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1. A pilot study on biaxial mechanical, collagen microstructural, and morphological characterizations of a resected human intracranial aneurysm tissue

   https://doi.org/10.1038/s41598-021-82991-x  

   Laurence, Devin W. ; Homburg, Hannah ; Yan, Feng ; Tang, Qinggong ; Fung, Kar-Ming ; Bohnstedt, Bradley N. ; Holzapfel, Gerhard A. ; Lee, Chung-Hao ( February 2021 , Scientific Reports)

   Intracranial aneurysms (ICAs) are focal dilatations that imply a weakening of the brain artery. Incidental rupture of an ICA is increasingly responsible for significant mortality and morbidity in the American’s aging population. Previous studies have quantified the pressure-volume characteristics, uniaxial mechanical properties, and morphological features of human aneurysms. In this pilot study,for the first time, we comprehensively quantified themechanical,collagen fiber microstructural, andmorphologicalproperties of one resected human posterior inferior cerebellar artery aneurysm. The tissue from the dome of a right posterior inferior cerebral aneurysm was first mechanically characterized using biaxial tension and stress relaxation tests. Then, the load-dependent collagen fibermore »architecture of the aneurysm tissue was quantified using an in-house polarized spatial frequency domain imaging system. Finally, optical coherence tomography and histological procedures were used to quantify the tissue’s microstructural morphology. Mechanically, the tissue was shown to exhibit hysteresis, a nonlinear stress-strain response, and material anisotropy. Moreover, the unloaded collagen fiber architecture of the tissue was predominantly aligned with the testingY-direction and rotated towards theX-direction under increasing equibiaxial loading. Furthermore, our histological analysis showed a considerable damage to the morphological integrity of the tissue, including lack of elastin, intimal thickening, and calcium deposition. This new unified characterization framework can be extended to better understand the mechanics-microstructure interrelationship of aneurysm tissues at different time points of the formation or growth. Such specimen-specific information is anticipated to provide valuable insight that may improve our current understanding of aneurysm growth and rupture potential.

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2. Novel quantification of mechanical load induced latent TGF-beta activation in articular cartilage

   Kim SY, Mosscrop M ( April 2020 , Summer Biomechanics, Bioengineering, and Biotransport Conference)

   Measuring LTGF-beta activation in live tissues in situ is a major challenge due to the short half-life of activated TGF-beta in cartilage (due to rapid receptor internalization/degradation). As such, activation assessments typically require analysis of downstream events. However, assessments of intracellular TGF-beta signaling molecules (Smad2/3 phosphorylation) yield mostly qualitative measures and reporter cell assays are not compatible with intact cartilage tissues. Alternatively, in the current project, we proposed quantifying LTGF-beta activation in situ through a novel assay that capitalizes on TGF-beta’s robust autoinduction behavior; active TGF-beta activity induces a predictable increase in synthesis of soluble LTGF-beta. The dominant fraction ofmore »newly synthesized LTGF-beta is secreted from the tissue (not retained in ECM) and stable. Accordingly, measurements of LTGF-beta secretion into culture medium allows for quantifications of TGF-beta activity in cartilage. In order to confirm that LTGF-beta secretion enhancements result from TGF-beta activity (and not other load-initiated signaling cascades), a control group can readily be utilized, consisting of TGF-beta activity inhibition from a TGF-beta-receptor specific kinase inhibitor. Using this platform, we performed the first-ever measurement of the activity of TGF-beta in cartilage explants from load-induced activation. Results demonstrate that LTGF-beta secretion rates do indeed increase with cartilage mechanical loading. Upon exposure to a TGF-beta inhibitor, LTGF-beta secretion rates return to basal control levels, thus confirming that LTGF-beta secretion enhancements can be predominantly attributed to TGF-beta activity in the tissue. Upon standard curve conversion, autoinduction assay results demonstrate that mechanical load-induced activation of ECM-bound LTGF-beta gives rise to ~0.15ng/mL of TGF-beta activity in cartilage. Importantly, this measure represents the first quantitative assessment of TGF-beta activity in articular cartilage. While these levels represent the activation of only a small fraction of the total LTGF-beta stores in the cartilage ECM (~300ng/mL), they are indeed capable of giving rise to considerable chondrocyte biosynthesis enhancements in the tissue. As such, these measurements support the mechanobiological role of load-induced LTGF-beta activation in maintaining articular cartilage integrity. The assay platform advanced in this study sets the foundation for considerable advances in our understanding of the mechanistic details and physiologic importance of load-induced LTGF-beta activation in cartilage. In the future, we plan to use this quantitative platform to assess: 1) the influence of varying loading regimens on LTGF-beta activation rates (e.g., physiologic exercise, elevated stresses, high-impact trauma), and 2) changes to load-induced LTGF-beta activation with aging or joint degeneration. An abstract on this work was presented at the 2020 ASME SB3C Conference (virtual meeting) and a full-length manuscript is currently in preparation.« less
3. An ultra-compact x-ray free-electron laser

