Computed tomography-based structural rigidity analysis can assess tumor- and treatment-induced changes in rat bones with metastatic lesions.

BACKGROUND: Breast cancer (BrCa) is a predominant malignancy, with metastasis occurring in one in eight patients, nearly half of which target the bone, leading to serious complications such as pain, fractures, and compromised mobility. Structural rigidity, crucial for bone strength, becomes compromised with osteolytic lesions, highlighting the vulnerability and increased fracture risk in affected areas. Historically, two-dimensional radiographs have been employed to predict these fracture risks; however, their limitations in capturing the three-dimensional structural and material changes in bone have raised concerns. Recent advances in CT-based Structural Rigidity Analysis (CTRA), offer a promising, more accurate non-invasive 3D approach. This study aims to assess the efficacy of CTRA in monitoring osteolytic lesions' progression and response to therapy, suggesting its potential superiority over existing methodologies in guiding treatment strategies. METHODS: Twenty-seven female nude rats underwent femoral intra-medullary inoculation with MDA-MB-231 human breast cancer cells or saline control. They were divided into Control, Cancer Control, Ibandronate, and Paclitaxel groups. Osteolytic progression was monitored weekly using biplanar radiography, quantitative computed tomography (QCT), and dual-energy X-ray absorptiometry (DEXA). CTRA was employed to predict fracture risk, normalized using the contralateral femur. Statistical analyses, including Kruskal-Wallis and ANOVA, assessed differences in outcomes among groups and over time. RESULTS: Biplanar radiographs showed treatment benefits over time; however, only certain time-specific differences between the Control and other treatment groups were discernible. Notably, observer subjectivity in X-ray scoring became evident, with significant inter-operator variations. DEXA measurements for metaphyseal Bone Mineral Content (BMC) did not exhibit notable differences between groups. Although diaphyseal BMC highlighted some variance, it did not reveal significant differences between treatments at specific time points, suggesting a limited ability for DEXA to differentiate between treatment effects. In contrast, the CTRA consistently demonstrated variations across different treatments, effectively capturing bone rigidity changes over time, and the axial- (EA), bending- (EI), and torsional rigidity (GJ) outcomes from the CTRA method successfully distinguished differences among treatments at specific time points. CONCLUSION: Traditional approaches, such as biplanar radiographs and DEXA, have exhibited inherent limitations, notably observer bias and time-specific inefficacies. Our study accentuates the capability of CTRA in capturing real-time, progressive changes in bone structure, with the potential to predict fractures more accurately and provide a more objective analysis. Ultimately, this innovative approach may bridge the existing gap in clinical guidelines, ushering in enhanced Clinical Decision Support Tool (CDST) for both surgical and non-surgical treatments.

The effect of cannabinoids on single-level lumbar arthrodesis outcomes in a rat model.

