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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5554_Библиотеки_им_академика_М_И_Перельмана.pdf
35© Shanghai Scientic and Technical Publishers 2026
L. Li et al. (eds.), Endoscopic Therapy for Gastroesophageal Reux Disease,
https://doi.org/10.1007/978-981-95-5389-1_3
Chapter 3
Endoscopic Injection Therapy forGERD
LeiLiu
3.1 Background
The main causes of gastroesophageal reux disease (GERD) are anatomical defects
and neuromotor disorders. The functional dyskinesia by the inappropriately tran-
sient lower esophageal sphincter relaxation (TLESR) accounts for almost 90% of
the outcomes on the reux episode [1, 2].
Based on the main pathophysiology of GERD, it is a great signicance to restore
or re-establish the anti-reux anatomical barrier through surgical or endoscopic
intervention in the treatment of GERD, especially refractory GERD [3]. With the
development of endoscopic devices and technologies, endoscopic treatments have
attracted more and more attention, and could be primitively divided into injection
therapy and non-injection therapy, the latter mainly including radiofrequency treat-
ment and endoscopic plication or suturing [3–5].
Injection therapy has developed for more than 30years since rst reported in
1984. Compared with non-injection therapy, it seems convenient and practicable [6,
7]. As a relatively simple anti-reux method, endoscopic injection procedure for
gastroesophageal reux refers to the technique of injecting or implanting inert
materials near the gastroesophageal junction to enhance the tension of the lower
esophageal sphincter and establish an anatomical barrier to reduce reux [3].
L. Liu (*)
Department of Gastroenterology, The Ninth Medical Center of Chinese
PLA General Hospital, Beijing, China
36
According to comprehensive literature reports [8–11], patients with GERD who
meet the following criteria could experience endoscopic injection therapy:
1. Typical symptoms of GERD (heartburn with or without reux, some scholars
emphasize the rest LES pressure <10mmHg, pH examination, etc.).
2. Over 18years of age.
3. In the presence of erosive esophagitis, the severity should be lower than Los
Angeles Classication Grade C.
4. PPI treatment dependence (heartburn or reux recurs after drug withdrawal,
abnormal pH value of the esophagus), poor response to medication, or high risk
of surgery.
5. Body mass index (BMI) is less than 35kg/m
2
.
6. Hiatal hernia is less than 3cm.
7. No esophageal varices or bleeding.
8. No Barrett’s esophagus, esophageal cancer, and gastric cancer.
9. No dysphagia.
10. No serious autoimmune disease, connective tissue disease, infection, coagula-
tion disorders, and long-term use of anticoagulant drugs.
11. No prior radiotherapy, endoscopic or surgical treatment of GERD.
12. Female patients should not be pregnant or lactating.
13. No allergic reaction to the materials for injection.
The features of an optimal injection or implant were proposed below [7]:
1. Low viscosity
2. Bio inertia
3. No carcinogenicity, allergenicity, and immunogenicity
4. Low side effects
5. Non-biodegradable
6. High persistence at the site of implantation
7. Low economic cost
8. Resistant to mechanical strain
9. Asepsis
10. Benign exibility and plasticity
11. No adverse effect on adjacent muscle tissue
Now, the primary injected ingredient that has been tested in animals or human
beings includes bovine dermal collagen, polytef, sclerosing agents, and Enteryx.
Despite there are a variety of substances used for injection, but most of injected
methods seem to be analogous. The therapeutic substance was implanted into the
submucosa near the esophagogastric squamo-columnar junction (Z-line) using a
needle catheter through an endoscopic biopsy channel. The GEJ quadrant or loca-
tion, the dosage, and times of injection are not always constant, depending on the
patient’s condition. In general, visible mucosal swelling under the endoscope is
required to terminate the injection procedure (Figs.3.1 and 3.2).
L. Liu
37
Fig. 3.1 Injection diagram
ab
Fig. 3.2 (a) GEJ image before injection. (b) GEJ image after injection
Endoscopic injection therapy for GERD is feasible theoretically, and it has
achieved certain results in animal experiments and a few patients. However, limited
to implanted materials and methods, several clinical studies have demonstrated that
its overall efcacy and safety appear to discontent; therefore, clinical application is
not recommended at this time [12, 13]. Currently, injected or implanted substances
could be divided into three categories:
Class I: Attempts have been made in both animals and human beings, but clinical
studies have shown that the treatment is ineffective or unsuitable for clinical
application exactly.
