fat grafting in burns prs jan 2016

Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.

www.PRSJournal.com302

Autologous fat grafting is a commonly used technique for treating volume and con-tour defects in aesthetic and reconstruc-

tive surgery. First described in the early 1900s, this procedure became popular in the late 1980s,

when liposuction increased the availability of fat stores and allowed surgeons to experiment with the therapeutic potential of autologous fat.1 There has been a recent emphasis on not only the filling capability of fat but also its regenera-tive capacity.2 The stromal vascular fraction of processed fat grafts contains multipotent stem cells that express adipogenic, osteogenic, and chondrogenic genes.3 Many studies have demon-strated the angiogenic, immunomodulatory, and

Disclosure: The authors declare no conflicts of interests with respect to the authorship and/or publica-tion of this article. The authors received no financial support for the research and/or authorship of this article.Copyright © 2015 by the American Society of Plastic Surgeons

DOI: 10.1097/PRS.0000000000001918

Alexandra Condé-Green, M.D.

Andrew A. Marano, B.A.Edward S. Lee, M.D.

Tom Reisler, M.D.Leigh Ann Price, M.D.

Stephen M. Milner, M.B.B.S., B.D.S., D.Sc.Mark S. Granick, M.D.

Baltimore, Md.; and Newark, N.J.

Background: There is an abundance of literature supporting the efficacy of fat grafting in aesthetic and reconstructive cases. There has been a recent emphasis on the regenerative capacity of adipose-derived stem cells and their utility in the improvement of wound healing and scarring provided by their cytokine and growth factor profiles. Despite the wealth of evidence supporting their efficacy, little attention has been paid to their utility in burn treatment. The authors’ purpose was to provide an analysis of the literature regarding the use of fat grafting and regenerative cells in the treatment of burn wounds to guide surgeons and scientists on their clinical use.Methods: A systematic review of the literature was performed by a thorough search of 12 terms using the PubMed, Medline, and Cochrane databases. Two hundred forty-one articles were subject to evaluation by predetermined inclu-sion and exclusion criteria.Results: Six murine and 12 human studies were selected, including case-con-trol studies, case series, and case reports. They describe histologic and clinical effects of fat grafting and regenerative cell therapy, including improvements in burn scar size and texture, enhanced angiogenesis, decreased inflammation, alleviation of pain, and return of function.Conclusions: There is a dearth of randomized controlled trials and quantitative analysis supporting the efficacy of fat grafting and adipose regenerative cells in burns. However, the subjective improvements in scars are encouraging. The authors hope that this review will be a foundation for future studies and will highlight the breadth of knowledge yet to be explored by this therapy. (Plast. Reconstr. Surg. 137: 302, 2016.)CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

From the Division of Burn Surgery, Department of Plastic and Reconstructive Surgery, Johns Hopkins University, School of Medicine; and the Division of Plastic Surgery, Department of General Surgery, Rutgers New Jersey Medical School. Received for publication April 7, 2015; accepted August 27, 2015.Presented at the Eighth International Workshop on Wound Technology, in Paris, France, January 18 through 20, 2015; and the Fifth International Fat Grafting Forum, in New Orleans, Louisiana, March 12 through 14. 2015.

Fat Grafting and Adipose-Derived Regenerative Cells in Burn Wound Healing and Scarring: A Systematic Review of the Literature

RECONSTRUCTIVE


Volume 137, Number 1 • Burn Wound Healing and Scarring

303

antiapoptotic capabilities of these cells, making them a valuable and effective tool in restoring devitalized tissue, as evidenced by their efficacy in improving radiation-damaged skin.4,5 Adipose-derived stem cells have also been shown to play a role in antiaging6 and skin regeneration by form-ing tissue consisting of hypodermis, dermis, and epidermis.7 It is this regenerative capacity that is of particular interest in burn wound therapy.

There is an abundance of literature support-ing the efficacy of fat grafting in both aesthetic and reconstructive cases. Recent studies have shown the utility of adipose-derived stem cells in the improvement of wound healing, describing their ability to regenerate soft tissues and their remodeling capacity provided by their unique cytokine and growth factor profiles. Despite the wealth of evidence supporting their efficacy in wound healing, little attention has been paid to their utility in the treatment of thermal injury. The purpose of this study was to provide a thor-ough analysis of the literature regarding the use of fat grafting and adipose-derived stem cells in the treatment of burn wounds to guide surgeons and scientists on their clinical use in burn wound healing and scar remodeling, and in pursuing fur-ther investigation.

