The Future of Bone Regeneration Part Two

As I discussed in my last article, doctors have numerous therapies lined up to help the bone healing process. But the limitations associated with these methods have led scientists to look for new ones. Let’s take a look at some of these promising new therapies.

Bone-tissue engineering

This involves creating a 3D tissue-like scaffold to encourage bone growth, which could be injected or surgically placed onto the fracture. Stem cells would be planted in the scaffold that, theoretically, would trigger cell growth1.

Bone tissue engineers are trying to replicate the extracellular matrix (ECM), a protein network that connects the bone cells together, providing them with structural support and store molecules which trigger cell growth2.

This is still in its infancy as researchers are struggling to work out which material(s) are suited for the job. The long list of sometimes contradictory demands makes finding the right material a challenge.

For example, a scaffold has to be durable enough to not break down during the healing phase, but also easily degradable so it’s removed when the bone is developed. Despite this, researchers are excited about bone tissue engineering, as the tissue wouldn’t be rejected like bones in bone grafts2.

Gene therapy 

Gene therapy transfers genes into the cells at the fracture, to make them express proteins which will begin bone regeneration. The genes are usually transferred by a virus, edited to contain the genes and be non-pathogenic. They already have the tools to transfer therapeutic genes3 as viruses inject DNA into cells for reproduction.

Diagram showing how gene therapy puts the gene into the cell to alter its DNA
A diagram showing how gene therapy puts the gene into the cell to alter its DNA.

This diagram visualises this process. When the virus is injected into the body, it binds to the outside of the cell (its membrane). Once the virus enters the cell, it’s transported by the vesicle to the nucleus that stores the cell’s DNA. The

virus injects the modified DNA which changes the cell’s DNA, beginning the bone regeneration process4.

Using viruses to transfer the genes into the patient’s cells have been popular as they’re really good at injecting DNA into human cells. But the ever-present threat of them mutating back to deadly pathogens has spurred research into non-viral alternatives3.

Whilst there have been some promising results in animal studies, researchers need to work out how these genes will reach the fractured site. They’re also unsure if the treatment is safe5, as early clinical trials showed an increased chance that tumours could develop as a side-effect.

Systemic enhancement therapy

This therapy includes a variety of hormones that encourage bone growth, which are turned into drugs. Parathyroid hormone (PTH) is one such hormone, with two PTHs (PTH 1-34 and PTH 1-84) in clinical use. PTH helps regulate calcium levels in the blood, triggering its release from calcium stores in the kidney and bones6. These hormones also send an initial signal to make growth factors, which are

proteins that triggers bone cell growth. Animal and human trials have shown an increase bone mass and strength7.

This might remind you of growth factor therapy from my last article, which is also based upon growth factors. However, a key difference is that growth factor therapy uses growth factors directly to trigger bone regeneration.

In contrast, PTH just sends signals to the cell which begin the process to create its own growth factors. This distinction makes all the difference. It means growth factors aren’t exposed in the body for a long period of time and won’t break down as they do in growth factor therapy. 

Sclerostin antibody

Sclerostin antibodies are antibodies which – unsurprisingly – bind to a protein called sclerostin. Sclerostin is found on osteocytes – the cells which control bone formation. Sclerostin is the off switch that shuts them down. And the antibodies block this switch without triggering it, preventing osteocytes from being shut down, which encourages bone growth8.

These antibodies, which would be delivered like a drug, are a potential new cure for osteoporosis. This is a crippling disease that weakens the bones, increasing the risk of them breaking. There has been evidence of bone regeneration, with several studies showing an increase in bone density9.

The FDA approved the first antibody treatment last year10, albeit with the caveat of an increased risk of strokes or heart diseases. Despite its effectiveness, there’s clearly a long way to manage these side effects.

Low-level laser therapy (LLLT)

a laser used in LLLT, being applied to the wrist. Credit John Leffmann CC BY 3.0
a laser used in LLLT, being applied to the wrist. Credit John Leffmann CC BY 3.0

LLLT involves shining a laser or LED light onto the damaged area of the body, absorbing the light and promoting the growth of bone repairing cells called osteoblasts11.

It sounds like science fiction, but there’s some evidence suggests it relieves pain for certain conditions, such as back pain and arthritis13. However, there’s no consensus on how effective it truly is, with other scientists finding no evidence that it improved healing outcomes12,14.

But it’s easy to see why researchers are invested in LLLT. The therapy itself is patient-friendly as the treatment doesn’t require surgery or drugs. It’s a completely non-invasive procedure – you don’t even feel heat from the laser. Its impact in repairing not just bone, but many other tissues in the body, gives the therapy almost unlimited potential11.

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Diluksha Prasad Jayawardana is a final year medical student at the University of Colombo, Sri Lanka. He specialises in orthopaedic surgery.

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References

1.Amini AR, Laurencin CT, Nukavarapu SP. Bone tissue engineering: recent advances and challenges. Critical reviews in biomedical engineering. 2012;40(5):363-408.

2. Koons GL, Diba M, Mikos AG. Materials design for bone-tissue engineering. Nature Reviews Materials. (2020): 1-20.

3. Balmayor ER & Griensven M. Gene therapy for bone engineering. Frontiers in bioengineering and biotechnology 3 (2015): 9

4. Gene therapy diagram, originally made by the National Institute of Health, US Department of Health and Human Services.

5. Calori GM, Donati D, Di Bella C, Tagliabue L. Bone morphogenetic proteins and tissue engineering: future directions. Injury. 2009;40 Suppl 3:S67-76.

6. https://www.yourhormones.info/hormones/parathyroid-hormone/

7. Osagie-Clouard L, Sanghani A, Coathup M, Briggs T, Bostrom M, Blunn G. Parathyroid hormone 1-34 and skeletal anabolic action – The use of parathyroid hormone in bone formation. Bone & Joint Research. 2017; 6(1): 14–21.

8. McClung M. Sclerostin antibodies in osteoporosis: latest evidence and therapeutic potential. Therapeutic Advances in Musculoskeletal Disease (2017); 9(10): 263–270. 

9. Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody.  Journal of Bone and Mineral Research. 2011;26(1):19‐26.

10. Mullard A. FDA approves first-in-class osteoporosis drug. Nature Drug Discovery, News in Brief, 2020.

11. https://www.healthline.com/health/cold-laser-therapy#procedure

12. Ciljsen R, Brunner A, Barbero M, Clarys P, Taeymans J. Effects of low-level laser therapy on pain in patients with musculoskeletal disorders: a systematic review and meta-analysis. European journal of physical and rehabilitation medicine, 53(4), 603-613.

13. Babatunde O, Jordan J, Van der Windt D, Hill J, Foster N, Protheroe J.Effective treatment options for musculoskeletal pain in primary care: A systematic overview of current evidence. PLoS One. 2017; 12(6).

14. Huang ZY, Ma J, Chen J, Shen B, Pei FX, Kraus VB. The effectiveness of low-level laser therapy for nonspecific chronic low back pain: a systematic review and meta-analysis. Arthritis Research & Therapy (2015) 17:360

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