BACKGROUND CONTEXT: The opioid epidemic is a public health crisis affecting spine care and pain management. Medical marijuana is a potential non-opioid analgesic yet to be studied in the surgical setting since its effects on bone healing are not fully understood. Studies have demonstrated analgesic and potentially osteoinductive properties of cannabinoids with endocannabinoid receptor expression in bone tissue. PURPOSE: We hypothesize that tetrahydrocannabinol (THC) and cannabidiol (CBD) will not decrease bone healing in spinal fusion. STUDY DESIGN: Seventy-eight adult Sprague-Dawley rats were used for this study. Utilizing allogenic bone grafts (6 donor rats), posterolateral inter-transverse lumbar fusion at the L4-L5 level was performed. The animals were equally divided into four treatment groups, each receiving 0.1 ml intraperitoneal injections weekly as follows: placebo (saline), 5 mg/kg THC, 5 mg/kg CBD, and a combination of 5 mg/kg THC and 5mg/kg CBD (Combo). METHODS: Callus tissue was harvested 2- and 8-weeks post-surgery for qPCR assessment to quantify changes in the expression of osteogenic genes. Manual palpation was done to assess the strength of the L4-L5 arthrodesis on all rats. µCT image-based callus analysis and histology were performed. One-way ANOVA followed by post hoc comparisons was performed. RESULTS: µCT demonstrated no significant differences. Treatment groups had slightly increased bone volume and density compared to control. qPCR at two weeks indicated downregulated RANKL/OPG ratios skewing towards osteogenesis in the CBD group, with the THC and CBD+THC groups demonstrating a downward trend (p>.05). ALPL, BMP4, and SOST were significantly higher in the CBD group, with CTNNB1 and RUNX2 also showing an upregulating trend. The CBD group showed elevation in Col1A1 and MMP13. Data at eight weeks showed ALPL, RUNX2, BMP4, and SOST were downregulated for all treatment groups. In the CBD+THC group, RANK, RANKL, and OPG were downregulated. OPG downregulation reached significance for the THC and CBD+THC group compared to saline. Interestingly, the RANKL/OPG ratio showed upregulation in the CBD and CBD+THC groups. RANKL showed upregulation in the CBD group. At 2 and 8 weeks, the CBD treatment group showed superior histological progression, increasing between time points. CONCLUSION: This study demonstrates that CBD and THC have no adverse effect on bone healing and the rate of spinal fusion in rats. Osteogenic factors were upregulated in the CBD-treated groups at two weeks, which indicates a potential for bone regeneration. In this group, compared to control, the RANKL/OPG ratio at the early healing phase demonstrates the inhibition of osteoclast differentiation, enhancing bone formation. Interestingly, it shows promoted osteoclast differentiation at the later healing phase, enhancing bone remodeling. This aligns with the physiological expectation of a lower ratio in the early phases and a higher ratio in the later remodeling phases. CLINICAL SIGNIFICANCE: CBD and THC showed no inhibitory effects on bone healing in a spinal fusion model. Moreover, histologic and gene expression analysis demonstrated that CBD may, in fact, enhance bone healing. Further research is needed to confirm the safe usage of THC and CBD in the post-operative setting following spinal fusions.

Metaverse, virtual reality and augmented reality in total shoulder arthroplasty: a systematic review.

PURPOSE: This systematic review aims to provide an overview of the current knowledge on the role of the metaverse, augmented reality, and virtual reality in reverse shoulder arthroplasty. METHODS: A systematic review was performed using the PRISMA guidelines. A comprehensive review of the applications of the metaverse, augmented reality, and virtual reality in in-vivo intraoperative navigation, in the training of orthopedic residents, and in the latest innovations proposed in ex-vivo studies was conducted. RESULTS: A total of 22 articles were included in the review. Data on navigated shoulder arthroplasty was extracted from 14 articles: seven hundred ninety-three patients treated with intraoperative navigated rTSA or aTSA were included. Also, three randomized control trials (RCTs) reported outcomes on a total of fifty-three orthopedics surgical residents and doctors receiving VR-based training for rTSA, which were also included in the review. Three studies reporting the latest VR and AR-based rTSA applications and two proof of concept studies were also included in the review. CONCLUSIONS: The metaverse, augmented reality, and virtual reality present immense potential for the future of orthopedic surgery. As these technologies advance, it is crucial to conduct additional research, foster development, and seamlessly integrate them into surgical education to fully harness their capabilities and transform the field. This evolution promises enhanced accuracy, expanded training opportunities, and improved surgical planning capabilities.

Quantitative 1H Magnetic Resonance Imaging on Normal and Pathologic Rat Bones by Solid-State 1H ZTE Sequence with Water and Fat Suppression.

