Tough Adhesive Hydrogel for Intraoral Adhesion and Drug Delivery.

Oral lichen planus (OLP) and recurrent aphthous stomatitis (RAS) are common chronic inflammatory conditions, manifesting as painful oral lesions that negatively affect patients' quality of life. Current treatment approaches are mainly palliative and often ineffective due to inadequate contact time of the therapeutic agent with the lesions. Here, we developed the Dental Tough Adhesive (DenTAl), a bioinspired adhesive patch with robust mechanical properties, capable of strong adhesion against diverse wet and dynamically moving intraoral tissues, and extended drug delivery of clobetasol-17-propionate, a first-line drug for treating OLP and RAS. DenTAl was found to have superior physical and adhesive properties compared to existing oral technologies, with ~2 to 100× adhesion to porcine keratinized gingiva and ~3 to 15× stretchability. Clobetasol-17-propionate incorporated into the DenTAl was released in a tunable sustained manner for at least 3 wk and demonstrated immunomodulatory capabilities in vitro, evidenced by reductions in several cytokines, including TNF-α, IL-6, IL-10, MCP-5, MIP-2, and TIMP-1. Our findings suggest that DenTAl may be a promising device for intraoral delivery of small-molecule drugs applicable to the management of painful oral lesions associated with chronic inflammatory conditions.

Anti-inflammatory therapy enables robot-actuated regeneration of aged muscle.

Robot-actuated mechanical loading (ML)-based therapies ("mechanotherapies") can promote regeneration after severe skeletal muscle injury, but the effectiveness of such approaches during aging is unknown and may be influenced by age-associated decline in the healing capacity of skeletal muscle. To address this knowledge gap, this work used a noninvasive, load-controlled robotic device to impose highly defined tissue stresses to evaluate the age dependence of ML on muscle repair after injury. The response of injured muscle to robot-actuated cyclic compressive loading was found to be age sensitive, revealing not only a lack of reparative benefit of ML on injured aged muscles but also exacerbation of tissue inflammation. ML alone also disrupted the normal regenerative processes of aged muscle stem cells. However, these negative effects could be reversed by introducing anti-inflammatory therapy alongside ML application, leading to enhanced skeletal muscle regeneration even in aged mice.

Bioinspired mechanically active adhesive dressings to accelerate wound closure.

Inspired by embryonic wound closure, we present mechanically active dressings to accelerate wound healing. Conventional dressings passively aid healing by maintaining moisture at wound sites. Recent developments have focused on drug and cell delivery to drive a healing process, but these methods are often complicated by drug side effects, sophisticated fabrication, and high cost. Here, we present novel active adhesive dressings consisting of thermoresponsive tough adhesive hydrogels that combine high stretchability, toughness, tissue adhesion, and antimicrobial function. They adhere strongly to the skin and actively contract wounds, in response to exposure to the skin temperature. In vitro and in vivo studies demonstrate their efficacy in accelerating and supporting skin wound healing. Finite element models validate and refine the wound contraction process enabled by these active adhesive dressings. This mechanobiological approach opens new avenues for wound management and may find broad utility in applications ranging from regenerative medicine to soft robotics.

Supraspinatus Tendons Have Different Mechanical Properties Across Sex.

Sex differences in the mechanical properties of different musculoskeletal tissues and their impact on tendon function and disease are becoming increasingly recognized. Tendon mechanical properties are influenced by the presence or absence of sex hormones and these effects appear to be tendon- or ligament-specific. The objective of this study was to determine how sex and hormone differences in rats affect supraspinatus tendon and muscle properties. We hypothesized that male supraspinatus tendons would have increased cross-sectional area but no differences in tendon material properties or muscle composition when compared to supraspinatus tendons from female or ovariectomized (OVX) female rats. Uninjured supraspinatus tendons and muscles from male, female, and OVX female rats were collected and mechanical and histological properties were determined. Our analysis demonstrated decreased dynamic modulus and increased hysteresis and cross-sectional area in male tendons. We found that male tendons exhibited decreased dynamic modulus (during low strain frequency sweep and high strain fatigue loading), increased hysteresis, and increased cross-sectional area compared to female and OVX female tendons. Despite robust mechanical differences, tendon cell density and shape, and muscle composition remained unchanged between groups. Interestingly, these differences were unique compared to previously reported sex differences in rat Achilles tendons, which further supports the concept that the effect of sex on tendon varies anatomically. These differences may partially provide a mechanistic explanation for the increased rate of acute supraspinatus tendon ruptures seen in young males.

Aging leads to inferior Achilles tendon mechanics and altered ankle function in rodents.

