Controlling the nutritional status score: a new tool for predicting postoperative mortality in patients with infrarenal abdominal aortic aneurysm treated with endovascular aneurysm repair.

Background: AAA is a fatal condition that commonly occurs during vascular surgery. Nutritional status exerts a significant influence on the prognosis of various pathological conditions Scores from the CONUT screening tool have been shown to predict outcomes of certain malignancies and chronic diseases. However, the ramifications of nutritional status on AAA patients undergoing EVAR have not been elucidated in prior studies. In this study, we aimed to elucidate the correlation between CONUT scores and postoperative prognostic outcomes in patients with AAA undergoing EVAR. Methods: This was a retrospective review of 177 AAA patients treated with EVAR from June 2018 to November 2019 in a single center. Patient characteristics, CONUT scores, and postoperative status were collected. These patients were stratified into groups A and B according to CONUT scores. Subsequently, a comparative analysis of the baseline characteristics between the two cohorts was conducted. Cox proportional hazards and logistic regression analyses were employed to identify the autonomous predictors of mid-term mortality and complications, respectively. Results: Compared with group A, patients in group B had higher midterm mortality (p < 0.001). Univariate analysis showed that CONUT scores; respiratory diseases; stent types; preoperative Hb, CRP, PT, and Fb levels were risk factors for death. Multivariate analysis confirmed that CONUT score [HR, 1.276; 95% CI, 1.029-1.584; p = 0.027] was an independent risk factor for mortality. Logistic regression analysis showed that prior arterial disease, smoking, and D-dimer levels were risk factors, although multivariate analysis showed smoking (OR, 3.492; 95% CI, 1.426-8.553; p = 0.006) was an independent risk factor. Kaplan-Meier curves showed that patients in group B had shorter mid-term survival than those in group A (log-rank p < 0.001). Conclusion: Malnutrition was strongly associated with mid-term mortality in patients with infrarenal AAA treated with EVAR.

MALDI-mass spectrometry imaging as a new technique for detecting non-heme iron in peripheral tissues via caudal vein injection of deferoxamine.

As one of the most common iron-chelating agents, deferoxamine (DFO) rapidly chelates iron in the body. Moreover, it does not compete for the iron characteristic of hemoglobin in the blood cells, which is common in the clinical treatment of iron poisoning. Iron is a trace element necessary to maintain organism normal life activities. Iron deficiency can lead to anemia, whereas iron overload can cause elevated levels of cellular oxidative stress and cell damage. As a consequence, detection of the iron content in tissues and blood is of great significance. The traditional techniques for detecting the iron content include inductively coupled plasma-mass spectrometry and atomic absorption spectrometry, which cannot be used for imaging purposes. Laser ablation-ICP-MS and synchrotron radiation micro-X-ray fluorescence can map the concentration and distribution of iron in tissues. However, these methods can only be used to measure the total iron levels in blood or tissues. In recent years, due to the deepening understanding of iron metabolism, diseases related to iron overload have attracted increasing attention. Therefore, we took advantage of the properties of DFO in terms of chelating iron and investigated different sampling times following DFO injection in the tail vein of mice. We used mass spectrometry imaging (MSI) technology to detect the DFO and ferrioxamine content in the blood and different tissues to indirectly characterize the non-heme iron content.

Healthy Tendon Stem Cell-Derived Exosomes Promote Tendon-To-Bone Healing of Aged Chronic Rotator Cuff Tears by Breaking the Positive-Feedback Cross-Talk between Senescent Tendon Stem Cells and Macrophages through the Modulation of Macrophage Polarization.

The re-tear rate of rotator cuff tears (RCT) after surgical repair is high, especially in aged patients with chronic tears. Senescent tendon stem cells (s-TSCs) generally exist in aged and chronically torn rotator cuff tendons and are closely associated with impaired tendon-to-bone healing results. The present study found a positive feedback cross-talk between s-TSCs and macrophages. The conditioned medium (CM) from s-STCs can promote macrophage polarization mainly toward the M1 phenotype, whose CM reciprocally accelerated further s-TSC senescence. Additional healthy tendon stem-cells derived exosomes (h-TSC-Exos) can break this positive feedback cross-talk by skewing macrophage polarization from the M1 phenotype to the M2 phenotype, attenuating s-TSCs senescence. S-TSC senescence acceleration or attenuation effects induced by M1 or M2 macrophages are associated with the inhibition or activation of the bone morphogenetic protein 4 signaling pathway following RNA sequencing analysis. Using an aged-chronic rotator cuff tear rat model, it is found that h-TSC-Exos can shift the microenvironment in the tendon-to-bone interface from a pro-inflammatory to an anti-inflammatory type at the acute postoperative stage and improve the tendon-to-bone healing results, which are associated with the rejuvenated s-TSCs. Therefore, this study proposed a potential strategy to improve the healing of aged chronic RCT.

