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Title: Novel fibrinogen hydrogels for cell encapsulation and delivery
Author: Lindsay, Sarah
ISNI:       0000 0004 6421 8789
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2017
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Osteoarthritis is a debilitating disease that is predicted to affect 130 million people worldwide by 2050. Despite being a global problem, there is no cure for osteoarthritis. Therefore, there is a need for cell therapies to repair injured cartilage. Delivering and localising cells at the injury site is a major challenge, the use of hydrogels as cell carriers may overcome this challenge. Fibrin is a natural hydrogel and is formed by the proteolytic action of thrombin on fibrinogen creating a fibrous network of fibrin fibres. Cell encapsulation in fibrin has been demonstrated, these natural gels suffer from batch and manufacturer variability. Haemostatix Ltd. have developed novel cross-linked fibrinogen gels by attaching the active fibrinogen binding sequence (GPRP) to different molecules. This active sequence binds to fibrinogen without the need for thrombin, creating a multi-branched fibrin-like gel. This has the potential to provide opportunities to tailor gel properties for cell delivery. The aim of this research was therefore to investigate the potential use of the novel fibrinogen gels for the encapsulation and culture of chondrocytes and mesenchymal stem cells (MSCs). The cell encapsulated fibrinogen gels were cultured under chondrogenic conditions for twenty-one days, fibrin gels were used as a reference material. This research has shown that chondrocytes and MSCs exhibited good survival and differentiation in both fibrinogen and fibrin gels. Chondrocytes remained in encapsulation throughout, and extracellular matrix (ECM) deposition was detected by measuring glycosaminoglycan (GAG) content and Toluidine blue staining. MSC's behaved differently, with evidence for cell migration from the fibrinogen and fibrin gels and degradation of the gels. This behaviour was inhibited by incubation with aprotinin. Gel degradation and MSC migration also occurred in serum-free culture conditions. In the presence of aprotinin, cell activity and GAG deposition suggested that the encapsulated MSCs survived and differentiated in the fibrinogen and fibrin gels. The fibrinogen gels were comparable to fibrin for both chondrocyte and MSC encapsulation for cell activity and ECM deposition. The MSC migration and gel degradation was inhibited by aprotinin and therefore was most likely due to the activation of plasminogen. Removing plasminogen i.e. serum from the culture conditions resulted in gel degradation and MSC migration, suggesting that an aprotinin sensitive serine protease was produced that had activated fibrinogen and degraded the fibrinogen gels. The fibrinogen gels were comparable to natural fibrin, but offer the distinct advantage that the cross-linking density may easily be modified making the fibrinogen gel more versatile for use in different applications. In conclusion, this novel fibrinogen system supported chondrocyte and MSC survival and differentiation, and these new biomaterials show great promise for use in cell encapsulation and delivery for cartilage regeneration.
Supervisor: Crawford, Aileen ; Hatton, Paul ; Zbozien, Renata Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available