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27 Treatment by Over-the-Scope-Clip 447
of the clip’s teeth in the tissue with consecutive early clip detachment. The earlier
clip loss occurs, the more likely fistula healing fails. As seen in our analysis, clip loss
within the first 4 weeks is associated with a fistula persistence rate of 67% (Prosst
and Joos 2016). Similar to all other fistula surgery techniques, the clip shows less
favorable results in IBD-associated fistulas when compared with cryptoglandular
fistulas. This can be explained by the underlying general inflammatory condition and
poor wound healing and tissue regeneration . The clip could also be a surgical option
for rectovaginal fistula following proctectomy or pelvic radiotherapy, obstetric
trauma, and inflammatory bowel disease. However, the success rate of 43.7%, as
indicated in the relevant study, is only moderate (Tong et al. 2019). The anatomical
situation with a relativel y thin recto-vaginal septum without sufficient tissue volume
that can be compressed by the clip might limit its application in these cases.
It may be beneficial to combine two different surgical techniques and principles
like OTSC Proctology and VAAFT (Seow-E n et al. 2016). The synergetic effect of
closing the internal fistula opening by the clip and coagulation and occluding the
fistula lumen by VAAFT may lead to a better outcome. Thus, it could be assumed
that by replacing VAAFT by FiLaC, which also thermally destroys and occludes the
fistula tract, better healing rates could be expected.
Although clip surgery appears to be simple and fast, it should be restricted to
experienced rectal surgeons who are familiar with all aspects of fistula surgery. The
design of OTSC Proctology then allows an intuitive use of the device in the hands of
rectal surgeons, limiting the operative time to about half an hour. There are some
crucial steps during clip surgery: their disregard will lead to severe complications
and disappointing results (Gautier et al. 2015). If tight closure of the internal fistula
opening is not achieved and confirmed by irrigation, the clip position has immediately to be corrected. Stool or pus discharge from the fistula directly after surgery
indicates that the clip has apparently not been properly placed or that the orifice is too
large or anatomically unsuitable to be closed by clips. If sufficient external drainage
of the remaining fistula tract is not guaranteed by conical excision of the external
fistula opening, inflammatory complications, such as abscesses and systemic infections, are unavoidable. A standardized procedural conduct, adequate patient selection, and management are of major importance for successful clip use (Schurr and
Prosst 2016).
Although OTSC Proctology is currently becoming more widesprea d and hundreds of patients with anorectal fistulas have been treated with the clip so far, there
are some issues, such as preoperative bowel preparation, perioperative antibiotic
prophylaxis, or postoperative diet and nutrition, which remain unclear in their
influence on the success rate. However, these are unanswered topics in all kinds of
fistula surgery and not only in the clip technique. Although no clear recommendations exist, it is believed that any changes in digestion and stool consistency, caused
by bowel irrigation or food restrictions, may be disadvantageous in fistula healing.
In conclusion, OTSC Proctology is part of the novel armamentarium for the
treatment of complicated and complex anorectal fistulas, which is based on hightechnology devices. In the hands of experienced rectal surgeons, OTSC Proctology
is an intuitive surgical instrument which allows a sphincter-preserving minimally
448 R. L. Prosst
invasive fistula operation. The patient’s subjective burden and postoperative pain
after clip surgery is relatively low leading to a short hospitalization and recovery
time. The experiences gained with clip procedure in many international centers so far
demonstrates that it is feasible, safe, and effective and renders reproducible data. The
clip shows favorable results especially in crypt oglandular fistulas and when OTSC is
used as a first-line treatment. OTSC Proctology has proven not only to be a “salvage
technique” or “plan B” after the failure of other fistula procedures. The technique can
repeatedly be used without causing major tissue damage or hamper other surgical
interventions. There is reason to believe that the combination of the clip with other
modern surgical techniques with a different principle of fistula healing, such as
VAAFT or FiLaC, may have a beneficial synergistic effect.
