Closure of Long Surgical Incisions with Hemostatic Tissue Adhesive in a Porcine Skin Model.

OBJECTIVE: Skin adhesives offer many advantages over traditional wound-closure devices. Recently, the current research group reported on tissue adhesives composed of natural polymers (gelatin and alginate), which are biocompatible with mechanical properties suitable for tissue adhesion. The objective of the present study was to conduct clinical and histologic assessment of this hemostatic bioadhesive in the healing of long skin incisions (≥4 cm) in comparison with traditional and commercially available methods. METHODS: Researchers created 24 long incisions on the ventral side of two domestic pigs to compare four different treatment modalities: two topical bioadhesives based on gelatin and alginate combined with the hemostatic agent kaolin, nylon sutures, and commercial tissue adhesive N-butyl-2-cyanoacrylate. The bioadhesive compounds were spread on the incision surface and then mixed either manually or with a double-headed syringe. After 14 days, clinical and histologic measurements were performed to evaluate the healing phase of the wounds. RESULTS: The bioadhesive formulation that contained a relatively low crosslinker concentration demonstrated superior results to the formulation that contained a standard crosslinker concentration. However, no significant statistical differences were observed compared with the control incisions (sutures and commercial adhesive N-butyl-2-cyanoacrylate). This was verified by immunohistochemical analysis for epithelial integrity and scar formation as well as by clinical assessment. CONCLUSIONS: This newly developed bioadhesive demonstrated suitable properties for the closure of long incisions in a porcine skin model.

Structuring of composite hydrogel bioadhesives and its effect on properties and bonding mechanism.

Bioadhesives are polymeric hydrogels that can adhere to a tissue after crosslinking and are an essential element in nearly all surgeries worldwide. Several bioadhesives are commercially available. However, none of them are ideal. The main limitation of current tissue adhesives is the tradeoff between biocompatibility and mechanical strength, especially in wet hemorrhagic environments. Our novel bioadhesives are based on the natural polymers gelatin (coldwater fish) and alginate, crosslinked by carbodiimide (EDC). Two types of hemostatic agents with a layered silicate structure, montmorillonite (MMT) and kaolin, were loaded in order to improve the sealing ability in a hemorrhagic environment. The effect of the adhesive's components on its mechanical strength was studied by three different methods - burst strength, lap shear and compression. The viscosity, gelation time and structural features of the adhesive were also studied. A qualitative model that describes the effect of the bioadhesive's parameters on the cohesive and adhesive strength was developed. A formulation based on 400mg/mL gelatin, 10mg/mL alginate and 20mg/mL EDC was found as optimal, enabling a burst strength of 387mmHg. Incorporation of kaolin increased the burst strength by 25% due to microcomposite structuring, whereas MMT increased the burst strength by 50% although loaded in a smaller concentration, due to nano-structuring effects. This research clearly shows that the incorporation of kaolin and MMT in gelatin-alginate surgical sealants is a very promising novel approach for improving the bonding strength and physical properties of surgical sealants for use in hemorrhagic environments. STATEMENT OF SIGNIFICANCE: The current manuscript focuses on novel bioadhesives, based on natural polymers and loaded with hemostatic agents with a layered silicate structure, in order to improve the sealing ability in hemorrhagic environment. Such composite bioadhesives have not been developed and studied before. The effect of the adhesive's components on its mechanical strength was studied by three different methods, as well as the physical properties and structural features. Thorough understanding of these unique biomaterials resulted in a qualitative model which describes the effect of the bioadhesive's parameters on the cohesive and adhesive strength. Thus, structure-property-function relationships are presented. Structuring of the composite bioadhesives and its effect of the properties and bonding mechanism, are expected to be of high interest to Acta readership.

Effect of hemostatic agents on properties of gelatin-alginate soft tissue adhesives.

