Pain management has long been a focus in medicine, its history dating back to ancient times. Early Egyptian, Chinese and Persian physicians first considered pain as purely a manifestation of emotions rather than the physical senses. Different theories on the expression and perception of pain have evolved through the years, but it wasn’t until 1924 that the term “neuropathy” was first used to describe a disease of the nerves. Today, it is estimated that more than 20 million people in the US have some form of neuropathy.

Research in the past decade has demonstrated that adipose-derived stem and regenerative cells (ADRCs) are effective at promoting nerve repair and thus have the potential to help improve the symptoms, function and quality of life of patients who have nerve damage in their arms and hands, legs, feet, and skin. ^{[1] [2] [3]}

The scientists investigating ADRCs have reported that this mixed population of cells reduce inflammation, rebalance the immune system, restore blood flow and regenerate tissues, nerves and organs. Through multiple biologic activities, these cells have been used safely and effectively in a wide range of conditions including the treatment of neuropathy. ADRCs are akin to having a personalized biologic “fire, rescue and repair crew” that naturally resides in our bodies. They wait quietly for a sign of trouble—inflammation—and then home to that site to do their jobs. ^{[4] [5] [6]}

Nerve Damage

Neuropathic pain arises from damage to the nervous system itself. It’s often stabbing, electrical, or burning, but any quality of pain is possible. Unfortunately, it’s also more likely to lead to chronic pain: nerves don’t heal well on their own. System-wide inflammation is a key player in the disease process of neuropathies.^[7] The effects of neuropathy depend on the type of nerves they affect. Many neuropathies affect all three kinds of nerves.

Motor neuropathy impairs the movement of muscles under conscious control, such as those used for walking, grasping things, or talking.

Sensory neuropathy changes how we feel light touch, temperature, body position, or the pain from a cut.

Autonomic neuropathy interrupts the automatic control of organs to regulate things like digesting food, breathing, and heart and gland functions.

Causes of Neuropathy

Physical injury is the most common cause of single nerve damage. Accidents and surgeries can stretch, crush, swell, or compress peripheral nerves.

Diabete is the leading cause of polyneuropathy, and it can affect sensory, motor, and autonomic nerves.

Poor blood flow to nerves diminishes the delivery of oxygen, and results in damaged nerves.

Systemic (body-wide) autoimmune diseases, in which the immune system mistakenly attacks a number of the body’s own tissues, can target the nerves. For example, Sjögren’s syndrome, lupus, and rheumatoid arthritis can cause neuropathic pain.

Infections and viruses such as varicella-zoster virus (which causes chicken pox and shingles), West Nile virus, cytomegalovirus, and herpes simplex target sensory fibers, causing attacks of sharp, lightning-like pain. Lyme disease, a bacterial infection transmitted by tick bites, can cause a range of neuropathic symptoms. Autoimmune diseases that attack nerves only are often triggered by infectious agents, such as seen in Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy.

Medications can cause neuropathy, particularly cancer chemotherapy drugs.

Chemical toxins can target the nervous system, such as insecticides and solvents, or heavy metals like lead, mercury, and thallium.

Unfortunately, a large number neuropathies are idiopathic, with no known cause. Several new reports now show evidence for peripheral nerve abnormalities in fibromyalgia patients that could contribute to their chronic pain.^[8]

Demyelination – Remyelination

Neuropathy is a neuro-inflammatory disease in which the immune system attacks the insulation (myelin sheathing) of the nerves of the PNS, leading to demyelination.^[9] Myelin sheathing is similar to the idea of coating an electrical wire with insulation to protect the metal underneath it. A nerve without myelin sheathing transmits the electrical nerve impulse very slowly, defectively, or not at all.

Studies have demonstrated that adipose-derived stem cells have the potential to remyelinate demyelinated nerves associated with neuropathy and other demyelinating diseases.^{[10] [11]}

Risposta infiammatoria-immunitaria

Acute inflammation can be triggered by a trauma, infection, chemicals, environmental toxins, lifestyle choices (e.g. smoking), hereditary factors or any combination of these or other factors. This type of inflammation is essential for repairing the body, and is usually short-lived, disappearing once the healing process has taken place.

Inflammation is only problematic when it lingers, becoming chronic, and affects the entire body, becoming systemic. Chronic, systemic inflammation is often a final common pathway of neuropathy.^[12] L'infiammazione sistemica è un fattore comune nelle malattie dell'invecchiamento, che comprendono un ampio spettro di condizioni gravi, debilitanti e, talvolta, pericolose per la vita.^[13]

An inflammatory response begins a vicious and detrimental process. It recruits the immune system, which is there to fight infections and other disease processes, to assist healing. The cells in the immune system (immune cells) are there to guard the body. When they sense the enemy, they send out troops of molecules called “cytokines” to fight them off. When this process goes out of control, it is called an inflammatory-immune response.

The immune response is tantamount to having a backseat driver who is chronically overreacting while “helping” you drive your car. It then leads to reduced blood flow (ischemia). Without good circulation, cells die off. In neuropathy, this causes the myelin sheathing to degenerate which will then lead to scar to form in its place. We call this the Spiral of Degeneration.

