Tissue adhesives and Medical Sealants

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Soft tissue adhesives are substances that hold tissues together, and could be broadly applicable in medicine and surgery. In appropriate circumstances, such materials could be attractive alternatives to sutures and staples since they can be applied more quickly, causes less pain and may require less equipment. In addition, there is no risk to the practitioner from sharp instruments, and they may obviate the need for suture removal. In addition to their use for topical wound closure, supplementing or replacing sutures or staples in internal surgical procedures, soft tissue adhesives can also be used for bleeding control and as sealants. Such medical sealants can be used in broad medical applications. In the gastroenterological field they can for example be used to fill fistula tract and as reinforcement of colorectal anastomosis. Other potential applications include seal air leakage from the lungs, repair aortic dissections and seal blood vessels in bypass and other procedures. An ideal tissue adhesive should allow rapid adhesion/sealing and maintain strong and close apposition of wound edges for an amount of time sufficient to allow wound healing. It should not interfere with body’s natural healing mechanisms and should degrade without producing an excessive localized or generalized inflammatory response. In addition, it should be viscous liquid before curing (easy to apply) and solidify quickly with low gelation time.
Novel tissue adhesives based on gelatin, with alginate as a polymeric additive and crosslinked by carbodiimide, were recently developed by our research group. Gelatin, a water-soluble natural polymer derived from collagen, has become one of the most extensively investigated materials for tissue adhesives due to its suitable natural qualities. Alginate, a natural polysaccharide which is extracted from marine algae, was chosen as the polymeric additive for the gelatin adhesive because it is a natural source for high concentrations of carboxylic groups which are essential for the crosslinking reaction of carbodiimides. Our novel gelatin-alginate bioadhesives demonstrated high bonding strength with high biocompatibility and appropriate viscosity and curing time. Understanding the effects of the adhesives' components on the bonding strength enabled us to elucidate the bonding strength mechanisms. This can lead to proper selection of the adhesive formulation and may lead to tailoring of the bioadhesive for various medical applications. This research focuses on the following directions:

  • Drug-loaded bioadhesives Delivering an antibiotic drug locally using our bioadhesive could decrease the risk of infections and increase the therapeutic effect of the bioadhesive.
  • Bioadhesives containing hemostatic agents Our thought is that in addition to providing an attractive alternative for traditional wound closing applications, our bioadhesive will also induce hemostatic effects and thus improve adhesion and overall function in a hemorrhagic environment. Such formulations can be extremely beneficial as both, adhesives or sealants.
  • Composite bioadhesives loaded with fillers for bone fixation applications The idea of being able to glue small bone fragments with a suitable biocompatible adhesive is highly attractive to orthopedic surgeons. A suitable bioadhesive would provide a simple and quick method of fixing highly comminuted fractures where there may be many small fragments that are difficult to fix by conventional means and experience only minor mechanical stress.

Figure 1: SEM micrographs showing the structure of composite gelatin-alginate-carbodiimide bioadhesives:
(a) loaded with hemostatic agent kaolin,
(b) loaded with the analgesic drug bupivacaine,
(c) loaded with hydroxyapatite.

Hybrid (Synthetic-Natural) Scaffolds for Wound Healing Applications

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Although natural polymers have the advantage of being similar or identical to macromolecules in our body, they suffer from inferior mechanical properties and rapid in vivo degradation by proteases. In contradiction, synthetic polymers exhibit good mechanical and physical properties, but do not fully promote cell adhesion and proliferation due to their inherently inert surface chemistry and do not allow smooth adherence to the wound bed, which may lead to bacterial infection. Therefore, hybrid structures are very promising, since they enable combining the advantageous properties of natural and synthetic polymers. However, such structures that combine both types of polymers are very challenging, due to the different nature of synthetic and natural polymers, which results in difficulties in binding between them.
An important biomedical application for such structures is scaffold for skin regeneration. The main goal in wound management is to achieve rapid healing with functional and esthetic results. An ideal wound dressing can restore the milieu required for the healing process, while simultaneously protecting the wound bed against bacteria and environmental threats. Novel bioresorbable hybrid layered structures which combine a synthetic porous drug-loaded top layer with a spongy collagen sub-layer were recently developed and studied by us. The upper dense "skin" layer is designed to control moisture transmission, prevent bacterial penetration and afford mechanical protection to the wound. The lower spongy layer is designed to absorb wound exudates, smoothly adhere to the wet wound bed and accommodate newly formed tissue. A method for effective binding between the two polymers at the interface, which is based on mechanical interlocking, was also developed by us. Another important feature of the top layer is that all types of bioactive agents, water soluble drugs, water-insoluble drugs and proteins can be incorporated in these novel structures without affecting their activity. In our study, the top layer contain analgesic drugs or antibiotics for controlled release to the wound site. Our investigation focus on the effects of the process parameters on the microstructure and on the resulting drug-release profile, physical and mechanical properties. Animal studies are conducted as well.

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Figure 2: The hybrid wound dressing (left) and the release profiles of the antibiotic drug gentamicin from the synthetic layer (right).

Soy-Protein as a Biomaterial for Tissue Regeneration Applications

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Interest in developing biodegradable materials from renewable biopolymers for biomedical applications has been on the increase in recent years. Proteins are preferable over carbohydrates and synthetic polymers for medical applications, because proteins comprise a major part of the human body, and are bio- and cyto-compatible. Furthermore, it is easier to maintain the functions of the extracellular matrix when proteins are used as scaffold materials than when synthetic polymers are used. Soybean is one of the most important and consumed legume crop in the world. Soy protein is attractive due to its low price compared to other proteins (such as collagen), non-animal origin that brings no risk of transmissible diseases, good water resistance and relatively long storage time. In spite of these good qualities, the potential of soy protein in the biomedical field has not been investigated yet.
We develop methods for soy protein processing into structures and study their mechanical, physical, and biological properties. Novel biodegradable wound dressings and skin substitutes based on soy protein are being developed and studied by us. These include dense structures, as well as porous structures and blends that are based on combination of soy protein with other natural polymers. These structures were found to combine good mechanical properties with desired physical properties, controlled release of various drugs and high biocompatibility. They can therefore be potentially very useful as burn and ulcer dressings and also in other biomedical applications, such as bone fillers and cartilage scaffolds.