Regenerative Medicine Halland Chen, MD Speaker Disclosures I disclose that I am not a consultant or have any financial interests. 2 What is regenerative medicine? Regeneration of human cells, tissues, or organs to restore or establish normal function. (Chris Mason, Ph.D.) Cell therapy is one of the maincomponents of regenerative medicine. Cell therapy uses cells, such as stem cells, to regenerate diseased tissue in the human body. 1
What are stem cells? A master cell in the body which can multiplyindefinitely and create many differenttypes of cells ( >200 ) in the human body (blood cells, skin cells, cartilage cells, etc.). Stem cells help to renew and repair cells in the human body. Where are stem cells found? Bone marrow Fat Tissues (heart, liver, kidneys, etc.) What are stem cell treatments? Autologous Stem Cell treatments (own cells) Allogenic Stem Cells (donor cells) Induced Pluripotent Stem Cells (cells converted to stem cells) Pharmaceutical treatments (activate stem cells) 2
What can stem cells treat in the future? FDA studies to find future cures FDA Phase I, II, III Studies Current FDA Phase III Studies: Bone marrow transplant rejection Crohn s Disease Heart attack prevention and treatment Heart failure Cancer treatments (bone marrow cancer) Diabetic foot ulcers Limb Ischemia (blood flow) Knee cartilage repair Multiple Sclerosis Parkinson s Disease Treatments are coming but will take time Q: What types of stem cell treatments can be done today? A: Orthopedicstem cell treatments 3
The science of stem cell treatments for orthopedic conditions Why are stem cells important? Because they are the body s repaircells. They are the onlycells that can renew and regrow. To repaira laceration, repair occurs by growth of fibroblasts (skin stem cells). To heala fracture, osteoblasts (bone stem cells) are needed. After a haircut, hair regrowth is thanks to hair follicle cells (hair stem cells). Without stem cell you would only live approximately two days! Classification of stem cells Who they come from Allogeneic (non-self) and autologous (self) Embryonic and Adult Where they come from Blood, bone marrow, adipose, and placenta What they do Hematopoeticand Mesenchymal 4
Embryonic Stem Cells By far the most controversial stem cells. Most ESC lines outlawedby President George W. Bush (2000-2008). Research reinstatedby President Barack Obama. U.S. government has lifted some bans but FDA has still significantly restricts ESC use in humans. Since an embryo (potential living human being) is destroyed creating ESCs, there are ethical issues. Embryonic Stem Cells Initiallywas to have the most potential for correcting and curing certain conditions due to their plasticity or ability to morph into many cell types. However, patients will inherit any potential diseases that the embryo may have. Embryonic Stem Cells There is a significant potential that the cells can grow unchecked and essentially act as a tumor. There are certain immunogenicfactors. Will the body attack the stem cells as being foreign invaders? The patient may be required to take drugs to ward off cell rejection. 5
Autologous Stem Cells Derived from the patient themselves. Noproblems with immunity or rejection. May notbe useful for auto-immune or genetic diseases has patient s problems. Type I diabetes, muscular dystrophy Age-specific changes. Efficacy, numbers Autologous Stem Cells Hematopoietic Stem Cells (HSCs) Commonly found in bone marrow Mesenchymal Stem Cells (MSCs) Commonly found in fat tissue (adipose) Induced Pluripotent Stem Cells (ipscs) MUSE Cells (Multi-lineage differentiating stress enduring cells) VSEL (Very Small Embryonic-Like Stem Cells) Thought to be the body's emergency stem cell supply Hematopoietic Stem Cells HSCs discovered in 1960 s by Dr. Till and Dr. McCulloch. Over 50 years of clinical use, mostly in bone marrow transplants for cancer. Located in redbone marrow (primarily), also para-aortic, fetal liver. Drive tissue regeneration 6
Autologous Stem Cells Mesenchymal Stem Cells In 1987, Dr. Arnie Caplan coined the term mesenchymal stem cell. MSCs were initially thought to be the most important cell because early technology was only capable of expanding and differentiating MSCs in vitro. It was initially felt that if sufficiently expanded and then transplanted, MSCs would produce clinical success. Mesenchymal Stem Cells 7
Mesenchymal Stem Cells Main sources Adipose tissue (largest source) Umbilical cord blood Red marrow (few) Amniotic fluid Dental pulp Hair follicles The highest MSC density is fat in lower abdomen. (more so in men than women) Mesenchymal Stem Cells Stem cell sources for clinical use Bone marrow Fat tissue Blood 8
Bone marrow stem cells Bone Marrow Aspirate Concentrate (BMAC) Obtained by centrifugation or with specialized needle. Most commonly aspirated from hip bone. Cell contents: HSCs > MSCs Typically remove about 20-60cc of bone marrow. Fat tissue stem cells Abundant in MSCs. Harvested as graft or lipoaspirate. Adipose tissue can act as biomaterial scaffold. Adipose tissue components: Adipocytes Stromal vascular fraction (MSCs) Connective tissue Fat tissue stem cells 9
