Abdominal Adhesions

Journal of Surgical Research 165, 91–111 (2011)
doi:10.1016/j.jss.2009.09.015
RESEARCH REVIEW
Abdominal Adhesions: Current and Novel Therapies
Brian C. Ward, Ph.D.,*,† and Alyssa Panitch, Ph.D.*,1
*Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana; and †Indiana University
School of Medicine, Indianapolis, Indiana
Submitted for publication July 13, 2009
An adhesion occurs when two tissues that normally Abdominal adhesions place a tremendous burden on
freely move past each other attach via a fibrous bridge. public health. Adhesions develop after nearly every ab-
Abdominal adhesions place a tremendous clinical and dominal surgery. Multiple studies cite that of patients
financial burden on public health. Adhesions develop who have abdominal surgery, 93% will have adhesions
after nearly every abdominal surgery, commonly caus- [3, 4]. Many of these adhesions require a second opera-
ing female infertility, chronic pelvic pain, and, most tion known as adhesiolysis to break the adhesion. A
frequently, small bowel obstruction. A National Hospi- comprehensive study of inpatient care and expendi-
tal Discharge Survey of hospitalizations between 1998
tures associated with adhesiolysis procedures in the
and 2002 reported that 18.1% of hospitalizations were
United States was conducted in 1994. This study found
related to abdominal adhesions annually accounting
for 948,000 days of inpatient care at an estimated cost that adhesiolysis accounted for 303,836 hospitaliza-
of $1.18 billion. tions (1% of the hospitalizations in the United States),
This review discusses the current or proposed thera- 846,415 days of inpatient care, and $1.33 billion in hos-
pies for abdominal adhesions. While many therapies pitalization and surgeon expenditures. Furthermore,
for abdominal adhesions have been attempted, the this enormous cost estimate did not include other
need for a definitive therapy to prevent or even reduce expenditures such as laboratory tests, endoscopies, im-
abdominal adhesions still exists. Ó 2011 Elsevier Inc. All rights aging, ambulance service, consulting physician costs,
reserved. post-discharge costs, workday or productivity losses,
Key Words: abdominal; adhesion; therapy; review; long-term morbidity costs, or the societal cost of early
inflammation; fibrosis; cytokine.
mortality [13]. Over the past decade, the number of ad-
hesiolysis procedures has increased [14]. In 2004, over
IMPORTANCE AND HEALTH RELEVANCE 342,000 procedures were performed to lyse peritoneal
OF ABDOMINAL ADHESIONS adhesions [14]. Finally, litigation stemming from com-
plications of intra-abdominal adhesions threatens to
Surgical procedures are the primary cause of adhe- drive healthcare costs related to abdominal adhesions
sions [1–5]. Moreover, adhesions can arise in many even higher [15]. Thus, the prevention of abdominal
parts of the body. Adhesions commonly occur during ab- adhesions has the potential to save the United States
dominal, gynecological, dental, thoracic, and cardiac healthcare market billions of dollars and improve the
procedures [1, 2, 6–12]. While many of the therapies lives of hundreds of thousands of Americans.
discussed will be applicable to all of these adhesion While female infertility and chronic pelvic pain are
types, the focus of this review is preventing abdominal common complications of abdominal adhesions, small
adhesions with an emphasis on small bowel adhesions bowel obstruction is often cited to have the highest
due to their enormous clinical significance and market incidence among abdominal adhesion complications
potential. [13]. In fact, adhesiolysis operations on the digestive
system accounted for $1.1 billion in surgeon expendi-
1
To whom correspondence and reprint requests should be ad- tures and hospitalization costs as well as 94% of the
dressed at Weldon School of Biomedical Engineering, Purdue Univer-
inpatient days associated with adhesiolysis procedures
sity, 206 Martin Jischke Drive, West Lafayette, IN 47907. E-mail:
[email protected]. in the United States in 1994 [13]. Moreover, 54% to 59%
91 0022-4804/$36.00
Ó 2011 Elsevier Inc. All rights reserved.
92 JOURNAL OF SURGICAL RESEARCH: VOL. 165, NO. 1, JANUARY 2011
of bowel obstruction occurrences in the United States cytokines and extracellular matrix signals and also
from 1979 to 1989 were due to abdominal adhesions, can actually develop a myofibroblastic phenotype
and 60% to 70% of these adhesions involved the small [20–23]. Fibroblasts and myofibroblasts secrete mas-
bowel [3]. According to a 2004 National Hospital Dis- sive amounts of extracellular matrix molecules includ-
charge Survey, approximately 305,000 operations ing fibronectin, hyaluronic acid, glycosaminoglycans,
were performed to treat intestinal obstruction [14]. and proteoglycans. This process establishes a weak
Thus, 180,000 of these operations were probably due fibrous bridge between tissues. Vascularization and
to abdominal adhesions. Even after adhesiolysis, recur- collagen deposition strengthen this bridge, forming
rent obstruction is common (8% to 32%) [3]. Most impor- a tough adhesion between the two tissues [2].
tantly, patients may die from bowel obstruction; as Although the mechanism that shifts the normal heal-
many as 3% to 5% die from a simple obstruction, and ing process to adhesion formation remains unclear, pos-
as many as 30% die if the bowel becomes strangulated, sible culprits include ischemia, surgical trauma,
necrotic, or perforated [3]. Clearly, abdominal adhe- inflammation, hemorrhage, thermal injury, chemical
sions, particularly adhesions involving the bowel, rep- injury, allergic reaction, tissue desiccation, genetic pre-
resent a clinically and financially significant problem. disposition, and reactions to foreign bodies introduced
during the procedure such as glove powder, sutures,
and gauze [13, 24, 25]. Regardless of the initiating
PATHOGENESIS OF ABDOMINAL ADHESIONS
factor, adhesions develop from the interplay of three
Normal Peritoneal Healing intertwined processes in the body: the fibrinolytic
system, extracellular matrix deposition and remodel-
To understand how to prevent adhesions, one must ing, and the inflammatory system (Fig. 1).
first understand how adhesions develop. Serosal sur-
faces are maintained by mesothelial cells. Mesothelial
cells make a phospholipid-based surfactant that provides LITERATURE REVIEW OF CURRENT OR PROPOSED
ABDOMINAL ADHESION PREVENTION THERAPIES
lubrication for sliding viscera, have fibrinolytic activity
that protects against adhesions and thromboses, and se- Methods of Literature Review
crete cytokines that play an active role in tissue repair
and extracellular matrix turnover [16]. When mesothe- Because of the massive number of abdominal adhe-
lial surfaces are injured, the coagulation cascade causes sion prevention strategies developed over the past sev-
fibrin deposition. Fibrin monomers polymerize to form eral decades, this review organizes the strategies into
a lattice of fibrin that can serve as a template for wound categories. The major categories selected are: solid bar-
healing or as a tissue bridge for adhesion development. riers, fluid and gel barriers, surgical protocols, cellular
The injured area is invaded by inflammatory cells strategies, pharmaceuticals, and combination prod-
from the vasculature or peritoneal fluid. Polymorpho- ucts. First, the category as a whole is critically evalu-
nuclear neutrophils (PMNs) appear first in the perito- ated. Some of the most notable strategies within the
neum and persist 1–2 d [17]. Macrophages appear category are also evaluated in the text, and more anal-
soon after PMNs and become the predominant cells in ysis is dedicated to products approved by the FDA and
the peritoneal fluid. Macrophage concentration in the to strategies with more extensive efficacy data. Human
peritoneal fluid peaks between ds 5 and 6 after surgery trial data is also given more consideration. Further-
[17]. Macrophages adhere to the wound area within more, each category contains a comprehensive table
24 h after surgery [18]. At approximately d 3, mesothe- listing abdominal adhesion prevention strategies in
lial cells begin to cover bound peritoneal macrophages this category along with notes concerning efficacy and
at the injured area, and macrophages embed deeper special features associated with the individual strat-
in the wound [18]. If normal healing occurs, the injured egy. Specific references listed in the table are not
area, regardless of size, is restored to a continuous sheet always repeated in the text.
of mesothelial cells in 7 to 10 d [2]. These categories and the literature and strategies
comprising these categories are critically evaluated ac-
When Peritoneal Healing Goes Wrong cording to several criteria. The most important criterion
is efficacy. Each strategy in each category is evaluated
Alternatively, the recovering mesothelial cells, fibro- for its ability or potential ability to reduce or prevent
blasts, and peritoneal macrophages can signal the abdominal adhesions. Only papers that included statis-
deposition of excessive extracellular matrix via cell tical analysis were selected to be included in the review
growth factors and cytokines [2]. Adhesion fibroblasts of strategy efficacy. Furthermore, other performance
develop a myofibroblast phenotype [19]. Recent evi- criteria are considered. These criteria include whether
dence suggests that these mesothelial cells respond to the category/strategy targets the pathogenesis of
WARD AND PANITCH: ABDOMINAL ADHESIONS: PATHOGENESIS AND SOLUTIONS 93
adhesions specifically, is biocompatible, and does not in- prevention products approved in the United States.
terference with normal wound healing. Additionally, Solid barriers have demonstrated some efficacy in de-
criteria concerning the delivery of the therapy are eval- creasing the severity of adhesions and, perhaps, in
uated. Criteria in this category include ease of use in the decreasing the incidence of adhesions in humans [2,
operating room, laparoscopic compatibility, open proce- 31, 32, 37–39]. Solid barriers are intended to prevent ad-
dure compatibility, and the ability for the technology to hesion formation by creating a physical barrier between
be applied only at the time of surgery to prevent adhe- two tissues. Clinicians insert the solid barrier between
