@article{corder_vachieri_martin_taylor_fleming_khan_2023, title={Linear and nonlinear rheology of liberase-treated breast cancer tumors}, volume={1}, ISSN={["2047-4849"]}, url={https://doi.org/10.1039/D3BM00038A}, DOI={10.1039/d3bm00038a}, abstractNote={Extracellular matrix (ECM) rigidity has been shown to increase the invasive properties of breast cancer cells, promoting transformation and metastasis through mechanotransduction. Reducing ECM stiffness via enzymatic digestion could be a promising approach to slowing breast cancer development by de-differentiation of breast cancer cells to less aggressive phenotypes and enhancing the effectiveness of existing chemotherapeutics via improved drug penetrance throughout the tumor. In this study, we examine the effects of injectable liberase (a blend of collagenase and thermolysin enzymes) treatments on the linear and nonlinear rheology of allograft 4T1 mouse mammary tumors. We perform two sets of in vivo mouse studies, in which either one or multiple treatment injections occur before the tumors are harvested for rheological analysis. The treatment groups in each study consist of a buffer control, free liberase enzyme in buffer, a thermoresponsive copolymer called LiquoGel (LQG) in buffer, and a combined, localized injection of LQG and liberase. All tumor samples exhibit gel-like linear rheological behavior with the elastic modulus significantly larger than the viscous modulus and both independent of frequency. Tumors that receive a single injection of localized liberase have significantly lower tumor volumes and lower tissue moduli at both the center and edge compared to buffer- and free liberase-injected control tumors, while tissue viscoelasticity remains relatively unaffected. Tumors injected multiple times with LQG and liberase also have lower tissue volumes but possess higher tissue moduli and lower viscoelasticities compared to the other treatment groups. We propose that a mechanotransductive mechanism could cause the formation of smaller but stiffer tumors after repeated, localized liberase injections. Large amplitude oscillatory shear (LAOS) experiments are also performed on tissues from the multiple injection study and the results are analyzed using MITlaos. LAOS analysis reveals that all 4T1 tumors from the multiple injection study exhibit nonlinear rheological behavior at high strains and strain rates. Examination of the Lissajous-Bowditch curves, Chebyshev coefficient ratios, elastic moduli, and dynamic viscosities demonstrate that the onset and type of nonlinear behavior is independent of treatment type and elastic modulus, suggesting that multiple liberase injections do not affect the nonlinear viscoelasticity of 4T1 tumors.}, journal={BIOMATERIALS SCIENCE}, author={Corder, Ria D. and Vachieri, Robert B. and Martin, Megan E. and Taylor, Darlene K. and Fleming, Jodie M. and Khan, Saad A.}, year={2023}, month={Jan} }
 @article{dufficy_corder_dennis_fedkiw_khan_2021, title={Guar Gel Binders for Silicon Nanoparticle Anodes: Relating Binder Rheology to Electrode Performance}, volume={13}, ISSN={["1944-8252"]}, url={https://doi.org/10.1021/acsami.1c10776}, DOI={10.1021/acsami.1c10776}, abstractNote={Binding agents are a critical component of Si-based anodes for lithium-ion batteries. Herein, we introduce a composite hydrogel binder consisting of carbon black (CB) and guar, which is chemically cross-linked with glutaraldehyde as a means to reinforce the electrode structure during lithiation and improve electronic conductivity. Dynamic rheological measurements are used to monitor the cross-linking reaction and show that rheology plays a significant role in binder performance. The cross-linking reaction occurs at a faster rate and produces stronger networks in the presence of CB, as evidenced from higher gel elastic modulus in guar + CB gels than guar gels alone. Silicon nanoparticle (SiNP) electrodes that use binders with low cross-link densities (trxn < 2 days) demonstrate discharge capacities ∼1200 mAh g-1 and Coulombic efficiencies >99.8% after 300 cycles at 1-C rate. Low cross-link densities likely increase the capacity of SiNP anodes because of binder-Si hydrogen-bonding interactions that accommodate volume expansions. In addition, the cross-linked binder demonstrates the potential for self-healing, as evidenced by an increased elastic modulus after the gel was mechanically fragmented, which may preserve the electrode microstructure during lithiation and increase capacity retention. The composite hydrogel with integrated conductive additives gives promise to a new type of binder for next-generation lithium-ion batteries.