Synthetic hydrogels as blood clot mimicking wound healing materials

Abstract

Excessive bleeding-or hemorrhage-causes millions of civilian and non-civilian casualties every year. Additionally, wound sequelae, such as infections, are a significant source of chronic morbidity, even if the initial bleeding is successfully stopped. To treat acute and chronic wounds, numerous wound healing materials have been identified, tested, and adopted. Among them are topical dressings, such as gauzes, as well as natural and biomimetic materials. However, none of these materials successfully mimic the complex and dynamic properties of the body's own wound healing material: the blood clot. Specifically, blood clots exhibit complex mechanical and biochemical properties that vary across spatial and temporal scales to guide the wound healing response, which make them the ideal wound healing material. In this manuscript, we review blood clots' complex mechanical and biochemical properties, review current wound healing materials, and identify opportunities where new materials can provide additional functionality, with a specific focus on hydrogels. We highlight recent developments in synthetic hydrogels that make them capable of mimicking a larger subset of blood clot features: as plugs and as stimuli for tissue repair. We conclude that future hydrogel materials designed to mimic blood clot biochemistry, mechanics, and architecture can be combined with exciting platelet-like particles to serve as hemostats that also promote the biological wound healing response. Thus, we believe synthetic hydrogels are ideal candidates to address the clear need for better wound healing materials.

Keywords: blood clot; hydrogel; wound healing.

Figure 1.

The diverse and multi-fold roles of blood clots. Among them, (A) blood clots occlude the initial wound site to stop hemorrhage. Additionally, blood clot constituents, such as platelets, release chemokines that attract immune cells. (B) As wound healing progresses, blood clots also provide a substrate for migrating matrix-synthesizing cells to infiltrate the clot and remodel the clot’s fibrin mesh with collagen. (C) Eventually, the blood clot is replaced by the repaired tissue. Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature, Pediatric Research [10], Copyright © 2013, International Pediatric Research Foundation, Inc.

Figure 2.

Blood clots are biocomposites in which platelets and red blood cells are entrapped in a semi-flexible biopolymer network of fibrin fibers. The fibrin network arises following a complex cascade of reactions among coagulation factors that lead to (A) cleavage of fibrinogen into fibrin, (B) the assembly of cross-linked fibrin molecules into fibers, and (C) network formation that entraps red blood cells and other blood-borne elements. Scale bar is 10 μm. Republished with permission of American Society of Hematology Publications, from [19], 2016; permission conveyed through Copyright Clearance Center, Inc..

Figure 3.

Blood clots show highly nonlinear, time-dependent mechanics. (A) Strain-stiffening behavior that evolves during thrombus maturation with more mature thrombus being stiffer, ((B) and (C)) viscoelastic behavior, including stress-relaxation and creep, hysteresis, and set, and finally (D) active stress due to platelet activity and fibrin contraction.

Figure 4.

During wound healing a blood clot performs diverse roles that span multiple orders of spatial and temporal scales. Among them, a blood clot provides a fibrinous and—in the course of maturation—collageneous scaffold that acts as a substrate for immune and matrix-synthesizing cells as well as a bed for newly sprouting blood vessels. Finally, a blood clot evolves into scar tissue that seals the injury site upon conclusion of the wound healing response. Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature, Pediatric Research [10], Copyright © 2013, International Pediatric Research Foundation, Inc.

Figure 5.

Wound healing hydrogels offer the potential for mimicking blood clots, bridging the gap between synthetic and natural materials.

Figure 6.

Synthetic hydrogels can mimic the properties of blood clots through the use of structural, chemical, and biological strategies. These strategies include the use of semiflexible polymers to induce strain-stiffening behavior, dynamic crosslinks to elicit viscoelasticity, and inclusion of synthetic platelets to generate active contraction.