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Gelatin microribbon-based macroporous hydrogels for enhancing stem cell-based bone regeneration

Bone loss due to trauma, disease, or cancer resection remains a large clinical concern and causes significant pain and discomfort to patients of all ages. To this day, bone grafting remains the gold standard in treating such defects, making bone the second most transplanted tissue after blood. Bone grafting, however, suffers from insufficient donor supply as well as significant donor site morbidity. Bone tissue engineering approaches offer a promising alternative to bone grafting by using stem cells, biomaterials, and biochemical cues to regenerate bone. Mesenchymal stem cells (MSCs) are a particularly attractive cell source as they are well characterized, can differentiate into all skeletal tissues including bone and cartilage, and are known to be immunoprivileged, making them a promising allogenic cell source. The load-bearing environment of bone requires the use of biomaterials to provide cells mechanical and structural support. To this end, our lab recently developed gelatin-based microribbons (µRBs) using a two-step crosslinking mechanism that remain injectable upon mixing in cells homogenously. After filling any irregular shaped defect, the µRBs can then be crosslinked into any desirable 3D shape or form with interconnected macroporosity. Encouraged by the highly desirable properties, this thesis aims to investigate the potential of gelatin-based µRBs as a universal scaffold for bone tissue engineering. As bone develops through two distinct pathways (endochondral ossification and intramembranous ossification), the ability of µRBs to recapitulate both pathways using MSCs was examined. First, gelatin µRBs were compared to a gelatin hydrogel in forming the required cartilage template before the full endochondral ossification pathway was studied in vivo. In order to examine the ability of µRBs to support intramembranous ossification, the role of substrate stiffness and the incorporation of osteoinductive hydroxyapatite into the scaffold was analyzed. The gelatin-based µRB platform described in this thesis may offer a universal scaffold material for bone tissue engineering and provide a clinical alternative to bone grafts for treating bone defects. The strategies to form bone in this thesis were intentionally designed to use only the minimum required materials and signals to reduce costs and support clinical translational potential. However, gelatin-based µRBs could support additional complexity, such as drug-releasing strategies to further enhance tissue formation. Furthermore, this work exclusively focused on MSCs, however, gelatin-based µRBs also supports other stem cell populations (i.e. pluripotent stem cells), adding additional versatility to the platform. While this thesis investigated bone regeneration, gelatin-based µRBs have many desirable properties that suggest it could also be used for engineering other tissue types such as cartilage, fat, and even ligaments and tendons.