Abstract
Regenerative engineering combines stem cell therapies with materials science and developmental biology for clinical translation to regenerate complex tissues and organ systems and restore function. Biomaterials are integral to regenerative engineering therapies because they can support cell infiltration, provide important environmental cues, and enhance tissue regeneration. Hydrogels are a class of biomaterials frequently used in regenerative engineering due to their mechanical and structural characteristics that are similar to many soft tissues. The material properties of synthetic hydrogels, including mechanical stiffness, degradation rates and mechanisms, and covalent attachment of bioactive cues, are highly tunable to match the native tissue microenvironment for improved integration. Additionally, hydrogel scaffolds can be engineered with cell-scale microporosity to enable immediate in situ cell infiltration, promoting better tissue integration and faster regeneration.
Microporous Annealed Particle (MAP) scaffolds are an injectable hydrogel platform composed of individual microspheres that undergo a secondary crosslinking reaction in situ to form a bulk scaffold with a network of interconnected, cell-scale pores for enhanced integration with native tissue. MAP is highly tunable in many of its properties and has demonstrated efficient healing in applications such as wound healing, muscle regeneration, and neural repair, but its defining feature, unhindered integration, remains understudied. Furthermore, MAP’s highly interconnected pore network hinders its ability to withstand mechanical stress, limiting its applicability in environments with strong mechanical forces.
In this dissertation, we study MAP scaffold integration in the context of two clinical applications: diabetic foot ulcers (DFUs) and osteochondral defects (OCDs). DFUs, a common complication of diabetes, are a chronic wound with a sustained inflammatory response that fails to regenerate, often resulting in a large-volume wound. Conventional wound dressings do not support cell infiltration into these large voids and thus fail to expedite healing. MAP has demonstrated efficient wound healing properties due to its interconnected porosity, providing immediate cell infiltration and support to the surrounding tissue. Here, we study the effect of microporosity on cell infiltration and uncover a complex relationship between pore size and cell migration behavior.
OCDs are non-healing lesions in cartilage tissue, resulting from trauma or repetitive mechanical forces. Cartilage tissue is non-regenerative due to a dense, avascular extracellular matrix (ECM) and low chondrocyte proliferation. Treatment options for OCDs aim to manage pain but do not regenerate cartilage tissue and are often highly invasive. Regenerative therapies use stem cells to stimulate regeneration, either through stem cell delivery or marrow stimulation, and often utilize a biomaterial as a delivery or stabilizing mechanism; however, these therapies tend to fail because they cannot withstand the high shear forces of cartilage tissue or they do not retain the mesenchymal stem cells (MSCs) within the defect. Here, we design an augmented MAP platform with greater stability and mechanical strength. We also design a bioactive MAP scaffold that mimics native cartilage ECM to improve MSC proliferation and retention. Additionally, we created a novel chondrogenic scaffold to support MSC chondrogenesis in situ for enhanced regeneration outcomes.
