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1. Autologous Plasma and Regenerative Techniques for Chronic Pain Due to Musculoskeletal Conditions, Neuropathy, and Scar Tissue Dr. John Hughes, DO | OMED – VIRTUAL | October 2020

2. Disclosure The content of this presentation has been peer reviewed for fair balance and evidence- based medicine. Dr. John Hughes, DO has no relevant financial relationships to disclose.

3. Dr. John Hughes, DO • Doctor of Osteopathy • From Georgia • Arizona College of Osteopathic Medicine – 2007 • Aspen Integrative Medicine – 2009 • TBI Therapy – 2014

4. Learning Objectives • Define and distinguish chronic pain • Define and understand methods of obtaining autologous plasma • Understand the benefits of regenerative medicine

5. But first, what is pain? • Pain results from tissue damage • It is a part of the body’s defense mechanism • Acute: intense and short-lived • Chronic: continuous and long-lived

6. What Causes Chronic Pain? • Arthritis • Joint problems • Back pain • Headaches • Muscle strains and sprains • Repetitive stress injuries • Fibromyalgia • Nerve damage • Broken bones • Cancer • Acid reflux or ulcers • IBD or IBS • Endometriosis • Surgery • And more

7. Chronic Pain in the Body • Bombardment of the central nervous system (CNS) • Nociceptive impulses • Inflammation

8. 3 Types of Pain Nociceptive Normal response to noxious insult or injury of tissues such as skin, muscles, visceral organs, joints, tendons, or bones Neuropathic Pain initiated or caused by a primary lesion or disease in the somatosensory nervous system Inflammatory Activation of an inflammatory cascade attempting to heal the injured area involving biochemical reactions

9. Physiology of Pain from Injury Nociceptive Triggers the nervous system to react Neuropathic An overly sensitized nerve response due to nerve injury, impingement, or CNS dysfunction Inflammatory Triggers biochemical reactions to heal the area May not reach full healing potential = chronic pain

10. What happens when you strain your back? • Activation of nociceptive nerve fibers • A signal is sent down the neuron via the spinal cord to the brain • Signals upregulate the feeling of pain and initiates the inflammatory response 1) Nociception

11. What happens when you strain your back? • Damaged cells release cytokines and other mediators • Initiates vascular dilation and permeability • PMLs, followed by macrophages enter the scene • Stimulates the migration and proliferation of fibroblasts 2) Inflammatory Response

12. What happens when you strain your back? • Connective tissue begins to heal • Fibroblasts encourage synthesis of procollagen matrix (2-3 days after injury) • Vascular buds form increasing blood supply (3-4 days) 3) Proliferation Phase

13. What happens when you strain your back? • Collagen type I changes to collagen type III • Fibrils increase along lines of stress to become tightly packed (2-3 weeks) • Collagen thickens and increases to preinjury length but with only 50 to 70 % tensile strength • With severe injury, the healing process may stop before the tissue is sufficiently competent for everyday use 4) Remodeling Phase

14. Scar Tissue • Aka Fibrosis and Tendinosis • Due to injury or long-term inflammation • Forms a web around the injured area in an attempt to support the muscle while it heals itself

15. Histology of Scar Tissue in Tendons Adapted from The Journal of Bone and Joint Surgery Normal Tendon with distinct elongated, parallel fibers Scar tissue (fibrosis) early: disorganized collagen, fibroblasts infiltrate: loose and pale appearance

16. Bone Spurs • Aka Osteophytes or Enthesophytes • Bony projections that form along joints • Enthesophytes are bony projections which form at the attachment of a tendon or ligament • Often seen in conditions such as arthritis • Largely responsible for limitations in joint motion and can cause pain

17. Neuromas • Morton’s Neuroma • Thickening, or enlargement of a nerve leading to compression and irritation of the nerve • Usually located between the 3rd and 4th metatarsals • Largely due to sodium channels, which are upregulated in neuromas • Accumulation of PN1 and PN3 sodium channels in painful human neuroma- evidence from immunocytochemistry.

