Regenerative Medicine and the Future of Interventional Orthopaedics: Repair, Regenerate, Restore

Mark W. McFarland, D.O.

Orthopaedic & Spine Center

Overview • Existing pain management treatments have been great for

suppressing pain by masking discomfort with medications such as:

• Cortisone

• Opiates

• NSAIDs

Overview • These treatments work great for pain relief but don’t actually

fix the problem

• Placing band-aid over the issue

• Underlying condition still remains

Overview • How are these injections different from cortisone shots?

• Stem cell injections have as goal to treat the damaged tissue, so that the body can heal. Not only to heal the problem, but to provide pain relief at the same time. Cortisone shots, on the other hand, do not have any other role than pain relief by providing anti-inflammation. While cortisone (steroid) injections are effective, they are not long term.

Overview • So how do we repair the problem at hand?

• Joint arthritis

• Back or neck pain

• Tendonitis or ligament injury

• Bursitis

Regenerative Medicine

The 10 Basic Things to Know

1. Ethics

• Modern Stem Cell Procedures Have NO Ethical Issues

• No fetal tissue

• Only adult stem cells or amniotic derived from consenting donors after c-section.

2. Uses • They are showing promise

for: • Degenerative & Rheumatoid

Arthritis

• SI Joint and Spinal Joints/Discs

• Tendonitis – achilles, rotator cuff, elbow, plantar fasciitis

• Ligament Injury

• Sports Injury

• Bursitis

• Stress Fractures

3. Blank Slate • Stem Cells are like a

blank slate:

• Start from an undifferentiated state and convert into any number of necessary cells.

• A lot of it depends on what environment they are placed into.

4. Healing Stem Cell Procedures Can HEAL Injury

• Traditional treatments with cortisone reduce pain but do not heal

• Potential to heal the damaged soft tissue and cartilage

• This is cutting edge, and helps get athletes back on the field faster, avoiding surgery.

• Can delay or avoid the need for joint replacement.

5. Source Current treatments do NOT use Embryonic Stem Cells

• Use of adult stem cells in research and therapy is less controversial than ES cells • production does not require the destruction of

an embryo.

• Amniotic fluid stem cells are intermediate between embryonic stem cells and adult stem cells. • They have potential to develop into different

cell types

6. Types

There are 4 Different Types of Regenerative Medicine Procedures

• Bone Marrow Derived

• Fat Derived

• Amniotic Derived

• PRP Therapy – Indirect Stem Cell Therapy

7. Amniotic Cells Amniotic Derived Stem Cells have Several Amazing Qualities

• Obtained from Consenting Donors after a scheduled C-section.

• Processed at an FDA regulated lab.

• Contains impressive qualities: • High Concentration of Stem Cells

• Hyaluronic Acid

• Growth Factors & Proteins

• Antimicrobial Properties

• Used tens of thousands of times worldwide without adverse events

8. Non-Orthopedic Uses Small Studies to date are showing excellent results:

• Leukemia

• Macular degeneration

• Spinal cord injury

• MS

• Stroke

• Burns/ Diabetic ulcers

• Heart disease

• Diabetes

9. Coverage • Not yet covered by insurance.

• Considered experimental

• Despite the exceptional results being reported, it usually takes insurance companies several years to cover new technology.

• The cost of the procedures ranges. If surgery can be avoided that can save considerable cost and disability

10. Risk Outpatient and Exceptionally Low Risk Procedures

• Does not require general anesthesia

• PRP Therapy – blood draw

• Fat and Bone Marrow Derived = Autologous

• Amniotic Derived = immunologically privileged (no rejection)and long track record (proven safe)

• Minimal adverse event potential

Treatment Decision Tree Interested Patient

Amniotic Stem Cells

+/- PRP

BMAC Stem Cells

Workup (Exam, Xrays, MRI, etc)

Mild/Moderate DJD/RA

Severe bone on bone

Sports/Overuse

Injuries

Elite Athletes

Joint

Replacement

PRP Therapy

Stem cells • Blank slate

• Receive chemical signals from the environment in which they are placed telling them which differentiation “pathway” to go down

• Stem cells contribute to the body’s ability to renew and repair its tissues

• Skin, cartilage, tendon, ligament, muscle

Is one type of stem cell better ?

• Theoretically the answer is yes • Pluripotent:

• Embryonic stem cells are pluripotent and can differentiate into over 200 cell types • Ethical concerns over how they are obtained, and also the cells themselves often do not know

when to stop replicating

• Multipotent: • Non-embryonic stem cells • obtained from one’s bone marrow or from amniotic fluid • can still differentiate into several important cell types, but not 200. • Able to turn into cartilage, muscle, tendon, ligament and most vital organ cells

• Multipotent stem cells have not been shown to form tumors like the pluripotent variety

Non-embryonic Stem Cells

• Derived from:

• Amniotic derived processed at an FDA regulated lab

• Patients own Bone Marrow or fat

• PRP (platelet-rich plasma)

Amniotic Stem Cells • Derived from amniotic fluid obtained during

scheduled c-sections from consenting donors

• Amniotic fluid surrounds fetus during pregnancy, feeding it

• Normally, this fluid is simply discarded

• Researchers have discovered that amniotic fluid has an extremely high concentration of stem cells

• more than bone marrow in adults

• Amniotic stem cells are actually immunopriviliged, so they do not create a rejection reaction when injected into a patient

Amniotic Stem Cells • Amniotic derived stem cell rich injections have

been used over 10,000 times in the US with no reported adverse events.

