Hydrogels in Trauma: Our experiences with Hemorrhage and Burn Models

A. Nazarian
Harvard Medical School,
United States

Keywords: biomaterials, hydrogels

Summary:

Uncontrolled hemorrhage is the leading cause of pre-hospital death following military and civilian trauma. Early control of hemorrhage can improve immediate care and delay mortality through the prevention of massive blood loss, hypotension, coagulopathy, metabolic derangements, and infection. A number of observational reports support the use of sealants when bleeding cannot be controlled using pressure dressings alone. An ideal sealant does not require manual pressure to properly control external bleeding, is suitable for the management of internal hemorrhage, and can be removed without mechanical debridement. We have developed an on-demand dissolvable dendritic thioester hydrogel sealant for traumatic hemorrhage control that will safely provide non-clotting cascade dependent hemostasis in abdominal and extremity wounds. The hydrogel is composed of a lysine-based dendron, which was synthesized in high yield, and a PEG-based crosslinker. The dendron was characterized by 1H and 13C NMR spectroscopy and MALDI. The on-demand hydrogel dissolution relies on the mechanism of thiol-thioester exchange. The hydrogel sealant has been shown to adhere to and seal injured tissues: when compared to untreated controls, it reduced blood loss by 35% in a rat model of severe hepatic hemorrhage (23.57 ± 8.27 mL/kg v. 35.21 ± 7.47 mL/kg; p = 0.02) and by 20% in a rat model of aortic injury (17.95 ± 3.84 mL/kg v. 23.09 ± 3.80 mL/kg; p = 0.03). A unique feature of our hydrogel sealant is its capability to be gradually dissolved with biocompatible thiol-based solutions following its initial application – thus the wound area can be re-exposed in a controlled manner to allow for definitive surgical care in an operative setting.​ Current second-degree burn wound dressings absorb wound exudate, reduce bacterial infections, and maintain a moist environment for healing, but are surgically or mechanically debrided from the wound, causing additional trauma to the newly formed tissues. We have developed a hydrogel-based dressing which possesses the favorable characteristics of conventional dressing along with the unique capability to be dissolved on-demand, via thiol-thioester exchange, allowing for an atraumatic burn dressing change. The efficacy of the hydrogel in preventing wound infection and sepsis was evaluated in an animal model of second-degree burns. This study was approved by the Animal Care and Use Committee (IACUC) at Beth Israel Deaconess Medical Center and Boston University. Deep partial-thickness burns, covering approximately 5% of total body surface area, were induced on adult female Sprague-Dawley rats and the animals were divided into three groups: 1) burn only (negative controls, n = 5), 2) burn + bacterial contamination (positive controls, n = 5), or 3) burn + hydrogel + bacterial contamination (hydrogel-treated group, n = 5). Bacterial contamination in the positive controls and hydrogel-treated group was achieved by covering the burn and the burn + hydrogel wounds with a gauze containing 2x108 CFU of log-phase Pseudomonas aeruginosa. The hydrogel prevented the occurrence of detectable local infections (defined as those with >100 CFU/g of tissue) when compared to positive controls (20 ± 17% v. 100 ± 0%; P = 0.001). Additionally, the bacterial burden of the wound in the positive controls was significantly higher than in the hydrogel group and the negative controls (1.39x108 ± 8.30x107 CFU/g v. 4.04x103 ± 3.99x103 CFU/g v. 6.88x102 ± 6.38x102 respectively; P = 0.009). The hydrogel also effectively decreased the prevalence of detectable systemic infections (sepsis) when compared to positive controls (0 ± 0% v. 60 ± 21%; P = 0.038). The total systemic bacterial burden in the positive controls was significantly higher than the hydrogel group and the negative controls (9x102 ± 7.76x107 CFU/g v. 5x101 ± 0 FU/g v. 5x101 ± 0 CFU/g, respectively; P = 0.031). From a clinical perspective, engineering a hydrogel dressing that seals the wound, prevents bacterial infection, and dissolves on-demand for atraumatic removal offers significant promise for a more effective treatment for second-degree burn patients