F at G raf t ing f or F ac ial

R e j u v e n a t i o n t h ro u g h
I n jecta ble Tissue Replac ement
and Regeneration
A Differential, Standardized, Anatomic
Approach
Steven R. Cohen, MDa,b, Hayley Womack, DOa,c,*, Ali Ghanem, MD, PhDd

KEYWORDS
 Fat grafting  Anatomic fat grafting  Injectable tissue  Facial rejuvenation  Regenerative medicine
 ITR2

KEY POINTS
 Injectable Tissue Replacement and Regeneration (ITR2) is a standardized fat grafting technique,
which anatomically addresses losses of facial volume, laxity, and sun damage of the skin.
 Anatomic components of volume loss are diagnosed through evaluation of facial surface topog-
raphy and used to formulate unique, individualized treatment plans.
 Three sizes of fat grafts, millifat, microfat, and nanofat, are used to structurally replace losses in
facial fat occurring at different depths and anatomic regions in the face.
 Regenerative effects of ITR2 fat grafts often are augmented with regenerative cells obtained via me-
chanical fragmentation or through addition of stromal vascular fraction cell enrichment, platelet-rich
plasma, and topical nanofat biocrème application.

Video content accompanies this article at http://www.plasticsurgery.theclinics.com.

INTRODUCTION soft tissue and bony volume loss. Lambros1 docu-

mented photometric changes that showed that
Recent advances in understanding of facial aging soft tissue of the face deflates with aging. Kahn
have resulted in significant insights into facial

Disclosure Statement: Dr S.R. Cohen has stock options and royalties with Millennium Medical Technologies,
Carlsbad, CA; has royalties with Tulip Medical; is a shareholder in the Mage Group, UK; and receives royalties
plasticsurgery.theclinics.com

on the Nanocube Device. He is an advisor for the Mage Group and Lipocube. He is an investigator for Allergan
and Ampersand, Inc., and an investigator with Thermigen. The other listed authors have no competing finan-
cial disclosures or commercial associations. Ms H. Womack and Dr A. Ghanem have nothing to disclose.
a
FACES1 Plastic Surgery, Skin and Laser Center, 4510 Executive Drive, #200, San Diego, CA 92121, USA;
b
Division of Plastic Surgery, University of California San Diego, 4510 Executive Drive, #200, San Diego, CA
9212, USA; c Division of Plastic Surgery, University of California San Diego, San Diego, CA, USA; d Blizard Insti-
tute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark
Street, London E1 2AT, UK
* Corresponding author. 315 Goldenrod Avenue, Corona Del Mar, CA 92625.
E-mail address: [email protected]

Clin Plastic Surg 47 (2020) 31–41

https://doi.org/10.1016/j.cps.2019.08.005
0094-1298/20/Ó 2019 Elsevier Inc. All rights reserved.
32 Cohen et al

