In the future it could fulfil the dream of aiding the body’s tissues to regenerate such that they actually regain their original condition after an injury. Even now, a number of blood derivatives, such as PRP or Orthokine, that this relatively young branch of medicine has developed support and accelerate healing after sports injuries. Dr. Jesús Olmo is CEO of the Football Science Institute in Granada, works in London for the Isokinetic Group, and was Director of the Medical Services of Real Madrid from 2013 to 2017. We took the opportunity to ask this friendly and expert colleague a few questions.

Dear Dr. Jesús Olmo, could you please tell us in which cases you prefer PRP and in which cases you use orthokine? 

It is important to know that there is not enough scientific evidence that one blood product outperform the others. According to my clinical experience, I prefer PRP for Knee OA management and Orthokine both for small joints (AC, hands, spine…) OA and for ligament injuries, where I find an important analgesic effect. Anyway, I use both as coadjutants of the first line treatment, which is biomechanics correction through specialized exercise.

Do you have different experience ­between LR-PRP and LP-PRP? Which type of PRP is more efficient?

As said, it is not clear in the scientific literature if one is more efficient than the other. LR-PRP composition is richer in leukocytes and also platelets, inflammatory/catabolic factors such as the sCD40L and MMP-1, anabolic factors such as PDGF and TGF-β, and the anti-catabolic IL-1βRa, so potentially could have a more powerful effect and maybe a better role in improving acute injuries healing if applied on the first hours. But it also has more adverse effects (15 – 20 % in terms of swelling and pain), and even if LR-PRP has shown to work better in pathologies such as epicondylitis, recent evidence seems to deny any clinical difference, so I feel that we still need to find the right indications for both products. 

Do you use some combinations of regenerative effective methods for example PRP and Hyaluronan acid?

I personally use the alternating combination of PRP and Hyaluronan for the management of the knee OA, as they have different effects: PRP elicit a biologic response, while hyaluronan is more related with a mechanical effect of cartilage protection. I´m finding good symptoms control with this combination and a prolongation of the time until a knee replacement is needed, but always if combined with biomechanics correction through specialized exercise as said before.

What are your experience with concentrated Bone marrow aspirate in comparison to vascular associated pluripotent stem cells from the adipose tissue?

I don’t have personal clinical experience with neither BMAC nor adipose-derived stem cells, as I use cultured bone marrow-derived stem cells, but it is impor­tant to highlight that any cell product must not be applied outside the proper legal framework (approved clinical trials or compassionate use in most countries) and there is no significant clinical evidence currently for the justification of the extra cost, morbidity and legal complexity of point-of-care procedures such as the BMAC, MFAT and SVF over blood products. On the other hand, cultured/expanded stem cells seem to offer a significantly higher potential effect on clinical outcomes, tissue healing and reversing of degenerative processes, with some game-changing results, so I think that – within a proper legal framework – bone marrow-derived mesenchymal stem cells can be the best option in top-level athletes, because there is an important difficulty and morbidity for fat tissue harvesting in lean, fit athletes, and also because their high cost is relative to the transcendency of many of these cases.

Biological repair of the musculoskeletal system is one of the main purposes in orthopedics and traumatology. Where do you see the future? Which type of regenerative methods will be the most important in the subject of sportsmedicine?

Regenerative medicine ultimate goals in sportsmedicine are two: Accelerating / Enhancing Acute Injury Healing and Slowing down / Reversing Chronic Pathology. So far, blood products are not clear to achieve these objectives, but provide a very useful clinical relief at mid-term, most in mild/moderate degenerative process. I think that cultured stem cells have the potential to achieve this goals, but we need to find methods that are more simple and practical, affordable, and better defined in terms of dosage, indications and timing. And of course, as associated therapy for the first-line treatment: control of the mechanical etiology of the injuries through biomechanics reconditioning.

PRP Definition Dr. Jesús Olmo „Any blood product with increased platelet (>blood x 2) concentration“

This is based not only on ethical concerns and the risk of development of certain tumors derived from embryonic stem cells, but also on the fact that these cells are not the patient’s own cells. This may cause transplant rejection reactions, and prevent integration of cells derived from embryonic stem cells into the host tissue. Even for so-called induced pluripotent stem cells (iPS cells) clinical applications are missing, not only for the complexity of the procedure, but particularly based on the risk of the development of cancer by these cells.

To better understand the general idea behind the application of stem cells in regenerative medicine, one should realize that, under physiological conditions, maintenance and restoration of organ function is mostly achieved by local cells, including so-called tissue resident stem cells. However, in the event of acute trauma or disease, the sudden demand of new cells during the healing response may exceed the plasticity of the local cell populations. Furthermore, the ability of the tissue resident stem cells to re-enter the cell cycle and to asymme­trically divide is limited: this eventually limits the extent of self-renewal (and, thus, the self-healing power of the body) following major loss of cells in damaged tissue. 

However, there is a further type of stem cells present in the adult body, with the potential to develop (differentiate) into cells of all three embryonic germ layers (ectoderm, mesoderm, endoderm). These cells, which are termed vascular associated pluripotent stem cells (vaPS cells), are located in the walls of small blood vessels. Since blood vessels are the basis for the formation of tissue and organs in a developing body, these vaPS cells are also found in every organ of the adult body. It is currently unknown to which extent these vaPS cells participate in the physiological maintenance and restoration of organ functions. In any case, unlike embryonic stem cells and iPS cells, vaPS cells do not have their own, intrinsic program for the formation of new tissue, but become active in response to specific signals released and transmitted by diseased tissue. Considering this fundamental difference, the vaPS cells have become an attractive option for regenerative therapy purposes without the risk of malignant transformation.

As long as the aforementioned local self-healing power of the body is sufficient to restore physiological body structures and functions in the event of trauma or disease, all treatment efforts should primarily focus on this. A variety of methods, including but not limited to physiotherapy, osteopathy, extracorporeal shock wave therapy (ESWT), laser therapy and the injection of platelet-rich plasma (PRP), can make valuable contributions through stimulation of local regeneration.

However, a patient’s body’s localized self-healing power can eventually exhaust. As a consequence, physiological body structures and functions can no longer be restored by the local stem cell pool. If this happens in the musculoskeletal system, further conservative measures will have a high risk of failure. In essence, one can treat the patient with as much physiotherapy, ESWT, laser or other modalities as desired, and one can inject as much PRP as one wishes and patients request: these interventions will not work, or they only work to a limited extent because the cells that are supposed to effect the repair are simply not there any longer, or cannot adequately react to stimulation. 

This is exactly where the targeted use of the body’s own vaPS cells comes into play, because they can be harvested and isolated from the body’s own adipose tissue. Practically every one of us has a certain amount of body fat, which the orga­nism can spare, and which can be obtained by mini-liposuction on the abdomen, the flanks or the thighs in an outpatient procedure with low risk and without general anesthesia; 100 grams of adipose tissue are sufficient in most instances. Adipose derived regenerative cells (ADRCs) (which contain the va­PS cells]) can then be isolated from the adipose tissue using relatively simple technologies. ADRCs are a mixture of cells including vaPS cells, progenitor cells, cells of the walls of the blood vessels (pericytes, endothelial cells, endothelial precursor cells and fibroblasts) and blood cells. Until a few years ago, it was thought that it was important to isolate the stem cells from the ADRCs in the next step and to multiply them in the laboratory (i.e. in cell culture) before using them thera­peutically, resulting in so-called adipose derived stem cells (ADSCs). However, there is now good evidence that uncultured ADRCs are superior to cultured ADSCs for regeneration of tendons and bone. One of the reasons for this is that uncultured ADRCs contain cell types that can no longer be found in cultured ADSCs. 

