A Passive Ankle Dorsiflexion Testing System for an In Vivo Model of Overuse-induced Tendinopathy.

Tendinopathy is a chronic tendon condition that results in pain and loss of function and is caused by repeated overload of the tendon and limited recovery time. This protocol describes a testing system that cyclically applies mechanical loads via passive dorsiflexion to the rat Achilles tendon. The custom-written code consists of pre- and post-cyclic loading measurements to assess the effects of the loading protocol along with the feedback control-based cyclic fatigue loading regimen. We used 25 Sprague-Dawley rats for this study, with 5 rats per group receiving either 500, 1,000, 2,000, 3,600, or 7,200 cycles of fatigue loads. The percentage differences between the pre- and post-cyclic loading measurements of the hysteresis, peak stress, and loading and unloading moduli were calculated. The results demonstrate that the system can induce varying degrees of damage to the Achilles tendon based on the number of loads applied. This system offers an innovative approach to apply quantified and physiological varying degrees of cyclic loads to the Achilles tendon for an in vivo model of fatigue-induced overuse tendon injury.

A passive ankle dorsiflexion testing system to assess mechanobiological and structural response to cyclic loading in rat Achilles tendon.

Tendinopathy is thought to be caused by repeated overload of the tendon with insufficient recovery time, leading to an inadequate healing response and incomplete recovery of preinjury material strength and function. The etiology of tendinopathy induced by mechanical load is being explored with a variety of mechanical load scenarios in small animals. This study establishes a testing system that applies passive ankle dorsiflexion to a rat hindlimb, estimates the force applied to the tendon during cyclic loading and enables the assessment of subsequent structural and biological changes. We demonstrated that the system had no drift in the applied angle, and the registered maximum angle and torque inputs and outputs were consistent between tests. We showed that cyclic loading decreased hysteresis and loading and unloading moduli with increasing cycles applied to the tendon. Histology showed gross changes to tendon structure. This work establishes a system for passively loading the rat Achilles tendon in-vivo in a physiological manner, facilitating future studies that will explore how mechanics, structure, and biology are altered by mechanical repetitive loading.

Effect of intraarticular pressure on glenohumeral kinematics during a simulated abduction motion: a cadaveric study.

BACKGROUND: The current understanding of glenohumeral joint stability is defined by active restrictions and passive stabilizers including naturally-occurring negative intraarticular pressure. Cadaveric specimens have been used to evaluate the role of intraarticular pressure on joint stability, although, while the shoulder's negative intraarticular pressure is universally acknowledged, it has been inconsistently accounted for. HYPOTHESIS: During continuous, passive humeral abduction, releasing the native intraarticular pressure increases joint translation, and restoring this pressure decreases joint translations. STUDY DESIGN: Descriptive Laboratory Study. METHODS: A validated shoulder testing system was used to passively abduct the humerus in the scapular plane and measure joint translations for seven (n = 7) cadaveric specimens. The pressure within the glenohumeral joint was measured via a 25-gauge needle during passive abduction of the arm, which was released and subsequently restored. During motion, the rotator cuff muscles were loaded using stepper motors in a force feedback loop and electromagnetic sensors were used to continuously measure the position of the humerus and scapula. Joint translation was defined according to the instant center of rotation of the glenohumeral head according to the recommendations by the International Society of Biomechanics. RESULTS: Area under the translation versus abduction angle curve suggests that releasing the pressure within the capsule results in significantly less posterior translation of the glenohumeral head as compared to intact (85-90˚, p < 0.05). Posterior and superior translations were reduced after 70˚ of abduction when the pressure within the joint was restored. CONCLUSION: With our testing system employing a smooth continuous passive motion, we were able to show that releasing intraarticular pressure does not have a major effect on the path of humeral head motion during glenohumeral abduction. However, both violating the capsule and restoring intraarticular pressure after releasing alter glenohumeral translations. Future studies should study the effect of simultaneous external rotation and abduction on the relationship between joint motion and IAP, especially in higher degrees of abduction. CLINICAL RELEVANCE: Thoroughly simulating the glenohumeral joint environment in the cadaveric setting may strengthen the conclusions that can be translated from this setting to the clinic.

