 |
| Dr. Joel Aronowitz |
Mark J. Landau3
Zoe E. Birnbaum2
Lauren G. Kurtz2
Joel A. Aronowitz MD 1,2,3
Disclosures:
None of the authors have any financial interest
in any of the products, devices, or drugs mentioned in this paper.
Introduction:
Autologous fat grafting (AFG)
is not a new technique. It was first described by Neuber in 1893 to fill a
depressed facial scar [1]. Used only sparingly for the greater part of the next
century, AFG was mostly overlooked in plastic and reconstructive surgery until
the early 1980’s. In 1987, as the popularity
of AFG surged, the American Society of Plastic and Reconstructive Surgeons
(ASPRS) issued a position paper on the use of autologous fat grafting in the
breast. At the time, they did not condone the use of autologous fat grafting on
the grounds that “much of the injected fat will not survive and the known
physiological response to necrosis of this tissue is scarring and
calcification. As a result, detection of early breast carcinoma through
xenography and mammography will become difficult [2, 3].”
Since
1987, the popularity of fat grafting for a variety of indications has only
increased and a significant body of literature
demonstrated that artifacts resulting from fat grafting, mainly calcifications
and oil cysts, can be readily differentiated
from malignancy in early breast cancer screening [4-9]. This is due to
improvements in imaging techniques as well as an expanded body of data on the
subject. In 2009, the American Society of Plastic Surgeons (ASPS) published a
new position paper evaluating the safety and efficacy of autologous fat
grafting. The ASPS task force determined that autologous fat grafting was a
safe procedure with a relatively low rate of complications. In addition, they
stated that artifacts could indeed be identified and distinguished from
malignancy in early breast cancer screenings [10].
In recent years AFG has
become a widely accepted and utilized technique in the field of plastic surgery
due to its application in soft tissue augmentation and its regenerative effects
on local tissue such as reversal of hyperpigmentation, softening of
hypertrophic scars, increased local vascularity, and improvement of radiated
tissue [11-13]. The diverse applications of fat grafting within the field of plastic
surgery include facial rejuvenation, hand rejuvenation, breast reconstruction
and volume enhancement, treatment of skin photoaging, correction of contour
deformities and improvement of senile and diabetic plantar fat pad atrophy.
[14-20]. AFG is useful
for both cosmetic and reconstructive indications because there is no scarring
at the injection site, no foreign material implanted, a low rate of serious
complications, and a typically desirable donor site.
Despite the beneficial
effects, there are some drawbacks associated with AFG. Post-fat grafting soft
tissue lesions such as calcifications and oil cysts are observed
postoperatively. But it is clear that lesions appearing more than one year
after fat grafting are not directly related to the procedure. [14,21].
The most troublesome and persistent issue in
fat grafting however is the unpredictable degree of volume retention of fat
grafts after transplant. Across the literature, studies have reported a wide
range of reabsorption rates after transplantation [22]. While some of the
variability is no doubt due to inconsistent methods of pre and post operative
volume assessment used in various clinical studies reported, a lack of
predictable volume retention is clearly a characteristic of autologous fat
grafting. A better understanding of the fat graft microenvironment in which
engraftment occurs is clearly critical to improvement of clinical outcomes. The
current state of knowledge of fat graft failure points toward cellular hypoxia
as the major factor adversely affecting the engraftment process and thus long
term volume retention. Studies demonstrate that mature adipocytes can tolerate
hypoxia for approximately 24 hours at normal core body temperature due to the
relatively active metabolic demand of their intracellular cytoplasm. In vivo, fat grafting involves placement
of a 1-4 mm diameter adipose tissue fragments, each consisting of thousands of
individual cells, into a profoundly ischemic adipose tissue recipient site
microenvironment. Ideally the graft fragment is initially nourished by
diffusion of oxygen and glucose from the surrounding tissue and quickly
revascularized through microvascular inosculation and neovascularization. The
clinical success of fat grafting attests to the efficiency of this
revascularization process. A significant proportion of injected fat, however,
fails to successfully engraft due to irreversible anoxic injury suffered by
adipocytes before revascularization can occur. Passive diffusion of oxygen and
glucose is not sufficient to sustain adipocytes located centrally in the
individual graft tissue fragment, i.e., at a depth of more than about 10 cells
from the fragment surface and thus anoxia-induced apoptosis and resorption is
the fate of the central core of the graft fragment. Improvement in AFG
technique is aimed at reducing the number of mature adipocytes located
intermediate between the well-perfused outer cell layers and the anoxic central
core of the graft fragment that enter an apoptotic pathway and fail to engraft
[23].
