Structures of human exonuclease 1 DNA complexes suggest a unified mechanism for nuclease family.

Human exonuclease 1 (hExo1) plays important roles in DNA repair and recombination processes that maintain genomic integrity. It is a member of the 5' structure-specific nuclease family of exonucleases and endonucleases that includes FEN-1, XPG, and GEN1. We present structures of hExo1 in complex with a DNA substrate, followed by mutagenesis studies, and propose a common mechanism by which this nuclease family recognizes and processes diverse DNA structures. hExo1 induces a sharp bend in the DNA at nicks or gaps. Frayed 5' ends of nicked duplexes resemble flap junctions, unifying the mechanisms of endo- and exonucleolytic processing. Conformational control of a mobile region in the catalytic site suggests a mechanism for allosteric regulation by binding to protein partners. The relative arrangement of substrate binding sites in these enzymes provides an elegant solution to a complex geometrical puzzle of substrate recognition and processing.

An Adaptable Computed Tomography-Derived Three-Dimensional-Printed Alignment Fixture Minimizes Errors in Radius Biomechanical Testing.

Biomechanical testing of long bones can be susceptible to errors and uncertainty due to malalignment of specimens with respect to the mechanical axis of the test frame. To solve this problem, we designed a novel, customizable alignment and potting fixture for long bone testing. The fixture consists of three-dimensional-printed components modeled from specimen-specific computed tomography (CT) scans to achieve a predetermined specimen alignment. We demonstrated the functionality of this fixture by comparing benchtop torsional test results to specimen-matched finite element models and found a strong correlation (R2 = 0.95, p < 0.001). Additional computational models were used to estimate the impact of malalignment on mechanical behavior in both torsion and axial compression. Results confirmed that torsion testing is relatively robust to alignment artifacts, with absolute percent errors less than 8% in all malalignment scenarios. In contrast, axial testing was highly sensitive to setup errors, experiencing absolute percent errors up to 50% with off-center malalignment and up to 170% with angular malalignment. This suggests that whenever appropriate, torsion tests should be used preferentially as a summary mechanical measure. When more challenging modes of loading are required, pretest clinical-resolution CT scanning can be effectively used to create potting fixtures that allow for precise preplanned specimen alignment. This may be particularly important for more sensitive biomechanical tests (e.g., axial compressive tests) that may be needed for industrial applications, such as orthopedic implant design.

Immersion in Raloxifene does not significantly improve bone toughness or screw pull-out strength in multiple in vitro models.

BACKGROUND: Failure of surgical fixation in orthopaedic fractures occurs at a significantly higher rate in osteoporotic patients due to weakened osteoporotic bone. A therapy to acutely improve the mechanical properties of bone during fracture repair would have profound clinical impact. A previous study has demonstrated an increase in mechanical properties of acellular cortical canine bone after immersion in raloxifene. The goal of this study was to determine if similar treatment yields the same results in cancellous fetal bovine bone and whether this translates into a difference in screw pull-out strength in human cadaveric tissue. METHODS: Cancellous bone from fetal bovine distal femora underwent quasi-static four-point bending tests after being immersed in either raloxifene (20 µM) or phosphate-buffered saline as a control for 7 days (n = 10). Separately, 5 matched pairs of human osteoporotic cadaveric humeral heads underwent the same procedure. Five 3.5 mm unicortical cancellous screws were then inserted at standard surgical fixation locations to a depth of 30 mm and quasi-static screw pull-out tests were performed. RESULTS: In the four-point bending tests, there were no significant differences between the raloxifene and control groups for any of the mechanical properties - including stiffness (p = 0.333) and toughness (p = 0.546). In the screw pull-out tests, the raloxifene soaked samples and control samples had pullout strengths of 122 ± 74.3 N and 89.5 ± 63.8 N, respectively. CONCLUSIONS: Results from this study indicate that cancellous fetal bovine samples did not demonstrate an increase in toughness with raloxifene treatment, which is in contrast to previously published data that studied canine cortical bone. In vivo experiments are likely required to determine whether raloxifene will improve implant fixation.