sions. Both open and laparoscopic compatibility are im- two tissues that might adhere prior to closing the surgi-
portant because while the percentage and breadth of cal entry point. Genzyme Corporation’s Seprafilm and
laparoscopic procedures is steadily increasing, not all Johnson and Johnson’s Interceed, both solid barriers,
procedures can be performed laparoscopically [26–30]. are the only two adhesion prevention products approved
Overall, these performance and delivery criteria are by the FDA in the United States. Seprafilm is the FDA
crucial for adoption of the technology by surgeons. While approved product for ‘‘patients undergoing abdominal
criteria associated with execution of the technology or pelvic laparotomy as an adjunct to reduce the inci-
(such as cost of manufacture and marketing, manufac- dence, extent, and severity of postoperative adhesions
turability, intellectual property access, regulatory path- between the abdominal wall and the underlying viscera
way time and cost, potential off-label use, and product . . . and between the uterus and surrounding structures’’
stability and storage) are all crucial to the success of [40, 41]. Interceed’s FDA approval is narrower in scope.
any abdominal adhesion prevention strategy, these Interceed is approved as ‘‘as an adjuvant in open (lapa-
topics are beyond the scope of this review. rotomy) gynecologic pelvic surgery for reducing the inci-
While efficacy is the most important criterion for dence of postoperative pelvic adhesions after meticulous
evaluating abdominal adhesion products, efficacy is hemostasis is achieved consistent with microsurgical
also the most difficult criterion to assess. Investigators principles’’ [42]. Since these two products are the most
use a wide range of animal and human models, methods used products in adhesion prevention, extensive review
for inducing adhesions, methods for assessing adhesion and analysis of the strengths and limitations of these
formation, methods for grading adhesion severity, products will help in the design of a superior adhesion
times for assessing adhesion formation, incisions for prevention strategy.
assessing adhesions, and dosing regimens for the
same therapy (reviewed in detail in reference [5]). Fur- Seprafilm
thermore, the outcome of each study is dependent on
the surgical skill and on whether the surgeons properly While Seprafilm has several strengths, the product
and consistently apply the strategy. Thus, for all crite- still has many limitations. A recent market analysis
ria, the body of literature is emphasized rather than shows that Genzyme’s Seprafilm is the industry stan-
individual publications. For efficacy, specifically, dard in abdominal adhesion prevention with a market
a strategy is considered more efficacious if the strategy share of 58% of the market [4]. Seprafilm, a solid sheet
has multiple reports of efficacy from different investiga- of biodegradable carboxymethylcellulose and hyaluronic
tors. Additionally, the data is more convincing if the acid, is designed to be effective in a single application.
strategy has been attempted successfully in humans While Seprafilm is one of the most studied and used ad-
and if the human population participating in the study hesion prevention therapies, surgeons still argue about
was large. In the field of surgical prevention products, the efficacy of the product. The product has shown
randomized, controlled human trials are considered some efficacy in adhesion prevention in mouse, rat, rab-
the gold standard in determining product efficacy. bit, and dog models [43–59]. In addition, randomized,
controlled, human trials comprising greater than 5,000
total patients show that Seprafilm has some efficacy in
Discussion of Literature
reducing the incidence, severity, extent, and/or area of
While the problem of surgical adhesions is not a new abdominal adhesions (not all citations evaluate inci-
problem, review articles written by surgeons as late as dence, severity, extent, and area) [32, 40, 60–66]. Fur-
2008 cite no definitive strategy to prevent adhesion thermore, Seprafilm is one of the few adhesion
formation [1, 2, 31–36]. The therapies attempted can products tested and shown to have some efficacy in pedi-
be grouped into six major categories. atric populations [67]. However, not all trials support the
use of Seprafilm. Several investigators show that Sepra-
Solid Barriers film merely decreases adhesion severity, not incidence,
in humans [68, 69]. Another review of 15 randomized,
Solid barriers represent the most clinically successful controlled trials that focuses on preventing pelvic adhe-
adhesion barriers and the major category of adhesion sions in women reports that Seprafilm had no efficacy in
adhesion prevention versus controls [70]. While many of control in efficacy studies. Whenever appropriate data
the randomized, controlled human trials conflict, the exists, this review compares the efficacy of other
majority of the data seems to support that Seprafilm re- adhesion therapies to Seprafilm.
duces the severity of adhesions and may reduce the inci-
dence of adhesions, particularly adhesions between the Interceed
bowel and abdominal wall. Thus, even though Seprafilm
is the industry standard in adhesion prevention, few Like Seprafilm, Interceed has several strengths but
surgeons would cite that Seprafilm is the definitive also several limitations. Interceed, a sheet of oxidized
solution for adhesion prevention [71]. regenerated cellulose that typically biodegrades in 1
The biocompatibility and impact on wound healing of to 2 wk, is designed to be effective in a single application
Seprafilm are also controversial. Seprafilm shows no [2]. Like Seprafilm, physicians should not need to make
negative effects on wound healing in several rat and any more interventions concerning abdominal adhe-
rabbit animal models [44, 45, 52]. While most human sions if the product works effectively. Also like Sepra-
trials support this conclusion, approximately five case film, surgeons and researchers argue about the
reports note severe inflammatory reactions in humans efficacy of Interceed in preventing abdominal adhe-
[72–74]. In fact, several investigators have raised con- sions. While many animal models have supported the
cerns about the use of Seprafilm in the presence of bac- use of Interceed, some animal models have shown
teria. One group of researchers show increased that Interceed is not effective in preventing abdominal
adhesion formation in the presence of bacterial perito- adhesions versus untreated controls [83–86]. Human
nitis in a rat model [75]. While another group of re- trials generally find Interceed to reduce the severity,
searchers contradict this claim, these researchers extent, and/or incidence of pelvic adhesions (n > 50 pa-
base their claim on serum cytokines rather than fluid tients for all studies; not all studies evaluate severity,
samples taken directly from the peritoneal cavity [76]. extent, and incidence) [32, 87–93]. A meta-analysis of
Thus far, no studies show significant increases in infec- seven human studies (n ¼ 389 patients) found that the
tion rates with Seprafilm use in human patients [40, 69, barrier merely reduced extent and severity of adhe-
77]. Additionally, the Seprafilm product label and other sions, not adhesion incidence [94]. In contrast, one
investigators warn about Seprafilm use in anastomotic prominent review of 15 randomized, controlled trials
(joining of two segments of bowel) repairs because the in humans finds that Interceed reduces adhesion inci-
film can cause leakage [40, 77]. This effect has not dence and has superior performance to Seprafilm in
been observed in several rat models of anastomotic pelvic operations [70]. Thus, although Interceed may
healing [78, 79]. In fact, one investigator noted a signif- have superior efficacy to Seprafilm in some pelvic proce-
icant increase in the burst strength of anastomosed rat dures, few surgeons would cite that Interceed is the
bowel treated with Seprafilm [80]. However, the same definitive solution for adhesion prevention.
investigator noticed no decrease in adhesions with Se- Most literature supports that Interceed is biocompat-
prafilm use for this application [80]. Some investigators ible and does not impact wound healing, but the product
associated this increase in burst strength with in- may actually enhance adhesion formation in some in-
creased collagen synthesis (determined by measuring stances. Most large clinical studies show that Interceed
hydroxyproline levels) [50, 78]. However, other investi- use is not associated with any increase in adverse
gators found hydroxyproline levels similar to untreated events [70, 94]. However, the material does seem to pro-
controls in a similar rat model [52, 79]. The body of lit- voke a large leukocyte response and can cause mesothe-
erature seems to support Seprafilm’s biocompatibility lial cell sloughing in mice [95, 96]. This inflammatory
and limited impact on normal wound healing. However, response may enhance or prevent adhesion formation.
Seprafilm may be less useful in the presence of bacterial However, even Interceed’s product label warns against
peritonitis and in procedures with bowel anastomoses. using Interceed in the presence of peritoneal infection
Besides these clinical use limitations, Seprafilm’s use [42]. In a rat model of bacterially induced peritonitis,
is also limited in the operating room. Multiple surgeons Interceed actually enhances adhesion formation [75].
cite that Seprafilm is brittle and sticky [1, 2, 31, 81, 82]. Interceed also has a myriad of limitations in the oper-
These material properties make the product very diffi- ating room. Surgeons concede that Interceed is easier to
cult to apply. Furthermore, these properties limit Se- handle than Seprafilm and matches tissue contours well
prafilm’s use to open procedures. Seprafilm cannot be without need for suturing [1, 33]. However, Interceed
applied laparoscopically [1, 2, 31]. Even with all of these must be handled very carefully. The product label states
limitations, Seprafilm remains the standard of care in that, ‘‘postoperative, adhesions may be induced by GY-
adhesion prevention, and all future adhesion preven- NECARE INTERCEED application if adjacent tissues
tion strategies, with the exception of bowel anastomosis (e.g., ovary and tube) and structures are coated or
