#751 Kesten FINAL

Advanced Wound Healing

SURGICAL TECHNOLOGY INTERNATIONAL XXIX

Autologous Adipose
Derived Regenerative Cells:
A Platform for Therapeutic Applications
STEVEN KESTEN, MD JOHN K. FRASER, PHD
CHIEF MEDICAL OFFICER CHIEF SCIENTIST
CYTORI THERAPEUTICS, INC. CYTORI THERAPEUTICS, INC.
SAN DIEGO, CALIFORNIA SAN DIEGO, CALIFORNIA

ABSTRACT
dipose derived regenerative cells (ADRCs) are a heterogeneous population of cells including multipo-

A tent adipose derived stems cells, other progenitor cells, fibroblasts, T-regulatory cells, and

macrophages. Preclinical data exist supporting benefits that are predominantly through angiogenesis,

modulation of inflammation, and wound remodeling. Such effects are likely paracrine in nature. The applica-

tion of autologous ADRCs has been investigated across multiple therapeutic areas. While there are numerous

publications, there is a relative lack of double-blind, well-controlled, randomized clinical trials in the litera-

ture. Nevertheless, a consistency in outcomes and a consistency with preclinical and laboratory studies sug-

gests a true positive effect. The therapeutic areas reported include orthopedics, autoimmune disease, wounds

and reconstruction, cardiology, peripheral vascular disease, genitourinary disorders, gastrointestinal fistulas,

and neurology. Case reports have documented wound healing in otherwise intractable wounds such as

ischemic- and radiation-related cutaneous ulcers and enterocutaneous fistulas. An open label, 12-patient-

study indicated substantial improvement in hand manifestations of scleroderma across multiple endpoints.

Post-radical prostatectomy urinary incontinence improved in a study of 11 patients with local delivery of

ADRCs. Small studies of intramyocardial delivery have been associated with trends towards benefit. The stud-

ies also indicate that same day fat harvest through liposuction, cell processing, and cell delivery is feasible

and can be performed with an acceptable safety profile. The objective of this review is to highlight the inter-

est, potential, and trends that support the need to continue evaluation and exploration for the role of ADRCs

as a therapeutic agent.

