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Application of Platelet Rich Plasma (PRP) in the Field of Neuropathic Pain

Neuropathic pain refers to the abnormal sensory function, pain sensitivity and spontaneous pain caused by the injury or disease of the somatic sensory nervous system. Most of them can still be accompanied by the pain in the corresponding innervated area after the elimination of the injury factors, which is manifested as spontaneous pain, hyperalgesia, hyperalgesia and abnormal sensation. At present, the drugs for relieving neuropathic pain include tricyclic antidepressants, 5-hydroxytryptamine norepinephrine reuptake inhibitors, anticonvulsants gabapentin and pregabalin, and opioids. However, the effect of drug therapy is often limited, which requires multimodal treatment schemes such as physical therapy, neural regulation and surgical intervention. Chronic pain and functional limitation will reduce the social participation of patients and cause serious psychological and economic burden to patients.

Platelet rich plasma (PRP) is a plasma product with high purity platelets obtained by centrifuging autologous blood. In 1954, KINGSLEY first used the medical term PRP. Through research and development in recent years, PRP has been widely used in bone and joint surgery, spine surgery, dermatology, rehabilitation and other departments, and plays an important role in the field of tissue engineering repair.

The basic principle of PRP treatment is to inject concentrated platelets at the injured site and start tissue repair by releasing a variety of bioactive factors (growth factors, cytokines, lysosomes) and adhesion proteins. These bioactive substances are responsible for starting the hemostatic cascade reaction, the synthesis of new connective tissue and vascular reconstruction.

 

Classification and pathogenesis of neuropathic pain The World Health Organization released the 11th revised version of the International Classification of Pain in 2018, dividing neuropathic pain into central neuropathic pain and peripheral neuropathic pain.

Peripheral neuropathic pain is classified according to etiology:

1) Infection/inflammation: postherpetic neuralgia, painful leprosy, syphilis/HIV infected peripheral neuropathy

2) Nerve compression: carpal tunnel syndrome, spinal degenerative radicular pain

3) Trauma: trauma/burn/post-operative/post radiotherapy neuropathic pain

4) Ischemia/metabolism: diabetes peripheral neuropathic pain

5) Drugs: peripheral neuropathy caused by drugs (such as chemotherapy)

6) Others: cancer pain, trigeminal neuralgia, glossopharyngeal neuralgia, Morton’s neuroma

 

The classification and preparation methods of PRP generally believe that the platelet concentration in PRP is four or five times that of the whole blood, but there has been a lack of quantitative indicators. In 2001, Marx defined that PRP contains at least 1 million platelets per microliter of plasma, which is a quantitative indicator of the standard of PRP. Dohan et al. classified PRP into four categories: pure PRP, leukocyte rich PRP, pure platelet rich fibrin, and leukocyte rich platelet fibrin based on the different contents of platelet, leukocyte, and fibrin in PRP. Unless otherwise specified, PRP usually refers to white cell rich PRP.

Mechanism of PRP in the Treatment of Neuropathic Pain After injury, various endogenous and exogenous activators will promote platelet activation α- The granules undergo degranulation reaction, releasing a large number of growth factors, fibrinogen, cathepsin and hydrolase. The released growth factors bind to the outer surface of the cell membrane of the target cell through transmembrane receptors on the cell membrane. These transmembrane receptors in turn induce and activate endogenous signaling proteins, further activating the second messenger in the cell, which induces cell proliferation, matrix formation, synthesis of collagen protein and other intracellular gene expression. There is evidence that cytokines released by platelets and other transmitters play an important role in reducing/eliminating chronic neuropathic pain. The specific mechanisms can be divided into peripheral mechanisms and central mechanisms.

 

Mechanism of platelet rich plasma (PRP) in the treatment of neuropathic pain

Peripheral mechanisms: anti-inflammatory effect, neuroprotection and promotion of axon regeneration, immune regulation, analgesic effect

Central mechanism: weakening and reversing central sensitization and inhibiting glial cell activation

 

Anti-inflammatory Effect

Peripheral sensitization plays an important role in the occurrence of neuropathic pain symptoms after nerve injury. A variety of inflammatory cells, such as neutrophils, macrophages and mast cells, were infiltrated in the nerve injury site. The excessive accumulation of inflammatory cells forms the basis of excessive excitation and continuous discharge of nerve fibers. Inflammation releases a large number of chemical mediators, such as cytokines, chemokines and lipid mediators, making nociceptors sensitive and excited, and causing changes in local chemical environment. Platelets have strong immunosuppressive and anti-inflammatory effects. By regulating and secreting various immune regulatory factors, angiogenic factors and nutritional factors, they can reduce harmful immune reactions and inflammation, and repair different tissue damage in different microenvironments. PRP can play an anti-inflammatory role through a variety of mechanisms. It can block the release of pro-inflammatory cytokines from Schwann cells, macrophages, neutrophils and mast cells, and inhibit the gene expression of pro-inflammatory factor receptors by promoting the transformation of damaged tissues from an inflammatory state to an anti-inflammatory state. Although platelets do not release interleukin 10, platelets reduce the production of large amounts of interleukin 10 by inducing immature dendritic cells γ- The production of interferon plays an anti-inflammatory role.