Evaluating the toxicity of the roots of Asarum heterotropoides var. mandshuricum extracted using the decoction method: Genotoxicity, single-dose toxicity, and 13-week repeated-dose toxicity studies.

ETHNOPHARMACOLOGICAL RELEVANCE: The roots of Asarum heterotropoides F. Maekawa var. mandshuricum F. Maekawa (AR) is a traditional herbal medicine used across Asia, including Korea, China, and Japan. AR exhibits a range of biological activities, such as anti-inflammatory, anti-cancer, cold treatment, and anti-nociceptive effects. Various extraction methods, including decoction, which utilizes traditional knowledge and techniques. The AR decoction extract expected to contain fewer toxicants and have reduced toxicity due to the use of hot water in the extraction process. However, scientific evidence on the toxicity of AR decoction extracts is lacking, necessitating further studies for safe usage. AIM OF THE STUDY: This study aimed to evaluate the genotoxicity and toxicity of single and repeated administration of AR decoction extracts. MATERIALS AND METHODS: The genotoxicity was assessed using a bacterial reverse mutation (Ames test), an in vitro mammalian chromosome aberration test (CA test), and an in vivo micronucleus test (MN test) in Sprague-Dawley (SD) rats. The general toxicity was evaluated through single-dose and 13-week repeated-dose toxicity studies. In the single-dose toxicity study, 40 SD rats were orally administered AR decoction extract at doses of 1000, 2000, and 5000 mg/kg. In the 13-week repeated-dose toxicity study, 140 SD rats received daily oral doses of 0, 250, 500, 1000, 2000, and 5000 mg/kg of AR decoction extract. RESULTS: The genotoxicity tests revealed that AR decoction extract was not genotoxic. The single-dose toxicity study showed no changes in body weight, clinical pathology, or macroscopic findings, with the approximate lethal dose (ALD) exceeding 5000 mg/kg. The 13-week repeated-dose toxicity study demonstrated no treatment-related changes in body weight, general symptoms, hematology, clinical chemistry, or urinalysis. Histopathological findings revealed hyperplasia of squamous cells in the forestomach after AR decoction extract administration, a treatment-related effect that resolved during the recovery period. The no observed adverse effect level (NOAEL) for both male and female rats was estimated to be 2000 mg/kg. CONCLUSIONS: This study establishes the non-toxic dose of AR decoction extract, providing a foundation for further non-clinical and clinical evaluations AR safety.

Prognostic Significance of Programmed Cell Death Ligand 1 Expression in High-Grade Serous Ovarian Carcinoma: A Systematic Review and Meta-Analysis.

(1) Background: High-grade serous ovarian carcinoma (HGSOC) is an aggressive subtype of ovarian cancer. Recent advances have introduced prognostic markers and targeted therapies. Programmed cell death ligand 1 (PD-L1) has emerged as a potential biomarker for HGSOC, with implications for prognosis and targeted therapy eligibility; (2) Methods: A literature search was conducted on major databases, and extracted data were categorized and pooled. Subgroup analysis was performed for studies with high heterogeneity. (3) Results: Data from 18 eligible studies were categorized and pooled based on PD-L1 scoring methods, survival analysis types, and endpoints. The result showed an association between high PD-L1 expression and a favorable prognosis in progression-free survival (HR = 0.53, 95% CI = 0.35-0.78, p = 0.0015). Subgroup analyses showed similar associations in subgroups of neoadjuvant chemotherapy patients (HR = 0.6, 95% CI = 0.4-0.88, p = 0.009) and European studies (HR = 0.59, 95% CI = 0.42-0.82, p = 0.0017). In addition, subgroup analyses using data from studies using FDA-approved PD-L1 antibodies suggested a significant association between favorable prognosis and high PD-L1 expression in a subgroup including high and low stage data in overall survival data (HR = 0.46, 95% CI = 0.3-0.73, p = 0.0009). (4) Conclusions: This meta-analysis revealed a potential association between high PD-L1 expression and favorable prognosis. However, caution is warranted due to several limitations. Validation via large-scale studies, with mRNA analysis, whole tissue sections, and assessments using FDA-approved antibodies is needed.