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Autologous Adipose Derived Regenerative Cells: A Platform for Therapeutic Applications
KESTEN/FRASER
INTRODUCTION
The discovery approximately 15
years ago of a multipotent stem cell
population present within human adi-
pose tissue led to an enormous increase
in research into the regenerative prop-
erties of adipose-derived cells.1-3 Subse-
quent work has demonstrated that this
multipotent population—adipose-
derived stromal cells (ADSCs)—has
several properties in common with
marrow-derived stromal cells (also
referred to as mesenchymal stem cells
or mesenchymal stromal cells);4,5 how-
ever, in many other ways they are quite
distinct in that they exhibit differences
in cell surface marker expression6 and
response to different culture
conditions.7,8 ADSCs are usually pre-
pared by culturing the stromal vascular
fraction (SVF) of adipose, a population
derived by digesting the tissue with col-
lagenase, though they can also be
expanded using other starting material
(e.g., lipoaspirate fluid 9) albeit with
reduced efficiency and recovery. Even
when enzymatic methods are applied,
there are important differences between
the safety profile of a cell population
prepared using poorly characterized
approaches and that prepared using sys-
tems, methods, and reagents that are
suited for subsequent clinical use of the
cells (e.g., use of pharmaceutical grade
reagents and enzymes). We have used
the term ADRCs to refer to a SVF cell
preparation that is “clinical grade” (i.e.,
specifically designed for human use as a
cell therapy product) as distinct from
SVF prepared under laboratory research
conditions.
Composition and Mechanisms
of Action
COMPOSITION AND MECHANISMS
OF ACTION
SVF, as the name indicates, is com-
prised primarily of stromal and vascular
cell types. As such, it contains tissue-
resident fibroblasts, macrophages, and
immune cells (including regulatory T
cells) as well as vascular endothelial
cells, endothelial progenitor cells, vas-
cular smooth muscle cells, and peri-
cytes.9,10 SVF also contains cells from
blood extravasated during liposuction
that was not washed away prior to tissue
digestion and from blood within vessels
present in the tissue and released upon
#751 Kesten FINAL
digestion. One of the key features of
SVF is the relatively high frequency of
cells with stem cell-like properties.11,12
Specifically, using the standard colony
forming unit for fibroblasts (CFU-F)
assay, the frequency of these cells in
marrow of a 30- to 40-year-old adult is
approximately 1 in 250,000 nucleated
marrow cells, whereas CFU-F frequen-
cy in SVF is approximately 1–2 in 100;
a 250-fold difference.13
This heterogeneous population has
been reported to improve outcome in
preclinical animal models, represent-
ing a very broad range of disease and
injury states.14-19 However, the bene-
fits observed in these preclinical stud-
ies do not appear to be provided
solely by ADSCs but der ive from
other cells present within the SVF
including immunoregulatory T cells,
macrophages, and other subpopulations
such as blood and lymphatic vessel
endothelial cells and their progenitors.
That is, the multiplicity of beneficial
effects apparently mediated by SVF
appears to be a direct reflection of the
multiplicity of cell types present within
the population and are likely paracrine
in nature rather than effects of differen-
tiation from transplanted progenitor
cells. These mechanisms fall into three
