Influence of Decorin and Biglycan on Tensile Viscoelastic Properties in Knockout Mice

Tendons have a complex, viscoelastic mechanical behavior that depends on their composition and structure. Understanding these structure-function relationships may help elucidate important differences in the varying functional behaviors of specific tendons as well as guide targeted treatment modalities and tissue engineered constructs. The tendon extracellular matrix (ECM) can be described as a biocomposite material consisting of collagen fibers surrounded by an extrafibrillar matrix. Many studies have focused on the role of the fibers on the tensile properties of tendon; however, fibers alone do not completely explain the viscoelastic and non-linear response of tendon. The interactions of small leucine-rich proteoglycans (SLRPs) with other ECM molecules, such as collagen fibrils, as well as their association with water suggest that SLRPs may play a role in tendon viscoelasticity. Some studies have assessed the role of SLRPs or glycosaminoglycans in the mechanical response of tendon, but few have explored their role in more sophisticated viscoelastic properties. Therefore, the objective of this study was to evaluate the viscoelastic response of the patellar tendon in two different SLRP knockout mice compared to wildtype. We hypothesized that the absence of SLRPs would lead to a stiffer dynamic tissue response compared to wildtype.</jats:p

Mechanical, compositional, and structural properties of the mouse patellar tendon with changes in biglycan gene expression

Tendons have complex mechanical properties that depend on their structure and composition. Some studies have assessed the role of small leucine-rich proteoglycans (SLRPs) in the mechanical response of tendon, but the relationships between sophisticated mechanics, assembly of collagen and SLRPs have not been well characterized. In this study, biglycan gene expression was varied in a dose dependent manner using biglycan null, biglycan heterozygote and wild type mice. Measures of mechanical (tension and compression), compositional and structural changes of the mouse patellar tendon were evaluated. Viscoelastic, tensile dynamic modulus was found to be increased in the biglycan heterozygous and biglycan null tendons compared to wild type. Gene expression analyses revealed biglycan gene expression was closely associated in a dose-dependent allelic manner. No differences were seen between genotypes in elastic or compressive properties or quantitative measures of collagen structure. These results suggest that biglycan, a member of the SLRP family, plays a role in tendon viscoelasticity that cannot be completely explained by its role in collagen fibrillogenesis

Influence of Decorin on the Mechanical, Compositional, and Structural Properties of the Mouse Patellar Tendon

The interactions of small leucine-rich proteoglycans (SLRPs) with collagen fibrils, their association with water, and their role in fibrillogenesis suggests that SLRPs may play an important role in tendon mechanics. Some studies have assessed the role of SLRPs in the mechanical response of the tendon, but the relationships between sophisticated mechanics, assembly of collagen, and SLRPs have not been well characterized. Decorin content was varied in a dose dependent manner using decorin null, decorin heterozygote, and wild type mice. Quantitative measures of mechanical (tension and compression), compositional, and structural changes of the mouse patellar tendon were evaluated. Viscoelastic, tensile dynamic modulus was increased in the decorin heterozygous tendons compared to wild type. These tendons also had a significant decrease in total collagen and no structural changes compared to wild type. Decorin null tendons did not have any mechanical changes; however, a significant decrease in the average fibril diameter was found. No differences were seen between genotypes in elastic or compressive properties, and all tendons demonstrated viscoelastic mechanical dependence on strain rate and frequency. These results suggest that decorin, a member of the SLRP family, plays a role in tendon viscoelasticity that cannot be completely explained by its role in collagen fibrillogenesis. In addition, reductions in decorin do not cause large changes in indentation compressive properties, suggesting that other factors contribute to these properties. Understanding these relationships may ultimately help guide development of tissue engineered constructs or treatment modalities.</jats:p

Validation of an Empirical Damage Model for Aging and \u3cem\u3ein Vivo\u3c/em\u3e Injury of the Murine Patellar Tendon

While useful models have been proposed to predict the mechanical impact of damage in tendon and other soft tissues, the applicability of these models for describing in vivo injury and age-related degeneration has not been investigated. Therefore, the objective of this study was to develop and validate a simple damage model to predict mechanical alterations in mouse patellar tendons after aging, injury, or healing. To characterize baseline properties, uninjured controls at age 150 days were cyclically loaded across three strain levels and five frequencies. For comparison, damage was induced in mature (120 day-old) mice through either injury or aging. Injured mice were sacrificed at three or six weeks after surgery, while aged mice were sacrificed at either 300 or 570 days old. Changes in mechanical properties (relative to baseline) in the three week post-injury group were assessed and used to develop an empirical damage model based on a simple damage parameter related to the equilibrium stress at a prescribed strain (6%). From the derived model, the viscoelastic properties of the 300 day-old, 570 day-old, and six week post-injury groups were accurately predicted. Across testing conditions, nearly all correlations between predicted and measured parameters were statistically significant and coefficients of determination ranged from R(2 )= 0.25 to 0.97. Results suggest that the proposed damage model could exploit simple in vivo mechanical measurements to predict how an injured or aged tendon will respond to complex physiological loading regimens

