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TISSUE ENGINEERING

Volume 13, Number 6, 2007


# Mary Ann Liebert, Inc.
DOI: 10.1089/ten.2006.0278

Autologous Bone MarrowDerived Cultured Mesenchymal


Stem Cells Delivered in a Fibrin Spray Accelerate
Healing in Murine and Human Cutaneous Wounds*

VINCENT FALANGA, M.D.,1,35 SATORI IWAMOTO, M.D., Ph.D.,1,3,5 MOLLY CHARTIER, M.D.,1
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TATYANA YUFIT, M.D.,1,3 JANET BUTMARC, B.A.,1,3 NICHOLAS KOUTTAB, Ph.D.,2,3


DAVID SHRAYER, M.D., Ph.D.,1 and POLLY CARSON, C.W.S.1,3

ABSTRACT

The nonhematopoietic component of bone marrow includes multipotent mesenchymal stem cells (MSC)
capable of differentiating into fat, bone, muscle, cartilage, and endothelium. In this report, we describe the
cell culture and characterization, delivery system, and successful use of topically applied autologous MSC
to accelerate the healing of human and experimental murine wounds. A single bone marrow aspirate of
3550 mL was obtained from patients with acute wounds (n = 5) from skin cancer surgery and from
patients with chronic, long-standing, nonhealing lower extremity wounds (n = 8). Cells were grown in vitro
under conditions favoring the propagation of MSC, and flow cytometry and immunostaining showed a
profile (CD29+, CD44+, CD105+, CD166+, CD34, CD45) highly consistent with published reports of
human MSC. Functional induction studies confirmed that the MSC could differentiate into bone, carti-
lage, and adipose tissue. The cultured autologous MSC were applied up to four times to the wounds using a
fibrin polymer spray system with a double-barreled syringe. Both fibrinogen (containing the MSC) and
thrombin were diluted to optimally deliver a polymerized gel that immediately adhered to the wound,
without run-off, and yet allowing the MSC to remain viable and migrate from the gel. Sequential adjacent
sections from biopsy specimens of the wound bed after MSC application showed elongated spindle cells,
similar to their in vitro counterparts, which immunostained for MSC markers. Generation of new elastic
fibers was evident by both special stains and antibodies to human elastin. The application of cultured cells
was safe, without treatment-related adverse events. A strong direct correlation was found between the
number of cells applied (greater than 1106 cells per cm2 of wound area) and the subsequent decrease in
chronic wound size ( p = 0.0058). Topical application of autologous MSC also stimulated closure of full-
thickness wounds in diabetic mice (db/db). Tracking of green fluorescent protein (GFP)+ MSC in mouse
wounds showed GFP+ blood vessels, suggesting that the applied cells may persist as well as act to stimu-
late the wound repair process. These findings indicate that autologous bone marrowderived MSC can be
safely and effectively delivered to wounds using a fibrin spray system.

Departments of 1Dermatology, 2Pathology, and 3Center of Biomedical Research Excellence (COBRE), Roger Williams Medical
Center, Providence, Rhode Island.
Departments of 4Dermatology and 5Biochemistry, Boston University School of Medicine, Boston, Massachusetts.
*This work was supported by NIH grants DK067836 (VF) and P20RR018757 (VF).

1299
1300 FALANGA ET AL.

INTRODUCTION Roger Williams Medical Center. To determine the validity


of the topical delivery method and the safety of the ap-

T HERE IS AN IMPORTANT NEED to stimulate the healing of


acute and chronic wounds to a level that is not presently
possible with standard care measures or recently developed
proach, two types of human wounds were studied: acute
wounds resulting from the removal of a nonmelanoma skin
cancer from the trunk or limbs and considered likely to heal
innovative approaches. An area of research that holds prom- properly with secondary intention but not ideally suitable
ise for the treatment of difficult-to-heal wounds is stem cell for primary closure; and chronic wounds of the lower ex-
application. The bone marrow is an important source of he- tremities and feet, which had not been healing for a period
matopoietic stem cells that regularly regenerate components of at least 12 months in spite of appropriate standard care
of the blood, and nonhematopoietic stem cells including and more innovative approaches including topical appli-
mesenchymal stem cells (MSC). There are several poten- cation of PDGF and bioengineered skin products.
tial mechanisms by which autologous stem cells could sig- A single bone marrow aspirate (3550 mL) was taken from
nificantly contribute to wound healing. Under appropriate
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each patients iliac crest. To prevent clotting, the aspiration


conditions stem cells can rejuvenate or rebuild tissue com- needle was primed with sterile heparin sulfate (1000 U/mL).
partments.1 Considerable evidence from our laboratory and The bone marrow aspirate was aliquoted immediately after
from others suggests that the resident dermal fibroblasts in collection. Each 4 mL of the aspirate was layered onto 3 mL
nonhealing wounds have acquired an abnormal phenotype of sterile Ficoll-Paque TM Plus (GE Healthcare Biosciences,
that is not conducive to appropriate tissue repair.25 Spe- Piscataway, NJ) in 15 mL conical tissue culture polypropyl-
cifically, fibroblasts cultured from nonhealing wounds are ene tubes (Becton Dickinson Labware, Franklin Lakes, NJ).
unresponsive to the action of certain growth factors, such as The resulting suspension was centrifuged at 400 g for 30
platelet-derived growth factor-BB (PDGF-BB)2 and trans- minutes at room temperature. The mononuclear layer at the
forming growth factor-b1 (TGF-b1).4,5 The unresponsive- interface between the Ficoll-Paque and plasma was removed
ness to TGF-b1 may be due to down regulation of type II and plated onto T-25 tissue culture flasks containing 7 mL
TGF-b receptors and decreased phosphorylation of key of media, consisting of basic MSC media supplemented
signaling molecules, including Smad3 and MAPK.5 Ac- with 10% mesenchymal stimulatory supplements (StemCell
cordingly, the addition and incorporation of stem cells to the Technologies, Vancouver, BC, Canada). The flasks were in-
wound, particularly if they are potentially capable of dif- cubated and kept at 378C, 5% carbon dioxide (CO2) for the
ferentiating into a number of cells types, is promising. initial 48 hours. The media were then removed and 7 mL
Recently, increasing focus is being placed on the use of of fresh media were added every 34 days. When the cell
bone marrowderived MSC. In a first but preliminary report, monolayers achieved confluence (generally 1 week later),
we showed that such autologous cultured cells could bring they were passaged to T-75 flasks and supplemented with
about closure of long-standing and hard-to-heal wounds.6 15 mL of new media every 34 days. Periodically, cell cul-
However, there are several difficulties encountered in the tures were tested for the presence of mycoplasma using the
use of this type of emerging technology. First, MSC or other Mycoalert mycoplasma detection assay (Cambrex Bio Sci-
stem cell types must be grown in sufficient numbers for ence, Baltimore, MD), and with appropriate positive and neg-
meaningful topical application. Proper characterization of ative controls. The measurements were made by performing
the cultured cells is also important. This step requires ap- a bioluminescent assay.
propriate collection and separation of the bone marrow and
the use of tissue culture techniques that can yield cells with a
stable phenotype. An even greater challenge is the actual Flow cytometry to characterize cultured cells
application of stem cells to a wound. The cells need to be Flow cytometry analysis was used to determine specific
delivered in a preparation that remains in contact with the markers on the cultured cells, from both mouse and human
wound bed and keeps them viable in the often-hostile wound bone marrow aspirates and preparations. Cells in suspen-
microenvironment. Ultimately, the cells have to enter the sion were mixed with fluorochrome-conjugated antibodies
wound to effect a therapeutic response. Using human acute against CD29, CD31, CD34, CD44, CD45, CD105, CD166,
and chronic nonhealing wounds, we provide in this report SCA-1 (BD Biosciences, St. Jose, CA). Appropriate isotype
promising solutions to these difficulties. The results also antibodies were used to control for nonspecific staining.
indicate that the cultured MSC can accelerate healing of Staining was performed according to manufacturers re-
both murine and human cutaneous wounds. commendations. Immunostained cells were acquired and an-
alyzed on a FACS Calibur flow cytometer (BD Biosciences),
using cellQUEST software (BD Biosciences). Cells were
MATERIALS AND METHODS first visualized on forward scatter versus side scatter, and a
gate was constructed around viable cells, thus eliminating
Culture of bone marrowderived cells nonviable cells and debris. To insure the stability of the
All clinical materials and components used in this study phenotype of cultured cells, flow cytometry was performed
were approved by the Institutional Review Board (IRB) of at passages 35 and again at passages 1011. On the day of
DELIVERY OF STEM CELLS TO HUMAN AND MURINE WOUNDS 1301

