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Review
Evaluating the quality of studies reporting on clinical applications of
stromal vascular fraction: A systematic review and proposed reporting
guidelines (CLINIC-STRA-SVF)
Marcio Yuri Ferreira
a
,
*
, Jos
e da Conceiç~
ao Carvalho Junior
b
, Lydia Masako Ferreira
b
a
Translational Surgery Graduate Program of Universidade Federal de S~
ao Paulo - Unifesp, S~
ao Paulo, SP, Brazil
b
Plastic Surgery Division, Universidade Federal de S~
ao Paulo - Escola Paulista de Medicina, SP, Brazil
article info
Article history:
Received 14 June 2023
Received in revised form
26 July 2023
Accepted 13 August 2023
Keywords:
Stromal vascular fraction
Adipose-derived stem cells
Regenerative medicine
Scientific rigor
Guideline
abstract
Background: The stromal vascular fraction (SVF) has been widely explored in a number of therapeutic
applications in several specialties. Its therapeutic potential is being increasingly demonstrated, although
its mechanism of action is still unclear.
Objective: To evaluate the quality of studies reporting on clinical applications of SVF.
Method: This is a systematic literature review that followed the PRISMA guidelines with the search of the
studies from December 1, 2012, to December 1, 2022, in the following databases: MEDLINE, LILACS and
EMBASE. The level of evidence of the studies was assessed using the GRADE system, and the rigor used in
the publication of the results was assessed in relation to adherence to the guidelines indicated by the
EQUATOR Network Group. The CLINIC eSTRA-SVF reporting guideline was developed after the
completion of this systematic review.
Results: A total of 538 articles were found, and 77 articles were selected after reading the titles and
abstracts and removing duplicates. Then, 15 studies were removed for not meeting the inclusion criteria,
leaving 62 studies. The CLINIC eSTRA-SVF was developed and consists of 33 items and two tables.
Conclusion: There is scientific evidence, although mostly with a low level of evidence, that the use of SVF
in clinical applications is safe and effective. The information published in these studies should be
standardized, and the CLINIC eSTRA-SVF reporting guideline proposed in this study may assist in the
design, conduct, recording and reporting of clinical trials and others clinical studies involving the SVF.
©2023, The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V. This is
an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/
4.0/).
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................ 333
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................ 333
3. Results and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................ 334
3.1. Therapeutic applications . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . ...............................................335
3.2. Prevalence of studies that reported clinical benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...............................335
3.3. Summary study details . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...............................................335
3.4. Route of administration of the SVF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........................................335
3.5. Design, methodological rigor and level of evidence of the studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....................336
3.6. Follow-up ...................................................................................................................337
Abbreviations: ADSCs, adipose tissue stem cells; VEGF, vascular endothelial growth factor; HGF, hepatocytic growth factor; PDGFB, platelet-derived growth factor subunit
B; bFGF, basic fibroblast growth factor; SVF, stromal vascular fraction; BM-MSCs, bone marrow-derived stem cells; EPCs, endothelial progenitor cells; CLINICeSTRA-SVF,
Strengthening Reporting in Therapeutic Applications of the Stromal Vascular Fraction Guideline; FDA, United States Food and Drug Administration; AEs, Adverse events.
*Corresponding author: Pedro de Toledo St., 650-2ºFloor, P.O. Box: 04039-002., S~
ao Paulo, SP, Brazil.
E-mail address: marcioferreiramed@gmail.com (M.Y. Ferreira).
Peer review under responsibility of the Japanese Society for Regenerative Medicine.
Contents lists available at ScienceDirect
Regenerative Therapy
journal homepage: http://www.elsevier.com/locate/reth
https://doi.org/10.1016/j.reth.2023.08.003
2352-3204/©2023, The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Regenerative Therapy 24 (2023) 332e342
3.7. Details and scientific rigor applied in the evaluation of the AEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...............................337
3.8. Details about the SVF: characterization, viability, total cells, and nomenclature used by the author . . . . . . . . . . . . . . . . . . . . . . ..............338
3.9. Studies with therapeutics with any relationship with oncological pathologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....................338
3.10. CLINIC eSTRA-SVF Guideline development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . ...............................338
3.11. Present, future, needs and encouraging highlights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . ...............................339
3.12. Study limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...............................................340
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................ 340
Financial disclosure statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................ 340
Declaration of competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........................................340
References .................................................................... .....................................................340
1. Introduction
One of the most important characteristics of adipose tissue, in
addition to its thermoregulation, impact absorption and energy
storage, is that it is a source of regenerative cells [1]. In 1893,
Neuber et al. removed fat from the forearm and used it to fill in
volume and correct irregularities in the contour of the face caused
by a scar, and reported excellent cosmetic results [2]. Two decades
later, Morrestin was the first to clinically and beneficially apply
regenerative adipose tissue cells by transferring adipose tissue
particles to the wounds of soldiers injured in World War I [3]. Since
then, fat has been increasingly investigated, and hundreds of
studies have been published. Today, the scientific medical com-
munity continues to develop, modify, refine and innovate tech-
niques for exploiting the potential of adipose tissue [4].
In 2001, Zuk et al. demonstrated in vitro that populations of cells
isolated from adipose tissue obtained by liposuction can differen-
tiate into adipocytes, chondrocytes, osteocytes and myocytes [1].
Today, it is known that in addition to this ability, adipose tissue
stem cells (ADSCs), have antiapoptotic [5], antioxidant, anti-
inflammatory and immunomodulatory properties [6].