general categories: angiogenesis and
vessel function, inflammation and
immunity, and fibrosis/scarring.
The angiogenic and vascular func-
tions appear to derive from unique
properties intrinsic to adipose tissue.
Adipose tissue is alone amongst adult
tissues for its capacity to undergo very
large increases and decreases in volume
as an individual gains or reduces weight.
When an individual gains weight the
primary response is not an increase in
the number of adipocytes but rather an
increase in the volume of existing
adipocytes. This process is necessarily
coupled with a corresponding lengthen-
ing of the capillaries within the tissue
through a process of angiogenesis.
Indeed, studies have shown that anti-
angiogenic agents can block adipose tis-
sue volume increases.20 Similarly, during
weight loss, the individual adipocytes
shrink and the capillary bed is pruned
back in a corresponding fashion. Several
years ago it was shown that this capacity
for rapid expansion and contraction is
made possible by the fact that adipose
tissue vascular cells appear to be main-
tained in a unique state of plasticity
compared with those of more stable tis-
-2-
sues.21 This plasticity may explain the
particularly robust angiogenic capacity
of SVF cells. For example, treatment
with SVF cells leads to increased blood
vessel density in a number of different
injury models including acute and
chronic heart injury, thermal burn,
cutaneous scleroderma, and limb
ischemia. 14-17,22 In support of these
observations, studies have shown that
medium conditioned by brief culture of
SVF cells improves the viability and
migration capacity of both blood and
lymphatic endothelial cells.22,23
In addition to its angiogenic capacity,
SVF has been shown to be capable of
modulating vessel function. For exam-
ple, Morris et al. reported that SVF
treatment improves vasomotor tone fol-
lowing vascular cuff injury in vivo.24 This
proper ty appears to derive from
CD11b+ cells within the SVF as saphe-
nous artery relaxation in response to
intravascular pressure change was signif-
icantly enhanced in mice injected intra-
venously with the SVF cells, but not
those with SVF where approximately
94% of CD11b cells have been removed
by immunodepletion. The authors
attribute this observation to tissue resi-
dent macrophages which represent the
majority of CD11b+ SVF cells. Other
studies have shown that intravascular
treatment with SVF leads to down-reg-
ulation of the vasoconstrictive factor
endothelin-1 and its receptors.18
SVF cells also appear to modulate
the inflammatory response, inflammato-
ry cell infiltration, and the activation
state of different cell types that play a
role in inflammation.14,18,19,22 For exam-
ple, it has been reported that SVF cells
are capable of promoting polarization of
macrophages towards the M2 (anti-
inflammatory) phenotype through a
mechanism that involves expression of
prostaglandin E2.22 Indeed, a substantial
fraction of macrophages present within
SVF express the CD206 marker associ-
ated with M2 phenotype.25 Similarly,
ADSCs expanded from SVF have been
reported to modulate T lymphocyte
activation.26,27 There is evidence that
this property is also present, in some-
what diluted form, in SVF itself, per-
haps as a reflection of the relatively high
frequency of stem cells (CFU-F). 27
These immunoregulatory properties are
apparent in several in vivo studies with
SVF which have demonstrated that
delivery of SVF cells after acute or
chronic injury leads to a reduction in

