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Mechanisms of Wound Healing: Studies with the Bilayered Cellular Matrix, OrCelTM

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Rachel Tewari. Tina Huang. Nameeta Chimanji. Lara Silberklang. Melissa Steiner. Flora Elequin ... Moore. Kathy Tygum. Nitya Ray. Hsin-Chien Tai. Alla Laufer ... – PowerPoint PPT presentation

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Title: Mechanisms of Wound Healing: Studies with the Bilayered Cellular Matrix, OrCelTM


1
Mechanisms of Wound Healing Studies with the
Bilayered Cellular Matrix, OrCelTM
  • Melvin Silberklang, Ph.D.
  • Chief Scientific Officer and
  • Vice President, RD
  • Ortec International, Inc.

2
Clinical Application of OrCelTM
3
Description
  • OrCelTM (Bilayered Cellular Matrix) is a
    preformed bovine collagen sponge matrix,
    gel-coated on one side, in which normal human
    allogeneic skin cells are cultured
  • dermal fibroblasts within the porous sponge
  • epidermal keratinocytes on the gel-coated,
    non-porous side of the sponge.

4
Development from Epidermolysis Bullosa to Wound
Healing
  • 1986 collagen sponge matrix-cultured autologous
    keratinocyte technology adapted to treat
    junctional Epidermolysis Bullosa (M. Carter, et
    al.)
  • 1989 first use of allogeneic bilayered composite
    cultured skin (CCS) in recessive dystrophic
    Epidermolysis Bullosa hand surgery (M. Eisenberg
    D. Llewelyn)
  • 1990 optimized CCS in normal volunteers
  • 1991 Ortec founded to commercialize CCS
  • 1994 FDA approval to launch 1st U.S. Clinical
    trial of CCS in burn surgery
  • 2001 FDA PMA approval for OrCelTM

5
FDA Approvals for OrCel
  • Humanitarian Use Device Exemption (HDE)
  • for the treatment of surgical wounds and
    donor sites associated with mitten hand
    deformities in patients with Recessive
    Dystrophic Epidermolysis Bullosa (RDEB)
  • Split thickness Donor Sites in Burn Patients

6
OrCel Manufacturing Process
Neonatal Foreskin

Enzymatic Detachment of Epidermal and Dermal
Layers
Cryopreservation (P1)
Cryopreservation (P1)
Keratinocyte Cell Line Expansion
Fibroblast Cell Line Expansion
Cryopreservation (P3)
Cryopreservation (P3/P4)
Collagen Sponges
Lamination with Collagen Gel
Inoculation with Cells
Culture 9 14 Days
OrCel
7
Scanning EM of Collagen Sponge (cross-section)

8
Safety Testing of Donor and of Allogeneic Cells
9
P-63
10
Bcl-2
11
OrCelTM Wound Healing Rationale Facilitated
Tissue Regeneration
  • Clinical Rationale
  • Co-Cultured Keratinocytes and Fibroblasts
    Supply


    Optimal Composition of Growth
    Factors/Cytokines
  • Cell-deposited Biomatrix Creates Optimal
    Scaffold for Wound Area Cell Migration and
    Proliferation
  • Product Resorbs Rapidly In Vivo (7 - 14
    days)

12
Biological Profiles
  • OrCel cells are in growth phase
  • OrCel cells demonstrate high viability
  • OrCel cells are highly productive for
    wound-healing cytokines and growth factors
  • Co-cultured, compartmentalized cells produce more
    extracellular factors than either keratinocytes
    or fibroblasts alone

