The role of regenerative medicine in musculoskeletal pain management

Platelet-rich plasma holds significant potential for enhancing recovery and rehabilitation of athletes, ultimately contributing to improved outcomes in the field of sports medicine

The positive impact sport has on health is well recognised. However, each spring sees the inevitable rise in presentations of, often preventable, sports injuries in the primary care clinic or on a physiotherapist’s table.

The incidence of injury in sports has increased in recent years due to a rise in participation, poor injury prevention strategies, and faulty or inadequate training. In fact, the prevalence of injury was highlighted in a 12-month, prospective study carried out on 324 Irish athletes involved at a high level of sports participation in one of the following categories: endurance, contact, non-contact, or explosive sports. The findings show that a significant portion of athletes (40 per cent) suffer an injury within a year. The average athlete sustains around 1.17 acute and 0.93 overuse injuries per year, leading to an average of 52 days of lost time due to injury. 

The most common injuries include lumbar muscle strains, ankle sprains, and bone fractures. Not surprisingly, contact sports tend to have higher acute injury rates compared to non-contact sports. Key factors associated with higher injury rates include increased training hours, inadequate facilities, and inappropriate training loads. The younger athlete is at greater risk mainly due to limited knowledge to avoid injury. For the professional athlete these factors can inadvertently shorten their career, and have significant implications in their quality-of-life.

For most people, individual musculoskeletal injuries (MSK) in sports are a consequence of chronic misuse or overuse. Many of these problems can be treated conservatively with rest, non-steroidal anti-inflammatory drugs (NSAIDs), physiotherapy and rehabilitation. Unfortunately, some individuals do not respond well to rehabilitation and formal intervention.

Pathology of MSK injuries

In practising athletes, tendons and the entheses (where tendons attach to bone) experience higher biomechanical stress compared to non-athletes, due to the repetitive and intense nature of athletic activities. These activities may also affect the muscle, cartilage, and place bone under chronic stress.

The underlying pathology in persistent cases of MSK injury can be related to irreversible microstructural changes in connective tissue that have failed to recover and adapt to rehabilitation. Typically, recovering from any injury is regarded as a three-phase process, as outlined in Table 1.

These problems do not have an effective treatment modality, and this is the grey area where orthopaedic surgeons and sports physicians are now attempting to employ biological therapy to hasten repair and, thereby, bring about recovery.

In regenerative medicine, which is a growing therapy globally, procedures like platelet-rich plasma (PRP) injections have shown promise. From a clinical perspective, regenerative sports medicine focuses on injuries related to sports activities and ageing, involving various components of the MSK system such as menisci, ligaments, tendons, cartilage, and bones. PRP has shown its utility as an interventional therapy for sports injuries in specific cases.

Emergence of PRP

The concept of using the body’s own inherent healing mechanism to assist in repair, and to potentially replace or restore damaged tissue through the use of autologous or allogenic biologics, has always been considered a possibility. In the clinical setting, the use of PRP began as early as the 1980s when it was found to be effective in treating blood loss during cardiac surgery. Its effect on bone was then examined in the field of dentistry for its regenerative properties on bone maturation and formation. In time, its use in MSK medicine has grown, and a role in tendon and tissue healing has been heavily investigated. Over the last 10 years there has been an increase in the use of PRP among medical clinicians, especially for its potential in treating tendinopathy and degenerative cellular diseases.

Within the specialty of pain management, the use of regenerative medicine is a relatively new treatment option. PRP contains numerous growth factors and cytokines that potentially offer an alternative treatment modality to assist in the healing of multiple MSK issues. The use of PRP is expanding exponentially, creating new frontiers for the treatment of MSK and spinal pain.

One reason for the growth in interest in PRP is because, according to World Anti-doping Agency regulations, PRP is not prohibited. Although individual growth factors are still prohibited when given separately as purified substances. PRP therapy is only prohibited if it offers performance-enhancing effects, or if the PRP was altered in a way that can produce performance-enhancing benefits.

Why does PRP work?