18. Treatment for Chronic Pain

19. Are Cortisone Injections the Answer? • Blocks inflammation • Stops the healing / inflammation cascade • Decreases immune function (risking microbial infection) • Causes tendon weakening, atrophy, or ruptures

20. Are Anti- Inflammatory Drugs the Answer? • Non-Steroidal Anti-Inflammatories (NSAIDS) • Inhibit COX enzymes and reduce the formation of prostaglandins • Damages the gastrointestinal track • Opiates • Block spontaneous firing fibres and nociceptive activity • Damages the body and brain

21. Other Treatments for Pain Surgery TENS Physical Therapy Psychological Treatment Acupuncture Chiropractic Treatment Therapeutic Touch / Reiki Nutritional Supplements Herbal Remedies Cannabinoids Proliferative Injections …

22. Proliferative Injections • Proliferation: the growth or production of cells by multiplication of parts • Proliferative therapy: injection of irritant or proliferant solutions into the affected ligaments, tendons, and/or joints • Leads to local inflammation in the injected area • Localized inflammation triggers a wound healing cascade

23. Prolotherapy • Causes a temporary, low grade inflammation at the injection site • Activates fibroblasts to the area, which, in turn, synthesize precursors to mature collagen and thus reinforce connective tissue • Direct exposure of fibroblasts to growth factors causes new cell growth and collagen deposition • Inflammation creates secondary growth factor elevation • Initiates a new connective tissue repair sequence which had prematurely aborted or never started

24. Prolotherapy • Dextrose is thought to “dehydrate” the injected tissues, causing an injury signal for the body, and initiating the healing process. • Dextrose has been shown to be a growth stimulant • Inflammation restarts the normal healing cascade that would occur with an acute injury

25. Prolotherapy: Clinical Evidence • 1800 patients followed for 2 years – 80% showed marked improvement in upper and lower body pain • Hackett GS: Prolotherapy in whiplash and low back pain. Postgrad Med 27:214-219, 1960 • Two RCTs (160 participants) found that prolotherapy injections, given with spinal manipulation, exercise, and other therapies, are more effective than control injections for chronic low-back pain and disability. •

26. Prolotherapy: Clinical Evidence • 60% increase in collagen fibril diameter measured at 3 months after 6 weekly injections in patients with low back pain • Klein RG, Dorman TA, Johnson CE: Proliferant Injections for Low Back Pain: Histological Changes of Injected Ligagments and Objective Measurements of Lumbar Spine Mobility Before and After Treatment J Neurol Orthop Med Surg 10: 141-144, 1989 • Osmolarity studies: Elevation osmolarity by as little as 50 mOsm has been found to activate multiple growth factors including PDGF

27. Prolotherapy: Clinical Evidence • Response of Knee Ligaments to Prolotherapy in a Rat Injury Model • Am J Sports Med July 2008 vol. 36 no. 7 1347-1357 • Conclusion: Dextrose injections increased the cross- sectional area of MCLs compared with saline-injected and uninjured controls. Dextrose injections did not alter other measured properties in this model.

28. Prolotherapy: Clinical Evidence • A systematic review of four injection therapies for lateral epicondylitis: prolotherapy, polidocanol, whole blood and platelet-rich plasma • British Journal of Sports Medicine 2009;43:471-481 • Conclusions: There is strong pilot-level evidence supporting the use of prolotherapy, polidocanol, autologous whole blood and platelet-rich plasma injections in the treatment of LE.

29. PRP = The Supercharged Proliferative Injection

30. What is Platelet Rich Plasma (PRP)? • From autologous blood • Contains levels of platelets above baseline levels • Cell ratios in normal blood contain only 6% platelets, in PRP contains 94% platelets • Contains over 300 growth factors

31. Process of PRP 1) Collect blood 2) Separate the platelets 3) Extract platelet- rich plasma 4) Inject injured area with PRP

32. How Does PRP Work? 1) Formulates Collagen • The main component of connective tissue • Found in ligaments, tendons, skin, blood vessels, cartilage, and many other parts of the body • New collagen shrinks as it matures – tightening damaged tissue – making it stronger

