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 bioengineering 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 α 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 production, the rhFS has the potential to be more economical and abundant than the pdhFS, while having a decreased risk of blood-borne pathogen transmission.
Subject(s)
Fibrin Tissue Adhesive/pharmacology , Hemorrhage/drug therapy , Lacerations/drug therapy , Liver/injuries , Recombinant Proteins/pharmacology , Animals , Animals, Genetically Modified , Cattle , Cells, Cultured , Disease Models, Animal , Factor XIIIa/genetics , Factor XIIIa/pharmacology , Fibrinogen/genetics , Fibrinogen/pharmacology , Hemostasis , Humans , Liver/drug effects , Male , Recombinant Proteins/genetics , Sus scrofa , Thrombelastography , Thrombin/genetics , Thrombin/pharmacology , YeastsABSTRACT
Human fibrinogen is a biomaterial used in surgical tissue sealants, scaffolding for tissue engineering, and wound healing. Here we report on the post-translational structure and functionality of recombinant human FI (rFI) made at commodity levels in the milk of transgenic dairy cows. Relative to plasma-derived fibrinogen (pdFI), rFI predominantly contained a simplified, neutral carbohydrate structure and >4-fold higher levels of the γ'-chain transcriptional variant that has been reported to bind thrombin and Factor XIII. In spite of these differences, rFI and pdFI were kinetically similar with respect to the thrombin-catalyzed formation of protofibrils and Factor XIIIa-mediated formation of cross-linked fibrin polymer. However, electron microscopy showed rFI produced fibrin with much thicker fibers with less branching than pdFI. In vivo studies in a swine liver transection model showed that, relative to pdFI, rFI made a denser, more strongly wound-adherent fibrin clot that more rapidly established hemostasis.
Subject(s)
Blood Coagulation/physiology , Fibrin/chemical synthesis , Fibrinogen/chemical synthesis , Recombinant Proteins/chemical synthesis , Wound Healing/physiology , Animals , Animals, Genetically Modified , Blood Coagulation/drug effects , Cattle , Fibrin/administration & dosage , Fibrinogen/administration & dosage , Humans , Recombinant Proteins/administration & dosage , Recombinant Proteins/chemistry , Swine , Wound Healing/drug effectsABSTRACT
Three studies examined the relationship between engagement in different types of tasks, performance on those tasks, and reactions to performance outcomes. The three studies included voting in the 2004 presidential election, test performance in an undergraduate course, and completion of personal projects during the course of the semester. Engagement in voting predicted voting in the presidential election and magnified positive feelings of voting for the winning candidate. Test engagement predicted performance on the test, and magnified positive feelings of not showing a discrepancy between expected and actual test performance. Engagement in personal projects interacted with task complexity to predict project completion, with engagement being related to goal completion for tasks high in complexity. Project engagement also magnified the positive effects of a high probability of completing the project. The results provide support for task engagement as a predictor of performance and as a facilitator of positive feelings following success.
Subject(s)
Achievement , Emotions , Motivation , Self Concept , Social Responsibility , Adolescent , Female , Goals , Humans , Internal-External Control , Male , Politics , Young AdultABSTRACT
A change in the type of cranial deformities (plagiocephaly) presenting to certain clinics has occurred. The purpose of this study was to compare infant head shapes against head shapes of their biologic parents to explore the roles of heredity and environment on cranial shape. Standardized family photographs and anthropometric measurements demonstrated that 30% of the infants had cranial widths 2 standard deviations above norm, while 4.6% had widths exceeding 3 standard deviations. Despite a mean age of only 8 months, 11.6% had widths that were already greater than that of 1 parent. These results demonstrate that plagiocephaly has taken on a new configuration, presenting not only with asymmetry, but also with excessive cranial width.
