Magical hydrogel for rapid hemostasis

Despite the improvement in trauma management and operative procedures, traumatic rupture of the thoracic aorta and cardiovascular penetrating injuries continue to be a source of significant mortality1. Currently, surgical suture is the only clinical method for aortic rupture and heart wound sealing but this is not feasible outside surgical units and not attempted in most emergency situations2. Though many experimental chemical agents have been tested for rapid wound sealing, such as fibrin glue, gelatin and collagen3-4. However, none of these materials are suitable for aortic and heart trauma hemostasis and sealing because of their slow hemostatic performance, poor wet tissue surface adhesion and weak or inflexible bonding mechanics.

May 15, 2019
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To overcome these challenges, our lab has been working hard to design a tissue-adhesive hydrogel that meet the following needs: 1. strong wet and dynamic tissue adhesion; 2. suitable mechanical property; 3. good biocompatibility; 4. easy to use. We realized that the human body is the most amazing material created by nature, therefore we chose human tissue components as basic materials, and have tried multiple crosslinking strategies to seek a biomimic tissue-adhesive hydrogel. After screening a large amount of material, we noticed that a novel small molecule (NB: N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy) butanamide)5synthesized by Zhu’s lab could help us achieve the goal. This small molecule could generate aldehyde group after UV irradiation and it could bond to tightly to tissues through Schiff base reactions. So, we contacted Prof. Linyong Zhu and teamed up with him to design the current project involving this small molecule published on Nature Communications.  

Figure 1 Constituent chemical structures and a schematic diagram illustrating the formation of the photo-triggered-imine-crosslinked matrix hydrogel. 

The hydrogel design was inspired by the extracellular matrix composition of biological tissues. They are generally consisted of collagen (10–15%), glycosaminoglycans (3–6%) and water (70–80%), and possess strong and flexible bio-mechanical properties. The matrix hydrogel bio-adhesive used here was composed of 5% methacrylated gelatin (GelMA), 1.25 % N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy) butanamide (NB) linked to the glycosaminoglycan hyaluronic acid (HA-NB) with 0.1% of the polymerization initiator lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) (Figure 1).  

The hydrogel could gelate very fast and withstand up to 290 mmHg blood pressure, significantly higher than blood pressures in most clinical settings (systolic BP 60 to 160 mmHg). While the commercially available surgical gules such as fibrin glue and SurgifloTM showed lower blood pressure. We were very excited with these results, so we decided to do further investigation to examinethe sealant and hemostatic performance of this hydrogel.

Figure 2.Hemostatic properties of the matrix gel in a pig cardiac puncture injury model

After achieving amazing results in small animal models (rats and rabbits), we next validated the hydrogel’s ability to seal blood leakage on a pid heart penetration model. Heart is the central organ of vertebrate circulatory physiology and when cardiac penetration injuries occur, massive hemorrhage results in lives being lost within a very short time. Our hydrogel can stop high pressure bleeding from pig carotid arteries with 4~5 mm long incision woundsand from pig hearts with 6 mm diameter cardiac penetration holes (Figure 2). Treated pigs survived after hemostatic treatments with this hydrogel, which is well-tolerated and appears to offer significant clinical advantage as a traumatic wound sealant.

Ref.

  • Pfeifer, R., Tarkin, I. S., Rocos, B. & Pape, H.-C. Patterns of mortality and causes of death in polytrauma patients—Has anything changed?Injury40, 907-911 (2009)
  • Reddy, D. & Muckart, D.J.J. Holes in the heart: an atlas of intracardiac injuries following penetrating trauma. Interactive CardioVascular and Thoracic Surgery19, 56-63 (2014).
  • Laurenti, J.B., et al.Enhanced pro-coagulant hemostatic agents based on nanometric zeolites. Micropor Mesopor Mat239, 263-271 (2017).
  • Quan, K., et al.Diaminopropionic Acid Reinforced Graphene Sponge and Its Use for Hemostasis. Acs Appl Mater Inter8, 7666-7673 (2016).
  • Yang, Y., et al.Tissue‐Integratable and Biocompatible Photogelation by the Imine Crosslinking Reaction. Advanced Materials28, 2724–2730 (2016).

Hongwei Ouyang

Professor, Zhejiang University

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