Page 363 - IJB-9-1

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

like in cases where blood loss is associated with severe chemical configuration, which regulates the natural
tissue damage . Such severity often demands enormous course of the wound healing process. The natural wound
[3]
tissue regeneration or repair following blood clots, healing process occurs in various overlapping stages,
which can be effectively managed by multifunctional including hemostasis, inflammation, proliferation, and
3D hemostats. Micro/nanostructure-enabled hemostat remodeling (Figure 1A). Each stage requires extensive
availability is favorable for clinical use because these communication between different cellular constituents
novel agents have shown excellent inherent biomimetic of various compartments of the skin and its extracellular
properties following the body’s natural wound healing matrix (ECM) , creating a dynamic and complex
[18]
process . For instant, fabricating hemostatic agents environment caused by the activation and influence of
[4]
capable of inducing angiogenesis, immune responses, different signaling pathways of the coagulation cascade on
and desired signaling pathways following blood clotting each other. Interruption or deregulation of one or more
might serve as an effective hemostat [5-10] . Another reason overlapping phases may lead to non-healing (chronic)
why micro/nanostructured hemostatic agents have wounds in the wound healing process. Thus, the efficient
gained popularity is because of their ability to respond design of functional micro/nanostructures to accelerate
to intracellular and extracellular stimuli through their the physiological process of hemostasis is essential ; and
[19]
physical architecture . Their architecture allows them elucidation of the body’s natural hemostasis mechanisms,
[4]
to adapt quickly, closely connecting the structural and such as the natural blood coagulation cascade, is imperative
functional aspects of the biointerface. Additionally, when for the fabrication of effective hemostatic agents . The
[20]
fabricating multifunctional 3D hemostats, characteristics body’s priority after an injury is to stop blood loss. The
such as desired topography, biocompatibility, mechanical fibrin clot stops blood loss while trapping inflammatory
stability, biodegradability, and antibacterial properties are cells like neutrophils, monocytes, macrophages,
fundamental properties under consideration, for which Langerhans cells, dermal dendritic cells, and T cells, among
surface modification has shown excellent outcomes . others [21,22] . The closure of the inflammatory phase follows
[11]
Because of this, choosing materials with biocompatible the onset of angiogenesis, which involves endothelial cell
and anti-infection properties should be heavily considered proliferation, activation of pericytes, migration, and neo-
when designing micro/nanostructures for rapid hemostasis. blood vessel formation. While neo-angiogenesis prevails,
However, it is more advantageous to select materials and fibroblasts proliferate and deposit ECM, indicating the
use fabrication techniques most appropriate to the needs of growth stage of the healing tissue [23-29] . Re-epithelization
the individual based on the specific condition at hand [12-16] . occurs simultaneously, involving the proliferation of both
Hence, innovation in the fabrication and use of 3D micro/ unipotent epidermal stem cells and de-differentiation
nanohemostats is necessary for improved medication. of terminally differentiated epidermal cells . Re-
[30]
Current technologies allow us to fabricate these epithelialization also involves the reconstruction of all skin
structures via extrusion methods, electrospinning, appendages, including the formation of sebaceous glands,
soft lithography, stereolithography (SLA), digital light sweat glands, and hair follicles.
processing (DLP), 3D/4D printing, and combined methods 2.1. Cellular and molecular mechanisms of
to create hemostats with excellent biocompatibility, zero to physiological hemostasis
low cytotoxicity, long-term stability, antibacterial activity, Hemostasis marks the first stage of wound healing,
and among others . including vasoconstriction, primary hemostasis, and
[17]
Thus, this paper aims to review the multifunctional 3D secondary hemostasis. The key factor in hemostasis is
platforms, which are designed using advanced fabrication the platelets, while the critical matrix component is the
techniques, for rapid hemostasis and wound healing. fibrinogen. A healthy endothelial cell monolayer in an
It also aims to interpret the relevance of 3D micro/ unruptured blood vessel prevents the platelets’ untimely
nanotopography in the functional prospect at the wound- activation, thereby preventing their adhesion to the vessel
implant interface. We anticipate this work will provide wall or clumping among each other. Vasoconstriction
valuable information to develop future innovations and formation of a fibrin clot in the bleeding site prevents
concerning smart hemostats for biomedical applications. blood loss after injury. The clot is formed from the
adherence and aggregation of platelets. The generation
2. Mechanism of wound healing and of fibrin is then established from the activation of
hemostasis prothrombin to thrombin, where thrombin cleaves
fibrinogen to form fibrin. A blood clot is followed by
Each hemostat’s mode of operation is determined by the primary and secondary hemostasis. Primary hemostasis
degree of intrinsic variation in the material’s physico- involves platelet aggregation and platelet plug formation

V 355 https://doi.org/10.18063/ijb.v9i1.648
Volume 9 Issue 1 (2023)olume 9 Issue 1 (2023)