BACKGROUND: Osteoporosis (OP) and osteomalacia (OM) are metabolic bone diseases characterized by mineral and matrix density changes. Quantitative bone matrix density differentiates OM from OP. MRI is a noninvasive and nonionizing imaging technique that can measure bone matrix density quantitatively in ex vivo and in vivo. PURPOSE: To demonstrate water + fat suppressed 1H MRI to compute bone matrix density in ex vivo rat femurs in the preclinical model. STUDY TYPE: Prospective. ANIMAL MODEL: Fifteen skeletally mature female Sprague-Dawley rats, five per group (normal, ovariectomized (OVX), partially nephrectomized/vitamin D (Vit-D) deficient), 250-275 g, ∼15 weeks old. FIELD STRENGTH/SEQUENCE: 7T, zero echo time sequence with water + fat (VAPOR) suppression capability, µCT imaging, and gravimetric measurements. ASSESSMENT: Cortical and trabecular bone segments from normal and disease models were scanned in the same coil along with a dual calibration phantom for quantitative assessment of bone matrix density. STATISTICAL TESTS: ANOVA and linear regression were used for data analysis, with P-values <0.05 statistically significant. RESULTS: The MRI-derived three-density PEG pellet densities have a strong linear relationship with physical density measures (r2 = 0.99). The Vit-D group had the lowest bone matrix density for cortical bone (0.47 ± 0.16 g cm-3), whereas the OVX had the lowest bone matrix density for trabecular bone (0.26 ± 0.04 g cm-3). Gravimetry results confirmed these MRI-based observations for Vit-D cortical (0.51 ± 0.07 g cm-3) and OVX trabecular (0.26 ± 0.03 g cm-3) bone groups. DATA CONCLUSION: Rat femur images were obtained using a modified pulse sequence and a custom-designed double-tuned (1H/31P) transmit-receive solenoid-coil on a 7T preclinical MRI scanner. Phantom experiments confirmed a strong linear relation between MRI-derived and physical density measures and quantitative bone matrix densities in rat femurs from normal, OVX, and Vit-D deficient/partially nephrectomized animals were computed. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Quantitative 31P magnetic resonance imaging on pathologic rat bones by ZTE at 7T.

BACKGROUND: Osteoporosis is characterized by low bone mineral density (BMD), which predisposes individuals to frequent fragility fractures. Quantitative BMD measurements can potentially help distinguish bone pathologies and allow clinicians to provide disease-relieving therapies. Our group has developed non-invasive and non-ionizing magnetic resonance imaging (MRI) techniques to measure bone mineral density quantitatively. Dual-energy X-ray Absorptiometry (DXA) is a clinically approved non-invasive modality to diagnose osteoporosis but has associated disadvantages and limitations. PURPOSE: Evaluate the clinical feasibility of phosphorus (31P) MRI as a non-invasive and non-ionizing medical diagnostic tool to compute bone mineral density to help differentiate between different metabolic bone diseases. MATERIALS AND METHODS: Fifteen ex-vivo rat bones in three groups [control, ovariectomized (osteoporosis), and vitamin-D deficient (osteomalacia - hypo-mineralized) were scanned to compute BMD. A double-tuned (1H/31P) transmit-receive single RF coil was custom-designed and in-house-built with a better filling factor and strong radiofrequency (B1) field to acquire solid-state 31P MR images from rat femurs with an optimum signal-to-noise ratio (SNR). Micro-computed tomography (µCT) and gold-standard gravimetric analyses were performed to compare and validate MRI-derived bone mineral densities. RESULTS: Three-dimensional 31P MR images of rat bones were obtained with a zero-echo-time (ZTE) sequence with 468 µm spatial resolution and 12-17 SNR on a Bruker 7 T Biospec having multinuclear capability. BMD was measured quantitatively on cortical and trabecular bones with a known standard reference. A strong positive correlation (R = 0.99) and a slope close to 1 in phantom measurements indicate that the densities measured by 31P ZTE MRI are close to the physical densities in computing quantitative BMD. The 31P NMR properties (resonance linewidth of 4 kHz and T1 of 67 s) of ex-vivo rat bones were measured, and 31P ZTE imaging parameters were optimized. The BMD results obtained from MRI are in good agreement with µCT and gravimetry results. CONCLUSION: Quantitative measurements of BMD on ex-vivo rat femurs were successfully conducted on a 7 T preclinical scanner. This study suggests that quantitative measurements of BMD are feasible on humans in clinical MRI with suitable hardware, RF coils, and pulse sequences with optimized parameters within an acceptable scan time since human femurs are approximately ten times larger than rat femurs. As MRI provides quantitative in-vivo data, various systemic musculoskeletal conditions can be diagnosed potentially in humans.

While the Incidence of Venous Thromboembolism After Shoulder Arthroscopy Is Low, the Risk Factors Are a Body Mass Index Greater than 30 and Hypertension.