Processo di riparazione

Through a mechanism of cell-to cell communication known as the paracrine effect, ADRCs mobilize nearby cells to work more efficiently.

Recruiting additional “repairmen” at the site (resident stem cells) to get back on the job and do their part, ADRCs assemble an extended team and work first to decrease inflammation and the overactive immune responses. Once the backseat driving diminishes, they continue their work by increasing circulation with new blood vessel growth, preventing further cell death, decreasing scar size and finally the regeneration of healthy tissue and nerves.

This is the body’s natural healing process, sometimes it just needs reinforcements. We call this the Process of Repair.

Bioactive Molecules

ADRCs emit hundreds of bioactive molecules that address the complex effects in the peripheral nervous system as well as other tissues and organs that are affected by or causes of neuropathy. Very relevant and important to PN are a family of biomolecules you could think of as an organic fertilizer for our nerves. These are called neurotrophic factors (NTFs). (Neuro-, relating to nerve; –trophic from Ancient Greek τροφικός [trophikós] meaning “pertaining to food or nourishment.”)

NTFs support the growth, survival, and differentiation of both developing and mature nerve cells (neurons) including new myelin sheathing. It has been shown that adipose-derived stem cells release brain-derived neurotrophic growth factor (BDNF) which promotes nerve healing and nerve growth. ^{[14] [15] [16] [17]}

AMBROSE Cell Therapy for Neuropathy

AMBROSE Cell Therapy represents a minimally invasive option to improve symptoms, function and quality of life for patients with neuropathy. The AMBROSE protocol includes a dual treatment approach for neuropathy, addressing both the deep and shallow nerves. Local nerve pain is addressed by injecting on the sides of the neurovascular bundles (perineural) under ultrasound guidance.

Per favore contattateci per ulteriori informazioni sul trattamento, sulla candidatura e su come diventare un paziente.

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[2] JY Zhou et al Cellule staminali mesenchimali per il trattamento della neuropatia diabetica: un percorso lungo e faticoso dal banco alla clinica Cell Death Discovery (2016) 2, e16055

[3] R Zhang, JM Rosen. Il ruolo delle cellule staminali indifferenziate di derivazione adiposa nella riparazione dei nervi periferici. Neural Regen Res 2018;13:757-63.

[4] JK Fraser PhD e S. Kesten MD Cellule rigenerative di derivazione adiposa autologhe: Una piattaforma per applicazioni terapeutiche Advanced Wound Healing Surgical Technology International XXIX

[5] A Nguyen, A et al Frazione vascolare stromale: Una realtà rigenerativa? Parte 1: Concetti attuali e revisione della letteratura Journal of Plastic, Reconstructive & Aesthetic Surgery (2016) 69, 170e179

[6] Guo et al Frazione vascolare stromale: Una realtà rigenerativa? Parte 2: concetti attuali e revisione della letteratura Journal of Plastic, Reconstructive & Aesthetic Surgery (2016) 69, 180e188

[7] R Pop-Busui et al Inflammation as a Therapeutic Target for Diabetic Neuropathies Curr Diab Rep. 2016 March; 16(3): 29

[8] AL Oaklander et al Prove oggettive che la polineuropatia a piccole fibre è alla base di alcune malattie attualmente etichettate come fibromialgia. PAIN: Novembre 2013 - Volume 154 - Numero 11 - p 2310-2316

[9] A Ellis, D.L.H. Bennett Neuroinflammation and the generation of neuropathic pain, British Journal of Anaesthesia, Volume 111, Issue 1, 2013, Pagine 26-37

[10] A Hedayatpour et al. Promozione della rimielinizzazione mediante trapianto di cellule staminali mesenchimali adipose in un modello di sclerosi multipla con cuprizone. Cell J. 2013; 15(2): 142-151

[11] N Ghasemi Effetti terapeutici delle cellule staminali mesenchimali derivate dall'adipe sul processo di rimielinizzazione nelle malattie demielinizzanti infiammatorie Journal of Histology & Histopathology 2015

[12] S. Amor L'infiammazione nelle malattie neurodegenerative Immunologia, 129, 154-169

[13] C. Franceschi e J. Campisi L'infiammazione cronica (Inflammaging) e il suo potenziale contributo alle malattie associate all'età J Gerontol A Biol Sci Med Sci 2014 June;69(S1): S4-S9

[14] Razavi, Shahnaz et al. "Fattori neurotrofici e loro effetti nel trattamento della sclerosi multipla". Ricerca biomedica avanzata 4 (2015): 53. PMC. Web. 28 settembre 2018.

[15] J. K. Huang et al Rigenerazione della mielina nella sclerosi multipla: Targeting. Cellule staminali endogene", Società americana di neuroterapia sperimentale, Inc. 2011.

[16] T Lopatina et al. (2011) Le cellule staminali di derivazione adiposa stimolano la rigenerazione dei nervi periferici: Il BDNF secreto da queste cellule promuove la guarigione dei nervi e la crescita degli assoni de novo. PLoS ONE 6(3): e178991

[17] S. Seigo et al, Uncultured adipose-derived regenerative cells promote peripheral nerve regeneration, Journal of Orthopaedic Science, Volume 18, Issue 1,2013, Pagine 145-151