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Enthesis LSJL May 21st, 2015 Update #1

Here’s the things that I’ve been keeping in mind while performing LSJL loading.  First, is that bone adapation itself can not make you taller.  Bone adapts to the stimulus provided to it but not always in the way you want.  If you stretch the bone it won’t get longer but rather stronger and more resistant to stretching(unless you stretch it with enough force as to get into the plastic deformation range).

Since the loads to cause plastic deformation would be extreme and difficult to apply properly the goal is to affect other types of stimulus within the bone to encourage longitudinal bone growth like the stem cells, attached ligament enthesis’, the periosteum, and other surrounding soft tissue.

The previous method of LSJL involved clamping the synovial joint region whereas enthesis LSJL involves clamping two bones against each other.  The enthesis attaches into the bone so it would be a potential region where a new growth plate could form.  The enthesis structurally resembles the zone of ranvier where stem cells reside to provide for the growth plate.

This was the regime I was using.

I noticed that I was getting better results with my arms than my legs as my wingspan had increased from 72.5″ to 74.5″.  The arm method I use with the enthesis method is the same as the standard LSJL method but the leg method is different.  The structure of all the joints is different so the loads are applied differently.  In the LSJL studies, the scientists found that the amount of bone deformation induced by LSJL was actually very small and they theorized that the results(including partially longitudinal bone growth) due to lateral knee loading could be due to the creation of a pressure gradient.  As fluid flows more easily from a lateral direction than an axial one.  However, it’s also possible that the LSJL results were due to the loading of bone against each other(which are attached by ligaments).  The screw that was used to load the rats knee and ankle was huge relative to the size of the knee and ankle so the screw would’ve easily been loading the bones against each other.  This is in contrast to our method where the clamps are small relative to the knee and ankle.

With this new enthesis LSJL method I have not been getting definitive results on my arms and legs.  However, it was a significant amount of time before I noticed that my arms grew longer by about 1 inch each.  With the old method I loaded my arms by about a count of 500(with instances of stopping) with a clamp every other day.  Now I do it for about 30-40 counts several times a day.

It’s possible that the sustained session was more effective than the intermittent sessions.  I don’t think mechanosensitivity is a big issue.  Mechanosensitivity is the decreased response of a tissue to load. We know that increased longitudinal bone growth is not going to come from bone directly.  All cells have mechanosensitivity but not to the degree that osteocytes seem to have in bone.  Osteocytes are more mature cells than stem cells and chondrocytic like cells so they would likely be less prone to adaptation.

So, I don’t think that cycling off of loading would be an issue for enthesis loading.  And you probably need a minimum amount of time for it to be effective.

So I’m going to try to sustain the load on the sites for longer.  I know for sure that I gained about an inch of arm length it’s just a matter of reproducing it.

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3D Printing New Functional Epiphyseal Growth Plates Cartilage – Major Updates

I have not written a major post in maybe 4 months and the reasons are personal. However, what I will write will be major updates to our research.

In the last month, I was able to get new information on where the cutting edge of printing is actually at.

Here is what I have found. When I attended a 3D Printing Expo last year, I talked to multiple companies and all of them said that the their current 3D Printings can NOT be used to print human tissue. Almost all the printers could only handle ABS or PLA.

There was only maybe 1 or 2 hints that some company was out there making human tissue that can be implanted back in the body, and work en vivo. The main company that was mentioned was Organovo. I have been aware of Organovo for a while now.

The stories you hear about the biomedical team in Wake Forest University who printed out the ears show that the academic researchers are still being very cautious. However, I think we know that there is a much bigger potential here.

I recently came across this company based in China called Qingdao Unique Group, website www.sinounic.com who have one type of 3D Printer which has been purposely designed to print human tissue, layer by layer.

Now, they have purposely have said that their current model is to print out the tough, non-living organic scaffold, with injectors which add cells into the porous scaffold structure, which eventually overtakes the non-living scaffold. However, I can see that it has much more possibilites.

I managed to get a quote on one model that they are selling which is for $60,000 for one unit. I am not sure if that includes also the modifications that I asked for.

They will be attending this conference in Boston at the Wyndam, Beacon Hill from Jul 8-9 called the Organ-On-A-Chip World Conference & 3D Printing held by SelectBio. I plan to attend that conference and see just how far the various groups of biomedical researches in the universities around the world have actually gotten. The cost for a non-student from industry is about $1,300 just for a ticket but for a student it is only $300.

I am hoping that Dr. Robert T. Ballock, Jean Welter of Case Western University, and Warren Grayson at Johns Hopkins are able to attend something like this.