The use of fresh, uncultured ADRCs instead of cultured ADSCs has two other important advantages for the patient: (i) as the cells are not cultivated in a laboratory, the possible risk of conta­mination by bacteria and viruses is avoided, and (ii) treatment with uncultured ADRCs is a real point of care procedure. Within a very short time span and in the same surgical setting, the adipose tissue can be obtained by mini-­liposuction and the ADRCs can be injected to the point in the body where they are needed.

As evidenced by a large number of ani­mal studies, treatment of pathologies of the musculoskeletal system with ADRCs is safe (i.e. does not lead to the develop­ment of cancer and other undesirable side effects) and treatment with ADRCs or ADSCs leads to a significant improvement of the structure and function of a damaged organ or tissue. Based on these highly positive results, treatment of human patients specifically with uncultured ADRCs started a few years ago. Both of us have been involved in a feasibility study approved by the U.S. Food and Drug Administration (FDA), that demonstrated for the first time that in patients suffering from symptomatic, partial-thickness rotator cuff tear (sPTRCT) who had not responded to over six weeks of conser­vative management, a single application of ADRCs led to rapid and long-lasting improvement in the clinical situation, with an improvement in the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) total score from 58.7 ± 19.2 (mean ± standard error of the mean) before treatment to 86.1 ± 4.9 at 24 weeks post treatment and 89.4 ± 4.9 one year post treatment (Hurd et al., J Orthop Surg Res 2020;15(1):122). The results of a control group of patients treated with corticosteroid injections (a standard therapy for the condition at hand) were statistically significantly worse than the results of the patients treated with ADRCs (in the control group the mean ASES score was 50.6 ± 6.7 before treatment, 60.8 ± 6.2 at 24 weeks post treatment and 68.4 ± 4.4 one year post treatment). In retrospect, the poor performance of the standard the­rapy (injection of corticosteroid) is not really surprising when it becomes clear that, when the local self-healing power of the body is exhausted, the injection of corticosteroids certainly leads to reduction of inflammation (and thus pain relief) in the affected shoulder, but cannot result in healing. To verify the results of this initial safety and feasibility pilot study in a larger patient popu­lation, a randomized controlled trial on 246 patients suffering from sPTRCT is currently ongoing.

Of note, no special follow-up treatment is necessary after the application of ADRCs. Accordingly, patients can return to routine care immediately after the application of ADRCs.

Summary

In summary, the use of ADRCs in the management of pathologies of the musculoskeletal system (including tendons) seamlessly fits into modern orthopedic treatment concepts. The patients receive treatment with their own body’s self-­healing power, which is just recovered and transferred from one “healthy” site to another site of the body in need for repair. This reflects a natural and intrinsically existing mechanism of the body, to mobilize stem cells from adipose tissue (however, in often not sufficient amounts) and transfer cells for “self-­healing” to damaged organs and tissues in need for repair.

Two carefully selected groups:

• Eccentric loading group (N=34) – control group involved patients with an established diagnosis of mid-portion tendinopathy of the Achilles tendon who underwent eccentric training. Patients performed 3 sets of 15 repetitions with 1 minute of rest between the sets twice a day 7 days per week for 12 weeks.
• Eccentric loading with repetitive low-energy shock-wave therapy (SWT) group (N=34). Patients
  with an established diagnosis of mid-portion tendinopathy of the Achilles tendon underwent an identical eccentric training regimen and, after 4 weeks, SWT.  

Repetitive low-energy shock-wave the­rapy consisted of 3 sessions at weekly intervals. DolorClast® Radial Shock Waves device (Electro Medical Systems, Nyon, Switzerland) was used for shock wave treatment. (2000 impulses with a pressure of 3 bar (equals an energy flux density of 0.1 mJ/mm²)) – 8 pulses per second. Following the principle of clinical focusing, the authors have treated the area of maximal tenderness, beginning at the point of ma­ximum pain level. No local anesthesia was applied.

Outcomes and Results

The VISA-A questionnaire was used to evaluate clinical severity, 6-point Likert scale was used for general assessment, the 11-point numerical rating scale was used for pain assessment. In order to allow time for collagen turnover and remodeling, observer-blinded outcome assessments were performed 16 weeks after baseline assessment. An increase in VISA-A Score has been demonstrated in both groups, from 50 to 73 points in group 1 (eccentric loa­ding) and from 51 to 87 points in group 2 (eccentric loading with shock-wave treatment). A Likert scale of 1 (defined as complete recovery) or 2 points (defined as “much improved’’) was reported in 56 % of patients in group 1 and as much as 82 % of patients in group 2. A pain rating decrease has been demonstrated in both groups, from 7 to 4 points in group 1 and from 7 to 2 points in group 2.

Side effects & Conclusion

The authors reported a zero occurrence of serious complications. All patients who underwent SWT experienced transient reddening of the skin after low-energy SWT but no bruising. There were no device-related complications. Although patients reported an ache in the calf due to eccentric loading, there was no interruption of the eccentric loading training regimen. Throughout the study period, there was no incidence of Achilles tendon rupture. “Eccentric loading alone was significantly less effective when compared with a combination of eccentric loading and repetitive low-energy shock-wave treatment. Combined treatment allows to substantially alleviate pain.”

This study has conclusively proven that combined treatment of eccentric loading and repetitive low-energy shock-wave treatment allows to significantly reduce pain and improve function. Shock wave therapy constitutes a highly valuable addition to eccentric loading as it stimulates soft tissue healing and inhibition of pain receptors. Patients wishing for quick and effective relief of chronic symptoms together with a return to full activity should opt for the combined treatment.

More Studies at EMS Scientific studies library: https://www.ems-dolorclast.com/studies-library

Copyright: Electro Medical Systems, Nyon, Switzerland

Lower back pain was about twice as common as upper back pain; 15.5 % of those questioned said they suffered from chronic back pain [1]. The causes of back pain are manifold. A distinction is drawn between specific and non-specific back pain. In the SK2 guidelines on specific lumbar or back pain, lumbar discogenic pain syndrome is mentioned alongside others as a separate entity in vertebral osteochondrosis, i.e. intervertebral disc-induced back pain [2].