Lacerations and traumatic wounds are considered to be among the most prevalent scenarios encountered in hospitals and emergency rooms. Reattachment of the lacerated soft tissue edges is traditionally performed using sutures. Use of tissue adhesives, i.e. substances that have the ability to firmly attach lacerated tissues back together, has raised interest as an alternative, due to several advantages. Novel tissue adhesives based on the natural polymers gelatin and alginate, and cross-linked by carbodiimide (EDC), were recently developed by our research group. In the current research, two types of hemostatic agents, tranexamic acid and kaolin, were loaded into our gelatin-alginate bioadhesive, in order to improve the adhesion abilities in the hemorrhagic environment of the wound. Their effects on the ex vivo adherence properties, physical properties, and biocompatibility were investigated. Incorporation of kaolin significantly improved the ex vivo bonding strength of the gelatin-alginate-EDC bioadhesives through a combination of three physical mechanisms and decreased the swelling ratio without affecting weight loss. In contradiction, incorporation of tranexamic acid into the bioadhesive formulation resulted in a lower ex vivo bonding strength and a higher swelling ratio and weight loss, probably due to reduced efficiency of the cross-linking reaction between the molecules of the natural polymers and the cross-linking agent EDC. The hemostatic agent-loaded bioadhesives showed good biocompatibility when tested in vitro on fibroblast cells. This research clearly shows that the incorporation of kaolin in our gelatin-alginate tissue adhesives may be a very promising novel approach for improving the bonding strength and physical properties of the tissue adhesives for use in hemorrhagic environments.

Functionalized PLGA-doped zirconium oxide ceramics for bone tissue regeneration.

Bone tissue engineering is an alternative approach to bone grafts. In our study we aim to develop a composite scaffold for bone regeneration made of doped zirconium oxide (ZrO2) conjugated with poly(lactic-co-glycolic acid) (PLGA) particles for the delivery of growth factors. In this composite, the PLGA microspheres are designed to release a crucial growth factor for bone formation, bone morphogenetic protein-2 (BMP2). We found that by changing the polymer's molecular weight and composition, we could control microsphere loading, release and size. The BMP2 released from PLGA microspheres retained its biological activity and increased osteoblastic marker expression in human mesenchymal stem cells (hMSCs). Uncapped PLGA microspheres were conjugated to ZrO2 scaffolds using carbodiimide chemistry, and the composite scaffold was shown to support hMSCs growth. We also demonstrated that human umbilical vein endothelial cells (HUVECs) can be co-cultured with hMSCs on the ZrO2 scaffold for future vascularization of the scaffold. The ZrO2 composite scaffold could serve as a bone substitute for bone grafting applications with the added ability of releasing different growth factors needed for bone regeneration.

Gelatin-alginate novel tissue adhesives and their formulation-strength effects.

Interest in tissue adhesives as alternatives for conventional wound-closing applications such as sutures and staples has increased in the last few decades due to numerous possible advantages, including less discomfort and lower cost. Novel tissue adhesives based on gelatin, with alginate as a polymeric additive and crosslinked by carbodiimide, were recently developed by our research group. The effects of the formulation parameters on the adhesives' function were investigated in the current study. We examined the effects of gelatin and alginate concentrations and their viscosities on the ability of the bioadhesives to bind soft tissues. The effect of the crosslinking agent's concentration was studied as well. A qualitative model describing these effects in terms of adherence mechanisms was developed. Our results show that the adherence properties of our new bioadhesives are achieved by a combination of two main mechanisms: mechanical interlocking and chemical adsorption. The former mechanism is probably more dominant. The polymer's molecular weight and concentration affect the mechanical interlocking through mobility and penetration ability, entanglement of the three-dimensional structure and crosslinking density. The crosslinking agent's concentration as well as the polymer's concentration affect the crosslinking density and contribute to higher strength, achieved through both the mechanical interlocking and the chemical adsorption mechanisms. Understanding the effects of the adhesives' components and their viscosities on the bonding strength enabled us to elucidate the bonding strength mechanisms. This can lead to proper selection of the adhesive formulation and may enable tailoring the bioadhesives to the desired applications.