studies, should use Seprafilm as a benchmark, positive conjoined by the device, or if GYNECARE INTERCEED
is folded, wadded, or layered’’ [42]. Furthermore, blood laparoscopically compatible than others, but all solid
infiltration renders the product completely ineffective barriers are either difficult or impossible to apply lapa-
in preventing adhesions, so surgeons must ensure that roscopically [1, 101]. A subset of these barriers has fur-
all blood is cleared from the surgical field prior to using ther handling limitations. For instance, ePTFE must
Interceed [1, 2, 31, 33, 42]. Excess peritoneal fluid must be sewn into place, and because the material is nondis-
also be removed prior to applying the product [81]. solvable, the surgeon must typically subject the patient
Thus, surgeons must risk desiccating the tissue, a risk to a subsequent surgery to remove the barrier [31, 102,
factor for adhesion formation, to apply an adhesion pre- 103]. The silicone elastomer in Table 1 is also nonbiode-
vention product. Also, while the product is used laparos- gradable, and any nonbiodegradable material requires
copically by some surgeons, the product is only approved a second surgical intervention that puts the patient at
for use in open procedures [42]. In fact, the FDA warns risk for more adhesions or surgical complications. Based
surgeons that when Interceed is used laparoscopically, on all the limitations of solid barrier materials, adhesion
patients have more adhesions than patients in the prevention strategies that avoid these limitations
control group [97]. Thus, while Interceed is still used should be more readily adopted by surgeons.
clinically, the product has deficiencies in several delivery
and performance criteria. Fluid and Gel Barriers
Assessment of Other Solid Barriers Overall, fluid and gel barrier strategies attempted to
date do not show sufficient performance in preventing
Unfortunately, other solid barriers besides Interceed abdominal adhesions. To date, only Adept, a 4% icodex-
and Seprafilm are also not ideal adhesion prevention trin solution, has been approved by the United States
strategies. Overall, the strategies listed in Table 1 can- FDA [104]. Made by Baxter Healthcare, Adept is a non-
not be recommended for clinical use based on efficacy in viscous, iso-osmotic solution that is laparoscopically
preventing abdominal adhesions. While several strate- compatible (see Table 2). In the U.S., Adept is only ap-
gies show statistical superiority to Interceed and Sepra- proved for laparoscopic gynecological surgery [104]. In
film in small animal models, human trials are rare fact, the product is contraindicated for patients with in-
among these strategies. Of the solid barrier alterna- fection or allergies to cornstarch as well as procedures
tives to Interceed and Seprafilm, only expanded polyte- involving laparotomy incision, bowel resection, or
trafluoroethylene (ePTFE) has been tested in humans, appendectomy [104]. If used in these contraindicated
and the sample size reported in these studies is small. procedures, patient may experience dehiscence, cuta-
In fact, the majority of investigators fail to provide neous fistula formation, anastomotic failure, ileus,
rationale for why their solid barrier approach is supe- and/or peritonitis [104]. Thus, application and adoption
rior to Interceed or Seprafilm. The common premise is of this product have been very limited.
that another solid barrier made of a different material Otherwise, the data listed in Table 2 are not strong
may work better. Furthermore, none of these strategies enough to support the use of any other fluid or gel bar-
report biocompatibility or wound healing information rier for abdominal adhesion prevention. While many
in animal models. Many of the investigators use estab- studies show adhesion prevention efficacy in animals,
lished biomaterials with a relatively low inflammatory strategies that do have human trial data appear to be
response. However, human trials will be needed to truly ineffective. Also, the strategies lack randomized, con-
assess the material’s biocompatibility and impact on trolled human trials. Several therapies were superior
wound healing. Finally, these solid barriers do not try to Seprafilm in some animal models, but these strate-
to target the cellular or molecular pathogenesis of adhe- gies have not been compared with Seprafilm in human
sions. Solid barriers are simply solid barriers between trials. These barriers target adhesion pathogenesis bet-
two tissues. ter than solid barriers because they match tissue geom-
These strategies also have limitations in the operat- etry better, but the strategies are still simply barriers
ing room. For all solid barriers, the area of injury must that do not address the cellular and molecular patho-
be precisely identified and covered completely, the bar- genesis of adhesions.
riers are hard to apply to the complex geometries of the While most of the materials used to make the fluids
abdominal cavity, the surgeon must apply the barriers and gels in Table 2 are generally regarded as biocom-
manually, risking more tissue trauma, and the barriers patible, some of these materials cause tissue reactions
have limited applications [1, 2, 31]. Furthermore, recent in the peritoneum and may impact wound healing. Sev-
evidence attained in horses and rats suggests that eral strategies may enhance adhesion and abscess
patients may benefit more from pan-abdominal adhe- formation if bacterially induced peritonitis is present.
sion prophylaxis versus site-specific therapies, such Strategies that use materials that are metabolized
as solid barriers [99, 100]. Some barriers are more into sugars seem particularly susceptible to this
TABLE 1
Other Solid Barrier Adhesion Prevention Strategies
Therapy Efficacy reports and special features
Expanded polytetrafluoroethylene (Preclude) Some efficacy in rat [199], rabbit [83, 111] and human [112] models
Inferior efficacy to Seprafilm in pigs [113]
Performance superior to Interceed in mouse, monkey, and human
models [70, 95, 96, 114], but more difficult to handle [33]
Requires suturing, nonbiodegradable, and difficult to apply
laparoscopically [1, 2, 31, 33, 44, 70]
No studies concerning fertility outcomes, incidence of bowel
obstruction, or chronic pelvic pain post use [1]
Silicone elastomer Effective in 36 h rat model [83]
Similar limitations to ePTFE, but causes more inflammation [115]
Ethylene oxide (EO) and lactic acid (LA) films (REPEL) Efficacy comparable to Seprafilm in rabbits [116]
Not effected by presence of blood [116]
Use in Europe for adhesions other than abdominal adhesions
[117–119]
Bilayered methoxy poly(ethylene glycol)-poly(L-lactide-co-glycolide) Designed to promote wound healing while preventing tissue adhesion
film and a crosslinked collagen-hyaluronic acid membrane with [120]
fibronectin coating Only in vitro studies of efficacy [120]
Collagen membrane Some efficacy in rat and models [56, 121]
Fewer and less severe adhesions versus Interceed in rat model [121]
Difficult to handle during surgery [121]
Poly(vinyl alcohol) membrane Authors claims advantages to Seprafilm in rabbit model but no
statistics provided for this relationship [122]
Material is not adherent to tissue and requires suturing [ 122]
Crosslinked polygalacturonic acid/1-ethyl-3-(3- Significantly better performance than Seprafilm in rat model and no
dimethylaminopropyl) carbodiimide film acute inflammatory reaction [57]
Authors postulate efficacy may be due to higher water content post
implantation than Seprafilm [57]
Poly(g-glutamic acid) crosslinked by gamma-irradiation Significantly more effective than Seprafilm and Interceed in a rat
model [123]
Absorbs water and forms a thick, biodegradable hydrogel in vivo [123]
Hyaluronate film (Carbylan-SX film) Superior (not statistically) to Seprafilm in rat model [124]
A chemically modified hyaluronate derivative in film form [125]
Polylactic acid film (Surgiwrap) Some efficacy in rat model [126–129]
Efficacy comparable to Seprafilm in rat model but induced
significantly less inflammation [128]
No efficacy in pigs [130]
D,L-polylactide-epsilon-caprolactonetrimethylenecarbonate Some efficacy in rat model [131]
Investigators laparoscopic compatibility [131]
limitation. Other strategies seem to elicit a local and/or keep the tissues separated. The peritoneum has enor-
systemic inflammatory response. Some of the mate- mous absorptive capacity. Regardless of the volume of
rials, especially therapies that are delivered with large fluid applied, the peritoneum absorbs the liquid in 1
volumes of fluid, also appear to cause edema, which to 2 d [31]. Since the majority of investigators agree
causes patients symptoms of bloating, abdominal that adhesion pathogenesis occurs during the seven to
pain, and weight gain. Physicians have even reported ten days post surgery, multiple large volume fluid treat-
low viscosity solutions, such as 32% dextran 70, leak ments would need to be applied to the peritoneum [2].
from incisions after surgery [105]. Other therapies This strategy would cause more hospital care costs.
appear to have some negative impact on healing. Over- Also, the large volume of fluid would likely cause edema
all, the necessary information regarding the effect of and other postoperative complications. Finally, one
these strategies on tissue histology and mechanical investigator who studied many gel and fluid adhesion
properties is not sufficient to state that the materials prevention products found that the efficacy of the prod-
are biocompatible and do not impact healing. uct was related to residence time at the site of injury
However, these strategies may fulfill delivery criteria [83]. Another benefit of the strategies listed Table 2
better than solid barriers. Gels could be designed for versus some solid barriers is that the materials are all
one-time use, but fluids are unlikely to be effective as biodegradable and would not require removal.
a single treatment. Low viscosity fluids and gels proba- Furthermore, these strategies are compatible with
bly cannot reside at the site of injury long enough to open or laparoscopic procedures. Assuming the correct
TABLE 2
Fluid and Gel Barrier Adhesion Prevention Strategies
4% icodextrin Some efficacy in rat and rabbit models [38, 132–136]