cultured cell application, cell monolayers in T-75 flasks adipogenic maintenance media alone. The cells were ob-
were trypsinized with 0.05% trypsin-EDTA (Invitrogen, served for oil droplet formation and were also stained with Oil
Carlsbad, CA), collected in regular mesenchymal media, Red O. This technique allowed bright orange-red staining of
and centrifuged for 5 minutes, 400 g at room temperature. fat and blue staining of nuclei. To better emphasize cell out-
The cells were then resuspended and washed twice with lines and nuclei, the cells were incubated with 1 mL of he-
sterile saline, repelleting at the same centrifuge conditions. matoxylin counterstain for 2.5 minutes. Pictures were taken
A sample of cell suspension was taken prior to the final spin using a Nikon Coolpix camera on an Olympus phase-contrast
for determining cell count using a hemacytometer and for inverted scope. Osteogenic induction requires cells aliquoted
calculating the number of cells delivered per cm2 of the into 6-well plates to be grown to confluence in osteogenic in-
wound surface. duction media. To measure calcium deposition as a marker
of bone formation, cells were washed, scraped off the plates,
and digested overnight with hydrochloric acid. A calcium re-
Immunohistochemistry for further characterization porter assay (Stanbio Total Calcium LiquiColor) was then
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of cultured cells used to determine the amount of calcium in the cell lysate.
Per this procedure, 550 nm absorbance ratings were made us-
Immunohistochemistry was performed as previously de-
ing a spectrophotometer. Cells being induced into chondro-
scribed.7 Cells from passages 5 to 7 were trypsinized with
cytes were counted and spun into pellets containing 3104 to
0.05% trypsin-EDTA (Gibco, Grand Island, NY), diluted in
4105 cells. The pellets were supplemented with chondro-
MSC media, and allowed to adhere to sterile glass slides for
genic induction media containing TGF-b3 every 23 days for
15 minutes. These slides were then placed in 10015 mm
4 weeks and kept under standard conditions. The pellets were
dishes, covered with 10 mL of MSC media, and allowed to
then processed, externally stained with eosin, embedded, and
grow at 378C, 5% CO2 for 24 hours. The slides were washed
cut into 4-mm sections for staining with Safranin O. Known
in phosphate buffered saline (PBS), air-dried, fixed in cold
cartilage tissue was used as a positive staining control and cell
acetone, placed in 1 PBS, and immunostained. Cluster des-
pellets that had been kept in regular mesenchymal media
ignation marker primary antibodies included the following:
without induction served as negative controls.
monoclonal CD29 (Serotec, Raleigh, NC), monoclonal CD34
(Immunotech, Marseilles, FR), monoclonal CD44, mono-
clonal CD45, monoclonal CD105, polyclonal CD117 (Dako
Cytomation, Carpinteria, CA), monoclonal CD90 (Oncogene, Fibrin spray system to deliver cells topically
San Diego, CA). In addition, adjacent 4-mm tissue sections to wounds
from formalin-fixed biopsy specimens of the wound bed were
The fibrin delivery method made use of the Tisseel VH
also analyzed with identical antibodies for MSC markers,
fibrin sealant system and the Tissomat application device
as well as using a monoclonal antibody to human prolyl-4-
and spray set (Baxter Healthcare, Glendale, CA). This prep-
hydroxylase beta (Acris antibodies, Germany, distributed by
aration contains human fibrinogen and thrombin. The fol-
Novus Biologicals, Littleton, CO). To analyze whether tissue
lowing protocol was used to make a fibrin gel with final
regeneration might be occurring, we focused on the reestab-
concentrations of 5 mg/mL fibrinogen and 25 U/mL throm-
lishment of elastic fibers. This was done using special stains
bin, utilizing a 1 mL Tisseel VH kit (Baxter). This kit uti-
(Verhoeff-van Gieson) as well as a specific elastin monoclonal
lizes two liquid phases that can be either extruded through a
antibody obtained from Vision Biosystems/Novocastra (Nor-
dual chamber applicator or sprayed through the applicator
well, MA).
with an inert gas carrier. To make the thrombin component,
1 mL of calcium chloride (CaCl2) mixture from the kit was
added using a sterile syringe to the 1 mL bottle of thrombin,
Functional assays to determine the differentiation
and the mixture was allowed to dissolve. One part of this
capacity of cultured MSC solution was then added to 9 parts of sterile 30 mM CaCl2
Bone marrowderived cultured cells between passages in normal saline (0.9% sodium chloride [NaCl]). The
3 and 9 were tested for their ability to differentiate into os- fibrinogen/sealer protein component was made by adding
teocytes, chondrocytes, and adipocytes using specific dif- 1 mL of sterile normal saline to the sealer protein bottle. One
ferentiation assays (Cambrex). For positive controls an MSC part of this solution was then added to 9 parts of sterile
strain (Cambrex PoeticsTM human mesenchymal stem cells) normal saline. The protease inhibitor aprotinin included with
was utilized. Negative controls consisted of the patients cells the kit was not used. All solutions were used within 4 hours.
grown in standard MSC media, and were used to demonstrate The total volume of fibrin gel was predetermined by the size
that the phenotypic changes were nonspontaneous. Briefly, of the wound to be covered. At the time of application to
for adipocyte differentiation, cells were plated onto 6-well each wound, a small amount of the fibrin gel was placed on a
plates and grown to confluence. They were then exposed to tissue culture plate, covered in media, and incubated under
3 cycles of adipogenic induction media alternating with adi- standard conditions to verify and confirm cell viability and
pogenic maintenance media. Negative control cells received migration of the cells from the fibrin.
1302 FALANGA ET AL.

