Growth Plate Regeneration

This is from the Google Preview of the Book Bone: Fracture Repair and Regeneration.  Specifically the chapter: Prospects of Regeneration of Growth Plates in Mammals written in 1992. 

The author Richard M. Libbin is old.  I believe he is still alive in New York but I couldn't find contact info.  The book was available for $8 so I bought it so I'll have more information from it.

Overall the book doesn't have new revolutionary information but it makes several statements that provide evidence for the possibility of height increase by LSJL or other mechanical means.

One interesting theory he presents is that the osseous bridge formed during growth plate fracture decreases height by decreasing blood flow to the growth plate.  Blood flow has been shown to affect growth plate and height growth via genes like HSP90.

The author mentions a regrowth of the hemiephysis occurring in some instances but "physeal regeneration does not occur innately in the distal humerus of the rat."

"Physeal regeneration [sites may be] formed via chondrocyte reorganization within the junctional cartilage."

"Regions of physeal regrowth were observed in the cartilage which had formed distal to the skeletal transection surfaces, and also within the junctional cartilage proximal to them."

"Proliferation of periosteal cartilage similar in morphology to fracture callus is the starting point for physeal regeneration"

"Regeneration of growth plate cartilage does not occur at forelimb amputation sites of rats [because] while exuberant periosteal chondrogenesis rapidly encloses the hindlimb bone ends within a mass of hyaline cartilage, in the forelimb the equivalent process occurs less frequently and less vigrous, newly formed cartilage rarely extending beyond the plane of amputation.  The failure of rat forelimb growth plate cartilage to regenerate may reflect a deficiency in the chondrogenic potential of its periosteum."

On page 274, he mentions an argument that states that regenerative capacity is never completely lost in higher level vertebrates.  In frogs, which can regenerate as tadpoles but not as full frogs the lack regenerative capacity as adults because cells lose the ability to dedifferentiate.  Maybe this relates to genes such as OCT4, Sox2, Klf4, and Myc.  Once dedifferentiation was induced through trauma, regeneration was achieved.  Maybe LSJL can help induce dedifferentiation.  Dedifferentiation may be a key step before neo-growth plates can be formed.

"In [instances of] regrown junctional cartilage, [that cartilage] now contained extended regions of growth plate cytoarchitechture, suggesting that physeal organization is not restricted to the ends of long bones, but may be provoked to occur at other sites as well."

On page 280, it's mentioned that cartilage formed off the periosteum is very similar to the growth plate in terms of cellular organization.

"Any cartilage or cartilage forming tissue may be able to reform a growth plate."<-MSCs and the periosteum is cartilage forming tissue.  The problem with MSCs is the microenvironment of the adult bone.  The goal with LSJL is induce mesenchymal condensation thus allowing MSCs to become cartilage forming tissue.

"Physeal cartilage may be provoked to form anywhere along the length of the bone"

"growth plate cartilage phenotype may be expressed wherever cartilage is present"

"After complete physeal ablation following division of the limb, it is periosteal cartilage which forms the regenerate, the characteristic ordered arrangement of growth plate chondrocytes appearing within an expanse of nonphyseal, hyaline cartilage as had occurred during the development of bone in fetal and neonatal life."

Mention of voluntary muscle at the skeletal end being important to cartilage regrowth.  This is a place of cutoff so when I get the book, I'll analyze it.

Other Chapters:

Synthesis and Stability during Fracture Repair


"[A lack of blood vessals may not lead] to chondrogenesis because some large, sinusoid-like vessels [was detected] in the cartilage of rat tibial fractures."

"[Some] areas of cartilage, or chondroid bone, are transient, persisting for only a few days, and so the proteoglycans may not mature to their normal levels of sulfation."


Regeneration of the growth plate.

"in 5 different series of experiments reported between 1950 and 1986 regeneration of injured parts of growth plates in long bones of rabbits and pigs could be demonstrated. The 1st series implied partial X-ray injury of growth plates in rabbits aged 3–6 weeks.The 2nd series implied autotransplantation of the head of the fibula in rabbits aged 10–21 days. The 3rd, 4th and 5th series implied transplantation of autologous fat grafts into provoked defects of growth plates in rabbits and pigs. The findings show that regeneration of a growth plate occurs when a part of it is injured in such a manner that a bone bridge is not formed between the epiphysis and the metaphysis. Regeneration of a plate is much faster in relation to the growth in length of the bone in the rabbit than in the pig. The 1st and 2nd series suggest that regeneration takes place by interstitial proliferation of cells from the germinal layer of the uninjured parts of the plate. Signs of partial regeneration of growth plates have been seen in radiographs after operation for partial closure of growth plates in children. "

Interesting that fat tissue was implanted to prevent bone fusion.

IGF-I RELEASING PLGA SCAFFOLDS FOR GROWTH PLATE REGENERATION

"rat bone marrow cells (BMCs) [were seeded] on the top of IGF-I encapsulated PLGA scaffolds, and the results showed an increase in cell multiplication and glycosaminoglycan content. "  They were then implanted into injured growth plates.  Of course, the question is what would be the effect of this implantation in a bone with no active growth plate.

"The practical difficulty in the use of IGF-I is due to its short biological half life. Encapsulation of IGF-I with PLGA protects the bioactivity and stability of IGF-I."

"Stacks of chondrocytes were observed in the case of the native growth plate. In the regenerated growth plate the chondrocytes were not found in the usual stacked manner. Single chondrocytes were distributed in the extra cellular matrix in the regenerated growth plate."<-maybe this is due to lack of some chemicals like BMP-2 or Ihh?