(Adept) No efficacy in rabbit model [137, 138]
Some efficacy in humans, but not statistically significant [139]
One randomized, controlled trial in humans supports use versus Ringer’s lactate solution; 4% icodextrin
reduced the number of visceral adhesion but did not reduce the extent and severity of adhesions [140]
Efficacy superior to Seprafilm in rat model; also, increased hydroxyproline levels and intestinal bursting
pressures [78]
Efficacy inferior to Seprafilm in rat model [136]
Enhanced adhesion and abscess formation in rat peritonitis model [141]
Activated systemic and peritoneal inflammation in humans [142]
Approved in Europe and recently approved by FDA [104, 143]
Ringer’s lactate solution Some efficacy in rat model [135]
No efficacy in rabbit[138] or human models [33, 83, 139]
32% dextran 70 fluid Contradictory efficacy in rat and rabbit models [83, 144, 145] [85, 146–149]
(Hyskon) No clinical efficacy in humans [33, 109, 150, 151]
Negative patient experiences (leakage through incisions, swelling, bloating, abdominal pain, weight gain)
[105, 151, 152]
Linked to abscess formation and infection in humans [152, 153]
Allergic reactions in humans [109, 153, 154]
Carboxymethylcellulose Contradictory efficacy in rat and rabbit models [83, 144, 148] [43, 149, 155]
solutions Documented adverse effects on healing in rat model [156]
Increased peritoneal inflammation in rat model if bacteria present [157]
Decrease in adhesion formation when moving from 1% to a more viscous 2% carboxymethylcellulose
solution [83]
Hyaluronate gel (Tenalure, Some efficacy in reducing adhesion incidence and severity in human females undergoing myomectomy
Hylagel, Carbylan-SX, (n ¼ 52) [158]
Orthovisc, Incert, Some reduction in adhesion formation in mouse and rat models [38, 159, 160]; [124]
Hyalobarrier) Contradictory efficacy in animal models [43, 161]
Only efficacious if administered before tissue injury and may not persist long enough to prevent adhesion
formation in humans [1, 33]
A chemically modified hyaluronate derivative that can be used as an injectable hydrogel [125]
0.5% Ferric hyaluronate Some efficacy in rat model [135]
gel (Intergel) Some efficacy in rabbits [161]
Initially shown to prevent the number, severity, and extent of adhesions throughout the abdomen in
humans [31, 101, 162].
Subsequent studies found Intergel to be ineffective in reducing adhesions [1, 33, 37, 163]
Increased peritonitis in the presence of bacteria in rat model [157]
Can lead to significant postoperative morbidities such as pain, foreign body reactions, tissue adherence in
humans [1, 33, 164, 165]
Hyaluronate ionically cross-linked with trivalent iron [161]; withdrawn from market in 2003 [166]
Fibrin sealant Some efficacy in rat and rabbit models [83, 167, 168]
Some efficacy in humans [169, 170]
No statistically significant difference in adhesion prevention but no impaired peritoneal healing [167]
Gel form superior to solid [170]
Poly-L-lysine and Some efficacy in rat model [171]
polyethylene glycol (PEG) Polymerizes in situ on tissue surfaces [171, 172]
Dextran sulfate No randomized, controlled trials support use in humans [173]
Shown to induce colitis in animal models [174]
Carboxymethylcellulose þ Some efficacy in rat and rabbit models [48, 175–177]
hyaluronate gel (Sepracoat) Some efficacy in reducing the incidence, extent, and severity of de novo adhesions in humans
(n ¼ 270) [178]
Must be applied prior to injury; may function in reducing tissue desiccation [1]
Abandoned after poor human clinical trial results [31]
Carboxymethylcellulose þ Reduced incidence of adnexal adhesions in humans (n ¼ 18 and n ¼ 49) [179, 180]
polyethyleneoxide Some efficacy in rabbits [181]
(Intercoat) Some efficacy in rat model but performance inferior to Seprafilm [136]
Targeted for laparoscopic gynecologic use [182]
Polyethylene glycol hydrogels Some efficacy in pig model, but not statistically [183]
(SprayGel, CoSeal) Some efficacy in rat (reduced incidence) and rabbit (only reduced extent and severity) models [184]
Some efficacy in rat model, but performance inferior to Seprafilm, Adept, and Intercoat [136]
Some efficacy in human trials (n ¼ 14 [185] and n ¼ 71 [186])
Significantly reduces severity of adhesions but not frequency and extent in human trials (n ¼ 24) [187]
No randomized, controlled trials support use in humans [173]
SprayGel formulation available in Australia, Europe, New Zealand, South Africa, and Middle East, but the
product is currently in FDA approval process (Phase I) according to the manufacturer [188]
(Continued )
TABLE 2
(Continued )
Photopolymerized hydrogels Some efficacy in rat model [189, 190]

