Characterization of TGFß1-induced tendon-like structure in the scaffold-free three-dimensional tendon cell culture system.

The biological mechanisms regulating tenocyte differentiation and morphological maturation have not been well-established, partly due to the lack of reliable in vitro systems that produce highly aligned collagenous tissues. In this study, we developed a scaffold-free, three-dimensional (3D) tendon culture system using mouse tendon cells in a differentially adherent growth channel. Transforming Growth Factor-ß (TGFß) signaling is involved in various biological processes in the tendon, regulating tendon cell fate, recruitment and maintenance of tenocytes, and matrix organization. This known function of TGFß signaling in tendon prompted us to utilize TGFß1 to induce tendon-like structures in 3D tendon constructs. TGFß1 treatment promoted a tendon-like structure in the peripheral layer of the constructs characterized by increased thickness with a gradual decrease in cell density and highly aligned collagen matrix. TGFß1 also enhanced cell proliferation, matrix production, and morphological maturation of cells in the peripheral layer compared to vehicle treatment. TGFß1 treatment also induced early tenogenic differentiation and resulted in sufficient mechanical integrity, allowing biomechanical testing. The current study suggests that this scaffold-free 3D tendon cell culture system could be an in vitro platform to investigate underlying biological mechanisms that regulate tenogenic cell differentiation and matrix organization.

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.

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.

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.

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.

Tension-activated nanofiber patches delivering an anti-inflammatory drug improve repair in a goat intervertebral disc herniation model.

Conventional microdiscectomy treatment for intervertebral disc herniation alleviates pain but does not repair the annulus fibrosus, resulting in a high incidence of recurrent herniation and persistent dysfunction. The lack of repair and the acute inflammation that arise after injury can further compromise the disc and result in disc-wide degeneration in the long term. To address this clinical need, we developed tension-activated repair patches (TARPs) for annulus fibrosus repair and local delivery of the anti-inflammatory factor anakinra (a recombinant interleukin-1 receptor antagonist). TARPs transmit physiologic strain to mechanically activated microcapsules embedded within the patch, which release encapsulated bioactive molecules in direct response to spinal loading. Mechanically activated microcapsules carrying anakinra were loaded into TARPs, and the effects of TARP-mediated annular repair and anakinra delivery were evaluated in a goat model of annular injury in the cervical spine. TARPs integrated with native tissue and provided structural reinforcement at the injury site that prevented aberrant disc-wide remodeling resulting from detensioning of the annular fibrosus. The delivery of anakinra by TARP implantation increased matrix deposition and retention at the injury site and improved maintenance of disc extracellular matrix. Anakinra delivery additionally attenuated the inflammatory response associated with TARP implantation, decreasing osteolysis in adjacent vertebrae and preserving disc cellularity and matrix organization throughout the annulus fibrosus. These results demonstrate the therapeutic potential of TARPs for the treatment of intervertebral disc herniation.

Glisson's capsule matrix structure and function is altered in patients with cirrhosis irrespective of aetiology.

Background & Aims: Glisson's capsule is the interstitial connective tissue that surrounds the liver. As part of its normal physiology, it withstands significant daily changes in liver size. The pathophysiology of the capsule in disease is not well understood. The aim of this study was to characterise the changes in capsule matrix, cellular composition, and mechanical properties that occur in liver disease and to determine whether these correlate with disease severity or aetiology. Methods: Samples from ten control patients, and six with steatosis, seven with moderate fibrosis, and 37 with cirrhosis were collected from autopsies, intraoperative biopsies, and liver explants. Matrix proteins and cell markers were assessed by staining and second harmonic generation imaging. Mechanical tensile testing was performed on a test frame. Results: Capsule thickness was significantly increased in cirrhotic samples compared with normal controls irrespective of disease aetiology (70.12 ± 14.16 µm and 231.58 ± 21.82 µm, respectively), whereas steatosis and moderate fibrosis had no effect on thickness (90.91 ± 11.40 µm). Changes in cirrhosis included an increase in cell number (fibroblasts, vascular cells, infiltrating immune cells, and biliary epithelial cells). Key matrix components (collagens 1 and 3, hyaluronan, versican, and elastin) were all deposited in the lower capsule, although only the relative amounts per area of hyaluronan and versican were increased. Organisational features, including crimping and alignment of collagen fibres, were also altered in cirrhosis. Unexpectedly, capsules from cirrhotic livers had decreased resistance to loading compared with controls. Conclusions: The liver capsule, similar to the parenchyma, is an active site of disease, demonstrating changes in matrix and cell composition as well as mechanical properties. Impact and implications: We assessed the changes in composition and response to stretching of the liver outer sheath, the capsule, in human liver disease. We found an increase in key structural components and numbers of cells as well as a change in matrix organisation of the capsule during the later stages of disease. This allows the diseased capsule to stretch more under any given force, suggesting that it is less stiff than healthy tissue.