From a completely technical perspective, 3D Printing cartilage and bone is probably the easiest of all of the human tissues to print out and get correct. The application of Bio-printers to create functional growth plates just seems so obvious and easy.

 

Found a good paper about mechanical factors on longitudinal bone growth

I recommend reading this because it is more informal than typical scientific papers and has some good insights.

The mechanical factors which influence bone growth

“the uptake of dye ‘madder’ by bone [is] only deposited where osteoblast activity was present”

“the shaft of the bone actually expanded, so that the bone cells grew apart as interstitial bone formed. ”

” in a deformed bone the internal structure was radically altered as a response to the static forces working on it. A normal bone will alter to meet a change in its function{But that doesn’t mean that the change will be what you want.  The body will adapt to you playing basketball but not the desired effect of growing taller}.  If such change in mechanical environment is rectified, the bone will resume its former shape and structure.”

” the assumption of the right posture will be associated with a change of cranial length as the centre of gravity of the cranium is required to rest over the feet.”<-So the predominant poster that a child uses will affect his cranium length.

“The hydroxy-apatite crystals are the pressure absorbing component of bone. The collagen fibres give the bone its tensile strength and elasticity. Compression and elongation give rise to electrical charges at the boundaries of the crystals and seem to produce appositional growth and reabsorption by triggering off the chemical processes leading to the formation of the metabolites which control these processes. Bone thus responds in its structure to the different forces such as compression, tension and torsion. The torsional strength of bone is about a third of its compressive strength, so it is not surprising to find that the tibia and humerus have a spiral arrangement of collagen fibres to protect them from the torsional forces to which they are particularly subjected. The bones of infants have a much lower modulus of elasticity than those of children, as though walking only becomes possible once the bone has stiffened.”<-So if one method to grow taller involves decreasing bone age then it might suggest that the bone age has decreased via weaker bone.

” the individual apatite crystals rather than the long glass rods enable the cracks, which always develop before a material fails under stress, to remain isolated rather than spreading rapidly as they do in fibreglass. Thus any lack or excess of muscle pull or body weight will have a significant effect on bone growth.”

“Sustained pressure on the growth plates of the distal femur and proximal tibia may compress the anterior portion and distract the posterior portion of the upper tibial growth plate”

” a simple piezo-electric effect on the apatite bone crystals [responds] to unusual pressure just as a crystal gramophone needle does. The effect is to stimulate growth on the side compressed by body weight until spontaneous correction occurs.”

“The medial femoral condyle tends to force the upper tibial epiphysis laterally so that the cells which bud off from the epiphysis, on which all longitudinal growth depends, will not only be excessively compressed but also subject to lateral sheer. The result may be a cessation of growth in the area where the abnormal stress is greatest. As the lateral half of the growth plate continues to grow, the result is a steadily increasing deformity and all the changes characteristic of tibia vara develop. The medial portion of the growth plate will become grossly abnormal and the histology shows not the normal beautifully ordered vertical columns of cells but total disorganization. I personally believe that this has a purpose, because the tongue of disordered cartilage and bone which is readily palpable, acts as a claw and, rather like a climber’s hands, holds the epiphysis in place and prevents any further lateral shift.”<-So would it be possible to avoid this and get a longer femur?

Here’s another good more traditional technical paper that’s related but still possible for a layman to understand:

The Developing Bone: Slave or Master of Its Cells and Molecules?

“A large number of molecular, cellular, and epidemiologic factors have been implicated in the regulation of bone development. A major unsolved problem is how to integrate these disparate findings into a concept that explains the development of bone as an organ. Often events on the organ level are simply presented as the cumulative effect of all factors that individually are known to influence bone development. In such a cumulative model it must be assumed that each bone cell carries the construction plan of the entire skeletal anatomy in its genes. This scenario is implausible, because it would require an astronomical amount of positional information. We therefore propose a functional model of bone development, which is based on Frost’s mechanostat theory. In this model the genome only provides positional information for the basic outline of the skeleton as a cartilaginous template. Thereafter, bone cell action is coordinated by the mechanical requirements of the bone. When mechanical challenges exceed an acceptable level (the mechanostat set point), bone tissue is added at the location where it is mechanically necessary. The main mechanical challenges during growth result from increases in bone length and in muscle force. Hormones, nutrition, and environmental factors exert an effect on bone either directly by modifying the mechanostat system or indirectly by influencing longitudinal bone growth or muscle force. Predictions based on this model are in accordance with observations on prenatal, early postnatal, and pubertal bone development. We propose that future studies on bone development should address topics that can be derived from the mechanostat model.”