Studies have improved
understanding of the cellular processes affecting the success of fat grafting
and offer the possibility of improving the reliability and predictability of
fat grafting. This work for example revealed hypoxia-induced factors expressed
by adipocytes which are exposed to
ischemic conditions. But the identification of an adipose-specific apoptosis
pathway induced by hypoxic conditions and which might be affected by changes in
operative technique or medication remains an unrealized research goal. Still,
it is possible to identify several factors that contribute to high rates of
adipocyte apoptosis and ultimately fat graft resorption. These factors include
the threshold parameters tolerated by grafted cells to specific hyponutritional
microenvironments, anoxia, and physical trauma which occurs before
revascularization. The clinical value of this knowledge is supported by studies
that show administration of pro-angiogenic factors such as erythropoietin and
vascular endothelial growth factor improve the survival of transplanted fat
tissue in mouse models [24, 25]. Another salient factor in successful
engraftment is the presence of adipose derived stem cells (ASC’s). These cells
are pluripotent mesenchymal stem cells which reside in large numbers in adipose
tissue. They are concentrated in the stromal vascular fraction of lipoaspirate.
These small stellate shaped cells are identified by surface antigens such as
CD134 and their ability to form colonies in
vitro. It is estimated that 1-3 million of these small stellate shaped
cells typically reside in proximity to small vessels of adipose tissue. Adipose
stem cells are known to tolerate the conditions associated with harvest and
graft injection more successfully than mature adipocytes, participate in the
tissue response to these stresses, and direct adipose tissue regeneration.
Importantly, the liposuction fat graft harvest process depletes the number of
ASC’s in fat graft material. [54, 55].
These observations, as well
as other factors known to affect successful engraftment, suggest several
strategies which may be expected to improve volumetric retention by optimizing
the processes of fat graft harvest, graft preparation and the fat graft
injection. The most salient factors amenable to adjustment are fat graft
particle size, graft physical trauma, graft hypoxic time, number of ASC’s in
the fat graft material and the recipient microenvironment. In this article, we
review proposed methods to improve the effectiveness of AFG, the relevant basic
research basis of the strategy and the results of the relevant clinical
research.
Harvest,
Handling, and Grafting Technique:
Many groups have attempted
to determine the optimal techniques for harvest, processing, and transplantation
but there is still no general consensus on the most effective technique. This
lack of consensus regarding technique contributes to the wide range of graft
retention rates reported across the literature. Part of the problem stems from
the fact that AFG actually consists of a multiplicity of individual steps from
fat harvest, to graft preparation, to fat injection. Most of the component
steps at each stage are likely to substantially affect survival of each small
adipose tissue fragment which constitutes the injected graft, thereby affecting
the permanent graft volume. Compounding the problem of controlling these
multiple variables in clinical studies is the difficulty of studying the major
end point, i.e., volume retention. Volumetric measurements, although simpler
today with more advanced photographic methods, are notoriously difficult and
results are often difficult to compare due to significant differences in both
the harvest and recipient site. Nevertheless, there is a significant body of knowledge
concerning the factors known to affect
graft viability and the engraftment process. These factors fall under
graft harvest methods, fat graft processing methods, and grafting technique.
They are reviewed below.
Fat
Harvest Methods:
In 2013, Fisher et al.
investigated fat harvest techniques used in AFG [26]. They compared fat
harvest using either suction-assisted liposuction or ultrasound-assisted
liposuction. In terms of graft retention and stromal vascular fraction (SVF) content, there was no significant difference between
the two methods. This was reinforced by Chung et al. in 2014 who reported no
decrease in viability with ultrasound-assisted or suction-assisted liposuction;
however, when comparing suction-assisted liposuction with laser-assisted
liposuction, they noted that laser-assisted liposuction reduced viability of
graft material [27].
Another factor which was
proposed as a point of variance in producing lipoaspirate graft material is the
location of harvest. Numerous studies have investigated fat graft
characteristics and AFG results based on harvest location. In 2004, Rohrich et
al. [28] examined fat harvested from four body parts: the abdomen, the flank,
the thigh, and the medial knee. They determined that there was no significant effect
on adipocyte viability or survival based on harvest site. In general, harvest
location has not been determined to not
be a significant factor in the outcomes of AFG procedures. This information is
beneficial because it allows the surgeon more versatility to harvest based on
tissue availability and patient aesthetic preferences without compromising the
outcomes.
