Kelly M. Schultz’s research while affiliated with Lehigh University and other places

Covalent adaptable networks are designed for applications including cell and drug delivery and tissue regeneration. These applications require network degradation at physiological conditions and on a physiological timescale with microstructures...

Injectable poly(ethylene glycol, PEG)-based hydrogels were reversibly crosslinked through thia-conjugate addition bonds and demonstrated to shear thicken at low shear rates. Crosslinking bond exchange kinetics and dilute polymer concentrations were leveraged to tune hydrogel plateau moduli (from 60 - 650 Pa) and relaxation times (2 - 8 seconds). Under continuous flow shear rheometry, these properties affected the onset of shear thickening and the degree of shear thickening achieved before a flow instability occurred. The changes in viscosity were reversible whether the shear rate increased or decreased, suggesting that chain stretching drives this behavior. Given the relevance of dynamic PEG hydrogels under shear to biomedical applications, their injectability was investigated, and injection forces were found to increase with higher polymer concentrations and slower bond exchange kinetics. Altogether, these results characterize the nonlinear rheology of dilute, dynamic covalent tetra-PEG hydrogels and offer insight to the mechanism driving their shear thickening behavior.

Injectable poly(ethylene glycol)-based hydrogels were reversibly crosslinked through thia-conjugate addition bonds and demonstrated to shear thicken at low shear rates. In this system, crosslinking bond exchange kinetics and polymer concentration were leveraged to tune hydrogel plateau moduli (about 60 - 650 Pa) and relaxation times (2 - 8 seconds). These properties affected the shear thickening behavior of the hydrogels, including the onset of shear thickening (at a Weissenberg number of 0.2) and the degree of shear thickening (up to 4.5 fold) that was achieved before a flow instability occurred. Despite the shear thickening behavior of the hydrogels at low shear rates, the hydrogels were injectable, with injection forces that increased with a higher polymer concentration and slower bond exchange kinetics. Altogether, these results demonstrate shear thickening in reversibly crosslinked, injectable tetra-PEG hydrogels and show design parameters by which the shear thickening behavior and injection force can be tuned.

Biological materials have length scale dependent structure enabling complex cell-material interactions and driving cellular processes. Synthetic biomaterials are designed to mimic aspects of these biological materials for applications including enhancing cell delivery during wound healing. To mimic native microenvironments, we must understand how cells manipulate their surroundings over several length scales. Our work characterizes length scale dependent rheology in a well-established 3D cell culture platform for human mesenchymal stem cells (hMSCs). hMSCs re-engineer their microenvironment through matrix metalloproteinase (MMP) secretions and cytoskeletal tension. Remodeling occurs across length scales: MMPs degrade cross-links on nanometer scales resulting in micrometer-sized paths that hMSCs migrate through, eventually resulting in bulk scaffold degradation. We use multiple particle tracking microrheology (MPT) and bi-disperse MPT to characterize hMSC-mediated length scale dependent pericellular remodeling. MPT measures particle Brownian motion to calculate rheological properties. We use MPT to measure larger length scales with 4.5 µm particles. Bi-disperse MPT simultaneously measures two different length scales (0.5 and 2.0 µm). We measure that hMSCs preferentially remodel larger length scales measured as a higher mobility of larger particles. We inhibit cytoskeletal tension by inhibiting myosin-II and no longer measure this difference in particle mobility. This indicates that cytoskeletal tension is the source of cell-mediated length scale dependent rheological changes. Particle mobility correlates with cell speed across length scales, relating material rheology to cell behavior. These results quantify length scale dependent pericellular remodeling and provide insight into how these microenvironments can be designed into materials to direct cell behavior.

Covalent adaptable hydrogels (CAHs) reversibly adapt their structure in response to external stimuli, emerging as a new platform for biological applications. Due to the unique and complex nature of these materials, a characterization technique is needed to measure the rheology of these CAHs in biological processes. μ²rheology, microrheology in a microfluidic device, is a technique that can fully characterize real-time CAH degradation in a changing environment, such as the pH environment of the GI tract. This characterization will enable design and tailoring of these materials for controlled and targeted oral drug delivery. Using μ²rheology, we can exchange the fluid environment without sample loss and measure the change in CAH rheological properties. We show degradation kinetics and material property evolution are independent of degradation history. However, the initial cross-link density at each pH exchange can be decreased by degradation history which decreases the time for the CAH to degrade to the gel-sol transition. These results indicate that CAH degradation can be tuned by changing the initial material properties by varying polymer concentration and ratio of functional groups. We also show that μ²rheology will enable the design of new dynamic materials for targeted drug delivery by enabling these materials to be characterized and tailored in vitro.

Multiple particle tracking microrheology (MPT) is a passive microrheological technique that measures the Brownian motion of probe particles embedded in a sample to characterize material rheological properties. MPT is a powerful tool that quantifies material rheology in the low moduli range while requiring only small sample volumes and relatively simple data acquisition using video microscopy. MPT quantitatively characterizes spatiotemporal rheological properties and is particularly well suited for the investigation of evolving materials with complex microenvironments. MPT has expanded the study of a variety of materials including biofilms, colloidal gels, hydrogels, stimuli-responsive materials, and cell-laden biomaterials. The aim of this Tutorial is to summarize the fundamentals, illustrate the versatility, and highlight recent advances in MPT. In each application, we will highlight how MPT is uniquely positioned to gather rheological properties, which would be difficult, if not impossible, to attain with other rheological characterization techniques and highlight how MPT can be used to supplement other measurement techniques. This Tutorial should provide researchers with the fundamental basis and skills needed to use MPT and develop new MPT techniques to characterize materials for their unique applications.

The feasibility of a covalent adaptable hydrogel (CAH) as an oral delivery platform is explored using μ²rheology, microrheology in a microfluidic device. CAH degradation is initiated by physiologically relevant pHs, including incubation at a single pH and consecutively at different pHs. At a single pH, we determine CAH degradation can be tuned by changing the pH, which can be exploited for controlled release. We calculate the critical relaxation exponent, which defines the gel-sol transition and is independent of the degradation pH. We mimic the changing pH environment through part of the gastrointestinal tract (pH 4.3 to 7.4 or pH 7.4 to 4.3) in our microfluidic device. We determine that dynamic material property evolution is consistent with degradation at a single pH. However, the time scale of degradation is reduced by the history of degradation. These investigations inform the design of this material as a new vehicle for targeted delivery.