Mouse experiments to determine cell delivery


RESULTS
and efficacy with the fibrin spray system
For initial in vivo screening of cell delivery using the Cell culture and characterization, and delivery
fibrin spray, red fluorescencelabeled fluorescent protein in a fibrin spray
(FP) mouse MSC were delivered to wounds created in the
No adverse events occurred during the harvesting of bone
back of C57BL/6 mice. For red-fluorescence labeling, cells
marrow from patients, and separation of the bone marrow
were stained and washed using the PKH26 red fluorescent
aspirate using Ficoll and subsequent cell culture also pro-
linker kit (Sigma, St. Louis, MO) 2 hours prior to applica-
ceeded without problems. All cell cultures tested negative
tion. Just prior to wounding, the backs of mice were shaved
for mycoplasma. We first focused on the morphology of the
and anesthesia was administered. A 11.5 cm elliptical full-
cultured cells. This is shown in Figures 1AD. After pri-
thickness wound was made in the upper back of the mice. A
mary plating of the Ficoll-separated bone marrow aspirate
polymer film (Cavilon, 3M, St. Paul, MN) was used to cover
and change of media at 48 hours, fusiform or polygonal
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the wound, followed by silicone dressings (Mepitel, Mol-


cells with multiple small, knob-like cytoplasmic projec-
nilcke, Sweden). The dressing was secured to the unwounded
tions could be seen adhering to the tissue culture plastic
dorsal skin with clips. On day 5, the mice were sacrificed
(Figure 1A). By approximately 5 days, many of the flasks
by CO2 inhalation. The dressing was removed and the
contained spindle-shaped cells. In many cases, the cells were
wounded area was excised. Frozen sections were prepared
extremely elongated, and in fact appeared to be aligning
by snap freezing the skin in isopentane on OTC mounting
themselves end to end along their long axis (Figure 1B).
compound. Thereafter, 5 mm sections were cut and observed
Cells for application to patients were used within the first 10
for red fluorescence. In other experiments, mouse MSC
passages. After multiple passages (>1012) the cell mor-
cultures were established from the bone marrow of green
phology became more bizarre and polygonal (Figure 1C).
fluorescent protein (GFP) mice (UBI-GFP/BL/6; Jackson
Occasionally and in very early passages (<5), one in ap-
Laboratory, Bar Harbor, ME) and db/db mice (BKS.Cg-m/
proximately 10 culture dishes, more complex structures
Leprdb/J, former name C57BLKS-m Leprdb, Jackson
formed, consisting of many cells adhering to one another
Laboratory).8 For actual wounding experiments, we used
along their sides and their long axis, appearing like a three-
female mice (2530 grams) under previously described
dimensional structure (Figure 1D). In general, within a week
conditions.3 The fibrin spray system was then used to spray
the cells became confluent. Cell proliferation slowed with
the GFP cells onto the wound. In experiments designed to
increasing in vitro passage, so that doubling times, initially
measure efficacy and tracking, we delivered GFP cultured
34 days, increased to 14 days or more with passages greater
MSC to full-thickness tail wounds of db/db mice and control
than 1012. When placed in tissue culture flasks within the
(db/) littermates using a model we have recently de-
fibrin polymer matrix described in the Materials and Meth-
scribed.3 Imaging of histological and immunofluorescent
ods section, the cells were able to migrate out of the fibrin
sections for these experiments was performed using the Zeiss
onto tissue culture plastic as early as 4 hours (Figure 1E).
Axioplan 2 system with the Axio CAM, and sections were
This migration from the fibrin polymer could also be seen
analyzed by filters for fluorescein isothiocyanate (FITC)
in vivo (see below). Indeed, we used the mouse wounds to
(510560 nm), light microscopy, Texas Red (645/75 nm),
identify an ideal and suitable make up of the fibrin gel. The
and DAPI (435475 nm). Using these filters, a composite
exact concentration of gel components was selected by ti-
photomicrograph was obtained, which helped to determine
tration to provide the most dilute system that would still form
the specificity of the green fluorescence.
an adherent semi-solid. Eventually, using the mouse wounds
for initial screening, the fibrin system we selected provided
a minimum amount of fibrin so that cell migration and gel
Statistical analysis breakdown would be maximized. We found that a final di-
The work on human subjects was analyzed by deter- lution of less than 5 mg/mL of fibrinogen and 25 U/mL of
mining the effect of each application of MSC and any fibrin was associated with a visible run-off of the sprayed
correlation with the cell numbers on subsequent change in solution, before a gel formed on contact with the wound.
wound size within the immediate 2 4 weeks following the Therefore, this was used as the most suitable concentration of
topical application. This analysis was done using the non- both fibrinogen and thrombin and for cell delivery. Increas-
parametric Spearman Rank Correlation with no Gaussian as- ing the concentration of thrombin, while keeping the fibrin-
sumption. For further analysis of the number of cells needed ogen concentration constant at 5 mg/mL also led to a suitable
for a clinically meaningful biological effect, the two-sided gel. However, it was our goal to minimize all reagents for
Fishers Exact Test was used, which helped to determine the application to wounds. As explained in the Materials and
effect of greater or less than 1106 cells/cm2 of the wound on Methods section, the protease inhibitor aprotinin was not
any decrease (at least 10%) in ulcer size. Comparisons with included in the spray system, since gel stability was not our
mice experiments were obtained using the Bonferroni Multi- goal and the purpose was to create a gel that would break
ple Comparisons Test. down relatively quickly and release cells.
DELIVERY OF STEM CELLS TO HUMAN AND MURINE WOUNDS 1303
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FIG. 1. Morphologic appearance of bone marrowderived cul-


tured cells and their exit from fibrin. (A) Appearance of cultured
cells on tissue culture plastic by day 2 after seeding from Ficoll-
separated bone marrow aspirate. A variety of morphologies is
seen, ranging from round to spindle cells. (B) As early as day 5 in
culture, cells began to assume a spindle shape, often with cells
FIG. 3. Functional assays for differentiation of cultured MSC.
joined together along their long axis. (C) At later times in culture
(A) Representative results of bone formation, using calcium as-
(1012 passages), cells became larger and generally lost the
says, for four consecutively tested cultured cells from four dif-
spindle-shape morphology, and assumed a more bizarre polygonal
ferent patients. Positive (established strain of MSC) and negative
shape. (D) During early passage of cells grown on tissue culture
(human dermal fibroblasts) controls are also included in the graph.
plastic (up to 10 passages), one can often see extremely spindle cell
(B) Adipose tissue formation, using Oil Red O, of lipid droplets in
morphology, with the development of islands of three-dimensional
a representative example of cultured cells; the red-staining cells
structures. (E) Migration by 4 hours of spindle-shaped bone
indicate fat-laden cells. (C) Representative example of a pellet of
marrowderived cells seeded in culture as a spray of fibrin con-
cultured cells staining positive for cartilage, using Safranin O.
taining bone marrowderived cells. All figures are at a magnification
(D) Negative control for cartilage, using human dermal fibro-
of 10.
blasts. (E) Positive control for cartilage, using archival cartilage
tissue. Magnification 10 in all cases.