• Anecdotal reports for treating tendinosis and tendinitis including both golfer’s elbow and tennis elbow

• Anecdotal reports for joint arthritis in both the spine and extremities has also been encouraging.

• Surgeons have started using the amnion to supplement surgical repair and reconstruction of ACL’s, Achilles tendons and rotator cuff tendons.

Benefits of Amniotic Cells • 1. Immunologically Privileged- do not create a rejection reaction

• 2. High Concentration of Stem Cells (hybrid)

• 3. Hyaluronic Acid (joint lubrication)

• 4. Full Complement of Growth Factors

• 5. Anti-inflammatory and Anti-Adhesion Qualities

• 6. Anti-Microbial - minimal infection risk

• 7. Readily Available after scheduled C-sections

• 8. No Ethical Concerns - no fetal tissue

• 9. Do not form tumors (Reprod Biomed Online. 2009;18 Suppl 1:17-27)

• 10. Show benefits for an immense number of medical conditions.

Amniotic Stem Cells

• Are there Ethical Concerns? NO • Fetus is untouched. The placenta and amniotic

fluid are normally discarded after birth • Donors are consented, thoroughly tested, and

compensated • There are NO embryonic stem cells in Amniotic

Fluid

Amniotic Stem Cells • What are the Potential Medical Indications?

• Degenerative Arthritis

• Degenerative Disc Disease

• Soft Tissue Injury- Tendonitis, Tendonosis, Tendon Tears, Ligament Injury, Plantar Fasciitis

• Non-healing Wounds

• Crush Injuries

• Adhesion Barrier

• Fracture healing

• Ophthalmology

• Limb Salvage

• Cosmetic/Plastic

Amniotic Stem Cells • Is Amniotic Fluid FDA Approved?

• It is not FDA approved or disapproved. It is not a drug, therefore it does not have a label.

• Rather, amniotic fluid is FDA regulated as a biologic allograft according to CGTP Regulation 21 CFR 1271. (Current Good Tissue Practice)

• What are the Outcomes with Treatment? • Smaller studies showing good results:

• JOFAS 2013 - Prospective Study of 20 Foot/Ankle Wounds = 90% healed in 3 months and no amputations.

• Clinical review of stem cells for musculoskeletal conditions - Stem Cells Transl Med. 2012 - Application for bone defects, avascular necrosis, spinal fusion, cartilage lesions, tendon/ligament healing

Bone Marrow Derived

• Bone marrow contains a significant amount of the biologic materials necessary for regeneration

• Comes from the patient’s own body

• Bone marrow produces cells that are vital to existence including platelets, white blood cells and red blood cells.

• Three types of adult stem cells in the human body

• 1. blood components

• 2. lining of the endometrium

Mesenchymal Stem Cells

• 3. The third, and most important for musculoskeletal regenerative medicine, are mesenchymal stem cells found in bone marrow.

• They have been used in animal models to regenerate cartilage and in human models to regenerate bone. (Centeno et al, 2008)

• The richest sources of stem cells in the body for concentrated amounts of bone marrow are in the iliac crest of the hip and the bones of the spine

Bone Marrow Procedure

• Bone marrow extracted from the patient’s hip bone at the iliac crest

• Skin is sterilized and anesthetized with lidocaine

Bone Marrow Procedure • The patient’s cells are harvested in the

morning, isolated and processed, then re-injected into the patient’s injured area – all within a period of a few hours.

• Approximately 30 to 60 cc’s of bone marrow is acquired

• placed in a centrifuge and spun until a concentrated substance is obtained consisting of the most important regenerative cells

Bone Marrow Procedure • Is the procedure painful?

• There will be some mild to moderate discomfort. This may persist for a few days to weeks and slowly subside as the area heals.

• The injection into the intended site is no more painful than a typical cortisone injection

• For a few days afterwards, the joint may have slight increased pain due to the inflammatory reaction generated. This reaction is normal, as inflammation is the first stage of healing

PRP – Platelet Rich Plasma • The treatment of arthritis along with sports and overuse injuries

with platelet-rich plasma has received considerable attention because of its use in the successful treatment of injuries of high-profile professional athletes: • Peyton Manning • Kobe Bryant • Dwight Howard • Rafael Nadal • Tiger Woods • Hines Ward

PRP – Platelet Rich Plasma

• Consists of drawing blood from a patient and then spinning it down to concentrate platelets and growth factors.

• Plasma makes up the liquid part of human blood, and it contains red cells, white cells, and platelets.

• Play a significant role in blood clotting during an injury and with injury repair.