Fat
Processing Methods:
Fisher et al. also compared
three common processing techniques: filtration, cotton gauze rolling, and
centrifugation. In the filtration method,
lipoaspirate is passed through an 800
µm filter. In the centrifugation method, often referred to as the Coleman
technique, lipoaspirate is centrifuged at 3,000 rpm for 3 minutes. The adipose
layer is then separated from the aqueous and oil layers. In the cotton gauze rolling
method, fat is gently rolled on a non-adherent cotton gauze dressing for 5
minutes using a sterile scalpel in order to remove the liquid portions. When
grafted, the cotton gauze method was reported to have the highest volume
retention compared to the other methods, with 70% retention. The filtration
method retained 58% and the centrifugation method retained only 47%. Fisher et
al. suggested that cotton-gauze was the preferred method for cosmetically
sensitive parts of the body where less fat is required, but filtration and
centrifugation were more practical options for large volumes.
Grafting
Technique:
No strict
recommendation can be made about the best processing
technique for AFG based on the literature. Various individual studies have found different methods to be
superior depending on the protocols used in each study [29]. However, there are
common trends and observations reported across many studies. One observation is
that grafts prepared using simple decantation contained the highest number of
viable adipocytes, but also the highest number of contaminants. Additionally,
grafts prepared using centrifugation at a speed above 400 g have decreased viability of adipocytes.
Platelet Rich Plasma (PRP):
A method receiving a significant amount of attention for its
potential to improve volumetric retention of fat grafts is the supplementation
of graft tissue with autologous platelet-rich plasma (PRP). PRP is a growth
factor-rich injectable which can be generated quickly and cost effectively from
a patient’s own blood. Over 800 different proteins have been identified to be
secreted by platelets into the plasma, which affect a wide range of cells in
the body [30].
Platelets are a vital part of the immune system response to
endothelial injury. Platelets, normally inactive, become activated when they
come in contact with damaged endothelial tissue and can also be quickly activated
in vitro by contact with glass,
freezing cycles, or the addition of calcium or thrombin. Once activated,
platelets release stores of growth factors which
facilitate tissue repair. Growth factor secretion is most intense in the first
hour but continues for about 7 days [31]. The growth factors synthesized by
platelets stimulate healing and tissue repair through intercellular mediators
and cytokines which stimulate angiogenesis and
promote cell proliferation, cell differentiation, and extracellular matrix
formation [32-34].
While synthetic forms of these growth factors have been previously studied,
they are more readily available and more easily acquired for clinical use in
the form of autologous PRP. PRP has been used over the last 30 years to promote
bone regeneration, wound healing, tendon and cartilage repair, corneal repair,
and skin rejuvenation [35-40]. It should, however, be noted that results across
different applications of PRP can sometimes be difficult to compare. This is
because since the 1970’s a variety of different methods have been used to
prepare PRP, leading to significant variation
in the composition and outcomes [41, 42].
In terms of improving fat grafting, PRP has multiple potential
beneficial qualities. The growth factor stores in PRP allow cells to resist the
hypoxic stress experienced within the first few days after fat transfer
and promote proper arrangement of
transplanted tissue by facilitating production of the extracellular matrix. The
growth factors in PRP also promote angiogenesis which facilitates recovery from
the ischemia associated with fat transfer. PRP has been shown to improve fat
survival rate as well as promote stem cell proliferation and differentiation in vitro [43, 44].
Numerous animal studies have shown a positive relationship between
PRP-enhancement and fat graft survival. A study published by Nakamura et al. in
2010 [45] demonstrated that fat grafts enhanced with PRP retained significantly
more volume than non-enhanced fat grafts in rats. A similar result was achieved
by Pires Fraga et al. in 2010 using rabbits [46], demonstrating greater volume
retention and blood vessel formation and less necrosis and fibrosis. A study by
Rodriguez-Flores in 2011 compared the histological characteristics of grafted
tissue with and without PRP in rabbits [47]. They noted that when PRP was
included, there was less inflammation observed in the recipient site, fewer
instances of oil cyst formation, and increased survival of transplanted fat
cells.
Recently, additional studies have examined
clinical applications of PRP-enhanced fat grafting for wound healing, facial
reconstruction, and general aesthetic improvements [48]. Studies have demonstrated
that the application of SVF and PRP have similar effectiveness in the treatment
of post-traumatic lower extremity ulcers and facial scars [65-66].
