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Open access publications by faculty, postdocs, and graduate students in the Department of Biomedical Engineering.

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    Matrix Degradability Contributes to the Development of Salivary Gland Progenitor Cells with Secretory Functions
    (ACS Applied Materials and Interfaces, 2023-07-12) Metkari, Apoorva S.; Fowler, Eric W.; Witt, Robert L.; Jia, Xinqiao
    Synthetic matrices that are cytocompatible, cell adhesive, and cell responsive are needed for the engineering of implantable, secretory salivary gland constructs to treat radiation induced xerostomia or dry mouth. Here, taking advantage of the bioorthogonality of the Michael-type addition reaction, hydrogels with comparable stiffness but varying degrees of degradability (100% degradable, 100DEG; 50% degradable, 50DEG; and nondegradable, 0DEG) by cell-secreted matrix metalloproteases (MMPs) were synthesized using thiolated HA (HA-SH), maleimide (MI)-conjugated integrin-binding peptide (RGD-MI), and MI-functionalized peptide cross-linkers that are protease degradable (GIW-bisMI) or nondegradable (GIQ-bisMI). Organized multicellular structures developed readily in all hydrogels from dispersed primary human salivary gland stem cells (hS/PCs). As the matrix became progressively degradable, cells proliferated more readily, and the multicellular structures became larger, less spherical, and more lobular. Immunocytochemical analysis showed positive staining for stem/progenitor cell markers CD44 and keratin 5 (K5) in all three types of cultures and positive staining for the acinar marker α-amylase under 50DEG and 100DEG conditions. Quantitatively at the mRNA level, the expression levels of key stem/progenitor markers KIT, KRT5, and ETV4/5 were significantly increased in the degradable gels as compared to the nondegradable counterparts. Western blot analyses revealed that imparting matrix degradation led to >3.8-fold increase in KIT expression by day 15. The MMP-degradable hydrogels also promoted the development of a secretary phenotype, as evidenced by the upregulation of acinar markers α-amylase (AMY), aquaporin-5 (AQP5), and sodium-potassium chloride cotransporter 1 (SLC12A2). Collectively, we show that cell-mediated matrix remodeling is necessary for the development of regenerative pro-acinar progenitor cells from hS/PCs.
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    Individual Muscle Force Estimation in the Human Forearm Using Multi-Muscle MR Elastography (MM-MRE)
    (IEEE Transactions on Biomedical Engineering, 2023-06-06) Smith, Daniel R.; Helm, Cody A.; Zonnino, Andrea; McGarry, Matthew D.J.; Johnson, Curtis L.; Sergi, Fabrizio
    Objective: To establish the sensitivity of magnetic resonance elastography (MRE) to active muscle contraction in multiple muscles of the forearm. Methods: We combined MRE of forearm muscles with an MRI-compatible device, the MREbot, to simultaneously measure the mechanical properties of tissues in the forearm and the torque applied by the wrist joint during isometric tasks. We measured shear wave speed of thirteen forearm muscles via MRE in a series of contractile states and wrist postures and fit these outputs to a force estimation algorithm based on a musculoskeletal model. Results: Shear wave speed changed significantly upon several factors, including whether the muscle was recruited as an agonist or antagonist (p = 0.0019), torque amplitude (p = <0.0001), and wrist posture (p = 0.0002). Shear wave speed increased significantly during both agonist (p = <0.0001) and antagonist (p = 0.0448) contraction. Additionally, there was a greater increase in shear wave speed at greater levels of loading. The variations due to these factors indicate the sensitivity to functional loading of muscle. Under the assumption of a quadratic relationship between shear wave speed and muscle force, MRE measurements accounted for an average of 70% of the variance in the measured joint torque. Conclusion: This study shows the ability of MM-MRE to capture variations in individual muscle shear wave speed due to muscle activation and presents a method to estimate individual muscle force through MM-MRE derived measurements of shear wave speed. Significance: MM-MRE could be used to establish normal and abnormal muscle co-contraction patterns in muscles of the forearm controlling hand and wrist function.
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    Visual accuracy dominates over haptic speed for state estimation of a partner during collaborative sensorimotor interactions
    (Journal of Neurophysiology, 2023-07-01) Lakesh, Rakshith; Sullivan, Seth R.; Germain, Laura St.; Roth, Adam M.; Calalo, Jan A.; Buggeln, John; Ngo, Truc; Marchhart, Vanessa R. F.; Carter, Michael J.; Cashaback, Joshua G. A.