• Once activated, they start releasing proteins responsible for healing, called Growth Factors

PRP – Platelet Rich Plasma

• When administered to a patient, growth factors speed up the body’s natural capability to heal

• Will start to increase blood flow in the area, and create the grounds for healing the damaged tissue

• Platelets and growth factors call in the body’s stem cells as well to promote healing capability

• The tissue that was damaged will be replaced by new cells, and the cartilage has the potential to grow tougher and more resistant

• PRP has been shown to include the following growth and repair factors: • platelet-derived growth factor • transforming growth factor beta • fibroblast growth factor • insulin-like growth factor 1 • insulin-like growth factor 2 • vascular endothelial growth factor • epidermal growth factor • Interleukin 8 • keratinocyte growth factor • connective tissue growth factor

PRP – Platelet Rich Plasma

• PRP is prepared from the patient’s own venous blood.

• Cycling the blood through the centrifuge produces three layers: (1) the top layer of plasma; (2) the platelets and white blood cells (also known as “the buffy coat”); and (3) the red blood cells

• PRP can be concentrated to between three to eight times as much as normal blood

• Injected into the damaged area to stimulate growth and regeneration of healthy tissue, increase blood supply, and promote the repair of damaged tissue

PRP – Platelet Rich Plasma

Procedure

PRP – Platelet Rich Plasma

• PRP can be considered a promising intervention for sports injuries, and athletes looking for any advantage over their competitors may consider undergoing PRP for faster healing time

• Initial improvement may be seen within a few weeks, gradually increasing as the healing progresses.

• Both ultrasound and MRI images have shown definitive tissue repair after PRP therapy, confirming the healing process.

• The need for surgery can also be greatly reduced by treating injured tissues before the damage progresses and the condition is irreversible

Sports Agencies approve PRP • World Anti-Doping Association

• MLB

• MLS

• NBA

• NFL

Athletes treated • Peyton Manning

• Kobe Bryant

• Dwight

• Rafael Nadal

• Tiger Woods

• Hines Ward

Cell Placement • After the stem cells and platelets have been

processed, the patient is ready for the procedure.

• Great attention is given to both the processing and precise placement of the stem cells with every treatment.

• Real-time fluoroscopy or ultrasound is combined with careful planning to place the stem cells on the injured site with exact precision. This improves the likelihood that stem cells will adhere to the damaged tissue and promote healing.

Risks With the Procedure? • With the procedure being outpatient and minimally invasive,

the risks are low. But they do exist and include potential for infection, allergic reaction, bleeding, pain at the harvest site, wound drainage and failure to relieve a person’s pain. Risks should be discussed with your treating doctor.

• Treatment Failure

• Transmissible disease (amniotic only) - no cases ever reported and risk is @ 1 in 6,000,000,000,000

Results • Initial studies are showing great promise in regenerating and

healing injury while diminishing pain

Recent Study: RCR + Stem cells

• International Orthopaedics (2014;38:1811-1818)

• More than 25% of rotator cuff repairs re-tear after surgery. This rate has not improved much, despite the advent of new surgical techniques.

• Mesenchymal stem cells have the potential to aid healing because they can differentiate into tenocytes, chondrocytes, and osteoblasts, and are the source of multiple growth factors.

RCR + Stem cells

• 90 patients undergoing single row RTC repair

• 45 received repair plus harvested mesenchymal stem cells into tendon

• 45 received surgery only

• The RC repairs were monitored with ultrasound every month for 24 months, and with MRI at 3 and 6 months and at 1, 2, and 10 years.

• After 6 months, repairs in all 45 patients in the stem cell group but in only 30 patients in the control group had healed (100% vs 67%).

RCR + Stem cells

• Results at 10 Years Post-op: • 39 repairs in the stem cell group and only 20 in the control group

were still intact (87% vs 40%; P < .05)

• Evidence supporting mesenchymal stem cell implantation in rotator cuff surgery

• Injecting the cells into the tendon: • increases the fixation

• shortens the healing time, but also you

• increase the strength in the tendon

Results

Results

Results

• Current research is providing guidance in this rapidly evolving field with regard to determining the best way to employ various stem cell sources to harness these various effects to increase the effectiveness of cellular therapy treatment.

Summary

• Exact mechanism of what occurs after the placement of these cells in areas of injury is evolving

• In essence, these biologic treatments represent a manner of inducing an individual’s own healing response

Summary

• The potential benefit of most of these treatments have yet to be realized in the daily practice of medicine

• Research is ongoing and scientific data is building

• At present, these regenerative techniques remain “experimental” when viewed by Medicare and the various commercial health insurance carriers

Conclusion • There is great hope that these treatments will result in a new

paradigm of orthopedic treatment that facilitates tissue healing rather than the alteration, removal, and/or replacement of musculoskeletal tissue, i.e. meniscal resection and joint replacement, discectomy and spinal fusion.

• It will be only through the refinement of treatment protocols and the publications of compelling results of treatment that the medical community can accept their efficacy and clinical utility.

Conclusion

• In the end, these treatments represent a modern method of facilitating our own body’s inherent capabilities of healing, and offers an alternative to surgery and another treatment option in an constantly evolving field

Thank You!