Dehydration of the intervertebral discs

Intervertebral discs consist of a soft, inner gel-like core (nucleus pulposus) and an outer fibrous ring (annulus fibrosus). The ideal combination of a soft core and an outer ring acts as a cushion. In the course of life, however, the core dehydrates, i.e. loses water and “shrinks” (in much the same way as a grape becomes a raisin). The cause is a decline in chondrocytes, which produce chondroitin sulphate and proteoglycans. These molecules have a high water-­binding capacity. The loss of these mole­cules leads to dehydration/drying out of the intervertebral disc, a process which is known as discopathy. The wear-and-tear process is readily visible in an MRI. The modified Pfirrmann grading system is generally used to assess the severity of discopathy. It defines 8 grades of severity [3]. It has been shown in various studies that discopathy is far more common in elite athletes than in non-athletes (75 % as opposed to 31 %) [4]. This seems to be especially the case in sports involving rotation of the upper body (tennis, baseball, golf) and in those that tend to cause hyperlordosis (butterfly and breaststroke in swimming) particularly if trai­ning begins in early childhood and adolescence [4 – 6].

Treatment options

Initial treatment for discogenic back pain, usually associated with reflex muscle tension, involves physiotherapy and pain medication, but may also include shock wave therapy, acupuncture etc. Both anti-inflammatory nutritional supplements (e.g. Omega 3 fatty acids, turmeric, ginger, chilli and Indian frankincense) and special products such as glucosamine, chondroitin and MSN are suitable supporting treatments. Micronutrients, which protect against oxidative stress, enzymes such as papain and bromelain and secondary plant metabolites (flavonoids and carotenoids) can support the healing process. To reduce loading on the intervertebral discs, delordosing back braces such as the Aspen Elite Active + are suitable specifically in the damaged lumbar area. This often results in an improvement in the symptoms. However, should the acute pain become chronic, the question then arises as to what other treatment should then be considered. Various destructive intradiscal procedures, such as intradiscal electrothermal therapy (IDET), nucleoplasty and percutaneous endoscopic laser discectomy, have been attempted. Success with these procedures has been limited in most cases, and there is also the added disadvantage that the destruction ­involves the removal of vital chondrocytes, which tends more to accelerate the wear-and-tear process [7]. It is for this reason that the use of biologics is increasingly being tested in clinical practice to achieve long-term alleviation of the inflammation and some degree of repair of the intervertebral discs. Biomolecular, cell-based and tissue-­engineering strategies are followed, depending on the severity of the intervertebral disc damage [8]. With regard to biomolecular procedures, most of the clinical experience has been with the intradiscal application of platelet-­rich plasma (PRP). Unlike other platelet-rich plasma products, the auto­logous conditioned plasma (ACP) used here has a low concentration of white blood cells (e.g. neutrophil granulocytes), which can hinder the healing process at high concentrations. ACP is a blood concentrate that contains natural concentrations of growth factors and cytokines and which is ­currently widely used in clinical settings for tissue regene­ration and repair. It has the great potential of stimulating the cell proliferation and metabolic activity of intervertebral disc cells. Several studies have shown that an injection of platelet-rich plasma products into degenerated intervertebral discs can restore structural changes and improve matrix integrity. Furthermore, they can restore intervertebral disc height, ini­tiate the healing of annular lacerations and have an anti-inflammatory effect by down-regulating inflammatory factors, thus helping reduce pain and improve bodily function [9, 10]. The platelet-rich plasma pro­duct ACP is collected by separating the patient’s blood in a centrifuge. Venous blood is withdrawn using the special ACP double-syringe system, which allows rapid sterile separation and plasma collection with a 2-3-fold increased platelet concentration within a safe, closed system.

Case report

A 29-year-old recreational athlete (football) complained of back pain. The symptoms showed no signs of improvement despite conservative treatment with physiotherapy and pain medication. The patient complained of load-induced pain of 6 on the numerical rating scale (NRS) of 1–10. MRI was accordingly indicated. This showed grade IV discopathy at L4/5 and 5/S1 on the modified Pfirrmann scale [3]. There was also a high-intensity zone (HIZ) representing a fissure/tear in the posterior annulus at L4/5 (Fig. 1). High-intensity zones are a phenotype that shows as a hyperintense area of the intervertebral disc in a T2-weighted (T2W) MRI and which has been described as a potential ima­ging biomarker for identifying symp­tomatic intervertebral discs [11]. We consequently conducted provocative discography at L4/5 and 5/S1. Puncture of the intervertebral disc was performed in the trajectory/coaxial view. The patient lies in the prone position. The lumbar spine is delordosed with a roll. The entry point for the cannula is then marked. This involves positioning the image converter towards the centre of the intervertebral disc. For this, the base plate and cover plate are placed parallel to each other in the anterior-posterior (ap) beam view. The image converter is then swung to one side by approx. 45°, so that the annulus in the dorsal region is in the Parviz Kambin triangular safe zone (Fig. 2). We use coaxial cannulas size 23G/0.6, 100 mm or 21G/0.8, 120 mm for puncturing. These allow good guidance and their fineness significantly reduces the risk of nerve damage. Antibiotic prophylaxis is performed with Ampicillin 1 g iv 30 minutes before the procedure. The puncture is performed under sterile conditions. The position of the cannula is monitored in the ap beam and lateral beam view. Once the cannula is in the correct position in the centre of the intervertebral disc, contrast agent is applied via an injection pressure monitor to semiquantify the opening pressure. Depen­ding on the pressure, approx. 1 – 1.5 mL contrast agent is applied intradiscally. This results in a further increase in pressure and, with a positive outcome, in typical memory pain, i.e. the pain the patient otherwise also feels during corresponding pain attacks (Fig. 3). The contrast agent should not drain out, i.e. the fibrous ring should be closed so that the ACP also remains within the disc.

This manoeuvre was performed in our case study, thus allowing the intervertebral disc to be identified as the pain generator. The distribution of the contrast agent in the posterior section of the annulus is typical, as that is where the defects are localised (Fig. 3). As the patient had reacted positively to the provocative discography at both L4/5 and L5/S1, the application of ACP in both intervertebral discs was indicated. The puncture was performed for this purpose using the technique described above. Small amounts of contrast agent (0.2 – 0.3 mL) were applied to monitor the position of the cannula, followed by approx. 1.0 – 2.0 mL ACP up to a maximum of 20 PSI, depending on the pressure (Fig. 4). As expected, this provoked pain. Afterwards, the patient had to lie down on his back in the treatment room for approx. one hour to recover and was then able to leave the practice with an accompanying person. During this time, the ACP coagulates and becomes embedded in the intervertebral disc. We performed three injections at intervals of one week. As ACP therapy is an immunomodulatory therapy, improvements do not become manifest until at least six weeks after the start of treatment. Our patient presented three weeks after the last injection and reported a marked reduction in pain by approx. 50 % (NRS 3), with the pain often not occurring until after prolonged loading. He was also able to resume training. Physiotherapy was performed as an adjunct treatment to improve trunk stability.

Conclusion

Previous studies and our own experience show that the intradiscal injection of platelet-rich plasma products such as ACP is safe and feasible for the treatment of patients with back pain due to degene­rative intervertebral discs (discopathy). This treatment seems to be particularly suitable for young and middle-aged adults when the discopathy is still mo­derate (up to grade V on the Pfirrmann scale). It has also been shown that a significant effect does not become manifest until at least 6 – 8 weeks afterwards and that further improvement is possible up to 6 months after the start of treatment.