There is no single specific marker for MSC. Therefore,


for flow cytometry and immunohistochemistry a panel of
markers was chosen on the basis of published reports on
human MSC.9,10 In agreement with these reports, the bone
marrowderived cells in the present study demonstrated the
following characteristics and percentage positivity of sur-
face markers: CD29 (99%), CD44 (99%), CD90 (81%),
CD105 (99%), CD166 (99%), CD34 (1.5%), and CD45
(<1%). Therefore, the cultured cells were virtually negative
for CD34 and CD45. This overall flow cytometry profile
was consistently present in cells through passages 48 and
corresponded well with immunostaining of cells plated on
glass slides, which was performed on cells in passages 47.
The representative results for glass slides in Figure 2 were
quite consistent with the flow cytometry studies, indicating
positivity for MSC markers (CD29, CD44, CD90) and neg-
ativity for the hematopoietic marker CD34. It has been
reported that the most primitive bone marrow stromal cells
FIG. 2. Immunostaining of cultured cells for selected CD mark-
ers. Bone marrowderived cultured cells were grown on glass are CD34.11 The cells we cultured were consistently CD34
slides and immunostained with CD markers. These representative negative. While this may indicate that our cultured bone
examples show that the cultured cells were positive for MSC marrowderived cells may have had less stemness, it also
markers ((A) CD29, (B) CD44, (C) CD90) and negative for hemato- demonstrates that they were unlikely to be hematopoietic
poietic markers ((D) CD34). Magnification 10. precursors. To further demonstrate the stem cell characteristics
1304 FALANGA ET AL.

of the cultured cells, we performed functional assays to de- wound bed. Indeed, as Figure 4B shows, the spray could be
termine whether the cells could be induced to differentiate delivered to the wound in an upright position, and still
into osteocytes, adipocytes, and chondrocytes, which is an without run-off of the spray or of the formed gel. Generally,
established characteristic of MSC.12 Results are shown in the syringe was held at 458 to 608 from the wound bed and
Figure 3, which for a total of four representative cell strains in pointing from the edge toward the center of the wound. We
passages 39 confirmed the conversion of the MSC to a found that the use of CO2 flows greater than 5 psi would
phenotype of calcium production (Figure 3A), adipocyte and cause too forceful a spray and would result in splashing of
fat staining (Figure 3B), and cartilage formation (Figures 3C considerable amounts of the gel outside the wound area.
E). It should be noted that in Figure 3A, negative control refers Healing of the wound following a total of three applications
to human dermal fibroblasts, while positive control represents per patient at least 1 week apart occurred uneventfully and
established and commercially available MSC. by no later than week 8 (Figure 5). First, the wound bed
filled with granulation tissue by 2 weeks. Pain relief was
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considerable, practically disappearing with the cell-based


application. By 6 weeks, the large full-thickness wound al-
Application of cultured MSC to human
most completely resurfaced (Figure 4C) and healed com-
acute wounds pletely a week later. Figure 4D shows that complete wound
Having determined that bone marrowderived cultured closure was durable, and that the wound remained healed at
cells consistently display characteristics of MSC and could week 12. Follow-up of patients has continued to show per-
migrate from the fibrin matrix in vitro and in murine wounds, sistent wound closure by 412 months after the procedure.
we next applied autologous cultured MSC to human wounds. Although the study did not have effectiveness as a primary
We tested this approach with a fibrin spray delivery of the outcome, some interesting observations emerged. Two of
cells to both acute (n 5) and chronic nonhealing wounds the four subjects enrolled had more than one wound, thus
(n 8). For the acute wounds, one subject had her bone allowing the use of cell-containing fibrin in one wound and
marrow aspirated but later declined to participate in the fibrin alone in the other. Figure 5A shows the healing tra-
study. Therefore, a total of four patients with postsurgi- jectory in these four patients. One patient (#3) had two
cal acute wounds were treated. As per protocol, the acute wounds, while another (#4) had three wounds. In each of
wounds consisted of defects left by removal of skin cancers these two subjects, one of the wounds was treated with MSC
(basal cell and squamous cell carcinomas) and that would in fibrin, while the other(s) was treated with the fibrin spray
not be ideally suited for primary closure or flaps.13 Patients alone. No delay in healing was observed with the use of cells
had their bone marrow aspirated approximately 2 weeks in these two subjects. All wounds healed completely between
before the surgery to allow for proper in vitro establishment weeks 7 and 8 after the surgery. Interestingly, however, the
of MSC cultures by the day of surgery. The cells were ap- one wound that was dramatically larger at baseline, right
plied immediately after the removal of the skin cancer by after surgery (Figure 5A, subject #1, also shown in Figure 4),
Mohs surgery, an established procedure that helps insure healed more rapidly than the smaller wounds and by week 7.
complete cancer removal and tumor-free margins. There- This finding suggests that in acute wounds, which generally
fore, the applied cells were in their first 24 in vitro pas- heal uneventfully, MSC application could lead to more ac-
sages at the first application. Up to three applications were celerated resurfacing.
performed during the clinical course of the wound and, as In the subjects with the acute wounds described above,
stated in the Materials and Methods section, cells were not biopsies of the wound bed were obtained at day 8 after the
used beyond the 10th in vitro passage. The total fibrin application of cultured cells. Using sequential and adjacent
volume (fibrinogen and an equal volume of thrombin) was histological sections, we then determined whether immuno-
no greater than 2 mL, and the same applies to the treatment staining for specific markers could help support the hypoth-
of chronic wounds (see below). These postsurgical acute esis that the cultured cells had indeed migrated from the
wounds received approximately 2106 cells/cm2. Figure 4 fibrin and were present in the superficial layers of the wound.
illustrates this general approach of MSC application in a Figure 6 shows representative immunostaining results using
representative acute wound (subject #1 of Figure 5). Figure antibodies to CD29, CD45, and prolyl hydroxylase, a spe-
4A shows the double-barreled syringe used to load the cells cific human fibroblast marker, in a subject who received
in the fibrinogen fraction of one barrel and the thrombin either fibrin plus cells (left two panels) or fibrin alone (right
solution in the other. A gentle push on the common plunger panel).14 Labels a, b, and c in Figure 6 refer to
while activating the CO2 gas (2.55.0 psi) flowing through magnifications of 4, 10, and 2, respectively. CD29 is
the tip of the syringe allowed an even mist of mixed fi- one of the markers for mesenchymal type of cells.9 We
brinogen and thrombin to reach the wound as a fibrin spray found CD29 immunostaining in the upper levels of the
(Figure 4B). The syringe was held approximately 13 cm wound bed, and unassociated with immunostaining for
away from the wound bed, and the delivered spray poly- CD45, the leukocyte common antigen and a marker that
merized very quickly to a gel consistency adhering to the was not present in our cultured cells (see previous para-
DELIVERY OF STEM CELLS TO HUMAN AND MURINE WOUNDS 1305
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FIG. 4. Application of bone marrowderived cultured MSC to