Preclinical evaluation of general toxicity and safety pharmacology of a receptor-binding domain-based COVID-19 subunit vaccine in various animal models.

The coronavirus disease 2019 pandemic has resulted in the introduction of several naïve methods of vaccine development, which have been used to prepare novel viral vectors and mRNA-based vaccines. However, reluctance to receive vaccines owing to the uncertainty regarding their safety is prevalent. Therefore, rigorous safety evaluation of vaccines through preclinical toxicity studies is critical to determine the safety profiles of vaccine candidates. This study aimed to evaluate the toxicity profile of HuVac-19, a subunit vaccine of SARS-CoV-2 utilizing the receptor-binding domain as an antigen, in rats, rabbits, and dogs using single- and repeat-dose study designs. Repeat-dose toxicity studies in rats and rabbits showed transient changes in hematological and serum biochemical parameters in the adjuvant and/or vaccine groups; however, these changes were reversed or potentially reversible after the recovery period. Moreover, temporary reversible changes in absolute and relative organ weights were observed in the prostate of rats and the thymus of rabbits. Gross examination of the injection sites in rats and rabbits treated with the adjuvant- and HuVac-19 showed discoloration and foci, whereas histopathological examination showed granulomatous inflammation, inflammatory cell infiltration, and myofiber degeneration/necrosis. This inflammatory response was local, unassociated with other toxicological changes, and resolved. In a pharmacological safety study, no toxicological or physiological changes associated with HuVac-19 administration were observed. In conclusion, HuVac-19 was not associated with any major systemic adverse effects in the general toxicity and safety pharmacology evaluation, demonstrating that HuVac-19 is a vaccine candidate with sufficient capacity to be used in human clinical trials.

A malignant proliferating trichilemmal cyst arising on the elbow of a man: A case report and review of the literature.

INTRODUCTION: Trichilemmal cysts (TCs) are common benign cysts that form from the hair follicles in the skin. Proliferating trichilemmal cysts (PTCs) are rare types of TCs characterized by rapid cellular proliferation. Malignant transformation of PTC (MPTC) is a rare adnexal tumor that account for <0.1% of all skin cancers. TCs and PTCs are benign tumors; however, MPTCs grow rapidly and are prone to metastasis. CASE PRESENTATION: A 77-year-old man was referred to our hospital with a solitary pinkish mass on his left elbow. Trichilemmal carcinoma arising from a PTC was confirmed through excisional biopsy, and wide excision was performed. One month postoperatively, a cystic mass was observed and was suspected to have local recurrence; however, bursitis was confirmed after excisional biopsy. After 1 year of follow-up, the patient maintained an improvement without recurrence or any other surgical complications. CONCLUSIONS: In addition to being a very rare disease, MTPC occurred in the elbow of a man who does not fit the general etiology; therefore, it is considered an interesting case, and we report this case for academic contribution.

Preclinical Evaluation of interferon-gamma primed human Wharton's jelly-derived mesenchymal stem cells.

The potential of human mesenchymal stem cells (MSCs) for cell therapy has been investigated in numerous immune-mediated conditions; MSCs are considered one of the most promising cellular therapeutics to treat intractable diseases. Recently, approaches to prime MSCs have been investigated, thereby generating cellular products with enhanced potential for a variety of clinical applications. Interferon-gamma (IFN-γ) priming is a current approach used to increase the therapeutic efficacy of MSCs. In this study, we determined the systemic toxicity, tumorigenicity and biodistribution of IFN-γ-primed Wharton's jelly-derived (WJ)-MSCs in male and female BALB/c-nu/nu mice. There were no deaths or pathologic lesions in the mice treated with 5 × 106 cells/kg IFN-γ-primed MSCs in the repeated dose study. In the tumorigenicity study, one of the subcutaneously treated mice showed bronchioloalveolar adenoma in the lung but tested negative for human-specific anti-mitochondrial antibody, suggesting the spontaneous murine origin of the adenoma. A biodistribution study using real-time quantitative polymerase chain reaction demonstrated the systemic IFN-γ-primed MSC clearance by day 28. Based on the toxicity, biodistribution, and tumorigenicity studies, we concluded that IFN-γ-primed MSCs at 5 × 106 cells/kg do not induce tumor formation and adverse changes.

