CAREER: Determining the structure and properties of cell re-engineered microenvironments using rheology in synthetic wound healing scaffolds

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Human mesenchymal stem cells (hMSCs) play a critical role in wound healing by regulating inflammation after migrating to the wound site. One strategy to help wound healing is to implant a hydrogel containing isolated hMSCs directly into the wound site. The hydrogel provides structural integrity to the surrounding tissue. However, during wound healing, hMSCs remodel and degrade the hydrogel over time. These processes must be better understood to design hydrogels with the optimal properties for wound healing. This CAREER project will apply a combination of new and existing methods to characterize the region around cells during cell remodeling and degradation of the synthetic hydrogel material. The goal of the combined research and education effort is to: (1) use a novel interdisciplinary approach to provide new techniques to answer a critical problem in biomaterials and cell biology, (2) recruit and train a diverse work force and (3) educate a broad audience in biomaterials, materials characterization, and wound healing. The research will have a major impact on biomaterials design. These new materials have the potential to increase the rate of wound healing and prevent development of chronic wounds. In addition, the principle investigator will recruit, train and educate a broad audience. This will be done by: (i) outreach to the public at the Da Vinci Science Center in Allentown, PA, (ii) mentoring of middle and high school students and (iii) mentoring and training of undergraduate and graduate students.The overall goal of this work is to characterize the spatial and temporal rheological evolution of a synthetic hydrogel during cell-mediated degradation to determine viability as an implantable wound healing scaffold. The physical microenvironment is hypothesized to control hMSC degradation strategies during cell migration to efficiently deliver hMSCs to the wound and control material degradation. To test this, the research includes a) characterizing hMSC degradation strategies in homogenous hydrogels that mimic the stiffness of native tissues, b) determining the change in response to an interface in stiffness, and c) determining how gradients in scaffold stiffness change hMSC-mediated degradation and direct motility to increase cell delivery and material integrity. hMSCs will be encapsulated in 3D in a well-established photopolymerizable poly(ethylene glycol)-peptide hydrogel. The peptide cross-linker in this material is degraded by cell-secreted enzymes. Dynamic scaffold properties will be measured with bulk rheology and microrheology. Multiple particle tracking microrheology (MPT) will measure the spatio-temporal degradation profile created in the scaffold by encapsulated hMSCs. These measurements will determine the unique degradation strategies hMSCs use in response to changes in their microenvironment. Bulk rheology will quantify the change in material integrity as hMSCs permanently degrade the synthetic scaffold. Using this knowledge, the viability of these materials as implantable wound healing scaffolds and the microenvironments that most efficiently deliver hMSCs to an injury while providing structure to the surrounding tissue will be determined. The research outcomes will be: i) identification of the microenvironment cells engineer during motility in response to homogeneous and heterogeneous environments in the scaffold and ii) determination of microenvironments that increase cell delivery and material integrity.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.