PATIENTS AND METHODSThe foundation for this review was a system-

atic method for finding and evaluating the lit-erature on the efficacy of fat and adipose stem cell therapy in the treatment of thermal injury. A comprehensive search was conducted by two independent reviewers in April of 2015 using the following terms alone or in combination in the PubMed, MEDLINE, and Cochrane databases: “burn,” “fat grafting,” “fat transplant,” “fat har-vesting,” “fat transfer,” “adipose stem cell,” “lipo-filling,” “lipoinjection,” “lipotransfer,” “wound healing,” and “scar treatment.” In addition, the terms “exp burn/”and “exp adipose tissue/” were used in MEDLINE to search all articles including burn and adipose tissue exploded subheadings. Because one of the authors is fluent in Portuguese and French, filters were set to include all articles in English, Portuguese, and French.

Prospective inclusion criteria were the use of fat or adipose stem cell therapy and reporting of the effects on wound healing when used as an early intervention, the effects on scar formation when used on an old wound, and the effects on quality of life. Studies included were case-control studies, case series, case reports, animal studies

using human fat, animal studies using animal fat, clinical trials, and randomized controlled tri-als. Exclusion criteria were articles on fat graft-ing for nonburn wounds, burn to a surface other than skin (e.g., cornea, bone), fat transfer as part of another graft (dermal grafts), and radiation injury. Necessarily excluded were articles we were not able to access and those in languages other than English, Portuguese, and French.

A formal statistical analysis of the eligible studies was not performed because of the meth-odologic and clinical heterogeneity. A detailed systematic review of the diverse outcomes was undertaken instead.

RESULTSThe primary search yielded 544 articles. After

removal of duplicates, 241 of these were found to be distinct. The titles of remaining articles were screened for relevance, after which 75 abstracts were reviewed according to our inclusion crite-ria. The remaining 28 articles were read in their entirety and their references scoured for articles that escaped our primary search criteria. Of these, 12 were excluded based on predetermined crite-ria, and the remaining 16, along with one article that was discovered by review of references, were included in this review (Fig. 1). Thus, we present a total of 17 articles describing 18 studies, as one of the articles described two distinct studies.8

Human StudiesTwelve human studies were selected, includ-

ing case control studies (n = 3), case series (n = 7), and case reports (n = 2). Adipose tissue was har-vested from one or multiple sites, including the abdomen (n = 9), trochanteric region (n = 3), inner thigh (n = 1), and medial knee (n = 1), and discarded burn tissue (n = 1). Adipose tissue was processed by high-speed centrifugation (n = 9) and low-speed centrifugation (n = 2). Further processing included mincing and processing for adipose-derived stem cell isolation (n = 1), and supplementation of fat with stromal vascular frac-tion (n = 1) or platelet-rich plasma (n = 1).

Case-Control StudiesBruno et al. conducted a study on 93 chronic

burns scars divided into two halves, where half of each scar was treated with lipofilling and the other half served as a control.9 Improved vascu-larization of the dermal papillae and better colla-gen organization were shown in scars treated with lipofilling after 6 months. There was a statistically


304

Plastic and Reconstructive Surgery • January 2016

significant decrease in S100-positive cells on immunohistochemistry, indicating that lipofill-ing correlates with reduction of melanocytes in the wounds. There was a decrease in Langerin-positive cells, most likely resulting from efflux of trapped cells secondary to loose connective tis-sue. Increased visualization of Ki-67 in the basal layer of lipofilled wounds indicated that there was increased proliferation. A modified Vancouver Scar Scale was used to provide objective clinical evaluation of scars. Scores of 41 before treatment, 29 at 3 months, and 15 at 6 months were reported (range, 5 to 50, with low numbers representing close to normal skin).

Klinger et al. conducted two separate studies described in one article8 (which is reflected in a footnote in Table 1).10–24 The case-control study evaluated scars of 20 randomly selected patients. Each scar was treated half with fat and half with saline injection and evaluated by the Patient and Observer Scar Assessment Scale25 and Durom-eter measurement for scar firmness. Significant improvement of color, shape, thickness, and

movement was seen as early as 3 months postop-eratively in the fat-grafted side.

