ORIGINAL INVESTIGATION

Growth Differentiation Factor 5 Accelerates Wound

Closure and Improves Skin Quality During Repair
of Full-Thickness Skin Defects
Jennifer L. Schiefer, MD; Manuel Held, MD; Paul C. Fuchs, MD; Erhan Demir, MD; Frank Plöger, PhD, CPM;
Hans-Eberhard Schaller, MD; and Afshin Rahmanian-Schwarz, MD

ABSTRACT
BACKGROUND: A fast and stable wound closure is important,
especially for extended and unstable wounds found after burn
injuries. Growth can regulate a variety of cellular processes,
including those involved in wound healing. Growth differentiation
factor 5 (GDF-5) can accelerate fibroblast cell migration, cell
proliferation, and collagen synthesis, which are essential for
wound healing. Nevertheless, no standardized evaluation of the
effect of GDF-5 on the healing of full-thickness wounds has been
published to date.
METHODS: Five full-thickness skin defects were created on the
backs of 6 minipigs. Three wounds were treated with GDF-5 in
different concentrations with the help of a gelatin-collagen carrier,
and 2 wounds served as control group. The first was treated with the
gelatin carrier and an Opsite film (Smith & Nephew, Fort Worth, Texas),
and the other was treated solely with an Opsite film that was
placed above all wounds and renewed every second day.
RESULTS: Growth differentiation factor 5 accelerates wound
closure (10.91 [SD, 0.99] days) compared with treatment with
the carrier alone (11.3 [SD, 1.49] days) and control wounds
(13.3 [SD, 0.94] days). Epidermal cell count of wounds treated
with GDF-5 revealed a higher number of cells compared with
the control group. In addition, mean epidermal thickness was
significantly increased in GDF-5Ytreated wounds compared with
the control wounds.
CONCLUSIONS: Because of its ability to improve skin quality,
GDF-5 should be considered when developing composite
biomaterials for wound healing.
KEYWORDS: composite biomaterials, full-thickness skin defects,
GDF-5, minipig model, skin repair, wound healing
ADV SKIN WOUND CARE 2017;30:223Y9
INTRODUCTION
Skin is one of the largest organs in the human body, covering
the entire external surface. It has many important functions, such
as protecting the human body against external toxins and micro-
organisms; mechanical, chemical, and thermal damage; and dehy-
dration.1 Acute traumas, surgical interventions, or chronic ulcers
can lead to skin injury. In cases of extended skin damage, patients
are often burdened by trauma involving intense pain and lifelong
disfigurements. Therefore, a fast and stable skin repair that re-
stores function and achieves a satisfying cosmetic outcome is
highly desirable.2,3 The capability of spontaneous skin regenera-
tion and the necessity for skin replacement products depends on
the damaged skin layers.4 Adding special agents such as growth
factors to modern wound dressings can accelerate healing. Growth
factors are important for regulating a variety of cellular processes,
including those involved in wound healing.5-7
Because of these promising effects, this study evaluated the
effect of the growth differentiation factor 5 (GDF-5) on wound
healing in full-thickness dermal wounds. This growth factor,
also known as bone morphogenetic protein 14 (BMP-14), be-
longs to a subgroup of the BMPs, a group of the transforming
growth factor A superfamily.8
MATERIALS AND METHODS
This study was approved by the Animal Research Ethics Com-
mittee at the University of Tuebingen (AT 1/12). Animals were
treated according to the German Law on the Protection of Ani-
mals, and the study was performed with permission from the
Baden-Württemberg Animal Welfare Committee.
To achieve standardized wounds, researchers chose the minipig
model, which is widely used in wound-healing studies because
the skin of minipigs is very similar to the skin of humans.9

