SCIENCE BASED PRODUCT

Oct 2006 **RPP has been marketing and selling this type of regenerative medicine since 2014

Evolution of Orthobiologics Single human recombinant growth factors BMP-7 BMP-2 Sterile Derived Multiple Allogeneic Protein Paracrine Signaling (D- MAPPS) NovoMax Liquid Allograft Stem Cell Stimulator PRP 1997 1999 2000 2002 2014 Viscosupplementation HA Non-human sources Bacteria Avian Synthetic 4/11/2018 Older donors inferior to younger donors Proinflammatory Cellular therapies Bone marrow aspirate Stem cells DISADVANTAGES Older donors inferior to younger donors Donor site pain Single GF limited efficacy ADVANTAGES Off the shelf option 771 cytokines, chemokines & growth factors Sterile 10-6 SAL Injectable through 30g needle (pain free) No adverse events reported Natural Hyaluronic Acid

CURRENT CONFUSION WITH STEM CELLS AMONG PHYSICIANS AND SCIENTISTS Mes enc hymal s tem c ells P r o g e n ito r c e lls Peripheral blood-borne colony-forming units Stromal cells Fibroblasts Pericytes

Evolution of Stem Cells 1968 First Bone Marrow Transplant 1998 First Embryonic Stem Cell 2007 First Induced Pluripotent Stem Cell 2014 Novel Platform Technology Sterile Derived Multiple Allogeneic Proteins Paracrine Signaling D-MAPPS

Quantity of Stem Cells, Growth Factors such as GDF11 Decreases with Aging Example Diagram of Lifetime Human Stem Cell Count Stem Cells 1:400,000 Child Young Adult Middle Age Old Age Age

Mesenchymal stem cells Circulating MSC (PB-MSC) (Rare-to-none if not mobilized by growth factors) BM-MSC 1 in 10 4 10 5 1 in 10,000 100,000 1 in 10 8 1 in 100,000,000 PB-MSC Ref: Circulating Mesenchymal Stem Cells and Their Clinical Implications: Journal of Orthopaedic Translation, Vol 2, Issue 1, Jan 2014, Chinese Orthopaedic Society

PERICYTES STEM CELLS MESENCHYMAL STEM CELLS PERIVASCULAR MULTIPOTENT CELLS Contribute to the regeneration of various tissues in response to injury Distinctive role in Myogenesis (muscle) Neurogenesis (nerves) Adipogenesis (fat) Fibrogenesis (fibroblast) Angiogenesis (blood vessels) Osteogenesis (bone) Mechanism of Action: Physical Contact and Paracrine Signaling

Mesenchymal Stem Cells (MSCs) and Pericytes: To What Extent Can They be Stimulated? Microenvironment Milieu niche MSCs Sterile Derived Multiple Allogeneic Protein Paracrine Signaling Regeneration

Sterile D-MAPPS Derived Liquid Injectable Potential Mechanism of Action Cytokine Levels in Inflammatory State Interleukin 1β (IL-1β) Interleukin 1Ra (IL-1Ra) = Inflammation Sterile D-MAPPS Derived Products, including NovoMax, are proven to contain IL-1Ra, which ameliorates clinical signs and inflammatory changes seen in inflammatory disease states Interleukin 1Ra (IL-1Ra) = Reduced Inflammation Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3644509/ A Critical Role for the IL-1 Receptor in Lung Injury http://www.nature.com/pr/journal/v66/n3/full/pr2009198a.html The alarmin IL-1α is a master cytokine in acute lung inflammation induced by silica micro- and nanoparticles http://particleandfibretoxicology.biomedcentral.com/articles/10.1186/s12989-014- 0069-x

Perspectives on Scale Comparison Chemicals/Small Pharmaceuticals 1 gram 1000 milligrams (mg) Molecules Endocrine Hormones 1 gram 1 Billion Nanograms (Ng) 1x10-9 grams Paracrine & Autocrine Growth Factors & Cytokines 1 gram 1 Trillion Picograms (pg) 1x10-12 grams 1 gram 1 Quadrillionth Femtograms (fg) 1x10-15 grams

Molecular Mechanisms Underlying Therapeutic Potential of Pericytes C. Randall Harrell; Bojana Simovic Markovic; Crissy Fellabaum; Aleksandar Arsenijevic; Valentin Djonov; Vladislav Volarevic Journal of Biomedical Science SEM of Pericytes Co-authored by Dr. Harrell Ref. Int J Mol Sci. 2017 Jun; 18(6): 1129.