Disclosure of Conflicts of Interest Ruediger L. Prosst has advised Ovesco Endoscopy AG in
regulatory affairs and product development. The author did not receive any direct payments or
gratifications.
References
Adegbola SO, Sahnan K, Pellino G et al (2017) Short-term efficacy and safety of three novel
sphincter-sparing techniques for anal fistulae: a systematic review. Tech Coloproctol 21(10):
775–782
Bartell N, Bittner K, Kaul V, Kothari TH, Kothari S (2020) Clinical efficacy of the over-the-scope
clip device: a systematic review. World J Gastroenterol 26(24):3495–3516
Dango S, Antonakis F, Schrader D, Radzikhovskiy A, Ghadimi MB, Hesterberg R (2017) Long-
term efficacy and safety of a nitinol closure clip system for anal fistula treatment. Minim
Invasive Ther Allied Technol 26(4):227–231
Emile SH, Khan SM, Adejumo A, Koroye O (2020) Ligation of intersphincteric fistula tract (LIFT)
in treatment of anal fistula: an updated systematic review, meta-analysis, and meta-regression of
the predictors of failure. Surgery 167(2):484–492
Gautier M, Godeberge P, Ganansia R et al (2015) Easy clip to treat anal fistula tracts: a word of
caution. Int J Color Dis 30(5):621–624
Grossberg SJ, Harran N, Bebington B, Lutrin DL (2020) Use of the OVESCO OTSC
clip for closure of fistula-in-ano at Wits Donald Gordon Medical Centre – a single centre
experience. S Afr J Surg 58:74–77
Marinello F, Kraft M, Ridaura N, Vallribera F, Espín E (2018) Treatment of fistula-in-ano with
Mascagni D, Pironi D, Grimaldi G et al (2019) OTSC
Meinero P, Mori L, Gasloli G (2014) Video-assisted anal fistula treatment: a new concept of treating
Mennigen R, Laukötter M, Senninger N, Rijcken E (2015) The OTSC(
Nordholm-Carstensen A, Krarup PM, Hagen K (2017) Treatment of complex fistula-in-ano with a
Prosst RL, Ehni W (2012) The OTSC
®
Proctology clip device: short-term results. Tratamiento de la fístula anal mediante clip
OTSC
con el dispositivo OTSC
sphincter reconstruction as a treatment for low trans-sphincteric anal fistula in a randomized
controlled pilot trial. Minerva Chir 74(1):1–6
anal fistulas. Dis Colon Rectum 57(3):354–359
the closure of refractory anal fistulas. Tech Coloproctol 19(4):241–246
nitinol proctology clip. Dis Colon Rectum 60(7):723–728
fistula claw’: case report. Minim Invasive Ther Allied Technol 21(4):307–312
®
: resultados a corto plazo. Cir Esp 96(6):369–374
®
Proctology clip system for anorectal fistula closure: the ‘anal
®
Proctology vs. fistulectomy and primary
®
) proctology clip system for
®
Proctology
27 Treatment by Over-the-Scope-Clip 449
Prosst RL, Joos AK (2016) Short-term outcomes of a novel endoscopic clipping device for closure
of the internal opening in 100 anorectal fistulas. Tech Coloproctol 20(11):753–758
Prosst RL, Ehni W, Joos AK (2013) The OTSC
®
Proctology clip system for anal fistula closure: first
prospective clinical data. Minim Invasive Ther Allied Technol 22(5):255–259
Prosst RL, Joos AK, Ehni W, Bussen D, Herold A (2015) Prospective pilot study of anorectal fistula
closure with the OTSC proctology. Color Dis 17(1):81–86
Schurr MO, Prosst RL (2016) Comment on: easy clip to treat anal fistula tracts: a word of caution by
M. Gautier et al. Int J Color Dis 31(3):707–708
Seow-En I, Seow-Choen F, Koh PK (2016) An experience with video-assisted anal fistula treatment
(VAAFT) with new insights into the treatment of anal fistulae. Tech Coloproctol 20(6):389–393
Tong Y, Trilling B, Sage PY, Girard E, Faucheron JL (2019) Short-term outcomes of the over-the-
scope clip proctology system for rectovaginal fistula repair: a prospective study. Tech
Coloproctol 23(3):245–249
Weiland T, Rohrer S, Schmidt A, Wedi E, Bauerfeind P, Caca K, Khashab MA, Hochberger J,
Baur F, Gottwald T, Schurr MO (2020) Efficacy of the OTSC System in the treatment of GI
bleeding and wall defects: a PMCF meta-analysis. Minim Invasive Ther Allied Technol 29(3):
121–139