(polyethylene glycol-co-lactic Superior efficacy to physically cross-linked polyethylene glycol-co-propylene glycol hydrogels[190]
acid diacrylate) (FocalGel)
Polyvinyl alcohol þ carboxymethy- Some efficacy in rabbit model [191, 192]
lcellulose gel (A-part) Significantly better performance than 4% icodextrin in rabbit model [191]
Gelatin þ proteoglycan Some efficacy in cecal abrasion rat and mouse models [193]
gel (Adcon-P) Significantly better performance than Seprafilm [193, 194]
N,O-carboxymethylchitosan Some efficacy in humans without negative side effects (n ¼ 34) [195]
(NOCC)gel Some efficacy in rat and rabbit models [196–200]
Reduced size, strength, and number of adhesions [196]
More effective than hyaluronic acid in rat model [196]
No effect on bowel anastomosis healing [197]
rheologic properties, most of these therapies could be surgery to prevent adhesions may negatively impact the
sprayed through a laparoscope or surgical instrument. surgical procedure. In conclusion, gels have clear ad-
However, only a few of the papers analyzed report vantages over solid barriers and should continue to be
any rheology data. In fact, only a few investigators examined for adhesion prevention therapies.
even address viscosity of adhesion prevention therapies
[83, 106]. While fluids are unlikely to persist long Surgical and Noninvasive Strategies
enough to be effective, gels have significant delivery ad-
vantages in the operating room. Since gels can be dis- Another group of abdominal adhesion prevention
tributed evenly over a large surface, the area of injury strategies is to limit the surgeon’s impact on causing ad-
does not need to be precisely identified. Gels can coat hesions or to treat the patient noninvasively for adhe-
complex tissue geometries and should be effective for sions (see Table 3). While these strategies are logical
any organ in the abdominal cavity. In fact, one investi- and inexpensive, none of these strategies has been
gator who studied many gel and fluid adhesion preven- proven to significantly reduce adhesion formation [2].
tion products found that the efficacy of the product was The majority of these strategies simply involve using
related to the therapy’s ability to coat the wound surface principles of microsurgery—avoiding the use of pow-
[83]. In particular, gels that can polymerize in vivo, such dered gloves, minimizing tissue handling and trauma,
as photopolymerized hydrogels, show promise in being using constant irrigation, minimizing use of electrosur-
able to conform to the geometry of the native tissue. Fur- gery, implementing precise hemostasis, using small
thermore, if the gel has the appropriate rheologic char- and biocompatible sutures, and avoiding desiccation
acteristics for spraying, the surgeon does not have to of the tissue [31, 33, 107, 108]. These techniques are
handle the tissue, minimizing the risk for additional tis- currently used by the majority of surgeons, but clearly,
sue trauma. However, gels that need to be applied before abdominal adhesions still occur. Furthermore,
TABLE 3
Surgical and Noninvasive Adhesion Prevention Strategies
Laparoscopy Laparoscopy generally decreases the number of adhesions in animals and humans (reviewed in
references [8, 201])
Not all surgical procedures can be completed laparoscopically
Short-term laparoscopy (with variations in intra-abdominal pressure, light intensity, and choice
of dissection device) found to not affect the peritoneum’s fibrinolytic activity [202]
Hyperbaric O2 No benefit in reducing adhesions (in rats) but enhanced healing [203]
Carbon dioxide insufflation (CDI) Some efficacy in rats [204]
pneumoperitoneum (during laparoscopy) Caused no abnormal histopathology in rats [204]
Would not work in open procedures
Heated-humidified CO2 (during Prevented adhesions in laparoscopic rat model versus standard cold-dry CO2 [205]
laparoscopy)
3%–4% O2 in CO2 (during laparoscopy) Some efficacy in mouse model [206]
Lowering body temperature to 32 C Some efficacy in mouse model [206]
(during laparoscopy)
TABLE 4 need to store the materials at the appropriate conditions

