Boyce, NJBS 2008

Burn Repair with

Engineered Skin Substitutes

Dept of Surgery, University of Cincinnati

Shriners Hospitals for Children

Cincinnati, OH, Sacramento, CA and Galveston, TX

Steven Boyce PhD, David Greenhalgh MD

Tina Palmieri M D, Petra Warner MD

Kevin Yakuboff MD, Kevin Bailey MD, David Herndon MD,

Peggy Simpson RN, and Richard Kagan MD

Boyce, NJBS 2008

Burn Size Group (% TBSA)

Total, Full Thickness, Partial Thickness

National Burn Repository: 2005 Report Amer Burn Assn

0

5,000

10,000

15,000

20,000

25,000

30,000

35,000

40,000

45,000

50,000

0.1 - 9.9 10 - 19.9 20 - 29.9 30 - 39.9 40 - 49.9 50 - 59.9 60 - 69.9 70 - 79.9 80 - 89.9 9

No

. o

f C

ase

s

Total

Full

Partial

%TBSA

Num

ber

of

Cases

Boyce, NJBS 2008

Mortality from Burns

0

10

20

30

40

50

60

70

0.1-9.9 20-29.9 50-59.9 80-89.9

% TBSA Burned

% M

ort

alit

y

National Burn Repository: 2002 Report Amer Burn Assn

Boyce, NJBS 2008

Medical

Objectives

• Survival

• Earliest closure

• Least donor skin

• Minimum scar

• Acute burns

• Burn scars

• Congenital lesions

• Chronic wounds

Boyce, NJBS 2008

Human Skin:Structures & Functions

Three B’s:

• Barrier

• Basementmembrane

• Blood supply

Boyce, NJBS 2008

Isolate &Culture Cells

BiopolymerSubsrate

Cultured Skin Substitute

Skin Biopsy

Boyce, NJBS 2008

1

2

3

4

5

6

7

% TBSA

FT Burn

100

90

80

70

60

50

40

30

20

10

0

Months

43210

WoundsClosed

ICU

TIMELINE TO WOUND CLOSURE

• Earlier closure Less risk (sepsis/scarring) • Shorter ICU &• Fewer surgeries Less stress

1

2

3

4

Shorter ICU

ESS 1

ESS 2

EarlierClosure

Ope

Wo

Boyce, NJBS 2008

Selective Culture of Skin CellsFibroblasts

MelanocytesDMV Endothelial Cells

Keratinocytes

Boyce, NJBS 2008

Engineered Skin Substitu

• biopolymer (collagen sponge)

• partially stratified epithelium (e)

attached to a dermal substitute (d),

avascular, no appendages,

0.3-0.5 mm thick

• ~ 30 or 120 cm2 in area

0.1 mm

e

d

Boyce, NJBS 2008

Measure of Epidermal Barrier for QA

0

500

1000

1500

2000

2500

3000

Culture Days

+0.0mM Vitamin C

+0.1mM Vitamin C

7 343228211511

NHS

Cap

acita

nce

(pF

)

Boyce et al, J Invest Dermatol 107:8``2-87, 1996.

Boyce, NJBS 2008

Quality Assurance Pre-op

single set of 32

Boyce, NJBS 2008

Dermal-Epidermal Junction in ESS

AG

Col IV

ESS

LAM 5 Integin 4

BrdU

Boyce, NJBS 2008

Melanocytes in ESS: 5 weeks

103104

0 102

Boyce, NJBS 2008

Preclinical Projects with ESS

• Matching of skin color (melanocytes)

• Automation of manufacturing (bioreactors)

• Electro-spinning of biopolymers

• Vascularized device (endothelial cells)

• Suppression of scarring (fetal healing)

• Extended lifespan & adnexi (stem cells)

Boyce, NJBS 2008

Patient Demographics

5 - 88%26.5 ± 2.7% TBSA CSS / pt

24 – 5934.8 ± 1.0Days to 1st CSS

n.a.