Jennifer L. Schiefer, MD, is Chief Resident, Department of Plastic, Reconstructive, Hand and Burn Surgery, Hospital Cologne Merheim, University of Witten-Herdecke, Germany. Manuel Held, MD,
is a Resident, Clinic for Plastic, Reconstructive, Hand and Burn Surgery, BG Trauma Center, University of Tuebingen, Germany. Paul C Fuchs, MD, is Director, Department of Plastic, Reconstruc-
tive, Hand and Burn Surgery, Hospital Cologne Merheim, University of Witten-Herdecke, Germany. Erhan Demir, MD, is Chief Resident, Department of Plastic, Reconstructive, Hand and Burn
Surgery, Hospital Cologne Merheim, University of Witten-Herdecke, Germany. Frank Plöger, PhD, CPM, is Director of Research and Development, Biopharm GmbH, Heidelberg, Germany.
Hans-Eberhard Schaller, MD, is Director, Clinic for Plastic, Reconstructive, Hand and Burn Surgery, BG Trauma Center, University of Tuebingen, Germany. Afshin Rahmanian-Schwarz, MD, is
Director, Department of Plastic, Reconstructive, Aesthetic, and Hand Surgery, Hospital Traunstein, Germany. The authors have disclosed that this research was supported in parts by Freudenberg
New Technologies SE & Co KG Group, Weinheim, Germany, and Biopharm GmbH. Submitted June 18, 2015; accepted in revised form September 17, 2015.

