Table 1.

Topical and Externally Administered Hemostatic Biomaterials from Natural Sources

Materials and Technologies	Mechanism of Action	Example Evaluations and Characteristic Applications	Characteristic Findings
Cotton and cellulose-based materials, e.g., - Cotton gauze - Open weave cloth gauze soaked in paraffin, balsam and olive oil (e.g. tulle dressings) - Oxidized Cellulose (OC) - Oxidized Regenerated Cellulose (ORC) etc. - Carboxymethyl cellulose hydrogel system etc.	Provides high absorption at the wound site in addition to possibly triggering the contact pathway of coagulation; Tulle dressings maintain a moist wound bed while allowing absorption of exudate to pass into a secondary dressing and also reduces adherence of the dressing to the wound bed; Cellulose fibers initiate clotting cascade through contact activation, and can also decrease the pH at the wound site leading to platelet activation and aggregation, degradation of interleukins, antimicrobial defense and scavenging of reactive oxygen species	Cotton gauze materials have been historically evaluated and used as absorbents, dressings and packing materials in managing all forms of bleeding; Several licensed cotton-based products are approved in clinical use as dressings and bandages; Tulle gauze has been evaluated as wound dressings in partial-thickness wound models in rats; Various FDA approved products like Traumastem and Surgicel are approved in clinical use as dressings	Effectively absorbs blood and fluids but can adhere to wound bed causing discomfort and hinder wound healing; Tulle dressings were found to capture granulocytes that enhance the antimicrobial effects, but caused disturbed pattern of epithelial growth due to being embedded in the wound; OC and ORC dressings evaluated in porcine femoral artery bleeding models revealed improved hemostatic efficiency compared to cotton gauze
Collagen- based materials and technologies, e.g., - AviteneTM: sheet, foam or powder of partial hydrochloric acid salt of purified bovine collagen - Helistat™: Collagen sponge material - Instat™: Microfibrillar bovine collagen etc.	Collagen promotes platelet adhesion, activation and aggregation and these aggregated active platelets further release pro-coagulant molecules (e.g. ADP, Ca++ etc.), as well as, allow co-localization and activation of coagulation factors on their membrane to augment thrombin generation and fibrin formation to accelerate clotting	In vitro studies have characterized blood interactions with collagen, platelet adhesion, activation and aggregation, platelet secretions; In vivo studies have characterized bleeding time and inflammatory responses, e.g. in canine spleen incision model and porcine transectional lacerations of spleen, liver and kidney; Approved for topical and surgical hemostat applications	In vitro, collagen based hemostats show significant adhesion and activation of platelets, leading to augmentation of platelet-mediated clotting mechanisms; In vivo, collagen-based hemostats showed significant reduction of bleeding time to allow control of bleeding within 2–5 min, with minimal immune reaction
Composite spray consisting of bovine collagen, bovine thrombin and autologous plasma e.g. CoStasis®	Collagen can adhere to injury site and wound bed to initiate adhesion, activation and aggregation of platelets; thrombin augments platelet activation and aggregation, and also augments conversion of fibrinogen to fibrin in situ to enhance clot formation	In vitro studies have characterized platelet adhesion, activation and aggregation; In vivo studies have evaluated the material in midline laparotomy model of liver and spleen in rabbits; Phase I and Phase II clinical evaluations performed in patients undergoing cardiac, hepatic, iliac and general surgery; Approved as surgical hemostat	In vitro studies have shown increased platelet adhesion, activation and aggregation within 2–5 minutes; In vivo, complete hemostasis achieved within 2 minutes or less in rabbit models even on 50% depletion of either platelets or fibrinogen; No detectable adverse effects associated with antibody production; Clinical studies showed cessation in intraoperative bleeding within 10 min in 90% of CoStasis treated patients compared to 58% of control patients
Gelatin based materials and technologies, e.g., - GelFoam: gelatin solid sponge - FloSeal: Matrix containing a mixture of crosslinked bovine gelatin granules and human thrombin - GRF Glue, GR-Dial etc.: Mixture of gelatin, resorcinol with formaldehyde and glutaraldehyde activator	Since gelatin is collagen-derived, it possibly causes activation and aggregation of platelets, accelerates clot formation and structurally supports the clot being formed; Facilitates coagulation cascade propagation via augmenting thrombin generation; Tamponande effect of swollen granular gelatin at wound site reduces bleeding and promotes formation of clotting matrix; For aldehyde-containing glue, protein crosslinking results in adherence of the glue to the wound tissue, while gelatin promotes hemostatic mechanisms and resorcinol provides bacteriostatic action	In vivo studies performed in bilateral ultrasound-guided percutaneous renal cryoablation (PRC) of swine kidney; In vivo studies performed in heparinized porcine