Wilhelm A, Fiebig A, Krawczak M (2017) Five years of experience with the FiLaC™ laser for
fistula-in-ano management: long-term follow-up from a single institution. Tech Coloproctol
21(4):269–276
Stem Cells in Cryptoglandular Anal Fistulas
28
Gabriele Naldini
, Alessandro Sturiale, Bernardina Fabiani,
Felipe Celedon Porzio, Rebecca Aglietti, and Claudia Menconi
Contents
1 Introduction . ............... .................................................................. 452
2 History of a Novel Approach .................. ............................. ................ 453
2.1 Mesenchymal Stem Cells ................ ............................. ................ 453
2.2 Adipose Tissue: The Ideal MSCs Source ............................................. 454
2.3 Adipose Tissue Graft .................................................................. 455
3 Results .............................. ....................................................... .. 458
3.1 Literature Review . ..................................................................... 458
3.2 Personal Experience ... . ................................ ............................... 463
Ethical Approval
All procedures performed in studies involving human participants were in accordance with the
ethical standards of the institutional and/or national research committee and with the 1964 Helsinki
declaration and its later amendments or comparable ethical standards
Originality
This chapter is an original work, has not been published before, and is not being considered for
publication elsewhere in its final form, in either printed or electronic media. The authors declare that
any republication of the data (e.g., in secondary analysis or translation) will not constitute redundant
publication, will not breach copyright, and will reference the original publication.
G. Naldini · C. Menconi
Division of General, Mini-invasive and Obesity Surgery, University of Study of Campania “Luigi
Vanvitelli”, Naples, Italy
Proctology and Pelvic Floor Clinical Centre, Cisanello University Hospital, Pisa, Italy
e-mail: g.naldini@ao-pisa.toscana.it; claudia.menconi14@gmail.com
A. Sturiale (
Proctology and Pelvic Floor Clinical Centre, Cisanello University Hospital, Pisa, Italy
e-mail: bernardina@hotmail.it; aglietti.rebe@gmail.com
F. C. Porzio
Department of Coloproctological Surgery, Hospital de la Fuerza Aerea de Chile, Santiago de Chile, Chile
Proctology and Pelvic Floor Clinical Centre, Cisanello University Hospital, Pisa, Italy
e-mail: felipe.celedon.porzio@gmail.com
© Springer Nature Switzerland AG 2022
C. Ratto et al. (eds.), Anal Fistula and Abscess, Coloproctology,
https://doi.org/10.1007/978-3-030-76670-2_30
*) · B. Fabiani · R. Aglietti
451
452 G. Naldini et al.
4 Discussion and Conclusion ................................................................. 463
References ............................ ............................................... ............ 466
Abstract
Anal fistula is an abnormal communication between anus and perianal skin. Several
sphincter-saving procedures were proposed to achieve fistula healing preserving
anal sphincters, and among these, regenerative surgery is raising interest. It is
mainly based upon Mesenchymal Stem Cells (MSCs) which are multipotent
stromal cells that can differentiate into a variety of cell types, revealing as starting
point to promote tissue regeneration. Adipose tissue is the ideal source of MSCs
because it is easy to obtain with minimally invasive harvest and it contains a high
concentration of regenerative cells whose differentiation capability is independent
from the donor’s age. Only few studies were published about the use of cell-based
therapy to treat cryptoglandular complex anal fistulas, and they lack of uniformity
of the different treatments proposed which basically differ for the adipose tissueprocessing steps and association to other materials injected such as fibrin glue.
