NANOFACTOR FLOW Stem Cell Therapy

An Alternative in Managing Knee Arthritis

Phil Davidson, MDPark City, UT

NSAIDS PT Weight loss Bracing Injection Therapy

◦ Corticosteroids◦ Viscosupplementation◦ PRP◦ Autologous MSC’s (BMA derived)◦ Amniotic Tissue Graft-Allogeneic MSC

Non-Operative Management of Knee OA

Corticosteroids-good and bad…. Viscosupplementation: unpredictable, often ineffective, only potential to address aching, no reparative capacity, many insurances are not authorizing

Legacy Injection Therapies

CORTICOSTEROID BENEFITS Rapidly reduce pain due to inflammation Last for several weeks to months Joints, Spine radiculopathy, Bursitis, Tendonitis, Neural

inflammation (CTS)

CORTICOSTEROID SIDE EFFECTSSHORT TERM USE Atrophy Depigmentation Hyperglycemia Infection Post injection flare Tissue structure weakening, tendon ruptures

Chondrocytes and MSCs exposed to PRP show increased cell proliferation and cartilage extra-cellular matrix synthesis of PG and Type II collagen

Synoviocytes cultured in PRP produce more HA-better lubrication and chondroprotective?

Better pain scale outcomes with PRP injections versus HA injections for management of knee OA

PRP preps highly variable Over 6000 articles on PRP/only 50% of them

show an effect-platelets, leucocytes?

PRP in Cartilage Repair

Biologic treatment is interactive KEY ELEMENTS ALL REQUIRED:

◦Growth factors, cells, scaffold◦Mechanically favorable environment

A “Nutrient Rich Soup” includes-◦Cells (RBC, white cells, MSC)◦Growth factors (from platelets or plasma)◦Scaffolds

Potential sources of this “Soup”: ◦Bone Marrow Aspirate, Amniotic Fluid

BIOLOGICSKnee OA

MSC’s are undifferentiated cells:◦ Capacity for prolonged self-renewal◦ Ability to differentiate into specialized cell types

Have shown enhanced cartilage, tendon and meniscus healing

These results have increased patient awareness and demand

High-profile professional athletes are signing up for relatively untested cell-based therapies

MSC’s in Sports Medicine

Attractive to patients-they want regeneration technology rather than replacement

Harness your own body’s ability to heal Not taking exogenous drugs You are using your cells to heal your tissues Perception that stem cells are reversing the

trend not just treating it

Mesenchymal Stem Cells in Sports Medicine

MSCs do not recreate tissue Modify the environment to enhance healing Patients feel better-anti-inflammatory effect May have role for Osteoarthritis May be a role for augmenting surgical

procedures-ACLR, RCR, cartilage restoration We don’t know the ideal type or number of

stem cells in specific indications

Mesenchymal Stem Cells in Sports Medicine

Increased meniscal volume in post-menisectomy patients who received adult MSC injections into the knee

MSC implanted for knee OA showed improved activity levels and cartilage regeneration

One-step MSC treatment for large full thickness chondral defects showed improvement and significant cartilage fill

Mesenchymal Stem Cells Reparative Promise in Knee OA

Current MSC treatments for OA include BMA derived autogenous stem cells that are immediately injected into the knee

Jim Andrews MD at the Andrews Institute believes it controls swelling and inflammation and eases pain in knee OA

Results in a pilot study of 31 NFL players, at 10 months, showed efficacy

Reported decreased pain up to 45% with scores & improved by 50% from baseline at 6 months