acute human wounds. (A) The cells were applied directly to the
wound using a fibrin polymer spray delivered from a double-
barreled syringe. The arrows point to the individual barrels filled
with either thrombin or the cell-containing fibrinogen solution.
The tubing, attached to the common spray jet area below the
syringe, was connected to CO2. (B) Application of the cultured
cells to the wound, in this panel at baseline and immediately after FIG. 5. Rate of healing of the human wounds. The autologous
surgery, was done by pressing on the common plunger of the bone marrowderived cultured MSC were applied using a fibrin
double-barreled syringe shown in (A), and approximately 2 cm spray to both acute and chronic human wounds. (A) Healing
away from the wound bed. The inset shows the large wound on the trajectory of four subjects with acute wounds after removal of skin
back of the subject, who was sitting up. No run-off of the sprayed cancer. The numbers refer to the four individual patients, and
material is observed. (C) Appearance of the wound at week 6, or next to the numbers indicates wounds treated with either
showing complete filling of the wound bed and almost complete MSC in the fibrin spray or the fibrin spray alone, respectively. The
epithelial resurfacing. (D) Complete healing of the wound oc- dashed lines also represent the healing of wounds treated with
curred by week 7, and the wound remained healing by week 12, as fibrin alone. Patient #4 had one wound treated with cells, and two
shown. The pink area to the right of the healed wound indicates a with fibrin alone (-a and -b). (B) Healing trajectory of subjects
healed biopsy site. with chronic wounds treated with MSC in a fibrin spray.

with a specific antibody directed against human elastin.


graph). Similar spindle cells in the upper layer of the Comparable immunostaining for elastin was not observed
wound bed also stained with the prolyl hydroxylase fibro- in control biopsies (not shown).
blast marker (FibM). Taken together, these results suggest
that at least some of the cultured cells may have migrated
Application of cultured MSC to human
into the upper layers of the wound bed and possibly may
have differentiated into a fibroblast phenotype. In contrast,
chronic wounds
as shown in the right panel (c) of Figure 6 for the wound Chronic wounds are very difficult to heal. In the context
in the same subject treated with fibrin alone, the upper of studying the feasibility of our experimental approach in
layers of the wound bed do not contain a substantial density humans, we applied cultured MSC from autologous bone
of CD29 cells. Indeed, there is a deeper infiltrate that marrow to wounds of more than 1 year duration in the leg
appears to be CD29 and FibM positive and probably rep- and foot of eight subjects that had not healed with a number
resents endogenous cells that are participating in the heal- of therapeutic approaches, including standard care, topically
ing process. We also determined the possibility of tissue applied PDGF-BB, and living bioengineered skin constructs.
regeneration by focusing on the deposition of new elastic These chronic wounds were due to venous insufficiency or
fibers.1517 Since these wounds were full-thickness, one diabetic neuropathy, but there was no evidence of significant
would not expect the presence of elastic fibers in the upper arterial insufficiency. As with acute wounds, the patients
wound bed. However, as shown in Figure 7, definite elastic were treated with MSC delivered topically in a fibrin spray,
fibers were present when looked for both by the traditional using the same methodology with respect to fibrinogen and
Verhoeff-van Gieson special stain and by immunostaining thrombin concentrations and total volume of fibrin (no more
1306 FALANGA ET AL.

than 2 mL). Because chronic wounds show considerable var- wound were able to migrate from the fibrin matrix and had
iation in baseline size, we tracked very carefully the number a mesenchymal phenotypic morphology.
of cells delivered per cm2 of wound surface, which was
measured by computerized planimetry. A total of six sub-
Use of autologous MSC in full-thickness
jects with chronic wounds were evaluated from the eight
enrolled; two had to be excluded. One excluded subject was murine wounds
a woman with mild mental retardation who was found to Tracking of MSC in humans is obviously difficult because
chronically manipulate her foot wound. The other excluded of our inability to safely and reliably label cells prior to
subject was a man who was concomitantly found to have a application. Moreover, we could only biopsy the human
systemic malignancy and thus could no longer continue to wounds early on after MSC application, and not after com-
be in the protocol. No safety problems occurred during bone plete closure had occurred. Therefore, we next used mouse
marrow aspiration and the application of cultured MSC in a models of wounding to determine whether MSC would persist
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fibrin spray. As with acute wounds, the protocol called for in the healed wound and lead to the formation of new
up to three applications of the stem cells. Figure 5B shows structures, and whether a biological effect could be demon-
the healing trajectory of the six patients, and indicates a trend strated in animals, such as the db/db diabetic mouse, which
toward a decrease in ulcer size or complete wound closure are known to heal with more difficulty. We approached this
by 1620 weeks. Figure 8 shows the example of one woman problem in the mouse in two different ways. We labeled
with a nonhealing venous ulcer of the ankle, complicated autologous bone marrow derived cultured MSC with a red
by rheumatoid arthritis, which achieved complete wound fluorescence dye (see Materials and Methods) and also
closure using this approach. Her wound had not healed in used GFP MSC. Figures 11A and B show the histological
over 10 years. Of the remaining five subjects, a mean wound hematoxylin and eosin appearance and the red fluorescence
area reduction of 40% was found in four, while one subject of adjacent tissue sections 5 days after the application of red
showed no change in the size of his wound. No adverse fluorescently labeled MSC to wounds made on the back of
events were noted. Of great importance is the healing re- C57BL/6 mice. As the figures indicate, the labeled cells are
sponse within the first 24 weeks after each application of able to penetrate into the wound bed. It should be noted that
MSC in the subjects with chronic wounds. We analyzed this some of these studies were done just prior to the application
by determining the number of cells applied per cm2 of total of MSC to human wounds, and actually were instrumental in
wound surface, as measured by computerized planimetry. determining the proper application technique and concen-
The graph in Figure 9 represents the correlation between the trations of fibrinogen and thrombin for the delivery of cells
number of MSC applied to chronic wounds and the percent in a spray system (see first part of Results section). However,
change in ulcer area at 2 4 weeks after each application wounds made in the back of mice have the drawback that
(n 17 data points). There was a very strong correlation they heal mostly by contraction and a large dead space makes
indicating that, the greater the number of applied cells, the it difficult to know for certain whether the applied cells will
larger the reduction in ulcer area. Thus, using Spearmen remain in place. Therefore, we turned to a full-thickness
Rank Correlation, we found r 0.6389 (corrected for ties) model we recently established and that is now being used by
with a 95% confidence interval of 0.8606 to 0.2135; other investigators also.18 This model consists of creating
p 0.0058. As also suggested by the data points in Figure 9, full-thickness wounds, down to fascia, on the dorsal aspect of
additional statistical evaluation showed that only applica- the tail, approximately 1 cm distal to the body.3 These exci-
tions of greater than 1106 cells/cm2 of the wound were sions take up to 3 weeks to heal in normal mice, and reflect
associated with a subsequent (24 weeks) decrease in ulcer resurfacing by epithelial migration rather than by contraction.
size of at least 10% (Fishers Exact Test two-sided; p Using this model in db/db mice and their control (db/) lit-
0.0345). termates, we delivered immediately after wounding a single
One of the treated subjects had bilateral plantar ulcers application of either fibrin alone or fibrin containing autolo-
from diabetes, and had his wounds treated with either the gous bone marrowderived cultured MSC. As with human
fibrin spray alone or cultured cells in a fibrin spray. Biopsies MSC, we determined mouse cluster designation markers
were taken from each of his plantar wounds, and sequential by flow cytometry and immunohistochemistry. The applied
adjacent sections were analyzed by immunostaining. Figure cells had the following profile: CD29, CD44, SCA-1,
10 shows that there was minimal or no overlap between CD34, CD45/LCA, CD31. Figure 11C shows the re-
CD45 and CD29 immunostaining in the wound bed of the sults in tail wounds in db/db mice and their control littermates
MSC-treated wound. Interestingly, CD29 immunostaining treated with either fibrin alone or MSC-containing fibrin. We
was dramatically present in the MSC-treated wound but not used the Bonferroni Multiple Comparisons Test to determine
in the one treated with fibrin alone. The dermal cells were the significance of the results. By day 10 after wounding, the
spindle shaped, a pattern that was also observed when se- control mice showed accelerated healing with MSC appli-
quential sections were immunostained with antibodies to a cation ( p < 0.01) compared to fibrin alone, while a strong
specific fibroblast marker (Figure 10). These results, as with trend but no statistically significant difference was detected in
the acute wounds, suggest that the cells delivered to the the db/db mice. By day 20 after wounding, MSC application
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FIG. 6. Immunostaining of acute wounds at day 8 after MSC application. Sequential sections of formalin-fixed biopsy specimens were
immunostained for CD29, CD45, and prolyl hydroxylase as a specific marker for human fibroblasts (fibroblast marker: FibM). The a,
b, and c refer to magnifications of 4, 10, and 2, respectively. The blue staining is due to the marker blue ink applied to the top
of the biopsy specimens. The left two columns of photomicrographs represent sequential sections of a representative wound treated with
MSC in fibrin, while the right single column of photomicrographs represents a control wound treated with fibrin alone. For the MSC-
treated wounds, spindle-shaped cells positive for both CD29 and the fibroblast marker (FibM) are present in the superficial layers of the
wound bed, which is where the cultured cells were applied. The immunostained cells appear to be distinct from those positive for CD45,
the leukocyte common antigen (LCA). Conversely, as seen in the fibrin-only group, the superficial bed of the wound treated with fibrin
alone is cellular poor for CD29 and the fibroblast marker (FibM). Only the deep aspect of the wounds shows immunostaining for these
markers, most likely representing an endogenous and deeper cellular component.