Flexor Pollicis Longus Tendon Wear Associated With Volar Plating: A Cadaveric Study.

PURPOSE: This study examined the effect of low-profile volar rim plates (VR), proximally placed standard variable-angle locking plates (pVA-LCP), and distally placed standard variable-angle locking plates (dVA-LCP) on the flexor pollicis longus (FPL) tendon in a cadaver model. We hypothesized that tendons from the VR and pVA-LCP groups would exhibit similar contact pressures, wear patterns, and post-fatigue testing mechanical properties, whereas dVA-LCP tendons would exhibit higher contact pressures, increased tendon wear patterns, and decreased mechanical properties. METHODS: Nine matched pairs of cadaveric specimens were used in this study. Thin-film pressure sensors were used to measure the initial contact loads between plates and FPL tendons. Specimens were cyclically loaded for 10,000 cycles by actuating the FPL tendon. Cycled tendons were harvested, photographed with a stereomicroscope, and graded for wear on a Likert scale by 5 observers who were blinded to the study protocol. Uniaxial tensile testing measured mechanical properties of the tendon: ultimate failure load, ultimate stress, percent stress relaxation, elastic modulus, and stiffness. RESULTS: With regard to the cadaveric FPL tendon, VR and dVA-LCP had increased contact pressure and tendon wear compared with pVA-LCP. There were no significant differences in contact pressure or tendon wear between dVA-LCP and VR. There was no major difference in the tested mechanical properties of the FPL tendon among any of the groups. CONCLUSIONS: Plates placed directly on or beyond the volar rim demonstrate increased contact pressures and increased tendon wear in a cadaveric model. CLINICAL RELEVANCE: Although low-profile plates allow for fixation of smaller volar fragments in the distal radius, they cause substantial contact with the FPL tendon, which may rupture if the plate is not removed.

A cadaveric comparison of two methods for isolated talonavicular arthrodesis: Two-screws versus plate with integrated compression screw.

BACKGROUND: This study compared stiffness between two constructs for talonavicular arthrodesis: a dorsomedial plating system and two partially threaded cannulated cancellous screws. We hypothesized that the plate would exhibit greater stiffness and resistance to deformation during cyclic loading. METHODS: The constructs were implanted in eight matched pairs of cadaveric feet and subjected to axial torsion, cantilever bending in two directions, and cyclic loading to failure. RESULTS: The two-screw constructs were significantly stiffer in plantar-dorsal bending (p = .025) and trended towards a higher number of cycles before failure than the plate group (p = .087). No significant differences were observed in internal torsion (p = .620), external torsion (p = .165), or medial-lateral bending (p = .686). CONCLUSIONS: This study provided the first biomechanical assessment of a plating system with an integrated compression screw, which was significantly less stiff than a two-screw construct when loaded from plantar to dorsal.

Finite Element-Predicted Effects of Screw Configuration in Proximal Humerus Fracture Fixation.

Internal fixation with the use of locking plates is the standard surgical treatment for proximal humerus fractures, one of the most common fractures in the elderly. Screw cut-out through weak cancellous bone of the humeral head, which ultimately results in collapse of the fixed fracture, is the leading cause of failure and revision surgery. In an attempt to address this problem, surgeons often attach the plate with as many locking screws as possible into the proximal fragment. It is not thoroughly understood which screws and screw combinations play the most critical roles in fixation stability. This study conducted a detailed finite element analysis to evaluate critical parameters associated with screw cut-out failure. Several clinically relevant screw configurations and fracture gap sizes were modeled. Findings demonstrate that in perfectly reduced fracture cases, variation of the screw configurations had minor influence on mechanical stability of the fixation. The effects of screw configurations became substantial with the existence of a fracture gap. Interestingly, the use of a single anterior calcar screw was as effective as utilizing two screws to support the calcar. On the other hand, the variation in calcar screw configuration had minor influence on the fixation stability when all the proximal screws (A-D level) were filled. This study evaluates different screw configurations to further understand the influence of combined screw configurations and the individual screws on the fixation stability. Findings from this study may help decrease the risk for screw cut-out with proximal humerus varus collapse and the associated economic costs.

