Anyone who has every considered the idea of possibly going through with the process of limb lengthening surgery to make their body longer aka taller has also asked the question “Will I still look proportional after the surgery?”.

This point was mentioned once again in a comment as a response to the previous post, about the good news of the research Dr. Alsberg has been working on. That news was definitely a game changer.

The obvious concern is that while height and looker taller is important, it is equally important that their body still looks proportional. The feared result after the procedue to make one’s tibia or femur longer is that either the torso, the arms, limbs, or head might look small or short now.

To get a more in depth access to people who ask such questions, visit the forum website www.limblengtheningforum.com 

In response to people who have this type of fear or concern, I would like to refer them to multiple studies that I have accumulated over the last 3 years. The average person on the street who doesn’t think about their height and body proportions as we do (the regulars of this website) probably have not heard of the concept of a person’s “Wingspan”. The wingspan of a person is the length from the tip of one’s left middle finger to the tip of the right middle finger, when the person has fully stretched out their arms.

In many sports, particularly basketball, boxing, and football (quarterback position), the length of one’s arm’s (aka reach) is very important. In athletics, while height is almost always mentioned, the wingspan will also be brought up in these sports.

The generally accepted rule (based on probably Leonardo Da Vinci’s Vetruvium Man sketch) is that the wingspan of a person will be the same as one’s height. The data that has come out from national censuses, collection of data of anthropometric studies done over the decades is that the wingspan of a person is on average slightly longer than the height. In males, the wingspan/height ratio is even more skewed. I can’t find the study at this moment, but the average ratio of wingspan/height is around 1.02/1, for males.

Based on a just an initial hypothesis, it sort of makes sense when one realizes that while the feet and torso is always putting load/weight on the legs, the arms don’t have any load placed on them. While the growth plates in the legs have to push against the force of gravity, the growth plates in the arms are not, at least downwards. This means that the arms are on average, going to grow just slightly more than the legs, without the constraint of gravity pushing down on them.

So my first point is, it is most likely that for the short male who is asking, their wingspan will be longer than their height. An extra 3-5 cm to their vertical length will not cause a big proportionality problem since their width length is already there.

Here is my 2nd argument. People who develop short stature, from some form of real medical condition develop a normal/proportional sized torso and head, but their limbs suffer. Achrondroplasia, which is the most common medical condition causing severe short stature, most often results in a person with a normal body, (with normal sized had and torso) but with exceptionally short limbs. This means that for their condition, it would makes sense just to lengthen the arms and legs, and never touch the skull, neck, spine, or torso area.

Achondroplasia is often caused by an increased level of FGFR3. Studies have shown that inhibiting the effect of FGFR3 removes the effects of achondroplasia. However, it only works by first realizing that one’s unborn child has the condition, and a gene therapist going into the embryo and editing the genetic makeup of the embryo before the baby is ever even born.

The same can be seen with GDF5 (growth-differentiation factor 5) – mice that were bred to not have this gene being expressed develop relatively normal torsos and bodies, but their limbs (arms and legs) were severely shortened. It seems that there are many ways to make a person shorter, and the most common ways to do that is to cause some genetic issue of their limb development.

So if a person is worried about proportionality, they should not be worried about the length or size of their torso.

In fact, in the beginning of this website, I made a theory/hypothesis from watching my own body, and the Olympic Swimmer Michael Phelps body. People who are big eaters when they are young, who develop to be taller than average, seem to have their height disproportionately in their torso. Thus the torso length/leg length ratio is larger. The next time you see an adult male who is both tall and obese, look to see whether their torso/body seem to be particularly long. More likely than not.

My point here is that, to increase the length of one’s torso, it seems to be possible by being a big eater when one was younger, before they stopped growing.

This is true with people like Yao Ming. In pictures of Yao Ming sitting down with other NBA Players which I analyzed years ago, it seems that Yao seems to get his great height from his torso. When he was sitting down, he would still tower over other professional basketball players, but when you look at his legs, he has similar leg length as the others. Compare this to someone like Wilt Chamberlain, who got his great height mainly from his long legs, specifically the femur.

However, I realize that I never really answered the original question, the title of this post. – “Can We Find A Way To Make People Taller And Also Keep Their Body And Limbs Proportional?”

My 1st Point – On average, for men, their wingspan is actually longer than their height. If they go through with surgery, they should not need to worry about the disproportionality of their arms to their new longer legs.