pro-inflammatory markers and reduced
inflammatory cell infiltration.14,18,19
SVF cells have been associated with
modulation of fibrosis following injury
with several studies demonstrating
reduced fibrosis/infarct size following
treatment with SVF cells.14,15,17,28 This
may be, at least in part, a secondary
effect as it is well-recognized that
approaches that reduce inflammation or
improve angiogenesis can lead to down-
stream reduction in fibrosis.
Logistics LOGISTICS
The observation that different cell
populations are capable of contributing
in complementary fashion to the func-
tion of SVF is important because the
process by which ADSCs are prepared
and expanded in culture inherently
eliminates the many other cell types
within SVF that possess regenerative
properties creating an essentially homo-
geneous population of ADSCs. This may
explain the observation in some head-
to-head studies that efficacy with SVF
cells appears greater than that with
ADSCs alone.29-31 The absence of the
need for cell culture creates several
other advantages including considerably
lower cost of manufacture and much
more rapid availability of the cell thera-
py product.
As noted above, enzymatic digestion
is the classic method for the preparation
of SVF and the only means by which
definitive SVF can be obtained. That is,
while non-enzymatic methods are capa-
ble of obtaining adipocyte cell popula-
tions from adipose tissue, the
composition of these populations
appears to be very distinct from that of
SVF. Even with the use of enzymes, dif-
ferences in the processing approach can
lead to quite different cell populations
through, for example, incomplete
removal of extravasated leukocytes
prior to digestion or from incomplete
digestion. There are many parameters
that distinguish SVF that has been pre-
pared to clinical standards (ADRCs)
from laboratory grade SVF. For exam-
ple, use of inadequately pure or insuffi-
ciently characterized reagents and
enzymes can lead to contamination of
the cell product with bacterial
lipopolysaccharide (endotoxin) or even
the risk of transmission of infectious
agents such as bovine spongiform
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SURGICAL TECHNOLOGY INTERNATIONAL XXIX
encephalitis. Different processing para-
meters can lead to potentially unsafe
levels of processing enzyme in the out-
put. These are not simply theoretical
concerns; a published comparative study
of several different commercially avail-
able devices for preparation of SVF cells
showed dramatically different cell yield,
composition (including CFU-F con-
tent), and, importantly, residual enzyme
levels.32 Automated approaches, if well-
validated, have the capacity to substan-
tially improve standardization of the
product, a key factor in complying with
regulations pertaining to any cell thera-
py product.
Each of these parameters feeds into
cell therapy product release criteria,
including the number, viability, and
types of cells present in the product,
and other materials present (microbes,
residual enzyme, endotoxin, debris or
clumps from processing, and lipid
droplets from damaged adipocytes). For
clinical use, these matters must be
addressed through step by step valida-
tion of the manufacturing processes and
should consider direct testing at the
time of release. For example, the
method by which the ADRCs are pre-
pared must be validated to ensure that
the residual enzyme level (or endotoxin
level or level of debris) is always and
invariably below a specified threshold.
Methods must be validated to demon-
strate that they are accurate, repro-
ducible, and are not confounded by
other materials likely to be present in
the product. Cell counting by simple
trypan blue dye exclusion can be con-
founded by the presence of small lipid
droplets within the output that could be
erroneously counted as living ADRCs.
This risk can be mitigated by the use of
dyes that stain the nucleus such that
lipid droplets are not included in the
count. While not needed for each pre-
pared treatment, cell characterization
from the methods should be understood
and demonstrate that the ADRC prod-
uct is comprised predominantly of stro-
mal and vascular cells in accordance
with published standards. 33 Sterility
testing as part of product release is
more problematic as most assays take
several days to yield a usable positive or
negative result; therefore, a well-vali-
dated process ensuring sterility of the
final product must be assured a priori.
The specific release criteria chosen and
the methods will be dependent upon
the methods, equipment, reagents, and
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Advanced Wound Healing
other parameters applied during ADRC
preparation. In general, automated
methods for which the manufacturer
has executed robust studies validating
the levels of key components in the out-
put will lead to a need for a substantial-
ly smaller set of on-site release criteria
testing that will speed and simplify dose
preparation and release to the clinic.
Finally, production of clinical benefit
through paracrine properties using a
heterogeneous population such as SVF
cells necessitates the use of an autolo-
gous preparation. The ability to prepare
such an autologous cell source without
the need for expansion or culture cre-
ates efficiencies, permits a same day
procedure (i.e., harvest, cell prepara-
tion and delivery in the same day), and
eliminates any risk of rejection or trans-
mission of donor-related infectious
agents.
ClinicalCLINICAL
Evidence
EVIDENCE
The application of ADRCs has been
investigated across multiple therapeutic
areas. While there are numerous publi-
cations, there is a relative lack of dou-
ble-blind, well-controlled, randomized
clinical trials in the literature. Virtually
all of the data is derived from case
series, case reports, and open-label
studies. Although publication bias is a
possible factor, a consistency in out-
comes and a consistency with the previ-
ously described preclinical and
laboratory studies exists suggesting a
true positive effect. The therapeutic
areas reported include orthopedics,
autoimmune disease, wounds and
reconstruction, cardiology, peripheral
vascular disease, genitourinary disor-
ders, gastrointestinal fistulas, and neu-
rology. Though it is not always clear
from the individual publications in the
information discussed below, it is
assumed that the cited clinical studies
applied SVF cells prepared using clinical
grade systems, methods, and reagents,
and, for that reason, the cells used are
referred to as ADRCs. This summary is
restricted to actual administration of
autologous ADRCs in humans and is not
designed to be comprehensive. Never-
theless, the objective is to highlight the
interest, potential, and trends that sup-
port the need to continue evaluation
and exploration for the role of ADRCs
as a therapeutic agent.

