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Abstract
Introduction and history While regenerative medicine may seem like a novel intervention in the chronic pain armamentarium, its evolution and in a sense its definition has been intricately related to the history of humankind.
The first concept of tissue regeneration comes to us from the Greek Mythology in the description of the Prometheus Myths. As such, in Hesiod Theogony, Prometheus is punished by Zeus by being bound to a rock as punishment for gifting humankind the secret of fire; in Aeschylus’ tragedy, Prometheus Bound, the god is described as nailed to the mountain of Caucasus while an eagle consumes his immortal liver, which constantly replenishes itself. This description may be the first ever mention of the concept of tissue regeneration and dates back 8–9th century BCE.
In the 4th century BC, Aristotle (384–322BCE), established methods to investigate and reason about the physical world around him and created a school of thought named natural philosophy, later named natural science. Using scientific reasoning, Aristotle attempted a theory on how embryos generate and develop; he believed that an organism develops gradually from undifferentiated material; the science of this process, later called epigenesis, contains elements and concepts of modern regenerative medicine.
Silence on this topic followed for almost 2 millennia until Schwann and Schleiden discussed in 1833 the concept of ‘Omnis cellula ex cellula’, or, in translation, ‘all cells come from cells’; however, it was Virchow who conducted microscopic experiments and provided confirmation of the process of differentiation. His findings are best summarized in his famous quote ‘when a cell exists, there must have been a pre-existing cell’.
The 20th and 21st century will see an expansion of these concept in their evolution towards the concept of regenerative medicine therapies.
Regenerative medicine in pain medicine-Definition, Biology
As a modern definition, regenerative medicine represents a type of translational medicine, part tissue engineering, part molecular biology that sits at the intersection of 3 elements: biomaterials, tissue engineering and stem cell therapies. Regenerative therapies do attempt to restore or re-establish normal function through replacing, engineering and regeneration of human cells, tissues, and organs. The most used techniques in pain medicine clinical practice are platelet rich plasma (PRP) therapies and stem cell bone marrow concentrates (BMC) treatments.
As we can see from Figure 1, the natural process of healing in human body does take time; usually after an initial injury, the pro-inflammatory phase lasts about 3–6 days and is followed by a proliferation phase of 4–30 days and a remodeling phase from day 21 to 1 year. Many biological processes do contribute to the activity of healing but using the regenerative therapies with PRP and BMC is believed to accelerate the natural healing cascade by delivering greater than normal concentration of cytokines releasing platelets, pro-inflammatory white blood cells, reparative cells, and progenitor cells. (Figure 1)
Plasma rich plasms (PRP)
Platelet rich plasma products deliver a supraphysiologic concentration of platelets to the affected area; they are used primarily in the acute/subacute musculo-skeletal conditions and some chronic pain states.
Their primary role is not to replace a damaged tissue but to rather facilitate recovery. The platelets, anucleate cytoplasmic fragments derived from megakaryocytes, contain factors that are released during their activation; those are granules containing high level of signaling molecules and growth factors that are capable to signal mesenchymal stem cells and speed healing process. Table 1 summarizes the most common biological active proteins and their functions
PRP derived products bring the platelet concentration of blood to 3–8 times higher, contributing to the high count of growth factors and subsequently high concentration of signaling proteins. Many factors do influence obtaining an effective PRP product; some of them are listed below:
• Volume of blood used
• Use of anticoagulant, pre-procedure platelet and WBC count
• Type of injury or disease treated
• Number and interval between PRP injections
• Host microbiota and immune status
Providing optimal condition for achieving an optimal PRP product, and applied in optimal chronic pain condition, it is expected that all healing phases will decrease in length with the remodeling phase being the most affected and the inflammatory phase the least affected (Figure 2).