Hence, MSCs certainly represent the future of regenerative medicine and surgery.
However, future researches need to better clarify their action mechanisms trying to
propose a low-cost, easily reproducible, safe, and effective procedure.
Keywords
Mesenchymal stem cell (MSC) · Adipose tissue · Anal fistula · Regenerative
surgery
1 Introduction
Anal fistula is an abnormal communication between anus and perianal/perineal skin.
It affects more frequently men (Sainio 1984; Zanotti et al. 2007) with an overall
incidence of about 2/10,000 people per year and an estimated prevalence in Europe
of 1.69/10,000 (García-Olmo et al. 2019). Anal fistulas have characteristic clinical
manifestations such as local pain and discomfort frequently associated with purulent
drainage and impaired health-related quality of life (García-Olmo et al. 2019). They
may be a de novo disease but, in more than one-third of patients, represent the
chronic expression consequent to an acute ano-rectal abscess (Amato et al. 2020).
Anal fistula can also be categorized as simple or complex even if the treatment of
simple fistulas is not simple and free of bothersome consequences. Simple fistulas
are intersphincteric or low transphincteric involving less than 30% of anal sphincter.
On the other hand, complex fistula includes high transphincteric or suprasphincteric
fistula, anterior track in female patients, or whatever Parks’ type (Parks et al. 1976)
with one of the following conditions: inflammatory bowel disease, malignancy,
incontinence, chronic diarrhea, or previous irradiation (Sandborn et al. 2003).
In most patients, anal fistulas may be successfully treated with surgery, especially
those classified as simple to be lay open with a success rate around 98% (Atkin et al.
2011). For those, instead, classified as complex, the surgical treatment is still a
28 Stem Cells in Cryptoglandular Anal Fistulas 453
challenging procedure as no single technique is appropriate in every case, with a
fairly high recurrence rate and frequent side effects (Garcia-Aguilar et al. 2000;
Narang et al. 2017). There are a lot of so-called sphincter-saving procedures,
proposed to achieve fistula healing preserving anal sphincters integrity and function,
and among these, regenerative surgery is raising interest.
One of the first studies about the use of adipose-derived Mesenchymal Stem Cells
(MSCs) to treat perianal fistula was published in 2003 from the group of
Garcia-Olmo (García-Olmo et al. 2003). They supposed to take advantages from the
anti-inflammatory and immunomodulatory properties of MSCs promoting the healing
process. The vast majority of studies were focused on complex anal fistula in patients
affected by Crohn’s Disease (CD) (Cheng et al. 2019; Kotze et al. 2019; Laureti et al.
2020;Zhouetal.2020); however, the experience obtained in this field was shifted to
the cryptoglandular fistula treatment (Garcia-Arranz et al. 2020; Naldini et al. 2018).
2 History of a Novel Approach
2.1 Mesenchymal Stem Cells
MSCs is a term firstly coined by Caplan in 1991 (Caplan 1991), and their concept
has the basis in those experiments that demonstrated as Bone Marrow (BM) transplantation into different sites induces a de novo ectopic bone and marrow. Although
similar studies were already reported back in the nineteenth century (Goujon 1869),
the paper which stated the real osteogenic capacity of BM was published in 1968
(Tavassoli and Crosby 1968). Later on, it was demonstrated that the osteogenic
potential was related only to a minor cells subpopulation inside the BM which have a
fibroblast-like appearance (Friedenstein et al. 1870, 1974, 1987).
In addition, in vivo transplantation of MSCs revealed that a single BM cellular
lineage may generate multiple skeletal tissues such as bone, cartilage, adipose tissue
(Bianco 2009), and also others, thus opening the doors to new perspectives.