and Shaw2 and Mendelson and Wong3 docu- 3. Replaces these anatomic losses of fat with 2 to
mented how the facial skeleton loses broad sur- 3 different sizes of autogenous fat grafts opti-
face areas of bone without corresponding mized in size for structural replacement for
shrinkage of the soft tissue envelope. Rohrich areas of bone and deep fat compartment los-
and Pessa4 clarified the anatomy of the superficial ses, superficial fat compartment replacement,
and deep fat compartments and recommended and dermal and epithelial replacement and/or
that fat be injected into specific deep fat compart- regeneration
ments in the face because fat lies both above and
below the facial musculature and ligaments. From Regenerative effects of fat grafts may be
the authors’ own cadaver observations, fat is more augmented with regenerative cells obtained via
tightly clustered in the superficial compartments mechanical fragmentation. For example, ITR2
above the muscles and larger and more loosely nanofat is primarily a matrix-rich product that is
organized in the deep compartments below the processed through microcutting of the aspirated
facial musculature. adipose tissue using the Nanocube (Lipocube,
Advances in genetics have provided a basis for London, United Kingdom) and contains matrix,
measuring early interventions that have the poten- adipocyte-derived stem cells, SVF cells and
tial to slow aging of cells, and the finding of stem growth factors, PRP, and/or mechanically dissoci-
cells and regenerative cells in fat introduced the ated SVF.13–16 This combination of anatomic
possibility of regenerating aging tissues, which fat replacement is supplemented with a menu of
was shown by Rigotti et. al5–7 and supported by regenerative ingredients can be tailored to
recent work by Cohen8 and others.9,10 There are patient-specific needs.
almost no other therapies in aesthetics other
than fat grafting, stromal vascular fraction (SVF)- PREOPERATIVE EVALUATION AND MARKINGS
enriched fat grafting, nanofat grafting, platelet-
rich plasma (PRP), and growth factors, that have The patient is marked with a white makeup pen
demonstrated neoangiogenesis and trophic ef- while sitting in the upright position (Video 1). Scalp
fects to some degree in virtually all subjects.7,11 hair quality and/or loss are noted to determine if a
When patients come in for a facial aging consul- restorative treatment a regenerative approach
tation, they are evaluated at that particular might be beneficial. The epidermal, dermal, and
moment in time. Yet, aging is an evolution of inter- subcutaneous tissue thickness and the degree of
dependent processes taking place over a lifetime. bone recession in the glabella and along the su-
Growth dominates human development during the praorbital rims are noted in analyzing the upper
first 2 decades of life followed by a continual and third of the face. The degree of photodamage is
gradual decay of tissues until death. The anatomic noted. Deeper rhytids are noted for possible
and histologic changes due to aging are seen indi- sharp-needle intradermal fat grafting (SNIF) tech-
vidually in the skin, fat compartments, and under- nique.17 Temporal depression is associated with
lying bone as well as dynamically in the deep fat loss, whereas increased show of the tem-
interdependent relationships between them.12 poral veins is associated with superficial fat loss.
Facial aging can be anatomically and visually Often both are present. The upper and lower eye-
modeled from analysis of the topography of the lids and periorbital region are inspected. Loss of
face. The concept of injectable tissue replacement fullness of the lateral brow, loss of convexity of
and regeneration (ITR2) attempts to answer a the skin caudal to the eyebrow, and supratarsal
fundamental question: Can a dynamic model be fold depth are noted. In the inferior orbit, the rim
used to determine the specific losses in facial fat is evaluated as is the prominence of the intraorbital
compartments and bone and replace and/or fat.
regenerate these tissues in a way that reduces The tear trough and lid cheek junction are eval-
and to some extent reverses the facial aging uated. The position of the globe is noted from the
process? vertex view to determine the degree of proptosis.
The ITR2 procedure is a new, standardized The lid to pupil position is noted and the degree
method of differential fat grafting, which of senile enophthalmos is evaluated. In the middle
third, the zygomatic arch and body are outlined in
1. Diagnoses the anatomic components of vol- white. The superior arch corresponds with the infe-
ume loss by evaluating the surface topography rior temporal region. The deep lateral and medial
of the face suborbicularis occuli fat (SOOF) are noted as is
2. Addresses specific anatomic losses of different the deep medial fat compartment of the cheek.
tissues, including skin, facial fat in the deep and The degree of buccal hollowing is evaluated.
superficial compartments, and bone The nose is assessed for any aesthetic
 Fat Grafting for Facial Rejuvenation 33

deformity and/or aging and the degree of pyriform to reduce blood contamination. Based on new
recession is noted. The lips are evaluated along research on fat preparation and degree of engraft-
with the peri-oral tissues and degree of thinning ment, filtration systems, such as Puregraft (Solana
and rhytids. In the lower third, the marionette basin Beach, California), and centrifugation are probably
is evaluated as the chin and labiomental fold. Chin not necessary and add to the cost.19,20 Simple
texture may be improved with nanofat micronee- washing, gravity separation, and decantation to
dling and fractional laser with topical delivery of remove the tumescent solution are necessary to
nanofat biocrème. The prejowl area just lateral to process the fat. When cleaning is complete, a
the mandibular retaining ligaments, if scalloped, portion of millifat is set to the side to replenish
is addressed as is the inferior border of the deep fat compartment loss and facial bone reces-
mandible and the gonial angle. Chin projection is sion. The remaining fat is transferred into 20-mL
evaluated, and the neck is inspected for degree syringes and processed into microfat and nanofat
of subcutaneous loss, deep and fine rhytids and using the Nanocube kit, which has a total of 4 ports
severity of sun damage. whose functions are to resize fat using a special
cutting technique (see Video 1). Other systems
SURGICAL PROCEDURES that can process the various sizes of fat grafts
Preoperative Preparation and Anesthesia can be used.