The Tendon Injury Response is Influenced by Decorin and Biglycan

Defining the constituent regulatory molecules in tendon is critical to understanding the process of tendon repair and instructive to the development of novel treatment modalities. The purpose of this study is to define the structural, expressional, and mechanical changes in the tendon injury response, and elucidate the roles of two class I small leucine-rich proteoglycans (SLRPs). We utilized biglycan-null, decorin-null and wild type mice with an established patellar tendon injury model. Mechanical testing demonstrated functional changes associated with injury and the incomplete recapitulation of mechanical properties after 6 weeks. In addition, SLRP deficiency influenced the mechanical properties with a marked lack of improvement between 3 and 6 weeks in decorin-null tendons. Morphological analyses of the injury response and role of SLRPs demonstrated alterations in cell density and shape as well as collagen alignment and fibril structure resulting from injury. SLRP gene expression was studied using RT-qPCR with alterations in expression associated with the injured tendons. Our results show that in the absence of biglycan initial healing may be impaired while in the absence of decorin later healing is clearly diminished. This suggests that biglycan and decorin may have sequential roles in the tendon response to injury

The Tendon Injury Response is Influenced by Decorin and Biglycan

Defining the constituent regulatory molecules in tendon is critical to understanding the process of tendon repair and instructive to the development of novel treatment modalities. The purpose of this study is to define the structural, expressional, and mechanical changes in the tendon injury response, and elucidate the roles of two class I small leucine-rich proteoglycans (SLRPs). We utilized biglycan-null, decorin-null and wild type mice with an established patellar tendon injury model. Mechanical testing demonstrated functional changes associated with injury and the incomplete recapitulation of mechanical properties after six weeks. In addition, SLRP deficiency influenced the mechanical properties with a marked lack of improvement between three and six weeks in decorin-null tendons. Morphological analyses of the injury response and role of SLRPs demonstrated alterations in cell density and shape as well as collagen alignment and fibril structure resulting from injury. SLRP gene expression was studied using RT-qPCR with alterations in expression associated with the injured tendons. Our results show that in the absence of biglycan initial healing may be impaired while in the absence of decorin later healing is clearly diminished. This suggests that biglycan and decorin may have sequential roles in the tendon response to injury

Postoperative continuous positive airway pressure to prevent pneumonia, re-intubation, and death after major abdominal surgery (PRISM): a multicentre, open-label, randomised, phase 3 trial

Background: Respiratory complications are an important cause of postoperative morbidity. We aimed to investigate whether continuous positive airway pressure (CPAP) administered immediately after major abdominal surgery could prevent postoperative morbidity. Methods: PRISM was an open-label, randomised, phase 3 trial done at 70 hospitals across six countries. Patients aged 50 years or older who were undergoing elective major open abdominal surgery were randomly assigned (1:1) to receive CPAP within 4 h of the end of surgery or usual postoperative care. Patients were randomly assigned using a computer-generated minimisation algorithm with inbuilt concealment. The primary outcome was a composite of pneumonia, endotracheal re-intubation, or death within 30 days after randomisation, assessed in the intention-to-treat population. Safety was assessed in all patients who received CPAP. The trial is registered with the ISRCTN registry, ISRCTN56012545. Findings: Between Feb 8, 2016, and Nov 11, 2019, 4806 patients were randomly assigned (2405 to the CPAP group and 2401 to the usual care group), of whom 4793 were included in the primary analysis (2396 in the CPAP group and 2397 in the usual care group). 195 (8\ub71%) of 2396 patients in the CPAP group and 197 (8\ub72%) of 2397 patients in the usual care group met the composite primary outcome (adjusted odds ratio 1\ub701 [95% CI 0\ub781-1\ub724]; p=0\ub795). 200 (8\ub79%) of 2241 patients in the CPAP group had adverse events. The most common adverse events were claustrophobia (78 [3\ub75%] of 2241 patients), oronasal dryness (43 [1\ub79%]), excessive air leak (36 [1\ub76%]), vomiting (26 [1\ub72%]), and pain (24 [1\ub71%]). There were two serious adverse events: one patient had significant hearing loss and one patient had obstruction of their venous catheter caused by a CPAP hood, which resulted in transient haemodynamic instability. Interpretation: In this large clinical effectiveness trial, CPAP did not reduce the incidence of pneumonia, endotracheal re-intubation, or death after major abdominal surgery. Although CPAP has an important role in the treatment of respiratory failure after surgery, routine use of prophylactic post-operative CPAP is not recommended