33. How Does PRP Work? 2) Releases Growth Factors • Regulates cell division and cell survival • Activates cellular proliferation and differentiation • Promotes cell growth • Functions as hormones-like regulator signals • Improves metabolism of nutrients • Guide stem cells to area of injury • Nurture stem cells to maturity

34. Growth Factors Growth Factor Cellular Factor PDGF Platelet Derived Growth Factor Macrophage activation and angiogenesis Fibroblast chemotaxis and proliferative activity Enhances collagen synthesis Enhances the proliferation of bone cells IGF-1 Insulin-like Growth Factor-I Chemotactic for myoblast and fibroblasts and stimulates protein synthesis Mediator in growth ad repair of skeletal muscle Enhances bone formation by proliferation and differentiation of osteoblasts TGF-p Transforming Growth Factor-β Enhances the proliferative activity of fibroblasts Stimulates biosynthesis of type I collagen and fibronectin Induces deposition of bone matrix Inhibits osteoclast formation and bone resorption Regulation in balance between fibrosis and myocyte regeneration. PDEGF Platelet Derived Endothelial Growth Factor Promotes wound healing by stimulating the proliferation of keratinocytes and dermal fibroblasts PDAF Platelet Derived Angiogenic Factor Induces vascularization by stimulating vascular endothelial cells EGF Endothelial Growth Factor Cellular proliferation Differentiation of epithelial cells VEGF Vascular Endothelial Growth Factor Angiogenesis Migration and mitosis of endothelial cells Creation of blood vessel lumen Creation of fenestrations Chemotactic for macrophages and granulocytes Vasodilation (indirectly by release of nitrous oxide) HGF Hepatocyte Growth Factor Stimulates of hepatocyte proliferation and liver tissue regeneration Angiogenesis Mitogen for endothelial cells Antifibrotic

35. Growth Factor Animal Studies • Autologous PRP was injected into normal patellar tendons of New Zealand White rabbits • Histological analysis at 6- and 12-weeks post-injection revealed a robust angiogenic response • Locally injected PRP into a wounded rat patellar tendon • Resulted in an increased number of circulation-derived cells involved in the tendon healing • Combined PRP/Losartan injections resulted in improved muscle strength, as measured in peak twitch and tetanic forces • Suggesting that combination treatment with PRP/Losartan can improve muscle healing by exerting anti-fibrosis, pro-angiogenesis, and pro-myogenesis effects through inhibition of TGFβ1 • PRP-mediated effects on tendon healing could be secondary to improved vascularity (with careful consideration of the potential degradative properties of angiogenesis) • Anti-inflammatory effects of growth factors known to increase with exogenous administration of platelets • PRP has been shown to suppress cyclooxygenase (COX)-1, COX-2, and membrane prostaglandin E synthase (mPGES) expression in vitro – all involved in the inflammatory pathway

36. How Does PRP Work? 3) Secretes Cytokines • Proteins released by cells • Lymphokine, monokine, chemokine, and interleukin • There are anti- and pro-inflammatory cytokines

37. PRP Helps Treat Unresponsive Chronic Pain & Injuries Over time, the body stops recognizing the area as something to repair PRP creates a purposeful, mild inflammation response to the damaged tissue This restarts the healing process and allows new fibers to grow back

38. Injuries Treated by PRP • Chronic Sports Injuries (ex. Tennis Elbow, Achilles Tendonitis, and Runner’s Knee) • Degenerative Joint & Disc Disease • Chronic Sprains and Strains • Cervical, Thoracic, and Lumbar Spine Strains • Traumatic Brain injuries • Arthritic Joints • Shoulder Pain, Hip Pain, and Knee Pain • Ligament Laxity or Tears • Tendon and Ligament Injuries • Carpal Tunnel Syndrome

39. PRP Reduces Tendonitis Symptoms • 30 – 50% of all sports-related injuries are tendon disorders • 93% reduction of pain at the 2 year follow up • Achilles tendon or elbow, extensor or flexor tendonitis/tendinosis or tears • Collateral ligament tears