A Validated Three-Dimensional, Heterogenous Finite Element Model of the Rotator Cuff and The Effects of Collagen Orientation.

Continuum mechanics-based finite element models of the shoulder aim to quantify the mechanical environment of the joint to aid in clinical decision-making for rotator cuff injury and disease. These models allow for the evaluation of the internal loading of the shoulder, which cannot be measured in-vivo. This study uses human cadaveric rotator cuff samples with surface tendon strain estimates, to validate a heterogeneous finite element model of the supraspinatus-infraspinatus complex during various load configurations. The computational model was considered validated when the absolute difference in average maximum principal strain for the articular and bursal sides for each load condition estimated by the model was no greater than 3% compared to that measured in the biomechanical study. The model can predict the strains for varying infraspinatus loads allowing for the study of load sharing between these two tightly coordinated tendons. The future goal is to use the modularity of this validated model to study the initiation and propagation of rotator cuff tear and other rotator cuff pathologies to ultimately improve care for rotator cuff tear patients.

Minimally invasive, sustained-release relaxin-2 microparticles reverse arthrofibrosis.

Substantial advances in biotherapeutics are distinctly lacking for musculoskeletal diseases. Musculoskeletal diseases are biomechanically complex and localized, highlighting the need for novel therapies capable of addressing these issues. All frontline treatment options for arthrofibrosis, a debilitating musculoskeletal disease, fail to treat the disease etiology-the accumulation of fibrotic tissue within the joint space. For millions of patients each year, the lack of modern and effective treatment options necessitates surgery in an attempt to regain joint range of motion (ROM) and escape prolonged pain. Human relaxin-2 (RLX), an endogenous peptide hormone with antifibrotic and antifibrogenic activity, is a promising biotherapeutic candidate for musculoskeletal fibrosis. However, RLX has previously faltered through multiple clinical programs because of pharmacokinetic barriers. Here, we describe the design and in vitro characterization of a tailored drug delivery system for the sustained release of RLX. Drug-loaded, polymeric microparticles released RLX over a multiweek time frame without altering peptide structure or bioactivity. In vivo, intraarticular administration of microparticles in rats resulted in prolonged, localized concentrations of RLX with reduced systemic drug exposure. Furthermore, a single injection of RLX-loaded microparticles restored joint ROM and architecture in an atraumatic rat model of arthrofibrosis with clinically derived end points. Finally, confirmation of RLX receptor expression, RXFP1, in multiple human tissues relevant to arthrofibrosis suggests the clinical translational potential of RLX when administered in a sustained and targeted manner.

Plaster of Paris: Squeeze, But Not Too Hard!

Plaster of Paris (PoP) has been the predominant treatment option for most acute and chronic orthopedic conditions. Water immersion significantly decreases the PoP bandage strength. Moreover, concerns have been raised about the possibility of breaks in PoP splints and cast failures once solid. The current study was designed to account for the increase in weight associated with increased PoP layers. The authors hypothesized that by controlling for weight variation as layers increased, they could determine the number of layers of PoP bandage that truly results in optimal mechanical properties. They assessed whether adequate plaster weight control while increasing layers could improve the mechanical properties of the splint. [Orthopedics. 2022;45(1):e57-e61.].

Tendinopathy and tendon material response to load: What we can learn from small animal studies.

Tendinopathy is a debilitating disease that causes as much as 30% of all musculoskeletal consultations. Existing treatments for tendinopathy have variable efficacy, possibly due to incomplete characterization of the underlying pathophysiology. Mechanical load can have both beneficial and detrimental effects on tendon, as the overall tendon response depends on the degree, frequency, timing, and magnitude of the load. The clinical continuum model of tendinopathy offers insight into the late stages of tendinopathy, but it does not capture the subclinical tendinopathic changes that begin before pain or loss of function. Small animal models that use high tendon loading to mimic human tendinopathy may be able to fill this knowledge gap. The goal of this review is to summarize the insights from in-vivo animal studies of mechanically-induced tendinopathy and higher loading regimens into the mechanical, microstructural, and biological features that help characterize the continuum between normal tendon and tendinopathy. STATEMENT OF SIGNIFICANCE: This review summarizes the insights gained from in-vivo animal studies of mechanically-induced tendinopathy by evaluating the effect high loading regimens have on the mechanical, structural, and biological features of tendinopathy. A better understanding of the interplay between these realms could lead to improved patient management, especially in the presence of painful tendon.

