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30 June, 2020

A PIONEERING STUDY IN PATELLAR TENDINOPATHY: TREATMENT WITH BONE MARROW MESENCHYMAL STEM CELLS

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Patellar tendinopathy – pain and degeneration in the patellar tendon – is a frequent injury among athletes: it does not allow them to practice sport regularly. Occasionally the pain can be chronic and does not respond to conservative treatments: especially among elite athletes, their retirement can come ahead of time.

Different models have been proposed to understand its pathophysiology, and hypoxia has recently been seen as key for its evolution. An editorial published in the British Journal of Sport Medicine1 by Dr Tero Järvinen states that “stabilizing the oxygen supply can be decisive in its resolution”. Hypoxia in the injured area can activate neovascularisation mechanisms that perpetuate the pathology by creating a network of blood vessels with a chaotic and non-functional structure. The deleterious neoinnervation accompanying neovascularization has even been proposed as the source of pain2.

Although the most common treatment and the one with the most scientific evidence is a rehabilitation program with a progressive increase of loads, not all patients respond well to this exercise regimen. On the other hand, surgery can improve the symptoms, but it does not regenerate the tendon tissue. Dr Nicola Maffulli, a leading sports orthopaedic surgeon says “I have no doubts that what we are doing now with surgery is fairly gross: we may be removing the pain, but we are producing scar tissue which does not reproduce the original structure of the tendon.” In recent years, a new therapeutic proposal has been presented, which aims at tissue regeneration by means of bone marrow Mesenchymal Stem Cells that are isolated and cultivated under strict and correct standards for clinical application. The effects of its implantation in the tendon, are currently being investigated with animals3.

The doctors Robert Soler and Lluis Orozco, from the Regenerative Tissue Therapy Institute at the Teknon Medical Centre (ITRT), mention that “the expanded mesenchymal stem cells are those that ITRT has used for the regeneration of bone, cartilage and disc tissues4. For that reason, we will study their effects on tendons, since their immunomodulatory and regenerative potential is well established. Other cell lineages with mature cells have no regenerative effect. The use of mesenchymal from other sources, such as fat or Wharton’s jelly, or from other cell types such as embryonic or adult reprogrammed stems (IPS), would require a phase of preclinical and prior clinical research, such as the one we are doing now.” In this regard, Dr Maffulli believes that “mesenchymal stem cell therapy is at the forefront of regenerative medicine: by aiming to restore the normal structure and function of the affected tendon, we return the athletes to their normal capabilities and their sports practice.

As a surgeon, I am always keen to explore new possibilities to prevent athletes to come under my surgical knife: surgery is by no means a panacea and surely not a shortcut.”

Thus, an ongoing pioneering study5 is being carried out by doctors Gil Rodas (head of the medical area at Barça Innovation Hub), Robert Soler and Lluis Orozco (researchers from the Barcelona Institute of Tissue Regenerative Therapy), Nicola Maffulli (from the University of Salerno School of Medicine, and the University of London and Keele University) and Lorenzo Masci (Institute of Sports Exercise and Health London), among others. For the first time, they are evaluating the role and effects of mesenchymal stem cell treatment in patellar tendon injuries with athletes. Two treatments will be compared, the one mentioned with stem cells and the Leukocyte-Poor Platelet-Rich Plasma (LP-PRP), both injected in the tendon defect under sedation and ultrasound control. The research project will allow comparing the analgesic, anti-inflammatory and regenerative effect of mesenchymal stem cells to that of LP-PRP.

The research will be randomized and double-blinded, analysing twenty patients diagnosed with patellar tendinopathy, with clear signs of a rupture in the proximal pole of the patellar tendon, pain symptoms and a functional disability for more than 6 months.

The research has two goals. First, to determine whether there is clinical improvement after treatment by evaluating the patients’ strength with a dynamometry and their pain using two scales, the visual analogue scale (VAS) and the Victorian Institute of Sport Assessment for patellar tendon (VISA-P). The second goal is to determine whether the treatment regenerates the tendon injury. This will be evaluated by using different imaging techniques: ultrasound, Doppler ultrasound, Ultrasound tissue characterization (UTC) and ultrashort echo time magnetic resonance imaging (MRI-UTE). With these last two techniques, tissue regeneration can be quantified by visualizing the structural defects and quantifying the alignment of collagen fibres, which would not be possible with conventional images.

The athletes will be followed up at regular intervals, with the initial evaluation 6 months after treatment. If the patient is from the LP-PRP group and there is no evidence of pain relief or regeneration, they will be offered treatment with expanded mesenchymal cells. All the patients will be assessed after one and two years.

This clinical trial compares the regenerative capacity, the relief of pain and inflammation using mesenchymal stem cells and LP-PRP in athletes with patellar tendinopathy.

 

 

Adrián Castillo

 

REFERENCES

 

  1. Järvinen, T. A. H. Neovascularisation in tendinopathy: from eradication to stabilisation? Br. J. Sports Med. bjsports-2019-100608 (2019) doi:10.1136/bjsports-2019-100608.
  2. Pufe, T., Petersen, W. J., Mentlein, R. & Tillmann, B. N. The role of vasculature and angiogenesis for the pathogenesis of degenerative tendons disease. Scand. J. Med. Sci. Sports 15, 211–222 (2005).
  3. Godwin, E. E., Young, N. J., Dudhia, J., Beamish, I. C. & Smith, R. K. W. Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon. Equine Vet. J. 44, 25–32 (2012).
  4. Soler, R. et al. Final results of a phase I-II trial using ex vivo expanded autologous Mesenchymal Stromal Cells for the treatment of osteoarthritis of the knee confirming safety and suggesting cartilage regeneration. Knee 23, 647–654 (2016).
  5. Rodas, G. et al. Autologous bone marrow expanded mesenchymal stem cells in patellar tendinopathy: protocol for a phase I/II, single-centre, randomized with active control PRP, double-blinded clinical trial. J. Orthop. Surg. Res. 14, 441 (2019).

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