40. PRP Helps Decrease Osteoarthritis Symptoms • Restores hyaluronic acid concentrations • Improves angiogenesis • Reverses joint damage and stops disease progression

41. PRP Reduces Lower Back Pain • Treats structural ligaments (such as iliolumbar, sacroiliac, lumbosacral and supraspinous ligaments), muscle strains, and muscle fibrosis • Improve stability and dispersion of weight

42. Other Uses of PRP • Reversing hair loss • Facial rejuvenation

43. Celebrities for PRP Angelina Jolie: It has been reported that Angelina Jolie took the PRP skin rejuvenation treatment to boost her collagen. Tiger Woods: In 2008, Tiger Woods had a serious ACL injury. After reconstruction Woods received PRP injections to recover faster. And due to his speedy healing, 2009 was one the best years of his golfing career. Alex Rodriguez: The Yankees player A-Rod had 5 PRP sessions after his hip surgery back in 2009. He was able to get back into shape for playing again way sooner than anticipated by his physician. Kobe Bryant: Kobe Bryant would fly to Germany to heal his knee faster with PRP and avoid the threat of having to retire early.

44. Other Regenerative Treatment Options for Chronic Pain

45. Prolozone • Injection of ozone into the tissue • Increases blood supply and flow of healing nutrients • Stimulates the deposition and activity of fibroblasts and chondroblasts • Synthesize collagen and cartilage to repair damaged ligaments and joints • Natural, highly reactive, and safe = highly therapeutic • Antimicrobial and sterilizing This Photo by Unknown Author is licensed under CC BY-SA

46. Intervertebral O3 injections– Italian Study • 1999 to 2001 • 600 patients aged 20–80 years • Treated with a single dose of oxygen-ozone therapy • 300 patients (Group A) received an intradiscal (4 mL) and periganglionic (8 mL) injection of an oxygen-ozone mixture with an ozone concentration of 27 µg/mL • The other 300 patients (Group B) received identical oxygen-ozone injections, followed by a periganglionic injection of corticosteroid (1 mL of Depo-Medrone 40 mg and anesthetic (2 mL of Marcain 0.5%

47. Puncture at L4-L5 performed under CT guidance. The L4–5 level was the most frequently treated (61.8%); L1–2, 0.7%; L2–3, 1.2%; L3–4, 8.7%; L5-S1, 27.6%.

48. Therapeutic outcome 6 months after oxygen- ozone therapy. Light gray bars indicate group A (n=300); dark gray bars, group B (n=300). Numbers at top of bars are percentages.

49. Combining Prolotherapy, PRP, Prolozone • If prolotherapy, PRP, and prolozone all are effective in their own ways, would it not be synergistically better to combine all of these therapies in one procedure? • Unfortunately, many practitioners do not have the skills or knowledge yet on how to do this alchemy. The secret mix, however, is pretty simple. • Here’s the Steps in the next slides

50. Combining Prolotherapy, PRP, and Prolozone 1. Make up the local anesthetic/light prolotherapy solution — Start with preservative free 1% ropivacaine*. Dilute with normal saline to 0.3%. Note: Do not use lidocaine, procaine, nor any other local anesthetic. Create a 8 cc solution in a 10 or 12 cc syringe. –Add 2 cc of D50 to the 0.3% ropivacaine make a D10 solution. Then add ¼ cc of magnesium chloride to the solution. 2. Make up the PRP/plasma solution using peripheral autologous blood — Add 10cc of ozone at 20ug/cc to a 30 or 60 cc syringe. Pull up the desired amount of blood from an IV catheter from the patient. Keep in mind that plasma is roughly 55% of total blood volume –Add the whole plasma to yellow top 8.5 ml sodium citrate tubes (You do not need a special kit for PRP—most of them are waste of money) –Spin the plasma at 3400 rpm for 8-10 min. A standard lab/blood draw centrifuge will work. –Pull off all the plasma, not just the bottom layer using a 20g 3.5 inch spinal needle; be careful not to pull up any red cells. If you get a small amount of red cells, it’s okay but too many red cells can damage joints. –Add the PRP to a 20cc syringe containing 10cc of ozone at 20ug/cc and 2 cc D50, ½ of 3% HCL, ¼ cc Ascorbate (nutrients) –Activate the PRP cocktail by adding ¼ cc Magnesium chloride to the solution and let sit for 5-10 min (or use a green laser light for 10 min) *Ropivacaine is used because it does not harm the growth factors or stem cells in the PRP