Patients are given oral prophylactic antibiotics

Delivery Techniques
1 day before the procedure, if planned under
local anesthesia, or intravenously before the According to the topographic assessment, fat
procedure. Patients are given their choice of grafts are assigned to anatomic locations in
anesthesia, but for ITR2, local or intravenous the face according to their parcel sizes of millifat
anesthesia and tumescent lipoharvest are used (2–2.5 mm), microfat (1 mm), and nanofat (500
unless the patient is having other facial proced- mm and less) (see Video 1). Placement starts with
ures. Patients are offered the possibility of un- the deep compartments of the face and pro-
dergoing a fixed focused ultrasound treatment, gresses superficially, using millifat first, then
a week to a couple days before the procedure, microfat, and ending with nanofat.
for its potential release of endogenous angio- Up to 12 puncture sites are made with an 18G
genic growth factors to prepare the recipient needle and are reused whenever possible in deliv-
facial tissues.18 ering the 3 sizes of fat grafts, shown in Fig. 1. Safe
volume recommendations and sites for fat grafting
Adipose Tissue Harvest are shown in Fig. 2.
If only fat grafting is being performed, the sur-
gery itself takes approximately 45 minutes to MILLIFAT (2–2.5 MM PARCELS)
an hour (see Video 1). Fat is harvested from Middle Third/Temporal Region
any area of excess subcutaneous fat and/or
areas of patient preference if sufficient fat is Millifat is first placed through an 18G needle punc-
available. The patient is prepped and draped un- ture in the nasolabial fold lateral and superior to
der sterile conditions. Harvest begins with a 14G the oral commissure, into the areas of bone reces-
needle puncture followed by infiltration of sion in the pyriform region. The cannula is then
tumescent fluid (500 mL of Ringer lactate with directed cephalad to graft the deep medial fat
25 mg lidocaine and 1 vial of epinephrine compartment and the medial then lateral SOOF.
[1:1000]). A 12-holed cannula, with openings The deep temporal region is grafted along with
measuring 2.5 mm in diameter (Marina Medical, the preperiosteal lateral supraorbital brow. The up-
Davie, Florida), is inserted into a slightly dilated per and lower hemilip are injected with millifat at
14G needle hole. Using a 60-mL syringe with a the commissure.
lock, fat is aspirated. Generally, 120 mL of fat
is removed. These punctures are often allowed Upper Third
to close by secondary intention or by Derma-
bond (Ethicon, Bridgewater, New Jersey, US) The glabella, medial supraorbital rims, and nasal
wound adhesive. radix are injected through a needle puncture in
the central glabella, approximately 1.5 cm to
2 cm above the nasofrontal junction. The nasal
Fat Processing
dorsum, tip, and columella are then grafted
Once the fat is removed, the tumescent fluid is through an entry point between the domes of the
decanted, and the fat is rinsed with Ringer lactate nasal tip.
34 Cohen et al

Fig. 1. Puncture site chronology and injection vectors used in ITR2 fat grafting.

Lower Third is given intravenous clindamycin, and the intra-

oral mucosa just below Stensen duct is prepped
Attention is directed to the chin, mandibular
with betadine and then punctured with an 18G
border, and gonial angle. Modest retrogenia can
needle. It is important to place only small
be improved with millifat grafting. The area just
amounts of fat into the deep buccal compart-
lateral to the mandibular ligament and along the
ment and reinspect the area frequently to deter-
mandibular border is grafted in the preskeletal
mine if the proper amount is injected. It is
level through the same puncture. Millifat is placed
important not to overfill this lowlight area.
along the inferior mandibular border and into the
gonial angle to define the jawline, camouflage
MICROFAT (1-MM PARCELS)
mild jowls, or lower an obtuse mandibular angle
Middle Third and Temporal Regions
(see Fig. 1, puncture site “7” [P7]).
If the buccal fat compartment shows volume For the perioral skin, microfat is grafted superfi-
loss, it is injected using an intraoral approach cially above the muscle from the nasolabial nee-
(see Fig. 1, puncture site “8” [P8]). The patient dle incision for the upper lip and the oral
 Fat Grafting for Facial Rejuvenation 35