TM Sterile Derived Multiple Proteins Paracrine Signaling (D-MAPPS ) 771 cytokines, chemokines, and growth factors: Stem Cell Stimulators Niches Patented Platform Technology Pericytes Mechanism of Action Biological effects through signal transduction pathways

tested & proven to be contained in:

Wnt Signaling For the treatment Of osteoporosis tested & proven to be contained in: McClung et al., NEJM 2014

tested & proven to be contained in: Minear et al., Science TM 2014 17

tested & proven to be contained in: Jing et al., Biomaterials 2015 18

Patented Sterile D-MAPPS Overview Modulates Inflammation with its Cocktail of Anti-Inflammatory Cytokines Has Potential to Restore Nerve Function by Recreating Embryonic Environments Has Potential to Regenerate Cells and Cartilage Demonstrated Safety Profile with No Reported Adverse Events

Patented Sterile D-MAPPS Overview Successful Trials Case studies show successful therapy for patients suffering from chronic pain, wound management, and burns. Reduce Inflammation Anti-inflammatory cytokines communicate with the cells in your body to reduce inflammation and redness Decreased Pain & Discomfort As inflammation reduces, pain and discomfort decrease and the next stage of healing begins Heal & Regenerate Growth factors will stimulate the body s natural healing power to bring soothing relief

Injuries heal SLOWLY

Treatment of Chronic Pain: Significant Unmet Needs 2016 To Our Knowledge, The First Documented Human Cartilage May Regeneration 24, 2016 Palm Harbor, FL TM Sterile D-MAPPS Injectable 10 9 8 7 6 5 4 3 2 1 0 55 PATIENTS CHRONIC PAIN PERCENT IMPROVEMENT 67.3% 71.6% 79.4% 8.673 2.836 2.460 1.786 Base Line 3 mos. 6 mos. 12 mos. LEFT KNEE NON-CONTRAST MAGNETIC RESONANCE IMAGING MRI FINDINGS 2016 compared to 2013 Complete regeneration of an area of focal cartilage loss along the anterior aspect of the lateral femoral condyle and restoration of normal subchondral marrow signal. Dramatic improvement with degree of effusion. This is real. - Ryan Polselli, M.D., Board Certified Radiologist This is real. Ryan Polselli, M.D. Board Certified Radiologist

Sterile D-MAPPS Derived Liquid Allograft Injections: Case Studies Sterile D-MAPPS Derived Liquid Allograft Wound Injection Study Patient with diabetic ulceration on right first metatarsal head, very fibrotic, and with neuropathic pain. End of study results shows improved vascularity, less pain, increased sensations, and much less fibrotic. Patient with densely neuropathic plantar foot diabetic ulceration. Increased vascularity and sensation after 1 week, and no open lesions. Wound healed at 4 week visit without need to re-inject.

Sterile D-MAPPS Derived Liquid Allograft Injections: Case Studies Peripheral neuropathy case study CASE STUDY PATIENT 001 PERIPHERAL NEUROPATHY Patient complains of severe pain, diagnosed with PAD (Peripheral Artery Disease) of the feet. Previously treated with Cortisone injections, Lyrica, Neurontin and Gabapentin. Patient has been through physical therapy and stents have been placed to improve blood flow in large vessels of the legs. These therapies have helped but patient is still in pain and blood flow is not optimal. Patient was treated with Sterile D-MAPPS Derived Liquid Allograft 0.5 cc injected without dilution into the peri-arterial region of the medial lateral plantar artery. Immediately, patient reported significant pain relief, and a feeling of warmth. Ultrasound taken before the Sterile D-MAPPS injection and 5 minutes after the Sterile D-MAPPS injections captures impressive vascular changes as seen below on the right. 2016 - First Documented Increase Blood Flow

Sterile D-MAPPS Derived Liquid Allograft Injections: Case Studies CASE STUDY PATIENT 002 PERIPHERAL NEUROPATHY Patient complains of pain and is diagnosed with PAD (Peripheral Artery Disease) of the feet. Patient has been treated with Cortisone injections, Lyrica, Neurontin and Gabapentin. Patient has also received physical therapy. These therapies have helped but patient still has severe pain and blood flow is not optimal. Patient was treated with Sterile D-MAPPS Derived Liquid Allograft 0.5 cc injected without dilution into the peri-arterial region of the medial lateral plantar artery. Immediately, patient communicated significant pain relief and a feeling of warmth. The ultrasound below captured vascular changes before and 5 minutes after the Sterile D-MAPPS injection. You can see confirmed remarkable vascular changes from the before and after ultrasound. 2016 - First Documented Increase Blood Flow

Sterile D-MAPPS Derived Liquid Allograf Injections Sterile D-MAPPS Derived Liquid Allograft Average Pain Level 38 Patients 10 Point Scale *Population mean is greater than 70% improvement in pain at 3 months post injection (p<0.001)

Sterile D-MAPPS Derived Liquid Allograft Injections: Case Studies