Cellular Adhesion Prevention Strategies to maintain the viability of the tissue. Furthermore, sur-
geons would need to handle the materials delicately
Efficacy reports and since they contain live cells. Also, the materials would
Therapy special features have rapid expiration dates. While these therapies are
Mesenchymal stem Some efficacy in rat model [207] novel, much more research will be needed to make these
cells delivered in saline May provide a source of mesothelial strategies fulfill performance and delivery criteria
progenitor cells for healing necessary for a successful adhesion prevention therapy.
Human amniotic Some efficacy in adhesion prevention
membrane in rat model [47]
Not as efficacious as Seprafilm [47] Pharmaceuticals
To date, pharmaceutical approaches also do not have

randomized, blinded clinical trials of bad versus good the performance characteristics necessary to prevent
surgical technique would be unethical [31]. However, adhesions. The efficacy data listed in Table 5 is not
one study performed in a rat model did find that using strong enough to support the use of any pharmaceutical
powder-free gloves was as effective as Seprafilm in pre- for preventing abdominal adhesions. Moreover, multi-
venting abdominal adhesions versus a powdered glove ple adhesion prevention technology reviews by sur-
control [58]. Overall, these strategies seem to be bio- geons support this assertion [2, 31, 109]. Many classes
compatible, have limited impact on proper wound heal- of drugs show some efficacy in animal models. Some
ing, and try to prevent the injuries that cause adhesions drugs even show some efficacy in humans, but no ran-
from occurring, but these strategies alone do not appear domized, controlled trials definitively support the use
to prevent abdominal adhesions. [Specific limitations in of any of these drugs in preventing abdominal adhe-
delivering each therapy are also noted in Table 3. sions. All of these strategies target some part of adhe-
sion pathogenesis, but no drug listed in Table 5
Cellular Strategies specifically prevents cells from signaling the overag-
gressive fibrotic response that causes adhesions. All of
The performance characteristics of cellular strategies these drugs were designed to treat other diseases, not
are not sufficient to prevent abdominal adhesions. The abdominal adhesions. Furthermore, the literature
data listed in Table 4 is not strong enough to support shows that diminishing one extracellular mediator is
the use of any cellular strategy for abdominal adhesion not enough to prevent adhesions. For instance, reduc-
prevention. The therapies are only supported by very ing extracellular mediators, such as IL-1, TNF-a, and
small animal studies, and lack human studies. These TGF-b, has some impact on adhesion formation (see Ta-
strategies target adhesion pathogenesis by replacing ble 5). Indeed, inhibiting multiple mediators seems to
the mesothelial defect with live tissue or cells. However, show a synergistic effect. Thus, multiple extracellular
these strategies carry significant risks in wound heal- mediators probably contribute to adhesions. However,
ing and in biocompatibility. The authors do not identify these extracellular mediators have multiple effects on
an abundant tissue source for these therapies (see the cell. Some of these actions include cell metabolism
Table 4) in humans. Mesenchymal stem cells are rare and survival regulation. Thus, inhibiting multiple
and difficult to purify. Also, amniotic membrane is extracellular mediators may be lethal to the cell. There-
only available after a woman gives birth. Furthermore, fore, if an intracellular target specifically associated
if the source of tissue is not autogenic, the cellular with the adhesion formation process could be identified,
materials may elicit a significant immune response the therapy could bypass the redundant pro-adhesion
from the patient. activation signals and avoid side effects. In most cases,
These strategies are also difficult to administer. the impact of these drugs on biocompatibility and
Potentially, these therapies could be administered only wound healing after abdominal surgery is not known.
once after an abdominal procedure. The materials would Nearly every drug listed in the table is approved by
be degraded by the body or be integrated into the body. the FDA for some indication. However, histologic and
The surgeon would not need a second surgery to remove mechanical analyses of any of treated peritoneal tissues
the material. Additionally, the stem cells should be com- are rare. Furthermore, the systemic distribution of any
patible with open or laparoscopic procedures because drug applied to the peritoneum can cause undesired
they can be delivered in a fluid or a gel. However, the am- side effects.
niotic membrane would be challenging to use in laparo- The delivery characteristics of these therapies also
scopic procedures because it faces many of the same limit the impact of these drugs on preventing abdominal
limitations as solid barriers. Both strategies face signif- adhesions. The majority of these pharmaceuticals are
icant hurdles in the operating room. Surgeons would administered locally in saline and are intended to
TABLE 5
Pharmaceutical Adhesion Prevention Strategies
Pharmaceutical class (examples) Why drug may work Efficacy reports and special features
Anticoagulants (Heparin, low Fibrin blood clots can serve as LMWH shows some success in rats without impacting normal
molecular weight heparin a nexus for adhesions. These coagulation or healing [203, 208]; efficacy comparable to Seprafilm
[LMWH], danaparoid, drugs prevent clot formation. [209]
enoxaprin, lerpirudin, Heparin had comparable efficacy to Seprafilm in rat model [210]
warfarin) Heparin solution ineffective in humans [37, 109, 211].
Thrombin inhibitor showed some efficacy in rabbit models [212].
Fibrinolytics (tissue Fibrin blood clots can serve as Mixed efficacy in rabbit and rat models [189, 216-219] [43, 149]
plasminogen activator, a nexus for adhesions. These Ineffective post adhesiolysis in humans [211]
streptokinase, inhibitors drugs destroy formed blood Uncontrolled hemorrhage in rabbits [149]
of plasminogen activator clots. Causes cecum hematomas in rats [219]
inhibitor type I [PAI-1]) Fibrinolytic activity virtually
absent after first day of injury
[213, 214]; thus, pro-fibrinolytic
drug may decrease adhesion
formation [215]
Thromboxane A2 receptor Inhibits platelet activation; Some efficacy in rabbit model [220]
blockers (ridogrel) platelets may release mediators Risk of bleeding
that promote adhesions.
Anti-inflammatories Prolonged inflammation may Tolmetin and tenoxicam (NSAIDs) had some efficacy in rat and rabbit
(nonsteroidal anti- enhance adhesion formation. models [221–226].
inflammatory drugs Rofecoxib (COX-2 inhibitor) diminished adhesion formation in and mice
[NSAIDs], phospholipase rats (oral delivery) [227, 228]
A2 inhibitors [i.e., anti- Celecoxib (COX-2 inhibitor) reduced adhesion formation in mice;
inflammatory peptide 2], superior to rofecoxib (oral delivery) [228]
COX-2 inhibitors, Anti-inflammatory peptide 2, lazeroid, and meclofenamate had some
prostaglandins) efficacy in rabbit models [229-231]
Dexamethasone and tolmetin sodium not effective in rat model [43]
Some efficacy of steroids in reducing adhesion incidence and severity in
human randomized, controlled trials; evidence insufficient to
recommend use [109, 173]
Hydrocortisone shows some efficacy in humans [150]
Ibuprofen not effective in humans [232]
Ibuprofen hinders wound healing in rabbits [232]
Lack of inflammatory cells may enhance adhesions in rabbits [233, 234]
Antihistamines (i.e., Used to attenuate allergic Efficacy comparable to Seprafilm in rat model [51]
diphenhydramine) response; inflammation Role of allergic inflammatory response not clear in adhesion formation
associated with foreign bodies
entering the abdomen may
cause or enhance adhesions [2].
Growth factor inhibitors and Inhibit extracellular mediators Anti-TGF-b1 and TGF-b2 antibodies deceased adhesion formation in
modulators (Antibodies versus that may enhance rats and mice [235, 236]
inflammatory or pro-fibrotic inflammatory or fibrotic Anti-TGF-b1 antibody reduced cellularity of adhesions in rats, not
cytokines [i.e., TGF-b]) processes incidence [237]
Monotherapy with anti-IL-1 antibody decreased adhesions in rat model
[238]
Therapy with anti-IL-1 and anti-TNF-a antibodies decreased adhesions
in rat model; effect superior to either monotherapy [238]
sunitinib (vascular endothelial growth factor receptor 2 antagonist)
reduced adhesion formation in mice [239]
Epidermal growth factor Possibly increase cell proliferation Some efficacy in rat model [240]
and accelerate healing process Did not affect hydroxyproline content of tissue [240]
Angiotensin-converting enzyme Acts in pro-fibrotic signaling Some efficacy in rat model [241]
inhibitors (ACE-I) cascade which may inhibit Impaired wound healing at high doses in rat model [244]
(Benazepril, captopril, adhesion formation (may act Acute side effects include hypotension, renal insufficiency,
enalapril, fosinopril, lisinopril, through EGF and/or TGF- hyperkalemia, and coughing [245]
moexipril, quinapril, ramipril) b signaling pathways)[241];
high levels of angiotensin II in
peritoneal fibrosis [242, 243]
(Continued )
TABLE 5
(Continued )
Angiotensin II receptor blockers Acts in pro-fibrotic signaling More benign side effect profile than ACE-I [2]
(ARB) (losartan) cascade which may inhibit In vitro studies demonstrate ARBs reduce TGF-b1 production [246]
adhesion formation (may act Acute side effects include hypotension, renal insufficiency, and
through EGF and/or TGF- hyperkalemia [245]
b signaling pathways)[241];
high levels of angiotensin II in
peritoneal fibrosis [242, 243]
Matrix metalloproteinases Destroy extracellular matrix No efficacy data
(MMPs) (collagenase MMPs, implicated in adhesion Inhibitor of MMP did not enhance adhesion formation in rats [247]
stromelysins MMPs, formation Deficient MMP activity in human organs where adhesions commonly
stromelysin-like MMPs) occur [248, 249]
May destroy ‘‘healthy’’ extracellular matrix
Immunosuppressives Suppress cells associated with No efficacy data
(cyclosporine, sirolimus) immune response decreasing Documented adverse effects on healing [156]
pro-adhesion cytokines
Octreotide Shown to decrease EGF receptor Some efficacy in rat model [250–252]
and plasmin activator inhibitor Treatment reduces TGF-b1 and VEGF in rats [253]
levels while increasing tPA Decreases neutrophil migration [251]
levels in rats [250]; may Lack of inflammatory cells may enhance adhesions in rabbits [233, 234]
enhance fibrinolysis
Systemically administered Pathogen contamination can No efficacy in rabbits [155]
antibiotics (trimethoprim- enhance inflammatory Some efficacy in rats and hamsters [254, 255]
sulfadiazine, cefepime HCl, response in peritoneum;
metronidazole) response may enhance adhesion
formation
Locally administered antibiotics Pathogen contamination can Some efficacy in rats [256]
(penicillins, chloramphenicol, enhance inflammatory Antibiotic solutions tested actually enhanced adhesion formation
macrolides) response in peritoneum; [257–259]
response may enhance adhesion
formation.
Taurolidine Antimicrobial and anti- Some efficacy in rat model [260]
lipopolysaccharide qualities.
Phospholipids Phospholipids adhere to Mixed efficacy in rat and rabbit models [219, 263, 264], [134, 261, 262,
(phosphatidylcholine) mesothelial lesions preventing 265–267]
adhesions [261, 262].
Collagen inhibitors (N-(3,4- Inhibition of collagen synthesis Some efficacy in rabbit models [268]
dimethoxycinnamoyl) may prevent adhesion Transilast is mast cell stabilizer [269]
anthranilic acid [Transilast]) formation. May impact healing
Medroxyprogesterone and Progesterone to estrogen ratio Some efficacy of medroxyprogesterone in rat model when administered
leuprolide acetate may affect frequency of two weeks before surgery via intramuscular injection [86]
adhesions in women [86]; both Preoperative leuprolide administration found superior to Interceed in
drugs increase this ratio via rabbit uterine horn model [39]
different mechanisms. Side effects of impotence and hot flashes [245]
Hypoestrogenic environment Decrease estrogen levels; believe Some efficacy in rat and primate models [270–272]
inducers (GnRH antagonists, to alter fibrinolysis and Ineffective in reducing severity and extent of adhesions in women
mifepristone) extracellular matrix (n ¼ 20) [273]
remodeling [270]
Aromatase inhibitors May work via down-regulating Some efficacy of anastrozole in rat model [275]
(tamoxifen, anastrozole) TGF-b1 production [274]
Phosphodiesterase-5 Increases cGMP leading to Some efficacy in rat models (oral delivery) [278, 279]
inhibitors (sildenafil) reduced collagen synthesis and Increased colonic bursting pressure and angiogenesis in rat model in the
increases in fibroblast apoptosis presence of infection [279]
[276, 277]
Methylene blue Inhibits NO synthase; reduces Some efficacy in rat models [280–282]
free radical oxygen but May induce adhesions at high doses [280]
mechanism in preventing Impairs anastomotic healing [282]
adhesions unknown [280]
Catalase Reduces oxidative stress Some efficacy in rat model [283]
Vitamin E Antioxidant Efficacy comparable to Seprafilm in rat model [284]
Opioids (opium, morphine) Unknown mechanism; postulated Some efficacy in rat model (reduced length, thickness, and severity)
that opium receptor decreases [285]
inflammation [285]
(Continued )
TABLE 5
(Continued )
Anesthetics (lidocaine, May reduce oxidative stress [286] Some efficacy in rat bacterial peritonitis model [286]
prilocaine) Mixture of lidocaine and prilocaine more effective than lidocaine alone
[286]
Honey Unknown mechanism; may Some efficacy in rat model (oral delivery [288] and peritoneal
reduce oxidative stress [287] delivery [287])
Improved histology and anastomotic busting pressure in rats [288]
Sphingosine kinase 1 Enhances mesothelial cell Some efficacy in rat model [289]
delivered by adenovirus migration accelerating wound
healing [289]
neurokinin-1 receptor Increases peritoneal fibrinolytic Some efficacy in rat model (no oral efficacy) [290, 291]
antagonist (aprepitant, and matrix metalloproteinase
CJ-12-255] activities and reduced levels of
oxidative stress by blocking
binding of substance P [290]
TABLE 6
Combination Adhesion Prevention Strategies
Therapy Unique assets or limitations
Interceed þ heparin Some efficacy in animal model [292)