51. Combining Prolotherapy, PRP, and Prolozone 1. Make up the ozone solution — Use a 10-60 cc syringe and pull up ozone at 20 ug/cc 2. Identify the areas for injection by palpation or ultrasound 3. Injection of Local/Prolotherapy and Gentle Curettage — Inject the ropivacaine/D10 cocktail first; most small tendon/ligament areas require 3-5 cc and larger ligament areas 7-10 cc. Large joints such as the hip joint can require 12 or more cc depending on the patient’s injury and pain tolerance –Scrape away any fibrosis, enthesopathy, or bone cysts present

52. Combining Prolotherapy, PRP, and Prolozone 4. Injection of PRP cocktail — Most areas will require an equivalent amount of PRP 5. Injection of Ozone — Inject 5-10 cc of ozone gas into the affected tendon, ligament, or joint In sum, the local/prolotherapy solution and PRP act like guided missiles to break down fibrosis/bone spurs while also regenerating damaged tissues. Acting like a bomb, the ozone accelerates this regenerative process and naturally steriles the area

53. Stem Cells • Undifferentiated biological cells • Divide and generate all cell types of the organ from which they originate • Stimulate tissue re-growth and greater blood flow to the affected areas

54. What Are Stem Cells? Embryonic • Mostly derived from embryos that develop from eggs in vitro • Expensive • Not autologous • Ethically controversial • Not readily available – research only

55. What Are Stem Cells? Tissue-Specific • For the specific tissue or organ in which they live • Lung – Lung • Heart – Heart • Do not self-renew as easily • Difficult to find

56. What Are Stem Cells? Mesenchymal • From bone marrow, fat, and cord blood • Immunomodulatory properties • On a development trajectory towards specific target tissues (aka lineage committed) • Therapeutic effects are short-lived

57. What Are Stem Cells? Pluripotent • Recently discovered in peripheral blood • Behave like embryonic stem cells • Give rise to all the cell types • Long lifespan

58. Stem Cell Potency Totipotent *Pluripotent* Multipotent Embryonic Peripheral Blood Mesenchymal

59. Stem Cell Uses Embryonic Peripheral Blood Mesenchymal • Research • Degenerative Diseases • Degenerative Diseases: • Diabetes • Osteoarthritis • Osteoporosis • Alzheimer’s Disease • Regeneration: • Brain Injuries • Joint/Ligament Repair • Anti-aging • Post Cancer Treatment • Fertility • Same tissue Replacement • Systemic Inflammatory Conditions

60. Regenerative Stem Cell Uses • Chronic Sports Injuries (ex. Tennis Elbow, Achilles Tendonitis, and Runner’s Knee) • Degenerative Joint & Disc Disease • Chronic Sprains and Strains • Cervical, Thoracic, and Lumbar Spine Strains • Traumatic Brain injuries • Arthritic Joints • Shoulder Pain, Hip Pain, and Knee Pain • Ligament Laxity or Tears • Tendon and Ligament Injuries • Carpal Tunnel Syndrome

61. How to Treat Chronic Pain • Surgery – expensive, risky, potential side effects • Physical Therapy – only manages pain, therapeutic but not long term • Cortisone Injections – temporary fix, manages inflammation, rarely solves source of pain, potentially damaging • Regenerative Injection Therapy – natural, autologous, treats cause of pain rather than symptom, long term

62. Chronic Pain Treatment Costs • Surgery = $40,000 – $100,000 • Physical Therapy = $50 – $350 per session • Embryonic Stem Cells = only research purposes • Mesenchymal Stem Cells = $7,000 – $300,000 • Pluripotent Stem Cells = $8,000 – $10,000 • Platelet Rich Plasma (PRP) = $1,200 – $2,500

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