Autologous Adipose Derived Regenerative Cells: A Platform for Therapeutic Applications
KESTEN/FRASER
Orthopedics
The majority of the investigations
have examined osteoarthritis. An early
report of two elderly patients with
chronic osteoarthritis described treat-
ment improvement in pain and in mag-
netic resonance imaging following
intraarticular ADRCs cells.34 Koh et al.
have published three open label studies
(n=25, n=18, n=30) in which ADRCs
obtained from the infrapatellar fat pad
or buttocks along with platelet rich
plasma (PRP) were used to treat
patients with knee osteoarthritis; how-
ever, the dose of cells in the first two
studies can be considered low relative
to other studies.35-37 The first study used
a control group (PRP without cells)
with both groups showing symptomatic
improvement; however, there were no
objective measures such as magnetic
resonance imaging.35 The second study
did not have a control group and noted
significant improvement in pain (visual
analogue score) and in knee function
scores—Western Ontario and McMas-
ter Universities Osteoarthritis Index
(WOMAC) and Lysholm scoring,
p<0.001.36 WOMAC scores decreased
over the study period (49.9 pre-opera-
tively to 38.3—12 months—and
30.3—24 to 26 months). Whole Organ
MRI Score (WORMS) also improved
(p<0.001), suggesting effects on
pathology.36 No adverse events related
to the cells were reported. The third
study harvested more fat (liposuction of
buttocks) and injected a larger quantity
of cells.37 Significant clinical improve-
ment (i.e., Knee Osteoarthritis Out-
comes Score—KOOS) was noted at
three months and maintained through
two years. In addition, repeat (“second-
look”) arthroscopy was performed in 16
patients of which 14 (88%) were char-
acterized as improving or maintaining
cartilage status. None of the patients
required total knee arthroplasty during
the follow-up period.
Michalek and colleagues reported a
series of 1,128 patients, 478 of whom
received a form of ADRCs prepared
using an enzyme and 650 of whom
received a cell product described as SVF
but which was prepared without an
enzyme in a process with very low yield
of cells per unit volume of adipose tis-
sue processed (compared with the
enzyme product).38 The cell composi-
tion of these two different preparations
was not reported. Cells were delivered
in a saline carrier (not in PRP) and the
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study did not include a control arm.
Cells were delivered into synovial tissue
or into the articular space. Adverse
events reported included one synovial
infection, a low rate of synovitis, local
pain and swelling at the injection site,
and two instances of deep vein throm-
bosis. Results showed that 91% of
patients repor ted at least a 50%
improvement in KOOS score at 12
months. Patients receiving ADRCs
rather than cells prepared without
enzyme exhibited slightly superior out-
come at three months but not at any
later time point.
Jo and colleagues treated 18 patients
with different doses of ADRC (no PRP)
delivered by intraarticular injection to
the knees for osteoarthritis. As with
previous reports, cell related adverse
events did not occur.39 The high dose
group was associated with improve-
ments in WOMAC score, decreases in
cartilage defects (arthroscopic evalua-
tion), and regeneration of hyaline-like
articular cartilage (histology from biop-
sy). A phase II randomized, double-
blind, placebo-controlled safety and
feasibility study of ADRCs for
osteoarthritis of the knee is being per-
formed in the United States and should
provide the highest level evidence to
date regarding ADRCs in osteoarthritis
(NCT02326961).
Pak reported two patients treated
for avascular necrosis of the femoral
head with a mixture of ADRCs,
hyaluronic acid, and PRP, both of whom
improved symptomatically, functionally,
and by MRI, suggesting that bone
regeneration was occuring.40
Autoimmune Disease
An open label, single arm study of
ADRCs for the treatment of hand mani-
festations of scleroderma has recently
been published. 41,42 Twelve patients
with impaired hand function from scle-
roderma (Cochin Hand Function
Scale—CHFS—score > 20 units) were
enrolled. ADRCs were delivered under
local anesthesia via 20 subcutaneous
injections (one per side per finger) of
0.5 mL per injection. All patients were
women, with a mean age of 54.5 years.
Data at 6 and 12 months indicated a
mean improvement of approximately
50% in the CHFS score, Raynaud’s
severity score, and in the Scleroderma
Health Assessment Questionnaire
(SHAQ) (p<0.05 for all compared to
baseline). In addition, the number of
-4-
active digital ulcers decreased relative
to baseline and grip and pinch strength
increased. The procedure was tolerated
well without complications. No serious
adverse events occurred during follow-
up. No digital ischemic or infectious
complications occurred.
Wounds and Reconstruction
Investigators described an 89-year-
old patient treated with ADRCs for a
chronic, intractable, sacro-coccygeal
radiation ulcer caused by a therapeutic
radiation delivered for uterine cancer
40 years previously. 43 ADRCs were
directly injected into the wound bed
and margins and loaded onto the sur-
face of a collagen-based skin substitute.
Basic fibroblast growth factor was
sprayed over the wound for three
weeks. The wound healed uneventfully
by day 82 with no sign of recurrence
for more than two years after treat-
ment. Two additional patients with
similarly chronic non-healing wounds
were treated with ADRCs. 44 In both
cases, the wounds healed within 75
days without recurrence. No adverse
events were reported.
Cervelli published a case series of
10 patients with post-traumatic chron-
ic ulcers of the lower extremity. 45
Patients were treated with a combina-
tion of ADRCs mixed with fat and
injected around and into the wound. In
a second arm of the study, a further 10
patients were treated with injection of
fat supplemented with platelet-rich
plasma (PRP). The results were com-
pared to two control groups: 10
patients treated with PRP alone and 10
patients treated with a control of
hyaluronic acid only. By 16 weeks, all
10 patients treated with ADRCs had
complete wound closure. The same
was true for the group treated with fat
supplemented with PRP. Eight of 10
patients treated with PRP alone and 7
of 10 patients treated with hyaluronic
acid alone showed wound closure at
week 16. One adverse event was
reported in the ADRC-treated group;
a hematoma at the tissue harvest site.
Perez-Cano reported a prospective
67 patient, single arm, open label
study in which ADRCs mixed with
undigested adipose tissue was implant-
ed into the subcutaneous and subglan-
dular space of the breast to restore
post-lumpectomy contour defects.46 In
follow-up, one patient had pelvic
metastasis deemed part of the natural