Efficacy no better than Interceed alone in human trials (n ¼ 40) [293]
Seprafilm þ heparin Efficacy no better than Seprafilm or heparin alone [210]
Seprafilm þ Vitamin E Efficacy no better than Seprafilm or Vitamin E alone [284]
Tissue plasminogen Some efficacy in preventing abdominal adhesions in rat model; combination more effective
activator þ hydrogel than either component alone [189]
Tissue plasminogen activator þ Some efficacy in rat model; reduced strength and extent of adhesion [43]
carboxymethylcellulose solution Colonic bowel anastomosis bursting strength not affected by therapy [294]
Poly-L-lactic acid/polyethylene glycol Some efficacy in rat model and in vitro [295]
gel film þ ibuprofen Limits systemic distribution of drug
Hyaluronic acid gel þ tolmetin Some efficacy in rabbit model but hyaluronic acid and tolmetin not tested separately as
controls [296]
Viscous emulsion þ RGD Some efficacy in rabbit model [297]
containing peptide R ¼ arginine, G ¼ glycine, D ¼ aspartate
poly(p-dioxanone) fiber rods þ N-(3, Product combination superior to either component in rabbit model [268]
4-dimethoxycinnamoyl) Systemic administration of drug ineffective in rabbits [268]
anthranilic acid (Transilast) Later formulations combine this product in a sodium carboxymethylcellulose aqueous gel [298]
Carboxymethylcellulose (CMC), Film and gel forms have shown efficacy in animals (pigs, rabbits, rats) [299]
poly(ethylene oxide) (PEO), þ Some efficacy in humans [179, 300]
calcium (Oxiplex) CMC functions as tissue-adherent barrier [176, 181, 299]
PEO hinders protein deposition onto tissue surfaces [181, 301].
Calcium controls rheology [181]
Crosslinked hyaluronan hydrogel þ More effective in rat model than crosslinked hyaluronan films alone [302]
covalently bound mitomycin C Mitomycin C is an antibiotic that inhibits DNA synthesis; may prevent adhesion formation by
killing pro-adhesion
cells or preventing cell migration to potential adhesion site
May impact wound healing
Electrospun poly(lactide-co-glycolide) 100% efficacy in rat model [303]
(PLGA) nonwoven nanofibrous Synergy seen between drug and scaffold [303]
membranes þ cefoxitin (antibiotic) Nanofibrous scaffolds shown to enhance cell adhesion, proliferation, and differentiation; may not
be optimal for an anti-adhesion therapy [304, 305]
Poly(epsilon-caprolactone) pad þ Authors claim combination significantly enhanced efficacy versus pad alone (macroscopic and
ornidazol (antibiotic) histologic assessment) [306].
Interceed þ leuprolide Combination reduced microscopic fibrosis in rabbit uterine horn model; leuprolide alone
(decreases estrogen) just as effective in adhesion prevention [39]
3%–4% O2 in CO2 þ dexamethasone or Synergistic efficacy in mouse model; 3%–4% O2 in CO2 þ Hyalobarrier slightly more effective [206]
Hyalobarrier (during laparoscopy)
Phosphatidylcholine þ tPA Significantly more effective in rat model versus Seprafilm or either constituent alone [219]
fibrin þ tranexamic acid (Adhexil) Some efficacy in rat and rabbit models [98, 307]
Performance superior to Seprafilm, SprayGel, and Interceed in rabbit model [307]
Tranexamic acid is an antifibrinolytic agent [98]
Abnormal tPA recently proposed, and biocompatibility and wound