Effect of rotator cuff muscle activation on glenohumeral kinematics: A cadaveric study.

Healthy shoulder function requires the coordination of the rotator cuff muscles to maintain the humeral head's position in the glenoid. While glenohumeral stability has been studied in various settings, few studies have characterized the effect of dynamic rotator cuff muscle loading on glenohumeral translation during shoulder motion. We hypothesize that dynamic rotator cuff muscle activation decreases joint translation during continuous passive abduction of the humerus in a cadaveric model of scapular plane glenohumeral abduction. The effect of different rotator cuff muscle activity on glenohumeral translation was assessed using a validated shoulder testing system. The Dynamic Load profile is a novel approach, based on musculoskeletal modeling of human subject motion. Passive humeral elevation in the scapular plane was applied via the testing system arm, while the rotator cuff muscles were activated according to the specified force profiles using stepper motors and a proportional control feedback loop. Glenohumeral translation was defined according to the International Society of Biomechanics. The Dynamic load profile minimized superior translation of the humeral head relative to the conventional loading profiles. The total magnitude of translation was not significantly different (0.805) among the loading profiles suggesting that the compressive forces from the rotator cuff primarily alter the direction of humeral head translation, not the magnitude. Rotator cuff muscle loading is an important element of cadaveric shoulder studies that must be considered to accurately simulate glenohumeral motion. A rotator cuff muscle activity profile based on human subject muscle activity reduces superior glenohumeral translation when compared to previous RC loading profiles.

Tendon lengthening after achilles tendon rupture-passive effects on the ankle joint in a cadaveric pilot study simulating weight bearing.

BACKGROUND: In recent years, primary Achilles tendon ruptures have increased due to the aging population's participation in physically demanding activities. These injuries commonly occur during recreational sports and frequently lead to a long-term reduction in activity despite treatment. Non-operative methods of treatment for Achilles tendon ruptures may result in the Achilles healing in a lengthened position compared to the pre-injury state. This study uses a cadaveric model that simulates static weight bearing to explore the effect of a lengthened Achilles tendon on ankle joint load distribution. METHODS: Five lower limb cadaveric specimens were placed on a custom jig, where a 334 N (75 lb) load was applied at the femoral head, and the foot was supported against a plate to simulate static double-leg stance. A pressure mapping sensor was inserted into the ankle joint. A percutaneous triple hemiresection tendo-Achilles lengthening procedure (Hoke procedure) was performed on each specimen to simulate tendon lengthening after conservative treatment. Contact pressure, peak pressure, and center-of-pressure were measured for native and tendon-lengthened conditions. RESULTS: Tendon rupture did not significantly alter average contact pressure, peak contact pressures, or center-of-pressure in the ankle joint compared with native tendon. CONCLUSION: Achilles lengthening does not significantly change contact pressures of the ankle joint in this model . This result suggests that the passive restraint on ankle joint translation imposed by the Achilles tendon is minimal without muscle activation.

Intraarticular injection of relaxin-2 alleviates shoulder arthrofibrosis.

Arthrofibrosis is a prevalent condition affecting greater than 5% of the general population and leads to a painful decrease in joint range of motion (ROM) and loss of independence due to pathologic accumulation of periarticular scar tissue. Current treatment options are limited in effectiveness and do not address the underlying cause of the condition: accumulation of fibrotic collagenous tissue. Herein, the naturally occurring peptide hormone relaxin-2 is administered for the treatment of adhesive capsulitis (frozen shoulder) and to restore glenohumeral ROM in shoulder arthrofibrosis. Recombinant human relaxin-2 down-regulates type I collagen and α smooth muscle actin production and increases intracellular cAMP concentration in human fibroblast-like synoviocytes, consistent with a mechanism of extracellular matrix degradation and remodeling. Pharmacokinetic profiling of a bolus administration into the glenohumeral joint space reveals the brief systemic and intraarticular (IA) half-lives of relaxin-2: 0.96 h and 0.62 h, respectively. Furthermore, using an established, immobilization murine model of shoulder arthrofibrosis, multiple IA injections of human relaxin-2 significantly improve ROM, returning it to baseline measurements collected before limb immobilization. This is in contrast to single IA (sIA) or multiple i.v. (mIV) injections of relaxin-2 with which the ROM remains constrained. The histological hallmarks of contracture (e.g., fibrotic adhesions and reduced joint space) are absent in the animals treated with multiple IA injections of relaxin-2 compared with the untreated control and the sIA- and mIV-treated animals. As these findings show, local delivery of relaxin-2 is an innovative treatment of shoulder arthrofibrosis.