Elucidating the Multimodal Anticancer Mechanism of an Organometallic Terpyridine Platinum(II) N-Heterocyclic Carbene Complex against Triple-Negative Breast Cancer In Vitro and In Vivo.

Treatment of triple-negative breast cancer (TNBC) has long been a medical challenge because of the lack of effective therapeutic targets. Targeting lipid, carbohydrate, and nucleotide metabolism pathways has recently been proven as a promising option in view of three heterogeneous metabolic-pathway-based TNBC subtypes. Here, we present a multimodal anticancer platinum(II) complex, named Pt(II)caffeine, with a novel mode of action involving simultaneous mitochondrial damage, inhibition of lipid, carbohydrate, and nucleotide metabolic pathways, and promotion of autophagy. All these biological processes eventually result in a strong suppression of TNBC MDA-MB-231 cell proliferation both in vitro and in vivo. The results indicate that Pt(II)caffeine, influencing cellular metabolism at multiple levels, is a metallodrug with increased potential to overcome the metabolic heterogeneity of TNBC.

Implementation of Systematic Bioanalysis of Antibody-Drug Conjugates for Preclinical Pharmacokinetic Study of Ado-Trastuzumab Emtansine (T-DM1) in Rats.

Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies covalently bound to cytotoxic drugs by a linker. They are designed to selectively bind target antigens and present a promising cancer treatment without the debilitating side effects of conventional chemotherapies. Ado-trastuzumab emtansine (T-DM1) is an ADC that received US FDA approval for the treatment of HER2-positive breast cancer. The purpose of this study was to optimize methods for the quantification of T-DM1 in rats. We optimized four analytical methods: (1) an enzyme-linked immunosorbent assay (ELISA) to quantify the total trastuzumab levels in all drug-to-antibody ratios (DARs), including DAR 0; (2) an ELISA to quantify the conjugated trastuzumab levels in all DARs except DAR 0; (3) an LC-MS/MS analysis to quantify the levels of released DM1; and (4) a bridging ELISA to quantify the level of anti-drug antibodies (ADAs) of T-DM1. We analyzed serum and plasma samples from rats injected intravenously with T-DM1 (20 mg/kg, single dose) using these optimized methods. Based on these applied analytical methods, we evaluated the quantification, pharmacokinetics, and immunogenicity of T-DM1. This study establishes the systematic bioanalysis of ADCs with validated assays, including drug stability in matrix and ADA assay, for future investigation on the efficacy and safety of ADC development.

Radiological and Histological Analyses of Nonrigid Versus Rigid Fixation for Free Bone Block Procedures in a Rabbit Model of Glenoid Defects.

BACKGROUND: Nonrigid fixation techniques have been recently introduced in free bone block (FBB) procedures to treat substantial glenoid bone loss in patients with anterior shoulder instability. However, the radiological and histological effectiveness of nonrigid fixation versus conventional rigid fixation have not been comprehensively understood in vivo. PURPOSE: To (1) explore the radiological and histological characteristics of nonrigid fixation for FBB procedures in a rabbit model of glenoid defects and (2) further compare them with those of conventional rigid fixation. STUDY DESIGN: Controlled laboratory study. METHODS: Unilateral shoulder glenoid defects were created in 36 mature New Zealand White rabbits, of which 24 underwent FBB procedures using allogenic iliac crest bone and were randomly divided into rigid fixation (RF) and nonrigid fixation (N-RF) groups, with the remaining divided into 2 control groups: 6 with sham surgery for glenoid defects (GD group) and 6 native glenoids (normal group). In the RF and N-RF groups, 6 rabbits were sacrificed at 6 or 12 weeks postoperatively for radiological and histological analyses of the reconstructed glenoid, and all rabbits in the GD and normal groups were sacrificed at 12 weeks. The radiological glenoid morphology was evaluated via micro-computed tomography. Moreover, the graft-glenoid healing and graft remodeling processes were determined using histological staining. RESULTS: At 6 weeks, both the N-RF and RF groups had similarly improved radiological axial radian and en face area of the glenoid compared with the GD group, but the N-RF group showed superiority in restoration of the glenoid radian and area compared with the RF group at 12 weeks, with the native glenoid as the baseline. Histologically, the bone graft in both groups was substantively integrated into the deficient glenoid neck at 6 and 12 weeks, showing similar osseous healing processes at the graft-glenoid junction. Moreover, the bone graft histologically presented similar regenerated vascular density, total graft bone, and integrated graft bone in both groups. In contrast, the N-RF group had a different remodeling profile on radiological and histological analyses regarding regional bone resorption, mineralization, and fibrous tissue replacement during osseointegration. CONCLUSION: Compared with rigid fixation, nonrigid fixation resulted in superior reconstructed glenoid morphology radiologically and similar graft-glenoid osseous healing histologically, showing different graft remodeling profiles of regional bone resorption, mineralization, and fibrous tissue replacement. CLINICAL RELEVANCE: The nonrigid fixation technique can be feasible for FBB procedures to treat glenoid bone loss in anterior shoulder instability. More clinical evidence is required to determine its pros and cons compared with conventional rigid fixation.