Pooled Safety Analysis of IncobotulinumtoxinA in the Treatment of Neurological Disorders in Adults.

The pooled incidences of treatment-emergent adverse events (TEAEs) were examined by indication using the integrated clinical database of Merz-sponsored, placebo-controlled, or repeat-dose studies of incobotulinumtoxinA in adults with cervical dystonia, blepharospasm, limb spasticity, sialorrhea, or essential tremor of the upper limb. Overall incidences of TEAEs, serious TEAEs, TEAEs leading to discontinuation, fatal TEAEs, TEAEs of special interest (TEAESIs; indicating possible toxin spread), and treatment-related (TR) events were determined for incobotulinumtoxinA and placebo after a single injection and for repeated dose cycles of incobotulinumtoxinA. The most frequent events after a single dose of incobotulinumtoxinA are summarized. After a single cycle, incidences of overall TEAEs were similar between incobotulinumtoxinA and the placebo in most indications, although between-indication differences were observed. Few TEAEs led to incobotulinumtoxinA discontinuation; there were no fatal TEAEs with incobotulinumtoxinA. In general, repeated cycles did not increase the incidence of any event. The most frequent TR-TEAEs were indication-dependent, including dysphagia for indications affecting the head or neck. The TR-TEAESIs across all indications were most commonly muscular weakness, dysphagia and dry mouth. Overall, the results of this pooled analysis support and extend the favorable safety and tolerability profile of incobotulinumtoxinA for the treatment of adult neurological disorders established by individual clinical studies.

Great debates in trauma biomechanics.

At the 2021 annual meeting of the Orthopaedic Trauma Association, the Basic Science Focus Forum hosted its first ever debate-style symposium focused on biomechanics and fracture repair. The 3 subjects of debate were "Mechanics versus Biology-Which is 'More Important' to Consider?" "Locked Plate versus Forward Dynamization versus Reverse Dynamization-Which Way Should I Go?" and "Sawbones versus Cadaver Models-What Should I Believe Most?" These debates were held because fracture healing is a highly organized synergistic response between biological factors and the local mechanical environment. Multiple studies have demonstrated that both factors play roles in governing bone healing responses, and the causal relationships between the 2 remain unclear. The lack of clarity in this space has led to a spectrum of research with the common goal of helping surgeons make good decisions. Before reading further, the reader should understand that the questions posed in the debate titles are unanswerable and might represent a false choice. Instead, the reader should appreciate that the debates were held to gain a more thorough understanding of these topics based on the current state of the art of experimental and clinical studies, by using an engaging and thought-provoking format.

3-D Printed Fracture Models Improve Resident Performance and Clinical Outcomes in Operative Fracture Management.

