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Modeling the Effects of Treating Diabetic Wounds with Engineered Skin SubstitutesWound Repair and Regeneration, Volume 15, 2007

Helen V. Waugh, PhDJonathan A, Sherratt, PhD

•Woundhealingcanonlybeachievedifeitherfibroblastsorhyaluronanareaddedtothewound

•Onceatthewoundsite,fibroblastssynthesizehyaluronanandcollagenandthewoundstartstoheal

•HyaluronanappearstobeakeycomponentinhowDermagraftandApligrafhealdiabeticwounds

key points

100% density (per mm3)

TGF-ß=transforming growth factor-ß; PDGF=platelet derived growth factor

Approximate Healing time

# of Pieces / Application

Frequency of Application

Dermagraft®

Once 1 140 days

Once 8 90 days

Weekly for 8 Wks 1 90 days

2 85 days

3 80 days

Approximate Healing time

# of Pieces / Application

Frequency of Application

Apligraf®

Once 1 No Healing Predicted

Once 5 No Healing Predicted

Weekly for 5 Wks 1 100 days

2 85 days

3 75 days

frequency of application

Component Dermagraft® Apligraf®

Neonatal �broblasts 8000 cells 500 cells

TGF-ß 0.4 pg 4 pg

PDGF 1 pg 1 pg

Collagen 18.75 µg 2 µg

Hyaluronan 80 µg 7.45 µg

The simulation predicted that an 8-week course

of Dermagraft shows wound closure within

approximately 9-10 weeks and 5-week course

of Apligraf heals the wound within approximately

10-11 weeks. Application of a single piece of

Dermagraft shows that healing can be induced,

although the wound does not appear to heal

for several weeks. A single piece of Apligraf

was insufficient to induce wound healing in a

diabetic wound.

Within the context of this model, the key

component to successful healing in diabetic

wounds was found to be hyaluronan. Further,

these therapies were shown to work by increasing

the amount of hyaluronan available in the wound

environment. The time-to-healing results of the

model correlate with those observed in clinical

trials and, thus, the model goes some way to

establishing an understanding of why diabetic

wounds do not heal, and how engineered skin

substitutes affect the diabetic wound environment

to promote wound closure.

In this paper, a novel mathematical model of

wound healing in both normal and diabetic cases

is presented, focusing upon the effects of adding

two currently available commercial engineered

skin substitute therapies to the wound (Apligraf

and Dermagraft). Our work extends a previously

developed model, which considers inflammatory

and repair macrophage dynamics in normal and

diabetic wound healing. Here, we extend the

model to include equations for platelet-derived

growth factor concentration, fibroblast density,

collagen density, and hyaluronan concentration.

This enables us to examine the variation of

these components in both normal and diabetic

wound healing cases, and to model the treatment

protocols of these therapies.

Five Dermagraft application scenarios were

simulated: single piece, 8 pieces as single

treatment, 1 piece a week for 8 weeks, 2 pieces

a week for 8 weeks, and 3 pieces a week for

8 weeks. Similarly, the five Apligraf applications

scenarios were a single piece, 5 pieces as single

treatment, 1 piece a week for 5 weeks, 2 pieces

a week for 5 weeks, and 3 pieces a week for 5

weeks. Individual components of each product

were also used to determine whether they act

alone or synergistically. For this simulation, the

standard approved treatment protocol of 8

weekly applications for Dermagraft and 5 weekly

applications for Apligraf was used, but only one

component was added.

abstract

materials and methods

results conclusions