FIG. 7. Elastic fibers in acute human wounds at day 8 after MSC


application. The left side of the pictures indicates the two different
methods of elastic fibrin staining. The Verhoeff-van Gieson stains FIG. 8. Application of bone marrowderived cultured cells to
the elastic fibers black, while the elastic fibers immunostained with human chronic wounds. (A) Nonhealing wound over the ankle of
a specific elastic antibody stain red. Arrows point to individual and a subject at baseline; (B) Third application of MSC in a fibrin
representative elastic fibers. The left upper and lower panels spray to the now healing wound; (C) At 3 months, the wound is
(A) and (C) represent control normal skin, while the right upper almost healed. The wound bed has filled in completely, and only a
and lower panels (B) and (D) are from the superficial wound bed to small eroded surface is present; (D) The wound then went on to
which the MSC had been applied. Using both stains, there appears heal. The photographs show final documentation of complete
to be definite new formation of elastic fibers. Magnification 10. wound closure at 6 months.

1307
1308 FALANGA ET AL.

ters and overlay of images to eliminate false positivity,


indicate a blood vessel that shows definite green fluores-
cence. These results suggest that the applied cells, at least
those that are GFP, may not persist in great numbers in the
healed wound. The acceleration of healing clearly present
with the application of MSC to db/db mice wounds indicates
that the MSC may play a stimulatory role in spite of the lack
of long-term persistence.

DISCUSSION
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We report the successful culture and propagation of MSC


from human and mouse bone marrow for topical delivery to
autologous animal and human wounds. The establishment
of these cell cultures was rapid, and their characterized
MSC phenotype was evident and stable in culture, as shown
FIG. 9. Correlation of wound healing with the number of MSC by morphology, flow cytometry, immunostaining, and func-
applied. The graph represents the correlation between the number tional assays. We show that these cells can be successfully
of MSC applied to wounds in a fibrin spray and the percent change applied to the wound bed using a fibrin spray system. For
in ulcer area at 24 weeks after each application in patients with this, we modified the concentrations of both fibrinogen and
chronic wounds (n 17 data points). Analysis was done using thrombin so as to deliver a fine spray that polymerized to
Spearmen Rank Correlation; r 0.6389 (corrected for ties) with fibrin immediately and on contact with the wound bed.
the 95% confidence interval of 0.8606 to 0.2135; p 0.0058.
Using a very low CO2 flow for fibrin delivery, there was no
Application of greater than 1106 cells/cm2 of the wound was
highly associated with a subsequent (24 weeks) decrease of at
run-off of the preparation from the wound bed. MSC in the
least 10% in ulcer size (Fishers Exact Test two-sided; p 0.0345). fibrin spray remained viable and were able to migrate from
the fibrin matrix, as determined by both in vitro and in vivo
studies. Thus, the application of autologous cultured MSC
led to a statistically significant difference from fibrin alone to human acute and chronic wounds is safely accomplished.
in the db/db mice ( p < 0.001), and this difference continued The applied cells appear to establish themselves in the
to be present by day 25 ( p < 0.05). The application of fibrin wound bed. A decrease in size of the chronic wounds cor-
alone did not stimulate healing when compared to air-exposed related very strongly and with a great degree of statistical
wounds ( p > 0.05, not shown). significance with the number of MSC applied per cm2 of
In other mouse tail-wound experiments designed to track the wound surface. Indeed, a concentration of 1106 cells
the fate of topically delivered cells, we applied mouse au- per cm2 was clearly required to stimulate a decrease in
tologous GFP MSC immediately after tail wounding and wound size. Animal studies showed that mouse autologous
analyzed frozen sections from the wound site for the pres- bone marrowderived MSC can accelerate the healing of
ence of green fluorescence. Because of the very friable full-thickness wounds in db/db mice as well as their con-
nature of the wounded site at early time points, which made trol littermates. Tracking of GFP MSC in full-thickness
it difficult to obtain intact sections, we took shave biop- mouse wounds suggests that most of these cultured cells may
sies for frozen sections at later times and immediately af- not persist, in spite of the stimulation of wound healing. Taken
ter wound closure. For imaging, we used different filters together, these results indicate the feasibility of using a
capable of detecting false green fluorescence positivity modified fibrin spray system to deliver cells to wounds, and
from GFP (see legend to Figure 12). Thus, we used filters for also offer considerable promise that bone marrowderived
FITC (510560 nm), light microscopy, Texas Red (645/ cultured MSC can accelerate healing. Of crucial importance is
75 nm), and DAPI (435475 nm). Using these filters, we that our studies were performed not only in experimental
were also able to construct composite photomicrographs, animal wounds but also in difficult-to-heal human wounds.
again to confirm the specificity of any green fluorescence. There is substantial and increasing interest in the use of
We found that, by day 18 after wounding, definite clusters of adult stem cells to accelerate healing.1,19,20 While there have
GFP cells could no longer be demonstrated at the wound been advances in the treatment of difficult-to-heal wounds
site, and only rare individual GFP cells, not due to auto- in the last few years, there is still a considerable percentage
fluorescence, could be detected. Similarly, keratinocytes (up to 50%) of chronic wounds, particularly those that are of
were not GFP. Interestingly, however, we uncommonly more than 1 year in duration, that remain unresponsive to
found stable endothelial structures that were clearly GFP advanced treatment approaches.21,22 With the inherent dif-
(approximately one per 20 high-power fields). The repre- ficulties involved in using embryonic stem cells, both from
sentative photomicrographs in Figure 12, using different fil- the technical and regulatory standpoints, adult autologous
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FIG. 12. Identification of GFP MSC in mouse wounds. Photo-