OBJECTIVE: To determine if preoperative examination of patient additive manufactured (AM) fracture models can be used to improve resident operative competency and patient outcomes. DESIGN: Prospective cohort study. Seventeen matched pairs of fracture fixation surgeries (for a total of 34 surgeries) were performed. Residents first performed a set of baseline surgeries (n = 17) without AM fracture models. The residents then performed a second set of surgeries randomly assigned to include an AM model (n = 11) or to omit it (n = 6). Following each surgery, the attending surgeon evaluated the resident using an Ottawa Surgical Competency Operating Room Evaluation (O-Score). The authors also recorded clinical outcomes including operative time, blood loss, fluoroscopy duration, and patient reported outcome measurement information system (PROMIS) scores of pain and function at 6 months. SETTING: Single-center academic level one trauma center. PARTICIPANTS: Twelve orthopaedic residents, between postgraduate year (PGY) 2 and 5, participated in this study. RESULTS: Residents significantly improved their O-Scores between the first and second surgery when they trained with AM models for the second surgery (p = 0.004, 2.43 ± 0.79 versus 3.73 ± 0.64). Similar improvements were not observed in the control group (p = 0.916, 2.69 ± 0.69 versus 2.77 ± 0.36). AM model training also significantly improved clinical outcomes, including surgery time (p = 0.006), fluoroscopy exposure time (p = 0.002), and patient reported functional outcomes (p = 0.0006). CONCLUSIONS: Conclusions: Training with AM fracture models improves the performance of orthopaedic surgery residents during fracture surgery.

Turnover Tendon Lengthening Does Not Alter Biomechanical Strength of Pronator Teres-to-Extensor Carpi Radialis Brevis Tendon Transfer.

BACKGROUND: The pronator teres (PT) to extensor carpi radialis brevis (ECRB) tendon transfer reestablishes wrist extension. Occasionally, the PT periosteal extension is of suboptimal quality to support a strong transfer. In these instances, turnover lengthening techniques can increase usable tendon length. This study characterized the optimal length of tendon turnover and the effect of lengthening on transfer strength. METHODS: Twenty-seven cadaveric extensor tendons were lengthened using the turnover lengthening technique with 1 to 3 cm of tendon overlap. PT-to-ECRB tendon transfers were performed with native or lengthened ECRB tendons. Tensile testing was used to evaluate stress relaxation and load to failure. RESULTS: The median maximum load to failure increased with increasing overlap length, measuring 35.6 N (quartile 1, 30.2 N; quartile 3, 38.6 N) for 1 cm, 66.0 N (quartile 1, 59.1 N; quartile 3, 74.7 N) for 2 cm, and 96.6 N (quartile 1, 85.9; quartile 3, 114.9 N) for 3 cm of overlap ( P < 0.05). Failure occurred most frequently at the junction of the central overlap and native tendon. Tendons lengthened with 2 and 3 cm of overlap displayed greater stiffness than those with 1 cm ( P < 0.05). Lengthening the ECRB tendon with 2 or 3 cm of overlap did not disrupt the strength or stiffness of subsequent PT-to-ECRB tendon transfers. CONCLUSIONS: Turnover tendon lengthening does not detrimentally affect PT-to-ECRB tendon transfer. Greater overlap lengthening distance confers greater stiffness and resistance to rupture. When the periosteal extension of the PT tendon avulses or is of poor quality, the ECRB tendon can be lengthened using the turnover tendon lengthening technique to facilitate a robust transfer.

Similar Biomechanics Between the Double-Cortical Button and Docking Techniques for Ulnar Collateral Ligament Reconstruction: A Cadaveric Evaluation.

Background: The docking technique is widely used to perform ulnar collateral ligament (UCL) reconstructions because of its high failure torque and reliable clinical outcomes. A double-cortical button technique was recently described, with advantages including the ability to tension the graft at the ulnar and humeral attachments and the creation of single bone tunnels. Purpose/Hypothesis: To compare the biomechanics between the docking and double-button UCL reconstruction techniques using cadaveric specimens. We hypothesized that there would be no difference in postoperative stiffness or maximum strength between the techniques. Study Design: Controlled laboratory study. Methods: Eight matched pairs of cadaveric elbow joints underwent controlled humeral valgus torsion cycles in a test frame. Toe region stiffness, elastic region stiffness, and maximum torque were measured during a 4-step protocol: intact, injured, reconstructed (10 and 1000 cycles), and ramp to failure. Graft strains were calculated using 3-dimensional motion capture. Results: After 10 cycles, intact ligaments from the docking and double-button groups exhibited mean ± SD elastic torsional stiffness of 1.60 ± 0.49 and 1.64 ± 0.35 N·m/deg (P = .827), while docking (1.10 ± 0.39 N·m/deg) and double-button (1.05 ± 0.29 N·m/deg) reconstructions were lower (P = .754). There were no significant differences in maximum torque between the docking (3.45 ± 1.35 N·m) and double-button (3.25 ± 1.31 N·m) groups (P = .777). Similarly, differences in maximum graft strains were not significant between the docking (8.1% ± 7.2%) and double-button (5.5% ± 3.1%) groups (P = .645). The groups demonstrated similar decreases in these measures after cyclic loading. Ramp-to-failure testing showed no significant differences in ultimate torque between the docking (8.93 ± 3.9 N·m) and double-button (9.56 ± 3.5 N·m) groups (P = .739). Conclusion: The biomechanical behavior of the double-button technique was not significantly different from that of the docking technique. Both reconstruction techniques restored joint stability, but neither fully recapitulated preinjury joint stiffness. Clinical Relevance: With its procedural advantages, results preliminarily support the use of the double-button reconstruction technique for UCL reconstruction as a reliable single-tunnel technique for primary or revision cases.

