Shortcomings of Current Treatment Technologies
Some preclinical studies have been performed using commercial biomaterials designed for general surgery or other specific needs. All these materials have shown some limitations and drawbacks. Both non-absorbable and absorbable materials are being studied, although absorbable materials seem to have several advantages over non-absorbable reinforcement.
Expanded poly(tetrafluoroethylene) sleeves (ePTFE – Gore®) represent a practical device with good biocompatibility, but they are non-resorbable.
Collagen-based patches have been used in anastomotic sealing: small intestinal porcine sub-mucosal patches have shown some beneficial effects in porcine models, although possible limitations are the risk of animal source contamination and contraction of the material causing bowel obstruction in the long term and induction of ulcers on the luminal surface.
A fibrin-collagen patch (TachoComb® – Nycomed) was used to evaluate its effect during early colonic anastomotic healing in rats; although in the early period this biomaterial supports anastomotic integrity, it also causes an inflammatory reaction which may increase the time necessary for the healing process.
A collagen patch coated with coagulation factors fibrinogen and thrombin (TachoSil®- Nycomed) was used for the sealing of colorectal anastomosis in a mice model; the study revealed a beneficial effect on the healing process although the underlying molecular mechanisms need to be elucidated. On the other hand, this material was tested for the sealing of gastrointestinal anastomoses on a porcine model, but the results did not point out any difference between sealed and unsealed controls.
Autogenic grafts displayed bad anastomotic healing attributed to avascularity of grafts and to aggravated adhesions between intestine and intra-abdominal organs.
The copolymer poly(glycolic acid):trimethylene carbonate is used to produce synthetic resorbable fibre webs in the form of sheets (Gore® Bio-A®); this material was developed for the general treatment of soft tissues and not specifically designed for intestinal anastomosis.
Knitted calcium alginate sheets (ForeSeal® – Brothier) have shown to display haemostatic and healing properties and can be used with surgical staplers, but clinical trials are related to lung applications. Alginate-based fibres (Hemoionic® – Brothier) have been used as a non resorbable haemostatic agent for rectal cancer surgery; although this product may reduce the drainage volume, it does not show any clinical advantage. As shown by this literature overview, to date there are not materials capable of satisfy entirely the clinical needs in the prevention and treatment of AL.
A preliminary patent search showed the wide interest on natural polysaccharides for the preparation of biomedical membranes. Among various polysaccharides, alginate fibres, gels and foams are known extensively to be useful for the preparation of surgical dressing. Various types of dressing formed from alginate fibres are patented. Most of them are developed as a surgical absorbent haemostat, wound dressing and anti-adhesion barrier at the site of an intra-body trauma. In particular, in patent U.S. No. 2010/0114313 the invention relates to anti-adhesion surgical alginate-based membranes. In some patented works, alginate is used in combination with other polymers to tailor specific properties. The most relevant ones include patent WO/2007/093805, where methods are described to create composite fibres and films of alginate with carboxymethylcellulose, pectin, hyaluronic acid, chondroitin sulfate, chitosan and other biopolymers. A patent by Edwards et al. (U.S. Pat. No. 6,809,231) concerns a wound dressing composed of cellulose-containing material and alginate, wherein alginate is crosslinked through a poly(carboxylic acid) ester bond to the cellulose of the material. Patent U.S. No. 7,226,972 describes the process to cross-link hyaluronic acid with other polymers as alginate to create biomaterials in the form of a film or sheet. These patents prove the interest on alginate for applications in biomaterial field. To the best of our knowledge there are no patented materials based on these polysaccharides specifically designed for AL. A key component (butyrate-derivated hyaluronic acid) used in this project to develop the final product is based on a patent owned by an SME (Sigea) which is one of the Partners of the AnastomoSEAL Consortium. Patents related to the formulation of biopolymers into self-gelling systems as well as foams and composites are part of the patent portfolio of FMC, another project Partner.