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 ORIGINAL INVESTIGATION
Furthermore, minipigs are small and easy to handle compared
with normal pigs.10
Animals
After a time of acclimatization and conditioning, standardized
surgical wounding was performed on 6 female Göttingen minipigs
(A/S, Dalmose, Denmark), with an average age of 39 weeks at ar-
rival and an average weight of 25 kg on procedure day. They were
fed 400 g of a standard minipig diet daily (SDS SMP; Special Diets
Services, Witham, Essex, United Kingdom) and had free access to
water. During their stay, the minipigs were weighed weekly to
ensure proper growth and good health.
GDF-5 and the Gelatin Carrier
For easy application, GDF-5 was incorporated into the fibers of
a gelatin-collagen carrier in 3 different concentrations per m2
(100, 1000, and 5000 ng). A homogeneous precursor solution
consisting of water, gelatin, collagen, and GDF-5 was processed
into fibers through rotary spinning. Liquid jets of precursor solu-
tion leaving the rotor are cooled during the flight and therefore
first turn into gel and afterward into a stable fiber. During this
process, the water is removed from the precursor, and the jet
dries into fibers. All other components remain homogeneously
distributed in the stable fibers and are stored in form of the
gelatin-based collagen carrier. The fibers are distributed bimodally,
with a diameter of approximately 2 to 10 Km and a pore size of
35 to 70 Km (Figure 1). The binding of GDF-5 can be regulated
through choice of the extracellular matrix protein mass ratio. In
this case, matrix components were chosen that release the in-
corporated GDF-5 over 3 days to the wound during liquid con-
tact through matrix proteases. After contact to the wound fluid,
the fibers absorb water, and the gelatin begins to swell until the
Figure 1.
FIBER STRUCTURE OF THE CARRIER
ADVANCES IN SKIN & WOUND CARE & VOL. 30 NO. 5
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
volume of liquid is sufficient to solve the gelatin. During this pro-
cess, the GDF-5 is also hydrated and starts to move in the matrix.
During this diffusion process, it moves into the wound and to the
cells. Through continuous water absorption, the viscosity of the
gelatin is increasingly reduced, which also leads to an increased
mobility of GDF-5, resulting in a faster diffusion. A maximum dif-
fusion is reached after complete dissolution and absorption of the
gelatin in the wound. The 3-day dissolution period was chosen
to facilitate regular wound evaluation and dressing changes. After
dissolution, collagen carriers lead to a reduced mobility of GDF-5
through complexation between collagen and the growth factor.
This phenomenon is explained through the larger hydrodynamic
radius of the collagen complex and the inferior water solubility of
collagen compared with gelatin, which was the main component
of the selected carrier.
Surgical Wounding
Beginning with sterilization and shaving, circles with a diame-
ter of 2.0 cm and squares of 4.0  4.0 cm around each circle were
tattooed on each minipig’s back (Figure 2). Excision of all marked
circles followed, creating 5 circular wounds on the pig’s dorsum
with a diameter of 2.0 cm and a depth of 0.6 cm (Figure 2). The
standardized distance between each wound measured 6.0 cm in
each direction to avoid cross contamination.
Then GDF-5 was applied in 3 different concentrations to the
wounds in the gelatin carrier measuring 5.0  5.0 cm (Figure 3).
The carrier was placed in the center of the wound, and the edges
were folded on top, leading to complete filling of each wound. A
sterile Opsite film (Smith & Nephew, Fort Worth, Texas) was placed
on top of each wound to keep the wound fluid and dressing on
the wound. One of the control wounds was treated with a carrier
without GDF-5, and the second control wound was solely treated
with the semipermeable Opsite film.
Documentation and Dressing Change
Every second day, standardized photographic documentation for
evaluation was performed during bandage renewal, renewal of
the GDF-5 + carrier, and/or renewal of the Opsite film. Complete
wound closure was determined individually by evaluating the
taken photographs. Wounds were considered closed if granula-
tion tissue was no longer apparent, and the wound appeared to
be covered with new epithelium.11 Percent of wound closure over
time was determined using computer-aided photo image analy-
sis. For this, images were acquired into Adobe Photoshop (Adobe
Systems, San Jose, California; Figure 3).
Histologic Evaluation
Biopsies for histologic evaluation were taken after 21 days.
Paraffin-fixed slides, 5 Km thick, were prepared and stained
with hematoxylin-eosin, as well as Masson trichrome stain.
224 WWW.WOUNDCAREJOURNAL.COM
 ORIGINAL INVESTIGATION
Figure 2.
VIEW OF WOUND WITH THE CARRIER
Intraoperative view of the created skin defects (2-cm diameter and 0.6-cm depth) on the dorsum of the minipig during the filling of a wound with the carrier.
Epidermal thickness (from stratum basale to stratum corneum)