Gentile et al. compared fat grafts to fat-enhanced grafts with stromal vascular fraction or platelet-rich plasma in 30 patients with burn and posttraumatic scars.10 In stromal vascular frac-tion– and platelet-rich plasma–enhanced groups, 63 percent and 69 percent of wounds maintained their volume after 1 year, respectively, compared with 39 percent of the control group, indicating less fat resorption in enhanced grafts.

The first case-control study9 was the strongest, as clinical results following treatment with fat grafting were corroborated by immunohistochem-ical findings achieving statistical significance, and clinical evaluation was double blinded. The sec-ond case-control study8 showed objective statisti-cally significant clinical findings in treated scars, but there was no histologic confirmation. The third study10 exposed three different preparation techniques of fat grafting to scars and showed that fat supplemented with stromal vascular fraction or platelet-rich plasma achieved better contour maintenance, with increased graft take. However, they did not compare them to untreated controls with no fat grafting.

Case SeriesKlinger et al. reported improvement in mimic

features, skin texture, and skin thickness in three burn patients with facial hypertrophic scars and keloids after fat injection into the dermohypoder-mal junction performed twice, 3 months apart.11 Although findings were not compared to controls or subjected to statistical analysis, new collagen deposition, increased vascularity, and dermal hyperplasia were observed. Although the sample size was small, the clinical results were corrobo-rated with histologic findings.

Caviggioli et al. performed fat grafting in the nipple-areola complex of 12 patients who specifi-cally suffered burns to the chest.12 The average nipple projection was 4.6 mm at 2 weeks, with patients rating the results as excellent; and the projection was 2.9 mm at 2 years, with the major-ity rating the results as good. These were objec-tive clinical findings with a good follow-up period; however, there was no control, histologic report, or statistical analysis.

Brongo et al. reported evidence of new collagen deposition, angiogenesis, and dermal hyperplasia in scars of 18 burned patients treated with lipo-filling three times at 3-month interval.13 Improve-ments in texture, softness, thickness, and color of treated scars based on a questionnaire completed

Fig. 1. Flow diagram of the search and selection strategy of included articles.



305

by patients, surgeons, and external observers 1 year after treatment were reported. Clinical improve-ment of scars was supported by histologic findings with a good follow-up period, but there was no control, and no statistical analysis was conducted.

Viard et al. treated 15 patients with postburn facial scars that had an average of 7.5 operations 1 year before fat grafting.14 Patients received two to three sessions. Subjective improvements in mimic features, skin texture, and skin thickness were reported without controls or statistical analy-sis of the results.

The second study of the 2013 article of Klinger et al. reported improvements in scar elasticity, skin softening, and mobility in periarticular regions of 376 patients with retractile and painful scars treated with lipofilling.8 This was a large study where subjective clinical findings were reported; however, the authors did analyze a group of 20 patients that we mentioned above in the case-con-trol study group.

Keck et al. harvested adipose tissue from dis-carded burn tissue. It was spread on a bovine col-lagen-elastin scaffold and applied on the fascia of previously excised wounds covered with skin graft in five patients.15 Ninety percent of the skin graft was viable at postoperative day 10 in three patients. Flow cytometry, microscopy, and AdipoRed (Lonza, Walkersville, Md.) staining revealed that adipose cells from debrided tissues were compa-rable to abdominal fat in quantity, proliferative capacity, and differentiation. This study lacked

controls, was limited in number of cases, but rep-resents a novel technique with much potential.

Piccolo et al. described their 3-year experi-ence using fat grafting in acute and subacute burn wounds, and burn scars. They treated 240 patients who presented with burn, vascular, or traumatic injuries. For acute and subacute wounds, fat was injected at 2- to 4-week intervals until a defini-tive procedure such as skin graft or flap coverage was performed. Subsequent scars were treated at 3-month intervals. The authors reported sub-jective improvements in wound healing, fibrosis, and scar suppleness.16 This study was large, with adequate follow-up, but lacked statistical analysis and controls.