These cells also exhibit angiogenic function, through the regu-
lation of the expression of vascular endothelial growth factor
(VEGF), hepatocytic growth factor (HGF), platelet-derived growth
factor subunit B (PDGFB) and basic fibroblast growth factor (bFGF)
genes [7] and may also aid wound healing by stimulating collagen
synthesis by fibroblasts [8].
Through the processing of fat, which can be enzymatic or me-
chanical, it is possible to obtain the stromal vascular fraction (SVF),
which is a rich source of ADSCs [9]. In addition, the SVF represents a
convenient source of ADSCs because it is easily obtained and yields
a higher proportion of stem cells than other methods of isolating
mesenchymal stem cells [9]. The field of application of ADSCs is
greater than that of bone marrow-derived stem cells (BM-MSCs) in
regenerative medicine, due to their greater availability and because
they involve an easier isolation technique than BM-MSCs [10]. In
addition, 1 g of fat contains 1000 times more stem cells than 1 g of
bone marrow, and the quality and proliferation capacity of these
cells do not decrease with age [1,12].
The SVF includes cells of the immune system, especially T helper
lymphocytes, pericytes, fibroblasts, endothelial cells and stromal
precursor cells [13,14]. The two main stem cell phenotypes present
in SVF are endothelial progenitor cells (EPCs) and ADSCs; the main
actions of SVF are pro-angiogenic, anti-apoptotic, antifibrotic,
immunomodulatory, anti-inflammatory and trophic. Some of these
actions can be attributed to the presence of ADSCs (2e10%), while
others are associated with the vascular niche, and, alternatively, the
interactions between all cellular phenotypes present in SVF
together with the various growth factors [15].
The SVF is an important source of blood vessel-associated
cellular phenotypes, including pericytes (adventitial location),
endothelial progenitors (luminal location), mesenchymal pro-
genitors, supra-adventitial adipose stromal cells (vessel sheath),
and endothelial cells [16].
The SVF has been widely explored by various medical specialties
in various clinical situations. Because its use is a promising possi-
bility for clinical applications, there is a need to investigate all
clinical studies, compare them and understand the benefits of the
SVF to formulate appropriate protocols for its use. The objective of
the present study was to evaluate the quality of studies reporting
on clinical applications of SVF.
2. Methods
The present study is a systematic literature review performed in
the Medline, Lilacs, and Embase databases following the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines [17], therefore complying with the Enhancing
the Quality and Transparency Of health Research (EQUATOR) guide-
lines [18], covering studies published in the period from January 12,
2012 to January 12, 2022, in Portuguese, Spanish and/or English.
In the Medline database, the following search strategy was used:
(“stromal vascular fraction”[MeSH Terms]) AND (“clinical applica-
tion”OR “wound healing”[MeSH Terms] OR burn OR “face rejuve-
nation”OR cicatrix [MeSH Terms] OR therapeutics [MeSH Terms] OR
“cardiovascular diseases”[MeSH Terms] OR “musculoskeletal dis-
eases”[MeSH Terms] OR “respiratory tract diseases”[MeSH Terms]
OR “female urogenital diseases”[MeSH Terms] OR “male urogenital
diseases”[MeSH Terms] OR “Eye Diseases”[MeSH Terms] OR
“regenerative medicine”[MeSH Terms] OR “autoimmune diseases”
[MeSH Terms] OR “neurodegenerative diseases”[MeSH Terms] OR
“pressure ulcer”[MeSH Terms] OR “plantar fat pad atrophy”).
The following was used in the Embase database: ‘stromal
vascular fraction’and ‘clinical application’. And the following was
used in the Lilacs database: “stromal vascular fraction”.
Studies were included if they were clinical trials, prospective
and retrospective cohorts, case series and case reports, only in
humans and that used enzymatically extracted stromal vascular
fraction. We excluded experimental studies, secondary studies,
studies that did not use freshly isolated SVF, studies that were
retracted for ethical reasons, studies that used SVF extracted by
ultrasound or mechanical cavitation, and studies that did not
describe the method of SVF processing.
After reading the title and abstract, all retrieved articles were
tabulated and included in a database. The selection and reading
process of the articles were performed by two of the authors (MYF
and JC). All articles selected by the two authors were definitively
included in the systematic review. The articles selected by only one
of the authors were analyzed by the senior author (LMF) and
included only when there was agreement among the threeauthors.
The full text was obtained for the full evaluation and final inclusion
of the articles.
M.Y. Ferreira, J.C. Carvalho Junior and L.M. Ferreira Regenerative Therapy 24 (2023) 332e342
333
The level of evidence of the studies was classified by the authors
according to the levels determined by the Grading Recommenda-
tions, Assessment, Development and Evaluations (GRADE) System
[19]. The studies were evaluated regarding adherence to the
EQUATOR Network Guidelines [18]; specifically, each type of study
design was evaluated according to the appropriate guidelines:
randomized clinical trials eCONSORT [20]; clinical trials e
Guidelines for reporting non-randomised studies [21]; case studies
series ePROCESS [22]; case reports eCARE [23], and observational
studies eSTROBE [24].
The studies were evaluated in relation to the methodology for
evaluating the manifestations and monitoring of adverse events
(AEs), following the recommendations of the study “Reporting
Adverse Events in Plastic Surgery: A Systematic Review of Ran-
domized Controlled Trials”[25].