My 2nd Point – I theorized from a few examples of people’s bodies that one can increase the length of one’s torso, at least when one is still growing, by eating more, (meat, grains, vegetables, dairy). After one stops growing, obviously it won’t be possible.

My 3rd point – Most people are not as height and proportion obsessed as us. They either don’t care or will never notice. After the leg lengthening, one may look at the mirror and focus only on the shortness of one’s arms or body, but most people will not even notice a difference.

Real Answer: In theory, anything is possible. Maybe one day in the far future, we will be able to make people not just taller, but also get the other organs and structures in the body to grow with the leg bones. However, in my educated opinion, after looking at this problem over and over again for over 3 years, there is only 2 ways that I can see. Technically, the 2 techniques that I propose are in essence the exact same physiological process. The difference is whether one chooses a very hard problem to solve, or an insanely hard problem to solve.

Technique #1: To be able to make the entire body to grow again, scientists will have to find the solution to reverse aging of the human body itself, to the extreme case of Benjamin Button. This would most likely require that the human body be placed in a chamber with amniotic fluid, which is a similar function to acid in Ph to soften/rubberize the bones to remove the Base-like (Ph-wise) hydroxyapatite crystals which makes bone hard. The fluid the body is in seeps into the human body, and converts the bones back into cartilage or cartilagenuous type tissue.

This technique would involve probably decades (if not centuries) of research in learning how to not just stop aging, but also to reverse aging, to actually turn a 60 year old women with skin full of wrinkles. to a 16 year old girl with supple, wrinkle free skin. Scientists would need to study how telomeres work, how the junk microRNAs work, which of the thousands of the genes in our chromosomes control the role of height, how to use the CRISPR-Cas9 technique, gene editing, gene therapy, how to increase the Hayflick Limit, how to stop oxidation chemical reactions from causing free radical buildup in the cells, particularly around the mitochondria area. To give a reference of what this would be like, we would have to reach the technological level of the Kryptonians from the Superman story. A true galactic master race/species who have already conquered inter-space travel. To have this type of technology, we would need to be a much, MUCH more technological advanced species to build this type of technology.

This proposal, I am not holding my breathe for, at least in my lifetime. It is way too science fiction for me.

Technique #2: Scientists figure out how to get transdifferentiation to work out – changing bone tissue to cartilage tissue. Eben Alsberg has proposed this idea, which would suggest that if he is successful, and other researchers pursue his ideas further, maybe in 50 years, they would figure out how to get the bones to turn into cartilage with a series of simple needle injections of various material (growth factors, chondromodulin, TGF-Beta, GDF5, chondrocyte seeds, pathway signalling proteins, MSCs) in the local area of where the growth plate once was, the bone area will magically turn into a “new growth plate”. This would basically be “reopening the growth plate”. If it is successful in one area of the body, the same series of needle injections will be injected in the 20-30 other areas of the adult skeleton where there once was epiphyseal hyaline cartilage tissue to work with.

This idea, it seems more viable, but I don’t see anything like this coming about at least for another 50-70 years down the line, and that is being super optimistic and making a guess at the exponential rate of technological growth based on Kurzweil’s Law of Exponential Growth.

This is going to be one of those posts which will definitely change the direction and content of this website. It is game changing, since it shows that we are getting much, much closer than before. Much closer than I expected, which is a shock to me. I am just amazed at just how close we just might be. Its seems like all the technical difficulties in theory has almost all been removed. Now, I feel like all that is standing in our way is funding, to get this laboratory success to be taken into the public/real world and applied.

Just 10 minutes ago I found out that one of the primary researchers I have been tracking, Professor Eben Alsberg, has been working on the exact, the EXACT same type of research that I have been proposing we should be working on.

Not only that, I barely missed meeting Dr. Alsberg. Apparently he was one of the speakers that was attending the 2015 World Termis Conference on Regenerative Medicine in Boston back in August. I was in Boston at the exact same time, at the sister conference of Termis, the Organ-On-A-Chip one. Apparently the Termis Conference was going on at the exact same days (off by 1 day) and around the exact same Boston area. Alsberg was in attendence maybe just 1000 feet away from me. Many of the people who went to the conference I went to, like the company representatives of Cellink (from Sweden), were going to the Termis Conference as well. At the time, I thought that it would only be Dr Atala of Wake Forest who would be there, and no one really close to doing the type of research I was hoping for. Well, I was wrong, extremely wrong.