PAI-1
fibrinolysis healing properties require further study. However,
Inflammatory combining a therapeutic with a gel or solid can
system
TNF-α
overcome some of the delivery drawbacks noted for
the individual therapies above. This class of therapies
IL-1
has the potential to synergize the benefits of several
IL-6 adhesion prevention strategies while minimizing the
IL-8 TGF-β1
TGF- detriments of the separate therapies.
Aberrant Collagen
Cell adhesion
MCP-1 ECM molecules
remodeling Cell migration Conclusions About the State of Abdominal
Matrix
degradation Adhesion Prevention Strategies
FIG. 1. A schematic showing the complex interplay between the
fibrinolytic and inflammatory systems and ECM remodeling in perito- While many therapies for abdominal adhesions have
neal healing. been attempted, this critical analysis of adhesion pre-
vention literature shows that the need for a definitive
prevent adhesions with one use (exceptions are noted in therapy to reduce or prevent abdominal adhesions still
Table 5). Therefore, these pharmaceuticals should be exists. According to www.clinicaltrials.gov, a myriad of
compatible with open or laparoscopic procedures be- clinical trials are underway primarily on simple fluids,
cause they can be delivered in a fluid. Thus, these phar- gels, or solid barriers. However, even the promising
maceuticals would face the same advantages and strategies presented in this analysis are likely years
limitations as delivering a fluid in the operating room. away from impacting human patients.
However, many of these pharmaceuticals may be more This critical analysis yields insights into designing
effective if delivered in a local, controlled manner. The a superior adhesion prevention therapy. Clearly, good
mesothelium’s enormous absorptive capacity quickly surgical principles should be used in any procedure.
distributes pharmaceuticals to the rest of the body However, any simple change in surgical technique is
[31]. This effect decreases local efficacy and increases unlikely to change the incidence or severity of
systemic side effects from the treatment. Delivering adhesions. Likewise, cellular therapies present signifi-
the pharmaceutical in a solid or gel barrier may be cant implementation challenges. In comparison, solid
more efficacious. The therapy could be delivered directly and fluid barriers as well as pharmaceuticals have
to cells of the peritoneum. Also, the pharmaceutical re- shown some efficacy in preventing adhesions in
lease could also be modulated by the substrate to last humans. In particular, combinations of barriers and
hours to days after surgery. Additionally, designing pharmaceuticals have the potential to cause some syn-
a pharmaceutical that remains in the cell after diffusing ergism between the individual therapies. Since the ma-
from the delivery vehicle may limit side effects and re- jority of adhesion pathogenesis appears to occur over
quire less pharmaceutical delivery. While simply using the first 10 days post-abdominal surgery, a barrier
a pharmaceutical to prevent abdominal adhesions is an may allow for the controlled release of a therapeutic
appealing strategy, the literature in this field shows during the entire pathogenesis of adhesions [2]. This
that the appropriate pharmaceutical may not exist. analysis has demonstrated key design parameters for
the ideal therapeutic and ideal barrier. Combining an
Combination Products ideal barrier with an ideal therapeutic should result
in a more efficacious adhesion prevention strategy.
Combination therapies have the potential to combine The ideal therapeutic targets specific pathogenesis of
some of the positive performance characteristics of adhesions without impacting wound healing. Inher-
therapeutic strategies mentioned above into a superior ently, adhesions are caused by an overly aggressive
adhesion prevention product. The efficacy data listed in fibrotic response. A therapeutic should specifically
Table 6 is not strong enough to support the use of any diminish this fibrotic response without deterring
combination product for preventing abdominal adhe- wound healing. Due to the multiple extracellular medi-
sions. Many of these studies show some efficacy in ani- ators of fibrosis, the therapy should also target an intra-
mal models. However, few combination products have cellular molecule specifically associated with the
been tested in humans. Interestingly, many of these fibrotic process to eliminate the redundant pro-fibrotic
combinations of a gel or solid with a pharmaceutical activation signals of extracellular mediators. Ideally,
show that the combined therapy is more efficacious the therapy would target only the cells implicated in
than either therapy alone. Combination products allow the pathogenesis of adhesions—mesothelial cells, mac-
the therapy to inhibit multiple steps in the pathogene- rophages, and fibroblasts of the peritoneum. Also, the
sis of adhesions. Many of these strategies have been therapeutic should act locally and not be distributed
to places outside of the peritoneal cavity to avoid side 4. Frost, and Sullivan U.S. Markets for Hemostats - Tissue Seal-
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December 2004.
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ACKNOWLEDGMENTS differentiation of mesothelial cells is mediated by RAGE and
contributes to peritoneal fibrosis in uraemia. Nephrol Dial
Transplant 2006;21:2549.
The authors acknowledge support for this research in part by the
21. Lopez-Cabrera M, Aguilera A, Aroeira LS, et al. Ex vivo analy-
NIH (National Institutes of Health; Bethesda, MD) (grant number
sis of dialysis effluent-derived mesothelial cells as an approach
K25HL074968). BW was supported in part by an NIH Medical Scien-
to unveiling the mechanism of peritoneal membrane failure.
tist Training Program grant (grant number GM077229) and by the
Perit Dial Int 2006;26:26.
Purdue Research Foundation.
22. De Vriese AS. The John F. Maher recipient lecture 2004: Rage
in the peritoneum. Perit Dial Int 2005;25:8.
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Abdominal Adhesions

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Journal of Surgical Research 165, 91–111 (2011)

Submitted for publication July 13, 2009

Therapy Efficacy reports and special features

Therapy Efficacy reports and special features

4% icodextrin Some efficacy in rat and rabbit models [38, 132–136]

Photopolymerized hydrogels Some efficacy in rat model [189, 190]

Therapy Efficacy reports and special features

TABLE 4 need to store the materials at the appropriate conditions

To date, pharmaceutical approaches also do not have

Therapy Unique assets or limitations

Interceed þ heparin Some efficacy in animal model [292)

Abnormal tPA recently proposed, and biocompatibility and wound

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