53 - 95%73.9 ± 1.6% TBSA burn

0.6 – 187.6 ± 0.7Age in years

(38 / 16)Gender ratio (M / F)

32 - 95%70.3 ± 2.2% TBSA FT burn

RangeMean ± SEMParameter

n = 54 patients; 1998-2005

Boyce et al., J Burn Care Res, 2006; J Trauma, 2006

Boyce, NJBS 2008

Surgical

Methods

• ESS were:

- ~ 6 X 6 cm, or 12 X 12 cm

- covered with N-Terface™

- attached with staples

• Dressings were:

- fine mesh gauze

- coarse gauze

- irrigated with antimicrobials

- stretched Spandex™

Boyce, NJBS 2008

Results

POD 14 POD 28

ESSESS

AG

Boyce, NJBS 2008

Results

POD 69 POD 479

Boyce, NJBS 2008

Results (54 subjects)

Engraftment Closed:donor area

ESS AG

% A

rea C

losed a

t P

OD

14

0

20

40

60

80

100

12079.5 95.7

*

Clo

sed :

Donor

Are

as a

t P

OD

28

0

20

40

60

80

100

*

4

61.5 *, p < 0.0

ESS AG

Boyce, NJBS 2008

Results

TBSA closed: POD 28

ESS AG

% T

BS

A C

losed a

t P

OD

28

0

20

40

60

80

50.5

*19.1

p<0.05

TBSA covered vs % FT bur

% TBSA Full-thickness Burn

20 30 40 50 60 70 80 90

% T

BS

A C

losed w

ith C

SS

, P

OD

28

-40

-20

0

20

40

60

80r = 0.64

p < 0.0001

Boyce, NJBS 2008

Results: Vancouver Score

POD range

14-27 28-62 63-182 183-364 >364

Vancouver

0

1

2

3

4

5

ESSSS

AG

* * *

*, p<0.05

normal

scar

Boyce, NJBS 2008

Outcome:

81% TBSA, PBD Weeks 6 & 7

Week 9

Week 8 Week 10

Week 11

Boyce, NJBS 2008

Outcome after 95% TBSA Burns

ESS

AG

3-6 months after treatment

Boyce, NJBS 2008

Scar ReconstructionEpiCel failure ESS success

Right arm

Left arm

ESS

ESS

Boyce, NJBS 2008

Extramural Engineered Skin

33

1

3

14

15

# enrolled

19

1

1

7

10

# treated

72Totals

11Edmonton

1Boston

33Galveston

27Sacramento

# operationsCity

1898 devices: 4.9 m2

Boyce, NJBS 2008

Commercialization of ESS

• Technology licenses to Cutanogen

Corporation

• Cutanogen acquired (2006) by

Cambrex/Lonza

• Tech Transfer (cGMP manufacture)

• Regulatory filings

• HDE being prepared

• IDE/PMA being planned

• FDA audits pending completion

Boyce, NJBS 2008

Therapeutic Opportunities with ESS

• Reduced morbidity from burns

• Burn scar reconstruction

• Chronic wounds

• Congenital skin lesions

Boyce, NJBS 2008

Engineered Skin CollaboratorsClinical Laboratory University

Richard Kagan, MD Chris Lloyd, BS Dorothy Supp, PhD

Petra Warner, MD Liz Maier, BS John Kitzmiller, MD

Kevin Yakuboff, MD John Besse, BS Steven Hoath, MD

Kevin Bailey, MD Rachel Zimmerman, BS Gerald Kasting, PhD

Peggy Simpson, RN Jill Pruszka, BS Randy Wickett, PhD

Mary Rieman, RN Rachel Rice, BS Zalfa Abdel-Malek, PhD

Alice Neely, PhD Deanna Snider, BSHT David Butler, PhD

Extramural Past

David Greenhalgh, MD Richard Ham, PhD

Joachim Kohn, PhD John Hansbrough, MD

George Muschler, MD Glenn Warden, MD

Arnold Caplan, PhD Ian Alan Holder, PhD

Heather Powell, PhD Mary Williams, MD

Adam Katz, MD Residents, post-docs and staff

David Herndon, MD

Boyce, NJBS 2008

Project Sponsors

• Shriners Hospitals for Children

• National Institute of General Medical Sciences

• US Department of Defense

• State of Ohio Department of Development

• FDA Office of Orphan Product Development