Case ReportsCaviggioli et al. reported lasting correction of

epiphora, xerophthalmia, and lagophthalmos, 1 year after performing fat grafting in one patient with medial ectropion secondary to chemical burn.17 Khouri et al. reported scar softening and increased range of motion after performing lipofill-ing and percutaneous aponeurotomy (transform-ing a restrictive scar into a neomatrix scaffold into which fat grafts can settle) in patients with retractile scars of the upper extremity, hands, and chest sec-ondary to burns, radiation therapy, and congenital restriction bands.18 Five of the patients presented scars from burns, with objective measurement of functional improvement, but lacked controls.

Table 1. List of Articles Included in This Systematic Review According to Inclusion and Exclusion Criteria, Stratified by Level of Evidence

Reference Study TypeLevel ofEvidence

No. of Subjects or Burn Scars

Human studies (n = 12) Bruno et al., 20139 Case-control III 93 burn scars Klinger et al.. 20138* Case-control III 20 patients with scars† Gentile et al., 201410 Case-control III 30 patients with scars† Klinger et al., 200811 Case series IV 3 patients with burn scars Caviggioli et al., 201012 Case series IV 12 patients with burn scars Brongo et al., 201213 Case series IV 18 patients with burn scars Viard et al., 201214 Case series IV 15 patients with burn scars Klinger et al., 20138* Case series IV 376 patients with scars† Keck et al., 201315 Case series IV 5 patients with burns Piccolo et al., 201516 Case series IV 240 patients† Caviggioli et al., 200817 Case report V 1 patient with burn scar Khouri et al., 201318 Case reports V 5 patients with burn scars†Murine studies (n = 6) Sultan et al., 201219 Murine — 20 mice Shokrgozar et al., 201220 Murine — 10 rats Huang et al., 201421 Murine — 30 rats Loder et al., 201422 Murine — 20 mice Karimi et al., 201423 Murine — 30 mice Atalay et al., 201424 Murine — 20 rats*Two studies were part of the same article.†Three studies included burns and other types of wounds (trauma, ulcers).


306


Murine StudiesSix murine studies assessing clinical and bio-

chemical outcomes of applying fat (n = 2) or adipose stem cells (n = 4) to burn wounds were selected. Subjects were delivered burn injury by contact with a metal object submerged in hot water (n = 4) or by direct exposure to hot water (n = 2). The injury was located on a depilated dorsum (n = 5) or a hind paw (n = 1). Adipose tissue was harvested from mice or rats, as autografts (n = 5); or discarded human fat, as a xenograft (n = 1).

Sultan et al. conducted a controlled study describing the physical and biochemical effects of human fat on burn scars of 20 mice, where they injected saline in one half and fat in the other. Fat-grafted mice expressed significantly elevated levels of stromal cell–derived factor-1, vascular endothe-lial growth factor, and CD31 expression (indica-tive of greater vascularity), and wound remodeling expressed by transforming growth factor-β and matrix metalloproteinase-9, compared with con-trols. They showed greater flux on laser Doppler scanning and less fibrosis.19 This study was the strongest murine study, as there were untreated control animals, and objective and statistically sig-nificant macroscopic and histologic evaluations.

Shokrgozar et al. supplemented collagen scaf-folds with adipose-derived stem cells and showed epi-dermal regeneration in burn wounds treated in 10 rats compared with controls.20 Wound surface area and histopathologic findings with formation of der-mis and epidermis on the scaffolds supplemented with adipose-derived stem cells were reported; how-ever, statistical analysis was not mentioned.

Huang et al. investigated the effects of autolo-gous fat on burn-induced neuropathic pain in 30 rats.21 Rats that received fat grafting had reduced burn-induced neuropathic mechanical allodynia by suppression of phosphorylation of p38 in microglial cells. The clinical and histologic findings were statistically significant, and there were untreated controls.

Loder et al. studied the effects of isolated autologous adipose-derived stem cells, fat, adipose-derived stem cells and fat, and phosphate-buffered saline grafts on burns of 20 mice.22 There was a sig-nificant decrease in wound surface area in all groups compared to controls, but not to each other. Adi-pose-derived stem cells and mixed groups showed significant decrease in wound depth apoptosis.