The addition of cerclage wiring does not improve proximal bicortical fixation of locking plates for Type C periprosthetic fractures in synthetic humeri.

BACKGROUND: Treatment of proximal humerus periprosthetic fractures is challenging. It remains difficult to achieve robust fixation of the proximal fragment to the locking plate using cerclage wiring and/or unicortical screws. Use of polyaxial tangentially directed bicortical locking screws increases screw purchase, but it is unclear if this option provides robust fixation. This biomechanical study compares fixation of constructs using cerclage wires, bicortical locking screws, and a hybrid method utilizing both methods. METHODS: Uncemented humeral stems were implanted into synthetic humeri and Type C periprosthetic fractures were simulated with a 1 cm transverse osteotomy. Distal ends of locking plates were secured with bicortical non-locking screws. The proximal ends were supported by either isolated cerclage wires, polyaxial locking screws, or a hybrid combination of both (n = 6 for each group). A universal test frame was used for non-destructive torsion and cyclic axial compression tests. 3-D motion tracking was employed to determine stiffnesses and relative interfragmentary motions. FINDINGS: Isolated screw constructs showed significantly increased resistance against torsional movement, bending, and shear, (p < 0.05) in comparison to cerclage constructs. The hybrid construct provided no significant changes in stability over the isolated screw construct. INTERPRETATION: Addition of cerclage wires in this synthetic bone model of Type C periprosthetic humerus fractures did not add significant stability to proximal bicortical locking plate fixation. Considering risks of tissue stripping and nerve injury, usage of cerclage wires in a similar clinical setting should be chosen carefully, especially when bicortical fixation around the prosthetic stem can be achieved.

Biomechanical properties of common graft choices for anterior cruciate ligament reconstruction: A systematic review.

BACKGROUND: This systematic review explores the differences in the intrinsic biomechanical properties of different graft sources used in anterior cruciate ligament (ACL) reconstruction as tested in a laboratory setting. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, two authors conducted a systematic review exploring the biomechanical properties of ACL graft sources (querying PubMed, Cochrane, and Embase databases). Using the keywords "anterior cruciate ligament graft," "biomechanics," and "biomechanical testing," relevant articles of any level of evidence were identified as eligible and included if they reported on the biomechanical properties of skeletally immature or mature ACL grafts solely and if the grafts were studied in vitro, in isolation, and under similar testing conditions. Studies were excluded if performed on both skeletally immature and mature or non-human grafts, or if the grafts were tested after fixation in a cadaveric knee. For each graft, failure load, stiffness, Young's modulus, maximum stress, and maximum strain were recorded. FINDINGS: Twenty-six articles were included. Most studies reported equal or increased biomechanical failure load and stiffness of their tested bone-patellar tendon-bone, hamstring, quadriceps, peroneus longus, tibialis anterior and posterior, Achilles, tensor fascia lata, and iliotibial band grafts compared to the native ACL. All recorded biomechanical properties had similar values between graft types. INTERPRETATION: Most grafts used for ACL reconstruction are biomechanically superior to the native ACL. Utilizing a proper graft, combined with a standard surgical technique and a rigorous rehabilitation before and after surgery, will improve outcomes of ACL reconstruction.

Current concepts in fracture healing: temporal dynamization and applications for additive manufacturing.