Literature

[1] Robert Koch Institut. Journal of Health Monitoring | 2017/2 | Gesundheitsverhalten. 2017;
(2):1–120. Available from: https://www.rki.de/DE/Content/Gesundheitsmonitoring/Gesundheitsberichterstattung/GBEDownloadsJ/JoHM_2017_02_Gesundheitsverhalten.pdf?__blob=publicationFile

[2] S. Kroppenstedt, A. Halder. Spezifischer Kreuz­schmerz [Internet]. 2017. Available from: https://www.awmf.org/leitlinien/detail/ll/033-051.html

[3] Griffith JF, Wang YXJ, Antonio GE, Choi KC, Yu A, Ahuja AT, et al. Modified Pfirrmann grading system for lumbar intervertebral disc degeneration. Spine. 2007;32(24).

[4] Hangai M, Kaneoka K, Hinotsu S, Shimizu K, Okubo Y, Miyakawa S, et al. Lumbar intervertebral disk degeneration in athletes. American Journal of Sports Medicine. 2009;37(1):149 – 55.

[5] Ong A, Anderson J, Roche J. A pilot study of the prevalence of lumbar disc degeneration in elite athletes with lower back pain at the Sydney 2000 Olympic Games. British Journal of Sports Medicine. 2003;37(3):263 – 6.

[6] Fiani B, Jarrah R, Wong A, Alamah A, Runnels J. Repetitive Traumatic Discopathy in the Modern-Era Tennis Player. Cureus. 2020;12(8).

[7] Singh K, Ledet E, Carl A. Intradiscal therapy: a review of current treatment modalities. Spine [Internet]. 2005 Sep 1;30(17 Suppl):S20 – 6.

[8] Moriguchi Y, Alimi M, Khair T, Manolarakis G, Berlin C, Bonassar LJ, et al. Biological Treatment Approaches for Degenerative Disk Disease: A Literature Review of in Vivo Animal and Clinical Data. Global Spine Journal. 2016;6(5):497 – 518.

[9] Hirase T, Jack II RA, Sochacki KR, Harris JD, Weiner BK. Systemic Review: Is an Intradiscal Injection of Platelet-Rich Plasma for Lumbar Disc Degeneration Effective? Cureus. 2020;
12(6):6 – 13.

[10] Akeda K, Ohishi K, Masuda K, Bae WC, Takegami N. Intradiscal Injection of Autologous Platelet-Rich Plasma Releasate to Treat Discogenic Low Back Pain : A Preliminary Clinical Trial. 2017;11(3):380–9.

[11] Teraguchi M, Cheung JPY, Karppinen J, Bow C, Hashizume H, Luk KDK, et al. Lumbar high-intensity zones on MRI: imaging biomarkers for severe, prolonged low back pain and sciatica 

Orthopaedics and regenerative medicine

The translation of preclinical results in regenerative research into products that can be used in clinical practice is slow. The reasons range from authorisation issues to ethical discussions about gaps in scientific understanding through to psychosocial issues. Nonetheless, ortho­paedics can be viewed as a pioneer in the clinical application of regenerative medical devices. Orthopaedics and traumatology is a broad field of regenerative medicine with the restoration of musculoskeletal structures, such as the menisci, cartilage, bone and intervertebral discs. Given the high prevalence of injury in athletes,  regenerative medicine is playing an increasingly important role in sports orthopaedics. This includes, on the one hand, tissue engineering, which involves the use of cultured cells of ­various origins on substrates and the addition of growth factors to support tissue regeneration and, on the other, the use of both complex blood deri­vatives (e.g. platelet and cell concentrates with a high proportion of mesenchymal stem cells (MSCs) from bone marrow or adi­pose tissue) and indi­­vi­dual factors such as vesicles or small molecules that intervene in healing and regeneration cascades. The methods have a low adverse effect profile and are often better tolerated than traditional pain and inflammation inhibitors, which furthermore provide only symptomatic relief and do not support any regene­rative potential. In sports medicine in particular, the natural regene­ration potential of the mostly young patients is high and should be researched more intensively.

General strategies in regenerative medicine

In general, regenerative strategies are based on 4 cornerstones:

• cells
• a supporting matrix (biomaterial)
•  

  signals for tissue and cell differentiation

•  

  and environmental factors, such as biomechanical stimuli.

Cells and their source

Cells are the first cornerstone for regene­rative medicine applications. Autologous cell transplants, as in chondrocyte transplantation, are already being used. The evidence for ACT has markedly improved and there are randomised stu­dies confirming by biopsy and MRI the clinical efficacy of the method with restoration of the cartilaginous joint surface in isolated cartilage defects. Long-term studies with a follow-up period of up to 20 years have also confirmed the sustained effect of ACT. In approx. 75 % of cases, the morphology of the joint cartilage is substantially regenerated, which also supports joint longevity and, compared to microfracture, results in improved outcomes, especially beyond the five-year threshold. Just the microfracture-induced bleeding alone results in repair tissue consisting of mixed fibrous tissue and, as recent studies have shown, often in increasing bone formation in the defect, which thins out the cartilage above and ultimately results in failure.

The above impressively demonstrates that repair methods such as microfracture are clinically successful in the short term but are unable to treat cartilage defects in the long term. It is essential, therefore, that cell transplantation be used for large defects in particular, not least because microfracture also negatively affects the outcome of any subsequent cartilage surgery in the long term. Despite these successes with ACT,  the logistics, administration and techno­logy costs are so high that their cost-effectiveness is hard to justify. These criticisms, however, always have to be seen against the background of joint long­evity and the associated improved qua­lity of life and social health economics. Modern approaches are increasingly focusing on stem cells and progenitor cells. Stem cells from bone marrow, umbilical cord blood and adipose tissue have long been used in clinical practice; embryonic stems cells would be another very promising option but for the ethical issues involved. A modern alternative to embryonic stem cells might be induced pluripotent stem cells (iPSC). These are primarily somatic cells that have been reprogrammed to an embryonic stem cell-like state.

Matrices

Matrices are the second cornerstone of regenerative medicine; they are primarily used to provide a support and attach the inserted cells at the defect site. They are thus a scaffold on which new tissue can form. Modern matrices actively emit signals to promote the regeneration process and accordingly provide impulses for regeneration, which can be biological, chemical, or physical. How they emit these signals depends on their design. Modern, smart matrices react to environmental stimuli, whereas more traditional matrices, which are typically absorbable, release their factors as they are absorbed. Matrices consist of a wide variety of natural and synthetic materials and are often copolymers of different components. Natural materials are natural collagens, hyaluronates and fibrin, which are sometimes manufactured recombinantly. Synthetic biomaterials are polylactides and polycaprolactones or combinations of the two. The type of material selected depends on a wide variety of factors, such as porosity, biocompatibility and absorption rate. Modern matrices may also have a micro or nano structure or even be manufactured according to the individual ana­tomy. In this instance, bioprinting allows cells and growth factors to be integrated into the individually manufactured construct. To support the minimally invasive character of modern regenerative approaches overall, increasing use is also being made of matrices made of injectable, self-hardening gels or pastes.