Parameterization of proximal humerus locking plate impingement with in vitro, in silico, and in vivo techniques.

BACKGROUND: Locked plating of displaced proximal humeral fractures is common, but rates of subacromial impingement remain high. This study used a multidisciplinary approach to elucidate the relationships between common surgical parameters, anatomic variability, and the likelihood of plate impingement. METHODS: The experiment was completed in 3 phases. First, a controlled in vitro experiment was conducted to simulate impingement. Second, a dynamic in silico musculoskeletal model modeled changes to implant geometry, surgical techniques, and acromial anatomy, where a collision detection algorithm was used to simulate impingement. Finally, in vivo shoulder kinematics were recorded for 9 activities of daily living. Motions that created a high likelihood of impingement were identified. RESULTS: Of simulated impingement events, 73.9% occurred when the plate was moved proximally, and 84% occurred when acromial tilt was 20° or 25°. Simulations of impingement occurred at cross-body adduction angles between 10° and 50°. Impingement occurred at an average of 162.0° ± 14.8° abduction with 10 mm distal plate placement, whereas the average was 72.1° ± 11.4° with 10 mm proximal placement. A patient may encounter these shoulder angles when performing activities such as combing one's hair, lifting an object overhead, and reaching behind one's head. DISCUSSION AND CONCLUSION: Proximal implant placement and decreases in acromial tilt play major roles in the likelihood of impingement, whereas plate thickness and humeral head center of rotation should also be considered. Careful preoperative planning that includes these factors could help guide operative decision making and improve clinical outcomes.

The Saline Load Test is Effective at Diagnosing Traumatic Arthrotomies of the Shoulder.

The purpose of this study is to evaluate the fluid volume required for a saline load test to detect intra-articular involvement of the glenohumeral joint after penetrating trauma. A human cadaver study was conducted with 22 thawed, fresh-frozen forequarter amputations. A standard posterior shoulder portal was made with an 11-blade scalpel. A 19-gauge needle was inserted into the anterior portal site, and intra-articular position of both the blade and needle was confirmed with fluoroscopy. The blade was removed and normal saline was injected through the needle until extravasation of fluid was observed through the posterior portal. Injection volume required for extravasation was recorded. A logarithmic distribution of the volumes was then calculated in order to obtain estimated sensitivity ranges. Using a logarithmic distribution, 90%, 95% and 99% of simulated glenohumeral arthrotomies could be detected using injections of: 62 ml [41-96], 81 ml [50-133] and 136 ml [72-252], respectively. (Journal of Surgical Orthopaedic Advances 28(4):268-271, 2019).

It's all relative: The role of object weight in toddlers' gravity bias.

Work over the past 20 years has demonstrated a gravity bias in toddlers; when an object is dropped into a curved tube, they will frequently search at a point immediately beneath the entry of the tube rather than in the object's actual location. The current study tested 2- to 3½-year-olds' (N = 88) gravity bias under consideration of object weight. They were tested with either a heavy or light ball, and they had information about either one of the balls only or both balls. Evaluating their first search behavior showed that participants generally displayed the same age trends as other studies had demonstrated, with older toddlers passing more advanced task levels by being able to locate objects in the correct location. Object weight appeared to have no particular impact on the direction of these trends. However, where weight was accessible as relative information, toddlers were younger at passing levels and older at failing levels, although significantly so only from around 3 years of age onward. When they failed levels, toddlers made significantly more gravity errors with the heavy ball when they had information about both balls and made more correct choices with the light ball. As a whole, the findings suggest that nonvisual object variables, such as weight, affect young children's search behaviors in the gravity task, but only if these variables are presented in relation to other objects. This relational information has the potential to enhance or diminish the gravity bias.