Karimi et al. reported significant increases in fibroplasia and collagen remodeling and a decrease in surface area of wounds treated with adipose-derived stem cells in comparison with

fat grafts in 30 mice.23 The differences in eschar thickness, inflammatory cell counts, epithelializa-tion, and angiogenesis were not significant.

Atalay et al. showed statistically significant decreased inflammation and fibroblastic prolifer-ation, and increased vascular endothelial growth factor expression, vascularization, and prolif-erating cell nuclear antigen index (suggesting improved wound healing) in acute burns of rats injected with stromal vascular fraction.24 There was no macroscopic evaluation of the wounds.

The first three murine studies were con-ducted in burn scars,19–21 and the last three were conducted in acute burns showing the effects of fat and adipose regenerative cells on wound heal-ing.22–24 The last two studies had histologic results reported by pathologists that were blinded to study groups (Tables 1 and 2).

DISCUSSIONAlthough limited in number, studies detailing

the use of fat grafts or adipose-derived regenera-tive cells on burn wounds and scars have had posi-tive results. Murine studies have suggested that fat grafting therapy can enhance vascularity, promote wound remodeling, and diminish neuropathic pain when administered weeks after injury.19,21 Such attributes are of particular utility when considering the common features of burn wounds: hypertro-phic scars are characterized by an overactive prolif-erative phase and an impaired remodeling phase of wound healing,26 and neuropathic pain may occur in more than 50 percent of burn victims.27 Murine studies have also suggested that adipose-derived stem cell therapy may improve outcomes when applied on a newly acquired burn wound. Although some studies had conflicting results regarding the effect on wound surface area, most concluded that the early use of adipose-derived stem cell therapy altered the course of the remodeling phase of heal-ing through decreased apoptosis22 and increased fibroplasia.23 Murine studies have limited applica-bility in human treatment; however, the human case-control studies, case series, and case reports have corroborating results.

With regard to treatment of burn scars, histo-logic analysis in human studies revealed that fat grafting may increase vascularity, new collagen deposition, and reorganization.9,11,13 Studies also reported improvements in mimic features, skin texture, thickness, color,11,13,14 and patient satisfac-tion.11,12,14 The utility of lipofilling as a secondary measure to improve previous treatments is also considerable. Although the regenerative capacity



307

Tabl

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Sum

mar

y of

Clin

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rosc

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Mic

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Fin

ding

s of

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icle

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view

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anta

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and

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udy

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Pro

cess

ing

T

echn

ique

sA

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Clin

ical

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rosc

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Fi

ndin

gsM

icro

scop

ic

Find

ings

Stud

y St

reng

ths

Stud

y W

eakn

esse

s

Hum

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tudi

es

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no

et a

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2013

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im

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abo

ve*)

Lac

k of

con

trol

s or

st

atis

tica

l an

alys

isL

ack

of o

bjec

tive

cl

inic

al e

valu

atio

nSc

ars

resu

ltin

g fr

om v

ari-

ous

inju

ries

(tr

aum

a,

afte

r

surg

ery,

radi

othe

rapy

, bu

rns)

K

eck

et

al.,

2013

15A

SC is

olat

ion

(fr

om

débr

ided

bur

n s

kin

)A

cute

bur

ns

Impr

oved

ski

n g

raft

ta

ke (

n =

3)H

isto

logy

sh

owed

dé

brid

ed b

urn

fa

t com

para

ble

to

abdo

min

al fa

tA

dipo

se ti

ssue

de

tect

ed in

rec

on-

stru

cted

are

as

Nov

el th

erap

euti

c

tech

niq

uePo

ten

tial

for

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ents

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ith

larg

e bu

rn s

urfa

ce

area

Lac

k of

con

trol

sSm

all s

ampl

e

size

(n

= 5)

Pi

ccol

o et

al

., 20

1516

Hig

h-s

peed

ce

ntr

ifug

atio

nA

cute

, sub

a-cu

te b

urn

s,

and

scar

s

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fi

bros

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len

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last

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ple

size

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0)A

dequ

ate

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p (3

-yr

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ce)

Lac

k of

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ack

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om v

ari-

ous

inju

ries

(tr

aum

a,

ulce

rs, b

urn

s)