   https://doi.org/10.1088/1367-2630/abb16c  

   Rosenzweig, J. B. ; Majernik, N. ; Robles, R. R. ; Andonian, G. ; Camacho, O. ; Fukasawa, A. ; Kogar, A. ; Lawler, G. ; Miao, Jianwei ; Musumeci, P. ; et al ( September 2020 , New Journal of Physics)

   In the field of beam physics, two frontier topics have taken center stage due to their potential to enable new approaches to discovery in a wide swath of science. These areas are: advanced, high gradient acceleration techniques, and x-ray free electron lasers (XFELs). Further, there is intense interest in the marriage of these two fields, with the goal of producing a very compact XFEL. In this context, recent advances in high gradient radio-frequency cryogenic copper structure research have opened the door to the use of surface electric fields between 250 and 500 MV m⁻¹. Such an approach is foreseenmore »to enable a new generation of photoinjectors with six-dimensional beam brightness beyond the current state-of-the-art by well over an order of magnitude. This advance is an essential ingredient enabling an ultra-compact XFEL (UC-XFEL). In addition, one may accelerate these bright beams to GeV scale in less than 10 m. Such an injector, when combined with inverse free electron laser-based bunching techniques can produce multi-kA beams with unprecedented beam quality, quantified by 50 nm-rad normalized emittances. The emittance, we note, is the effective area in transverse phase space (x,p_x/m_ec) or (y,p_y/m_ec) occupied by the beam distribution, and it is relevant to achievable beam sizes as well as setting a limit on FEL wavelength. These beams, when injected into innovative, short-period (1–10 mm) undulators uniquely enable UC-XFELs having footprints consistent with university-scale laboratories. We describe the architecture and predicted performance of this novel light source, which promises photon production per pulse of a few percent of existing XFEL sources. We review implementation issues including collective beam effects, compact x-ray optics systems, and other relevant technical challenges. To illustrate the potential of such a light source to fundamentally change the current paradigm of XFELs with their limited access, we examine possible applications in biology, chemistry, materials, atomic physics, industry, and medicine—including the imaging of virus particles—which may profit from this new model of performing XFEL science.

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4. Probing the subcellular nanostructure of engineered human cardiomyocytes in 3D tissue

   https://doi.org/10.1038/s41378-020-00234-x  

   Javor, Josh ; Ewoldt, Jourdan K. ; Cloonan, Paige E. ; Chopra, Anant ; Luu, Rebeccah J. ; Freychet, Guillaume ; Zhernenkov, Mikhail ; Ludwig, Karl ; Seidman, Jonathan G. ; Seidman, Christine E. ; et al ( January 2021 , Microsystems & Nanoengineering)