Safety of IncobotulinumtoxinA in the Treatment of Facial Lines: Results From a Pooled Analysis of Randomized, Prospective, Controlled Clinical Studies.

BACKGROUND: The safety and efficacy of incobotulinumtoxinA in aesthetics has been established in multiple studies. Although individual studies have been reported, a combined assessment of incobotulinumtoxinA safety across studies is not available. OBJECTIVE: To assess the frequency of adverse events (AEs) across prospective incobotulinumtoxinA studies in aesthetics. MATERIALS AND METHODS: Safety data were assessed from 9 placebo-controlled or active-controlled single-dose studies on glabellar frown lines (GFL), crow's feet (CF), and upper facial lines (UFL). Analyses by treatment cycle included 4 repeat-dose studies on GFL and UFL. RESULTS: One thousand three hundred seventy-seven subjects received incobotulinumtoxinA (GFL, n = 1,189; CF, n = 83; UFL, n = 105) in single-dose studies (placebo-controlled studies: incobotulinumtoxinA, n = 866; placebo, n = 395). Over 1,000 subjects received incobotulinumtoxinA in repeat-dose studies (GFL, n = 880; UFL, n = 290). In placebo-controlled single-dose studies, incidences of treatment-related AEs ranged from 5.4% (GFL) to 22.9% (UFL). The most frequent treatment-related AE in single-dose studies was headache (GFL, 4.8%; UFL, 11.4%). In repeat-dose studies, incidence of AEs was highest during cycle 1 (GFL, 8.9%; UFL, 17.2%) and decreased across treatment cycles. No serious treatment-related AEs were observed. CONCLUSION: Results confirm the favorable safety and tolerability of incobotulinumtoxinA. The frequency of treatment-related AEs was low and may decrease with subsequent treatments.

Efficacy of IncobotulinumtoxinA for the Treatment of Glabellar Frown Lines in Male Subjects: Post-Hoc Analyses From Randomized, Double-Blind Pivotal Studies.

BACKGROUND: Males are increasingly seeking minimally invasive cosmetic procedures such as botulinum toxin injection. However, few studies have specifically examined the efficacy of such procedures among men. OBJECTIVE: To assess the efficacy of incobotulinumtoxinA for treating glabellar frown lines (GFLs) in men. METHODS: Three incobotulinumtoxinA studies were included in post hoc analyses of responder rates: 2 pivotal Phase 3 US registration studies for GFLs (n = 55 males in a pooled analysis) and a European pivotal Phase 3 study for upper facial lines (UFLs; n = 21 males). RESULTS: In the pooled analysis of Phase 3 GFL studies, 55.9% of males and 81.4% of females were responders on the Facial Wrinkle Scale (FWS) at 30 days. Similarly, 54.5% and 88.0% of males and females, respectively, treated for GFLs in the upper facial line study were responders on the Merz Aesthetics Scales (MAS) at 30 days. Lower proportions of male responders on the Facial Wrinkle Scale /Merz Aesthetics Scales were consistent with results from onabotulinumtoxinA and abobotulinumtoxinA GFL studies. CONCLUSION: Compared with females, males demonstrate lower response rates on wrinkle severity scales in studies on all 3 available botulinum toxins. Variations in treatment response are potentially associated with key male anatomic differences (e.g., muscle mass). Results emphasize the need for customized treatment plans.

Structures of the T. brucei kRNA editing factor MRB1590 reveal unique RNA-binding pore motif contained within an ABC-ATPase fold.