Originally, I found out about Dr. Alsberg from a reader of the website who sent me a link to Alsberg’s paper on creating the first evidence of functional growth plates. Well, it turns out that for more than a decade (maybe 14 years after) after that 2001 paper came out, Alsberg and his team of researchers based in Case Western University has been fine-tuning the cartilage regeneration technique.

I would like the readers to refer to 6 sources I would like to use to validate my idea that Alsberg, like maybe 4-5 main other researchers, is working on something really close to our holy grail. I thought that no one was attacking the problem that we wanted to be solved. I was wrong again.

Alsberg is trying to regeneration the growth plate, and not just in 1 single approach. He is trying ideas which I thought was pure science fiction, the type you see in comic books.

Tyler and I have both agreed that the only way one could possibly “reopen” the growth plates is if a tissue engineering type biomedical engineer could solve the problem of converting bone tissue to cartilage tissue, which is basically one of many types of cell-to-cell transformation, known by the scientific term Transdifferentiation.{Tyler-also you could create miniature breaks in the bone and induce stem cell differentiation into cartilage;  but some growth plate cells may transdifferentiate into osteoblasts and may maintain the growth plate cartilage genetic material so by converting them back to chondrocytes may be a way to create new growth plates; however, bone still places a constraint on growth so you have to find a way to weaken or break it some how}

I have said at least twice that I don’t think it was possible to figure out transdifferentiation of bone tissue into cartilage tissue, at least this century. Even for the possibility that it would ever be possible, I was pessimistic. Well, it seems that Alsberg is trying to do just that. Since he has been working on this problem far longer and more in depth than me, he would be more aware of the exact technical details in getting this type of cell transformation to work out. If he is still trying to do it, it means that he honestly believes that it is possible. Given what I already know of Alsberg, I put my faith in his ability.

Now I refer to the reader who is somewhat knowledgeable on basic biology to read over the sources I provided below.

From the sources, I have been able to make multiple conclusion, all of them extremely positive, for our endeavor.

1. Alsberg is researching how to convert bone to cartilage. If he succeeds, which he believes is just a cell spatial-gradient and signaling issue, then we can create cartilage in the middle of bone tissue. This is a non-invasive way of growing taller!!{Tyler-Note that LSJL involves a pressure gradient and affects cell signaling}

2. Alsberg is researching how to implant cartilage (lab grown/in-vitro) back into the body.

3. Alsberg is researching how to grow cartilage tissue in the lab to be strong enough to handle the en vivo environment.

4. Alsberg already succeeded in growing growth plates almost 15 years ago, from a paper he wrote in 2001.

5. Alsberg believes that the trick to get the lab-grown osteo-chondrogenic tissue to expand is to get the spatial gradient of the cells inside the ECM to be in a certain orientation. So he already has figured that out.{Tyler-Interesting, maybe we can alter the spatial gradient within the bone via mechanical means}

6. If you look at the papers he has published from source 6 that I provided below, you can see that his research is basically circling around and around the research that is our holy grail. I did not believe that he would actually be doing the exact type of research we are hoping for, but he is. Technically, he never actually wrote that he is trying to grown functional growth plates to be reimplanted back in the body, but the 5 first sources reveal enough. A simple reader would be able to put the pieces together to form the overall picture. Alsberg is trying to to get growth plates to work out.

This type of research I did not expect for another 10 years., at least not someone who is actively tackling the exact problem. I suspect that probably by the year 2020, Alsberg with Ballock will have written a paper discussing the viability and possibility of implanting their lab grown physeal-like tissue into bone defects (from osteonomy) to increase the length of bone for people who are past the stage of bone maturity. If they believe that there is a financial windfall from taking their research into market, (aka a rich saudi prince funds them a 9-figure check to get the stuff from of lab-to public), the world will be changing in a dramatic way.

In another 15 years maybe, if they get the signaling correct, they might come out with a 2nd different way of making bones longer, by using transdifferentiation. If they are successful in doing that, we will have reached out holy grail. Imagine our grandchildren always having a non-invasive technique to make their bones longer. This is right out of a science fiction book.