and the total amount of epidermal cells within a 100-Km section
in the former sore center of epidermis were evaluated. Further-
more, cell count within the granulation tissue was performed in
a rectangular 100  50-Km (5-mm2) area underneath the stratum
basale (Figure 4).
GDF-5 Serum Concentration
Blood serum samples were taken from each subject to evaluate
a possible systemic effect of the locally applied GDF-5. The first
samples were taken prior to the study’s start, during the study,
and before necropsy. Blood values were determined, and the
serum concentration of GDF-5 was measured by means of a
GDF-5 enzyme-linked immunosorbent assay (Biopharm GmbH,
Heidelberg, Germany).
Data Analysis
The collected data of each group were examined using non-
parametric methods. After analysis of regression and variance,
P G .05 was considered a statistically significant difference. The
results were confirmed using the Student t test.
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RESULTS
Wound Closure
Within 10.91 (SD, 0.99) days, all wounds treated with GDF-5 were
closed. The untreated wounds took longer to close: 13.3 (SD, 0.94)
days (P = .002). The mean time until wound closure of the wounds
treated with the carrier alone was 11.3 (SD, 1.49) days.
The mean time until wound closure of wounds treated with
100 ng/m2 GDF-5 was 11.33 (SD, 0.94) days and significantly
faster than the control wound (P = .005). The mean time until
wound closure of the other wounds treated with GDF-5 was also
significantly faster than the control wound: 10.66 (SD, 0.94) days
for 1000 ng/m2 GDF-5 and 11.33 (SD, 0.94) days for 5000 ng/m2
GDF-5 (P = .005; Figure 5).
Therefore, GDF-5 1000 ng/m2 significantly accelerates wound
closure compared with the Opsite film control (P G .001). However,
GDF-5 1000 ng/m2 does not significantly accelerate wound closure
compared with the carrier alone (P = .394).
Histologic Analysis
The 21-day histologic analysis of the wounds treated with GDF-5
showed that the mean epidermal thickness was significantly
225 ADVANCES IN SKIN & WOUND CARE & MAY 2017
 ORIGINAL INVESTIGATION
Figure 3.
OPERATIONS AND PLANIMETRIC EVALUATION PROCEDURE
A and B, Intraoperative view before and after creation of the skin defects on the pig’s back. C and D, Examples of outlined wounds and squares (red) for planimetric evaluation.
increased compared with the Opsite film control wound with
thickness of 21.22 (SD, 6.2) Km. The 100 ng/m2 GDF-5Ytreated
skin had a mean thickness 50.7 (SD, 15.6) Km (P = .002); the
1000 ng/m2 GDF-5Ytreated skin averaged 59.6 (SD, 9.9) Km thick
(P G .001), and 5000 ng/m2 GDF-5 had an average thickness of
45.53 (SD, 13.5) Km (P = .002).
Epidermal thickness was increased significantly after treat-
ment with GDF-5 in the concentrations 100 and 1000 ng/m2 com-
pared with treatment with the carrier alone (30.89 [SD, 11.91] Km;
100 ng/m2 GDF-5, P = .033; and 1000 ng/m2 GDF-5, P = .010).
However, the epidermal thickness of 5000 ng/m2 GDF-5 (P =
.074) was not significantly higher than controls (Figure 6).
The epidermal cell count of wounds treated with GDF-5 re-
vealed a significantly higher number of cells within 100-Km epi-
dermis (100 ng/m2 GDF-5: 92.66 [SD, 34.1], P = .007; 1000 ng/m2
GDF-5: 82.5 [SD, 16.1], P = .001; 5000 ng/m2 GDF-5: 72.17 [SD,
24.4], P = .025), compared with the film-only control group, which
had 41.33 (SD, 15.1) cells within the determined 100-Km epider-
mis. The carrier control group amounted to 55.17 (SD, 11.10) cells
and was also significantly less than the groups with 100-ng/m2
GDF-5 (P = .028) and 1000 ng/m2 GDF-5 (P = .007). Again, the
difference in the number of epidermal cells after treatment with
5000 ng/m2 GDF-5 was not significant (P = .185; Figure 7).
ADVANCES IN SKIN & WOUND CARE & VOL. 30 NO. 5
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Overall, the collected data showed that treatment with GDF-5
led to a significantly thicker epidermis and a higher number of
epidermal cells (P e .01) compared with the untreated control
wound. Furthermore, GDF-5 (concentrations 100 ng/m2 and
1000 ng/m2) also led to a significantly higher number of epider-
mal cells and a significantly thicker epidermis compared with
treatment with the carrier alone.
Blood Serum Analyses
The analyzed blood serum showed no systemic effect of GDF-5
at any time.
DISCUSSION
This study was the first time the effect of GDF-5 on full-thickness
dermal wounds was evaluated in a model. Evaluation of wound-
healing products usually starts with in vitro studies. However, in
vitro models are not suitable for imitating the biologic conditions
of wounds. Therefore, animal models usually follow every in vitro
study before a product is tested in a clinical setting.12Y16 The
swine model is commonly used for in vivo large animal studies14
regarding the skin because of its similarities to human skin.
Bone morphogenetic proteins are a family of dimeric proteins
also containing the GDF-5 originally identified as proteins inducing
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 ORIGINAL INVESTIGATION