“the desired effect of bone homeostasis is to keep the mechanically induced deformation of bone (in biomechanical terminology called “strain”) close to a preset level, or set point. The deformation of a bone is a surrogate measure of its strength, because a strong bone will deform less than a weak bone when a mechanical challenge is applied. Bone deformation generates canalicular fluid flow”<-A bone’s goal is to aid strength and not length.  So we have to increase bone length in other ways at the stem cell level.

“Longitudinal growth increases lever arms and bending moments and therefore leads to greater bone deformation. Greater muscle force will also increase bone deformation during muscle contraction. Body weight alone puts relatively small loads on bones, but the effect of weight is amplified by muscle action”

More info about the enthesis

Since the new proposed LSJL modality, involves loading sites where bones attach to each other specifically at the enthesis, due to the similarity of the enthesis of the zone of ranvier which is where the pool of stem cells resides to help formulate the growth plate.

Here’s some images and quotations from the orthopaedics blog:

Note although this article mainly refers to tendon enthesis, a majority of the info should apply to ligament enthesis(which tend to be attached closer to the regions near where the growth plate used to be).

tendon enthesis

This next image shows in much more detail into how the enthesis really integrates into the bone and how enthesis stem cells could be stimulated to form a mini growth plate.  Bone erosion could occur allowing this growth plate to extend across the bone.  In fact, in arthritis which is associated with thickening of the enthesis’ bone erosion does occur.:

detailed view tendo enthesis
Note how the mineralized fibrocartilage integrates into the bone.  The thickening of the enthesis and the erosion of bone in some forms of arthritis, I could only find citations of it occuring in tendons and have not found instances of it resulting in increased length.  But that is likely a result of tendons being more subject to mechanical loading and this new method of LSJL being a novel way to mechanical load the ligaments.  Also ligaments in contrast to tendons are in a better position to contribute to longitudinal bone growth.  In fact, most of the studies I could find on mechanical loading on ligaments referred to loading on the ligament cells themselves rather than loading of the ligaments in the body.

Ligament injuries tend to occur due to heavy impact or overstretching of the ligament.  Pressing of the bones against each other is not a common way of ligament injury indicating that this method of LSJL loading is in fact a novel way of loading the ligaments.

“There is physiological thickening of the fibrocartilage with stress.”<-This tends to happen more with tendons as they are attached to muscle but with LSJL we can encourage it to happen at the ligament fibrocartilage.

” there are other components adjacent to the enthesis proper which also share the stress forces and are termed the “Enthesis organ”. These include the Periosteal fibrocartilage, the Sesamoid fibrocartilage, the Fat pad and Bursa. The Synovial entheseal complex is a concept that the adjacent bursa or joint lining share stress forces, especially compressive forces and are an integral part of the enthesis organ”<-These will be different for the ligament.

Here’s some info from another site that could be pertinent:

Bone Erosion at Normal Insertions

“Bone erosion is a process whereby the surface of a bone (the bone cortex) is degraded or eroded and is most typically seen in the setting of inflammation. However, the normal skeleton appears to be riddled with microscopic erosions. The enthesis is a highly mechanically stressed site which leads to microtrauma to the immediately adjacent bone. This is the basis for small erosions in the normal non-diseased skeleton which likely repair spontaneously.”<-Can we cause sufficient bone erosion as to allow for a new growth plate?

“The early phases of erosion may start to damage or loss of the shock absorbing fibrocartilage that covers the bone. “<-We don’t want this however as this would be the foundation of the neo growth plate.

“Normal small joints tend to develop microscopic erosions at sites where the ligament immediately adjacent to the enthesis compresses the bone. This is because the shape of the bone leads to the forces being spread over a wide area that contributes to damage. This occurs at a structure termed a synovio-entheseal complex.”

synovio epiphysis complex

“The black arrows show a microscopic erosion over a knuckle joint. The overlying ligament is shown. The yellow arrow shows the point of ligament attachment closest to the joint cavity. Small blood vessels in the base of the erosion are likely linked to attempted repair. ”

“Sometimes the bone compression by the enthesis organ transmits stresses to the underlying bone and this initially manifests as a small cyst. Later on the roof of this may cave in leading to erosion. ”

bone cyst enthesis

“This is an X-ray (A) and a corresponding tissue section (B). It shows a small bone cyst (BC). This is underneath the cartilage lining the side of the bone. (black arrow). Damage occurs here because the ligament (CL) presses against the bone as it runs between the joints. “<-We’d need more information about the bone cyst to see how promising it is in terms of neo growth plate formation.

LIPUS can affect face size

There have been conflicting reports on LIPUS for height but ultrasound has been shown to increase condylar growth in rats before.