 

Analgesic Effect

Activated platelets release many pro-inflammatory and anti-inflammatory neurotransmitters, which can induce pain, but also reduce inflammation and pain. The newly prepared platelets are dormant in PRP. After being directly or indirectly activated, the platelet morphology changes and promotes platelet aggregation, releasing its intracellular α- Dense particles and sensitized particles will stimulate the release of 5-hydroxytryptamine, which has pain regulation effect. At present, 5-hydroxytryptamine receptors are mostly detected in the peripheral nerves. 5-hydroxytryptamine can affect the nociceptive transmission in the surrounding tissues through 5-hydroxytryptamine 1, 5-hydroxytryptamine 2, 5-hydroxytryptamine 3, 5-hydroxytryptamine 4 and 5-hydroxytryptamine 7 receptors.

 

Inhibition of Glial Cell Activation

Glial cells account for about 70% of the central nervous system cells, which can be divided into three types: astrocytes, oligodendrocytes and microglia. Microglia were activated within 24 hours after nerve injury, and astrocytes were activated soon after nerve injury, and the activation lasted for 12 weeks. Astrocytes and microglia then release cytokines and induce a series of cellular responses, such as the upregulation of glucocorticoid and glutamate receptors, leading to changes in spinal cord excitation and neural plasticity, which is closely related to the occurrence of neuropathic pain.

 

Factors involved in relieving or eliminating neuropathic pain in platelet rich plasma

1) Angiopoietin:

Induce angiogenesis; Stimulate endothelial cell migration and proliferation; Support and stabilize the development of blood vessels by recruiting pericytes

2) Connective tissue growth factor:

Stimulate leukocyte migration; Promote angiogenesis; Activates myofibroblast and stimulates extracellular matrix deposition and remodeling

3) Epidermal growth factor:

Promote wound healing and induce angiogenesis by promoting the proliferation, migration and differentiation of macrophages and fibroblasts; Stimulate fibroblasts to secrete collagenase and degrade extracellular matrix during wound remodeling; Promote the proliferation of keratinocytes and fibroblasts, leading to re epithelization.

4) Fibroblast growth factor:

To induce chemotaxis of macrophages, fibroblasts and endothelial cells; Induce angiogenesis; It can induce granulation and tissue remodeling and participate in wound contraction.

5) Hepatocyte growth factor:

Regulate cell growth and movement of epithelial/endothelial cells; Promote epithelial repair and angiogenesis.

6) Insulin like growth factor:

Gather together fiber cells to stimulate protein synthesis.

7) Platelet derived growth factor:

Stimulate the chemotaxis of neutrophils, macrophages and fibroblasts, and stimulate the proliferation of macrophages and fibroblasts at the same time; It helps to decompose old collagen and up regulate the expression of matrix metalloproteinases, leading to inflammation, granulation tissue formation, epithelial proliferation, production of extracellular matrix and tissue remodeling; It can promote the proliferation of human adipose derived stem cells and help to play a role in nerve regeneration.

8) Stromal cell derived factor:

Call CD34+cells to induce their homing, proliferation and differentiation into endothelial progenitor cells, and stimulate angiogenesis; Collect mesenchymal stem cells and leukocytes.

9) Transforming growth factor β:

At first, it has the effect of promoting inflammation, but it can also promote the transformation of the injured part to the anti-inflammatory state; It can enhance the chemotaxis of fibroblasts and smooth muscle cells; Regulate the expression of collagen and collagenase, and promote angiogenesis.

10) Vascular endothelial growth factor:

Support and promote the growth of regenerated nerve fibers by combining angiogenesis, neurotrophic and neuroprotection, so as to restore nerve function.

11) Nerve growth factor:

It plays a neuroprotective role by promoting the growth of axons and the maintenance and survival of neurons.

12) Glial derived neurotrophic factor:

It can successfully reverse and normalize neurogenic proteins and play a neuroprotective role.

 

Conclusion

1) Platelet rich plasma has the characteristics of promoting healing and anti inflammation. It can not only repair damaged nerve tissues, but also effectively relieve pain. It is an important treatment method for neuropathic pain and has bright prospects;

2) The preparation method of platelet rich plasma is still controversial, calling for the establishment of a standardized preparation method and a unified component evaluation standard;

3) There are many studies on platelet rich plasma in neuropathic pain caused by spinal cord injury, peripheral nerve injury and nerve compression. The mechanism and clinical efficacy of platelet rich plasma in other types of neuropathic pain need to be further studied.

Neuropathic pain is the general name of a large class of clinical diseases, which is very common in clinical practice. However, there is no specific treatment method at present, and the pain lasts for several years or even for life after the illness, causing serious burden to patients, families and society. Drug treatment is the basic treatment plan for neuropathic pain. Due to the need for long-term medication, patients’ compliance is not good. Long term medication will increase adverse drug reactions and cause great physical and mental damage to patients. Relevant basic experiments and clinical studies have proved that PRP can be used to treat neuropathic pain, and PRP comes from the patient itself, without autoimmune reaction. The treatment process is relatively simple, with few adverse reactions. PRP can also be used together with stem cells, which has a strong ability of nerve repair and tissue regeneration, and will have broad application prospects in the treatment of neuropathic pain in the future.

 

 

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Post time: Dec-20-2022