Diagnostic Modalities for Acute Compartment Syndrome of the Extremities: A Systematic Review.

IMPORTANCE: Acute compartment syndrome (ACS) can cause catastrophic tissue damage leading to permanent muscle and nerve loss. Acute compartment syndrome is a clinical diagnosis, with intracompartmental pressure (ICP) used in equivocal cases. There are no reliable diagnostic methods. The clinical evaluation is impossible to standardize, and the threshold for ICP has been known to be unreliable; thus, guidelines for diagnosis can result in overtreatment or delayed diagnosis. OBJECTIVE: To present and review the advantages and disadvantages of each diagnostic modality and identify gaps that need to be addressed in the future and to review the most used and appropriate animal and human ACS models. EVIDENCE REVIEW: We included clinical studies and animal models investigating diagnostic modalities for ACS of the extremities. A MEDLINE and Web of Science search was performed. The protocol for the study was registered on PROSPERO (CRD42017079266). We assessed the quality of the clinical studies with Newcastle-Ottawa scale and reported level of evidence for each article. FINDINGS: Fifty-one articles were included in this study, reporting on 38 noninvasive and 35 invasive modalities. Near-infrared spectroscopy and direct ICP measurement using a Stryker device were the most common, respectively. Cadaveric studies used saline infusions to create an ACS model. Most studies with human participants included injured patients with acquired ACS or at risk of developing ACS. In healthy human participants, tourniquets formed the most commonly used ACS model. Application of tourniquets and infusion of saline or albumin were the most used ACS models among animal studies. CONCLUSIONS AND RELEVANCE: This article reports on the most common as well as many new and modified diagnostic modalities, which can serve as inspiration for future investigations to develop more effective and efficient diagnostic techniques for ACS. Future studies on diagnostic modalities should include the development of tools for continuous assessment of ICP to better identify the earliest alterations suggestive of impending ACS. With the advent of such technologies, it may be possible to develop far less aggressive and more effective approaches for early detection of ACS.

Development of a hybrid CFD-PBPK model to predict the transport of xenon gas around a human respiratory system to systemic regions.

Administering incorrect doses of conventional anesthetic agents through the pulmonary route can cause potential health risks such as blood coagulation, platelet dysfunction, and deteriorating organ function. As an alternative, xenon can minimize the impact on the cardiovascular system and provide the neuroprotective effect, hemodynamic stability, and fast recovery. However, the inhalation pattern still needs to be carefully monitored and controlled to avoid health risks caused by over administering xenon to patients during unconsciousness. Thus, high-resolution lung absorption and whole-body translocation data are critically needed to fully understand how to administer the gas and coordinate with the patient to accurately control the dose. Clinical studies are not able to provide accurate dosimetry data due to their limited operational flexibility and imaging resolution. Therefore, a computational fluid dynamics (CFD) model was employed in this study to simulate the transport and absorption of the inhaled xenon which is connected with a physiologically based pharmacokinetic (PBPK) model to predict the translocation into the systemic regions. To study the effects of different breathing patterns on xenon transport dynamics in the human body, a realistic breathing waveform and two steady-state flow rates with inhalation durations of 2 and 1.5 seconds were selected. For the realistic breathing cycle, the inhalation-exhalation periods are defined for a human at rest and the other two cases have a fixed volumetric flow rate of 15 L/min. As the two latter cases only simulate the inspiratory phase, a 1-second holding time was applied to represent the missing periods of the full breathing time. Simulations were performed in a subject-specific human upper airway configuration from mouth to G6. Numerical results show that with the accurate lung uptake predictions obtained from the CFD model, the hybrid CFD-PBPK model with TRANSIT compartments generates more precise and breath-specific trends compared to simple PBPK models. Numerical results demonstrate that breathing pattern can significantly influence the xenon uptake in the human body, which can be utilized as a critical factor to be coordinated by clinicians to achieve the optimized xenon dose. Furthermore, parametric analyses were performed for the influence of breathing patterns on local airflow distributions, gas species translocations, and lung elimination mechanisms followed by species diffusion into the systemic regions.