Purpose: This study aims to determine the overall incidence of venous thromboembolism (VTE) following shoulder arthroscopy and to define potential risk factors associated with its development that may help define guidelines for the use of thromboprophylaxis. Methods: A systematic review was performed using PubMed, Embase, Web of Science, CINAHL, and Cochrane databases per PRISMA guidelines. The search terms consisted of variations of "Venous Thromboembolism" and "Shoulder Arthroscopy." Information regarding arthroscopy indication, risk factors, outcomes, and patient demographics was recorded and analyzed, and pooled odds ratios were reported for each variable. Results: Six hundred eighty-five articles were identified in the initial search, and 35 articles reported DVT, PE, or VTE incidence following shoulder arthroscopy. Seventeen nonoverlapping articles with a unique patient population incidence rates. Four articles were then used for subgroup meta-analysis. The incidence rate of VTE was 0.24%, ranging from 0.01% to 5.7%. BMI >30 (OR = 1.46; 95% CI = [1.22, 1.74]; I2 = 0%) and hypertension (OR = 1.64; 95% CI = [1.03, 2.6]; I2 = 75%) were significant risk factors (P < .05) for developing VTE following shoulder arthroscopy. Diabetes (OR = 1.2; 95% CI = [0.97, 1.48]; I2 = 0%), insulin-dependent diabetes (OR = 5.58; 95% CI = [0.12, 260.19]; I2 = 85%), smoking (OR = 1.04; 95% CI = [0.79, 1.37]; I2 = 12%), male sex (OR = 0.95; 95% CI = [0.49, 1.85]; I2 = 86%) and age over 65 (OR = 4.3; 95% CI = [0.25, 72.83]; I2 = 85%) were not associated with higher VTE risk. Conclusion: The VTE incidence following shoulder arthroscopy is low at 0.24%. Patients with BMI >30 and hypertension are at a higher risk for VTE after shoulder arthroscopy. Level of Evidence: Level IV, systematic review and meta-analysis of Level I-IV studies.

An in silico testbed for fast and accurate MR labeling of orthopedic implants.

One limitation on the ability to monitor health in older adults using magnetic resonance (MR) imaging is the presence of implants, where the prevalence of implantable devices (orthopedic, cardiac, neuromodulation) increases in the population, as does the pervasiveness of conditions requiring MRI studies for diagnosis (musculoskeletal diseases, infections, or cancer). The present study describes a novel multiphysics implant modeling testbed using the following approaches with two examples: (1) an in silico human model based on the widely available Visible Human Project (VHP) cryo-section dataset; (2) a finite element method (FEM) modeling software workbench from Ansys (Electronics Desktop/Mechanical) to model MR radio frequency (RF) coils and the temperature rise modeling in heterogeneous media. The in silico VHP-Female model (250 parts with an additional 40 components specifically characterizing embedded implants and resultant surrounding tissues) corresponds to a 60-year-old female with a body mass index of 36. The testbed includes the FEM-compatible in silico human model, an implant embedding procedure, a generic parameterizable MRI RF birdcage two-port coil model, a workflow for computing heat sources on the implant surface and in adjacent tissues, and a thermal FEM solver directly linked to the MR coil simulator to determine implant heating based on an MR imaging study protocol. The primary target is MR labeling of large orthopedic implants. The testbed has very recently been approved by the US Food and Drug Administration (FDA) as a medical device development tool for 1.5 T orthopedic implant examinations.

Sliding Plate System: A Novel Method and Device for Shortening Osteotomy.

We report a novel sliding plate system (SPS) and its application for radial shortening osteotomy. We conceptualised, designed and introduced the SPS, which helps with precise shortening osteotomy in both radius and ulna. We implanted the SPS in a patient with Kienböck disease following a radius shortening osteotomy. The SPS was safe and efficient, and the surgical technique eliminated extra steps. The SPS affords precise shortening, optimum compression and anatomic alignment after radius shortening osteotomy. Level of Evidence: Level V (Therapeutic).

An In-Silico Testbed for Fast and Accurate MR Labeling of Orthopaedic Implants.