Objectives: Current surgical fracture treatment paradigms, which use rigid metallic constructs to heal bones, provide reasonable clinical outcomes; however, they do not leverage recent advances in our understanding of bone healing and mechanotransduction throughout bone healing. The objective of this review was to investigate the efficacy and potential clinical applicability of surgical techniques and implants that deliberately introduce interfragmentary motion throughout the healing process. Methods: The authors searched PubMed and Google Scholar databases for articles reporting on fracture repair using dynamic locking plates, dynamized surgical techniques, and reverse dynamization. Data collection also included assessment of additively manufactured (AM) implants that provide dynamic mechanical behaviors. Results: Forty articles were included for final review. It was found that accelerated rates of fracture healing can be achieved with staged 2-part surgeries or dynamic implant designs. Temporal dynamization, where static fixation of bones is followed by the introduction of micromotion and controlled loading, has been shown to improve callus volume and accelerate the healing response. Reverse dynamization, where micromotion is encouraged during early callus formation and arrested later, may represent a significant advance for the treatment of critical defect injuries. Advances in AM techniques will likely provide the ability to create high-resolution implants capable of dynamized and reverse dynamized modalities. Conclusions: There is no one-size-fits-all approach to optimization of fracture healing. However, it has been clearly demonstrated that fracture treatment can be enhanced by systematically altering the construct stiffness throughout the different phases of healing, which may be achieved with AM implant designs.

Efficacy and safety of two incobotulinumtoxinA injection intervals in cervical dystonia patients with inadequate benefit from standard injection intervals of botulinum toxin: Phase 4, open-label, randomized, noninferiority study.

IntroductionSome patients with cervical dystonia (CD) receiving long-term botulinum neurotoxin (BoNT) therapy report early waning of treatment benefit before the typical 12-week reinjection interval. Methods: This phase 4, open-label, randomized, noninferiority study (CD Flex; NCT01486264) compared 2 incobotulinumtoxinA injection schedules (Short Flex: 8 ± 2 weeks; Long Flex: 14 ± 2 weeks) in CD patients. Previous BoNT-responsive subjects who reported acceptable clinical benefit lasting < 10 weeks were recruited. Efficacy and safety were evaluated after 8 injection cycles. The primary endpoint was change in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) severity subscale 4 weeks after the eighth injection. Secondary endpoints included TWSTRS total and subscale scores. Immunogenicity was assessed in a subset of patients. Results: Two hundred eighty-two CD patients were randomized and treated (Short Flex, N = 142; Long Flex, N = 140), and 207 completed the study. Significant improvements in TWSTRS severity from study baseline to 4 weeks after cycle 8 were observed in both the Short Flex (4.1 points; P < 0.0001) and Long Flex (2.4 points; P = 0.002) groups; Short Flex was noninferior to Long Flex (LS mean difference = 1.4 points; 95% CI = [-2.9, 0.1] < Δ = 2.0). Key secondary endpoints favored Short Flex intervals. Adverse events (AEs) were comparable between groups. There was no secondary loss of treatment effect. Conclusion: Injection cycles < 10 weeks for incobotulinumtoxinA are effective (and noninferior to longer intervals) for treating CD patients with early waning of clinical benefit. Shorter injection intervals did not increase AEs or lead to loss of treatment effect.

Enhanced tendon healing by a tough hydrogel with an adhesive side and high drug-loading capacity.

Hydrogels that provide mechanical support and sustainably release therapeutics have been used to treat tendon injuries. However, most hydrogels are insufficiently tough, release drugs in bursts, and require cell infiltration or suturing to integrate with surrounding tissue. Here we report that a hydrogel serving as a high-capacity drug depot and combining a dissipative tough matrix on one side and a chitosan adhesive surface on the other side supports tendon gliding and strong adhesion (larger than 1,000 J m-2) to tendon on opposite surfaces of the hydrogel, as we show with porcine and human tendon preparations during cyclic-friction loadings. The hydrogel is biocompatible, strongly adheres to patellar, supraspinatus and Achilles tendons of live rats, boosted healing and reduced scar formation in a rat model of Achilles-tendon rupture, and sustainably released the corticosteroid triamcinolone acetonide in a rat model of patellar tendon injury, reducing inflammation, modulating chemokine secretion, recruiting tendon stem and progenitor cells, and promoting macrophage polarization to the M2 phenotype. Hydrogels with 'Janus' surfaces and sustained-drug-release functionality could be designed for a range of biomedical applications.