progression of the patient’s underlying
disease. Satisfaction with treatment
through 12 months was reported by
85% of physicians and by 75% of
patients. MRI assessment of the cell
enriched graft by an independent core
lab indicated improvement in 54/65
evaluations (88%) at 12 months.
Tiryaki evaluated the use of ADRCs
injected into soft tissue recently treat-
ed with a traditional fat graft. Soft tis-
sue deficiencies of the breast, face, and
lower extremities in 29 patients
including one with scarring secondary
to thermal burn injury were treated.47
The mean follow-up period was 10
months, with 19 of the 29 followed for
more than 12 months (36 months’
maximum follow-up). Minimal postop-
erative atrophy of the injected tissue
was reported which did not change
after eight weeks. Tiryaki and others
described cases of facial atrophy
including Parry-Romberg syndrome
being successfully treated with ADRC
enriched fat with cosmetic improve-
ment and maintenance of the graft.47-49
Cardiology
The safety and feasibility of autolo-
gous ADRCs delivered into the
myocardium in patients with chronic
myocardial ischemia not amenable to
revascularization was reported from a
randomized, placebo-controlled, dou-
ble-blind clinical study (n=27). 50 All
subjects received a liposuction proce-
dure to harvest adipose tissue that was
subsequently processed for the extrac-
tion of ADRCs for same day injection
into the myocardium (15 intramyocar-
dial injection, location determined
through electromechanical mapping).
Twenty-one patients received ADRC
treatment; six received control. This
trial reported that harvest and subse-
quent intra-myocardial administration
of ADRCs was feasible and associated
with an acceptable safety profile. Maxi-
mum oxygen consumption (mVO 2 )
measured during incremental treadmill
exercise testing at 6 and 18 months
was higher in the ADRC group com-
pared to the placebo (p<0.05).
Double-blind placebo-controlled
trials in the US have been conducted
(n=31) in a similar population with
intramyocardial delivery of ADRCs.
Twelve-month follow-up data indicate
symptomatic and health-related quality
of life improvement in the cell group
relative to the placebo arm without
#751 Kesten FINAL
SURGICAL TECHNOLOGY INTERNATIONAL XXIX
measurable physiologic changes. Of
note, the mean (95% confidence inter-
val) between group differences (ADRC
– placebo) in the Minnesota Living
with Heart Failure Questionnaire total
score at 12 months was -16.3 (-31.7, -
1.0) (p=0.038).51
Peripheral Vascular Disease
Marino published a report of 10
patients with chronic lower limb ulcers
from peripheral artery disease (ankle:
brachial index 0.30 to 0.40; age 61-70
years).52 All 10 patients were refracto-
ry to conventional surgical and enzy-
matic debridement, hyperbaric
oxygen, and advanced dressings for at
least five months. Autologous ADRCs
were injected ~1 cm into the tissue
surrounding the wound in all direc-
tions. No adverse reactions were
reported and no additional revascular-
ization procedures were required. In
all cases, the authors observed a reduc-
tion of the diameter of the ulcer and of
its depth, with a decrease of pain asso-
ciated with the ulceration process. By
day 90 after treatment, 6 of 10 patients
exhibited complete wound closure.
Genitourinary
Gotoh et al. recently described
improvements in urinary incontinence
following injections of ADRCs into the