Kinetoplastid RNA (kRNA) editing is a process that creates translatable mitochondrial mRNA transcripts from cryptogene encoded RNAs and is unique for kinetoplastids, such as Trypanosoma brucei. In addition to the catalytic 20S editosome, multiple accessory proteins are required for this conversion. Recently, the multiprotein mitochondrial RNA binding complex 1 (MRB1) has emerged as a key player in this process. MRB1 consists of six core proteins but makes dynamic interactions with additional accessory proteins. Here we describe the characterization of one such factor, the 72 kDa MRB1590 protein. In vivo experiments indicate a role for MRB1590 in editing mitochondrial mRNA transcripts, in particular the transcript encoding the ATP synthase subunit 6 (A6). Structural studies show that MRB1590 is dimeric and contains a central ABC-ATPase fold embedded between novel N- and C-terminal regions. The N-terminal domains combine to create a basic pore and biochemical studies indicate residues in this region participate in RNA binding. Structures capturing distinct MRB1590 conformations reveal that the RNA binding pore adopts closed and open states, with the latter able to accommodate RNA. Based on these findings, implications for MRB1590 function are discussed.

Phosphorylation of Calcineurin at a novel serine-proline rich region orchestrates hyphal growth and virulence in Aspergillus fumigatus.

The fungus Aspergillus fumigatus is a leading infectious killer in immunocompromised patients. Calcineurin, a calmodulin (CaM)-dependent protein phosphatase comprised of calcineurin A (CnaA) and calcineurin B (CnaB) subunits, localizes at the hyphal tips and septa to direct A. fumigatus invasion and virulence. Here we identified a novel serine-proline rich region (SPRR) located between two conserved CnaA domains, the CnaB-binding helix and the CaM-binding domain, that is evolutionarily conserved and unique to filamentous fungi and also completely absent in human calcineurin. Phosphopeptide enrichment and tandem mass spectrometry revealed the phosphorylation of A. fumigatus CnaA in vivo at four clustered serine residues (S406, S408, S410 and S413) in the SPRR. Mutation of the SPRR serine residues to block phosphorylation led to significant hyphal growth and virulence defects, indicating the requirement of calcineurin phosphorylation at the SPRR for its activity and function. Complementation analyses of the A. fumigatus ΔcnaA strain with cnaA homologs from the pathogenic basidiomycete Cryptococcus neoformans, the pathogenic zygomycete Mucor circinelloides, the closely related filamentous fungi Neurospora crassa, and the plant pathogen Magnaporthe grisea, revealed filamentous fungal-specific phosphorylation of CnaA in the SPRR and SPRR homology-dependent restoration of hyphal growth. Surprisingly, circular dichroism studies revealed that, despite proximity to the CaM-binding domain of CnaA, phosphorylation of the SPRR does not alter protein folding following CaM binding. Furthermore, mutational analyses in the catalytic domain, CnaB-binding helix, and the CaM-binding domains revealed that while the conserved PxIxIT substrate binding motif in CnaA is indispensable for septal localization, CaM is required for its function at the hyphal septum but not for septal localization. We defined an evolutionarily conserved novel mode of calcineurin regulation by phosphorylation in filamentous fungi in a region absent in humans. These findings suggest the possibility of harnessing this unique SPRR for innovative antifungal drug design to combat invasive aspergillosis.

Transition into distance education: A scoping review protocol.

The number of students choosing to complete their studies online rather than in-person is on the rise. The transition to university is crucial for subsequent success, regardless of whether the learning is done face-to-face or remotely. If students can effectively handle the critical requirements associated with the transition to distance learning, their likelihood of success increases. However, thus far, little information is available on this topic. To gather existing sources, we will conduct a scoping review according to the guidelines of the research organization JBI. The review aims to systematically record, evaluate, and subsequently present the existing body of literature regarding the subject "transition into distance education". By answering the research question, "What is known about transition into distance education in higher education?" we hope to shed light on individual experiences, challenges, adaptation strategies, life situations, etc. of distance learners in a higher education context. The review will identify and categorize relevant concepts and terminologies in the research field, as well as outline the content-related boundaries. The findings derived from the scoping review will provide conceptual clarification, summarize the given theoretical and empirical knowledge in the field and offer practical implications for designing the initial phase in distance education. This article presents the a-priori study protocol that provides a detailed outline of the planned methodology for conducting the Scoping Review.

