In vivo study of the efficacy of bupivacaine-eluting novel soy protein wound dressings in a rat burn model.

Dealing with wound related pain is an integral part of treatment. Systemic administration of analgesic and anesthetic agents is a common solution for providing pain relief to patients but comes at a risk of severe side effects as well as addiction. To overcome these issues, research efforts were madeto provide a platform for local controlled release of pain killers. We have developed a bilayer soy protein-based wound dressing for the controlled local release of bupivacaine to the wound site. The combination of a dense and a porous layer provides a platform for cell growth and proliferation as well as physical protection to the wound site. The current study focuses on the in vitro bupivacaine release profile from the dressing and the corresponding in vivo results of pain levels in a second-degree burn model on rats. The Rat Grimace Scale method and the Von Frey filaments method were used to quantify both, spontaneous pain and mechanically induced pain. A high burst release of 61.8 ± 1.9% of the loaded drug was obtained during the initial hour, followed by a slower release rate during the following day. The animal trials show that the RGS scores of the bupivacaine-treated group were significantly lower than these of the untreated group, proving a decrease of 51-68% in pain levels during days 1-3 after burn. Hence, successful pain reduction of spontaneous pain as well as mechanically induced pain, for at least three days after burn was achieved. It is concluded that our novel bupivacaine eluting soy protein wound dressings are a promising new concept in the field of local controlled drug release for pain management.

Bupivacaine-eluting soy protein structures for controlled release and localized pain relief: An in vitro and in vivo study.

Burn pain is known to be excruciating, and while burn care has greatly advanced, treatment for burn-related pain is lacking. Current pain relief methods include systemic administration of analgesics, which does not provide high drug concentration at the wound site. In the present study, soy protein was used as the base material for bupivacaine-loaded hybrid wound dressings. The effect of the formulation on the drug release profile was studied using high performance liquid chromatography, and the cytotoxicity was tested on human fibroblasts. A second-degree burn model in rats was used to quantify the efficacy of the wound dressings in vivo, using the Rat Grimace Scale. All tested films exhibited high biocompatibility, and the drug release profiles showed rapid release during the initial 5 hr and a continuous slower release for another 24 hr. Significant pain relief was achieved in the animal trials, proving a decrease of 51-68% in pain levels during days 1-3 post-burn. Hence, the results indicate a safe and controlled bupivacaine release for a period of more than 24 hr, effectively treating pain caused by second-degree burns. The understanding of the formulation-properties effects, together with our in vivo study, enables to advance this field toward tailorable systems with high therapeutic potential.

In vitro characterization of novel multidrug-eluting soy protein wound dressings.

Polymers derived from natural sources are of interest in the scientific and medical communities, especially soy protein which exhibits low immunogenicity and good mechanical properties, and supports cell proliferation. Soy protein is cost-effective compared to other natural polymers and is attractive also due to its non-animal origin and relatively long storage stability. In the current study, hybrid film structures were developed and studied as a novel wound dressing platform with controlled release of three bioactive agents. The dense top layer is designed to provide mechanical support, control the water vapor permeability and to elute the antibiotic drug cloxacillin and the analgesic drug bupivacaine to the wound site. The porous sub-layer is designed to absorb the wound exudates and release the hemostatic agent tranexamic acid for bleeding control. The results show that the formulation parameters, i.e. crosslinker and plasticizer concentrations, affected the mechanical properties of the wound dressings as well as relevant physical properties (water vapor transmission rate and swelling kinetics), but had almost no effect on the drug-release profiles. While the antibiotic drug and the analgesic drug were released within several hours, the hemostatic agent was released within several minutes, according to the well designed hybrid structure. In conclusion, our novel soy protein hybrid wound dressings are biocompatible, can deliver various drugs simultaneously in a controlled fashion for each drug individually, and can be adjusted to suit various types of wounds by altering their properties through formulation effects.

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.