Classification of the PRP products is made based on the presence of platelets, leucocytes, and fibrin. As such 4 categories can be mentioned:
• P-PRP-pure PRP
• L-PRP-leukocytes and PRP
• P-PRF-pure platelet rich fibrin
• L-PRF-leukocyte and platelet rich fibrin
Most common indications for the use of PRP are tendinopathies, ligamentous injuries, muscle injuries, cartilage pathology injuries, subchondral bone disease and bone injuries. Fitzpatrick et all in a metanalysis of randomized control studies evaluating the use of PRP in tendinopathies showed that Leukocyte rich PRP was more effective than the steroid injections in decreasing pain.1
For practical use of PRP in clinical practice, we identified several clinical pearls that can be used to adopt regenerative medicine techniques as treatment modalities for patients with chronic pain. Those are:
• An initial visit should consist of a detailed physical evaluation and diagnostic cell blood count,
• Advise patient to discontinue all NSAIDs, acetylsalicylic acid containing medications in the doses exceeding 81 mg one week prior to PRP treatment; those medications should be restarted more than 4 weeks after PRP treatment if possible.
• Advise patient to drink 3–4 glasses of water ½-1 hour prior to the procedure.
• Inform patient that a temporary restriction of movements in the treated area is advisable; the exception constitutes intra-articular injection of PRP.
Stem Cell Therapies-Bone Marrow Concentrates (BMC)
Bone marrow aspirates are usually used to concentrate stem cells; one of the common places to recruit those cells is the iliac crest; this location offers an easy accessibility, for needle insertion is easy and predictable. Furthermore, there is a high concentration of mesenchymal cells in the iliac crest aspirate; high volumes of 250cc or more can also be easily drawn from this location.
The technique used for aspiration can be performed using anatomical landmarks or under image guidance (fluoroscopy and ultrasound); regardless of the method, the use of multiple 10 cc syringes is preferred as it allows easy aspiration during many rotations of the aspiration needle placed in the iliac crest. Figure 3 shows our fluoroscopic guided technique for bone marrow aspirate with patient in prone position. By concentrating the bone marrow aspirate, the concentration of the desired cells increases to 2–8 times of original aspirate.
Effectiveness of the autologous mesenchymal stem cells was shown in a small study by D’Souza et al; the study showed that in knee osteoarthritis and chondropathy, decreased pain and enhanced function with PRP and autologous stem cells from bone marrow aspirate remain stable from end of treatment to 6 months post procedure.2
The use of regenerative medicine has also been investigated in spine disorders as an alternative to surgical treatments; conditions where effectiveness was seen are: intradiscal stem cells injections in disc pathology, intra-articular facet injections in chronic back pain, trigger point injections in whiplash, cervical and lumbar spine sprain. Data is currently emerging especially in the treatment of discogenic pain by stem cell therapies.
Other Regenerative medicine therapies
Several other regenerative medicine therapies have been used in clinical practice. Among those procedures, intradiscal sealing of annular fissures with fibrin sealants could potentially stop further herniation of nucleus pulposum. Several other techniques utilizing adipose tissue, placenta and amniotic cellular fluid have been used in various small case series and case reports, but those products are not considered autologous and as such their use may be subject to different regulation.
Common Biological active protein and their function in the process of regenerative medicine treatments
Naturally occurring healing process with the 3 phases, inflammatory, proliferative and remodeling varying from 3 days to more than 1 year.
Effects of the Platelet Rich Plasms (PRP) on the healing process.
Aspirate of the stem cells via a Jamshidi needle placed in the left iliac crest of a patient, optimally identified using fluoroscopic guidance
Conclusions Regenerative medicine is a novel, advancing way of treating chronic pain. There are limited studies currently, but evidence is evolving for the use and efficacy of regenerative medicine techniques as powerful tools in treating chronic pain
Indications for the PRP and BMC vary widely and are based on the regenerative technique and substance used. As such, platelet rich plasma (PRP) is more often used in musculo-skeletal conditions while use of mesenchymal stem cells have been reported to effectively treat intervertebral disc pathology.
References
Fitzpatrick et al. The effectiveness of platelet rich plasma in the treatment of tendinopathies: a meta-analysis of randomized controlled clinical trials. Am J Sports Med 2017; 45(1): 226–233
D’Souza, et al. Platelet rich plasma injections for knee osteoarthritis: systematic review of duration of clinical benefits. Tech Reg Anes and Pain Mgmt 2015; 19:67–72