Signals for differentiation

Signals/morphogenetic stimuli that stimulate cells to differentiate into specific tissue are the third cornerstone for regenerative medicine applications. The best known example of this are growth factors such as transforming growth factor beta (TGF-β), which plays an essential role in chondrogenesis. Alongside other stimuli such as transcription factors, trophic factors and small active molecules, the environmental milieu (e.g. hypoxia) can also initiate differentiation processes. A common problem here is that these factors can hardly ever be applied systemically but usually have to be applied locally at the site to be regenerated for days and even weeks. Local application over a prolonged period is the aim of smart scaffolds that are programmed to release such factors. However, to date it is often unclear what factor is required precisely when, in what concentrations it should be applied  and what precise form the kinetics should take.

One pragmatic approach which avoids this problem altogether involves once more MSCs  and other substances harvested from blood such as platelet-rich plasma (PRP). The abundance of individually different trophic factors automatically associated with these pro­ducts saves the user the task of providing the precise concentration/isolating the individual factors. But this also turns a critical eye on blood products such as ACP and PRP. Their clinical efficacy has been demonstrated in both destroyed tissue and degenerative processes such as osteoarthritis. The mixture of anti-­inflammatory, immunomodulatory and regenerative factors can act on the healing cascade and support tissue healing. With chronic pathologies in particular, the introduction of blood components reactivates healing processes through the release of platelet factors and with mesenchymal stem cell-derived microvesicles and can make good a failed attempt at healing that has become chronic.

Mechanical stimuli

Mechanical stimuli are the fourth cornerstone for the success of regenerative methods. They are crucial for the function and development of skeletal structures. The mechanical influence plays an essential role particularly in the initial differentiation phase but also in the later remodelling phase of healing. The use of continuous passive motion devices (CPM) plays an important role in the rehabilitation of cartilage defects. Much movement, little loading is the motto here and ensures optimum cartilage formation post cell transplantation. Another interesting application of mechanical stimuli to promote bone regene­ration is extracorporeal shock wave therapy (ESWT). This is essentially also a regenerative measure to mechani­cally reactivate stalled healing processes using shock waves. The field of mechani­cal stimuli would seem to be a fertile ground for innovative rehabilitation protocols and might come more to the fore in regenerative medicine due to the above mechanisms.

——————————————————————————

SPECIFICS: Blood-derived products in regene­rative orthopaedic sports medicine

The physiological support of blood-derived products for tissue repair and regeneration is attracting attention for many applications in regenerative medi­cine. Platelet-rich plasma (PRP) is one of the best known blood products commonly used as a supplement in in-vitro cell cultures and for therapeutic applications. The quantity of growth factors and cytokines available in the platelet alpha granules in PRP provides all the necessary anabolic factors to maintain proliferation, differentiation and cell phenotypes. Deviations that arise due to different PRP manufacturing protocols are responsible for the large number of different platelet-rich plasma products in laboratories globally.

Scientific value of PRP etc in tendon injuries

Tendon disorders of any kind make high demands in terms of diagnostics, treatment, rehabilitation and prevention at a fundamental level and often require interdisciplinary collaboration. Interest in and the use of orthobiologics (e.g. platelet-rich plasma and auto­logous conditioned plasma – PRP and ACP) has steadily grown in the last de­cade. Orthobiologics and the procedures followed for their application are often mentioned in the context of tendon injuries. The results of a current survey  in the AOSSM (American Orthopaedic Society for Sports Medicine) confirm just how frequently they are used in routine clinical practice. Tendon injuries, together with osteoarthritis, are the second most common indication for the use of platelet-rich plasma. How­ever, in this context it is viewed critically that with its increasing popularity the indications for its use are not always based on scientific evidence and therapeutic efficacy.

Acute tendon injuries and those due to overuse, together with functionally related structures (bone insertion areas, surrounding synovial tissue, myofascial interfaces), are one of the most common injuries and clinical pictures in athletes across all sports and ages. Epidemiologically, the (weight-bearing) tendons of the lower extremities (e.g. the Achilles tendon, patellar tendon) in particular are commonly involved. A large number of injuries in sports can be ascribed to different forms of overuse with or without concomitant risk factors. Fundamental knowledge of the pathogenesis is essential to understand damage mechanisms and be able to address them adequately and treat them successfully and appropriately depending on the stage. Where the aetiopathogenesis cannot be fully explained, an interaction between a change in metabolic activity (including tenocyte activity), a change in the structural integrity of the tendon and the presence of more or less inflammatory metabolic disorders can be assumed. The individually selected treatment methods share the goal of clinically identifying and impro­ving impaired tendon function in a continuous and progressive treatment process. Careful selection and structuring of the treatment methods is essential here.

Application and/or infiltration as a procedure routinely available in clinical practice

When PRP etc were first used, the available evidence was inadequate due to the inadequate methodological quality of the studies then available. The at times method-related limi­tations of these studies and the different methods used to collect PRP resulted in different compositions and dosages. Moreover, the application and follow-up protocols were not uniform and still hinder scientific analysis and thus ultimately the assessment of this treatment method today. In principle, the cytokines and growth factors found in PRP can enhance the inflammatory and healing process. PRP, applied at the  correct time and in the correct work-up, might thus have a positive effect on tissue regeneration. However, if the timing and work-up are inadequate, then the opposite effect may be triggered. It has now been generally established that the clini­cal efficacy of PRP  depends on both the biological milieu (application as a supplement perioperatively as opposed to purely conservatively) and localisation of the application. The question therefore is no longer whether PRP is gene­rally useful (e.g. irrespective of localisation and severity) but whether it should be applied in each individual case.

Positive effects for the patellar tendon, rotator cuff and radiohumeral epicondylopathy

The scientific data currently available demonstrate positive therapeutic effects, particularly for the patellar tendon, rotator cuff and radiohumeral epicondylopathy and for perio­perative application in Achilles tendon reconstruction. Application of PRP for Achilles tendinopathy does not appear to be superior to other treatment methods and, based on current knowledge, cannot be fully recommended.

Summary of the use of orthobiologics for tendinopathy

• Heterogeneous data available on clinical efficacy – biological milieu and localisation are crucial 
•  

  Indication must take into account the localisation and be adjusted to the underlying pathology

•  

  Solid data available: patellar  tendon, rotator cuff, radiohumeral epicondylopathy, Achilles tendon reconstruction

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  No monotherapy, no unique selling point!

NB: The indication for infiltration treatment in tendinopathy should always be subject to strict scrutiny irrespective of the active substance applied. The user is in each case responsible for the infiltration and must always check what specific treatment goal is being pursued with the infiltration. In tendino­pathy, the purpose of infiltrations (of any kind) is not to maintain sports activity or weight-bearing capacity at a symptomatic level. The goal of all those involved in the treatment should always be to enable, within a continuous rehabilitation process, a safe return to training and competition in line with the severity of the damage.

First published: GOTS* newsletter

GOTS*: The trinational (Germany, Austria, Switzerland) Society for Orthopaedic and Trauma Sports Medicine (GOTS) is the largest European association of sports orthopaedic and sports trauma specialists. It is the first point of contact in the care of sports injuries and a guarantee of quality in sports trauma care. Its goal is to improve the understanding of sports loads and injuries in order to maintain musculoskeletal function and quality of life. To this end, GOTS promotes trai­ning and continuing education, research and the sharing of information and expertise internationally among doctors active in sports orthopaedics and sports trauma and professional groups in related specialisms.