One limitation on the ability to monitor health in older adults using Magnetic Resonance (MR) imaging is the presence of implants, where the prevalence of implantable devices (orthopedic, cardiac, neuromodulation) increases in the population, as does the pervasiveness of conditions requiring MRI studies for diagnosis (musculoskeletal diseases, infections, or cancer). The present study describes a novel multiphysics implant modeling testbed using the following approaches with two examples: - an in-silico human model based on the widely available Visible Human Project (VHP) cryo-section dataset; - a finite element method (FEM) modeling software workbench from Ansys (Electronics Desktop/Mechanical) to model MR radio frequency (RF) coils and the temperature rise modeling in heterogeneous media. The in-silico VHP Female model (250 parts with an additional 40 components specifically characterizing embedded implants and resultant surrounding tissues) corresponds to a 60-year-old female with a body mass index (BMI) of 36. The testbed includes the FEM-compatible in-silico human model, an implant embedding procedure, a generic parameterizable MRI RF birdcage two-port coil model, a workflow for computing heat sources on the implant surface and in adjacent tissues, and a thermal FEM solver directly linked to the MR coil simulator to determine implant heating based on an MR imaging study protocol. The primary target is MR labeling of large orthopaedic implants. The testbed has very recently been approved by the US Food and Drug Administration (FDA) as a medical device development tool (MDDT) for 1.5 T orthopaedic implant examinations.

Assessment of Bone Healing: Opportunities to Improve the Standard of Care.

➤ Bone healing is commonly evaluated by clinical examination and serial radiographic evaluation. Physicians should be mindful that personal and cultural differences in pain perception may affect the clinical examination. Radiographic assessment, even with the Radiographic Union Score, is qualitative, with limited interobserver agreement.➤ Physicians may use serial clinical and radiographical examinations to assess bone healing in most patients, but in ambiguous and complicated cases, they may require other methods to provide assistance in decision-making.➤ In complicated instances, clinically available biomarkers, ultrasound, and magnetic resonance imaging may determine initial callus development. Quantitative computed tomography and finite element analysis can estimate bone strength in later callus consolidation phases.➤ As a future direction, quantitative rigidity assessments for bone healing may help patients to return to function earlier by increasing a clinician's confidence in successful progressive healing.

The Tyrosine Kinase Inhibitor Lenvatinib Inhibits Anaplastic Thyroid Carcinoma Growth by Targeting Pericytes in the Tumor Microenvironment.

Background: Anaplastic thyroid carcinoma (ATC) is a rapidly fatal cancer with a median survival of a few months. Enhanced therapeutic options for durable management of ATC will rely on an understanding of genetics and the role of the tumor microenvironment. The prognosis for patients with ATC has not improved despite more detailed scrutiny of underlying tumor genetics. Pericytes in the microenvironment play a key evasive role for thyroid carcinoma (TC) cells. Lenvatinib improves outcomes in patients with radioiodine-refractory well-differentiated TC. In addition to the unclear role of pericytes in ATC, the effect and mechanism of lenvatinib efficacy on ATC have not been sufficiently elucidated. Design: We assessed pericyte enrichment in ATC. We determined the effect of lenvatinib on ATC cell growth cocultured with pericytes and in a xenograft mouse model from human BRAFWT/V600E-ATC-derived cells coimplanted with pericytes. Results: ATC samples were significantly enriched in pericytes compared with normal thyroid samples. BRAFWT/V600E-ATC-derived cells were resistant to lenvatinib treatment shown by a lack of suppression of MAPK and Akt pathways. Moreover, lenvatinib increased CD47 protein (thrombospondin-1 [TSP-1] receptor) levels over time vs. vehicle. TSP-1 levels were downregulated upon lenvatinib at late vs. early time points. Critically, ATC cells, when cocultured with pericytes, showed increased sensitivity to this therapy and ultimately decreased number of cells. The coimplantation in vivo of ATC cells with pericytes increased ATC growth and did not downregulate TSP-1 in the microenvironment in vivo. Conclusions and Implications: Pericytes are enriched in ATC samples. Lenvatinib showed inhibitory effects on BRAFWT/V600E-ATC cells in the presence of pericytes. The presence of pericytes could be crucial for effective lenvatinib treatment in patients with ATC. Degree of pericyte abundance may be an attractive prognostic marker in assessing pharmacotherapeutic options. Effective durable management of ATC will rely on an understanding not only of genetics but also on the role of the tumor microenvironment.