The preparation of the CLINIC eSTRA-SVF eStrengthening
Reporting in Therapeutic Applications of the Stromal Vascular
Fraction Guideline was performed following the AGREE [26]
recommendations, in addition to “How to develop a reporting
guideline”[27] of the EQUATOR Network [18], and was guided by
the results obtained in the evaluation of the studies included in this
review. Before starting the preparation of the Guideline, a search on
the Equator Network [18] platform was performed to verify the
existence of published or under development reporting guidelines
applied to publications of clinical studies involving the stromal
vascular fraction, through December 2022.
The data contained in the included articles were independently
extracted by the researchers and evaluated together to obtain
consensus on the information therein.
3. Results and discussion
In total, 538 articles were initially identified. Of these, 77 articles
were selected after reading the titles and abstracts and removing
duplicates. Then, 15 studies were removed because they met the
exclusion criteria, leaving 62 studies [28e89]. (Fig. 1) After reading
Fig. 1. Prisma flow diagram.
M.Y. Ferreira, J.C. Carvalho Junior and L.M. Ferreira Regenerative Therapy 24 (2023) 332e342
334
and completely analyzing these articles, all of them were included
in the present review.
3.1. Therapeutic applications
A total of 41 different therapeutic applications were found in the
selected studies, as shown in Table 1. The most prevalent thera-
peutic applications in the studies were osteoarthritis of the knee
(n ¼9; 14.5%) and volume restoration in breast reconstruction
(n ¼6; 9.7%). The identified studies showed that several specialties
have a promising future in the use of SVF, especially in relation to
pathologies in which the available treatments do not offer a cure.
The therapeutic objectives ranged from the use of SVF for cosmetic/
aesthetic purposes such as facial rejuvenation, which enhances
aesthetic results in procedures involving fat grafting, to therapeutic
procedures in osteoarticular, neurological, cardiovascular diseases
and vocal cord injuries, infertility, neuromas, post-trauma and
poststroke sequelae, autoimmune diseases (e.g., systemic sclerosis
and ankylosing spondylitis), neurodegenerative diseases (e.g., Par-
kinson's and Alzheimer's), chronic and refractory fistulas and ul-
cers, erectile dysfunction, etc. (Table 1)
3.2. Prevalence of studies that reported clinical benefits
The data extracted from the studies included in this review are
encouraging regarding the use of SVF. Most studies reported sta-
tistically significant clinical benefits in the results (n ¼56; 90.3%); 3
studies were designed to evaluate safety only [63,82,89], and the
remaining 3 studies reported that the use of SVF did not offer
benefits in improving pain in 5 cases of painful neuromas [59]or
volume retention in breast reconstruction [53,77], although in the
latter application, another study reported the efficacy [81] and
another demonstrated the safety of SVFs [82]. (Table 2).
Although the mechanism of action of the SVF, in its various
clinical applications and methods of application, is not yet fully
understood, these studies demonstrate the therapeutic potential of
the SVF.
3.3. Summary study details
The year of publication of the studies, the country where the
study was conducted and the journal in which the article was
published are shown in Table 3. The years with the highest number
of published articles were 2020 (n ¼13; 21%) and 2016 (n ¼10;
16.1%), the countries with the highest number of published articles
were South Korea (n ¼12; 19.9%) and the USA (n ¼11; 16.6%), and
the journals with the largest number of published articles were
Stem Cell Res Ther (n ¼6; 9.6%) and Aesthet Surg J (n ¼5; 8%).
3.4. Route of administration of the SVF
The most prevalent routes of administration in the included
studies were subcutaneous (n ¼16; 25.8%) and intra-articular
(n ¼15; 24.2%). Two intravenous applications were performed
and demonstrated safety, with no reports of adverse effects [54,62].
Innovative forms of SVF application have been described, such as
intramyocardial, intraventricular (brain), suburethral, intravocal
folds, intracavernous, intratumoral, intrauterine and enriching
dermis grafts (Table 4).
In this review, the therapeutic applications of the SVF were used
alone and in combination (e.g., SVF þPRP - Platelet-Rich Plasma -,
SVF þL-PRP - leukocyte- and platelet-rich plasma -), SVF þFat
Graft, SVF þACAM2000); the routes were intravenous in a total of
26 patients, intraperitoneal in 4 patients, intratumoral in 17 pa-
tients, intracavernous in 17 patients, intramyocardial in 28 patients,
intrauterine in 6 patients, and intracerebral in 31 patients (with a
total of 113 applications were performed); among all of these, no
serious adverse effects were reported during the follow-up. One
patient received intravenous application of a thawed SVF after
cryopreservation, and with a 3-year follow-up, the study reported
an absence of AEs. One patient received a combination of SVF þPRP
that was frozen for 10 days for treatment of a refractory foot ulcer
that remained unhealed for 2 years, and the study reported treat-
ment efficacy and the absence of AEs.
Table 1
Therapeutic applications.