Through new scientific findings, their application in football practice and the transfer and exchange of knowledge, we are helping German football to return to the top of the world. With over 100 doctors and physiotherapists, we offer a large network of experts who are responsible for the medical care of our junior and senior national teams during international matches worldwide. The medical centre is also home to an outpatient clinic that provides all active athletes on the DFB campus with the best possible first aid for injuries and illnesses. Thanks to a long-term coope­ration with Frankfurt University Hospital, serious treatments and complex diagnostics such as MRIs can be carried out at the hospital as a maximum care facility. 

In addition, we conduct football-specific research projects together with the university hospital and other universities. For example, we are looking into football-specific nutrition, the influence of neuroathletic training on performance development, decision-making in complex situations or the healing process of muscular injuries at the cellular level. Interdisciplinary research groups consisting of scientists, doctors and coaches work together on the research project in order to transfer the results into practice in the best possible way. 

However, the Medical Centre has not only set itself the goal of researching and applying new findings, but also of sharing them with interested medical staff. Twice a year, for example, we run the certified advanced training course in football medicine, which is available in hybrid form in the winter and digitally in the summer as an advanced training course for national and international doctors from professional and amateur football. The from UEFA co-financed programme cover topics such as heart disease after COVID19 infection, rehabilitation after muscle injuries and the influence of head ball play on the brain. Furthermore, we provide information about the latest scientific studies on football medicine via www.dfb-akademie.de

Creating, applying and sharing know­ledge – this is our objective at the DFB Academy Medical Centre. The DFB Campus is a place of encounter. We would be delighted to welcome you to the new campus as well.

Due to pain in the region of the shortened musculature and the associated stiffness of the affected mobile segments, e.g. the atlanto-occipital and atlantoaxial joints in the cervical spine or the shoulder, the further course may lead to postural imbalance in more distant joints (ascending/descending chain) and to chronified pain syndromes that often have to be treated with drugs. One can differentiate between active myofascial trigger points that are frequently extremely painful and often weaken the affected muscle, latent myofascial trigger points that are only painful on movement, and associated myofascial trigger points that develop due to dysfunction of the neighbouring muscle groups.

In many cases the latter myofascial trigger points are areas of painful muscular tension in the muscles of the shoulder (girdle) (rhomboideus major/minor muscles) that react to muscular shortening, particularly at the superior border of trapezius or in the short cervical muscles. The causes of trigger points are many and varied: shortening of the muscle groups due to damp/cold/draughts, associated fascial adhesions, postural imbalance, overstrain, or blunt trauma. Ima­ging has only been of very limited use for trigger points to date. Many patients with chronified neck problems show no structural anomalies on imaging (MRI, digital volume tomo­graphy, radiographs of the cervical spine). Ultrasonography is also only of limited use for assessing trigger points. 

A dedicated manual examination gives indications of shortened muscle groups. Intensive examination of the ranges of movement of the atlanto-occipital and atlantoaxial joints often reveals muscular swelling at palpation. More recently clinicians have been turning their attention to thermography because this specific examination system can demonstrate hyperaemia in the affected muscular segment. Thus, for the first time ever, trigger points can be visualised without exposure to radiation, relatively problem-free, and in a short time.

Case example 

A young athletic woman presented at our surgery with progressive recurrent episodes of symptoms in the region of her left trapezius radiating cranially to the left occipital area that she had had for several weeks. She said she did sports re­gularly (tennis).The patient is right-handed and could not remember any trauma. She has a sedentary occupation (works at a computer). Her intensive stress situation had worsened over the last few weeks as she had had to take on additional work due to staff reductions as a result of coronavirus. She had treated herself with deep heat, massage and analgesic gels. Clinical examination showed marked elevation of the left shoulder with massive tension of the superior border of trapezius and considerably restricted mobility of the atlanto-occipital and atlantoaxial joints on right rotation. She had tenderness to pressure over the insertions of the short cervical muscles on the occiput and along the course of the left levator sca­pulae muscle. Palpable myogeloses /  trigger points, particularly at the superior border of trapezius and in the rhomboideus minor muscle. 

Slight pain relief in the affected muscle groups on extension of the neck. Clini­cal examination revealed no attributable radiculopathies. The MRI of the cervical spine the patient brought with her showed findings in the cervical spine that were compatible with her age without any higher-grade degenerative chan­ges of the facet joints/intervertebral discs. No neuroforaminal narrowing. In the infra-red thermography we ­initiated (FLIR E75 thermal imaging ­camera, Fig. 1) the camera displays more than 75,000 measuring points with a thermal sensitivity of < 0.04 degrees temperature difference, and can thus accurately demonstrate small areas of hyperaemia (trigger points). In the pre­sent case the clinically diagnosed trigger points in the region of the superior border of trapezius and in the short right cervical muscles are shown (Fig. 2, see black circles). In order to confirm the diagnosis further we also ran EMG tests on the muscles in the shoulder girdle that gave clear evidence of elevated resting tone in the left trapezius (Fig. 3 and 4). Therapy was given at the same sitting as treatment with neuroreflex cryotherapy (Cryolight). With the help of the applicator and a temperature probe, the entire muscle area (in this case the trapezius on the left) is “cooled down”. During the treatment, the entire trapezius muscle is treated from the shoulder area to the area of the short neck muscles for approx. 60 – 90 seconds and then a dosed stretching treatment is carried out. The total duration of therapy per session is a maximum of 2 minutes. Depending on the intensity of the symptoms, 3 – 5 sessions are usually necessary (Fig. 5). Taping was then applied (Fig. 6). The thermography we repeated directly after the cryotherapy showed marked regression of the size of the pre-existing left nuchal trigger points (Fig. 7). In the further course the follow-up (EMG) examination also showed a marked reduction of the imbalance with clear harmonisation of mus­cle tone (Fig.  8). The patient’s treatment was repeated once. After the se­cond sitting (six days after the first treatment session) there was almost complete regression of the symptoms with a considerably improved range of movement and no residual muscular limitations.

Summary

Thermal imaging (thermography) rea­dily demonstrates trigger points – especially in the region of the cervical spine – with associated muscle weakness, restricted mobility and chronified pain syndrome. The application of cryo­therapy is recommended for confirmed trigger points (neuroreflex cryotherapy) followed by taping. Furthermore, EMG testing (with concomitant biofeedback training) can be used for further diagnostics/treatment or used to evaluate the outcome of cryotherapy. Our EMG tests showed a marked reduction of muscular tension after cryotherapy indicating in summary that this technique, which is simple to apply, is a fast-acting form of treatment and is virtually free of side effects.