Constructing high-strength nano-micro fibrous woven scaffolds with native-like anisotropic structure and immunoregulatory function for tendon repair and regeneration.

Tendon injuries are common debilitating musculoskeletal diseases with high treatment expenditure in sports medicine. The development of tendon-biomimetic scaffolds may be promising for improving the unsatisfactory clinical outcomes of traditional therapies. In this study, we combined an advanced electrospun nanofiber yarn-generating technique with a traditional textile manufacturing strategy to fabricate innovative nano-micro fibrous woven scaffolds with tendon-like anisotropic structure and high-strength mechanical properties for the treatment of large-size tendon injury. Electrospun nanofiber yarns made from pure poly L-lactic acid (PLLA) or silk fibroin (SF)/PLLA blend were fabricated, and their mechanical properties matched and even exceeded those of commercial PLLA microfiber yarns. The PLLA or SF/PLLA nanofiber yarns were then employed as weft yarns interlaced with commercial PLLA microfiber yarns as warp yarns to generate two new types of nanofibrous scaffolds (nmPLLA and nmSF/PLLA) with a plain-weaving structure. Woven scaffolds made from pure PLLA microfiber yarns (both weft and warp directions) (mmPLLA) were used as controls.In vitroexperiments showed that the nmSF/PLLA woven scaffold with aligned fibrous topography significantly promoted cell adhesion, elongation, proliferation, and phenotypic maintenance of tenocytes compared with mmPLLA and nmPLLA woven scaffolds. Moreover, the nmSF/PLLA woven scaffold exhibited the strongest immunoregulatory functions and effectively modulated macrophages towards the M2 phenotype.In vivoexperiments revealed that the nmSF/PLLA woven scaffold notably facilitated Achilles tendon regeneration with improved structure by macroscopic, histological, and ultrastructural observations six months after surgery, compared with the other two groups. More importantly, the regenerated tissue in the nmSF/PLLA group had excellent biomechanical properties comparable to those of the native tendon. Overall, our study provides an innovative biological-free strategy with ready-to-use features, which presents great potential for clinical translation for damaged tendon repair.

Evaluation of genotoxicity and 13-week subchronic toxicity of root of Asarum heterotropoides var. seoulense (Nakai) Kitag.

