The Online Collection
 
Publication:
Surgical Technology International XVI - Surgical Overview
Article title:
Hyaluronan-Based Antiadhesive Agents in Abdominal Surgery: Applications, Results, and Mechanisms of Action

Contents:

 

 

 

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THE USE OF HYALURONAN IN INFECTIOUS CONDITIONS

 

The use of HA-based antiadhesives under infectious conditions remains controversial. The majority of the available data at this time results from experimental studies and presents contradicting outcomes. Reijnen et al. described the use of the HA-CMC membrane in a peritonitis model in rats.54 Although the contrary was hypothesized, the HA-CMC membrane did not reduce adhesions under these conditions. Tzianabos et al. stated that adhesion reduction devices might even potentiate intra-abdominal infection.55 In a rat model, they used HA-CMC and G-HA-CMC membranes after the insertion of a bacterial inoculum in the peritoneal cavity. Both membranes did not increase abscess rates. Mortality data were only available for HA-CMC membrane, which did not increase mortality. In this study, the effect of the membranes on adhesion formation was not evaluated. Ghellai et al. described use of the HA-CMC membrane after cecal ligation and puncture or cecal ligation alone in rats.56 Again, the HA-CMC membrane did not reduce the number or tenacity of adhesions. A trend toward increased abscess formation was associated with the use of the HA-CMC membrane in the cecal ligation group. Again using a cecal ligation and puncture model in rats, Tüzüner et al. found no differences between the control and HA-CMC membrane-treated groups regarding mortality, abdominal abscess formation, and median adhesion scores.57 On the contrary, the use of the HA-CMC membrane led to significantly less dense adhesions. The increased adhesion formation after use of the G-HA-CMC membrane in bacterial peritonitis in the study of Kayaoglu et al. was already mentioned earlier in this chapter.23 The only clinical prospective study that we are aware of describing the use of HA-CMC membrane in patients suffering from peritonitis is the above mentioned study of Vrijland et al.18 In this study, 81% of the patients treated with the HA-CMC membrane were diagnosed to have sigmoid diverticulitis with signs of peritonitis. Although the number of patients in this study was small, it is interesting to note that although the incidence of adhesions did not differ between groups, the severity of adhesions was reduced by the HA-CMC membrane.
In the above mentioned experimental study of Reijnen et al. showing no beneficial effect of the HA-CMC membrane, the 0.4% HA solution proved to reduce the incidence of adhesions and abscesses in a peritonitis model.54 The median severity of adhesions was significant lower using the HA solution at Day 7 and at Day 21 postoperatively. At Day 21, none of the rats treated with the HA solution had an intra-abdominal abscess, in contrast to 4 out of 12 (33%) rats in the control group. These results were confirmed by a second, larger study on this topic showing high volumes of 0.2% and 0.4% HA to be most effective, which may suggest a “hydroflotation” effect of the HA solution.58 These superior results of HA solution compared to the HA-CMC membrane under infectious conditions were confirmed by the quoted study of Tüzüner et al.57 Unfortunately, withdrawal of Sepracoat® from the market has prohibited further clinical studies.
There are no clinical data available on the use of ferric HA gel under contaminated and infectious conditions. The study of Tzianabos et al. describes the use of a preparation of ferric HA gel in an intra-abdominal model of infection in rats.55 This study focused on a potential propagation of the device on intra-abdominal infection. The use of ferric HA gels potentiated bacterial peritonitis and led to significantly increased mortality rates of 90% to 100%, compared to 49% in controls. This could be explained by the known increase in virulence of bacterial species by iron. Furthermore, some virulent strains of human pathogens are able to use iron for the survival and replication of the organism.
Sikkink et al. studied the use of auto-crosslinked HA gel in a rat peritonitis model.59 Bacterial peritonitis was induced using a cecal ligation and puncture model, and the animals were randomized to receive 4% auto-crosslinked HA gel or phosphate buffered saline. Different amounts of the gel were used and the effects on adhesion and abscess formation were evaluated at different time points. In this study, a trend toward increased mortality due to fecal peritonitis with subsequent sepsis in the auto-crosslinked HA gel treated groups was observed. There were no significant differences in median total adhesion scores and abscess rates between groups.