Cav

iggi

oli e

t al

., 20

0817

Hig

h-s

peed

ce

ntr

ifug

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nSc

ars

Cor

rect

ion

of f

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ion

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defi

cits

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erio

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onIm

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kin

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ure,

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ftn

ess,

ela

stic

ity

Non

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port

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p (1

yr)

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e of

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iest

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dies

sh

owin

g cl

inic

al

impr

ovem

ent

Smal

l sam

ple

size

(n

= 1

)L

ack

of o

bjec

tive

cl

inic

al e

valu

atio

n

K

hou

ri e

t al

., 20

1318

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-spe

ed

cen

trif

ugat

ion

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sSo

ften

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car,

incr

ease

m

obili

ty, t

extu

reN

one

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rted

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ecti

ve m

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rem

ent o

f fu

nct

ion

al im

prov

emen

tSm

all s

ampl

e si

ze

(n =

5)

Lac

k of

con

trol

s

Tabl

e 2.

Con

tinue

d

Ref

eren

ces

Pro

cess

ing

T

echn

ique

sA

cute

Wou

nds

vs. S

cars

Clin

ical

/Mac

rosc

opic

Fi

ndin

gsM

icro

scop

ic

Find

ings

Stud

y St

reng

ths

Stud

y W

eakn

esse

s

(Con

tinue

d )



309

Mur

ine

stud

ies

Su

ltan

et a

l.,

2012

19H

igh

-spe

ed

cen

trif

ugat

ion

Scar

sIm

prov

ed c

olor

, tex

ture

Gre

ater

flux

by

mea

ns

of

Dop

pler

Incr

ease

CD

31+ c

ells

, Pi

cros

iriu

s R

ed

stai

nin

gIn

crea

sed

SDF-

1,

VE

GF,

TG

F-β,

an

d M

MP9

Com

pari

son

to u

ntr

eate

d co

ntr

ol a

nim

als

Obj

ecti

ve m

acro

scop

ic

eval

uati

onSt

atis

tica

l sig

nifi

can

ce fo

r m

acro

scop

ic a

nd

his

to-

logi

c fi

ndi

ngs

Shok

rgoz

ar e

t al

., 20

1220

ASC

isol

atio

nSc

ars

Impr

oved

wou

nd

su

rfac

e ar

eaIn

crea

sed

epid

erm

al

rege

ner

atio

nC

ompa

riso

n to

un

trea

ted

con

trol

sO

bjec

tive

mac

rosc

opic

ev

alua

tion

Lac

k of

sta

tist

ical

an

alys

is

Hua

ng

et a

l.,

2014

21M

ech

anic

al m

inci

ng

Scar

sD

ecre

ased

forc

e

requ

ired

to p

rodu

ce

mec

han

ical

allo

dyn

ia

Dec

reas

ed p

38+ a

nd

OX

42+ c

ells

Incr

ease

d co

llage

n

depo

siti

on,

decr

ease

d ce

llu-

lari

ty

Com

pari

son

to u

ntr

eate

d co

ntr

ols

Obj

ecti

ve m

acro

scop

ic

eval

uati

onSt

atis

tica

l sig

nifi

can

ce fo

r cl

inic

al a

nd

his

tolo

gic

fin

din

gsL

oder

et a

l.,

2014

22H

igh

-spe

ed c

entr

ifug

atio

nH

igh

spe

ed c

entr

ifug

atio

n

plus

ASC

ASC

Acu

te b

urn

sD

ecre

ased

wou

nd

su

rfac

e ar

ea

(all

trea

tmen

t gro

ups)

Dec

reas

ed w

oun

d

dept

h (

ASC

an

d

mix

ed g

roup

s)

Dec

reas

ed c

aspa

se

stai

nin

g an

d in

crea

sed

CD

31

(ASC

an

d m

ixed

gr

oups

)

Com

pari

son

of A

SC, f

at

graf

t, fa

t plu

s A

SC, a

nd

untr

eate

d co

ntr

ols

Obj

ecti

ve m

acro

scop

ic

eval

uati

onSt

atis

tica

l sig

nifi

can

ce fo

r m

acro

scop

ic a

nd

his

to-

logi

c fi

ndi

ngs

Kar

imi e

t al.,

20

1423

Was

hin

g pl

us lo

w-

spee

d ce

ntr

ifug

atio

nA

SC

Acu

te b

urn

sD

ecre

ased

wou

nd

surf

ace

ar

ea fo

r A

SC g

roup

(n

ot s

ign

ifica

nt)