No. (%)
Therapeutic objective
Osteoarthritis of the knee 9 (14,5%)
Volume restauration in breast reconstruction 6 (9,7%)
Perianal fistulas of Crohn's disease 3 (4,8%)
Systemic sclerosis 3 (4,8%)
Androgenetic Alopecia 2 (3,2%)
Atrophic acne scars 2 (3,2%)
Diabetic ulcer 2 (3,2%)
Peripheral vascular disease 2 (3,2%)
Alopecia areata 1 (1,6%)
Asherman's Syndr 1 (1,6%)
Avascular necrosis femoral head 1 (1,6%)
Bone regeneration 1 (1,6%)
Breast aumengtation 1 (1,6%)
Chondromalacia patellae 1 (1,6%)
Chronic fatigue and depression in Ankilosing Spondylitis 1 (1,6%)
Contracted nose erev. rhinoplast 1 (1,6%)
Contracted scars 1 (1,6%)
Cosmetic and Recons approachs 1 (1,6%)
Cryptoglandular Fistulae-in-Ano 1 (1,6%)
Degenerative disc disease 1 (1,6%)
Erectile Disfunction 1 (1,6%)
Infraorbital Skin Rejuvenation 1 (1,6%)
Ischemic cardiopathy 1 (1,6%)
Lymphedema 1 (1,6%)
Neurodegenerative Disorders 1 (1,6%)
Nose after BCC excision 1 (1,6%)
Osteonecrosis of the jaw 1 (1,6%)
Orthopedic pathologies 1 (1,6%)
Painful neuroma 1 (1,6%)
Parkinson's disease 1 (1,6%)
Photoaging 1 (1,6%)
Posterior lumbar interbody fusion 1 (1,6%)
Rejuvenation 1 (1,6%)
Salvage of Ischemic Fasciocutaneous flap 1 (1,6%)
Scarred Vocal Folds 1 (1,6%)
Solid neoplasies 1 (1,6%)
Stroke rehabilitation 1 (1,6%)
Treatment of amputed site 1 (1,6%)
Treatment of ulcus cruris of venous/mixed venous arterial 1 (1,6%)
Urinary incontinence 1 (1,6%)
X ray injury 1 (1,6%)
Table 2
Authors reported benefits?
No. (%)
Yes 56 (90,3%)
No 3 (4,8%)
Only safety 3 (4,8%)
M.Y. Ferreira, J.C. Carvalho Junior and L.M. Ferreira Regenerative Therapy 24 (2023) 332e342
335
In all these applications, the safety of the applications was re-
ported, although at different levels of evidence, providing more
confidence for the scientific community to establish new trials that
demand such applications.
3.5. Design, methodological rigor and level of evidence of the
studies
Only 6 (9.7%) of the studies were randomized clinical trials, and
26 (41.4%) were nonrandomized clinical trials, demonstrating that
approximately 50% of the studies included in this review were case
series, case reports, and cohorts (Table 5). These data demonstrate
the low quality of the available evidence because without robust
and randomized studies, the evidence obtained will always be
limited or have a low level of confidence. This low level of confi-
dence was also the result obtained in the application of the Grade
System [20] classification on the included studies, which resulted in
56 (90.3%) articles with a low level of evidence and 6 (9.68%) arti-
cles with a high level of evidence.
The EQUATOR Network [16] is an initiative recognized and
endorsed by scientific medical journals worldwide. The platform
provides guidelines, materials and tools that offer solutions
necessary for studies to be prepared and published with the
maximum scientific rigor possible by the medical community and
an extensive list of guidelines that can be used in each design and/
or study area. The group is defined as “an ‘umbrella’organization
that brings together researchers, medical journal editors, peer re-
viewers, developers of reporting guidelines, research funding
bodies and other collaborators with mutual interest in improving
the quality of research publications and of research itself”[18]. The
data extracted from the studies regarding adherence to the
Table 3
Summary details of the 62 studies.
No. (%)
Year of publication
2022 6 (9,6%)
2021 5 (8%)
2020 13 (21%)
2019 5 (8%)
2018 9 (14,5%)
2017 6 (9,6%)
2016 10 (16,1%)
2015 5 (8%)
2014 1 (1,6%)
2013 1 (1,6%)
Country
South Korea 12 (19,3%)
USA 11 (17,7%)
France 7 (11,3%)
China 5 (8%)
Nicaragua 4 (6,4%)
Belgium 2 (3,2%)
Brazil 2 (3,2%)
Denmark 2 (3,2%)
Germany 2 (3,2%)
Iran 2 (3,2%)
Australia 1 (1,6%)
Greece 1 (1,6%)
Italy 1 (1,6%)
Japan 1 (1,6%)
Lebanon 1 (1,6%)
Pakistan 1 (1,6%)
Poland 1 (1,6%)
Spain 1 (1,6%)
Switzerland 1 (1,6%)
Taiwan 1 (1,6%)
The Neterlands 1 (1,6%)
Thailand 1 (1,6%)
Vietnam 1 (1,6%)
Journal
Stem Cell Res Ther 6 (9,6%)
Aesthet Surg J 5 (8%)
J Cosmet Dermatol 3 (4,8%)
J Transl Med 3 (4,8%)
Stem Cells Transl Med 3 (4,8%)
Aesth Plast Surg 2 (3,2%)
Ann Plast Surg 2 (3,2%)
BMC Musculoskelet Disord 2 (3,2%)
Cells 2 (3,2%)
Plast Reconstr Surg 2 (3,2%)
Stem Cell Res 2 (3,2%)
Surg Innov 1 (1,6%)
Adv Clin Exp Med 1 (1,6%)
Am J Sports Med 1 (1,6%)
Ann Rheum Dis 1 (1,6%)
Biomed Res Int 1 (1,6%)
Curr Res Transl Med 1 (1,6%)
EBioMedicine 1 (1,6%)
Eur J Obstet Gynecol Reprod Biol 1 (1,6%)
Eur Rev Med Pharmacol Sci 1 (1,6%)
Gastroenterology 1 (1,6%)
Health Phys 1 (1,6%)
Int J Low Extrem Wounds 1 (1,6%)
Int Orthop 1 (1,6%)
J Clin Neurosci 1 (1,6%)
J Eur Acad Dermatol Venereol 1 (1,6%)
J Int Med Res 1 (1,6%)
J Med Case Rep 1 (1,6%)
J Orthop Surg Res 1 (1,6%)
J Plast Reconstr Aesthet Surg 1 (1,6%)
J Stomatol Oral Maxillofac Surg 1 (1,6%)
JAMA Otolaryngo Head Neck Sur 1 (1,6%)
Medicine (Baltimore) 1 (1,6%)
Microsurgery 1 (1,6%)
Mol Biol Rep 1 (1,6%)
PLoS One 1 (1,6%)
Table 3 (continued )
No. (%)
Regen Med 1 (1,6%)
Reprod Sci 1 (1,6%)
Rheumatology (Oxford) 1 (1,6%)
Stem Cells Int 1 (1,6%)
Surg Cosmet Dermatol 1 (1,6%)
Table 4
Route of administration.
