Biomaterials are promising for the delivery and directed differentiation of mesenchymal stem cells (MSCs) for the regeneration of tissues throughout the body. While a range of properties have been identified for bone or cartilage regeneration, less is known about directing hMSC differentiation for connective tissue regeneration, such as ligament. In this work, we aimed i) to identify microenvironment conditions that promote ligamentogenic differentiation and ii) to design materials to deliver or present these cues in vitro and in vivo. We hypothesized that a combination of microenvironment cues found in developing connective tissue would promote MSC differentiation into ligament fibroblasts. To test this, we synthesized thiol-ene hydrogels formed by photoinitiated free radical step growth polymerization of multifunctional poly(ethylene glycol), creating a blank slate for examining the effects of key extracellular matrix cues: moduli mimicking developing collagenous tissues (10-100 kPa); integrin-binding peptides RGDS (mimic of fibronectin and vitronectin) and (POG)4POGFOGERG(POG)4 (mimic of collagen I); and various soluble factors. A statistical design of experiments was used to elucidate relative contributions, and conditions were identified that robustly promote the differentiation of hMSCs into ligament fibroblasts. Building upon this, we are designing scaffolds for the delivery of hMSCs and growth factors for the regeneration of ligament tissues. Specifically, injectable hydrogels were synthesized from poly(ethylene glycol) (PEG)-bis-maleimide (PEG-2MI) and 4-arm PEG functionalized with different thiol end groups for controlled degradation and release in response to stimuli. Hydrogel formation and degradation in aqueous or reducing microenvironments was monitored with rheometry, and release of a model protein, bovine serum albumin (BSA), was characterized, establishing conditions favorable for controlled release over days to weeks. Taken together, these materials show promise for the delivery of growth factors and cells for the regeneration of connective tissues.

Responsive materials for the directing and delivering stem cells and therapeutics

249th National Meeting (2015)

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