FIG. 10. Immunostaining of chronic wounds before and at micrographs of C57BL/6 mouse tail wounds 18 days after wounding.
week 3 after MSC application. Sequential sections of formalin- The tail wounds were treated with a fibrin spray containing GFP
fixed biopsy specimens from a representative chronic wound were syngeneic bone marrowderived cultured MSC. Frozen sections
immunostained for CD29, CD45, and prolyl hydroxylase as a were analyzed using the Zeiss Axioplan 2 imaging system with the
specific marker for human fibroblasts (fibroblast marker: FibM). Axio CAM. GFP blood vessels (arrows) were identified by FITC
All magnifications are 10. The left and right panels refer to the (510560 nm; (A)). Adjacent sections were analyzed by filters for
wound treated with fibrin alone or MSC-containing fibrin spray, light microscopy (C), Texas Red (645/75 nm; (D)), and DAPI (435
respectively. The blue staining is due to the marker blue ink ap- 475 nm; (E)). Using these filters, a composite photomicrograph was
plied to the top of the biopsy specimens. The panels show spindle- obtained, showing the specificity of the green fluorescence (B). Mag-
shaped cells positive for both CD29 and the fibroblast marker in nification 200.
the superficial layers of the wound bed, where the cultured cells
were applied. The immunostained cells appear to be distinct from
those positive for CD45, the leukocyte common antigen (LCA).

FIG. 11. Histology and effect on healing in mouse wounds treated with MSC. (A) Histology of a representative mouse wound 5 days
after application of syngeneic MSC in a fibrin spray. The wound bed contains a large number of cells; 4. (B) Red fluorescently labeled
MSC were applied in a fibrin spray to the mouse wounds. By day 5, the cells had migrated into the dermal component of the wound bed.
The photomicrograph represents a histological section adjacent to that shown in (A); 10. (C) The graphs represent the results of healing
when treating mouse tail wounds with syngeneic MSC. Both db/db mice and their control littermates were treated either with fibrin
alone or with MSC-containing fibrin spray. Each point represents the mean SEM from four mice.
1309
1310 FALANGA ET AL.

bone marrowderived stem cells become an attractive alter- not hematopoietic cells or leukocyte precursors. Some in-
native. Indeed, in a previous report, we showed promising vestigators have proposed that early or primitive stromal
results with the use of autologous bone marrowderived elements should be CD34 and thus exhibit more stem-
cultured cells in three subjects with previously nonhealing ness.11 However, our experiments do show that the cultured
leg ulcers.6 In that study, however, characterization of the cells could differentiate into bone, adipose, and cartilage
cultured cells was not performed. More importantly, at that components. Moreover, our goal was to develop an easily
time we did not have a proper method for cell delivery, and reproducible culture system that would insure that we were
the cultured cells were simply placed as a suspension under dealing with MSC and that MSC could be properly delivered
an occlusive film applied over the wound. That system topically and accelerate healing.
proved unsatisfactory, in that the cell suspension could easily An important feature of this report is that we studied hu-
run off the wound and definite and reliable delivery of the man wounds and determined the feasibility of fibrin as a de-
cultured cells could not be insured. In this report, we fully livery system in both acute and chronic wounds. Ultimately,
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characterize the autologous bone marrow derived cultured the feasibility of the fibrin spray had to be tested in human
stem cells and show their mesenchymal phenotype. More- wounds, and both in the acute and more hostile chronic
over, we found that a delivery system using a fibrin spray, wound microenvironments. The results presented here appear
which we have modified for this purpose, seems ideal in this very promising and, equally important, no adverse effects
situation. The choice of fibrin as a delivery method was were noted. We found that, for a possible therapeutic effect of
based on a number of previous observations and the fact that this approach in human acute wounds, larger wounds would
fibrin is a well-tested system already in use to stop bleeding need to be tested in future studies. This is actually not sur-
during surgery.2325 We have previously shown that cross- prising, for acute wounds generally heal without much dif-
linked fibrin stimulates cell attachment and spreading.26 ficulty. For chronic wounds, we chose subjects with very
This and work from others suggested that fibrin may be safe difficult-to-heal wounds, which were present for a long time
for cells, including MSC,27 and for the healing process.2830 and were unresponsive to even advanced therapies. Thus, the
The next important question was whether and how to modify results in these subjects are extremely promising. We found a
the fibrinogen and/or thrombin concentrations for the de- strong and statistically significant correlation between the
livery of cells to a wound. A recent report has shown ideal number of applied MSC and acceleration of healing. The
concentrations of these components for developing fibrin optimal number of applied cells needs to be at least 1106
constructs that, at least in vitro, allow fibroblasts to migrate cells per cm2 of the wound surface. This is very important
onto tissue culture plastic.27 In agreement with that report, information that could only be discovered empirically and by
we also found that the readily available commercial fibrin actually studying these difficult wounds. Identifying the num-
preparation, which is used to control bleeding, could not be ber of cells is also critical for larger studies in the future. The
used in the same way to deliver cells. In fact, our in vivo results obtained with the acceleration of healing of full-
studies found that full concentrations of fibrinogen and thickness wounds in db/db mice provide additional evidence
thrombin encased the stem cells to the point that they ap- for the effectiveness of MSC in stimulating wound repair. As
peared to be nonviable (not shown). The concentrations of expected, control littermates healed faster than db/db mice,
fibrinogen and thrombin used in this report, however, appear although they too showed a statistically significant healing
to be effective in cell delivery, as indicated by our histo- response to autologous mouse MSC.
logical and immunofluorescence analysis and by the accel- An understandable and obvious disadvantage of using
eration of wound healing. human wounds is that one cannot properly and safely mark
In culturing the Ficoll-separated bone marrow aspirate, cells and track them from the fibrin gel into the wound. We
we chose to test for a subset of high-yield cluster designa- therefore immunostained sequential adjacent sections for
tion markers to provide information on the lineage of the different markers. The results in both acute and chronic
cultured cells. While the cells were plastic adherent and had wounds showed that the introduced cells, positive for CD29
similar morphology to stromal cells, we were interested in and for prolyl hydroxylase as a specific human fibroblast
confirming that the cells were indeed mesenchymal in origin. marker,14 can be found in the dermis, immediately under the
There is no specific MSC marker, and we therefore selected site of fibrin gel delivery. The highly spindled morphologi-
a group of markers. We chose CD29, CD44, CD90, CD105, cal appearance we found in histological and immunostained
and CD166 as they are commonly cited as MSC markers sections, remarkably similar to what we documented in tis-
in the literature.9,10 For the sake of practicality and for de- sue culture, is also supportive of the fact that the stem cells
veloping a method that could be repeated on cultures from did indeed migrate from the applied fibrin gel and mobilize
multiple patients, we chose this previously reported subset. into the dermis. Moreover, using two separate methods to
Other markers described in reports of human MSC include detect elastic fibers, we found strong evidence that new
STRO-1, CD73, and CD49e.11 We also tested for CD34 and elastic fibers may have been deposited in the dermis of full-
CD45 to insure that we were culturing the stromal compo- thickness wounds treated with MSC. This possible regen-
nent of the bone marrow, and not hematopoietic cells. Our eration of elastic fibers, which normally does not occur in
cells were CD34 and CD45 negative, indicating that they are healing wounds or in scars,1517 is quite interesting. Similar
DELIVERY OF STEM CELLS TO HUMAN AND MURINE WOUNDS 1311

