Author's personal copy A totally recombinant human fibrin sealant Mark A. Carlson, MD, a,c, * Jennifer Calcaterra, PhD, d Jason M. Johanning, MD, b,c Iraklis I. Pipinos, MD, b,c Crystal M. Cordes, PhD, e and William H. Velander, PhD d a Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska b Department of Vascular Surgery, University of Nebraska Medical Center, Omaha, Nebraska c Department of Surgery, VA NebraskaeWestern Iowa Health Care System, Omaha, Nebraska d Department of Chemical and Biomolecular Engineering, University of NebraskaeLincoln, Lincoln, Nebraska e Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Nebraska article info Article history: Received 10 June 2013 Received in revised form 25 September 2013 Accepted 26 September 2013 Available online 2 October 2013 Keywords: Fibrin sealant Hemostasis Hemorrhage Swine Fibrinogen Factor XIII Thrombin Recombinant Human abstract Background: Applications of plasma-derived human fibrin sealants (pdhFS) have been limited because of cost, limited supply of pathogen-screened plasma, the need for bioen- gineering improvements, and regulatory issues associated with federal approval. We describe a totally recombinant human fibrin sealant (rhFS), which may engender an abundant, safe, and cost-effective supply of efficacious fibrin sealant. Materials and methods: A first-generation rhFS made from recombinant human fibrinogen (rhFI; produced in the milk of transgenic cows), activated recombinant human factor XIII (rhFXIIIa; produced in yeast), and recombinant human thrombin (rhFIIa; purchased, made in animal cell culture) was formulated using thromboelastography (TEG). The hemostatic efficacy of rhFS versus commercial pdhFS was compared in a nonlethal porcine hepatic wedge excision model. Results: The maximal clot strength of rhFS measured in vitro by TEG was not statistically different than that of pdhFS. TEG analysis also showed that the rhFS gained strength more quickly as reflected by a steeper a angle; however, the rhFS achieved this clot strength with a 5-fold lower factor I content than the pdhFS. When these fibrin sealants were studied in a porcine hepatic wedge excision model, the hemostatic scores of the rhFS were equivalent or better than that of the pdhFS. Conclusions: The bioengineered rhFS had equivalent or better hemostatic efficacy than the pdhFS in a nonlethal hemorrhage model, despite the factor I concentration in the rhFS being about one-fifth that in the pdhFS. Because the rhFS is amenable to large-scale pro- duction, the rhFS has the potential to be more economical and abundant than the pdhFS, while having a decreased risk of blood-borne pathogen transmission. Published by Elsevier Inc. 1. Introduction The use of dried plasma as a topical hemostatic aid was documented in 1909 [1]. The combination of relatively pure fibrinogen (factor I or FI) with thrombin to make fibrin glue or foam was described in 1944 [2], but it was not until improved purification technology became available that fibrin sealants (FS) became commercially available in the 1970s [1]. Since that time, the efficacy of FS products as a topical hemostat or tissue adhesive has been demonstrated in numerous elective clinical Presented in part at the 6th Annual Academic Surgical Congress; February 3, 2011; Huntington Beach, California. * Corresponding author. Surgery 112, VA Medical Center, 4101 Woolworth Ave, Omaha, NE 68105. Tel.: þ1 402 995 5371; fax: þ1 402 995 5370. E-mail address: macarlso@unmc.edu (M.A. Carlson). Available online at www.sciencedirect.com ScienceDirect journal homepage: www.JournalofSurgicalResearch.com journal of surgical research 187 (2014) 334 e342 0022-4804/$ e see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jss.2013.09.039