Shoulder biomechanics of RC repair and Instability: A systematic review of cadaveric methodology.

BACKGROUND: Numerous biomechanical studies have addressed normal shoulder function and the factors that affect it. While these investigations include a mix of in-vivo clinical reports, ex-vivo cadaveric studies, and computer-based simulations, each has its own strengths and limitations. A robust methodology is essential in cadaveric work but does not always come easily. Precise quantitative measurements are difficult in in-vivo studies, and simulation studies require validation steps. This review focuses on ex-vivo cadaveric studies to emphasize the best research methodologies available to simulate physiologically and clinically relevant shoulder motion. METHODS: A PubMed and Web of Science search was conducted in March 2017 (and updated in May 2018) to identify the cadaveric studies focused on the shoulder and its function. The key words for this search included rotator cuff (RC) injuries, RC surgery, and their synonyms. The protocol of the study was registered on PROSPERO and is accessible at CRD42017068873. RESULTS: Thirty one studies consisting of 167 specimens with various biomechanical methods met our inclusion criteria. All studies were level V cadaveric studies. Cadaveric biomechanical models are widely used to study shoulder instability and RC repair. These models are commonly limited to the glenohumeral joint by a fixed scapula, passively and discretely move the humerus, and statically load the RC without regard for the integrity of the glenohumeral capsule. CONCLUSION: All studies captured in this review evaluated shoulder biomechanics. Recent studies in patients suggest that some assumptions made in this space may not fully characterize motion of the human shoulder. With reproducible scapular positioning, dynamic RC activation, and preservation of glenohumeral capsule integrity, cadaveric studies can facilitate proper validation for simulation models and broaden our understanding of the shoulder environment during motion in healthy and disease states.

Rat Model of Adhesive Capsulitis of the Shoulder.

This proposal aims to create an in vivo rat model of adhesive capsulitis for researching potential treatment options for this condition and other etiologies of comparable arthrofibrosis. The model includes extra-articular fixation of the shoulder in rats via scapular to humeral suturing, resulting in a secondary contracture without invading the intra-articular space and resulting in decreased rotational ROM and increased joint stiffness. We used 10 Sprague-Dawley rats for the purpose of this study. Baseline ROM measurements were taken before glenohumeral immobilization. The rats were subjected to 8 weeks of immobilization before the fixation sutures were removed and changes in ROM and joint stiffness were evaluated. To evaluate whether immobilization resulted in a significant reduction in ROM, changes in kinematics were calculated. ROM was measured at each time point in the follow-up period and was compared to the baseline internal and external ROM measurements. In order to evaluate the stiffness, joint kinetics were calculated by determining the differences in torque (text and tint ) needed to reach the initial external rotation of 60° and initial internal rotation of 80°. After the removal of the extra-articular suture fixation on follow-up day 0, we found a 63% decrease in total ROM compared to baseline. We observed continuous improvement until week 5 of follow-up, with the progress slowing down around a 19% restriction. On week 8 of follow-up, there was still an 18% restriction of ROM. Additionally, on follow-up day 0, we found the torque increased by 13.3 Nmm when compared to baseline. On week 8, the total torque was measured to be 1.4 ± 0.2 Nmm higher than initial measurements. This work introduces a rat model of shoulder adhesive capsulitis with lasting reduced ROM and increased stiffness.

Pressure Distribution in the Ankle and Subtalar Joint With Routine and Oversized Foot Orthoses.