Infrared thermography has long been used in veterinary medicine as a routine diagnostic procedure (see the book by Barbara Bockstrahler MD: Physical medicine, rehabilitation and sports medicine in a nutshell – VBS (publisher) 2019). In just a few seconds it allows the visual assessment of internal inflammation in animals, compensating postures, impaired gait, hoof disorders, painful pressure points and muscle and joint inflammation. Based on these findings in veterinary medicine, we began to use this procedure two years ago in the diag­nostic assessment and rehabilitation of muscle injuries in professional football and have now also integrated infrared thermography as a complementary imaging procedure into our routine clinical practice for the clarification of musculoskeletal and neurological disorders. Case studies follow below as an illustration.

Case Studies

Case 1 (see Figs. 1 + 2)

presented with pain around the insertion of the right Achilles tendon. Clinical examination and imaging (ultrasound, X-ray and MRI) showed Haglund’s deformity with a partial tear in the deep layers of the Achilles tendon at the calcaneal insertion. Under ongoing treatment, the patient complained of sciatica on the right without a sensory motor deficit after returning to full sports loading. Clinical examination and ima­ging showed a facet joint cyst at L4/5 on the right with marked narrowing of the spinal canal on the right and nerve root compression at L5 and S1 on the right.

FIG. 1 Infrared thermography of the soles of both feet. Thermographic images assessed using the Thermohuman software, camera: X4VIson by HT ITALIA SRL. Temperature difference between the right and left heel, 2.19°

Case 2 (see Fig.3)

A 34-year-old male patient with bilateral cam-type femorocetabular impingement. Due to the lack of success under conservative treatment, hip arthroscopy was performed on the right with debridement of the torn labrum and offset restoration (removal of a bony hump).

Case 3 (see Fig. 4)

An 80-year-old female patient with activated osteoarthritis on the left confirmed by imaging and immobilising pain under weight-bearing. Alleviation of the symptoms under conservative treatment.

Case 4 (see Fig. 5)

A 48-year-old male runner with ongoing heel pain for the previous six months. Clinical examination and imaging (MRI) confirmed the diagnosis of plantar fas­ciitis with a degenerative partial tear of the plantar tendon at the calcaneal insertion.

Conclusion

Infrared thermography provides us in our orthopaedic and sports medicine practice with a complementary imaging procedure that is fast, non-invasive, painless, objective and above all radiation-free. The colour-coded visualisation of slight differences in skin temperature and the specialist Thermohuman software (camera: X4VIson by HT ITALIA SRL) allow assessment of thermographic images that is easily standardised. In an online article in the sportärztezeitung, the sports scientist Kornelius Kraus MD wrote about his many years of expe­rience in infrared thermography as an assessment method for sports medicine and performance physiology (www.sportaerztezeitung.com/rubriken/therapie/10735/infrarotthermografie/). This included the finding that pain correlates with coordination deficits and that the ability to relax was poorer in the warmer hamstrings (Kraus 2019). To date, the diagnostic interpretation of the images depends to a great extent on the investigator and requires experience. In our view, infrared thermography has the potential of becoming a valuable and innovative complementary imaging pro­cedure in orthopaedics and sports medi­cine alongside established diagnostic procedures such as ultrasound, MRI and electromyography. To date, there have been no randomised prospective studies comparing the informative value of this procedure with that of other ima­ging procedures. Well-designed studies are required to further investigate the value of this imaging procedure in musculoskeletal diagnostics.

Those having played in the lower leagues may need to find a job when they have finished playing-this obviously applies also to those who have had a career cut short due to illness or injury. Being able to work depends, in part, on good health. Although it has been reported that ex-footballers live longer, mental health problems, degenerative joint disease, and neurodege­nerative disease are the cause of appreciable morbidity, which can have an impact on day to day living and working.

Health risks and problems

A survey of players in the major European leagues, despite a low response, found the prevalence of mental health problems and/or psychosocial difficulties in current and former professional footballers to be high when compared to the normal population. Burn-out (5 % – 16% current-former players) and anxiety/depression (26 % – 39 % current-former players). Low self-esteem (3 % – 5 % current-former players) and adverse nutrition behaviour (26 % – 42 % current-former players) were the issues surveyed. 

Degenerative joint disease is something that ex-players encounter earlier in their lives than the normal population, with knee osteoarthritis being twice as common, and total knee replacement three time more common. Knee pain arrives 10 – 15 years earlier than might be expected. Degenerative changes in the hip are associated with a loss of quality of life for ex-players, and daily pain and arthroplasty are significant obstructions to leading a healthy and productive life, completely contrary to the experience of being a football player.

Neuro-degenerative disease is one of the hottest debated issues in football and the effect that heading the ball and head injuries (and just participation) have on players’ central nervous systems. It is well known that dementia pugilistica was described way back in the 1930’s (Millspaugh), after being first named ‘punch drunkenness’ in the previous decade (Martland). It is also well known that some high profile players have suffered with dementia in later life. A three-fold increase in mortality from neuro-degenerative conditions was noted in a study involving Scottish ex-footballers, versus matched controls. Hea­ding the ball has been associated with white matter changes, with one study counting headers in players over a season. Some of these players had headed the ball over 5000 times (!) in training and matches, with changes in memory scores and on MRI imaging when this figure exceeded 1800. Amyotrophic Lateral Sclerosis, or Motor Neurone Disease was noted to be more common and diagnosed earlier in life in two studies carried out on Italian footballers, with a relative risk of 11 and 18 across the two studies. Not to put all the blame on football, is some information from the U.S.A. ALS registry, which states that those who have exercised vigorously before the age of 35, were more likely to be diagnosed with ALS before the age of 60, although the point was made that the causes of ALS are multi-factorial. Another multi-national study concluded that vigorous physi­cal activity had an impact on the incidence of ALS, but an additive effect was seen in sports that involved repetitive central nervous trauma, such as football, with heading, and sustaining concussions. The now famous successful litigation achieved by players in the NFL in 2017 had a total timeline of 65 years, with $52.6 million the estimated total that would be paid out in that time. In fact, by 2018, $146.5 million had already been paid out (this is from an article in the New York Times). As stated earlier in this piece, ex-footballers do live longer, based on their lower incidence of cardio-vascular di­sease and cancer, but it is apparent that they do suffer disproportionate health issues after retirement, when compared to the normal population. 

The question is, what should we be doing about it?!

It is clear that those in the game are trying to holistically assess the size of the problem, so that resources can be accessed and applied appropriately. One prospective pan-European study is conducting a ten year survey of footballers transitioning from the playing side of the game to achieve this. Employers in other industries now conduct ‘exit interviews’ which give guidance to the soon ex-employee as well as take account of experiences whilst employed. Doing this for footballers may iron out some of the creases involved in such an event. As well as this, the hazards and potential health sequelae are shared with the employee in other work environments prior to the commencement of a contract, so that a career is undertaken with eyes wide open to the possible risks involved. Neither of these practices ­occur formally in football.

There is money in the game, and to set up any service will take resources. If, after their playing days, we are to support those who continue to entertain us, whether from our sofas or from the terraces, we need to determine what is needed, and undertake to provide such support.