accumulation of spindle cells having these markers in the 5. Kim, B.C., Kim, H.T., Park, S.H., Cha, J.S., Yufit, T., Kim,
upper dermis or new elastic fiber formation were not found S.J., and Falanga, V. Fibroblasts from chronic wounds show
in control sections where the wound received fibrin alone. altered TGF-beta-signaling and decreased TGF-beta type II
In order to further track the MSC applied to wounds, we receptor expression. J Cell Physiol 195(3): 33136, 2003.
performed experiments in mice by using GFP autologous 6. Badiavas, E.V., and Falanga, V. Treatment of chronic wounds
with bone marrow-derived cells. Arch Dermatol 139(4): 510
MSC isolated from syngeneic strains. For imaging the im-
16, 2003.
munofluorescence, we used a stringent system of optical fil-
7. Butmarc, J., Yufit, T., Carson, P., and Falanga, V. Human
ters to exclude the possibility of autofluorescence and other beta-defensin-2 expression is increased in chronic wounds.
situations of false positive green fluorescence. Our results Wound Repair Regen 12(4): 43943, 2004.
indicate that, at least at later time points, labeled MSC could 8. Sudres, M., Norol, F., Trenado, A., Gregoire, S., Charlotte, F.,
not be found in clusters, except for very occasional indi- Levacher, B., Lataillade, J.J., Bourin, P., Holy, X., Vernant,
vidual cells. We cannot fully explain these findings, but we J.P., Klatzmann, D., and Cohen, J.L. Bone marrow mesen-
Downloaded by 36.79.6.204 from online.liebertpub.com at 09/21/17. For personal use only.

propose some possibilities. One is that cultured and topically chymal stem cells suppress lymphocyte proliferation in vitro
applied MSC may participate in the stimulation of wound but fail to prevent graft-versus-host disease in mice. J Immunol
healing by the production of cytokines and/or stimulation of 176(12): 776167, 2006.
endogenous resident cells. Another explanation is that, be- 9. Kassis, I., Zangi, L., Rivkin, R., Levdansky, L., Samuel, S.,
Marx, G., and Gorodetsky, R. Isolation of mesenchymal stem
cause GFP is quite immunogenic,31 cells engineered with this
cells from G-CSF-mobilized human peripheral blood using
protein are removed by the host immune system. Studies are
fibrin microbeads. Bone Marrow Transplant 37(10): 96776,
going on to answer some of these questions. We did observe 2006.
rare but definitely GFP dermal blood vessels in the healed 10. Tuli, R., Tuli, S., Nandi, S., Wang, M.L., Alexander, P.G.,
wound. At this point, we do not know whether this could Haleem-Smith, H., Hozack, W.J., Manner, P.A., Danielson,
represent cell fusion or a rare event of MSC conversion to K.G., and Tuan, R.S. Characterization of multipotential mes-
endothelium. enchymal progenitor cells derived from human trabecular bone.
In summary, we describe methods for reliably culturing Stem Cells 21(6): 68193, 2003.
human and mouse MSC from bone marrow and for the de- 11. Simmons, P.J., and Torok-Storb, B. CD34 expression by stro-
livery of these cells to human wounds and experimental mu- mal precursors in normal human adult bone marrow. Blood
rine wounds. The approach appears reliable and safe and is 78(11): 284853, 1991.
12. Short, B., Brouard, N., Occhiodoro-Scott, T., Ramakrishnan,
very promising in terms of effectively stimulating the repair
A., and Simmons, P.J. Mesenchymal stem cells. Arch Med Res
process in injured tissue.
34(6): 56571, 2003.
13. Bowen, G.M., White, G.L., Jr., and Gerwels, J.W. Mohs mi-
crographic surgery. Am Fam Physician 72(5): 84548, 2005.
ACKNOWLEDGMENTS 14. Olerud, J.E., Chiu, D.S., Usui, M.L., Gibran, N.S., and Ansel,
J.C. Protein gene product 9.5 is expressed by fibroblasts in
We thank Dr. Gerald Colvin of the Division of Hema- human cutaneous wounds. J Invest Dermatol 111(4): 56572,
tology for performing the bone marrow aspiration on human 1998.
subjects. Dr. Peter Libbey, of the Department of Pathology, 15. Kumagai, N., Nishina, H., Tanabe, H., Hosaka, T., Ishida, H.,
helped us in the studies of MSC conversion to cartilage and and Ogino, Y. Clinical application of autologous cultured
adipose tissue. epithelia for the treatment of burn wounds and burn scars.
Plast Reconstr Surg 82(1): 99110, 1988.
16. Moiemen, N.S., Vlachou, E., Staiano, J.J., Thawy, Y., and
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and Falanga, V. Un-cross-linked fibrin substrates inhibit kera-
Professor and Chairman
tinocyte spreading and replication: correction with fibronectin
and factor XIII cross-linking. J Cell Physiol 174(1): 5865, 1998.
Department of Dermatology and Skin Surgery
27. Ho, W., Tawil, B., Dunn, J.C., and Wu, B.M. The behavior of Roger Williams Medical Center
human mesenchymal stem cells in 3D fibrin clots: dependence Elmhurst Building
on fibrinogen concentration and clot structure. Tissue Eng 50 Maude Street
12(6): 158795, 2006. Providence, RI 02908
28. Becker, J.C., Domschke, W., and Pohle, T. Biological in vitro
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