Fig. 2. The recommended safe volume ranges with corresponding anatomic fat grafting locations.

commissure incision for the marionette basin and puncture site as the deep temporal compartment
perioral tissue. The SNIF technique is used for the (see Fig. 1, puncture site “2” [P2]).
philtral columns (cupid’s bow) and rhytids
perpendicular to the white roll of the upper and
Upper Third
lower lips.
The superficial temporal fat compartment is For the forehead, the glabellar needle puncture
grafted with microfat using the same temporal site is used to inject superiorly and laterally into
36 Cohen et al

the medial brows (see Fig. 1, puncture site “5” exhibiting biologic functions, which modulate extra-
[P5]). Two more needle incisions are then placed cellular matrix repair and neocollagenases (Alastin
at the hairline on either side at the midpupillary Skincare, Carlsbad, California).22 In patients with a
line to graft the corresponding central, inferior, history of herpes simplex, perioperative prophylactic
and lateral forehead subcutaneous (superficial) antivirals treatment is prescribed.
fat compartment. Patients can expect some bruising and swelling,
The incision for the upper lid sulcus and lower with the lips swollen for approximately 5 days to
brow fat pad is located on the lateral superior 10 days. Patients can expect facial swelling and
orbital rim approximately 3 mm inferior to the tail mild ecchymosis, which generally dissipate by
of the eyebrow. For the lower eyelid, 2 access day 3 to day 5, with 15% of patients taking longer,
points are used: the tear trough point (see Fig. 1, even a few weeks.
puncture site “11” [P11]) and a second point just
lateral to the nasojugal groove (see Fig. 1, punc- EXPECTED OUTCOME AND MANAGEMENT
ture site “12” [P12]). Microfat placement is in the OF COMPLICATIONS
supraperiosteal, preseptal space.
Patients having nanofat microneedling and/or
Lower Third nanofat biocrème (neo-U) in conjunction with frac-
tional lasers of different wavelengths have experi-
The subcutaneous fat of the chin and jawline,
enced significant improvement in aesthetic
including the lateral superior gonial angle as well
outcomes with faster healing compared with his-
as the submental crease, are grafted with microfat
torical controls that were not treated with nanofat.
to restore a uniform silhouette of the lower face
In patients having facelifts with ITR2, facial volume
(see Fig. 1, puncture site “7” [P7]).
improves by approximately 45% at a month, drops
to approximately 25% to 30% from 7 months to
NANOFAT (500-mM PARCELS) 12 months, and then improves to 74% at 18
Nanofat is placed using either the SNIF approach, months to 24 months.19 This finding suggests
topically with microneedling or with a topical bio- that there may be a reversal of tissue decay using
crème. Until 2017, the authors prepared nanofat ITR2 in conjunction with facelift surgery.
in the gradual emulsification technique originally Complications from ITR2 have been rare and
described.13 Since 2018, however, ITR2 nanofat only related to excessive fat grafts in the lower
has been prepared using the Nancube. The advan- eyelids. Although rare, transconjunctival or trans-
tage of the latter processing method is a matrix- cutaneous lower blepharoplasty with removal of
rich product with less-traumatized regenerative fat has taken care of the problem. The authors
cells.21 When delivered through an SNIF technique no longer use microfat above the orbital retaining
for dermal rhytids, this cellularly optimized nanofat ligament, only matrix-rich nanofat. Since adopting
is injected intradermally using a 25G cannula ITR2, the authors have not experienced any over-
attached to a finger-activated grafting device, 3- growth with patient weight gain.
mL Celbrush (Cytori, San Diego, California), or an
automatic grafting device, Lipopen (Juvaplus, MAINTENANCE AND SUBSEQUENT
Neuchâtel, Switzerland). PROCEDURES
Finally, nanofat is delivered with a mechanical
microneedling device into the face, neck, and Additional procedures are recommended based
décolletage. A 5-mL to 20-mL aliquot of nanofat on a patient’s physical findings and individual ag-
is kept to combine with a transdermal liposomal ing patterns.
carrier to form a topical nanofat biocrème (neo-U
[Aries Biomedical, San Diego]). CASE DEMONSTRATIONS
Patient 1
POSTOPERATIVE CARE
A 39-year-old woman demonstrates 6 years of ag-
Postoperative care consists of analgesia, nonste- ing (Fig. 3A, B). In Fig. 3C, she is shown 6 months
roidal anti-inflammatory medications, and arnica post-ITR2 and 2 years after ITR2 (Fig. 3D). A total
for bruising. Direct application of ice is not permitted. of 34 mL of fat was placed to the temporal, brows,
Excessive swelling is treated as needed with a cheeks, tear trough, nose, nasolabial folds, lips,
tapering oral steroid regimen. In patients undergoing and marionette lines. Note the gradual and subtle
facelift surgery or laser resurfacing, preoperative changes that occur with aging, the replacement
skin care is maintained with products containing of fat losses in the deep and superficial fat compart-
matrikine (tripeptides and hexapeptides) ingredients ments, and her appearance after 8 years of aging.
 Fat Grafting for Facial Rejuvenation 37