No. (%)
Subcutaneous 16 (25,8%)
Intra-articular 15 (24,2%)
Intradermic 7 (11,3%)
Injected in the wound 5 (8%)
Peri/intra-fistular 4 (6,45%)
Between muscles 2 (3,2%)
Engineered dermis graft 1 (1,6%)
Into the corpo cavernosum 1 (1,6%)
Intradiscal 1 (1,6%)
Intralesional (contracted nose) 1 (1,6%)
Intramiocardic 1 (1,6%)
Intramuscular 1 (1,6%)
Intrauterine 1 (1,6%)
Intravenous 1 (1,6%)
Intravenous and/or intra-tumoral and/or intra-peritoneal 1 (1,6%)
Intraventricular (brain) 1 (1,6%)
Intra-vocal folds 1 (1,6%)
Peri-fascial and peri-chondral 1 (1,6%)
Suburethral 1 (1,6%)
M.Y. Ferreira, J.C. Carvalho Junior and L.M. Ferreira Regenerative Therapy 24 (2023) 332e342
336
EQUATOR guidelines and the guidelines suggested by the group
show that almost none of the studies related to therapeutic appli-
cations adhered to these guidelines; only 3 of the 62 studies
adhered to them, resulting in a 95.2% nonadherence rate. The three
studies that adhered to the study used the CONSORT (n ¼1; Mattei
et al. [45]) and STROBE (n ¼2; Moon KC et al. [50] and Lee JW et al.
[58]) recommendations.
The results of the GRADE classification and the adherence of the
studies to the EQUATOR guidelines demonstrate that the studies
related to the clinical applications of SVF are of low quality.
3.6. Follow-up
The follow-up time, the description of the presence or absence
of AEs, and the methodology used to assess the presence of AEs are
determining factors in the publication of the safety of the new
therapies studied. Regarding the follow-up, most studies involved a
period between 12 and 36 months (n ¼40; 64.5%), and the mean
was 18.6 months (Table 6). The studies were accessed to extract
data related to the methodology for evaluating the AEs according to
previously published guidelines [25]. Among the 62 studies, 59
(95.16%) did not use a validated method to access and classify the
AEs of the established therapies, and 55 (88.8%) did not define in
advance which AEs would be evaluated during the follow-up.
Furthermore, none of the 62 (100%) reported who the researcher
or collaborator responsible for documenting the AEs was, and a
total of 17 (27.4%) did not mention the presence or absence of AEs,
which should be considered a fundamental error in studies that
seek to describe clinical applications of new therapies (Table 7).
Of the 62 studies in this review, only 20 (32.26%) reported the
presence of AEs, among which 17 studies declared that the AEs
were somehow directly related to the type of intervention per-
formed, such as surgical site infection, knee inflammation after
intra-articular application, and pain resulting from liposuction. No
serious adverse events, such as death, thromboembolic events,
neoplastic transformations or hypersensitivity reactions that could
generate a risk of death and/or hemodynamic instability or
neurological changes related to the SVF were reported.
3.7. Details and scientific rigor applied in the evaluation of the AEs
Of the 62 studies, 59 (95.16%) did not use a validated method to
assess the AEs of the established therapies, 55 (88.8%) did not
define in advance which AEs would be evaluated during the follow-
up, 62 (100%) did not report who the researcher or collaborator
responsible for documenting the AEs was, 42 (67.74%) reported that
there were no AEs and 20 (32.26%) reported AEs. Of the 20 authors
who reported AEs, 17 (85% of the reported AEs) reported that the
effects were related to the instituted procedure and not directly
related to the SVF, and 3 (4.8% of all studies) reported that the AEs
were directly related to the SVF. None of the authors reported
neoplastic transformation during the follow-up of the studies, as
shown in Table 7.
Among the studies, a total of 17 (27.4%) did not mention the
presence or absence of AEs. The studies that used methods to
evaluate AEs used the following guidelines/methods: MOSES [93],
MedDRA [94] and the Common Terminology Criteria for Adverse
Events (CTCAE) [95].
The lack of validated methodologies and the lack of publication
of the methodology and the people involved in the evaluation of
the AEs hinder the reproducibility of the studies, which may make
the published evidence of safety questionable and incapable of
demonstrating its reliability per se using the published methods.