HA as well as PRP therapeutic applications show a positive effect regarding effectiveness, pain reduction and improvement of mobility over a period of up to 12 months, whereas HA levels off to a steady state of its positive effects after the first 6 months [12]. Although knee-­replacement surgery provides an effective solution for severe knee osteo­arthritis (OA), for younger and middle-­aged patients with earlier stages of Arthritis, conservative nonsurgical interventions have been proposed [6, 24, 9]. Thus, the International Osteoarthritis Society recommends non-surgical treatment as a first line therapy [33]. Conservative interventions include anal­gesics, non-steroid and steroid anti-­inflammatory drugs, corticosteroid and HA injections. More recently PRP, as a biological therapy, has become an intriguing treatment option to improve the status of the joint [5, 11, 10, 28, 29]. This raises the question whether the effects of HA and PRP is potentiated when a combination therapie of both is used and therefore leads to a possible therapy synergism.

Benefits of Hyaluronan

Currently, there is no evidence regar­ding the intraarticular therapy with PRP or HA, which advises one injection regimen superior to the other. The American Association of Orthopaedic Surgeons (AAOS) does not yet recommend HA in their guidelines for osteoarthritis, but current studies seem to update this recom­mendation [18, 23]. The Society of Orthopaedics and Orthopaedic Chi­rurgy (DGOOC) states in their updated S2k guideline of September 2020, “Intra-articular hyaluronic acid injection may be used in patients in whom the use of NSAIDs is contraindicated or in whom NSAIDs are not sufficiently effective” [27]. HA has viscoelastic as well as anti-­inflammatory and cytoprotective properties, in addition to stimula­ting endogenous HA synthesis [26, 1, 14, 3, 4]. The rheolo­gical and mucoa­dhesive properties are particularly important for artificial joint fluids, as this elastic matter is able to successfully absorb mechanical energy and protect cartilage from damage, tear or abrasion [2]. This properties gain importance especially at high loads such as in competitive sports. The thera­peutic effect and possible side effects of HA depend directly on the molecular weight of the biopolymer, its cross-linking, the dosage and its preperation [1, 26, 23, 17, 19] HA has its peak effect at about 2 months and lasts a total of about 6 months [10, 21]. (For further information please see sportärztezeitung 01/21 and Figure 1).

Benefits of PRP

The last few years, PRP has been used in various indications, including osteo­arthritis and cartilage damage. PRP, as an autologous therapy, releases local growth factors, which in turn stimulate chondrocyte production. This enodgenous effect stimulates the extracellular matrix and could promote cartilage repair [11, 2]. Moreover, PRP has anti-­inflammatory effects by increasing anti-­inflammatory mediators, decreasing proinflammatory mediators and the expression of pro-inflammatory enzy­mes [22]. Further, PRP improves patient reported outcomes in terms of pain, functionality and stiffness, over a period of 6 – 12 months [10, 11, 30, 25, 16, 8, 12]. In some cases, the outcome after additional PRP injection is better than single HA injection therapy [10, 12, 29]. Especially in long-term outcome, PRP seems to be superior to HA  solution [11, 15, 32]. Compared to saline, where significant functional impairment occurs after approximately 6 months, the improvement with PRP is consistently maintained over a 12-month period. This indicates that the improved outcome with PRP is not based on a placebo effect [10]. It was demonstrated in vitro that chondrocytes cultured with growth factors, which are also present in PRP, had higher proliferation rates than the control culture without growth factors [7]. Another topic that remains unclear is whether leukocyte-rich or leukocyte-­poor PRP shows more bene­fits regar­ding functional and pain outcome parameters. However, based on current knowledge, it appears that leukocyte-­rich PRP is more effective [5].

Combination Therapy – Potential for a therapy synergisms?

In case of a combination therapy, it can be differentiated between a direct combination therapy and an injection the­rapy with time intervals of e.g 48 h to 7 days between HA and PRP injection. With both therapy regimes a synergism would be conceivable. This synergism could be due to the anti-inflammatory and visco-elastic properties of action of HA and the additional chondrocyte stimulating and anti-inflammatory effect of PRP [33]. This synergistic effect has been partially demonstrated in experimental in-vitro cell and in-­vivo animal experiments [30]. Increased chondrocyte proliferation and increased gly­cosaminoglycan concentration, decre­ased apoptosis and therefore less cartilage damage were observed [20]. Furthermore, it has been shown that synovial fibroblasts and tendon cells exhibited improved cell mobility in a PRP plus HA solution than in a PRP-­only solution [33]. A current meta-ana­lysis by Zhang et al. (2020) showed that a combined therapy of PRP and HA leads to significantly higher improvments in terms of pain perception and functionality compared to PRP or HA alone (after 6 months). Additionally, the PRP-HA group achieved greater impro­vement in WOMAC function score, WOMAC total score and Lequesne score at 12 months [32]. Gilat et al. (2021) concluded that combination therapy was superior to HA alone in terms of functionality and pain after 6 and 12 months [15]. However, long-term studies (> 12 months) are still lacking. Moreover, combination the­rapy only referred to the simultaneous administration of PRP and HA in one injection session. There is currently no evidence regarding a therapy success in terms of an injection regimen with a 48 h to 7 days interval between injections [33, 16]. The combination therapy of PRP and HA is not to be expected lea­ding to an increased risk, compared to therapy with PRP or HA alone and shows comparable side effects [33]. No significantly increased rate of adverse events was demonstrated in either group [29, 28]. As described before, the pro­perties of PRP would conceivably reduce joint inflammation and stimulate chondrogenesis [5]. Yet only Xu et al. have included examination (Doppler Imaging for Synovium and Cartilage, Synovial fluid for Inflammatory parame­ters) regarding these parameters [30]. A comprehensive pathophysiological concept does not yet exist, but a common thera­peutic effect via the extracellular matrix is conceivable. This is activated by both the hydrophilic properties of HA and platelet growth factors. Future studies should investigate possible effects on various synovial parameters and the extent of cartilage damage on MRI, because evidence is lacking regarding objective parameters.

Limitations

One of the most frequently mentioned limiations is the heterogeneity in the preparation and injection of PRP, but also in the kind of injection of HA [11, 10, 5, 12, 8]. Too short follow-ups and lacking study designs were also criticized [33, 10, 25, 22]. Additionally, there were concerns about patient selection and heterogeneity among patients. The inclusion and exclusion criteria were not evaluated in detail and patients who had knee pain but no knee osteoarthritis were enrolled [8, 10, 33]. Some authors also missed post-injection radiographic or MRI data collected at follow-­up [22, 5, 21].

Conclusion

The current study designs appear to be very heterogeneous. Standardized designs with more homogenous groups will be needed in order to develop evidence-based therapy [12, 31, 10, 5, 20]. Based on the literature PRP seems to be superior to HA alone in terms of pain and functionality in mid- and long-term follow-up [12, 31, 22, 5, 21]. However, recent studies show that the combination therapy of HA and PRP shows promising results (VAS, WOMAC function and total, Lequesne Index) after 12 months than PRP alone [33]. It can be concluded that, at the present time, further high quality RCTs using a standardized method of preparation and injection are needed to establish an evidence-based therapy. As mentioned above, additional examinations of the synovia, as well as cartilage imaging should be included in the study design in order to make solid statements about the influence on inflammation and cartilage repair to refer to more objective parameters. Additionally this would lead to a more valid statement about the influence of the injection therapy on inflammation and cartilage repair.

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