartilaginous interfacial structure at the ends of the long bones that produces appendicular skeleton growth. Fracture, infection, and cancer can result in limb deformity and loss with significant morbidity and medical cost despite their status as rare disorders. Dr. Taboas and his research group are developing hydrogel and stem cell based point-of-care therapies to prevent and repair limb growth disruption in pediatric patients, and for endochondral repair of large boney defects in children and adults. They are currently evaluating the effect of hydrogel composition and zonal patterning on construct growth and architecture maintenance in an in vivo murine subcutaneous implantation model. These techniques may be applied to regenerate other skeletal tissues that require appropriate interfaces with bone for proper function, such as articular cartilage and ligament.

Here is something that the average reader needs to understand. There is a branch (or maybe sub-branch) in the medical research fields known as Orthopaedic Research. Technically, orthopaedic research refers to diseases and injuries of bones, joints, nerves, and muscles. However, there what is not written, but also implied is the cartilage and the tendons as well. Keep this note in mind as we go further along.

When I was at the 2nd Organ-On-A-Chip and 3D Bioprinting Conference in Boston a month ago, there was a presenter at the conference who revealed that she and her group was working on getting stem cells to build tendon tissue. Tendon tissue is what connects muscle tissue to bone tissue. It is similar to cartilage, because of the high level of collagen, although not the same type of collagen. Her presentation was ” Engineering Tissue Microenvironment Informed by Development, Healing and Disease”. Refer to Catherine Kuo, Assistant Professor at Tufts University. Apparently, she got her postdoctoral training in the Cartilage Biology and Orthopaedics Branch at the NIAMS of the NIH. The last I heard, she was changing positions to a different university. This shows that the field of stem cell technology is being applied to form every type of tissue.

There was a paper that was being passed around at the conference which asked all the people at the conference what type of tissue they planned to use the 3D Bioprinter on. The type of tissue that was most often formed from the 3D Printers was cartilage. Not bone, not vascular tissue (blood vessels like capillaries), not tendons, but cartilage. This reveals something critical. It seems that all of the major researchers understand what would be the easiest type of tissue one can print using this new form of technology. Everyone is thinking the same thing, and we are almost all pursueing the same idea: Cartilage.

I would guess that a large percentage of the research done in this well known field known as orthopaedics is on cartilage research, specifically cartilage growth and regeneration.

So what does Dr. Grayson, and Taboas have in common?

It turns out that they both were all at the 2011 Termis Regenerative Medicine Conference in Houston. Their names was on the list of Attendees. I was supposed to go to the 2015 Termis Conference in Boston, but the cost was just too high for me. Dr. Atala of Wake Forest was going to be there. If you plan to take this type of research seriously, you have to spend the money (about $2,000) to attend these types of exclusive conferences to learn what the real academic researchers are working on.

What about Dr. Ballock?

He is a medical doctor as well as a researcher since he has both a Ph. D.and M.D. (Smart guy). Like all academic researchers, he is involved in a lot of societies and academic groups. I am sure he flies around a lot to give presentations and talks in various conferences and conventions. Back in 1998 he was at this conference called “Bioengineering & Orthopedic Science – Gordon Research Conference” which is now known as “Musculoskeletal Biology & Bioengineering”. It was held from July 26-31 in Andover, New Hampshire. He gave a talk called “”Control of Cell Proliferation in the Growth Plate”. It seems that for almost 2 decades this guy has been working on getting the growth plate to work out. He was involved in this multidisciplinary conference back in 2008 called the “Cleveland Clinic Cartilage Innovation Summit”. The conference was basically a group of researchers gathering to talk about the subject of “The Clinical Science and Outcomes of Cartilage Repair, Maintenance, Regeneration and Replacement”.

So What Am I Trying To Conclude From All This Information?

Some people who are in industry who focus mainly on earning income and profit for their employers and no longer in academics (who focus mainly on the research, discovery, and learning more) would say that something along the lines that all the breakthrough research discoveries one finds in the university lab is still useless if one chooses not to bring their findings into real application and shared with the rest of the world.