   The structural and functional maturation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is essential for pharmaceutical testing, disease modeling, and ultimately therapeutic use. Multicellular 3D-tissue platforms have improved the functional maturation of hiPSC-CMs, but probing cardiac contractile properties in a 3D environment remains challenging, especially at depth and in live tissues. Using small-angle X-ray scattering (SAXS) imaging, we show that hiPSC-CMs matured and examined in a 3D environment exhibit a periodic spatial arrangement of the myofilament lattice, which has not been previously detected in hiPSC-CMs. The contractile force is found to correlate with both the scattering intensity (R² = 0.44)more »and lattice spacing (R² = 0.46). The scattering intensity also correlates with lattice spacing (R² = 0.81), suggestive of lower noise in our structural measurement than in the functional measurement. Notably, we observed decreased myofilament ordering in tissues with a myofilament mutation known to lead to hypertrophic cardiomyopathy (HCM). Our results highlight the progress of human cardiac tissue engineering and enable unprecedented study of structural maturation in hiPSC-CMs.

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5. Anterior Cruciate Ligament Graft Tunnel Placement and Graft Angle Are Primary Determinants of Internal Knee Mechanics After Reconstructive Surgery

   https://doi.org/10.1177/0363546520966721  

   Vignos, Michael F. ; Smith, Colin R. ; Roth, Joshua D. ; Kaiser, Jarred M. ; Baer, Geoffrey S. ; Kijowski, Richard ; Thelen, Darryl G. ( November 2020 , The American Journal of Sports Medicine)

   Graft placement is a modifiable and often discussed surgical factor in anterior cruciate ligament (ACL) reconstruction (ACLR). However, the sensitivity of functional knee mechanics to variability in graft placement is not well understood.

   To (1) investigate the relationship of ACL graft tunnel location and graft angle with tibiofemoral kinematics in patients with ACLR, (2) compare experimentally measured relationships with those observed with a computational model to assess the predictive capabilities of the model, and (3) use the computational model to determine the effect of varying ACL graft tunnel placement on tibiofemoral joint mechanics during walking.

   Controlled laboratory study.

   Eighteenmore »participants who had undergone ACLR were tested. Bilateral ACL footprint location and graft angle were assessed using magnetic resonance imaging (MRI). Bilateral knee laxity was assessed at the completion of rehabilitation. Dynamic MRI was used to measure tibiofemoral kinematics and cartilage contact during active knee flexion-extension. Additionally, a total of 500 virtual ACLR models were created from a nominal computational knee model by varying ACL footprint locations, graft stiffness, and initial tension. Laxity tests, active knee extension, and walking were simulated with each virtual ACLR model. Linear regressions were performed between internal knee mechanics and ACL graft tunnel locations and angles for the patients with ACLR and the virtual ACLR models.

   Static and dynamic MRI revealed that a more vertical graft in the sagittal plane was significantly related ( P < .05) to a greater laxity compliance index ( R²= 0.40) and greater anterior tibial translation and internal tibial rotation during active knee extension ( R²= 0.22 and 0.23, respectively). Similarly, knee extension simulations with the virtual ACLR models revealed that a more vertical graft led to greater laxity compliance index, anterior translation, and internal rotation ( R²= 0.56, 0.26, and 0.13). These effects extended to simulations of walking, with a more vertical ACL graft inducing greater anterior tibial translation, ACL loading, and posterior migration of contact on the tibial plateaus.

   This study provides clinical evidence from patients who underwent ACLR and from complementary modeling that functional postoperative knee mechanics are sensitive to graft tunnel locations and graft angle. Of the factors studied, the sagittal angle of the ACL was particularly influential on knee mechanics.

   Early-onset osteoarthritis from altered cartilage loading after ACLR is common. This study shows that postoperative cartilage loading is sensitive to graft angle. Therefore, variability in graft tunnel placement resulting in small deviations from the anatomic ACL angle might contribute to the elevated risk of osteoarthritis after ACLR.

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