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1. LIPUS far-field exposimetry system for uniform stimulation of tissues in-vitro: development and validation with bovine intervertebral disc cells

   https://doi.org/10.1088/2057-1976/ab8b26  

   Horne, Devante A. ; Jones, Peter D. ; Adams, Matthew S. ; Lotz, Jeffrey C. ; Diederich, Chris J. ( April 2020 , Biomedical Physics & Engineering Express)

   Therapeutic Low-intensity Pulsed Ultrasound (LIPUS) has been applied clinically for bone fracture healing and has been shown to stimulate extracellular matrix (ECM) metabolism in numerous soft tissues including intervertebral disc (IVD). In-vitro LIPUS testing systems have been developed and typically include polystyrene cell culture plates (CCP) placed directly on top of the ultrasound transducer in the acoustic near-field (NF). This configuration introduces several undesirable acoustic artifacts, making the establishment of dose-response relationships difficult, and is not relevant for targeting deep tissues such as the IVD, which may require far-field (FF) exposure from low frequency sources. The objective of this study was to design and validate an in-vitro LIPUS system for stimulating ECM synthesis in IVD-cells while mimicking attributes of a deep delivery system by delivering uniform, FF acoustic energy while minimizing reflections and standing waves within target wells, and unwanted temperature elevation within target samples. Acoustic field simulations and hydrophone measurements demonstrated that by directing LIPUS energy at 0.5, 1.0, or 1.5 MHz operating frequency, with an acoustic standoff in the FF (125–350 mm), at 6-well CCP targets including an alginate ring spacer, uniform intensity distributions can be delivered. A custom FF LIPUS system was fabricated and demonstrated reduced acoustic intensity field heterogeneity within CCP-wells by up to 93% compared to common NF configurations. When bovine IVD cells were exposed to LIPUS (1.5 MHz, 200 μs pulse, 1 kHz pulse frequency, and I_SPTA = 120 mW cm⁻²) using the FF system, sample heating was minimal (+0.81 °C) and collagen content was increased by 2.6-fold compared to the control and was equivalent to BMP-7 growth factor treatment. The results of this study demonstrate that FF LIPUS exposure increases collagen content in IVD cells and suggest that LIPUS is a potential noninvasive therapeutic for stimulating repair of tissues deep within the body such as the IVD.

    

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2. Key developments that impacted the field of mechanobiology and mechanotransduction: MECHANOBIOLOGY AND SIGNAL TRANSDUCTION

   https://doi.org/10.1002/jor.23707  

   Wall, Michelle ; Butler, David ; Haj, Alicia El ; Bodle, Josephine C. ; Loboa, Elizabeth G. ; Banes, Albert J. ( February 2018 , Journal of Orthopaedic Research)

   Advances in mechanobiology have evolved through insights from multiple disciplines including structural engineering, biomechanics, vascular biology, and orthopaedics. In this paper, we reviewed the impact of key reports related to the study of applied loads on tissues and cells and the resulting signal transduction pathways. We addressed how technology has helped advance the burgeoning field of mechanobiology (over 33,600 publications from 1970 to 2016). We analyzed the impact of critical ideas and then determined how these concepts influenced the mechanobiology field by looking at the citation frequency of these reports as well as tracking how the overall number of citations within the field changed over time. These data allowed us to understand how a key publication, idea, or technology guided or enabled the field. Initial observations of how forces acted on bone and soft tissues stimulated the development of computational solutions defining how forces affect tissue modeling and remodeling. Enabling technologies, such as cell and tissue stretching, compression, and shear stress devices, allowed more researchers to explore how deformation and fluid flow affect cells. Observation of the cell as a tensegrity structure and advanced methods to study genetic regulation in cells further advanced knowledge of specific mechanisms of mechanotransduction. The future of the field will involve developing gene and drug therapies to simulate or augment beneficial load regimens in patients and in mechanically conditioning organs for implantation. Here, we addressed a history of the field, but we limited our discussions to advances in musculoskeletal mechanobiology, primarily in bone, tendon, and ligament tissues. 

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3. Continuum interpretation of mechano-adaptation in micropatterned epithelia informed by in vitro experiments

   https://doi.org/10.1093/intbio/zyad009  

   Cook, Bernard L. ; Alford, Patrick W. ( August 2023 , Integrative Biology)

