Multisized Photoannealable Microgels Regulate Cell Spreading, Aggregation, and Macrophage Phenotype through Microporous Void Space.

Microgels are an emerging platform for in vitro models and guiding cell fate due to their inherent porosity and tunability. This work describes a light-based technique for rapidly annealing microgels across a range of diameters. Utilizing 8-arm poly(ethylene) glycol-vinyl sulfone, the number of arms available for crosslinking, functionalization, and annealing is stoichiometrically controlled. Small and large microgels are fabricated to explore how microgel diameter impacts void space and the role of porosity on cell spreading, cell aggregation, and macrophage polarization. Mesenchymal stromal cells spread rapidly in both formulations, yet the smaller microgels permit a higher cell density. When seeded with macrophages, the smaller microgels promote an M1 phenotype, while larger microgels promote an M2 phenotype. As another application, the inherent porosity of annealed microgels is leveraged to induce cell aggregation. Finally, the microgels are implanted to examine how different size microgels influence endogenous cell invasion and macrophage polarization. The use of ultraviolet light allows for microgels to be noninvasively injected into a desired mold or wound defect before annealing, and microgels of different properties combined to create a heterogeneous scaffold. This approach is clinically relevant given its tunability and fast annealing time.

Organ-on-a-chip model of vascularized human bone marrow niches.

Bone marrow niches (endosteal and perivascular) play important roles in both normal bone marrow function and pathological processes such as cancer cell dormancy. Unraveling the mechanisms underlying these events in humans has been severely limited by models that cannot dissect dynamic events at the niche level. Utilizing microfluidic and stem cell technologies, we present a 3D in vitro model of human bone marrow that contains both the perivascular and endosteal niches, complete with dynamic, perfusable vascular networks. We demonstrate that our model can replicate in vivo bone marrow function, including maintenance and differentiation of CD34+ hematopoietic stem/progenitor cells, egress of neutrophils (CD66b+), and niche-specific responses to doxorubicin and granulocyte-colony stimulating factor. Our platform provides opportunities to accelerate current understanding of human bone marrow function and drug response with high spatial and temporal resolution.

Functionally graded biomaterials for use as model systems and replacement tissues.

The heterogeneity of native tissues requires complex materials to provide suitable substitutes for model systems and replacement tissues. Functionally graded materials have the potential to address this challenge by mimicking the gradients in heterogeneous tissues such as porosity, mineralization, and fiber alignment to influence strength, ductility, and cell signaling. Advancements in microfluidics, electrospinning, and 3D printing enable the creation of increasingly complex gradient materials that further our understanding of physiological gradients. The combination of these methods enables rapid prototyping of constructs with high spatial resolution. However, successful translation of these gradients requires both spatial and temporal presentation of cues to model the complexity of native tissues that few materials have demonstrated. This review highlights recent strategies to engineer functionally graded materials for the modeling and repair of heterogeneous tissues, together with a description of how cells interact with various gradients.