Biomechanics of fracture healing: how best to optimize your construct in the OR.

Orthopaedic surgeons routinely assess the biomechanical environment of a fracture to create a fixation construct that provides the appropriate amount of stability in efforts to optimize fracture healing. Emerging concepts and technologies including reverse dynamization, "smart plates" that measure construct strain, and FractSim software that models fracture strain represent recent developments in optimizing construct biomechanics to accelerate bone healing and minimize construct failure.

Real-World Observational Analysis of Clinical Characteristics and Treatment Patterns of Patients with Chronic Sialorrhea.

Chronic sialorrhea is a condition characterized by excessive drooling, often associated with neurological and neuromuscular disorders such as Parkinson's disease, cerebral palsy, and stroke. Despite its prevalence, it remains underdiagnosed and poorly understood, leading to a lack of comprehensive data on patient demographics, clinical characteristics, and treatment patterns. This study aimed to help fill these existing gaps by analyzing real-world data using Optum's de-identified Clinformatics® Data Mart Database. Patients were required to have a diagnosis indicative of sialorrhea plus evidence of sialorrhea treatment between 1/1/2007 and 5/31/2022. Two cohorts were analyzed: patients with evidence of newly diagnosed sialorrhea and associated treatment, and sialorrhea patients initiating incobotulinumtoxinA. Clinical characteristics, comorbidities, symptoms, and treatment utilization were described before and after diagnosis and incobotulinumtoxinA initiation. No formal statistical comparisons were performed. Patients were predominantly aged 65 or older, male, and non-Hispanic white. Parkinson's disease and cerebral palsy were the most common comorbidities among adults and children, respectively. Treatment patterns suggest that anticholinergics are more commonly used than botulinum toxin therapy. The findings offer valuable information for improving diagnosis and treatment approaches and suggest a need for further research into treatment effectiveness, safety, and disease burden.

Patient Characteristics and Real-World Use of Botulinum Toxins for the Treatment of Cervical Dystonia, Blepharospasm, and Hemifacial Spasm.

Movement disorders such as cervical dystonia, blepharospasm, and hemifacial spasm negatively impact the quality of life of people living with these conditions. Botulinum toxin (BoNT) injections are commonly used to treat these disorders. We sought to describe patient characteristics, BoNT utilization, and potential adverse events (AEs) among patients with cervical dystonia, blepharospasm, and hemifacial spasm using Optum's de-identified Clinformatics® Data Mart Database. Patients were required to have a diagnosis of the specific condition plus evidence of treatment with BoNT between 8/1/2010 and 5/31/2022. Cervical dystonia patients were commonly females (76%) and aged 45 and older (78%); both blepharospasm and hemifacial spasm patients were commonly females (both 69%) and aged 65 and older (61% and 56%, respectively). Anticholinergics were commonly used (65-82% across cohorts), as were peripheral muscle relaxants for cervical dystonia patients specifically (31%). The median number of injections per year was 2 with the median weeks between injections being between 13 and 15. Of the AEs evaluated, dyspnea was identified frequently across all the cohorts (14-20%). The findings were similar for different BoNT formulations. More research is needed to thoroughly describe BoNT utilization, such as the doses injected, and to optimize treatment for patients with these conditions.

Functionally graded 3D printed plates for rib fracture fixation.