ETHNOPHARMACOLOGICAL RELEVANCE: Asarum heterotropoides var. seoulense (Nakai) Kitag is a traditional herbal medicine used in Korea and China. It is effective in aphthous stomatitis, local anesthesia, headache, toothache, gingivitis, and inflammatory diseases. However, information on the toxicity of the root of Asarum heterotropoides var. seoulense (Nakai) Kitag (AR) is limited. Therefore, preclinical toxicity studies on AR are needed to reduce the risk of excessive intake. AIM OF THE STUDY: We aimed to evaluate genotoxicity and the potential toxicity due to repeated administration of AR powder. MATERIALS AND METHODS: In vitro bacterial reverse mutation assay (Ames), in vitro chromosomal aberration assay (CA), and in vivo micronucleus (MN) assay in ICR mice were conducted. As positive results were obtained in Ames and CA assays, alkaline comet assay and pig-a gene mutation test were conducted for confirmation. For evaluating the general toxicity of AR powder, a 13-week subchronic toxicity test was conducted, after determining the dose by performing a single and a 4-week dose range finding (DRF) test. A total of 152 Sprague-Dawley (SD) rats were orally administered AR powder at doses of 0, 150, 350, 500, 1000, and 2000 mg/kg/day in the 13-week subchronic toxicity test. Hematology, clinical chemistry, urinalysis, organ weight, macro-, and microscopic examination were conducted after rat necropsy. RESULTS: AR powder induced genotoxicity evidenced in the Ames test at 187.5, 750, 375, and 1500 µg/plate of TA100, TA98, TA1537, and E. coli WP2uvrA in the presence and absence of S9, respectively; CA test at 790 µg/mL for 6 h in the presence of S-9; 75 µg/mL for 6 h in the absence of S-9, and 70 µg/mL for 22 h in the absence of S-9 in the stomach in the comet assay but not in MN and pig-a assays. In the 13-week subchronic toxicity study, clinical signs including irregular respiration, noisy respiration, salivation, and decreased body weight or food consumption were observed in males and females in the 2000 mg/kg/day group. In hematology tests, clinical chemistry, urinalysis, organ weight, and macroscopic examination, changes were observed in the dose groups of 500 mg/kg/day and above. Microscopic examination revealed hyperplasia of the stomach as a test-related change. Hepatocellular adenoma and changes in liver-related clinical chemistry parameters were observed. The rat No Observed Adverse Effect Level (NOAEL) was 150 mg/kg/day in males and <150 mg/kg/day in females. CONCLUSIONS: AR powder is potentially toxic to the liver and stomach and should be used with caution in humans. A long-term study on carcinogenicity is necessitated because DNA damage or changes in tissue lesions were observed in SD rats.

Left Atrial Appendage Aneurysm: A Case Report.

Left atrial appendage aneurysm (LAAA) is a rare heart anomaly caused by congenital dysplasia of the pectinate muscle or by an acquired pathological condition of the mitral valve or cardiac muscle. It is often incidentally discovered during chest CT or echocardiography as an abnormal dilatation of the LAA. LAAA is associated with life-threatening complications and most patients require surgical treatment. Therefore, it is important to evaluate associated complications as well as precise diagnoses. This report presents the case of a surgically confirmed LAAA in a 53-year-old female. We also discuss the pathophysiology of LAAA and significant findings related to mortality that can be detected on CT and MRI.

Tumorigenicity Assessment of Human Cancer Cell Lines Xenografted on Immunodeficient Mice as Positive Controls of Tumorigenicity Testing.

Recent advances in human pluripotent stem cell (hPSC)-derived cell therapies and genome editing technologies such as CRISPR/Cas9 make regenerative medicines promising for curing diseases previously thought to be incurable. However, the possibility of off-target effects during genome editing and the nature of hPSCs, which can differentiate into any cell type and infinitely proliferate, inevitably raises concerns about tumorigenicity. Tumorigenicity acts as a major obstacle to the application of hPSC-derived and gene therapy products in clinical practice. Thus, regulatory authorities demand mandatory tumorigenicity testing as a key pre-clinical safety step for the products. In the tumorigenicity testing, regulatory guidelines request to include human cancer cell line injected positive control group (PC) animals, which must form tumors. As the validity of the whole test is determined by the tumor-forming rates (typically above 90%) of PC animals, establishing the stable tumorigenic condition of PC animals is critical for successful testing. We conducted several studies to establish the proper positive control conditions, including dose, administration routes, and the selection of cell lines, in compliance with Good Laboratory Practice (GLP) regulations and/or guidelines, which are essential for pre-clinical safety tests of therapeutic materials. We expect that our findings provide insights and practical information to create a successful tumorigenicity test and its guidelines.

Modified Lemaire Lateral Extra-articular Tenodesis With the Iliotibial Band Strip Fixed on the Femoral Cortical Surface Reduces Laxity and Causes Less Overconstraint in the Anterolateral Lesioned Knee: A Biomechanical Study.