Fig. 3. Patient 1. Photo of 33-year old patient (A); Preoperative photo of the same patient at 39 years of age,
demonstrating 6 years of natural aging (B); 6 months post-ITR2 (C); 2 years post-ITR2 (D). [Fig A–C (From Cohen
SR, Womack H. Injectable tissue replacement and regeneration: anatomic fat grafting to restore decayed facial
tissues. Plast Reconstr Surg Glob Open. 2019;7(8):e2293; with permission.)]

Patient 2 the topographic planning and placement of micro-

fat grafts (Fig. 4C). The blue overlays show the
A 63-year-old woman is shown preoperatively,
topographic planning and placement of nanofat
who presented with moderately severe skin laxity
(Fig. 4D). The patient’s face data sheet with the
and volume loss (Fig. 4A). The purple overlays
volumes of fat injected (Fig. 4E). Finally, the patient
show the topographic planning and placement of
is shown 1 year postoperatively after being treated
millifat grafts (Fig. 4B). The green overlays show
with upper and lower blepharoplasties, a high
38 Cohen et al

Fig. 4. Patient 2. A preoperative 63-year-old woman who presented with moderately severe skin laxity and vol-
ume loss (A). Topographic planning and placement of millifat grafts (purple [B]), microfat grafts (green [C]), and
nanofat (blue [D]). Patient’s face data sheet with the volumes of fat injected (E); 1 year postoperatively after be-
ing treated with upper and lower blepharoplasties, a high SMAS face and neck lift, and ITR2 fat grafting,
including the deep buccal fat compartment via a transoral approach (F).
 Fat Grafting for Facial Rejuvenation 39