In the early phase of any injury the inflammatory phase predominates. Ice, rest, activity modification, and anti-inflammatory medications are generally included in the current mode of management. Many injuries settle but, in some cases, local steroid injections are required. While steroids are the gold standard to reduce inflammation, they do little to directly promote the healing phase. Occasionally, even steroids fail to resolve the symptoms, leaving the individual with a long uphill battle to recovery.

This is fundamentally where PRP therapy has an important role. PRP seeks to recruit and enhance the body’s own inherent healing mechanism to assist in repair, and to potentially replace or restore damaged tissue. PRP therapy can increase the rate of MSK healing by stimulating angiogenesis, cell proliferation, and chemotaxis. It has been demonstrated that PRP promotes healing in cases of tendinous, ligamentous injury and muscular strain. Thus, PRP has been utilised for the purpose of shortening the recovery period, and it has helped improve the recovery time of athletes.

How is PRP prepared?

Generally, the preparation of PRP involves obtaining autologous whole blood from the patient followed by a centrifugation process to separate plasma from red blood cells and leukocytes (Figure 1). The method of isolation plays a role in the final concentration of platelets and leukocytes in the PRP preparation. What was once a complex ‘event’ has been simplified into a three-step process.

1. Withdraw a blood sample in a specific collecting tube.

2. Centrifuge the sample to separate the plasma which is rich in several growth factors.

3. Reinjection of the product at the injury site. This is best undertaken using image guidance such as ultrasound or fluoroscopy to improve accuracy.

This preparation process, and the injection of the PRP, can be completed in a matter of minutes, using simple clinical equipment, and delivered safely to the affected site. Ultrasound guidance is preferable to increase the accuracy and improve treatment outcome.

What does PRP contain?

Platelets, which are one of the main components in PRP, help mediate the release of several growth factors that are essential in the healing process. These include platelet-derived growth factor, transforming growth factor, fibroblast growth factor, vascular endothelial growth factor, epidermal growth factor and insulin-like growth factor. These growth factors are essential for the three phases of healing: Inflammation, proliferation, and remodelling.

The proposed benefit of PRP is that it allows for the patient’s own blood to provide a high concentration of growth factors to promote healing at injury sites that have limited healing capacity due to blood supply. This matrix serves as a scaffold for sustained release of growth factors that drive chemotaxis and angiogenesis.

There are several basic science studies to support the use of PRP for tendon and ligament healing in the in vivo setting. PRP has been shown to:

a) Induce tendon cell proliferation along with induction of angiogenic factors. 

b) Have anabolic effects on tendon cells by increasing the total collagen synthesis in tenocytes. Collagen type I seems to be promoted by PRP and may help limit the development of fibrotic tissue. There is an important ratio between different types of collagen and a balance seems necessary to avoid increased fibrosis and reduced strength of a tendon.

What is the clinical evidence to support PRP?

The evidence in the literature reflects the greater use of the technique globally.

a) Lateral epicondylitis

Also known as tennis elbow, lateral epicondylitis has shown very favourable results when treated with PRP compared to traditional steroid injections. In a meta-analysis of randomised controlled trials (RCTs) examining the use of PRP, it was reported that PRP was significantly more effective at reducing pain intensity compared to various controls in both short-term (<6.5 months) and long-term (>one year) follow-up periods.

In 2017, a study was undertaken to compare outcomes between a single PRP injection and surgery for patients suffering from lateral elbow tendinopathy. It appears that both can provide at least similar pain relief in the first 12 months, but after two years arthroscopy was superior to PRP in terms of long-term pain and functional outcomes. Nevertheless, for some individuals, a 15-minute bedside procedure annually may be the preferred option.

b) Rotator cuff tendinopathy

The use of PRP in rotator cuff pathology has come with mixed results in the literature. Early studies on augmenting rotator cuff repair with PRP have been inconsistent with regard to clinical outcomes.  A more recent meta-analysis by Hurley et al examined over 18 randomised controlled studies comparing PRP to arthroscopic repair alone. Their study included over 1,147 patients and found that those treated with PRP had significantly decreased rates of incomplete tendon healing for small-medium and medium-complete tears. They also found a significant decrease in visual analogue scores (VAS pain score) at 30 days and final follow-up compared to the control group.

c) Patellar tendinopathy

Patellar tendinopathy, otherwise known as jumper’s knee, is characterised by chronic pain as a result of overuse. The clinical evidence suggests that PRP can improve pain and function, with up to 22-81 per cent of patients able to return to their pre-symptom level of activity.

