science based product · stem cells 1968 first bone marrow transplant 1998 first embryonic stem...

SCIENCE BASED PRODUCT

Oct 2006

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

Evolution of Orthobiologics

1997 1999 2000 2002 2014

DISADVANTAGES

Non-human sources

Older donors inferior to younger donors

Older donors inferior to younger donors

Single GF limited efficacyBacteria

Avian Pro-inflammatory

Donor site pain

Synthetic

|Viscosupplementation

HA

PRP|

|Cellular therapies

Bone marrow aspirateStem cells

Single human recombinant

growth factors BMP-7 BMP-2

|

Sterile Derived Multiple Allogeneic Protein Paracrine Signaling (D-

MAPPS)NovoMax Liquid Allograft

“Stem Cell Stimulator”

|

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 Acid4/11/2018

AMONG PHYSICIANS AND SCIENTISTSCURRENT CONFUSION WITH STEM CELLS

P r o g e n ito r c e lls

Peripheral blood-borne

colony-forming units

Stromal cells

PericytesFibroblasts

Mes enc hymal s tem c e lls

Evolution ofStem 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

Ste

m C

ells

Age

1:4

00,0

00

Child

Young

Adult

Middle

Age

Old

Age

Circulating MSC (PB-MSC)(Rare-to-none if not mobilized by growth factors)

BM-MSC1 in 104 – 105

1 in 10,000 – 100,000

PB-MSC1 in 108

1 in 100,000,000

Circulating Mesenchymal Stem Cells and Their Clinical Implications: Journal of Orthopaedic Translation, Vol 2, Issue 1, Jan 2014, Chinese Orthopaedic SocietyRef:

Mesenchymal stem cells

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

Cytokine Levels in

Inflammatory State

Interleukin 1β

(IL-1β)

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

Inflammation

=

Interleukin 1Ra

(IL-1Ra)Reduced

Inflammation=

Interleukin 1Ra

(IL-1Ra)

Treating inflammation by blocking interleukin-1 in a broad spectrum of

diseases

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644509/

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

A Critical Role for the IL-1 Receptor in Lung Injury

http://www.nature.com/pr/journal/v66/n3/full/pr2009198a.html

Sterile D-MAPPS™ Derived Liquid Injectable

Potential Mechanism of Action

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644509/

http://particleandfibretoxicology.biomedcentral.com/articles/10.1186/s12989-014-0069-x

Chemicals/Small Molecules

Pharmaceuticals 1 gram → 1000 milligrams (mg)

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

Perspectives on Scale Comparison

Ref. Int J Mol Sci. 2017 Jun; 18(6): 1129.

SEM of Pericytes

Molecular Mechanisms Underlying Therapeutic Potential of PericytesC. Randall Harrell; Bojana Simovic Markovic; Crissy Fellabaum; Aleksandar Arsenijevic; Valentin Djonov; Vladislav Volarevic

Journal of Biomedical Science

Co-authored by Dr. Harrell

Mechanism of Action

Niches

Patented Platform

Technology

Sterile Derived Multiple Proteins Paracrine Signaling (D-MAPPS )

771 cytokines, chemokines, and growth factors: “Stem Cell Stimulators”

Biological effects through signal transduction pathways

Pericytes

TM

tested & provento be contained in:

Wnt Signaling For the treatmentOf osteoporosis

McClung et al., NEJM 2014


17Minear et al., Science TM 2014


18Jing et al., Biomaterials 2015


• Modulates Inflammation with its “Cocktail” ofAnti-Inflammatory Cytokines

• Has Potential to Restore Nerve Function byRecreating Embryonic Environments

• Has Potential to Regenerate Cells and Cartilage

• Demonstrated Safety Profile with No ReportedAdverse Events

Patented Sterile D-MAPPS™ Overview

Successful TrialsCase studies show successful therapy for patients suffering from chronic pain, wound management, and burns.

Reduce InflammationAnti-inflammatory cytokines communicate with the cells in your body to reduce inflammation and redness

Decreased Pain & DiscomfortAs inflammation reduces, pain and discomfort decrease and the next stage of healing begins

Heal & RegenerateGrowth factors will stimulate the body’s natural healing power to bring soothing relief

Patented Sterile D-MAPPS™ Overview

Injuries heal

SLOWLY

Treatment of Chronic Pain: Significant Unmet Needs

8.673 2.836 2.460 1.7860

1

2

3

4

5

6

7

8

9

10

Base Line 3 mos. 6 mos. 12 mos.

67.3% 71.6%

PERCENT IMPROVEMENT

55 PATIENTS CHRONIC PAIN

79.4%

2016 – To Our Knowledge, The First Documented Human Cartilage

RegenerationMay 24, 2016 Palm Harbor, FL

LEFT KNEE NON-CONTRAST MAGNETIC

RESONANCE IMAGING

MRI FINDINGS2016 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

Ryan Polselli, M.D.

Board Certified Radiologist

“This is real.”

Sterile D-MAPPS InjectableTM

Sterile D-MAPPS™ Derived Liquid Allograft

Injections: Case Studies

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 – Wound Injection Study

•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



•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 andafter ultrasound.

2016 - First

Documented

Increase

Blood Flow




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 Allograf

Injections

science based product · stem cells 1968 first bone marrow transplant 1998 first embryonic stem...

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