Automated Bone Tumor Segmentation and Classification as Benign or Malignant Using Computed Tomographic Imaging.

The purpose of this study was to pair computed tomography (CT) imaging and machine learning for automated bone tumor segmentation and classification to aid clinicians in determining the need for biopsy. In this retrospective study (March 2005-October 2020), a dataset of 84 femur CT scans (50 females and 34 males, 20 years and older) with definitive histologic confirmation of bone lesion (71% malignant) were leveraged to perform automated tumor segmentation and classification. Our method involves a deep learning architecture that receives a DICOM slice and predicts (i) a segmentation mask over the estimated tumor region, and (ii) a corresponding class as benign or malignant. Class prediction for each case is then determined via majority voting. Statistical analysis was conducted via fivefold cross validation, with results reported as averages along with 95% confidence intervals. Despite the imbalance between benign and malignant cases in our dataset, our approach attains similar classification performances in specificity (75%) and sensitivity (79%). Average segmentation performance attains 56% Dice score and reaches up to 80% for an image slice in each scan. The proposed approach establishes the first steps in developing an automated deep learning method on bone tumor segmentation and classification from CT imaging. Our approach attains comparable quantitative performance to existing deep learning models using other imaging modalities, including X-ray. Moreover, visual analysis of bone tumor segmentation indicates that our model is capable of learning typical tumor characteristics and provides a promising direction in aiding the clinical decision process for biopsy.

Combined MPFL reconstruction and tibial tuberosity transfer avoid focal patella overload in the setting of elevated TT-TG distances.

PURPOSE: Objectives are (1) to evaluate the biomechanical effect of isolated medial patellofemoral ligament (MPFL) reconstruction in the setting of increased tibial tuberosity-trochlear groove distance (TTTG), in terms of patella contact pressures, contact area and lateral displacement; (2) to describe the threshold of TTTG up to which MPFL reconstruction should be performed alone or in combination with tibial tuberosity transfer. METHODS: A finite element model of the knee was developed and validated. The model was modified to simulate isolated MPFL reconstruction, tibial tuberosity transfer and MPFL reconstruction combined with tibial tuberosity transfer for patella malalignment. Two TT-TG distances (17 mm and 22 mm) were simulated. Patella contact pressure, contact area and lateral displacement were analysed. RESULTS: Isolated MPFL reconstruction, at early degrees of flexion, restored normal patella contact pressure when TTTG was 17 mm, but not when TTTG was 22 mm. After 60° of flexion, the TTTG distance was the main factor influencing contact pressure. Isolated MPFL reconstruction for both TTTG 17 mm and 22 mm showed higher contact area and lower lateral displacement than normal throughout knee flexion. Tibial tuberosity transfer, at early degrees of flexion, reduced the contact pressure, but did not restore the normal contact pressure. After 60° of flexion, the TTTG distance was the main factor influencing contact pressure. Tibial tuberosity transfer maintained lower contact area than normal throughout knee flexion. The lateral displacement was higher than normal between 0° and 30° of flexion (< 0.5 mm). MPFL reconstruction combined with tibial tuberosity transfer produced the same contact mechanics and kinematics of the normal condition. CONCLUSION: This study highlights the importance of considering to correct alignment in lateral tracking patella to avoid focal patella overload. Our results showed that isolated MPFL reconstruction corrects patella kinematics regardless of TTTG distance. However, isolated MPFL reconstruction would not restore normal patella contact pressure when TTTG is 22 mm. For TTTG 22 mm, the combined procedure of MPFL reconstruction and tibial tuberosity transfer provided an adequate patellofemoral contact mechanics and kinematics, restoring normal biomechanics. This data supports the use of MPFL reconstruction when the patient has normal alignment and the use of combined MPFL reconstruction and tibial tuberosity transfer in patients with elevated TT-TG distances to avoid focal overload.

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.

Management of arthrofibrosis in neuromuscular disorders: a review.