Class II: There are only animal experiments, no evidence of clinical efcacy.
Class III: Injection or implant has shown some effect in animal and clinical studies
but needed more research.
3 Endoscopic Injection Therapy forGERD
38
3.2 Not Suitable forClinical Application
3.2.1 Bovine Dermal Collagen
In 1984, O’Connor KW etal. rst tried to use inert materials, including bovine der-
mal collagen and polytef, for injection to inhibit gastroesophageal reux in the dogs
[6]. The experimental results indicated that bovine dermal collagen injected into the
submucosal near the distal esophagus could effectively improve gastroesopha-
geal reux.
After verifying the feasibility and availability of endoscopy injection of bovine
dermal collagen in dogs, O’Connor KW etal. carried out relevant experiments in
human beings [9]. Endoscopic implant treatment resulted in statistically signicant
improvement in symptom scores, the standard acid reux test, and lower esophageal
sphincter pressures. Nine out of ten patients had decreased symptoms, and eight of
nine patients had an increase in lower esophageal pressure after implant injection.
Subjective and objective improvements in reux parameters generally lasted
6–9months with return toward pretreatment status by 12months. In addition, anti-
bodies to bovine collagen were present in ve of the ten patients.
The clinical application of this method was limited by the injection volume of
nearly 100mL and the un-abiding efcacy [7, 9].
3.2.2 Polytef
Polytetrauoroethylene (PTFE or Polytef) is an opaque, milky, waxy material that
can be used as a medical biological material such as articial and tissue replacement
mesh. It is the rst material used for endoscopic treatment of vesicoureteral reux
(VUR) [14, 15].
It was rst reported in 1984 that endoscopic injection of polytetrauoroethylene
was used for the treatment of gastroesophageal reux [6]. During 4–6 injections,
5–30mL PTFE was injected endoscopically at the distal esophagus in 5 dogs, and
the therapeutic effect was poor. All ve dogs that were injected with PTFE lost
some of their implants, leading to an ulcer and decline of LES function. In addi-
tion, Chen CY etal. [16] injected PTFE in the gastroesophageal junction of the
New Zealand white rabbits. The results validated that PTFE could enhance LES
pressure in rabbits, but there was foreign body granuloma reaction at the implanta-
tion site.
In terms of clinical research, Shak A [17] selected 21 patients with reux
esophagitis whose esophageal sphincter pressure was signicantly lower than the
normal value for Polytef injection treatment. In the rst 3 post injection months,
symptoms disappeared and LES pressure was elevated. Endoscopically, esophageal
hyperemia and erosion disappeared in 16 patients. However, LES pressure decreased
L. Liu
39
in nine patients after 6months post injection, and signicant LES pressure decrease
was observed in more than half of the patients at 12months.
The major disadvantage of this procedure is its short-lived curative effect and the
need for continuous injection to maintain the efcacy [18].
3.2.3 Sclerosing Agents
Sclerosing agents fall into three categories: detergents, hypertonic solutions, and
chemical stimulants. It could give rise to endothelial cell injury through multifari-
ous mechanisms and eventually result in target vessel sclerosis. It is widely applied
in the interventional treatment of cirrhotic gastroesophageal varices, varicose veins
of lower limbs, and other diseases. The detergent mainly consisted of sodium poly-
phenol, sodium tetradecyl sulfate (STS), sodium cod liver oleate, and ethanolamine
oleic acid. The most used hypertonic solutions are a mixture of 23.4% sodium chlo-
ride, 25% glucose, and 10% sodium chloride, while chemical stimulants from alco-
hol, salt to heavy metals, iodine, and glycerin are widely used [19, 20].
Donahue PE etal. [21] found that endo-sclerosis injection had almost no effect
on the length and pressure of the esophageal sphincter, and had a preferable preven-
tive effect on atropine-induced reux by injecting sodium codsh oleate into the
submucosa of the proximal stomach of dogs. Subsequently, Carvalho PJ etal. [22,
23] further found that the esophagus in dogs receiving sclerosis therapy changed
little, the cardiac focal brosis was the largest in the greater curvature, and the endo-
scopic sclerosing agents’ injection led to cardiac brosis, thereby preventing reux.