I promise the readers that I will go into more detail in a 2nd post, going deeper on the science, and also creating a picture of what is possible, if Alsberg with Ballock are successful. From the looks of it, they are going to succeed, and it might not just be them. There seems to be at least another team that I am aware of, which are working on something very similar to them.

It might turn out that within 15-20 years, there will be more than 1 company who are racing towards getting this limb lengthening surgery alternative out into the market for the general public to use. As for the trandifferentiation possibility, that probably won’t come about for another 50 years at least, after I am gone. When that happens, I will be happy that finally the short statured people around the world can finally let out a breathe of relief.

Note: Of course, there is indeed a limit to how much we can length the bones of a person. Making a person who is 5 ft to 6 ft is technically possibly, but the result may be slightly weird. Not only that, what if an already tall person wants to go through with this treatment, turning themselves into 8 feet??

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Refer to source #1 – http://www.news-medical.net/news/20130919/Innovative-system-can-help-manipulate-stem-cells-to-repair-damaged-tissues-and-organs.aspx

Scientists know that physical and biochemical signals can guide cells to make, for example, muscle, blood vessels or bone. But the exact recipes to produce the desired tissues have proved elusive.

Now, researchers at Case Western Reserve University have taken a step toward identifying that mix by developing an easy and versatile way of forming physical and biochemical gradients in three dimensions.

Ultimately, one of their goals is to engineer systems to manipulate stem cells to repair or replace damaged tissues and organs.

“If we can control the spatial presentation of signals, we may be able to have more control over cell behavior and enhance the rate and quality of tissue formation,” said Eben Alsberg, an associate professor of biomedical engineering and orthopaedic surgery at Case Western Reserve and senior author of the research. “Many tissues form during development and healing processes at least in part due to gradients of signals: gradients of growth factors, gradients of physical triggers.”

Alsberg, postdoctoral scholar Oju Jeon and graduate student Daniel S. Alt of Case Western Reserve, and Stephen W. Linderman, a visiting undergraduate on a National Science Foundation Research Experience for Undergraduates summer fellowship, tested their system on mesenchymal stem cells, turning them toward bone or cartilage cells. They report their findings in Advanced Materials.

Regulating the presentation of certain signals in three-dimensional space may be a key to engineering complex tissues, such as repairing osteochondral defects, damaged cartilage and bone in osteoarthritic joints, Alsberg said.

“There must be a transition from bone to cartilage,” he said, “and that may require control over multiple signals to induce the stem cells to change into the different kinds of cells to form tissues where you need them.”

In their first test, the researchers found that stem cells changed into cartilage or bone cells in the directions of two opposing soluble growth factor gradients: one that promotes cartilage, called TGF-beta 1, and another that promotes bone, called BMP-2{Tyler-Interesting that BMP-2 has been used to promote cartilage in tissue engineering as well}. The stem cells were placed in a solution of modified alginate, a material derived from seaweed that can form a jello-like material called a hydrogel when exposed to low level ultraviolet light.

The solution was divided between two computer-controlled syringe pumps, with BMP-2 in one syringe and TGF-beta 1 in the other. By controlling the rate of injection with the pumps and using a mixing unit, a hydrogel with a BMP-2 gradient starting with a large amount and tapering to nearly none and an opposing TGF-beta 1 gradient from low-to-high was formed.

The hydrogels were further modified in such a way that the growth factors were retained for a longer period of time. This enabled prolonged exposure of stem cells to the growth factors and further control over their differentiation into bone or cartilage cells.

The researchers then modified the hydrogel with a gradient of adhesion ligands, molecular strings that allow the stem cells to attach to the hydrogel itself. After two weeks of culturing the cells, they found the highest number of cells in the hydrogel region where the concentration of ligands was highest.

In a third test, they created a gradient of crosslink density within the hydrogels. Crosslinks provide structure to the gels. The lower the density, the more flexible the hydrogel; the higher, the stiffer the gel.

After two weeks, more cells were found in the most flexible gel regions within the gradient. The flexibility may allow for more free movement of nutrients and removal of waste products, Alsberg explained.

“This is exciting,” Alsberg said. “We can look at this work as a proof of principle. Using this approach, you can use any growth factor or any adhesion ligand that influences cell behavior and study the role of gradient presentation. We can also examine multiple different parameters in one system to investigate the role of these gradients in combination on cell behavior.”

