Beyond Achondroplasia

Growing together with Clara

Accelerating bone formation during limb lengthening

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Currently, we stand in a great moment of drug development for achondroplasia with one drug in clinical trial, that just started phase 3 (Vosoritide) and another one, the TA-46, that maybe will start clinical trial phase 1 soon. And there is still another one, a repurposing drug (Meclizine) with chances of heading to phase 1 studies too.

In the next years there with be one or two medicines available for patients, but nevertheless, limb lengthening (LL) will keep being an approach for patients who wish to increase height and already have closed growth-plates or for those who don´t wish to take a drug treatment.

Limb lengthening process is based on the principle of distraction osteogenesis and until nowadays, it has improved significantly.

Distraction osteogenesis (DO)

“Is a surgical technique widely used in orthopedic surgery for the treatment of various pathological conditions such as leg length discrepancy, bone deformity or bone defects. The basic principle includes performing a transverse bone section before gradually distracting the two bone segments. New bone tissue is generated in the gap between the two segments. Bone regeneration during DO is believed to occur in response to the longitudinal mechanical strain applied to the callus during healing. One of the limitations of this technique is the long period of time required for the newly formed bone tissue to mineralize and consolidate. Various studies have reported that among growth factors, bone morphogenetic proteins (BMPs) may play a central role in the molecular signaling cascade leading to bone renegeration and remodeling in a DO procedure. ” Sailhan FBone lengthening (distraction osteogenesis): a literature review. Osteoporos Int. 2011 Jun

Limb Lengthening

The first case of limb lengthening was performed by Prof. G. A Ilizarov in 1972, in a person with achondroplasia on both legs. The first report on the principals and applications of distraction osteogenesis techniques was by Prof. Codivilla of Italy, in 1905.

 

 

Prof. Ilizarov Image credits – University of Jordan

Image credits: Al-Mohrej OA, Al-Ayedh NK, Al-Awlah AY, Al-Kenani NS. Current view of bone regeneration using mesenchymal stem cells. J Orthop Allied Sci 2016;4:1-4

Distraction osteogenesis is considered the best in vivo tissue engineering techniques as it has the ability to achieve spontaneous formation of de novo native bone without the need for bone grafts.

The Ilizarov device is still in use, but in 2011, appeared an innovative system was approved for the first time by FDA, the PRECICE system, “an intramedullary nail used for limb lengthening of the femur and tibia that utilizes an External Remote Controller (ERC) to non-invasively lengthen the implant. The key to the technology is the magnetic interaction between the PRECICE implant and the PRECICE ERC, a portable, hand-held unit that lengthens the PRECICE implant”. In 2013, the PRECICE 2 was approved and “improves on some of the characteristics of the original version, including allowing for a greater range of lengthening and a new narrower and longer nail that is compatible with more patient anatomies.

PRECICE Intramedullary Limb Lengthening System. (Image credits: Limb Lengthening and Reconstruction)

In 2014, PRECICE 2  system was presented and has improvements on some of the characteristics of the original version, including allowing for a greater range of lengthening and a new narrower and longer nail that is compatible with more patient anatomies.

Here you can read a presentation on application of the PRECICE system.

In the above image, are shown PRECICE 1 (P1) and PRECICE 2 (P2) tibial nails. The larger diameter part of the nail houses the mechanism. In the P1 there are welds at the upper and lower end of the mechanism (arrows). In the P2 there are no welds connecting the different parts of the larger diameter part of the nail.

How to accelerate the bone regeneration?

In the review article by Makhdom, Nayef, Tabrizian, Hamdy,” The potential roles of nanobiomaterials in distraction osteogenesis” Nanomedicine: Nanotechnology, Biology, and Medicine, 2014

“Distraction osteogenesis (DO) technique has been used worldwide to treat many orthopaedic conditions. Although successful, one limitation of this technique is the long time of fixator needs to be left in place until the bone is consolidated. The application of growth factors (GFs) is one promising approach to accelerate bone regeneration during DO. Despite the promising results from the animal data, its use still limited in the clinic. This is secondary to inherit limitations of these GFs. Therefore, a development of delivery systems that allow sustained sequential release is necessary. Nanoparticles and nanocomposites have prevailing properties that can overcome the limitations of the current delivery systems.”

Recently, Jauregui, et al. published a meta-analysis :”Regenerate bone stimulation following limb lengthening” present very relevant points related to Limb Lengthening:

Limb lengthening with external fixation is performed to treat patients with leg length discrepancy or short stature. Although the procedure has a high rate of success, one potential drawback from limb lengthening is the amount of time spent in the fixation device while regenerate bone consolidates”

In this article, the authors also approach different treatment modalities to increase bone regeneration velocity as low intensity pulsed ultrasound (LIPUS) or pulsed electromagnetic fields (PEMF), showing that these techniques have significant effects on regenerate bone growth.

“The LIPUS signal is transmitted through tissue to the bone, where cells translate this mechanical signal to a biochemical response via integrin mechano-receptors. The cells enhance the production of cyclo-oxygenese 2 (COX-2) which in turn stimulates molecules to enhance fracture repair. The aim of this review is to present the state of the art data related to LIPUS effects and mechanism”. Harrison et al., Mode & mechanism of low intensity pulsed ultrasound (LIPUS) in fracture repair, Ultrasonics, Volume 70, August 2016,

It was also proposed the use of pulsed electromagnetic fields (PEMF) and in the following article:  Erping Luo et al. “Pulsed electromagnetic fields promote osteogenesis and osseointegration of porous titanium implants in bone defect repair through a Wnt/β-catenin signaling-associated mechanism”Scientific Reports 6, 2016

Increase of osteoblast proliferation, or bone cells multiplication. Image credits: above article

Several modalities have been investigated to accelerate bone regeneration during DO including the
biophysical, mechanical, and biological methods, but the clinical use of most of these approachs is limited so far.

Future of limb lengthening

There is a finish company called SYNOSTE,  with a new approach in Limb Lengthening.

This new company is doing research on 3rd generation Limb Lengthening system, in order to make a quantum leap in performance and fulfill the newest trends in healthcare driven by Value-Based Healthcare and Personalized Medicine initiatives.

In the early 2000’s, expanding implantable nails using a procedure similar to intramedullary nailing were first used. The expense of these nails was offset by the reduced pain, less scarring, and less interruption to patient’s lives. The first generation nails promised a lot, but had their own set of problems. The second decade of the new millennium has introduced a second generation nail offering a degree of superiority over the fifteen year-old technologies.

The third generation needs to promise more than just an advancement in nail technology, it needs to be a complete package solution, offering a quantifiable improvement in outcomes and a new level of personal experience for both surgeons and patients.

2 Comments

  1. Thank you Ines, great work.

  2. Great informations.
    Thank you

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