Effect of nonviral plasmid delivered basic fibroblast growth factor and low intensity pulsed ultrasound on mandibular condylar growth: a preliminary study.

“Basic fibroblast growth factor (bFGF) is an important regulator of tissue growth. Previous studies have shown that low intensity pulsed ultrasound (LIPUS) stimulates bone growth. The objective of this study was to evaluate the possible synergetic effect of LIPUS and local injection of nonviral bFGF plasmid DNA (pDNA) on mandibular growth in rats.
Groups were control, blank pDNA, bFGF pDNA, LIPUS, and bFGF pDNA + LIPUS. Treatments were performed for 28 days. Significant increase was observed in mandibular height and condylar length in LIPUS groups{it is reasonable to assume that this increase can be extended to other long bones to which LIPUS was applied}. MicroCT analysis showed significant increase in bone volume fraction in bFGF pDNA + LIPUS group. Histomorphometric analysis showed increased cell count and condylar proliferative and hypertrophic layers widths in bFGF pDNA group.Current study showed increased mandibular condylar growth in either bFGF pDNA or LIPUS groups compared to the combined group that showed only increased bone volume fraction.”

“Growth factors like vascular endothelial growth factor (VEGF) and bFGF play an important role in the process of new blood vessel formation”

“blocking of bFGF leads to the prevention of bone formation at the craniofacial suture sites”

The condylar length and ramal height was about 1.5mm longer in the LIPUS group versus the control group.

LIPUS seemed to increase cell size in the growth plate for the hypertrophic zone while also increasing the number of cells in the proliferative zone(by increasing chondrocyte proliferation or causing resting zone stem cells to differentiate into chondrocytes?).

Although the one study “Application of low-intensity ultrasound to growing bone in rats.”, did not find that LIPUS increased longitudinal bone growth it’s possible that there methodology was not correct for inducing longitudinal bone growth.

The mandibular growth in this study indicates that LIPUS may have promise yet for being a part of increasing longitudinal bone growth at least for active growth plates.

Can eating oysters while actively growing increase height?

This study suggests that this may be the case.

Taurine, a major amino acid of oyster, enhances linear bone growth in a mouse model of protein malnutrition.

“we evaluated the effects of Oys or Tau on linear bone growth in a mouse model of protein malnutrition{So there’s no guarantee that it will increase height in those who are not malnourished}. To make the protein malnutrition in a mouse, we used a low protein diet. Growth plate thickness was increased by Oys or Tau. Bone volume/tissue volume, trabecular thickness, trabecular number, connection density, and total porosity were also improved by Oys or Tau. Oys or Tau increased insulin-like growth factor-1 (IGF-1) levels in serum, liver, and tibia-growth plate. Phosphorylations of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) were increased by Oys and by Tau.  Oys or Tau may increase growth plate thickness by elevating IGF-1 levels and by promoting the phosphorylations of JAK2-STAT5, and suggest that Oys or Tau are growth-promoting substances of potential use in the food and pharmaceutical industries.”

“When a child is undernourished, circulating IGF-1, and thyroid hormone levels decline and in adolescents, undernutrition causes reductions in sex steroids, and these endocrine changes suppress bone growth “<-However this does not guarantee that overnutrition will stimulate bone growth.

“GH is required for linear growth, and its actions are initiated by its binding to GH receptor (GHR) on cell surfaces. This binding induces receptor homodimerization and activation of GHR-associated tyrosine kinase Janus kinase 2 (JAK2). JAK2 is then phosphorylated and, in turn, phosphorylates GHR and signal transducers and activators of transcription (STAT). Upon phosphorylation, STAT undergoes homo or heterodimerization, translocates to the nucleus, binds to appropriate DNA response elements, and stimulate the transcriptions of GH-regulated genes. IGF-1 is one such gene and acts as a mitogenic factor for various cells and plays an important role in cell growth and survival. The majority of plasma IGF-1 is biosynthesized in liver”

Unfortunately there was no group in this study that had adequate protein and had additional taurine supplementation.

“the mRNA expression of IGF-1 was dose-dependently increased. The effects of 100 µg/mL of Oys and 50 µg/mL of Tau were greatest, and thus, we evaluated the effects of these doses in our in vivo mouse model.”

” Mean lengths of proximal tibial growth plate in the CON and PEM groups were 115.64 ± 3.40 and 84.98 ± 2.70, respectively, whereas growth plate lengths in the Oys and Tau groups were 125.97 ± 8.07 and 123.05 ± 7.52, respectively. Oys or Tau significantly enhanced longitudinal bone growth”

Growth plate thickness was a little bit shorter in the oyster and taurine group versus the control group as were IGF-1 and GH levels.