    We routinely have physical interactions with others, whether it be handing someone a glass of water or jointly moving a heavy object together. These sensorimotor interactions between humans typically rely on visual feedback and haptic feedback. Recent single-participant studies have highlighted that the unique noise and time delays of each sense must be considered to estimate the state, such as the position and velocity, of one’s own movement. However, we know little about how visual feedback and haptic feedback are used to estimate the state of another person. Here, we tested how humans utilize visual feedback and haptic feedback to estimate the state of their partner during a collaborative sensorimotor task. Across two experiments, we show that visual feedback dominated haptic feedback during collaboration. Specifically, we found that visual feedback led to comparatively lower task-relevant movement variability, smoother collaborative movements, and faster trial completion times. We also developed an optimal feedback controller that considered the noise and time delays of both visual feedback and haptic feedback to estimate the state of a partner. This model was able to capture both lower task-relevant movement variability and smoother collaborative movements. Taken together, our empirical and modeling results support the idea that visual accuracy is more important than haptic speed to perform state estimation of a partner during collaboration. NEW & NOTEWORTHY Physical collaboration between two or more individuals involves both visual and haptic feedback. Here, we investigated how visual and haptic feedback is used to estimate the movements of a partner during a collaboration task. Our experimental and computational modeling results parsimoniously support the notion that greater visual accuracy is more important than faster yet noisier haptic feedback when estimating the state of a partner.
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    Cholesterol-substituted 3,4-ethylenedioxythiophene (EDOT-MA-cholesterol) and Poly(3,4-ethylenedioxythiophene) (PEDOT-MA-cholesterol)
    (Giant, 2023-05-23) Wu, Yuhang; Nagane, Samadhan S.; Baugh, Quintin; Lo, Chun-Yuan; Chhatre, Shrirang S.; Lee, Junghyun; Sitarik, Peter; Kayser, Laure V.; Martin, David C.
    Cholesterol is a rigid, crystalline, non-polar natural substance that exists in animal blood and cell membranes. Some of its derivatives are known to form ordered liquid crystalline mesophases under suitable conditions. In this work, we carefully examined the influence of cholesterol substitution on the characteristics of 3,4-ethylenedioxythiophene (EDOT-MA-cholesterol) and its corresponding polymer poly(3,4-ethylenedioxythiophene) (PEDOT-MA-cholesterol) synthesized by both chemical and electrochemical polymerization. We found evidence for an ordered lamellar (smectic-like) structure in the EDOT-MA-cholesterol monomer by differential scanning calorimetry (DSC), polarized optical microscopy (POM), and X-ray diffraction techniques. The ordered phase was observed to form on cooling from the isotropic melt at about 80 °C. Due to the insulating and bulky cholesterol side group on the EDOT monomer, we found that there was a maximum charge density for electrodeposition at ∼ 0.155 C.cm−2. A series of electrodepositions were performed from 0 to 0.155 C.cm−2 for probing the change of the charge transport with more charges used for the electrodeposition. We found that the impedance increased in the high-frequency range (above 104 Hz) and decreased in the low-frequency range (below 102 Hz). Three equivalent circuit models were proposed for fitting impedance data at different charge densities for a better understanding of the film growth process. The suppressed cyclic voltammogram (CV) of PEDOT-MA-cholesterol showed that the charge storage capability was essentially eliminated in the thickest films. The limited doping of the films was corroborated by their diminished electrochromic behavior, polaron-dominating absorption in UV-vis, overoxidized S 2p X-ray Photoelectron Spectroscopy (XPS) signal of electrodeposited films, and proton Nuclear Magnetic Resonance (1H NMR) of chemically polymerized samples. Dense film morphologies were confirmed by scanning electron microscopy (SEM). Grazing incident X-ray diffraction (GIWAXS) indicated the disrupted stacking of conjugated chains, which correlated with the decreased conductivity of the PEDOT-MA-cholesterol films. The measurement of the electrical conductivity gave a value of around 3.30 × 10−6 S.cm−1 which is about six orders of magnitude lower than has been seen in PEDOT (∼3 S.cm-1). Graphical abstract available at: https://doi.org/10.1016/j.giant.2023.100163
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    Transcriptional regulation of Sis1 promotes fitness but not feedback in the heat shock response
    (eLife, 2023-05-17) Grade, Rania; Singh, Abhyudai; Ali, Asif; Pincus, David
    The heat shock response (HSR) controls expression of molecular chaperones to maintain protein homeostasis. Previously, we proposed a feedback loop model of the HSR in which heat-denatured proteins sequester the chaperone Hsp70 to activate the HSR, and subsequent induction of Hsp70 deactivates the HSR (Krakowiak et al., 2018; Zheng et al., 2016). However, recent work has implicated newly synthesized proteins (NSPs) – rather than unfolded mature proteins – and the Hsp70 co-chaperone Sis1 in HSR regulation, yet their contributions to HSR dynamics have not been determined. Here, we generate a new mathematical model that incorporates NSPs and Sis1 into the HSR activation mechanism, and we perform genetic decoupling and pulse-labeling experiments to demonstrate that Sis1 induction is dispensable for HSR deactivation. Rather than providing negative feedback to the HSR, transcriptional regulation of Sis1 by Hsf1 promotes fitness by coordinating stress granules and carbon metabolism. These results support an overall model in which NSPs signal the HSR by sequestering Sis1 and Hsp70, while induction of Hsp70 – but not Sis1 – attenuates the response.
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