If the technology enables them to unravel recipes that generate complex tissues, the biodegradable hydrogel mix could be implanted or injected at the site of an injury, the researchers say. The recipe would guide cell behavior until new tissue is formed, restoring function.

Refer to Source #2: Environmental cues to guide stem cell fate decision for tissue engineering applications

Abstract: The human body contains a variety of stem cells capable of both repeated self-renewal and production of specialised, differentiated progeny. Critical to the implementation of these cells in tissue engineering strategies is a thorough understanding of which external signals in the stem cell microenvironment provide cues to control their fate decision in terms of proliferation or differentiation into a desired, specific phenotype. These signals must then be incorporated into tissue regeneration approaches for regulated exposure to stem cells. The precise spatial and temporal presentation of factors directing stem cell behaviour is extremely important during embryogenesis, development and natural healing events, and it is possible that this level of control will be vital to the success of many regenerative therapies. This review covers existing tissue engineering approaches to guide the differentiation of three disparate stem cell populations: mesenchymal, neural and endothelial. These progenitor cells will be of central importance in many future connective, neural and vascular tissue regeneration technologies.

Refer to Source #3: http://www.termis.org/wc2015/docs/programWednesday.pdf

Refer to Source #4: New Method Grows Thicker, Stiffer Cartilage

Many research labs are busy working away at developing better tissue engineering techniques to grow replacement parts for aged and damaged human bodies. Here’s a lab at Case Western that has developed a new and promising cartilage growth technique.

A lab discovery is a step toward implantable replacement cartilage, holding promise for knees, shoulders, ears and noses damaged by osteoarthritis, sports injuries and accidents.

Self-assembling sheets of mesenchymal stem cells permeated with tiny beads filled with growth factor formed thicker, stiffer cartilage than previous tissue engineering methods, researchers at Case Western Reserve University have found. A description of the research is published in the Journal of Controlled Release.

“We think that the capacity to drive cartilage formation using the patient’s own stem cells and the potential to use this approach without lengthy culture time prior to implantation makes this technology attractive,” said Eben Alsberg, associate professor in the departments of Biomedical Engineering and Orthopaedic Surgery, and senior author of the paper.

Think of all the people with painful knees, fingers, and other joints because their cartilage has worn down. The ability to fix all these damaged joints would cut pain and increase mobility. Increased mobility would also increase exercise and muscle mass.

Among successful tissue engineering projects so far: functional replacement mouse pituitary glands, replacement urethras for kids, and bladders for adults. The list is going to grow every year and the rate of growth is going to accelerate.

Refer to Source #6: http://www.aptcenter.research.va.gov/pdfs/cvs/Alsberg-Eben-CV.pdf

Biochemical and physical signal gradients in hydrogels to control stem cell behavior.

“Cells continuously receive biochemical and biophysical stimuli from their microenvironment. These environmental stimuli drive cellular behavior and function during development and tissue regeneration.”<-We can alter the microenvironment via mechanical means to alter cellular behavior and ideally create neo-growth plates.

“Cell interactions with the extracellular matrix (ECM) and physical signals such as matrix rigidity and mechanical stimuli can also have strong effects on cellular phenotype and tissue formation.”<-The bone ECM likely has a strong negative regulatory effect on neo-growth plate formation.  But we can alter the bone ECM via mechanical means as well.

“[we prepared] HP-ALG hydrogels with incorporated gradients of heparin binding growth factors BMP-2, a potent osteogenic growth factor, and TGF-β1, a chondrogenic growth factor, in opposite directions. When the concentration of growth factors in segments of gradient HP-ALG hydrogels was quantified, linear gradient distributions of BMP-2 and TGF-β1 in opposite directions were observed”

“As the BMP-2 concentration increased, ALP expression significantly increased along the BMP-2 gradient. In contrast, GAG production of encapsulated hMSCs significantly increased as the TGF-β1 concentration increased”

Regulation of Stem Cell Fate in a Three-Dimensional Micropatterned Dual-Crosslinked Hydrogel System.

“By manipulating micropattern size while keeping the overall ratio of single- to dual-crosslinked hydrogel volume constant, the physical properties of the micropatterned alginate hydrogels are spatially tunable. When human adipose-derived stem cells (hASCs) are photoencapsulated within micropatterned hydrogels, their proliferation rate is a function of micropattern size. Additionally, micropattern size dictates the extent of osteogenic and chondrogenic differentiation of photoencapsulated hASC. The size of 3D micropatterned physical properties in this new hydrogel system introduces a new design parameter for regulating various cellular behaviors, and this dual-crosslinked hydrogel system provides a new platform for studying proliferation and differentiation of stem cells in a spatially controlled manner for tissue engineering and regenerative medicine applications.”