BACKGROUND: Foot orthoses are used to treat many disorders that affect the lower limb. These assistive devices have the potential to alter the forces, load distribution, and orientation within various joints in the foot and ankle. This study attempts to quantify the effects of orthoses on the intra-articular force distribution of the ankle and subtalar joint using a cadaveric testing jig to simulate weight bearing. METHODS: Five lower-limb cadaveric specimens were placed on a custom jig, where a 334-N (75-lb) load was applied at the femoral head, and the foot was supported against a plate to simulate double-leg stance. Pressure-mapping sensors were inserted into the ankle and subtalar joint. Mean pressure, peak pressure, contact area, and center of force were measured in both the ankle and subtalar joints for barefoot and 2 medial foot orthosis conditions. The 2 orthosis conditions were performed using (1) a 1.5-cm-height wedge to simulate normal orthoses and (2) a 3-cm-height wedge to simulate oversized orthoses. RESULTS: The contact area experienced in the subtalar joint significantly decreased during 3-cm orthotic posting of the medial arch, but neither orthosis had a significant effect on the spatial mean pressure or peak pressure experienced in either joint. CONCLUSION: The use of an oversized orthosis could lead to a decrease in the contact area and alterations in the distribution of pressure within the subtalar joint. CLINICAL RELEVANCE: The use of inappropriate orthoses could negatively impact the force distribution in the lower limb.

Functions at the junction - membrane proteins and myoblast fusion.

The fusion of myoblasts is an essential step in the formation of multinucleated muscle fibres and the molecular underpinnings of this process are being actively investigated. In this issue, Kim et al. report that the membrane protein Xkr8 plays a role in myotube fusion, adding another class of membrane proteins to the list of potential contributors to myoblast differentiation and fusion.

Cobalt-catalysed C-H carbonylative cyclisation of aliphatic amides.

A cobalt-catalysed C-H carbonylation of aliphatic carboxamide derivatives is described, employing commercially available Co(ii)-salts in the presence of a silver oxidant. This operationally simple process utilises an atmospheric pressure of CO and generates a range of substituted succinimide products bearing diverse functional groups that can be successfully accessed via this methodology.

Efficiency Analysis of an Interoperable Healthcare Operations Platform.

(1) Develop an enterprise platform to unify isolated information, software applications and team members. (2) Assess the efficiency of one benefit of the platform through comparative testing of employee document retrieval times. (3) Evaluate the level of satisfaction among our target audience. We developed an infrastructure to integrate information throughout our practice and make it available on a unified, secure, and remotely accessible platform. We solicited our practice for volunteers to test the new system. All interested volunteers participated. Thirteen employees searched for the same four items in both the new system and our legacy systems. Testing was performed in the pre-deployment stage. In our evaluation, we introduced an innovative method to precisely and objectively obtain data through the use of a widely available tool which could be leveraged for a variety of other studies. On average, it took our participants 7 min and 48 s to find four assigned items in our legacy systems. It only took our volunteers 1 min and 1 s to find the same items with the new platform (p-value 0.002). On a scale of 10 being the highest level of satisfaction, participants ranked the new system to be 8.7 while the traditional system was ranked at 6.3. An overarching enterprise platform is critical due to the ability to unify otherwise isolated applications, people and documents. Because navigating a new system would be expected to take longer than a familiar one, we were surprised by the dramatically improved efficiency and satisfaction of our new interoperable platform compared to the status quo. Since this platform was evaluated in the pre-deployment stage, we expect results to improve with employee experience as well as ongoing enhancements.

Mercury contamination in Southern New England coastal fisheries and dietary habits of recreational anglers and their families: Implications to human health and issuance of consumption advisories.

Total mercury (Hg) was measured in coastal fishes from Southern New England (RI, USA), and Hg exposure was estimated for anglers and family members that consumed these resources. Fish Hg was positively related to total length (n = 2028 across 7 fish species), and interspecies differences were evident among legally harvestable fish. Many recreational anglers and their families experienced excessively high Hg exposure rates, which was attributed to the enriched Hg content of frequently consumed fishes. Specifically, 51.5% of participants in this study had Hg exposures exceeding the US EPA reference dose, including 50.0% of women of childbearing years. These results are noteworthy given that Hg neurotoxicity occurs in adults and children from direct and prenatal low-dose exposure. Moreover, this study underscores the need for geographic-specific research that accounts for small-scale spatial variations in fish Hg and dietary habits of at-risk human populations.