What is more, there were ultrasonic dense lesions at the injection site under endo-
scopic ultrasonography which occupied almost the entire gastric wall after sclero-
therapy of sodium morrhuate [24].
This study also attempted to perform endoscopic sclerotherapy in 2 patients
with GERD. Sclerosing agent was injected four times into the submucosa at the site
1–2 cm proximal to the gastroesophageal junction, with approximately 3 mL admin-
istered at each injection point and a total dose of 15–18 mL. Endoscopic ultrasonog-
raphy revealed localized dense brotic lesions. Subsequently, sodium cod liver
oleate was evaluated in a study involving 15 patients: symptoms improved in
4 patients, while most patients showed no signicant improvement. This treatment
modality was therefore discontinued due to its poor efcacy [7].
3.2.4 Enteryx
Enteryx polymer is composed of polyethylene diene, molybdenum powder, and
dimethyl sulfoxide, used in the embolization treatment of arteriovenous malforma-
tions [25].
3 Endoscopic Injection Therapy forGERD
40
Some studies have suggested that Enteryx endoscopic injection had some effects
on GERD [26, 27], but more evidence did not support this therapy. Deviere etal.
[28] preliminarily studied 15 GERD patients and found that all but 3 patients had
elevated LES, which could still be observed after 6months of follow-up, but most
of the implant materials were lost after 6 months. In 2018, it was reported that
Enteryx was endoscopically injected into 21 patients with GERD, and the other 26
patients underwent endoscopic folding surgery [11]. The observation for up to
60months showed that Enteryx polymer injection under endoscopy was not effec-
tive for long-term control of GERD.
The Food and Drug Administration (FDA) approved it for market use, but some
patients have since developed serious complications, including perforation of the
esophagus, kidney failure, aortic stula, gastrointestinal bleeding, severe esopha-
geal stricture, and mediastinal emphysema. The FDA has banned Enteryx from
treating GERD because of its severe side effects [4, 29–32].
3.2.5 Gatekeeper
The Gatekeeper system adopted a hydrogel delivery system to inject polyacryloni-
trile hydrogel prosthesis into the submucosa of the esophagus [29].
Fockens etal. [33] treated 68 GERD patients who still had heartburn, reux, and
abnormal esophageal acid exposure after PPI treatment with up to 6 prostheses
placed at the gastroesophageal junction. At 6months, the 24-hour time when pH
<4.0 decreased from 9.1% to 6.1%; LES pressure increased signicantly from 8.8
to 13.8mmHg. The authors [34] subsequently recruited 204 patients for a prospec-
tive, randomized, international multi-center study. Due to lack of convincing ef-
cacy data (Gatekeeper group and control group showed some improvement in
symptoms of retrosternal pain and esophageal acid exposure from baseline at
6months, but there was no signicant difference), and the occurrence of 4 serious
adverse events (2 cases of perforation, 1 case of perforation caused by pulmonary
inltrates, and 1 case of severe chest pain), Gatekeeper research was terminated
ahead of time. Currently, this technology is out of service [35].
3.3 Animal Experiments Are Effective
3.3.1 Dextranomer Hyaluronic Acid Copolymer
Dextranomer hyaluronic acid copolymer (DxHA), also known as Deux
®
(Salix
Pharmaceuticals, Raleigh, NC), is a biocompatible polymer composed of right-
turning polymer microspheres with a diameter of 80–250μm, suspended in stable
hyaluronic acid from non-animal sources. Because of foreign body reactions or
L. Liu
41
brosis caused by DxHA at the injection site, and its satisfactory specialities includ-
ing non-migration, non-immunogenicity, long-term stability, a minimal long-term
adverse effect, this preparation has been used for vesicoureteral reux disease, tra-
cheal esophageal stula, repair of umbilical hernia, and treatment of urinary or fecal
incontinence [36–39].
Alshehri A etal. studied the effect of endoscopic injection of DxHA on LES in
the gastroesophageal reux model of 14 miniature Yucatan pigs [36]. A 45cm long,
special endoscope (Fiegert-Endotech, Sunrise, FL) was used as the injection tool.
Submucosal injections of 1mL DxHA or saline were performed in three different
quadrants away from the musculotomy site, where the muscle was decient. The
mucous immediately bulged, indicating successful implantation. Wait 30seconds
before pulling out the needle to inject DxHA steadily. It was found that DxHA
resulted in a 120% increase in LES stress and a 76% decrease in average regurgita-
tion duration, but there was no signicant difference.