Arthrofibrosis, or rigid contracture of major articular joints, is a significant morbidity of many neurodegenerative disorders. The pathogenesis depends on the mechanism and severity of the precipitating neuromuscular disorder. Most neuromuscular disorders, whether spastic or hypotonic, culminate in decreased joint range of motion. Limited range of motion precipitates a cascade of pathophysiological changes in the muscle-tendon unit, the joint capsule, and the articular cartilage. Resulting joint contractures limit functional mobility, posing both physical and psychosocial burdens to patients, economic burdens on the healthcare system, and lost productivity to society. This article reviews the pathophysiology of arthrofibrosis in the setting of neuromuscular disorders. We describe current non-surgical and surgical interventions for treating arthrofibrosis of commonly affected joints. In addition, we preview several promising modalities under development to ameliorate arthrofibrosis non-surgically and discuss limitations in the field of arthrofibrosis secondary to neuromuscular disorders.

Enhancing fracture repair: cell-based approaches.

Fracture repair is based both on the macrolevel modulation of fracture fragments and the subsequent cellular activity. Surgeons have also long recognized other influences on cellular behavior: the effect of the fracture or subsequent surgery on the available pool of cells present locally in the periosteum, the interrelated effects of fragment displacement, and construct stiffness on healing potential, patient pathophysiology and systemic disease conditions (such as diabetes), and external regulators of the skeletal repair (such as smoking or effect of medications). A wide variety of approaches have been applied to enhancing fracture repair by manipulation of cellular biology. Many of these approaches reflect our growing understanding of the cellular physiology that underlies skeletal regeneration. This review focuses on approaches to manipulating cell lineages, influencing paracrine and autocrine cell signaling, or applying other strategies to influence cell surface receptors and subsequent behavior. Scientists continue to evolve new approaches to pharmacologically enhancing the fracture repair process.

Lateral release associated with MPFL reconstruction in patients with acute patellar dislocation.

OBJECTIVE: Medial patellofemoral ligament (MPFL) injury occurs in the majority of the cases of acute patellar dislocation. The role of concomitant lateral retinaculum release with MPFL reconstruction is not clearly understood. Even though the lateral retinaculum plays a role in both medial and lateral patellofemoral joint stability in MPFL intact knees, studies have shown mixed clinical outcomes following its release during MPFL reconstruction surgery. Better understanding of the biomechanical effects of the release of the lateral retinaculum during MPFL reconstruction is warranted. We hypothesize that performing a lateral release concurrent with MPFL reconstruction will disrupt the patellofemoral joint biomechanics and result in lateral patellar instability. METHODS: A previously developed and validated finite element (FE) model of the patellofemoral joint was used to understand the effect of lateral retinaculum release following MPFL reconstruction. Contact pressure (CP), contact area (CA) and lateral patellar displacement were recorded. abstract. RESULTS: FE modeling and analysis demonstrated that lateral retinacular release following MPFL reconstruction with tibial tuberosity-tibial groove distance (TT-TG) of 12 mm resulted in a 39% decrease in CP, 44% decrease in CA and a 20% increase in lateral patellar displacement when compared to a knee with an intact MPFL. In addition, there was a 45% decrease in CP, 44% decrease in CA and a 21% increase in lateral displacement when compared to a knee that only had an MPFL reconstruction. CONCLUSION: This FE-based analysis exhibits that concomitant lateral retinaculum release with MPFL reconstruction results in decreased PF CA, CP and increased lateral patellar displacement with increased knee flexion, which may increase the risk of patellar instability.

Lateral Release With Tibial Tuberosity Transfer Alters Patellofemoral Biomechanics Promoting Multidirectional Patellar Instability.