BACKGROUND: Design freedom offered by additive manufacturing allows for the implementation of functional gradients - where mechanical stiffness is decreased along the length of the implant. It is unclear if such changes will influence failure mechanisms in the context of rib fracture repair. We hypothesized that our novel functionally graded rib implants would be less stiff than controls and decrease occurrence of secondary fracture at implant ends. METHODS: Five novel additively manufactured rib implants were tested along with a clinically used Control implant. Fracture reconstructions were modeled with custom synthetic rib bones with a transverse B1 fracture. Ribs were compressed in a cyclic two-point bend test for 360,000 cycles followed by a ramp to failure test. Differences in cyclic stiffness, 3D interfragmentary motions, ramp-to-failure stiffness, maximum load, and work to failure were determined. FINDINGS: The Control group had lower construct stiffness (0.76 ± 0.28 N/mm), compared to all novel implant designs (means: 1.35-1.61 N/mm, p < 0.05) and rotated significantly more about the bending axis (2.7° ± 1.3°) than the additively manufactured groups (means between 1.2° - 1.6°, p < 0.05). All constructs failed via bone fracture at the most posterior screw hole. Experimental implants were stiffer than Controls, and there were few significant differences between functional gradient groups. INTERPRETATION: Additively manufactured, functionally graded designs have the potential to change the form and function of trauma implants. Here, the impact of functional gradients was limited because implants had small cross-sectional areas.

Characterization of degradation kinetics of additively manufactured PLGA under variable mechanical loading paradigms.

Controlled degradation of biodegradable poly-lactic-co-glycolic acid (PLGA) trauma implants may increase interfragmentary loading which is known to accelerate fracture healing. Additive manufacturing allows us to tune the mechanical properties of PLGA scaffolds; however, little is known about this novel approach. The purpose of this study was to use in vitro and in vivo models to determine the degradative kinetics of additively manufactured test coupons fabricated with PLGA. We hypothesized that 1) increases in infill density would lead to improved initial mechanical properties, and 2) loss of mechanical properties would be constant as a function of time, regardless of implant design. Porous and solid test coupons were fabricated using 85:15 PLGA filament. Coupons were either incubated in serum or implanted subcutaneously in rats for up to 16 weeks. Samples were tested in tension, compression, torsion, and bending on a universal test frame. Variables of interest included, but were not limited to: stiffness, and ultimate force for each unique test. Infill density was the driving factor in test coupon mechanical properties, whereas differences in lattice architecture led to minimal changes. We observed moderate levels of degradation after 8 weeks, and significant decreases for all specimens after 16 weeks. Results from this study suggest substantial degradation of 3-D printed PLGA implants occurs during the 8- to 16-week window, which may be desirable for bone fracture repair applications. This study represents initial findings that will help us better understand the complicated interactions between overall implant design, porosity, and implant biodegradation.

Evaluation of tendon and ligament microstructure and mechanical properties in a canine model of mucopolysaccharidosis I.

Mucopolysaccharidosis (MPS) I is a lysosomal storage disorder characterized by deficient alpha-l-iduronidase activity, leading to abnormal accumulation of glycosaminoglycans (GAGs) in cells and tissues. Synovial joint disease is prevalent and significantly reduces patient quality of life. There is a strong clinical need for improved treatment approaches that specifically target joint tissues; however, their development is hampered by poor understanding of underlying disease pathophysiology, including how pathological changes to component tissues contribute to overall joint dysfunction. Ligaments and tendons, in particular, have received very little attention, despite the critical roles of these tissues in joint stability and biomechanical function. The goal of this study was to leverage the naturally canine model to undertake functional and structural assessments of the anterior (cranial) cruciate ligament (CCL) and Achilles tendon in MPS I. Tissues were obtained postmortem from 12-month-old MPS I and control dogs and tested to failure in uniaxial tension. Both CCLs and Achilles tendons from MPS I animals exhibited significantly lower stiffness and failure properties compared to those from healthy controls. Histological examination revealed multiple pathological abnormalities, including collagen fiber disorganization, increased cellularity and vascularity, and elevated GAG content in both tissues. Clinically, animals exhibited mobility deficits, including abnormal gait, which was associated with hyperextensibility of the stifle and hock joints. These findings demonstrate that pathological changes to both ligaments and tendons contribute to abnormal joint function in MPS I, and suggest that effective clinical management of joint disease in patients should incorporate treatments targeting these tissues.