In 2012,
Gentile et al. [49] published clinical results of a study comparing
PRP-enhanced AFG and normal AFG in breast reconstruction. They observed that
after 1 year, the PRP-enhanced group (n=50) retained 69% of the initial
3-dimensional volume while the control group (normal AFG, n=50) retained only
39%. In 2013, the same group published another paper expanding on their
results with the procedure they termed Platelet-rich Lipotransfer [50]. They
observed that when using a PRP concentration of 0.5 mL or 0.4 mL of PRP per mL
of fat tissue, 70% of the initial volume was retained at 1 year, compared to
only 31% in the control group.
Recipient Site Immobilization with Neurotoxin:
An interesting approach proposed by Baek et al. in 2012
[51] suggested that enhancement of fat grafts with Botulinum Toxin A (BoNTA)
could improve fat graft survival in the facial region, and they tested this
theory in a rat model. Fat was excised from the rat retroperitoneal area and
then digested with collagenase for 2 hours to create a homogenate. This
homogenized fat mixture was then centrifuged to remove the fluid components and
used for grafting. In each rat, Baek et al. grafted two separate tissue
deposits, one on each side of the back. One of these grafts was injected with
fat, saline and BoNTA (0.5 IU), while the other received only fat and saline.
Baek et al. observed a significant increase in the weight, volume, and cellular
integrity of the graft which received BoNTA compared to the control graft. They
reported 74% volume retention of the initial 0.5 mL of fat tissue grafted in
the BoNTA group and only 44% in the control group.
The authors proposed that the increased retention was due to
temporary muscle immobilization provided by the BoNTA, which decreases abnormal
muscle contractions in the face and preserves graft viability. For the cosmetic
treatment of facial aging, BoNTA injections to the face are commonly performed
shortly before or after facial fat grafting procedures are conducted [52]. This
method proposed by Baek et al. seeks to consolidate these two into one
procedure for patient convenience and potentially improved results. However,
more clinical evidence is required to validate this technique in humans.
Adipose-Derived
Stem Cells and Cell-Assisted Lipotransfer
In 2006, the research team led by Kotaro Yoshimura published a
paper in which they described a method of supplementing the lipoaspirate used
for fat grafting with progenitor cells found in adipose tissue, adipose-derived
stem cells (ASC’s). They termed this process cell-assisted lipotransfer (CAL)
[53]. The rationale behind this technique is that aspirated adipose tissue
(lipoaspirate) is generally poor in progenitor cells, which is a contributing
factor to poor survival in vivo.
Lipoaspirate is poor in progenitor cells for two main reasons. The first is
that ASC’s tend to be located closer to major blood vessels in adipose tissue
which are avoided during liposuction and other harvest techniques [54, 55]. The
second reason is that a portion of the progenitor cells are contained in the
fluid portion of the lipoaspirate, which is discarded before grafting [56]. To
combat this problem, Yoshimura and his team suggested harvesting excess
lipoaspirate and isolating the progenitor cells contained within, which then
can be used to supplement the lipoaspirate to create a progenitor-rich graft.
Adipose-derived stem cells have many characteristics which aid in
the retention of fat grafts. First, ASC’s are able to differentiate into new
adipocytes, replacing a portion of the
adipocytes which succumb to apoptosis due to
hypoxic or physical stress [57-59]. Second, ASC’s have been shown to actively
promote angiogenesis via growth factor secretion as well as through neovascular
differentiation [60, 61]. ASC’s have been shown to not only survive in hypoxic
conditions, but actually significantly increase their production of soluble
angiogenic growth factors, including vascular endothelial growth factor (VEGF)
and hepatocyte growth factor (HGF) [62, 63]. By promoting the development of
new vasculature in the grafted tissue, ASC’s are able to speed the recovery
from ischemia after transplantation and reduce the number of cells succumbing
to hypoxic stress, thereby improving graft volume retention.
Studies have been conducted using both the stromal vascular
fraction (SVF) and pure, cultured populations of ASC’s. SVF is a heterogeneous
population of cells which results from the processing of adipose tissue and is
composed mainly of various blood cells, pericytes, macrophages, smooth muscle
cells and both adipose-derived and vascular endothelial progenitor cells [64].