In fact, at the beginning of MSCs studies, b ack in the 1990s, it was shown that
a lawn of MSCs provided molecular cues to transform progenitors into various
blood cells (Majumdar et al. 1998). This was the basis for the first-in-man use of
MSCs culture following ablative chemotherapy and a BM transplantation (Lazarus et al. 1997).
Nowadays, stem cells may be subdivided into two different types, embryonic and
nonembryonic. The first type comes from the inner cell mass of the blastocyst, and
they may differentiate into all the three germ layers cells. On the contrary, the
nonembryonic stem cells, which are essentially those present in the adults, have
limited differentiation potential (Zhao 2013).
The assumption that MSCs come from connective tissue (stroma) of marrow or of
other tissues is actually wrong. In fact, they were recently identified in vivo deriving
from perivascular cells (Crisan et al. 2008). Therefore, when a blood vessel is
injured, the pericyte detaches from the small blood vessel and starts to differentiate
into an MSC which should be considered, as proposed by Caplan, “Medicinal
Signaling Cell.” They receive signals from the microenvironment of the injured
454 G. Naldini et al.
tissue and respond by producing and secreting a broad spectrum of bioactive
molecules whose role is, on the one hand, to be a barrier against the overaggressive
immune cells and, on the other, to secrete trophic factors thus inhibiting scar
formation and stimulating angiogenesis (Caplan 2017; Caplan and Dennis 2006;
da Silva Meirelles et al. 2008).
Hence, MSCs are multipotent stromal cells that can differentiate into a variety of
cell types, including mature adipocytes as well as chondrocytes, osteoblasts,
myocytes, hepatocytes, neuronal-like, and endothelial cells (Zuk et al. 2001,
2002), revealing as starting point to promote tissue regeneration.
2.2 Adipose Tissue: The Ideal MSCs Source
Human adipose tissue is composed by structural units named lobules. Each lobule is
constituted by two components of extracellular matrix such as septa and stroma, thus
defining the adipose niches (Estève et al. 2019). The adipose niche is a native
microenvironment containing adipocytes and other cells embedded in a collagen
scaffold with a vascular network.
Adipose tissue as well as BM, dental pulp, menstrual blood, and umbilical cord
matrix (Wharton jelly) is a source of MSCs progenitors, but differently from the
others, it represents an ideal source due to the following evidences. It is easy to obtain
with minimally invasive harvest, and it contains a high concentration of regenerative
cells whose differentiation capability is independent from the donor’s age. Indeed,
from 1 g of adipose tissue 5000 stem cells can be isolated, which is 500 times more
than from an equivalent amount of BM (Hass et al. 2011; Strem et al. 2005;Von
Heimburg et al. 2004). It has also a very low risk associated with autologous therapies.
Moreover, BM harvesting is a more invasive and traumatic procedure if compared with the common lipo-aspiration, and it is associated with a higher risk of
infection. At least, the viability and differentiation capacity of BM-derived MSCs is
inversely related to the age of donor (Stolzing et al. 2008).
Adipose-derived MSCs are historically obtained through a long enzymatic process inducing ex vivo expansion, with relevant senescence and a multipotency
decline of the cellular lineage (Bianchi et al. 2013). The processing steps are timespending with careful laboratory manipulation (Ren et al. 2016; Vangsness et al.
2015). Besides, this procedure must comply with strict regulatory issues minimizing
the advantages achieved by cell expansion itself.
For these reasons, the next step of biotechnological improvement was to ameliorate, trying to maximize, the therapeutic effects of the traditional fat transfer as
described by Coleman (Coleman 2006). Laboratory tissue engineering in vitro aims
to create final products containing a defined and optimal amount of MSCs through
the expansion of the Stromal Vascular Fraction (SVF) that is the precursor of MSCs
and the adult multipotent cells.
At present, however, the current challenge is to get a final product ready to be
injected which contains an effective amount of MSCs progenitors thus avoiding the
two-step procedure which uses a long enzy matic manipulation and has higher costs.