}, number={43}, journal={ACS APPLIED MATERIALS & INTERFACES}, publisher={American Chemical Society (ACS)}, author={Dufficy, Martin K. and Corder, Ria D. and Dennis, Kimberly A. and Fedkiw, Peter S. and Khan, Saad A.}, year={2021}, month={Nov}, pages={51403–51413} }
 @article{corder_gadi_vachieri_jayes_cullen_khan_taylor_2021, title={Using rheology to quantify the effects of localized collagenase treatments on uterine fibroid digestion}, volume={134}, ISSN={["1878-7568"]}, DOI={10.1016/j.actbio.2021.08.003}, abstractNote={Uterine fibroids are stiff, benign tumors containing excessive, disordered collagens that occur in 70-80% of women before age 50 and cause bleeding and pain. Collagenase Clostridium histolyticum (CCH) is a bacterial enzyme capable of digesting the collagens present in fibroids. By combining CCH with injectable drug delivery systems to enhance effectiveness, a new class of treatments could be developed to reduce the stiffness of fibroids, preventing the need for surgical removal and preserving fertility. In this work, we achieved localization of CCH via physical entrapment by co-injecting a thermoresponsive pNIPAM-based polymeric delivery system called LiquoGel (LQG), which undergoes a sol-gel transition upon heating. Toxicity study results for LQG injected subcutaneously into mice demonstrate that LQG does not induce lesions or other adverse effects. We then used rheology to quantify the effects of localized CCH injections on the modulus and viscoelasticity of uterine fibroids, which exhibit gel-like behavior, through ex vivo and in vivo digestion studies. Ex vivo CCH injections reduce the tissue modulus by over two orders of magnitude and co-injection of LQG enhances this effect. Rheological results from an in vivo digestion study in mice show a significant reduction in tissue modulus and increase in tissue viscoelasticity 7 days after a single injection of LQG+CCH. Parallel histological staining validates that the observed rheological changes correspond to an increase in collagen lysis after treatment by LQG+CCH. These results show promise for development of injectable and localized enzymatic therapies for uterine fibroids and other dense tumors. STATEMENT OF SIGNIFICANCE: Uterine fibroids are stiff, benign tumors containing high collagen levels that cause bleeding and pain in women. Fertility-preserving and minimally-invasive treatments to soften fibroids are needed as an alternative to surgical removal via hysterectomy. We demonstrate through ex vivo and in vivo studies that co-injecting a thermoresponsive polymer delivery system (LQG) alongside a bacterial collagenase (CCH) enzyme significantly increases treatment effectiveness at softening fibroids through CCH localization. We use rheology to measure the modulus and viscoelasticity of fibroids and histology to show that fibroid softening corresponds to a decrease in collagen after treatment with LQG+CCH. These results highlight the utility of rheology at quantifying tissue properties and present a promising injectable therapy for fibroids and other dense tumors.}, journal={ACTA BIOMATERIALIA}, author={Corder, Ria D. and Gadi, Sashi V and Vachieri, Robert B. and Jayes, Friederike L. and Cullen, John M. and Khan, Saad A. and Taylor, Darlene K.}, year={2021}, month={Oct}, pages={443–452} }
 @article{wang_ye_yu_kahkoska_zhang_wang_sun_corder_chen_khan_et al., title={Core-Shell Microneedle Gel for Self-Regulated Insulin Delivery}, volume={12}, number={3}, journal={ACS Nano}, author={Wang, J. Q. and Ye, Y. Q. and Yu, J. C. and Kahkoska, A. R. and Zhang, X. D. and Wang, C. and Sun, W. J. and Corder, R. D. and Chen, Z. W. and Khan, S. A. and et al.}, pages={2466–2473} }