“cell behaviors such as differentiation and proliferation are known to be affected by cell cluster size”

” micropattern size dictated the extent of osteogenic and chondrogenic differentiation of photoencapsulated hASC.”

“the aggrecan expression of hASCs gradually increased as the micropattern size increased”<-But some markers increased at 200 micrometers so the optimal micropattern size should be around 100-200 micrometers.

HEre’s a visualization of micropatterns:

Decellularized tissue and cell-derived extracellular matrices as scaffolds for orthopaedic tissue engineering.

“The reconstruction of musculoskeletal defects is a constant challenge for orthopaedic surgeons. Musculoskeletal injuries such as fractures, chondral lesions, infections and tumor debulking can often lead to large tissue voids requiring reconstruction with tissue grafts. Autografts are currently the gold standard in orthopaedic tissue reconstruction; however, there is a limit to the amount of tissue that can be harvested before compromising the donor site. Tissue engineering strategies using allogeneic or xenogeneic decellularized bone, cartilage, skeletal muscle, tendon and ligament have emerged as promising potential alternative treatment. The extracellular matrix provides a natural scaffold for cell attachment, proliferation and differentiation. Decellularization of in vitro cell-derived matrices can also enable the generation of autologous constructs from tissue specific cells or progenitor cells. Although decellularized bone tissue is widely used clinically in orthopaedic applications, the exciting potential of decellularized cartilage, skeletal muscle, tendon and ligament cell-derived matrices has only recently begun to be explored for ultimate translation to the orthopaedic clinic.“

“ECM is a product of cells that functions to maintain tissue and organ structure, organization and function. It is a complex network of proteins and polysaccharides forming an intricate meshwork within tissue that interacts with the resident cells to regulate cell behavior, such as migration, proliferation and differentiation. The ECM exists in a state of dynamic equilibrium with its resident cells and is constantly being built, reshaped and degraded in response to changing environmental conditions and to cellular, tissue and organ demands”<-So we should try to alter the bone ECM to be more favorable to cartilaginous tissues.

“Fracture healing requires an intricate and well-organized series of cellular and molecular events. It involves interactions between cortical bone, the periosteum, undifferentiated fascial tissue surrounding the fracture and the bone marrow. Fracture healing is divided into three stages: inflammation, repair and remodeling. After an injury, there is initial bleeding from the damaged bone ends and surrounding tissue resulting in the formation of a hematoma, which provides a source of hematopoietic cells capable of secreting growth factors. The invasion of inflammatory cells, fibroblasts, mesenchymal cells, and osteoprogenitor cells at the fracture site forms granulation tissue around the fracture ends{To induce neo-growth plates we have to allow this invasion}. Fractures that are anatomically aligned with absolute stability, such as those surgically repaired with compression plates, undergo primary bone healing or Haversian remodeling, in which there is direct osteonal healing within the cortex by intramembranous ossification”

” in closed reduced fractures, secondary bone healing occurs with the formation of a bridging soft callus consisting of cartilage tissue connecting the fracture ends. Over time, bone formation occurs under the periosteum and calcification of cartilage results in the formation of hard callus or woven bone by endochondral ossification”

“injuries that penetrate the subchondral bone often result in the formation of fibrocartilage which is biomechanically insufficient compared to hyaline cartilage, resulting in further damage over time”

“the peak force transmitted through the Achilles tendon while running is 9 kN, which is about 12.5 times the body weight”

A sesamoid is a bone formed within a tendon or muscle while we’re looking for is more interosseous chondroification(the formation of new cartilage tissue within the bone) or probably maybe even first interosseous epithelialification as you might need to transition mesenchymal to epithelial tissues first.

Coincident development of sesamoid bones and clues to their evolution.