Martin K etal. performed laparotomy on 12 white New Zealand rabbits and
injected DxHA into the GEJ muscle [40]. The data suggested that injection of
DxHA could strengthen LES pressure and induce foreign body reactions dominated
by broblasts and giant cells, providing a new enlightenment for GERD.
3.3.2 Cell Transplantation
The endoscopic injection of inert substances for GERD is still in the preliminary
stage, and the overall therapeutic effect is not ideal and awless enough. Since cell
injection had become an alternative strategy for vesicoureteral reux and urinary
incontinence, some researchers had attempted to inject cells to treat GERD [41].
Adult stem cells are undifferentiated cells residing in mature tissues and organs of
adult animals with the ability to regenerate and differentiate [42, 43]. Due to its dif-
ferentiation capacity, stem cells injected into the submucosa of the lower esophagus
may differentiate into skeletal muscle cells under special induction conditions to
enhance LES ability, even more differentiate into nerve bers, blocking some of the
nerve conduction that causes LES to relax theoretically [44].
Fascetti-leon F etal. rst reported muscle precursor cells (MPCs) with GFP
+
injected into GEJ [45]. Experimental results showed GFP
+
muscle neo-bers were
evident at 4week after injection, and co-expression of GFP and smooth muscle
actin was also observed at 2week. This study suggested that MPCs are readily
available, cultured, and amplied, and may be used as a new injectable substance to
treat patients with GERD.
In 2009, Pasricha PJ etal. reported that the endoscopic injection of muscle-
derived cells (MDCs) could improve the function of intestinal smooth muscle
sphincter [46]. MDCs injection resulted in a signicant increase in lower esopha-
geal sphincter pressure of dogs from baseline, and a remarkable reduction of acid
reux in one dog. Transplanted MDCs were seen adding bulk to the lower
3 Endoscopic Injection Therapy forGERD
42
esophageal area and were well integrated into the surrounding tissue.
Immunouorescence analysis revealed weak expression of skeletal muscle myosin
in grafted MDCs and no expression of smooth muscle actin in dogs. MDCs can
survive and integrate into gastrointestinal smooth muscle to augment their contrac-
tile response. Thus, they may have potentials to treat patients with GERD.
At present, the research on cell injection therapy for GERD is limited to the ani-
mal level, and numerous scientic problems remain unclear, but it provides a new
direction for the therapy of GERD.
3.3.3 Tissue Transplantation
Marsh R.E etal. had attempted to evaluate the inuence of endoscopic implantation
of small intestinal submucosa (SIS) on esophageal sphincter pressure in dogs [47].
Signicant augmentation of pressures was obtained at 4weeks in one dog, but none
had signicant changes in pressure at 8weeks and differences in length at either 4
or 8 weeks or signicant differences in the thickness of the examined layers.
Although SIS is a biologically compatible material, lack of an animal model for
GERD makes determining the ability of injections of SIS to combat reux
problematic.
Because autologous adipose tissue is abundant in sources, easy to obtain, and has
histocompatibility after transplantation, it is the most ideal lling material at present
and widely used in various clinical elds, including breast plastic surgery, facial
reconstruction, hip lling, and scar repair [48–50]. Therefore, we investigated the
effect of endoscopic adipose transplantation on gastroesophageal reux in white
New Zealand rabbits [51]. The results showed that eight rabbits were successfully
transplanted with autologous fat, the average pH value of the esophagus increased,
adipose cells survived in the submucosa, and new blood vessels formed. This ani-
mal experiment suggested that endoscopic esophageal fat transplantation is a rela-
tively safe and feasible method.
3.4 It Has Certain Curative Effect, but Needs Further Study
3.4.1 Durasphere
Durasphere is a new injectable bulking agent approved by the FDA in 1999 for the
treatment of stress incontinence due to endogenous sphincter deciency, with estab-
lished safety and long-term clinical benets for the disease. This dilatant has been
shown to be stable for at least 2years and to be free of migration and local or sys-
temic immune rejection [52, 53].
L. Liu
43
In view of wonderful implantation characteristics of Durasphere, Ganz RA etal.
attempted to treat ten GERD patients with Durasphere [8].
Materials: Durasphere consists of pyrolytic carbon-coated graphite beads
(90–212μm) suspended in water-based carrier gel containing 2.8% β-glucan.
