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The diaphragm is the "respiratory pump;" the muscle that generates pressure to allow ventilation. Diaphragm muscles play a vital function and thus are subjected to continuous mechanical loading. One of its peculiarities is the ability to generate distinct mechanical and biochemical responses depending on the direction through which the mechanical forces applied to it. Contractile forces originated from its contractile components are transmitted to other structural components of its muscle fibers and the surrounding connective tissue. The anisotropic mechanical properties of the diaphragm are translated into biochemical signals that are directionally mechanosensitive by mechanisms that appear to be unique to this muscle. Here, we reviewed the current state of knowledge on the biochemical pathways regulated by mechanical signals emphasizing their anisotropic behavior in the normal diaphragm and analyzed how they are affected in muscular dystrophies.
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An implantable soft robotic ventilator augments inspiration in a pig model of respiratory insufficiency
Abstract Severe diaphragm dysfunction can lead to respiratory failure and to the need for permanent mechanical ventilation. Yet permanent tethering to a mechanical ventilator through the mouth or via tracheostomy can hinder a patient’s speech, swallowing ability and mobility. Here we show, in a porcine model of varied respiratory insufficiency, that a contractile soft robotic actuator implanted above the diaphragm augments its motion during inspiration. Synchronized actuation of the diaphragm-assist implant with the native respiratory effort increased tidal volumes and maintained ventilation flow rates within the normal range. Robotic implants that intervene at the diaphragm rather than at the upper airway and that augment physiological metrics of ventilation may restore respiratory performance without sacrificing quality of life.
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- Award ID(s):
- 1847541
- PAR ID:
- 10425730
- Date Published:
- Journal Name:
- Nature Biomedical Engineering
- Volume:
- 7
- Issue:
- 2
- ISSN:
- 2157-846X
- Page Range / eLocation ID:
- 110 to 123
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Background Acute respiratory failure is generally treated with invasive mechanical ventilation or noninvasive respiratory support strategies. The efficacies of the various strategies are not fully understood. There is a need for accurate therapy-based phenotyping for secondary analyses of electronic health record data to answer research questions regarding respiratory management and outcomes with each strategy. Objective The objective of this study was to address knowledge gaps related to ventilation therapy strategies across diverse patient populations by developing an algorithm for accurate identification of patients with acute respiratory failure. To accomplish this objective, our goal was to develop rule-based computable phenotypes for patients with acute respiratory failure using remotely monitored intensive care unit (tele-ICU) data. This approach permits analyses by ventilation strategy across broad patient populations of interest with the ability to sub-phenotype as research questions require. Methods Tele-ICU data from ≥200 hospitals were used to create a rule-based algorithm for phenotyping patients with acute respiratory failure, defined as an adult patient requiring invasive mechanical ventilation or a noninvasive strategy. The dataset spans a wide range of hospitals and ICU types across all US regions. Structured clinical data, including ventilation therapy start and stop times, medication records, and nurse and respiratory therapy charts, were used to define clinical phenotypes. All adult patients of any diagnoses with record of ventilation therapy were included. Patients were categorized by ventilation type, and analysis of event sequences using record timestamps defined each phenotype. Manual validation was performed on 5% of patients in each phenotype. Results We developed 7 phenotypes: (0) invasive mechanical ventilation, (1) noninvasive positive-pressure ventilation, (2) high-flow nasal insufflation, (3) noninvasive positive-pressure ventilation subsequently requiring intubation, (4) high-flow nasal insufflation subsequently requiring intubation, (5) invasive mechanical ventilation with extubation to noninvasive positive-pressure ventilation, and (6) invasive mechanical ventilation with extubation to high-flow nasal insufflation. A total of 27,734 patients met our phenotype criteria and were categorized into these ventilation subgroups. Manual validation of a random selection of 5% of records from each phenotype resulted in a total accuracy of 88% and a precision and recall of 0.8789 and 0.8785, respectively, across all phenotypes. Individual phenotype validation showed that the algorithm categorizes patients particularly well but has challenges with patients that require ≥2 management strategies. Conclusions Our proposed computable phenotyping algorithm for patients with acute respiratory failure effectively identifies patients for therapy-focused research regardless of admission diagnosis or comorbidities and allows for management strategy comparisons across populations of interest.more » « less
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Mechanotransduction, also referred to as mechano-signal transduction, is a biophysical process wherein cells perceive and respond to mechanical stimuli by converting them into biochemical signals that initiate specific cellular responses. This mechanism is fundamental to the development and growth, and proper functioning of mechanically active tissues, such as the diaphragm—a respiratory muscle vital for breathing in mammals. In vivo, the diaphragm is subjected to transdiaphragmatic pressure, and therefore, its muscle fibers are subjected to mechanical forces not only in the direction of the muscle fibers but also in the direction transverse to the fibers. Previous research conducted in our laboratory uncovered that stretching the diaphragm in either the longitudinal or transverse direction activates distinct mechanotransduction pathways. This indicates that signaling pathways in the diaphragm muscle are regulated in an anisotropic manner. In this review paper, we discussed the underlying mechanisms that regulate the anisotropic signaling pathways in the diaphragmatic muscle, emphasizing the mechanical role of cytoskeletal proteins in this context. Furthermore, we explored the regulatory mechanisms governing mechanosensitive gene transcription, including microRNAs (mechanomiRs), within the diaphragm muscle. Finally, we examined potential links between anisotropic signaling in the diaphragm muscle and various skeletal muscle disorders.more » « less
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A comprehensive constitutive theory is developed for the diaphragm. The theory can describe the mechanical properties of the diaphragm muscle in its passive and active states in a unified manner. It also describes the mechanical properties of the diaphragm under mechanical loads in arbitrary directions. The theoretical model involves seven material constants that represent the nonlinear elastic moduli and activation strains of the diaphragm muscle. The values of these material constants are determined by using in vitro experimental data, including that from shear loading experiments which are documented in this work for the first time.more » « less
- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.1038/s41551-022-00971-6