“Sesamoid bones form within tendons in regions that wrap around bony prominences. They are common in humans but variable in number. Sesamoid development is mediated epigenetically by local mechanical forces associated with skeletal geometry, posture, and muscular activity. In this article we review the literature on sesamoids and explore the question of genetic control of sesamoid development. Examination of radiographs of 112 people demonstrated that the relatively infrequent appearances of the fabella (in the lateral gastrocnemius tendon of the knee) and os peroneum (in the peroneus longus tendon of the foot) are related within individual. This finding suggests that the tendency to form sesamoids may be linked to intrinsic genetic factors. Evolutionary character analyses suggest that the formation of these sesamoids in humans may be a consequence of phylogeny. These observations indicate that variations of intrinsic factors may interact with extrinsic mechanobiological factors to influence sesamoid development and evolution.”

“As many as 42 sesamoid bones can be found in some individuals. Mechanically, sesamoid bones serve to protect the tendon from damage and, in some cases, increase the efficiency or mechanical advantage of their associated muscle.”

“Most sesamoid bones in humans are 5 to 10 mm in diameter or smaller and are present in 1 to 100% of individuals.”

“Tendon chondrometaplasia[tendon turns into cartilage] and sesamoid bones tend to develop within tendons in areas that experience both tensile strain and hydrostatic compressive mechanical stresses.”<-So tendonous tissue may help form neo growth plates.  Tendon enthesis attach into the bone.  Tendon is capable of undergoing  chondrometaplasia.  So potentially you could form neo growth plates at these tendon entheses.  Originally I thought that ligament enthesis had more potential for neo-growth plate formation but tendon enthesis may have potential too.

” fibrous tendon tissue can form regions of fibrocartilage in areas that wrap around bony prominences (fibrocartilage is a tissue whose phenotype is intermediate between fibrous and cartilaginous tissue, consisting of chondrocytes embedded in aligned bundles of type I collagen)”

“compression loading and treatment with transforming growth factor beta (TGF-β) each resulted in upregulation of aggrecan and biglycan synthesis in fetal bovine tendon, suggesting that one aspect of the response of cells to compressive load is increased TGF-β synthesis which, in turn, stimulates synthesis of extracellular matrix proteoglycans and leads toward fibrocartilage formation. The process of fibrocartilaginous metaplasia in tendons, which is a direct response to an altered mechanical loading environment, appears to represent an intermediate step in the formation of a sesamoid cartilage.”

Sesamoid bones:

Their position won’t help you grow taller but they could if they were in the articular cartilage.  Maybe if tendonous tissue was inserted in the articular cartilage.

“Hox A11, had profound effects on the developing mouse skeleton, including abnormal sesamoid bone development in both the forelimbs and hindlimbs.”

How might we turn tendons(and especially tendenous enthesis) into cartilage tissues.  What if we form a sesamoid bone within the enthesis?

Expression of Bone Morphogenetic Protein-2 in the Chondrogenic and Ossifying Sites of Calcific Tendinopathy and Traumatic Tendon Injury Rat Models

“Ectopic chondrogenesis and ossification were observed in a degenerative collagenase-induced calcific tendinopathy model and to a lesser extent, in a patellar tendon traumatic injury model. We hypothesized that expression of bone morphogenetic protein-2 (BMP-2) contributed to ectopic chondrogenesis and ossification. This study aimed to study the spatial and temporal expression of BMP-2 in our animal models.
Seventy-two rats were used, with 36 rats each subjected to central one-third patellar tendon window injury (C1/3 group) and collagenase-induced tendon injury (CI group), respectively. The contralateral limb served as controls. At week 2, 4 and 12, 12 rats in each group were sacrificed for immunohistochemistry and RT-PCR of BMP-2.
For CI group, weak signal was observed at the tendon matrix at week 2. At week 4, matrix around chondrocyte-like cells was also stained in some samples. In one sample, calcification was observed and the BMP-2 signal was observed both in the calcific matrix and the embedded chondrocyte-like cells. At week 12, the staining was observed mainly in the calcific matrix. Similar result was observed in C1/3 group though the immunopositive staining of BMP-2 was generally weaker. There was significant increase in BMP-2 mRNA compared to that in the contralateral side at week 2 and the level became insignificantly different at week 12 in CI group. No significant increase in BMP-2 mRNA was observed in C1/3 group at all time points.
Ectopic expression of BMP-2 might induce tissue transformation into ectopic bone/cartilage and promoted structural degeneration in calcific tendinopathy.”

“the presence of chondrocyte phenotype and ectopic ossification in a collagenase-induced patellar tendon injury model”

Here’s potential chondrogenic lesions:

 

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.

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.