13
OrCelTM Cell Composition by Flow Cytometry
Ungated
7.6
92.3
Cells
Fluorescence (FITC pan-cytokeratin)
14
OrCel Histology
15
OrCelTM Histology (Ki67 Immunohistochemistry)
Confidential
16
Immunohistochemical Screening for HLA-DR Antigen
in Foreskin Tissue vs. OrCelTM
20X
10X
10X
20X
17
Cytokine Production by Fibroblasts, Keratinocytes
and Co-Cultured Cells
/24 hours
6000
/24 hours
Fibroblast-Only OrCel
Fibroblast-Only OrCel
Keratinocyte-Only OrCel
50
Keratinocyte-Only OrCel
2
Co-Cultured OrCel
2
Co-Cultured OrCel
4000
Rate of Secretion into Culture Medium, pg/cm
25
Rate of Secretion into Culture Medium, pg/cm
2000
0
0
GMCSF
PGE2
VEGF
bFGF
KGF-1
18
OrCel
OrCel
ABCD
Confidential
19
(No Transcript)
20
Immunodetection of VEGF in OrCel- Treated Nude
Mice
21
Comparative Histological Profiles
22
Output, OrCelTM and Apligraf
100000
OrCel
Apligraf
10000
Cytokine Productivity, pg/cm2/day
1000
100
10
bFGF
GM-CSF
HGF
KGF-1
VEGF
IL-1a
MMP-9
PGE-2
23
Effect of Fenestration on Cytokine Expression
1000
1000
Whole
Fenes.
Whole
Fenes.
100
Cytokine Per Unit Area, pg/cm2/day
100
Cytokine Per Unit Area, pg/cm2/day
10
10
Day 1
Day 2
Day 1
Day 2
Day 1
Day 2
Day 1
Day 2
Day 1
Day 2
Day 1
Day 2
bFGF
KGF-1
Il-1a
bFGF
KGF-1
Il-1a
24
Effect of Fenestration on Cytokine Expression
Cytokine Production by Whole vs. Fenestrated OrCel
Cytokine Production by Whole vs. Fenestrated
Apligraf
10000
10000
Whole
Fenes.
Whole
Fenes.
1000
1000
Cytokine Per Unit Area, pg/cm2/day
Cytokine Per Unit Area, pg/cm2/day
100
100
10
1
10
Day 1
Day 2
Day 1
Day 2
Day 1
Day 2
Day 1
Day 2
Day 1
Day 2
Day 1
Day 2
GM-CSF
MCSF
VEGF
GM-CSF
MCSF
VEGF
25
Challenges in Cryopreservation of Tissue
Engineered Products
  • Optimization of Cryoprotectants and Freeze Cycle
    -- Minimizing Ice Crystal Damage to Cells and
    Matrix
  • Shipping and Storage at End-User Sites -- Storage
    Condition and Shelf Life
  • Development of Thawing Procedure -- Minimizing
    Ice Crystal Damage
  • Post-thaw Rinse-out of Cryoprotectants --
    Practicality, User-Friendliness

26
Retention of Functionality after Cryopreservation
Cell Count
27
Cryo-OrCel vs. OrCelTM
10000
Fresh OrCel
Cryo OrCel
1000
Cytokine Productivity, pg/cm2/day
100
10
bFGF
GM-CSF
IL-1a
KGF-1
MCSF
VEGF
28
Cryo-ORCEL vs. Fresh ORCEL
  • Equivalent keratinocyte and fibroblast cell
    density
  • Equivalent cell viability
  • Equivalent or better metabolic activity
  • Essentially equivalent cytokine expression

29
DONOR SITES


? OrCel Standard of Care
22 Days
Days to 100 Healing (Median)
?
15 Days
  • PMA Claims
  • Accelerated healing
  • Less Scarring
  • Reduced time to recropping

Pivotal 2/01 Based on Photography
30
Venous Leg Ulcers
Cryo-OrCelTM Preliminary Results

Percentage of Patients Achieving 100 Wound
Closure
  • Cry0-OrCel
  • Standard of Care

Weeks
Pilot 8/00
31
Diabetic Foot Ulcers
OrCel Heals Wounds Faster
of Patients Achieving 100 Wound Closure By
12 Weeks
  • ? Ortec
  • ? Standard of Care

Ortec
Standard Of Care
32
ACKNOWLEDGEMENTS
Lee McDonald Avi Lasdun Sandy Lerman Stephanie
Knight Dan Dwyer
Sunny Luke Rachel Tewari Tina Huang Nameeta
Chimanji Lara Silberklang
Melissa Steiner Flora Elequin
Celina Choi Caroline Tang
Steven Peltier Liza Moore Kathy Tygum
Nitya Ray Hsin-Chien Tai Alla Laufer Ying Song
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