Spontaneous rupture of the Achilles tendon is increasingly common in the middle aged population. However, the cause for the particularly high incidence of injury in this age group is not well understood. Therefore, the objective of this study was to identify age-specific differences in the Achilles tendon-muscle complex using an animal model. Functional measures were performed in vivo and tissues were harvested following euthanasia for mechanical, structural, and histological analysis from young, middle aged, and old rats. Numerous alterations in tendon properties were detected across age groups, including inferior material properties (maximum stress, modulus) with increasing age. Differences in function were also observed, as older animals exhibited increased ankle joint passive stiffness and decreased propulsion force during locomotion. Macroscale differences in tendon organization were not observed, although cell density and nuclear shape did vary between age groups. Muscle fiber size and type distribution were not notably affected by age, indicating that other factors may be more responsible for age-specific Achilles tendon rupture rates. This study improves our understanding of the role of aging in Achilles tendon biomechanics and ankle function, and helps provide a potential explanation for the disparate incidence of Achilles tendon ruptures in varying age groups.

Males have Inferior Achilles Tendon Material Properties Compared to Females in a Rodent Model.

The Achilles tendon is the most commonly ruptured tendon in the human body. Numerous studies have reported incidence of these injuries to be upwards of five times as common in men than women. Therefore, the objective of this study was to investigate the sex- and hormone-specific differences between Achilles tendon and muscle between female, ovariectomized female (ovarian hormone deficient), and male rats. Uninjured tissues were collected from all groups for mechanical, structural, and histological analysis. Our results showed that while cross-sectional area and failure load were increased in male tendons, female tendons exhibited superior tendon material properties and decreased muscle fiber size. Specifically, linear and dynamic moduli were increased while viscoelastic properties (e.g., hysteresis, percent relaxation) were decreased in female tendons, suggesting greater resistance to deformation under load and more efficient energy transfer, respectively. No differences were identified in tendon organization, cell shape, cellularity, or proteoglycan content. Additionally, no differences in muscle fiber type distribution were observed between groups. In conclusion, inferior tendon mechanical properties and increased muscle fiber size may explain the increased susceptibility for Achilles tendon injury observed clinically in men compared to women.

Ground reaction forces are more sensitive gait measures than temporal parameters in rodents following rotator cuff injury.

Gait analysis is a quantitative, non-invasive technique that can be used to investigate functional changes in animal models of musculoskeletal disease. Changes in ground reaction forces following injury have been observed that coincide with differences in tissue mechanical and histological properties during healing. However, measurement of these kinetic gait parameters can be laborious compared to the simpler and less time-consuming analysis of temporal gait parameters alone. We compared the sensitivity of temporal and kinetic gait parameters in detecting functional changes following rotator cuff injury in rats. Although these parameters were strongly correlated, temporal measures were unable to detect greater than 50% of the functional gait differences between injured and uninjured animals identified simultaneously by ground reaction forces. Regression analysis was used to predict ground reaction forces from temporal parameters. This model improved the ability of temporal parameters to identify known functional changes, but only when these differences were large in magnitude (i.e., between injured vs. uninjured animals, but not between different post-operative treatments). The results of this study suggest that ground reaction forces are more sensitive measures of limb/joint function than temporal parameters following rotator cuff injury in rats. Therefore, although gait analysis systems without force plates are typically efficient and easy to use, they may be most appropriate for use when major functional changes are expected.

Achilles tendons from decorin- and biglycan-null mouse models have inferior mechanical and structural properties predicted by an image-based empirical damage model.

Achilles tendons are a common source of pain and injury, and their pathology may originate from aberrant structure function relationships. Small leucine rich proteoglycans (SLRPs) influence mechanical and structural properties in a tendon-specific manner. However, their roles in the Achilles tendon have not been defined. The objective of this study was to evaluate the mechanical and structural differences observed in mouse Achilles tendons lacking class I SLRPs; either decorin or biglycan. In addition, empirical modeling techniques based on mechanical and image-based measures were employed. Achilles tendons from decorin-null (Dcn(-/-)) and biglycan-null (Bgn(-/-)) C57BL/6 female mice (N=102) were used. Each tendon underwent a dynamic mechanical testing protocol including simultaneous polarized light image capture to evaluate both structural and mechanical properties of each Achilles tendon. An empirical damage model was adapted for application to genetic variation and for use with image based structural properties to predict tendon dynamic mechanical properties. We found that Achilles tendons lacking decorin and biglycan had inferior mechanical and structural properties that were age dependent; and that simple empirical models, based on previously described damage models, were predictive of Achilles tendon dynamic modulus in both decorin- and biglycan-null mice.