superficial musculoaponeurotic system (SMAS) of the face and should be placed in an anatomi-
face and neck lift, and ITR2 fat grafting, including cally correct fashion to avoid poor aesthetic re-
the deep buccal fat compartment via a transoral sults that can occur with weight gain. Because
approach (Fig. 4F). there is no fat present in the subcutaneous plane
of the eyelid, nanofat is used exclusively to regen-
Patient 3 erate tissue because there is no structural require-
Shown preoperatively, a 28-year-old man who ment. Using an anatomic and regenerative
was bothered by his lower eyelid hollowing and approach seems to have 2 important benefits: (1)
desired a regenerative approach (Fig. 5A). Shown it addresses the actual anatomic changes that
again 6 months postoperatively after a total of occur with aging, rather than simply using fat as
30 mL of millifat, microfat, and nanofat was used a natural aesthetic filler, and (2) neoangiogenesis
along with microneedling of the nanofat and post- improves tissue health, possibly delaying atrophy
operative nanofat biocrème (Fig. 5B). of rete pegs and functional matrix, thus reducing
the rate of laxity development and bone loss.
Patient 4 ITR2 is an umbrella concept that incorporates
knowledge of anatomic and histologic findings of
Shown preoperatively, a 52-year-old woman who
facial aging with the ability to diagnose the areas
presented with concerns of periorbital aging and
of anatomic changes from the skin’s surface to
loss of facial volume (Fig. 6A). Patient is shown
the bone. Although this approach may seem at first
1 year postoperatively after a total of 58.5 mL of
complex, it is simple, standardized, and routine to
fat was placed to the forehead, temporal regions,
perform. Much as high-definition techniques dur-
periorbital, perioral, midface, pyriform, and gonial
ing liposuction are predicated on an artistic under-
angles (Fig. 6B). The patient also underwent
standing of anatomy, likewise, ITR2 is based on
skin-only upper blepharoplasty and pinch lower
being able to observe the anatomic changes of
blepharoplasty. Note the improvement in globe
facial aging in different fat compartments, skin,
position from the intraorbital fat grafting.
and bone. Treatment is directed at all tissues
that have decayed from epithelium to bone, using
DISCUSSION
2 sizes of fat grafts to address structural changes,
Currently, most surgeons and dermatologists superficial fat losses and skin thinning. Treatment
inject fat aesthetically as if a filler, but fat is using ITR2 can be combined with other proced-
anatomically distributed in precise compartments ures on the eyelids and face. New ideas, such as

Fig. 5. Patient 3. A preoperative 28-year-old man who was bothered by his lower eyelid hollowing and desired a
regenerative approach (A); 6 months postoperatively after a total of 30 mL of millifat, microfat, and nanofat was
used along with microneedling of the nanofat and postoperative nanofat biocrème (B).
40 Cohen et al

Fig. 6. Patient 4. A preoperative 52-year-old woman who presented with concerns of periorbital aging and loss of
facial volume (A); 1 year postoperatively after a total of 58.5 mL of fat was placed to the forehead, temporal re-
gions, periorbital, perioral, midface, pyriform, and gonial angles (B). (From Cohen SR, Womack H. Injectable tis-
sue replacement and regeneration: anatomic fat grafting to restore decayed facial tissues. Plast Reconstr Surg
Glob Open. 2019;7(8):e2293; with permission.)

injectable cartilage gel and injectable decellular- bone, and intraorbital fat grafting to correct senile
ized bone, are actively being explored. enophthalmos, are presented as new concepts
It is possible to model the facial tissues as they under the umbrella of ITR2 and may play important
progress from the period of growth and develop- roles in the future of facial reconstruction and
ment to decay. The authors’ concept involves rejuvenation.
stimulating the tissue with PRP and/or cellularly
optimized nanofat at the earliest signs of decay SUMMARY
to prevent the rapidity of these changes. Sun dam-
age is treated with skin care and energy-based de- ITR2 presents a dynamic, anatomy-based
vices and lasers as needed. Skin care products approach to address patterns of facial aging,
with matrikine ingredients are used to clear the which occurs in specific superficial and deep fat
extracellular matrix of debris.22 Aesthetic prod- compartments in the face. In addition, the ITR2
ucts, such as fillers, are used for beauty enhance- technique delivers 3 structurally optimized fat
ment but have little to no effect on tissue health. grafts to replace and regenerate anatomic losses
Patients requiring more than one filler are excellent in the skin and deep and superficial fat compart-
candidates for their first ITR2 treatment of facial ments. The sizes of the nanofat, microfat, and milli-
volume loss. fat grafts are based on the structural differences of
Studies are under way to determine the fat in these different areas and also make sense
longevity of this approach, but the authors expect from a safety perspective.
large standard deviations because they are now
using the patient’s own materials; therefore, vari- SUPPLEMENTARY DATA
able results can be expected, that is, patients Supplementary data related to this article can be
who age more rapidly or prematurely will benefit found online at https://doi.org/10.1016/j.cps.
from different combinations of regenerative ap- 2019.08.005.
proaches, so some may require more treatments
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