Therapeutic procedure: Subjects were prepared for endoscopic examination with
standard methods. No antibiotics were used before and after surgery; 1–3 mL
Durasphere was injected into the 1/4 quadrant of submucosa at the esophagogastric
squamo-columnar junction 1cm up and down in 2 times by simple sclerotherapy
needle and conventional technique. The location of the submucosa was determined
visually by tissue enlargement and blackening. When the injection is too deep, quit
immediately, then reposition the insertion depth and continue injection in the same
or different area.
Therapeutic outcomes: Nine of ten patients completed the 12-month trial without
adverse events. The procedure was well tolerated with minimal patient discomfort
and no dysphagia. At 12months, 70% of patients discontinued all antacid medica-
tion completely; 90% of patients reduced PPI use by greater than 50%. DeMeester
scores improved from a mean of 44.5 at baseline to 26.5 at 12months; 4 patients
achieved normal pH scores. There was no esophagitis, erosion, ulceration, and
sloughing of material in any injection site at 12months. Moreove, the Durasphere
material did not appear to migrate. At present, there is still a lack of experimental
evidence with this material for the remedy of GERD [54] (Fig.3.3).
3.4.2 PMMA
As a non-absorbable biocompatible polymer, Polymethylmethacrylate (PMMA)
was rst used for human oral repair in 1936. It has been successfully applied in
areas such as plastic surgery because of its many characteristics of ideal implants
Fig. 3.3 Durasphere
3 Endoscopic Injection Therapy forGERD
44
through continuous improvement in manufacturing processes [55, 56]. PMMAs are
100μm microspheres with a smooth, completely round surface. It has the advan-
tages of injection by needle, not be phagocytic, not moving easily, and only causing
very weak foreign body rejection [57]. Due to the poor efcacy or serious adverse
reactions of other injected substances in the cure of GERD, some researchers began
to try to treat GERD by injecting PMMA.
Fornari F etal. conducted a study on gastroesophageal reux treated by endo-
scopic injection of PMMA in 10 pigs [58]. Materials: A solution consisting of 30%
PMMA microspheres (34.2–103.3μm size, average sphere diameter 59.9μm) sus-
pended in hydrogel of carboxy glyconate hydrolactic of magnesium. Treatment
effect: Injection of PMMA into the gastroesophageal junction could enhance the
anti-reux ability for 6months without complications.
Moreover, Freitag CP etal. measured esophageal pressure, gastric yield pres-
sure, and GYV volume of 18 large white pigs under general anesthesia, and
implanted PMMA at the distal esophagus [59]. Results: 14 of the 18 animals
implanted PMMA lived for 28days and four died, including 1 died of esophageal
perforation, 2 died of pneumonia, and 1 died of colon perforation. GYP and
GYV increased, while the resting LES pressure did not change signicantly.
Histological examination revealed acute inammatory and brosis around the
PMMA implant. The results suggested that PMMA implantation into distal
esophagus can strengthen the anti-reux barrier; however, esophageal perfora-
tion indicated that the technique of this study needed to be improved to guarantee
the operation safety.
Feretis C etal. studied PMMA injection therapy in ten patients with PPI depen-
dent or refractory GERD [10].
The operation method: Under intravenous sedation and pulse oxygen monitor-
ing, sigmoidoscopy (CF-140, Olympus America Corp., Melville, N.Y.) was per-
formed to observe the esophagogastric squamo-columnar junction (Z-line).
Sterilized PMMA implant material inhaled to a 3mL syringe was injected into the
submucosa 1–2cm near the Z-line through a 90cm catheter and a 4mm long, gauge
21 telescopic needle (GI Asp.N, Wilson-Cook, Winston-Salem, N.C.). Five to six
injections were given at different sites until the esophageal folds thickened and
approached. If reux symptoms (heartburn and reux) are not controlled, a second
or even a third course is added after 2weeks.
Therapeutic effect: Symptom severity score and time when mean total esopha-
geal pH<4 after PMMA implantation was signicantly reduced (p<0.05). Seven
of the ten patients did not receive any medication after PMMA implantation. There
were no serious implant-related complications. Endoscopic PMMA implantation
into the submucosa of the esophagus requires further study to determine the long-
term efcacy of this treatment (Fig.3.4).
L. Liu