 

 

ONCOLOGIC REPERCUSSIONS OF HYALURONAN

 

Little is known at this time about the use of HA during oncologic surgical procedures. Nevertheless, experimental studies have documented a critical role for HA in tumor growth and metastasis, as it interacts with cell behavior in various ways. The physical properties of HA contribute to tissue biomechanics. Furthermore, it acts as a template for the assembly of other pericellular macromolecules and interacts directly with cell surface receptors that transduce intracellular signals. Consequently, HA may promote anchorage, independent growth, and invasiveness of cancer cells as described by Toole.60,61
Haverlag et al. studied the influence of HA solution on tumor cell adhesion.62 In vitro, mesothelial cells were cultured in monolayers and the effect of HA solution on adhesion of tumor cells evaluated. The use of HA solution showed an inhibitory effect on tumor adhesion. In a uterine abrasion model in rats, HA solution tended to increase tumor load. In a laparotomy model, the mean total tumor scores did not differ significantly. Underwood et al. examined the effect of the HA-CMC membrane on tumor cell implantation at surgical wound and laparoscopic trocar sites in a hamster model.63 It was concluded that the HA-CMC membrane neither had a protective nor an adverse effect on tumor implantation or growth. On the contrary, Tan et al. demonstrated that the HA solution significantly increased tumor cell proliferation and motility in vitro.64 In vivo, a significantly higher total tumor nodule count was noted when using the HA solution in a rat model. Hubbard et al. examined the effect of the HA-CMC membrane on cancer cell growth and metastasis in a mouse model.65 The HA-CMC membrane did not affect tumor metastasis. However, the placement of the membrane on nontraumatized peritoneum led to increased local tumor growth. It was concluded that not the HA but the traumatic placement of the membrane was responsible for local increased tumor growth. Pucciarelli et al. studied the effect of auto-crosslinked HA gel, native HA, and HA-CMC membrane on experimental intraperitoneal tumor implantation in mice.66 Human HT29 colorectal cells were used, and the antiadhesives showed no negative impact on survival or tumor implantation. In an experimental laparoscopic study in mice by Sasaki et al., a protective effect of the HA-CMC membrane on port site metastasis was suggested.67 Sikkink et al. recently studied the influence of the G-HA-CMC membrane on intraperitoneal tumor implantation and growth in a mouse and rat model of peritoneal trauma.68 No major effects were found. However, a uniform conclusion cannot be drawn from these contradictory experimental results.
Human studies are even more scarce. Kusunoki et al. already described the use of the HA-CMC membrane in 1999 for the reconstruction of the pelvic floor after abdominoperineal rectal excision for oncologic reasons in three patients.69 No remarks were made about the safety of HA in these cases. In a retrospective study in patients with colorectal excisions and short follow-up, Oikonomakis et al. found no adverse effects of the HA-CMC membrane.70 More recently, Kusunoki et al. showed in a prospective randomized study that the use of the HA-CMC membrane had no adverse effects in a group of patients with rectal carcinoma who were treated with radiation therapy, two-stage surgery, and chemotherapy.71 The median follow-up period was 43.6 months. The treatment with the HA-CMC membrane reduced adhesions in this chemoradiated group. Meanwhile, no other prospective randomized human studies have been performed to our knowledge.
Thus far, manufacturers have not promoted the use of HA-based agents in patients with malignancies. The product information for 0.5% ferric HA (Intergel®) clearly states that the product was not studied and is not recommended for use in patients with cancer. The same accounts for other products, such as HA solution (Sepracoat®), HA-CMC membrane (Seprafilm®), G-HA-CMC membrane (Seprafilm II®), polypropylene HA-CMC mesh (Sepramesh®), and polypropylene polyglycolic acid HA-CMC polyethylene glycol mesh (Sepramesh® IP).