Sign

ifica

ntl

y in

crea

sed

fibr

o-pl

asia

, col

lage

n

rem

odel

ing

Com

pari

son

of A

SC, f

at

graf

t, an

d un

trea

ted

con

trol

sPa

thol

ogis

t blin

ded

to s

tudy

gr

oups

Obj

ecti

ve m

acro

scop

ic

eval

uati

onSt

atis

tica

l sig

nifi

can

ce fo

r h

isto

logi

c fi

ndi

ngs

Lac

k st

atis

tica

l si

gnifi

can

ce fo

r m

acro

scop

ic

fin

din

gs

Ata

lay

et a

l.,

2014

24SV

F is

olat

ion

Acu

te b

urn

sN

one

repo

rted

Dec

reas

ed in

flam

ma-

tion

, fibr

obla

stic

pr

olif

erat

ion

, in

crea

sed

va

scul

ariz

atio

nIn

crea

sed

PCN

A

inde

x (w

oun

d

hea

ling)

, VE

GF

ex

pres

sion

Com

pari

son

to u

ntr

eate

d co

ntr

ols

Path

olog

ist b

linde

d to

stu

dy

grou

psSt

atis

tica

l sig

nifi

can

ce fo

r h

isto

logi

c fi

ndi

ngs

Lac

k ob

ject

ive

m

acro

scop

ic

eval

uati

on

IHC

, im

mun

ohis

toch

emis

try;

PO

SAS,

Pat

ien

t an

d O

bser

ver

Scar

Ass

essm

ent S

cale

; PR

P, p

late

let-r

ich

pla

sma;

SV

F, s

trom

al v

ascu

lar

frac

tion

; MR

I, m

agn

etic

res

onan

ce im

agin

g; A

SC, a

dipo

se-

deri

ved

stem

cel

ls; S

DF-

1, st

rom

al c

ell–

deri

ved

fact

or 1

; TG

F-β,

tran

sfor

min

g gr

owth

fact

or-β

; VE

GF,

vas

cula

r en

doth

elia

l gro

wth

fact

or; M

MP9

, mat

rix

met

allo

prot

ein

ase

9; P

CN

A, p

rolif

erat

ing

cell

nuc

lear

an

tige

n.

*Tw

o st

udie

s w

ere

part

of t

he

sam

e ar

ticl

e.

Tabl

e 2.

Con

tinue

d

Ref

eren

ces

Pro

cess

ing

T

echn

ique

sA

cute

Wou

nds

vs. S

cars

Clin

ical

/Mac

rosc

opic

Fi

ndin

gsM

icro

scop

ic

Find

ings

Stud

y St

reng

ths

Stud

y W

eakn

esse

s


310


of adipose-derived stem cells is an alluring con-cept,28,29 there are notably few human studies detailing the use of adipose-derived stem cell–supplemented grafts in burns.10,15

There were two human studies that investi-gated wound healing in its acute phase. The large series studied by Piccolo et al.16 showed improved wound healing and fibrosis in acute and subacute wounds. Although there was lack of controls, this article had pertinent details on the procedure, and adequate follow-up. The case series using adipose cells from discarded burned tissue15 was a small case series that was difficult to assess, but these cells were shown to share the adipogenic, osteogenic, and chondrogenic potential of their abdominally derived counterparts.30–32 Therefore, they may represent a source of multipotent cells in patients with extensive burns, for whom there may not be enough viable tissue to perform subcutane-ous liposuction to obtain such cells from nonin-jured sites. Indeed, as the percentage of total body surface area affected by burn injury increases, so

does the availability of these adipose-derived stem cells from discarded burn tissue.

Adipose-derived regenerative cells have been used in the treatment of other burn sequelae such as heterotopic ossification.33 These studies were not included, as we focused on the effects on burn wounds.

Although nearly all documented uses of this therapy on burn wounds have had positive results, it should be noted that much of the current litera-ture consists of case reports or case series that lack rigorous statistical analysis (only two human stud-ies included statistical analysis) or power. There has yet to be a large, prospective, randomized, controlled study detailing its use in patients with burn wounds and scars.

