Page 365 - IJB-9-1

International Journal of Bioprinting Micro/nano-3D hemostats for rapid wound healing

2.4. Secondary hemostasis platelets, and other coagulation factors, thus creating a
Platelets are the templates for the assembly and activation of physical barrier to stop further hemorrhage. Due to the
coagulation complexes. The coagulation pathways involved inherent dynamic properties of all micro/nanostructures,
usually is classified as intrinsic and extrinsic pathways. both can create a suitable 3D microenvironment to support
The exposure of the subendothelial matrix activates both cell activities, such as adhesion, growth, and differentiation,
the pathways, which leads to the activation of factor X. for biomimetic wound healing and effective hemostasis
Following the activation of factor X, the prothrombin is modulation [41,42] . Some unique micro/nanostructures and
converted to thrombin which cleaves fibrinogen to fibrin. their hemostatic mechanisms are summarized in Table 1.
Factor XIII then covalently crosslinks fibrin, which binds Therefore, to effectively represent the spatiotemporal
the aggregated platelet forming the secondary hemostasis, functionality of the target tissue’s dynamic environment,
also known as the thrombus. The thrombus then serves as micro/nanostructure design for hemostasis requires a
the wound matrix for infiltrating other cells until wound conscientious selection of fabrication materials and close
healing . The various stages of wound healing and attention to its architectural constitution in addition to the
[36]
hemostasis are illustrated in Figure 1B. inherent physical and biochemical properties .
[43]
3. Structural and functional prospect of 3.1. Structural modulation
biomaterial at biointerface The micro/nanostructures in hemostats accelerate the
onset of hemostasis through multiple mechanisms,
Rapid promotion of hemostasis and subsequent including rapid blood absorption, faster blood clot
biomimetic wound healing is possible via different micro/ formation, and altered cell dynamics and behavior [44,45] .
nanostructures [37,38] . These structures include nanotubes, Microproperties of a hemostatic agent can be tuned
nanofibers, and micro/nanoparticles. Although the depending on the manufacturing technique used to shape
hemostatic mechanism of nanotubes have not yet been the materials used for its fabrication. For example, cell
fully elucidated, they have been utilized as hemostatic anchorage is a defining characteristic that can be tuned
agents for thousands of years in traditional Chinese in scaffolds for hemostasis via microstructures. This
medicinal applications [39,40] . However, it has been recently tunability is crucial to hemostat functionality because cell
discovered that nanotubes fabricated for rapid hemostasis anchorage to the scaffolds via microstructure interaction
have a high structural aspect ratio and surface area. can promote cell adhesion, facilitating the mediation of cell
Owing to this, hemostasis proceeds via plasma or fluid morphology and subsequent differentiation. For example,
interaction through one of these mechanisms: (i) efficient topographical features such as pillar height have proven
water absorption, leading to material concentration; (ii) relevant in affecting traction and reaction force upon cells
factor XII activation within the intrinsic coagulation when subject to lateral displacement, which directly affects
cascade, which in turn causes ionic bonding of amino cellular attachment and subsequent behavior (Figure 2A).
acids; or (iii) the formation of a physical barrier that stops Physical properties, such as stiffness and elasticity, have
further hemorrhage. The mechanism of hemostasis varies also been proven to affect cell morphology by altering the
depending on the structural aspect associated with the cytoskeletal organization and contractibility, guiding stem
type of materials used in their fabrication, but micro- and cell differentiation into specific lineages .
[46]
nanofibers tend to operate through a similar mechanism.
Molecules are self-assembled into a micro/nanofiber 3.1.1. Microscale structures
mat-like structure, leading to improved platelet binding. Polymeric microstructures with rough and random pores
This micro/nanofiber mat promotes blood clot formation (~5–10 µm) are promising topological attributes that
by accelerating fibrin, platelet, and red blood cell (RBC) facilitate interfacial interaction between RBC and the
coagulation on the material’s surface. Micro/nanoparticles, hemostat leading to rapid RBC aggregation (Figure 2B).
including micro/nanospheres and adhesive powders/gels, These microstructures often act as molecular sieves
are small and feature a high surface area. Although the that absorb water in the blood and concentrate RBC
molecular mechanism for micro/nanoparticles is not yet promptly [47,48] . Microscale structures are also favored in
well understood, we can confirm that there is a promotion the fabrication of on-demand hemostatic microbots. The
of blood cell and platelet aggregation on the surface of the micropatterns in the hemostat are often loaded with drug
micro/nanostructures due to physical factors of incurred materials to make them effective drug delivery vehicles
water absorption and consequent swelling. Some micro/ for rapid blood clotting. Furthermore, the microstructure
nanoparticles induce rapid hemostasis through liquid pattern mediates drug delivery for hemostasis
absorption in the formation of an in situ hydrogel. This spatiotemporally with stimuli-responsive materials. These
absorption leads to the concentration of blood cells, microstructure-oriented systems can be controlled via

V 357 https://doi.org/10.18063/ijb.v9i1.648
Volume 9 Issue 1 (2023)olume 9 Issue 1 (2023)