As important as it is to describe the adverse events, it is also
necessary that the authors adopt a method of identification, follow-
up, classification and publication of these events and that they
make this clear in the publication, ensuring that, from the study
Table 5
Methodological details of the studies.
No. (%)
Design of the study
Randomized clinical trial 6 (9,7%)
Non-randomized clinical trial 26 (41,4%)
Case series 9 (14,5%)
Case report 10 (16,1%)
Case-Control 1 (1,6%)
Retrospective Cohort 3 (4,8%)
Prospective Cohort 7 (11,3%)
EQUATOR network recommen-dations
Yes 3 (4,8%)
No 59 (95,2%)
GRADE classification
Low 56 (90,3%)
High 6 (9,68%)
Adoppted EQUATOR recommedend guideline
None 59 (95,2%)
CONSORT 1 (1,6%)
Nonrandomized guideline 0 (0%)
PROCESS 0 (0%)
CARE 0 (0%)
STROBE 2 (1,6%)
Other guidelines adopted
GPP eGuidelines 2022 [90] 1 (1,6%)
AIOM - follow-up guidelines [91] 1 (1,6%)
ICH-GCP [92] 2 (1,6%)
Tabela 6
Follow-up.
No. (%)
<1 months 1 (1,6%)
1e5 months 4 (%)
6e11 months 14 (%)
12e23 months 25 (%)
24e36 months 15 (%)
More than 37 months 3 (%)
Table 7
Details about adverse events (AEs).
No. (%)
A validated method to access AE was used?
No 59 (95,16%)
Yes 3 (4,8%)
Anticipated AE clearly defined
No 55 (88,7%)
Yes 7 (11,3%)
Was it clear who would be documenting any AE?
No 62 (100%)
Yes 0 (%)
Ocurrence of AE reported?
No 42 (67,74%)
Yes 20 (32,26%)
Authors declared that AE reported was common
and no serious AE of the type of the
proccedure and/or not related direct to SVF
17 (85% of 20)
Statement saying there where or no AE?
No 17 (27,4%)
Yes 45 (72,6%)
Total number of AE that authors declared that
there was a proba-ble relationship with SVF
3 (4,8%)
Neoplasy transformation reported 0 (0%)
Method for access AE 3 (4,8%)
CTCAE 1
MOSES 1
MedDRA 1
M.Y. Ferreira, J.C. Carvalho Junior and L.M. Ferreira Regenerative Therapy 24 (2023) 332e342
337
protocol, the AEs are accessed according to previously published
guidelines and following validated methods [25].
3.8. Details about the SVF: characterization, viability, total cells, and
nomenclature used by the author
Of the 62 studies, 28 (45.16%) did not report the total nucleated
cells in the SVF, 36 (58%) did not report the cell markers present in
the SVF used, and 32 (51.61%) did not describe the viability of the
SVF cells (Table 8). There are numerous variables that influence the
viability and quantity of cells present in the SVF, and to compare
doses, therapeutic effects, and adverse effects, it is necessary to
know exactly which and how many cells were present in the SVF
used and their corresponding viabilities.
Among the studies that published the markers of the cells
present in the SVF, there was a great difference in the way they
were published and in the number of markers that were evaluated.
To allow a comparison and abetter understanding of the SVF and its
clinical applications, works that involve the SVF must evaluate and
publish the markers of the cells present in a standardized manner
as previously described [15,96,97].
More than 60% of the SVF cells is CD34
þ
, a marker present in the
cells of the vascular niche. The composition of the SVF may vary
depending on the processing protocol [98e100], and in the studies
included, numerous protocols were used. The International Feder-
ation for Adipose Therapeutics (IFATS) and the International Society
for Cellular Therapy (ISCT) have provided guidelines and recom-
mendations for the minimum basic characterization of the SVF, i.e.,
CD45
CD235a-CD31
CD34
þ
[97].
Regarding the nomenclature used by the authors to describe the
stromal vascular fraction, a total of 7 different acronyms were used:
SVF (n ¼49; 79%), ADSVF (n ¼7; 11.3%), AD-SVF (n ¼1), ADSVCs
(n ¼1), ADRCs (n ¼1), ASCs (n ¼1) and ADSCs (n ¼1) (Table 8).
This difference in the use of acronyms to refer to the stromal
vascular fraction makes standardization and better indexing of
these articles, as well as future searches in databases, impossible,
generating confusion that can and should be avoided. On January
01, 2022, the term “stromal vascular fraction”was indexed as a
medical subject heading (MeSH) term and thus should be used in
future clinical studies involving the use of SVF.
3.9. Studies with therapeutics with any relationship with
oncological pathologies
An important concern in the context of the therapeutic appli-
cations of stem cells is the carcinogenic potential and the concern
generated, especially in patients who have or had affected by
neoplasms.
In this review, six of the included studies reported 184 onco-
logical related patients who were exposed to SVF therapies
[38,50,54,57,63,81], with a mean follow-up of 30.8 months and a
range of 6e96 months. None of the studies reported neoplastic
transformations and/or an increase in the number of relapses, thus
reinforcing the safety of the use of SVF (Table 9). These studies are
fundamental for the advancement of the application of SVF in new
therapies, serving as a basis for demonstrating evidence on the
safety of the SVF to regulatory agencies such as the FDA conferring
safety for the physician and the patient who will be treated with
such therapy.
3.10. CLINIC eSTRA-SVF Guideline development
No reporting guidelines published or under development were
identified on the EQUATOR platform with regard to studies
involving the SVF.