This applies to the field of Orthopedics (and most any other type of medical research). What I have found in the last 6 months from attending the conferences which talk about the rising field of 3D Printing, and specifically 3D Printing applied to tissue formation is that the researchers in the university labs are trying their hardest to bring their research to the public.

Dr. Grayson is going to help EpiBone succeed in getting bone implants to work. There is already too many companies who have gotten the theory and science down on getting lab grown stem cell derived bone tissue to be reimplanted into the subjects body with complete success. The 1st step in getting bone tissue to be grown from stem cells or mesenchymal stem cells has been multiple times with the academic researchers forming companies to get their research out to possibly make them millionaires. There is no problem with this since the academics see a way to make personal gain from their years of hard work and research.

When we then move towards the 2nd/next step of getting fibrocartilage to be printed from lab grown pieces of cartilage or chondrocyte, there are labs like Dr. Atala or Dr. Lawrence Bonassar who have already achieved that too. You have seen many pictures of the outer ear lobe being grown in the labs in cultures and even on the backs of lab mice. The same can be said about nose tips, which are also fibrocartilage.

The 3rd step is to get Hyaline Cartilage to be printed or grown in the lab. We are getting super close to getting Hyaline cartilage to be printed. There were 2 exhibitors at the Organ-On-A-Chip Conference, (Cellink and RoosterBio) who would be able to provide the raw materials, cell culture medium and seed mesenchymal stem cells, to let any professional lab to play around to eventually get the lamellar structure of hyaline structure to work out. I would be willing to guess that by the time the 2020 Termis World Conference comes around, we would have succeeded there.

Should we try to the traditional seed stem cell into scaffold method or should we try the more revolutionary way of growing cartilage tissue from scratch using the 3D Bioprinter? – We would have to make that decision eventually.

The 4th step would be to get Epiphyseal Hyaline Cartilage to be grown/printed. Ballock has been working on this problem for 20 years. He got a grant for the 2012-2014 time frame to go research on growth plate regeneration. It is not just him who is working on getting this thing to work out. In the grant, he wrote that if he is successful, the growth plate regeneration technology can be used by people who have already reached bone maturity. He knows what his research would mean and how it would effect the public.

Of course, orthopaedic research and development is something that thousands of people around the world are working on. He is not the only one trying to get growth plate regeneration to work out.

  • There has been teams in Hong Kong who got the chondrocyte implantation idea to work back in the early 2000s. Based on certain Non-Disclosure Agreements (NDAs) I signed early on, I can not reveal the exact details of those studies, only to say that the experiments were done and were successful.
  • I revealed early on, in the late 2012 that there were military hospitals in China who have gotten growth plate transplantations to be successful. Where did they get the growth plate in the first place is still suspicious though.
  • I wrote about the fact that even plastic surgeons in Russia, like Dr. Teplyashin have gotten the scaffold technique to be successful but this controversial technique is probably only offered to Russian millionaires in secret for maybe $200 K a pop. They got it to work out in sheep, but that doesn’t mean they have ever performed the same surgery on humans.

The truth is that we are getting quite close, with the best option being people like Ballock. If he is willing to write up his results from his work for the last 3 years, and take those results and form a company around it to develop growth plates grown out of scratch (ie 3D Printed) or based on the traditional tissue engineering method using scaffolds and growth factors, he would have something working in 10-15 years. Of course I could be way too optimistic.

To answer the original question, I would make a very tentative guess based on the idea of Kurzweil’s Law of Exponential Growth, if someone like Ballock is willing to form a company around his discoveries and try to bring it to public, we would have a limb lengthening alternative based on 3D Bioprinting, Stem Cells and Scaffolds, and tissue Engineering within 10-15 years with enough funding. When it comes to funding, I would say that biomedical engineers and researchers would need maybe at least $100-$300 Mil to get this procedure out to public. So who is willing to fund this type of project?