Six-Month Outcomes of Clinically Relevant Meniscal Injury in a Large-Animal Model.

BACKGROUND: The corrective procedures for meniscal injury are dependent on tear type, severity, and location. Vertical longitudinal tears are common in young and active individuals, but their natural progression and impact on osteoarthritis (OA) development are not known. Root tears are challenging and they often indicate poor outcomes, although the timing and mechanisms of initiation of joint dysfunction are poorly understood, particularly in large-animal and human models. PURPOSE/HYPOTHESIS: In this study, vertical longitudinal and root tears were made in a large-animal model to determine the progression of joint-wide dysfunction. We hypothesized that OA onset and progression would depend on the extent of injury-based load disruption in the tissue, such that root tears would cause earlier and more severe changes to the joint. STUDY DESIGN: Controlled laboratory study. METHODS: Sham surgeries and procedures to create either vertical longitudinal or root tears were performed in juvenile Yucatan mini pigs through randomized and bilateral arthroscopic procedures. Animals were sacrificed at 1, 3, or 6 months after injury and assessed at the joint and tissue level for evidence of OA. Functional measures of joint load transfer, cartilage indentation mechanics, and meniscal tensile properties were performed, as well as histological evaluation of the cartilage, meniscus, and synovium. RESULTS: Outcomes suggested a progressive and sustained degeneration of the knee joint and meniscus after root tear, as evidenced by histological analysis of the cartilage and meniscus. This occurred in spite of spontaneous reattachment of the root, suggesting that this reattachment did not fully restore the function of the native attachment. In contrast, the vertical longitudinal tear did not cause significant changes to the joint, with only mild differences compared with sham surgery at the 6-month time point. CONCLUSION: Given that the root tear, which severs circumferential connectivity and load transfer, caused more intense OA compared with the circumferentially stable vertical longitudinal tear, our findings suggest that without timely and mechanically competent fixation, root tears may cause irreversible joint damage. CLINICAL RELEVANCE: More generally, this new model can serve as a test bed for experimental surgical, scaffold-based, and small molecule-driven interventions after injury to prevent OA progression.

Examining the novel use of continuous compression implants in clavicle reconstruction: A biomechanical study.

BACKGROUND: Current implants for clavicle fractures are known to cause poor cosmesis and irritation, which may require implant removal. Low-profile shape-memory staples provide an attractive alternative, but their biomechanical utility in clavicle reconstruction is unknown. We hypothesized that shape-memory reconstructions would be more compliant compared to traditional constructs but would also outperform conventional plates during cyclic loading to failure. METHODS: This study was performed with 36 synthetic clavicles and 12 matched pairs of cadaveric specimens. The synthetic study tested four reconstructions: a single superiorly placed staple (n = 6), a single anteroinferiorly-placed staple (n = 6), a 3.5 mm reconstruction plate (n = 12), and two orthogonally placed staples (n = 12). The cadaveric study tested three constructs: reconstruction plate (n = 8), two orthogonal staples (n = 8), and a 2.7 mm reconstruction plate combined with a superior staple (n = 8). Non-destructive 4-point bending, compression, and torsion assays were performed prior to destructive cantilever bending and cyclic torsion tests. FINDINGS: The single staple and double staple groups demonstrated significantly decreased resistance to bending (p < 0.001) and torsion (p ≤ 0.027) when compared to reconstruction plate groups. The double staple group sustained significantly fewer cycles to failure than the reconstruction plate group in cyclic torsional tests (p = 0.012). The synthetic models produced higher stiffness and failure mechanisms that were completely different from cadaveric specimens. INTERPRETATION: Shape memory alloy implants provided inadequate stiffness for clavicle fixation but may have utility in other orthopaedic applications when used as a supplementary compression device in conjunction with traditional plated constructs. Synthetic bones have limited capacity for modeling fragility fractures.