At the conclusion of this systematic review, the CLINIC eSTRA-
SVF guideline was developed, producing a checklist with 33 items
and two tables that includes the fundamental information that
should be published in studies evaluating therapies related to SVF
(Tables 10e12).
The guideline was developed with the intention of being
applicable to the complete elaboration of a study, from the writing
of the initial project and research protocol to the execution during
the follow-up, and through the publication of the collected
information.
The present study investigated the clinical scope and the quality
of studies reporting the use of enzymatic-extracted stromal
vascular fraction in clinical application, through the level of evi-
dence of the publications, the methodologies used to perform the
research and publish the results, the quality of the information
related to the SVF, as well as the results obtained in these studies
and the safety of the use of the SVF in these applications. In an era
where regenerative medicine and cell therapies have emerged
promising therapeutic solutions for various pathologies and
regenerative applications, the worldwide medical-scientific com-
munity has begun to increasingly exploit the potential of ADSCs and
a worldwide dedication to investigating the relationship between
the fat, the stromal vascular fraction and its regenerative potential
in a wide range of preclinical and clinical studies in an expanding
Table 8
Details about SVF.
No. (%)
Was reported the total nucleated cells in SVF?
No 28 (45,16%)
Yes 34 (54,84%)
Was reported the markers of cells present in SVF?
No 36 (58,06%)
Yes 26 (41,94%)
Was reported the viability of SVF cells?
No 32 (51,61%)
Yes 30 (48,39%)
Nomenclature used for SVF
SVF 49 (79,03%)
ADSVF 7 (11,3%)
AD-SVF 1 (1,6%)
ADSVCs 1 (1,6%)
ADRCs 1 (1,6%)
ASCs 1 (1,6%)
ADSCs 2 (3,2%)
Table 9
Oncologic related studies.
No. (%)
Total patients exposed to SVF therapeutic 184
Medium follow-up 30,8 months
Range follow-up 6e96 months
Jeon HJ et al. [39]
N;¼20
Follow eup 12
Moon KC et al. [51]
N;¼77 (30 SVF group)
Follow-up 35 months/range - 1-8y
Minev BR et al. [55]
N;¼26
Follow-up 6 months
Calabrese et al. [58]
N;¼169 (41 SVF)
Follow - up At least 60 months
Mazur S et al. [64]
N;¼298 (56 SVF)
Follow-up 36 months
Tissiani LAL and Alonso N [82].
N;¼19 (11 SVF group)
Follow-up 36 months
M.Y. Ferreira, J.C. Carvalho Junior and L.M. Ferreira Regenerative Therapy 24 (2023) 332e342
338
global market [4,101e109]. This can be explained by its greater
availability and ease of extraction or its higher cell yield relative to
other forms of stem cell extraction [9e11]; thus, SVF has become
the focus of attention, discussion and investigation by both clinical
and surgical specialties. However, the literature is still recent, and
publications on clinical applications are not standardized and still
lack the necessary scientific rigor. This lack of standardization
makes reliable comparisons impossible, and thus, a systematic re-
view can aid in this regard by demonstrating the current scientific
evidence regarding the use, risks, efficacy, safety and other pecu-
liarities involved in the various possibilities of the application of the
SVF. Thus, in this panorama, the key aspects that will enable
progress in the methodological standardization of future publica-
tions on the clinical applications of SVF are emphasized.
3.11. Present, future, needs and encouraging highlights
The applications found in the articles included in this study,
their results and safety, confer legitimacy to the establishment of
new therapeutic hypotheses and deepening our understanding of
the investigations already conducted. The use of the SVF for the
benefit of patients, especially for diseases for which we currently do
not have well-established effective therapies such as neurodegen-
erative diseases (e.g., Parkinson's, Alzheimer's, Multiple Sclerosis),
autoimmune diseases (e.g., scleroderma, ankylosing spondylitis),
heart diseases involving areas of tissue necrosis, erectile dysfunc-
tion and many others, is encouraging, opening the possibility for
new studies to test new applications and further exploring the
regenerative, immunomodulatory and anti-inflammatory potential
of SVF.
New studies involving the clinical applications of the SVF should
focus on increasing the scientific rigor of investigations and pub-
lication of results, providing the necessary reproducibility, greater
transparency and level of confidence in the published evidence
[110 e112 ].
In summary, it was evident that there was a lack of standardi-
zation in publications and basic information related to SVF,
including the techniques used for collection, extraction, and
application, patient follow-up, and other factors. This lack of stan-
dardization hinders the availability of consistent information and
limits the ability to make comparisons and produce stronger sci-
entific evidence. Some studies, did not publish information such as
the age of the patients or the location of fat collection, which is
basic information for this type of study. As concluded by Kelleyet al.
[113 ], “unless the data are comparable and the original studies are
of high-quality, meta-analysis should be avoided in favor of a
comprehensive systematic review. Inappropriate pooling of data
should be avoided to preserve the quality of the research and to
Table 10
CLINIC eSTRA-SVF checklist.
Section Item Checklist Item
Study Design 1a Study conducted in accordance with EQUATOR network guidelines?
1b CONSORT (RCT), Guidelines for Reporting non-randomised studies (NRCT), STROBE (cohort, case-control or cross-sectional),
PROCESS (case series) or CARE (case report)
1c Validated method was used to access Adverse Events?