Mesenchymal Stem Cells Reparative Promise in Knee OA

So why use nanofactor FLOW if BMA works? Growth factors, scaffolding, and MSCs First used in 1910 Preservation techniques in 1940 Has been proven in ophthalmology, burns,

plastic surgery, foot and ankle, diabetic ulcers Amniotic fluid stem cells have a delayed/more

robust differentiation compared to bonemarrow derived MSC in recent studies

Amniotic Membrane and Fluid Allograft

Journal Transplantation, April 2015 Prospective Randomized Trial for Knee OA Allograft MSC vs Hyaluronic Acid injected in knee One year follow up MSC patients improved clinical outcomes,

including pain vs. HA MSC patients showed actual IMPROVEMENT in

cartilage quality and quantity on MRI vs. HA

Attributes of Amniotic Tissue• Immunoprivileged (no class 1 or 2 HLA antigens)

– No rejection reaction• Anti Inflammatory

• Transforming growth factor beta-1 (TGF-1)• Insulin-like growth factor I (IGF-I)

• Anti Microbial- defensing/peptides/ enzymes• Cells: MSC’s, Fibroblasts and Keratinocytes +++

Chen EH, et al. J Implant Adv Clin Dent. 2009;2(3):67-75.(2)Bongiovanni cd133+ cell as advanced medicinal product

for Myocardial and limb ischemiaStem cells and development vol23, 20, 2014

(3)Karantalis, MSc w CABG circulation research Feb 2014

NANOFACTOR™ FLOW 900,000 cells/mL 44% MSC’s; remainder-kerintinocytes, fibroblasts,

epidermal Collagen Types III, IV, V, VII Amino acid precursors – taurine, glutamine Growth factors: Epidermal growth factor,

Transforming growth factor alpha & beta-1, Insulin-like growth factor 1, Granulocyte colony stimulating factor

(AmnioTechnology LLC, with permission)

Nanofactor Flow:MSCs + Growth Factors + Scaffold

Nanofactor Membrane:NanoFx (MSCs) + Growth Factors + Scaffold

PRP1 Element TxBMA2 Element TxNanofactorAll Elements

Amniotic Membrane

Scanning Electron Microscopic image of cryofractured amniotic membrane particles.

Membrane particle

Amniotic ScaffoldingCryofractured Amnion

Nanofactor Minimally Manipulated Extracellular Matrix

Morcelized TissueDisrupted 3D Structure

CryoFractured TissueIntact 3D Structure

Growth factors Scaffolding Cells and lots of them and immature-pluri-

potential-900,000 viable cells/ml, 44% are MSCs in one ml

BMA has 1,500 CFU-f/ml, another article stating 2,300 CFU-f/ml (donors<1 yo) to 500 CFU-f/ml (donors>60)

BMA cells are senile

What makes Nanofactor Flow different?

Amnio vs BMA: MSC Volume Comparison

Amniotic 440,000 MSC’s/1ml

Bone Marrow Aspirate1,600 MSC’s/1ml

Jing Li et al: Chin J Cancer Res 23(1): 43-48, 2011

Human MSCs Decline with Age

Adopted from: Al Caplan. J Pathol 2009; 217:318-314, 2008

Age (Years)

MS

Cs

pe

r M

arr

ow

Ce

lls

Newborn Teen 30 50 80

_______1,000

1

_______100,000

1_______250,000

1_______400,000

1_______

2,000,000

1

Estimates obtained by

CFU- f assay

Relative Number of MSC’s by Age

Adopted from: Al Caplan. J Pathol 2009; 217:318-314, 2008

Age (Years)

MS

Cs

pe

r M

arr

ow

Ce

lls

Newborn Teen 30 50 80

2000 400 250 100 1

Amniotic Tissue AllograftNanofactor FLOW

Growth Factors/Peptides

Cellular Components

Extracellular Matrix+ +

Shipping to Manufacturing Facility

Overnight at 1-10o C

Amniotic Placental Tissue Collection Scheduled c-section

- Amniotic fluid (~ 650cc)- Amnion membrane (900 cm2)

ConsentInfectious Disease Testing

Tissue Processing

Processed in Class ISO 5 Bioburden Testing USP <61>Environmental MonitoringMicronized Amnion Growth Factors, Cytokines, ECM ProteinsViable Cells5% DMSO

Final Product Lot Release

Sterility Testing USP <71>Mycoplasma Testing USP <63>Endotoxin Testing USP < 85>

3-4 weeks

Product Packaging and Distribution

>65o C

“A multipotent stem cell population that is still of fetal origin and may be superior in proliferation and differentiation to cells deriving from adult tissues”

Francesco Alviano et al, BMC Developmental Biology

How do the sources compare?