Figure 4.
HISTOLOGIC EVALUATION

A, Histologic overview of untreated skin (scale bar: 50 Km, hematoxylin-eosin staining). B, Masson trichromeYstained section at the transition point between treated (right part) and
untreated (left part) skin (scale bar: 100 Km). C and D, Comparison between control wound (C) and wound treated with 1000 ng/m2 GDF-5 (D) 21 days after surgery (scale bar: 10 Km).

bone and cartilage formation.17Y19 In addition, BMPs regulate pro-
liferation, differentiation, migration, and apoptosis of many differ-
ent cell types.18Y20 They are expressed in different tissues, including
the skin, where vascular invasion and angiogenesis are important
steps in proliferation and formation cascades. By integrating growth
factors into modern wound dressings, wound healing can be en-
hanced, and a stable wound closure achieved.
Understanding the mechanism of wound healing is essential
to evaluating different wound dressings. Physiologic wound heal-
ing consists of 3 different phases: inflammation (days 0Y6), prolif-
eration (days 4Y14), and maturation (days 8Y16). The inflammatory
phase is also called cleansing, because bacteria are phagocytized,
and the wound is debrided by migrated inflammatory cells (neu-
trophils and macrophages). In the proliferative phase, the fibrin

Figure 5. Figure 6.
PLANIMETRIC EVALUATION EPIDERMAL THICKNESS

Planimetric evaluation shows time until complete wound closure in days of wounds treated Epidermal thickness in micrometers of wounds treated with GDF-5 in different concentrations,
with GDF-5, the control wounds, and wounds treated solely with the carrier. the control wounds, and wounds treated solely with the carrier.

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 ORIGINAL INVESTIGATION
Figure 7.
EPIDERMAL CELL COUNT
Epidermal cell count (the total amount of epidermal cells within a section of 100-Km width
of epidermis) of the wounds treated with GDF-5 in different concentrations, the control
wounds, and wounds treated solely with the carrier.
clot is replaced by granulation tissue: degrading of the extracellular
matrix and synthesis of a new collagen matrix by fibroblasts, angio-
genesis, contraction, and re-epithelialization are regulated under
the stimulus of cytokines. During the maturation or remodeling
phase, a new basement membrane is formed, the matrix is rear-
ranged, and the scar matures. In 1997, Yamashita et al17 showed
that GDF-5 induces angiogenesis in vivo using chick chorioallan-
toic membranes and rabbit corneas. They were able to show that
GDF-5 stimulated the polyamide activity consistent with angio-
genesis induction in vivo. Furthermore, GDF-5 stimulated mi-
gration in a chemotactic fashion.17 This positive effect, as well
as the fact that GDF-5 is able to stimulate fibroblast cell migra-
tion, cell proliferation, and collagen synthesis in animal models,20Y24
makes this growth factor especially promising for wound-healing
products.25
Especially in chronic wounds, a fast wound closure is essen-
tial to avoid infection and allow a fast recovery. Sufficient me-
chanical stability of the closed wound is of great interest. In
other studies, GDF-5Ydeficient mice demonstrated altered bio-
mechanic and compositional properties in collagen IYrich
tissues.26Y28 Collagen is an essential component of the skin and
strongly correlated with tensile strength.29,30 It is possible that
GDF-5 leads to a more stable wound closure through interaction
with the ultrastructure of collagen I filaments in the extracellular
matrix of skin.31 A higher mean epidermal thickness could also
be part of a higher mechanical stability. This study’s results underline
these findings, because an application of GDF-5 led to better skin
quality compared with control wounds.
Every treatment with GDF-5 led to faster wound closure, a
thicker epidermis, and a higher number of epidermal cells com-
pared with the 2 controls, although it was not always significant.
Interestingly, the highest dose of GDF-5 did not reveal the best
results. Instead, an application of 1000 ng/m2 GDF-5 showed
ADVANCES IN SKIN & WOUND CARE & VOL. 30 NO. 5
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
significant results in terms of a fast wound closure, a high number
of epidermal cells, and high epidermal thickness. The 100 ng/m2
GDF-5 seemed to be an underdosing, leading to a slower wound
closure and a thinner epidermis compared with the wounds treated
with 1000 ng/m2 GDF-5. Careful dosing seems to be essential to
achieve best results.
For better understanding of the role of GDF-5 during the
wound-healing process, further histologic analysis at different
times during the wound-healing process might be productive.
CONCLUSIONS
Especially for chronic wounds and extended burn injuries, a fast
and stable wound closure is of high interest to reduce the risk
of infection and restore function to avoid lifelong disfigurements.
Growth differentiation factor 5 accelerates wound closure and im-
proves skin quality during repair of full-thickness skin defects com-
pared with control wounds. This makes it especially promising for
inclusion in composite biomaterials for wound healing that aim to
achieve a fast and stable wound closure.
&
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CALL FOR PAPERS
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