We have attempted to summarize all articles relevant to this subject. Our inclusion criteria were necessarily broad and our search terms were diverse, and we included articles in languages other than English. Still, we may have missed studies that have been undertaken with the use

Fig. 2. Effects of fat grafting and adipose-derived regenerative cells on burn wounds and scars. VEGF, vascular endothelial growth factor; SDF-1, stromal cell–derived factor 1; TGF-β, transforming growth factor-β; MMP-9, matrix metalloproteinase 9.



311

of fat grafting and burns. Even so, the results are encouraging. Reports of clinical and histologic improvements highlight the potential of this therapy (Fig. 2), and show that much is yet to be explored in this field.

CONCLUSIONSAfter careful review of the literature regarding

the utility of fat grafting and adipose-derived regen-erative cells in the treatment of burns, it is apparent that this therapy has many documented benefits. Murine studies have shown histologic improve-ments in angiogenesis, collagen organization, and neuropathic pain. Human studies have shown similar biochemical effects in addition to improve-ments in clinical features such as skin texture, soft-ness, coloration, and function, bearing in mind that the human experience is anecdotal and the laboratory experiences are questionable because of experimental design and number of subjects. This review suggests that, at this time, there is no signifi-cant literature to suggest that fat grafting in acute burn wounds facilitates wound healing and ame-liorates subsequent scarring. There is substantial evidence that fat grafting in burn scars is helpful in modifying scar tissue. There is a dearth of ran-domized controlled trials and quantitative analysis supporting the efficacy of fat and adipose-derived stem cells in burns. However, this emerging ther-apy is encouraging. It is our hope that this review will be a foundation for future studies and high-light the breadth of knowledge yet to be explored by this therapy.

Alexandra Condé-Green, M.D.Division of Plastic Surgery

Department of General SurgeryRutgers New Jersey Medical School

Newark, N.J. [email protected]

REFERENCES 1. Coleman SR. Structural fat grafting: More than a permanent

filler. Plast Reconstr Surg. 2006;118(Suppl):108S–120S. 2. Condé-Green A, Baptista LS, de Amorin NF, et al. Effects of

centrifugation on cell composition and viability of aspirated adipose tissue processed for transplantation. Aesthet Surg J. 2010;30:249–255.

3. Zuk PA, Zhu M, Ashjian P, et al. Human adipose tis-sue is a source of multipotent stem cells. Mol Biol Cell 2002;13:4279–4295.

4. François S, Mouiseddine M, Mathieu N, et al. Human mesen-chymal stem cells favour healing of the cutaneous radiation syndrome in a xenogenic transplant model. Ann Hematol. 2007;86:1–8.

5. Agay D, Scherthan H, Forcheron F, et al. Multipotent mesenchymal stem cell grafting to treat cutaneous

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6. Charles-de-Sa L, Gontijo-de-Amorim NF, Maeda Takiya C, et al. Antiaging treatment of the facial skin by fat graft and adipose-derived stem cells. Plast Reconstr Surg. 2015;135:999–1009.

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18. Khouri RK, Smit JM, Cardoso E, et al. Percutaneous apo-neurotomy and lipofilling: A regenerative alternative to flap reconstruction? Plast Reconstr Surg. 2013;132:1280–1290.

19. Sultan SM, Barr JS, Butala P, et al. Fat grafting accelerates revascularisation and decreases fibrosis following thermal injury. J Plast Reconstr Aesthet Surg. 2012;65:219–227.

20. Shokrgozar MA, Fattahi M, Bonakdar S, et al. Healing potential of mesenchymal stem cells cultured on a colla-gen-based scaffold for skin regeneration. Iran Biomed J. 2012;16:68–76.

21. Huang SH, Wu SH, Chang KP, et al. Autologous fat graft-ing alleviates burn-induced neuropathic pain in rats. Plast Reconstr Surg. 2014;133:1396–1405.

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mailto:[email protected]


312


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28. Condé-Green A, Wu I, Graham I, et al. Comparison of 3 techniques of fat grafting and cell-supplemented lipotransfer in athymic rats: A pilot study. Aesthet Surg J. 2013;33:713–721.

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fat grafting in burns prs jan 2016

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