rhabdosphincter and ADRC-enriched
fat injections into the submucosa area
of the urethra in a case series of 11
men who underwent radical prostatec-
tomy for prostate cancer.53 Mean maxi-
mum urethra closing pressure
increased from 35.5 to 44.7 cmH20 at
one year. Progressive decreases in
stress urinary incontinence were
repor ted in 8/11 patients (mean
decrease of 59.8% in leakage). Pro-
gressive improvements in blood flow
to the injected area as demonstrated by
enhanced ultrasonography was
observed in all patients.
In addition to urinary incontinence,
erectile dysfunction (ED) is a common
complication of radical prostatectomy.
Seventeen such patients were treated
with intracaver nous injection of
ADRCs in an open-label study. No
complications of the procedure were
noted.54 Erectile function recovered in
8/17 patients (47%); however, 8/11
patients with continence recovered
erectile function (73%). International
Index of Erectile Function-5 and Erec-
tion Hardness Scores improved signifi-
-5-
Advanced Wound Healing
cantly in continent men but not in
those who were incontinent.
Gastrointestinal Fistula
Borowski reported three patients
with chronic cryptoglandular peri-anal
enterocutaneous fistula treated with
autologous ADRCs.55 All patients had
failed prior standard therapy. The fistula
tract was debrided and the inner open-
ing closed with a mucosal advancement
flap. ADRCs were mixed with 20–30
mL of undigested adipose and injected
into and around the fistula tract to pro-
vide bulking that closed the tract. Clo-
sure of all fistulae was maintained
through the two to three years of fol-
low-up. The author described similar
success in a follow-up report with seven
patients.56 Four of seven had closure at
six months. Several patients required
additional surgery, but closure was ulti-
mately complete in all patients.
Mizushima applied ADRCs with fibrin
glue to refractory post-surgical entero-
cutaneous fistula in six patients. Fistula
closure rates were 83% at 4 weeks and
100% at 24 weeks.57
Neurology
Riordon and colleagues reviewed the
rationale for ADRCs in multiple sclero-
sis and described three cases of relaps-
ing-remitting multiple sclerosis where
intravenous ADRCs were administered
for compassionate use treatment.58 In
addition, the authors administered
intravenous and intrathecal allogeneic
CD34+ and MSCs. Clinical improve-
ments were noted in all patients.
Conclusion
CONCLUSION
A population of stem and other cells
from adipose tissue (ADRCs) can be iso-
lated to produce a clinical grade thera-
peutic agent; however, the manufacturing
must consider multiple factors in the
process in order to have a safe and reli-
able product. The mechanism of action is
well-documented and includes promo-
tion of angiogenesis, modulation of
inflammation, and wound remodeling
(i.e., improvement in fibrosis). Numer-
ous clinical applications have been
explored, although studies are generally
small and uncontrolled. Double-blind and
randomized clinical trials will provide
more definitive data to guide future ther-
apeutic use of autologous ADRCs. STI

Autologous Adipose Derived Regenerative Cells: A Platform for Therapeutic Applications
KESTEN/FRASER
Authors’ Disclosures
AUTHORS’ DISCLOSURES
Dr. Kesten and Dr. Fraser are
employees of, and hold stock in, Cytori
Therapeutics. Inc.
References
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