Silk Fibroin-Based Biomaterials for Hemostatic Applications

Abstract

Hemostasis plays an essential role in all surgical procedures. Uncontrolled hemorrhage is the primary cause of death during surgeries, and effective blood loss control can significantly reduce mortality. For modern surgeons to select the right agent at the right time, they must understand the mechanisms of action, the effectiveness, and the possible adverse effects of each agent. Over the past decade, various hemostatic agents have grown intensely. These agents vary from absorbable topical hemostats, including collagen, gelatins, microfibrillar, and regenerated oxidized cellulose, to biologically active topical hemostats such as thrombin, biological adhesives, and other combined agents. Commercially available products have since expanded to include topical hemostats, surgical sealants, and adhesives. Silk is a natural protein consisting of fibroin and sericin. Silk fibroin (SF), derived from silkworm Bombyx mori, is a fibrous protein that has been used mostly in fashion textiles and surgical sutures. Additionally, SF has been widely applied as a potential biomaterial in several biomedical and biotechnological fields. Furthermore, SF has been employed as a hemostatic agent in several studies. In this review, we summarize the several morphologic forms of SF and the latest technological advances on the use of SF-based hemostatic agents.

Keywords: hemostatic agent; medical application; powder; sealant; silk fibroin; sponge.

Figure 1

Schematic mechanism of hemostasis. Primary hemostasis starts with vasoconstriction at the injury site, and platelet aggregates due to the interaction of fibrinogen and Willebrand factor (vWF). Secondary hemostasis involves the formation of insoluble, cross-linked fibrin via stimulated coagulation factors, especially thrombin.

Figure 2

Evaluation of the in vitro blood coagulation effect of the SF-based powder. SF powders containing calcium (SF + Ca) and phosphoric acid (SF + P) exhibited improved blood coagulation when it reacted with them. Unpublished data.

Figure 3

In vivo hemostasis of the SF-based powder using the femoral vein incision of the rat. After the femoral vein incision, SF-based powders were applied to stop bleeding for 30 s. Unpublished data.

Figure 4

Evaluation of the hemostasis of the SF/Gel/PVA sponges using rat femoral hemorrhage injury model. Before removing hemostatic agents (upper panel) and after (lower panel). (A) ChitoClot^®, (B) SF/Gel/PVA [70].

Figure 5

Hemostatic effect of SF-based sponges in a femoral artery wound of rat model. (A,E) Avitene, (B,F) Duck’s feet collagen (DFC), (C,G) Silk and (D,H) DFC/Silk [62].

Figure 6

Vascular adhesive and hemostatic effect of Sil-MAS on wet surfaces. (A) Images of ex vivo burst pressure test process for Sil-MAS. (i) The setup for the burst pressure experiment, (ii) Opening in the middle of the aorta, (iii) Appication of Sil-MAS on the wound site and UV exposure. (iv) Completion of the aorta burst pressure test. (B) Porcine aorta burst pressures on the incision shielded with Sil-MAS. (C) Porcine aorta burst pressures after end-to-end anastomosis by Nylon suture alone and Nylon suture with Sil-MAS. (D) In vivo vascular closure experiment of Sil-MAS. (i) Femoral artery incision and bleeding, (ii) Slight hemostasis using gauze, (iii) Use of Sil-MAS on the incision site and UV exposure, (iv) Cessation of bleeding, (v) Confirmation of hemostasis. (E) Images of the sealants used in an in vivo liver parenchymal injury model. (i) The bleeding from the injury site rose after a circular tissue extraction with a 0.5 cm long and 0.5 cm deep wound on the rat liver surface. (ii) After wiping the wound using gauze for slight hemostat, (iii) Sil-MAS (or Fibrin glue) was employed to the resected site, (iv) cross-linked by UV (for Sil-MAS) and thrombin (for Fibrin glue), and (v) bleeding stopped. [84].

Figure 7

Hemostatic effect of Sil-MAS on the rabbit liver laceration model. (A,B). Creating of the liver laceration (deep and superficial) by endoscopic scissors and suction. (C) Bleeding and hematom on the surface of the liver. (D) After briefly pressing with gauze on the bleeding liver laceration wounds (E) Application of the Sil-MAS (1.0 cc) using self-made laparoscopic Sil-MAS device. (F) UV (20 s) exposure via fiber optic lens in the device. (G) Examination of the re-bleeding or outflow of blood at the lesions using endoscopic forceps. (H) Completion of the adhesion and gelation of Si-MAS on liver laceration lesion [84].