1d Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts)
Therapeutic objective 2a Clear description of the therapeutic goal
2b Clear description if it's the first study in that scope or all previous studies published
2c Clear description about the outcomes that will be evaluated
General details 3a Objective description of the method of the outcome assessment (Validated tools, assessment method proposed by the author
and the reason it was chosen)
3b Description of the age and gender of the patients
3c Exact description of the fat harvest site
3d Complete description of the fat processing method (specifying whether it was extracted manually or by an automated method.
What device was used.)
3e Detailed description of the enzyme and concentration used for enzymatic digestion
3f Description of the amount of fat harvested, amount of fat processed by the enzymatic process, amount of SVF obtained, and ratio
of SVF yield/mL of fat processed.
3g Description of the time interval between fat collection, start and end of enzymatic processing
3h Description regarding the form of SVF used: immediately after processing cryopreserved other manipulations (describe which
manipulation was done)
3i The nomenclature used was SVF - Stromal Vascular Fraction?
SVF Charac-terization 4a Description of the SVF characteristics according to Table 12
4b Description of the characterization of the cells according to the markers
4c Characterization of the cells present in SVF by the markers
Application Details 5a Description of the application method with number of applications
5b Description of the applied quantity and/or combination used
5c Description of the interval time between fat collection and application of SVF
Pos-op 6a Description of dressing used
6b Description of post-procedure care/orientations
Follow-up 7a Description of the patients follow-up time
7b Description of the interval and number of evaluations performed during the patients' follow-up
Adverse events (AEs) 8a What validated method was used to access AEs?
8b How was classified the severity of the AEs?
8c The patients were informed about the possible and probable AEs?
8d Description of the evolution of the AEs and how it was treated
Outcome Results 9a Objective description of the results
Funding 10a Sources of funding and other support (such as supply of devices or drugs, products related with SVF), role of funders
Table 11
Model for evaluation and reporting the characteristics of stromal vascular fraction.
Stromal Vascular Fraction Mean/range
Adipose Tissue Harversted (cm [3])
Volume isolated (ml)
Number of viable nucleated cells (VNC) (millions) obtained
Recovery rate (VNC/cm [3] adipose tissue)
Number of VNC injected or applied (millions)
Viability (%)
M.Y. Ferreira, J.C. Carvalho Junior and L.M. Ferreira Regenerative Therapy 24 (2023) 332e342
339
avoid unjustifiable conclusions. Adherence to the principles of the
scientific methods outlined will improve publication acceptance
rates and the overall quality of literature in the field.”This is also a
concept that should be taken into account in the acquisition of
robust scientific evidence related to the SVF.
In addition to this context, the reproducibility of the studies
must be guaranteed by the author during the project preparation
period, during the research and at the time of publication of the
results. Corroborating the findings of Ascha et al. [111], this study
demonstrates that research reproducibility is a mandatory
component of the scientific method and is necessary for ensuring
the accuracy of the scientificfindings and for cultivating trans-
parency and reproducibility in scientific research.
In this context, the authors of this review, driven by the evident
need for standardization as observed during the preparation of this
systematic review, proposed the creation of the CLINIC eSTRA-SVF
Guideline. The checklist aims to be easy to apply, and the authors
encourage researchers to prepare their research projects and pro-
tocols using the guideline for the development of a highly scien-
tifically rigorous method. At the time of publication, the authors
should seek to fill in as many items in the guideline as possible
according to the reality and possibilities of their research projects to
ensure transparency, reproducibility, standardization and progress
in the construction of evidence related to the clinical applications of
the SVF.
Randomized clinical trials and prospective cohort studies, both
highly rigorous in methodological design, in the publication of re-
sults and detailed information, and validated methodologies for
evaluating the adverse effects of the clinical applications of SVF
should be encouraged, following the CLINIC eSTRA-SVF guideline
recommendations in the reporting of these studies.
3.12. Study limitations
Although this systematic review was prepared following the
PRISMA guidelines and sought through the EQUATOR guidelines
and the GRADE system to infer the level of evidence and identify
the global state of the clinical applications of SVF, it was difficult to
compare the information due to the low level of rigor in the
methodological approaches and the lack of standardization,
reproducibility and transparency of the included studies.
4. Conclusion
There is scientific evidence of the safety and effectiveness in the
clinical application of the SVF; however, the level of evidence of
most of the studies was low, and much of the evidence was pub-
lished in articles that do not follow the reporting methods used by
the scientific community worldwide and that do not use validated
methodologies for the evaluation of adverse effects. It is necessary
to standardize the information published in the studies involving
therapies with SVF, and the CLINIC eSTRA-SVF reporting guideline
proposed in this study may assist in the design, conduct, recording
and reporting of clinical trials, case series, and case reports
involving the SVF. The use of the CLINIC eSTRA-SVF guideline will
ensure the construction of studies and the publication of evidence
that guarantee the reproducibility, comparisons and transparency
necessary for future scientifically rigorous comparisons to be per-
formed by the world scientific community and thus the construc-
tion and accumulation of better evidence for the benefit of patients.
Financial disclosure statement
The authors have nothing to disclose.
Declaration of competing interest
None.
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Table 12
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Subpopulation Marker (%)
Hematopoietic cells CD45
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Monocytes CD45þ/CD14þ/CD206-
Macrophages CD45þ/CD14þ/CD206þ
Progenitor Endothelial Cells CD45-/CD34þ/CD31þ
Pericytes CD45-/CD34-/CD146þ
Supra-adventitial stromal cells
Early mesenchymal stem cells
CD45-/CD34þ/CD31-
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