Fat tissue stem cells: best collection sites Men: Abdomen Women: Biopsy region did not influence cell yield Ageand Body Mass Index (BMI) of donor did not influence cell yield. How are fat stem cells processed before use? Fat graft: As is, or some washing and rinsing steps. Lipogems: Advanced cleansing process. Bone marrow vs. fat stem cells These are both valuable sources of stem cells. However, there are significant differences. Fat has more MSCs compared to Marrow. Fat has the advantage in this department. Fat and marrow have similar numbers of HSCs but those of fat are short lived and seem to be different from the usual HSCs. Bone marrow has more effective HSCs and essentially greater numbers. Bone marrow has the advantage. 10
Bone marrow vs. fat stem cells Blood stem cells and growth factors Platelet Rich Plasma Blood cells 0% 6% Platelets Red Blood Cells White Blood Cells 94% 11
Platelet Rich Plasma Definition Portion of plasma fraction of autologous blood having platelet concentration above baseline. In clinical use since 1987. PRP properties Growth factor agonist Chemotactic (cell movement) Suppression of Cytokine release Antimicrobial activity (limited) Mitogenic(cell division) Tissue sealant Promote new capillary growth Platelet Rich Plasma A typical PRP treatment releases growth factors for about 5-7 days. By giving patents Nano doses of single recombinant growth factors, the extracellular microenvironment is sustained potentially boosting therapeutic effect and healing. In all repair processes, the catabolic mechanisms such as the overriding of anabolic growth factors by Tumor Necrosis Factor (TNF) inevitably occurs between day 6-12; by giving a TNF antagonist systemically can induce a higher anabolic repair rate, increasing healing and regeneration of tissue between clinical appointments. PRP Proteins Stromal Cell Derived Factor 1 Vascular Endothelial Growth Factor Platelet Derived Growth Factors Transforming Growth Factors Platelet Factor 4 Interleukin 1 Platelet Derived Angiogenesis Factor Epidermal Growth Factor Platelet Derived Endothelial Growth Factor Epithelial Cell Growth Factor Insulin-Like Growth Factor () (VEGF) (PDGF) (TGF-beta) (PF4) (IL-1) (PDAF) (EGF) (PDEGF) (ECGF) (IGF) 12
Activated platelets are critical to recruiting stem cells Bone marrow cells -recruits progenitor cells for tissue regeneration VEGF critical to vasculogenesis Dr. C. David B. M. Harrell, OF, FRIPH VEGF VEGF VEGF VEGF PRP Treatments Soft tissue injuries Disorders of the shoulder including bursitis and rotator cuff tears. Tendonitis of a variety of tendons (Tennis Elbow, Achilles Tendonitis, and Heel Spur Syndrome). Muscle tears, sprains, trigger points. Cartilage injuries Meniscus tears of the knee. Mild to moderate degenerative arthritis of various joints. Spinal disorders, especially facet joints. Clinical cases Avascular Necrosis (area of dead bone) 13
Clinical cases Frequently Asked Questions Where do you take the stem cells from? Your stem cells can be safely removed from your pelvis and the fat on either your belly or hip areas. Some stem cells can also be harvested from blood (VSEL). Small needles are used to remove a piece of bone marrow and some fat (mini-liposuction). Don t I need the stem cells where you are taking them from? No, you have plenty more stem cells in these areas. When you remove stem cells, new ones are formed to replace them. How long does it take for stem cells to work? After your doctor injects the stem cells where they are needed, they go to work right away. They will continue the repair process for up to1 year or longer. This does not mean that you have to wait for pain relief. Patients typically feel pain relief in the first few weeks to months. Frequently Asked Questions Can I still have surgery if this procedure fails? Yes, none of our procedures would impact your options to have surgery in the future. Do I have to take time off work for this procedure? Our BMAC procedure takes 2-4 hours to complete. So, we do recommend that you take the day off from work. Most patients have no difficulty returning to work the next day. When do I return to normal activity? You can return to most of your normal activities immediately. Depending on where the Stem Cells were injected, you may feel some soreness or stiffness. How can you tell if I am a candidate for the procedure? We will review your radiology studies, medical history, and perform a focused examination to determine if you are a candidate for our procedures. 14
Frequently Asked Questions What do you do with my blood or bone marrow to get the stem cells? In some cases, we remove a small amount of bone marrow, fat or blood, we placed them into a machine called a centrifugeto separate your stem cells and platelets from the other cells. Other times, we use specialized needles which can select the stem cells. How painful is the procedure to remove my stem cells and inject them? You doctor will use an anesthetic while your stem cells are removed and injected. Most patients experience very little discomfort during the procedure. What are the success rates? The great majority of our patients are very satisfied and would do the procedure again. Success rates vary by the severity of the condition, type of joint, age of the patient, etc. Conclusion Regenerative Medicine includes: PRP therapies joint pain Bone Marrow and Adipose therapy for regenerative Therapies 44 15