   Epithelial tissues adapt their form and function following mechanical perturbations, or mechano-adapt, and these changes often result in reactive forces that oppose the direction of the applied change. Tissues subjected to ectopic tensions, for example, employ behaviors that lower tension, such as increasing proliferation or actomyosin turnover. This oppositional behavior suggests that the tissue has a mechanical homeostasis. Whether attributed to maintenance of cellular area, cell density, or cell and tissue tensions, epithelial mechanical homeostasis has been implicated in coordinating embryonic morphogenesis, wound healing, and maintenance of adult tissues. Despite advances toward understanding the feedback between mechanical state and tissue response in epithelia, more work remains to be done to examine how tissues regulate mechanical homeostasis using epithelial sheets with defined micropatterned shapes. Here, we used cellular microbiaxial stretching (CμBS) to investigate mechano-adaptation in micropatterned tissues of different shape consisting of Madin–Darby canine kidney cells. Using the CμBS platform, tissues were subjected to a 30% stretch that was held for 24 h. We found that, following stretch, tissue stresses immediately increased then slowly evolved over time, approaching their pre-stretch values by 24 h. Organization of the actin cytoskeletal was found to play a role in this process: anisotropic ally structured tissues exhibited anisotropic stress patterns, and the cytoskeletal became more aligned following stretch and reorganized over time. Interestingly, in unstretched tissues, stresses also decreased, which was found to be driven by proliferation-induced cellular confinement and change in tissue thickness. We modeled these behaviors with a continuum-based model of epithelial growth that accounted for stress-induced actin remodeling and proliferation, and found this model to strongly capture experimental behavior. Ultimately, this combined experimental-modeling approach suggests that epithelial mechano-adaptation depends on cellular architecture and proliferation, which can be modeled with a field-averaged approach applicable to more specific contexts in which change is driven by epithelial mechanical homeostasis.

   Insight box Epithelial tissues adapt their form and function following mechanical perturbation, and it is thought that this ‘mechano-adaptation’ plays an important role in driving processes like embryonic morphogenesis, wound healing, and adult tissue maintenance. Here, we use cellular microbiaxial stretching to probe this process in vitro in small epithelial tissues whose geometries were both controlled and varied. By using a highly precise stretching device and a continuum mechanics modeling framework, we revealed that tissue mechanical state changes following stretch and over time, and that this behavior can be explained by stress-dependent changes in actin fibers and proliferation. Integration of these approaches enabled a systematic approach to empirically and precisely measure these phenomena.

    

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4. Engineered tissue vascularization and engraftment depends on host model

   https://doi.org/10.1038/s41598-022-23895-2  

   Brady, Eileen L. ; Prado, Olivia ; Johansson, Fredrik ; Mitchell, Shannon N. ; Martinson, Amy M. ; Karbassi, Elaheh ; Reinecke, Hans ; Murry, Charles E. ; Davis, Jennifer ; Stevens, Kelly R. ( February 2023 , Scientific Reports)

   Developing vascular networks that integrate with the host circulation and support cells engrafted within engineered tissues remains a key challenge in tissue engineering. Most previous work in this field has focused on developing new methods to build human vascular networks within engineered tissues prior to their implant in vivo, with substantively less attention paid to the role of the host in tissue vascularization and engraftment. Here, we assessed the role that different host animal models and anatomic implant locations play in vascularization and cardiomyocyte survival within engineered tissues. We found major differences in the formation of graft-derived blood vessels and survival of cardiomyocytes after implantation of identical tissues in immunodeficient athymic nude miceversusrats. Athymic mice supported robust guided vascularization of human microvessels carrying host blood but relatively sparse cardiac grafts within engineered tissues, regardless of implant site. Conversely, athymic rats produced substantive inflammatory changes that degraded grafts (abdomen) or disrupted vascular patterning (heart). Despite disrupted vascular patterning, athymic rats supported > 3-fold larger human cardiomyocyte grafts compared to athymic mice. This work demonstrates the critical importance of the host for vascularization and engraftment of engineered tissues, which has broad translational implications across regenerative medicine.

    

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5. Projection method as a probe for multiplexing/demultiplexing of magnetically enriched biological tissues

   https://doi.org/10.1039/D0RA01574A  

   Zamani Kouhpanji, Mohammad Reza ; Stadler, Bethanie J. ( April 2020 , RSC Advances)

   null (Ed.)

   The unmet demand for cheap, accurate, and fast multiplexing of biomarkers has urged nanobiotechnology to prioritize the invention of new biomarkers that make feasible the remote detection, identification, and quantification of biological units, such as regenerative tissues. Here, we introduce a novel approach that highlights magnetic nanowires (MNWs) with such capabilities. This method employs the stable magnetization states of MNWs as a unique characteristic that can be realized by projecting the MNWs' switching field on the backward field ( P Hb ), also known as the irreversible switching field. Experimentally, several types of MNWs were directly synthesized inside polycarbonate tissues and their P Hb characteristics were measured and analyzed. Our results show that the P Hb gives an excellent identification and quantification characteristic for demultiplexing MNWs embedded in these tissues. Furthermore, this method significantly improves the characterization speed by a factor of 50×–100× that makes it superior to the current state of the art that ceased the progression of magnetic nanoparticles in multiplexing/demultiplexing applications. 

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