liver abrasion model; Clinical studies performed in patients under cardiac and spinal surgeries; In vivo studies performed on bleeding control and tissue adherence in thermal injury and air-leak model on rat lung; Clinical trial carried out in patients in surgery for acute aortic dissection; GelFoam currently approved as topical hemostat, FloSeal approved for clinical use as a surgical sealant in emergency surgeries, Gelatin glues clinically approved as a surgical sealant to control intraoperative bleeding	Significantly reduced post-operative blood loss in porcine PRC kidneys; Stops bleeding within 2–3 minutes in patients undergoing cardiac, vascular, or spinal/orthopedic surgery; Glue adhered tightly to degenerated lung tissue surface and no air leaks observed 1 hr post operation at low intra-tracheal pressure; Deemed clinically safe method for acute aortic dissection surgery; In-hospital mortality in aortic surgery patients was reduced with GRF glue; Aldehyde containing materials are prone to adverse effects (dose dependence of activator) due to toxicity of formaldehyde
Alginate-based technologies, e.g., Algosteril	Negatively charged uronic acid chains of alginate sequester Ca++ which is a co-factor for platelet activation as well as several coagulation cascade reactions, and thus augments clotting mechanisms	Studies performed on human diabetic foot ulcer model, as well as, endo-nasal surgical procedures; Clinically approved for wound care dressing applications	Mean time to wound healing was significantly reduced compared to controls; Less severe and frequent bleeding incidents occurred compared to controls in surgical procedures
Chitosan-based materials and technologies, e.g., - TraumaStat: poly-ethylene fibers coated with chitosan and filled with precipitated silica - HemCon, ChitoFlex: bandages from lyophilized chitosan material - Celox: granular chitosan	High surface area to allow robust interaction with platelets and coagulation factors increasing the pace and strength of the resulting clot; Possible mobilization of Ca++ to augment platelet activation and coagulation factor activation for clot formation	Rigorous in vivo evaluation in porcine complex groin injury models, porcine femoral artery and vein transection hemorrhage model, porcine liver injury hemorrhage model etc.; Approved for bleeding management in civilian and military trauma	Significant reduction of blood loss in hemorrhagic models; Decreased post-compression blood loss and decreased fluid requirement; Improved survival rates in trauma models, compared to control treatment
Zeolite and kaolin powder based materials and technologies, e.g., QuikClot powder, QuikClot-modified gauze (Combat Gauze), Advanced Clotting Sponge, WoundStat etc.	Aluminosilicate inorganic powder material can rapidly absorb water from blood (hygroscopic action) to concentrate coagulation factors; The powder can release Ca++ in blood and can activate FXII to trigger the intrinsic coagulation pathway; The powder can possibly induce contact activation of platelets	Rigorous evaluation in porcine complex groin injury, porcine grade 4 and 5 liver injury, porcine partial nephrectomy, porcine femoral artery hemorrhage, rabbit complex groin injury, porcine and rabbit extremity hemorrhage models etc.; Approved for selective management of traumatic bleeding in civilian and military applications	Significant reduction in blood loss, robust clot formation, significant reduction in re-bleeding, significant improvement in survival rate compared to control treatments; Persistent issue of thermal damage to tissue due to the highly exothermic nature of hygroscopic action
Blood-derived or recombinant hemostatic factors and materials, e.g., Composite fibrin glues and adhesives (Tissel, Evicel, Vitagel etc.), Fibrinogen and thrombin mixture for in situ fibrin formation, Fibrin fleece (e.g. TachSeal), Fibrin fleece with aprotinin (e.g. TachoComb), Autologous plasma sealants (e.g. CryoSeal, Vivostat etc.)	Fibrin is the major physiological crosslinked biopolymer component of clot and therefore it is capable of hemostasis, platelet and other blood cells arrest, further activation and enhancement of coagulation mechanisms; Thrombin component can augment in situ conversion of fibrinogen into fibrin to enhance clot formation and clot mechanical stability; Components like aprotinin can prevent fibrinolysis and thereby maintain clot strength; Matrix can further contain other components like microfibrillar collagen etc. for added effect	Rigorous evaluation in rat femoral artery repair model, canine dura puncture and spinal surgery models, rat and pig non-cardiac thoracic surgery models, porcine liver injury model, porcine aortic injury model, etc. Clinical studies carried out for use as tissue sealant and hemostat in ophthalmology, hernia repair, non-cardiac thoracic surgery, fistula repair, orthopedic surgery, gastro-intestinal surgery, dental procedures etc.; Currently approved clinically as tissue sealant, tissue adhesive and hemostat in a variety of surgical procedures	Increased tissue adhesion, decreased blood loss, high hemostatic efficacy, reduced risks of re-bleeding; Presence of non-human sourced components (bovine, equine etc.) may result in various degrees of immunogenic effects