The use of a pure population of ASC’s was not shown to be superior to using SVF
cells. Using SVF cells is advantageous because they do not require culturing,
which can take weeks. Instead, these cells can be isolated and injected in the
same surgical procedure. Using cultured cells would require two procedures: one
to harvest cells and one for the actual grafting. In the initial paper
describing CAL, they reported a 35% increase in retention of grafted tissue
volume compared to normal fat grafting in a mouse model. This has led to many
projects investigating the therapeutic potential of CAL. In 2013, Kølle et al. [67] conducted a randomized
placebo-controlled trial to investigate the effects of ASC enhancement on graft
survival in humans. Using cultured ASC’s, Kølle et al. reported significantly higher levels of
volume retention compared to controls. The ASC-enhanced group retained 80.9% of
the initial volume on average, compared to the control group which only
retained 16.3% on average. Another study by Wang et al. published in 2012
reported CAL results from 18 patients [68]. They reported retention of only
about 50% of the grafted tissue at 6 months. While there is still absorption of
a significant portion of fat after grafting, studies on CAL have reported a
positive correlation with ASC enhancement and volume retention compared to
normal AFG, but how much the retention is improved is still debated and no
conclusive dose vs. effect relationship has been established [69].
The main application of CAL in the clinical setting has been for
cosmetic breast augmentation and reconstruction, but with these recent advances
in the field of AFG, essentially all previous applications of fat grafting are
now being reinvestigated using CAL, including the treatment of lipodystrophy
and contour defects, reduction of facial aging, and accelerated healing of
chronic wounds, among others.
CAL and PRP in Combination:
The independent advances observed with both PRP and ASC
enrichment of fat grafts naturally led to the attempt to combine the two. PRP
has been shown to increase the proliferation and differentiation of ASC in vitro [70, 71]. By supplementing ASC
enhanced fat grafting (CAL) with PRP, researchers and clinicians hope to boost
the regenerative effects of the stem cells, while still getting the benefit
afforded by PRP enhancement, in order to achieve a method superior to supplementation
with either alone.
In a recent study by Seyhan et al. [72], each of these 3 methods
(ASC only, PRP only, and ASC + PRP) were compared in rats. They reported that
after 12 weeks the PRP + ASC group had the highest weight and volume of fat
grafts while also having the highest number of viable adipocytes and blood
vessels. Growth factor levels were also the highest in the PRP + ASC group.
While in vitro and animal studies are
promising, there is relatively no clinical data available on the combination of
the two, most likely because of the lack of adequate clinical data on the use
of ASC’s alone. Studies have shown that the injection of ASC combined with PRP
accelerated wound closure rates in patients with chronic skin ulcers, but the
individual contributions of ASC and PRP to wound closure and their possible
synergism has not yet been elucidated. [73] There are also studies which
examine the combination of PRP and ASC’s in areas outside of fat grafting, such
as improvement of knee joint function [74].
Conclusion:
Fat
grafting continues to increase in popularity with new indications and novel
technical modifications reported frequently. AFG helps
augment and regenerate deficient, scarred, irradiated and aged subcutaneous soft tissue and skin in a wide variety of
clinical situations with a low complication rate and low donor site morbidity. However,
there is still no clinically vetted ideal technique that ensures maximum graft survival and predictability of lasting graft volume.There is currently
no consensus on the optimal autologous fat grafting technique that produces the
most predictable outcome for a given clinical situation. Unlike most
operations, successful fat engraftment
does not occur at the macroscopic tissue level and tissue viability can not be
assessed by more familiar parameters such as color, warmth, tension, and
bleeding. Now plastic surgeons are
compelled to delve to the level of very small tissue fragments and even individual
cells which are affected by such novel factors as local oxygen tension, glucose
concentration, micro physical stress, ambient temperature effects on cellular
metabolism and the like. But just as improved tissue rearrangement procedures
using muscle flaps emerged from an improved understanding of the axial blood
supply, it is expected that improved AFG outcomes will result from meticulous
attention to the factors which affect viability of small fat tissue fragments
and cells.
Studies have been conducted
to examine if using PRP, ASC, or a combination of both will help combat the low
fat graft retention rates, but no ideal method has been determined.
Although there is some anecdotal evidence, more clinical evidence is required
to validate the best technique to ensure the volumetric retention of adipose
tissue after autologous fat grafting. Future research will hopefully refine our
understanding of the effect of fat grafting on the local tissue
micro-environment and provide clues towards its optimization. Correlating
laboratory results with large-scale, controlled studies using human patients is
needed to advance our ability to tailor fat grafting techniques to specific
medical and cosmetic applications. Based on the results of cell biology
research and the long-term accumulation of objective patient data, we believe
that a standard technique of fat grafting for a given clinical scenario will
emerge.
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