Next Generation Hemostatic Materials Based on NHS-Ester Functionalized Poly(2-oxazoline)s

Abstract

In order to prevent hemorrhage during surgical procedures, a wide range of hemostatic agents have been developed. However, their efficacy is variable; hemostatic devices that use bioactive components to accelerate coagulation are dependent on natural sources, which limits reproducibility. Hybrid devices in which chain-end reactive poly(ethylene glycol) is employed as active component sometimes suffer from irregular cross-linking and dissolution of the polar PEG when blood flow is substantial. Herein, we describe a synthetic, nonbioactive hemostatic product by coating N-hydroxysuccinimide ester (NHS)-functional poly(2-oxazoline)s (POx-NHS) onto gelatin patches, which acts by formation of covalent cross-links between polymer, host blood proteins, gelatin and tissue to seal the wound site and prevent hemorrhage during surgery. We studied different process parameters (including polymer, carrier, and coating technique) in direct comparison with clinical products (Hemopatch and Tachosil) to obtain deeper understanding of this class of hemostatic products. In this work, we successfully prove the hemostatic efficacy of POx-NHS as polymer powders and coated patches both in vitro and in vivo against Hemopatch and Tachosil, demonstrating that POx-NHS are excellent candidate polymers for the development of next generation hemostatic patches.

Poly(2‐oxazoline) Hydrogels: State‐of‐the‐Art and Emerging Applications

“…The hemostatic dressing listed in the table below is the only animal study of a material resembling a PAOx hydrogel to date. In their study, Van Hest and co‐workers, together with tissue‐sealant company GATT Technologies, used N ‐hydroxysuccinimide (NHS) ester functional copolymer of 2‐ n ‐propyl‐2‐oxazoline (PropOx) and 2‐methoxycarbonylethyl‐2‐oxazoline (MestOx) coated onto a collagen sponge. Even though this is not a PAOx hydrogel, the excess NHS ester groups crosslinked with blood and extracellular matrix (ECM) proteins form an in situ hydrogel coating that induces blood clotting and stops bleeding ( Figure 2 ).…”

“…If, however, water soluble macromonomers are used with mild cross‐linking reactions, then it is possible to form gels under nontoxic conditions. Most of the studies to date include only proof‐of‐principle cell toxicity studies and no long‐term or in vivo data exist yet other than that of Van Hest and co‐workers discussed in Section .…”

Thermal treatment stimulus on erythrocyte compatibility and hemostatic behavior of one‐dimensional bioactive nanostructures

“…Nanotechnology provides a platform to engineer a hemostatic material with better properties at relevant situations. Boerman et al (2017) detailed about the hemostatic base materials, and further elaborated that polymeric components are the core factor of hemostatic products, such as chitosan, starch, oxidized cellulose, gelatine, and collagen. These biocompatible as well as biodegradable materials accelerate coagulation and also explained the limitations of these polymers specifically on hemostatics.…”

In situ forming gelatin/hyaluronic acid hydrogel for tissue sealing and hemostasis

“…It is well‐known that the rapid closure and repair of wounds, especially skin wounds and wounds from surgical or traumatic disruption, are the best ways to prevent infection and to accelerate healing (Lu, Wang, Li, Li, Wang, et al, ). One of the main challenges during surgical procedures on parenchymatous tissue is to control bleeding (Boerman et al, ). Excessive bleeding usually increases the risk of hemorrhagic shock, coagulopathy, infection, and multiple organ failures (Li et al, ).…”