Patients can benefit from this non surgical treatement modality

Many patients want/need to avoid surgery Large demographic of patients wants to “try

everything before considering surgery” This is only modality that has the actual ability

heal cartilage and tissues (vs steroid/HA) Easier to administer than PRP/BMA Cost is not out of line with PRP/BMA

Why do I offer my patients Nanofactor Flow?

Attractive option to include “stem cells” Safe, no rejection, no after-pain New technology without specific indication parameters I discuss the concept of orthobiologic treatment to

include the 3 key elements: cells, growth factors and scaffolding

I explain that senescent MSC’s make very little sense to me

It is not a magic bullet but it does have promise I explain that it is expensive and not covered by

insurance

How do I discuss Nanofactor Flow?

PHASE IGetting Started in the Office

+Dilutants & Nanofactor

CryoFreezer: If you plan to do

any volume

• (Pure) Lidocaine /Marcaine, (not in joints)• PRP (Platelet Rich Plasma): • PPP (Platelet Poor Plasma):• Hyaluronic acid (supartz, eufflexa): • Saline: Use Normal Saline:

– Types of Saline: • Normal: Sterile Solution of Sodium chloride in

water• Bacteriostatic: Sterile Solution with 0.9%

benzyl alcohol with no sodium chloride

Acceptable Dilutants

Flow

• Do Not Use – Glycerol (eg. Grafton DBM)– Glucose Solutions (eg. D5NS)– Epinephrine (in or around treatment site)– Lidocaine/ Marcaine (with preservative) in joints

• Do NOT Use Systemically – no IV or intra arterial injections• No literature to support this method of administration.

Unacceptable DilutantsFlow

Preparation & Mixing1. Remove the package from freezer or dry

ice container. Cut the package. *Outside of vial is not sterile

2. Defrost vial by holding still in hand for 3-5 minutes. *Do not shake vial

3. Fill syringe with dilutant. (typically 1:1 ratio)

4. Draw Nanofactor™ Flow into syringe with 18g needle.

5. Use a 22 or 23g needle for injection but nothing smaller than a 23g

Flow

Shoulder 1ml Flow Graft,1:2 up to 1:4 dilution Elbow 1ml Flow Graft,1:1 dilution Wrist, Fingers & Facets(per joint)0.25ml Flow Graft,1:1 dilution

Subtalar &Midfoot Joints 0.5ml Flow Graft,1:1 dilution MPJ’s & Toes(per joint)0.25ml Flow Graft,1:1 dilution

Hip2ml Flow Graft,1:2 up to 1:3 dilution Knee(per compartment)Stage 3: 0.5ml Flow Graft,Stage 4: 1ml Flow Graft,1:2 dilution Ankle1ml Flow Graft,1:1 dilution

Recommended Joint DosingFlow

PEARLS No anti-inflammatories or ASA (6 weeks pre & post) Increased tissue vascularity improves cellular

incorporation Lidocaine 1% preservative free as carrier Full activity (restrictions only if warranted by diagnosis) No issues with icing or polar care machine Not use – systemically, open growth plates, oncologic

process, active infection

Nanofactor Flow is an alternative therapy to treat inflammatory and degenerative musculoskeletal conditions.

It makes sense given what we know about orthobiologic principles with MSCs, growth factors and scaffolds

Patients are asking for this type of treatment The cost is not prohibitive Early observations very encouragin We need more prospective data at all levels

◦ Dosing◦ Efficacy◦ Indications/Contraindications

Summary

Thank You phildavidsonmd@gmail.com