A group of researchers recently published a paper in the journal ACS Biomaterials Science & Engineering that demonstrated the feasibility of using shape-recoverable macroporous nanocomposite hydrogels for rapid noncompressible wound hemorrhage hemostasis.
Study: Shape-Recoverable Macroporous Nanocomposite Hydrogels Created via Ice Templating Polymerization for Noncompressible Wound Hemorrhage. Image Credit: sfam_photo/Shutterstock.com
Significance of Developing Effective Hemostatic Agents for Noncompressible Wound Hemorrhage
Uncontrolled hemorrhage due to surgical operations or severe trauma has accounted for a significant number of trauma deaths worldwide, necessitating the development of hemostatic agents that can effectively and rapidly control bleeding for prehospital care to improve patient survival rates.
Although several hemostats were developed in the last decade, their performance for noncompressible wound hemorrhage hemostasis has been unsatisfactory.
Hydrogel matrices with an interconnected macroporous structure allow water to flow out when squeezed and then quickly recover to its original shape when coming into contact with water. These matrices are suitable for coagulopathy hemorrhage and fatal noncompressible hemorrhage hemostasis.
Hydrogels fabricated through the ice templating approach at sub-zero temperatures are endowed with an inherent interconnected macroporous structure, exceptional flexibility, and rapid shape-memory performance. For instance, shape-memory cryogels synthesized for lethal noncompressible hemorrhage hemostasis promoted red blood cell (RBC) aggregation and platelet adhesion at the bleeding site, which accelerated the thrombus formation.
However, covalently cross-linked gelatin hydrogels are usually brittle in nature due to the lack of an energy-dissipating bond, extensive entanglements, and heterogeneous cross-linking density, which limits their use in several applications.
Recent studies have demonstrated that nanoparticles (NPs) form a nano-enabled physical network with different polymers such as hydrogels through noncovalent interaction in order to improve the polymer toughness.
For instance, highly charged NPs such as disk-shaped Laponite nanoclays possess an anisotropic charge on their surface that comes into reversible electrostatic interaction with the gelatin, which improves the mechanical properties of gelatin. Moreover, Laponite nanoclays can promote blood coagulation by favoring platelet adhesion, endogenous hemostasis pathway activation, and cooperating with physical hemostatic performance. Thus, a Laponite nanoclay-gelatin-based macroporous hydrogel can potentially display an exceptional hemostasis efficiency for noncompressible bleeding.
Synthesis of Shape-recoverable Macroporous Nanocomposite Hydrogels
In this study, researchers fabricated a shape-recoverable macroporous nanocomposite hydrogel through the ice templating polymerization method and evaluated the effectiveness of the synthesized sample as a hemostatic agent.
Type A gelatin from porcine skin, methacrylic anhydride (MA), Laponite nanoclay, sodium hydroxide, N′N′N′N′-tetramethyl ethylenediamine (TEMED), and potassium persulfate (KPS) were used as the starting materials for the study. Methacrylate-modified gelatin was synthesized through an amidation reaction between gelatin and methacrylic anhydride.
The Laponite nanoclay-gelatin-based macroporous hydrogel was fabricated through redox-induced free-radical polymerization of Laponite nanoclay and methacrylate-modified gelatin at sub-zero temperatures. Initially, methacrylate-modified gelatin was dissolved into deionized (DI) water under robust magnetic stirring, and then Laponite nanoclays were mixed vigorously into the mixture to obtain a homogeneous transparent dispersion.
Subsequently, the initiator KPS was added to the mixture, followed by the accelerator TEMED, to initiate the polymerization reaction to obtain precursor solutions. Using a syringe, the precursor solutions were injected into cell culture plates and placed in a freezer for 16 hours to obtain macroporous hydrogels.
Characterization and Evaluation of Synthesized Samples
Proton nuclear magnetic resonance (1H NMR) characterization, Fourier transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), dynamic mechanical analysis (DMA), and confocal laser scanning microscopy (CLSM) were used to characterize the synthesized hydrogel samples. The shape-memory behavior of the hydrogel scaffolds was evaluated by the volumetric expansion ratio and recovery time within the water. Researchers also performed cytotoxicity test, hemolytic activity assay, biological safety evaluation, in vitro blood clotting evaluation, and in vivo hemostasis evaluation of the synthesized samples.
A shape-recoverable macroporous nanocomposite hydrogel with an interconnected macroporous structure was fabricated successfully. The FTIR spectroscopy and XPS confirmed the presence of gelatin and Laponite nanoclays in the synthesized nanocomposite hydrogel. The hydrogel was molded into different geometric shapes and sizes, indicating the potential to fabricate the hydrogel into various shapes for practical clinical applications.
The addition of small amounts of Laponite nanoclays enhanced the mechanical properties, such as compressive modulus and compression strain, of the nanocomposite hydrogel.
Rapid shape recovery was observed in all macroporous hydrogel samples, indicating that the hydrogels possess good shape-recovery properties. The samples withstood 60 percentage strain with load and then quickly regained their original shape after the load was released. The rapid water-triggered shape-memory property of the hydrogels was attributed to the macroporous and interconnected structure of the samples, which make them suitable as a hemostatic agent for noncompressible bleeding.
All synthesized samples demonstrated excellent hemocompatibility, biocompatibility, and cytocompatibility, which indicated their feasibility for deep-wound hemostasis. Additionally, the hydrogels displayed an effective blood-clotting performance for noncompressible liver bleeding. The synthesized hydrogels enabled rapid absorption of blood at the bleeding site to concentrate the coagulation factors.
The Laponite nanoclays then enabled one of the factors to activate the endogenic coagulation cascade mechanism, thereby accelerating the thrombus formation. The in vivo liver bleeding model also confirmed that the nanocomposite hydrogels can be used to achieve rapid hemostasis for noncompressible liver hemorrhage.
Taken together, the findings of this study demonstrated that the synthesized shape-recoverable hydrogels could act as reliable and fast hemostats to effectively achieve noncompressible wound hemorrhage hemostasis.
Zeng, Z., Peng, G., Teng, L. et al. (2022) Shape-Recoverable Macroporous Nanocomposite Hydrogels Created via Ice Templating Polymerization for Noncompressible Wound Hemorrhage. ACS Biomaterials Science & Engineering. https://pubs.acs.org/doi/10.1021/acsbiomaterials.2c00115