A mathematical model to serve as a clinical tool for assessing obstructive sleep apnea severity.

Obstructive sleep apnea (OSA) is a sleep disorder caused by periodic airway obstructions and has been associated with numerous health consequences, which are thought to result from tissue hypoxia. However, challenges in the direct measurement of tissue-level oxygenation make it difficult to analyze the hypoxia exposure pattern in patients. Furthermore, current clinical practice relies on the apnea-hypopnea index (AHI) and pulse oximetry to assess OSA severity, both of which have limitations. To overcome this, we developed a clinically deployable mathematical model, which outputs tissue-level oxygenation. The model incorporates spatial pulmonary oxygen uptake, considers dissolved oxygen, and can use time-dependent patient inputs. It was applied to explore a series of breathing patterns that are clinically differentiated. Supporting previous studies, the result of this analysis indicated that the AHI is an unreliable indicator of hypoxia burden. As a proof of principle, polysomnography data from two patients was analyzed with this model. The model showed greater sensitivity to breathing in comparison with pulse oximetry and provided systemic venous oxygenation, which is absent from clinical measurements. In addition, the dissolved oxygen output was used to calculate hypoxia burden scores for each patient and compared to the clinical assessment, highlighting the importance of event length and cumulative impact of obstructions. Furthermore, an intra-patient statistical analysis was used to underscore the significance of closely occurring obstructive events and to highlight the utility of the model for quantitative data processing. Looking ahead, our model can be used with polysomnography data to predict hypoxic burden on the tissues and help guide patient treatment decisions.

Diaphragm muscle fibrosis involves changes in collagen organization with mechanical implications in Duchenne muscular dystrophy.

In Duchenne muscular dystrophy (DMD), diaphragm muscle dysfunction results in respiratory insufficiency, a leading cause of death in patients. Increased muscle stiffness occurs with buildup of fibrotic tissue, characterized by excessive accumulation of extracellular matrix (ECM) components such as collagen, and prevents the diaphragm from achieving the excursion lengths required for respiration. However, changes in mechanical properties are not explained by collagen amount alone and we must consider the complex structure and mechanics of fibrotic tissue. The goals of our study were to 1) determine if and how collagen organization changes with the progression of DMD in diaphragm muscle tissue and 2) predict how collagen organization influences the mechanical properties of the ECM. We first visualized collagen structure with scanning electron microscopy (SEM) images and then developed an analysis framework to quantify collagen organization and generate image-based finite-element models. Image analysis revealed increased collagen fiber straightness and alignment in mdx over wild type (WT) at 3 mo (straightness: mdx = 0.976 ± 0.0108, WT = 0.887 ± 0.0309, alignment: mdx = 0.876 ± 0.0333, WT = 0.759 ± 0.0416) and 6 mo (straightness: mdx = 0.942 ± 0.0182, WT = 0.881 ± 0.0163, alignment: mdx = 0.840 ± 0.0315, WT = 0.759 ± 0.0368). Collagen fibers retained a transverse orientation relative to muscle fibers (70°-90°) in all groups. Mechanical models predicted an increase in the transverse relative to longitudinal (muscle fiber direction) stiffness, with stiffness ratio (transverse/longitudinal) increased in mdx over WT at 3 mo (mdx = 5.45 ± 2.04, WT = 1.97 ± 0.670) and 6 mo (mdx = 4.05 ± 0.985, WT = 1.96 ± 0.506). This study revealed changes in diaphragm ECM structure and mechanics during disease progression in the mdx muscular dystrophy mouse phenotype, highlighting the need to consider the role of collagen organization on diaphragm muscle function.NEW & NOTEWORTHY Scanning electron microscopy images of decellularized diaphragm muscle from WT and mdx, Duchenne muscular dystrophy model, mice revealed that collagen fibers in the epimysium are oriented transverse to muscle fibers, with age- and disease-dependent changes in collagen arrangement. Finite-element models generated from these images predicted that changes in collagen arrangement during disease progression influence the mechanical properties of the extracellular matrix. Thus, changes in collagen fiber-level structure are implicated on tissue-level properties during fibrosis.

In Silico and In Vivo Studies Detect Functional Repair Mechanisms in a Volumetric Muscle Loss Injury.

IMPACT STATEMENT: Despite medical advances, volumetric muscle loss (VML) injuries to craniofacial muscles represent an unmet clinical need. We report an implantable tissue-engineered construct that leads to substantial tissue regeneration and functional recovery in a preclinical model of VML injury that is dimensionally relevant to unilateral cleft lip repair, and a series of corresponding computational models that provide biomechanical insight into mechanism(s) responsible for the VML-induced functional deficits and recovery following tissue-engineered muscle repair implantation. This unique combined approach represents a critical first step toward establishing a crucial biomechanical basis for the development of efficacious regenerative technologies, considering the spectrum of VML injuries.