28 Stem Cells in Cryptoglandular Anal Fistulas 455
2.3 Adipose Tissue Graft
New processing devices were developed to obtain ready-to-use, minimally manipulated autologous MSCs products. Among these, there are the Puregraft
Solana Beach, CA) (Mestak et al. 2014), Tulip
Diego, CA) (Alexander 2011), and Lipogems
®
(Tulip Medical Products, San
®
(Lipogems International SpA,
®
(Puregraft,
Milan, Italy) systems (Bianchi et al. 2013).
These systems overcome the limits for the compliance with “cell manufacturing”
in accordance with current GMP Guidelines because the restrictions are not applied
in case of minimal manipulation (“Regulation (EC) No. 1394/2007 of the European
Parliament and of the Council,” n.d.). In this way, there is a simple and easily
accessible chance for clinical application.
2.3.1 Lipogems
Lipogems®system (PCT/IB2011/052204), shown in Fig. 1, is a device that allows to
harvest, process, and reinject human (or animal) lipoaspirates as a final product
which is a nonexpanded adipose tissue containing MSCs. This technology is based
on a gentle mechanical tissue size reduction (microfragmentation) in a closed
system, without any enzyme use. The progressive adipose cluster (adipose niche)
Fig. 1 Lipogems1 kit
456 G. Naldini et al.
size reduction starts from spheroidal clusters with a diameter of 1–3.5 mm to clusters
of 0.2–0.8 mm at the end of the procedure. The whole process happens in a full
immersion system reducing a real traumatic effect of the metallic spheres on the
harvested adipose tissue.
The surgical steps of tissue preparation are already published (Naldini et al. 2018)
and may be resumed as follows (Figs. 2 and 3):
Fig. 2 ( a) Skin Incision along the anterior axillary line 2 cm above the iliac crest. (b)Infiltration of
the subcutaneous tissue with modified Klein solution. (c and d) Liposuction is performed through a
cannula (13G) connected to vaclock syringe from both sides of subcutaneous adipose tissue o the
anterior abdominal wall. (e) Transfer the aspirated tissue in 10 cc syringes and put them flipped with
piston upwards. This position allows the stratification of the fluids and tissue. (f) Remove from the
syringe the fluid part of aspiration before use it
28 Stem Cells in Cryptoglandular Anal Fistulas 457
Fig. 3 (a) Connect the hose of blue filter to the bag of saline solution. Rotate the cylinder with the
grey filter upwards. Open both hoses. Fill the cylinder with the saline solution holding it vertically.
Once completely full, close both hoses. (b) Replace the cylinder with the blue filter upwards. Close
the blue filter hose and open the grey one. Connect the syringe with the adipose tissue aspirated to
the blue filter pushing it inside the processing cylinder. (c) Open both hoses to allow a continuous
flow of saline solution and the elimination of oily and bloody residual. Shake the cylinder until the
saline solution inside it becomes clear and then close both hoses. The action of the steels spheres
emulsifies and microfractures the adipose tissue. (d) Connect two luerlock syringes to the both
filters to remove lipogems product. Flip the processing cylinder with the grey filter at the top. Open
the blue filter hose and draw a full syringe of saline solution, then close the hose. (e) Hold the
cylinder vertically with the grey filter upwards. Push the saline solution from the syringe connected
to the blue filter inside the cylinder. The final product will flow through the grey filter into the
syringe connected to it. (f) The product was transferred in several1-cc syringes with 22G needle to
be injected in the patients. (g) Debridement of fistula tract. (h) Closure of internal opening through
2/0 PDS stitches for the muscular layer. (i) Injection of the final Lipogems
syringes around internal opening. (l) Mucosal flap closed with 2/0 Vicryl stiches. (m and n)
Injection of the final Lipogems
®
product through 1 cc syringes around the mucosal flap and the
®
product through 1 cc
fistula tract
• Harvesting subcutaneous adipose tissue from both sides of anterior
abdominal wall.
• Transfer the harvested adipose tissue into the dedicated device.