Fibrin Gels as Cell-Instructive Substrates for Regenerative Medicine
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Fibrin Gels as Cell-Instructive Substrates for Regenerative Medicine Kaitlin C. Murphy1, Hillary E. Davis1, Bernard Y-K Binder1, and J. Kent Leach1,2 1 Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616 2 Department of Orthopaedic Surgery, School of Medicine, University of California, Davis Sacramento CA 95817 ABSTRACT Fibrin hydrogels are an exciting platform for cell-based therapies, as they contain necessary cues for adhesion, can be remodeled by entrapped cells, and the biophysical properties can be modified with a plethora of strategies. Furthermore, fibrin acts as a provisional matrix in vivo for tissue regeneration. While the majority of studies seek to manipulate fibrin gel properties by changing the concentration of clotting proteins, these studies highlight our capacity to change bulk stiffness and fiber properties by supplementing the solutions with sodium chloride (NaCl). Physical properties including fiber thickness, porosity, compressive modulus, and fluid uptake capacity were dependent on NaCl content, with gels containing 2.60% (w/v) NaCl exhibiting compressive moduli threefold higher than gels without NaCl. These material properties, in turn, affected the gel morphology along with the osteogenic and pro-angiogenic response of entrapped mesenchymal stem/stromal cells (MSCs). The osteoconductivity of fibrin gels can be enhanced by inclusion of apatite-coated polymer substrata to nucleate mineral, while the efficacy of engineered fibrin gels to simultaneously deploy small molecules with cells to enhance endogenous angiogenic potential has been demonstrated. Collectively, these data demonstrate the broad capacity of engineered fibrin gels to regulate function of entrapped cells for use in tissue engineering and regenerative medicine. INTRODUCTION Bone has a remarkable capacity to heal and remodel following trauma or insult. However, native bone repair processes are insufficient for approximately 10% of patients whose bone defects either extend beyond a critical size or are associated with impaired native healing secondary to age or disease. Clinically, these defects can manifest through nonunion fractures, deep-seated infections that require debridement, tumor resection or irradiation, inherited bone disorders, necrosis secondary to compromised blood supply, and failed hip and knee replacements. In the United States alone, there are 1.6 million surgical procedures (at a cost of $5 billion) performed annually that require some type of bone substitute [1]. The current “gold standard” for bone substitutes is an autologous bone graft, where bone tissue is removed from an otherwise healthy site in the same patient and used to fill a bone defect [2]. However, these procedures may cause donor site morbidity, 5-10% failure rates, infection, and chronic pain [35]. Thus, there is a need to develop improved strategies for treating patients in whom native healing progression is insufficient. Cell-based therapies represent an exciting alternative to currently available bone grafts
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