PURPOSE: The purpose of this study was to develop and validate a finite element (FE) model of the patellofemoral (PF) joint to characterize patellofemoral instability, and to highlight the effect of lateral retinacular release in combination with tibial tuberosity transfer with respect to contact pressures (CP), contact area (CA), and kinematics during knee flexion. METHODS: A comprehensive, dynamic FE model of the knee joint was developed and validated through parametric comparison of PF kinematics, CP, and CA between FE simulations and in vitro, cadaveric experiments. Using this FE model, we characterized the effect of patellar instability, lateral retinacular release (LR), and tibial tuberosity transfer (TTT) in the setting of medial patellofemoral ligament injury during knee flexion. RESULTS: There was a high level of agreement in CP, CA, lateral patellar displacement, anterior patellar displacement, and superior patellar displacement between the FE model and the in vitro data (P values 0.19, 0.16, 0.81, 0.10, and 0.36, respectively). Instability conditions demonstrated the greatest CP compared to all of the other conditions. During all degrees of flexion, TTT and concomitant lateral release (TTT + LR) decreased CP significantly. TTT alone shows a consistently lower CA compared to nonrelease conditions with subsequent lateral release further decreasing CA. CONCLUSIONS: The results of this study demonstrate that the FE model described reliably simulates PF kinematics and CP within 1 SD in uncomplicated cadaveric specimens. The FE model is able to show that tibial tubercle transfer in combination with lateral retinacular release markedly decreases patellofemoral CP and CA and increases lateral patellar displacement that may decrease bony stabilization of the patella within the trochlear groove and promote lateral patellar instability. CLINICAL RELEVANCE: The goal of surgical correction for patellar instability focuses on reestablishing normal PF kinematics. By developing an FE model that can demonstrate patient PF kinematics and the results of different surgical approaches, surgeons may tailor their treatment to the best possible outcome. Of the surgical approaches that have been described, the biomechanical effects of the combination of TTT with lateral retinacular release have not been studied. Thus, the FE analysis will help shed light on the effect of the combination of TTT with lateral retinacular release on PF kinematics.

In situ gelling and dissolvable hydrogels for use as on-demand wound dressings for burns.

Currently, no dressings utilized in burn clinics provide adhesion, hydration or mechanical strength on the same order as human skin as well as the ability to be atraumatically removed. We report the synthesis, characterization, and in vivo evaluation of in situ polymerized and subsequent dissolvable hydrogels as burn wound dressings. Hydrogel dressings, from a small library of synthesized materials form in situ, exhibit storage moduli between 100-40 000 Pa, dissolve on-demand within 10 minutes to 90 minutes, swell up to 350%, and adhere to both burned and healthy human skin at 0.2-0.3 N cm-2. Further, results from an in vivo porcine second degree burn model demonstrate functional performance with healing equivalent to conventional treatments with the added benefit of facile, in situ application and subsequent removal via dissolution.

Conservative versus accelerated rehabilitation after rotator cuff repair: a systematic review and meta-analysis.

BACKGROUND: The purpose of this systematic review and meta-analysis is to compare the conservative and accelerated rehabilitation protocols in patients who underwent arthroscopic rotator cuff repair in terms of clinical outcomes and range of motions at 3, 6, 12, and 24-month follow-up. METHODS: According to PRISMA guidelines, a systematic review of the literature was performed. For each included article, the following data has been extracted: authors, year, study design, level of evidence, demographic characteristics, follow-up, clinical outcomes, range of motions, and retear events. A meta-analysis was performed to compare accelerated versus conservative rehabilitation protocols after arthroscopic rotator cuff repair. The retear rate, postoperative Constant-Murley score and range of motions at 3, 6, 12, and 24 months of follow-up were the outcomes measured. RESULTS: The search strategy yielded 16 level I-II clinical studies. A total of 1424 patients, with 732 patients and 692 in the accelerated and conservative group, were included. The average age (mean ± standard deviation) was 56.1 ± 8.7 and 56.6 ± 9 in the accelerated and conservative group. The mean follow-up was 12.5 months, ranging from 2 to 24 months. The meta-analysis showed no statistically significant differences in terms of retear rate between the groups (P = 0.29). The superiority of the accelerated group was demonstrated in terms of external rotation (P < 0.05) at 3-month follow-up; in terms of forward elevation, external rotation, abduction (P < 0.05), but not in terms of Constant-Murley score at 6-month follow-up; in terms of forward elevation (P < 0.05) at 12-month follow-up. No significant differences between the two group were highlighted at 24-month follow-up. CONCLUSIONS: No statistically significant differences in the retear rate among the accelerated and conservative group have been demonstrated. On the other hand, statistically and clinically significant differences were found in terms of external rotation at 3 and 6 months of follow-up in favour of the accelerated group. However, no differences between the two groups were detected at 24 months follow-up.