The number of PRP injections has also been shown to have an effect on the outcome of the treatment, with two injections found to improve outcomes significantly more than a singular injection.

d) Achilles tendinopathy

The Achilles tendon is a conjoined structure composed of the tendinous regions of the superficial posterior compartment musculature. The tendon resists forces up to 12 times body weight during exercise and is among the strongest in the body. Despite its robust structure, it is also among the most frequently ruptured tendons in the lower extremity, and accounts for 20 per cent of major tendon injuries.

Due to increased sports competitiveness, an ageing population and rising obesity rates, the incidence of Achilles tendon rupture is on the rise. The majority of severe Achilles tendon injuries occur as a result of sports activities, and professional athletes are thus more prone to Achilles tendon injury. Approximately 30-50 of 100 sports-related injuries involve tendon issues. Sports such as jogging, badminton, squash, or training in sub-zero weather put individuals at higher risk of an Achilles tendon injury.

Due to its relative non-invasiveness and minimal risk, PRP injections are being investigated with hopes of improving tendinopathy outcomes. Unfortunately, the initial results are not very encouraging.

e) Ulnar collateral ligament injury

Injury to the medial ulnar collateral ligament (MUCL) occurs as a result of extraneous valgus loads and is common in overhead-throwing athletes. A fully torn ligament or one that has not responded favourably to conservative treatment will be treated surgically; however, success rates have varied from 83-to-90 per cent for a return to the sports field within nine–12 months post-surgery. A case study by Hoffman et al detailed the outcome of an MUCL reconstruction in a 25-year-old professional baseball pitcher that was augmented with a dermal allograft reconstituted in PRP and mesenchymal stem cells. The authors found that their patient was able to return to pitching by four months post-op.

Despite various case reports, there are no available RCTs examining the effectiveness of PRP in MUCL injuries and it is still unclear whether PRP expedites return to play in conservative management.

f) Anterior cruciate ligament

The anterior cruciate ligament (ACL) is vital to the stability of the knee and its rupture requires surgical intervention to restore this functionality. A systematic review by Figueroa et al regarding ACL repair with the aid of PRP showed variable results in terms of clinical outcomes, bone tunnel healing/widening, and graft maturation.

The use of PRP may show more promise in partial tears. A systematic review by Di Matteo et al included two studies of PRP used for partial ACL tears, which showed that between 70-to-84 per cent of patients return to previous level of activity without surgery. Initial research regarding the use of PRP to treat ACL injuries shows promise in terms of its ability to help induce cell growth for various grafts; however, there is not sufficient research to conclude the best composition of PRP injections to induce the maximal amount of healing.

g) Other options

With the ease of preparation, improved ultrasound accessibility, and a growing awareness in the medical community, the probability is that different tendons and ligaments are going to be injected. For refractory cases such as gluteal tendonitis, ankle ligament, and hand injury, PRP therapy will continue to open up simple treatment options for more individuals. The initial feedback is very encouraging both in terms of pain reduction and improved functional capacity. Capturing this data in a form that can be shared to advance the treatment is a challenge.

While regenerative PRP management can be provided independently, it should be provided in conjunction with other modalities of treatment including a structured exercise programme, physical therapy, behavioural therapy, and appropriate conventional medical therapy as necessary. Appropriate precautions should be taken into consideration and followed prior to performing biologic therapy.

Conclusion

In conclusion, PRP has shown great promise as a treatment modality for sports injuries. Its regenerative properties and ability to promote tissue healing have made it a very valuable option for conditions such as tendon and ligament injuries commonly encountered in sports. PRP has demonstrated effectiveness in treating specific sports-related conditions like tennis elbow, jumper’s knee, and runner’s knee. Further research is needed to optimise PRP protocols and understand the mechanism of action in sports injury, but it is already clear that it holds significant potential for enhancing recovery and rehabilitation of athletes, ultimately contributing to improved outcomes in the field of sports medicine.

Disclosure

Prof Hegarty does not receive reimbursement from any specific company to use or promote the technique or products mentioned in this article.