PURPOSE: To compare the biomechanical effects of femoral cortical surface fixation and intra-tunnel fixation in modified Lemaire tenodesis on the restoration of native kinematics in anterolateral structure-deficient knees. METHODS: Eight fresh-frozen cadaveric knees were mounted in a knee-customized jig to evaluate anterior translation in anterior load and internal rotation degree in internal rotation torque at 0°, 30°, 60°, and 90°, as well as anterolateral translation (ALT) in a simulated pivot-shift test at 0°, 15°, 30°, and 45°. Kinematic tests were performed in the following states: intact; anterolateral knee lesion (AL-Les); modified Lemaire lateral extra-articular tenodesis (LET) with the femoral iliotibial band (ITB) strip fixed on the cortical surface (cortical fixation), deep to the lateral collateral ligament (LCL) (deep LET-C); and LET with the femoral ITB strip fixed into a tunnel (intra-tunnel fixation), deep to the LCL (deep LET-IT) or superficial to the LCL (superficial LET-IT). The knee kinematic changes in the AL-Les state and the 3 LET states were compared with each other, with the intact state as the baseline. RESULTS: In the AL-Les state, the increased anterior translation instabilities were significantly mitigated by the 3 LETs at 30°, 60°, and 90° (all P < .001), with overconstraint observed in both the deep LET-IT and superficial LET-IT states at 60° (P = .047 and P < .001, respectively) and 90° (both P < .001). Similarly, the 3 LETs significantly reduced the internal rotation instabilities in the AL-Les state at all flexion angles. The superficial LET-IT state overconstrained the knee at 60° (P = .009) and 90° (P < .001) during internal rotation torque, and the deep LET-IT state did so at 60° (P = .012). Furthermore, the ALT instabilities found in the AL-Les state were significantly reduced by the 3 LETs during the simulated pivot-shift test. At 30° and 45°, these LET states resulted in overconstraint when compared with the intact state, but the superficial LET-IT state (P < .001) or deep LET-IT state (P = .016) presented a larger overconstraint than that in the deep LET-C at 45°, respectively. CONCLUSIONS: The 3 Lemaire LET procedures evaluated reduced the anterior, internal rotational, and ALT laxities in AL-Les knees and restored these parameters to the native baseline of the intact state at most flexion angles. However, in deep flexion, some overconstraint occurred in all LETs when compared with the intact state, of which the deep LET-C state resulted in less overconstraint in anterior translation and internal rotation than the deep LET-IT and superficial LET-IT states. CLINICAL RELEVANCE: This biomechanical study supports using the femoral cortical fixation technique to fix the ITB strip in the modified Lemaire LET, which similarly improves knee kinematic stability and causes less overconstraint compared with conventional intra-tunnel fixation. These findings need more verification in clinical scenarios.

Arthroscopic Biceps Tenotomy Using a Single Portal for Working and Viewing: A Rabbit Model and Technique.

Biceps tenotomy (BT) is a common surgery used to address anterior shoulder pain and joint dysfunction in humans. Using animal models to simulate human conditions is an effective and essential research strategy to further understand histologic and biomechanical processes that occur after BT, including the pathology of the detached biceps, secondary tendinopathic conditions of the rotator cuffs, and glenohumeral functional changes. This Technical Note presents a comprehensive step-by-step description of an arthroscopic BT procedure in rabbits. This technique is particularly beneficial, as the mini-invasive arthroscopic technique in a rabbit model is similar to that performed in humans. which resulted in less scarring and injuries to other adjacent structures in comparison with open surgery.

An Arthroscopy-Assisted Mini-Invasive Technique to Create a Chronic Rabbit Model With Massive and Retracted Supraspinatus Rotator Cuff Tears.

Understanding the pathophysiology of rotator cuff tears (RCTs) in animal models is of great importance, as it helps in the development of repair strategies and therapeutic treatments for rotator cuff diseases in humans. This Technical Note describes a comprehensive step-by-step description of an arthroscopic-assisted minimally invasive RCT model in rabbits. This technique is beneficial because the rabbit has rotator cuffs anatomically similar to those of humans, and it has been widely used as a preclinical animal model in the basic science literature. Compared with other small animals (e.g., mice and rats), the advantage of the rabbit model is that it can test the effectiveness and healing process of new surgical repair techniques that require relatively larger anatomical structures. Moreover, it is more cost-effective compared with larger animal models, such as sheep and canines. This arthroscopic-assisted mini-invasive technique to create an RCT model may have a better effect on simulating the degenerative and chronic RCT state in humans than the commonly used open surgery, along with an earlier return to activities, less scarring and tissue adhesion, fewer injuries to the deltoid, and fewer complications.

Loading Mesenchymal Stem Cell-Derived Exosomes Into a Traditionally Designed Rotator Cuff Patch: A Potential Strategy to Enhance the Repair of Chronic Rotator Cuff Tear Associated With Degenerative Changes.

BACKGROUND: Retraction and degenerative changes of chronic rotator cuff tears limit the healing capacity after routine surgical repair. PURPOSE: To fabricate a mesenchymal stem cell-derived exosome (MSC-Exos) loaded patch and evaluate the effect of this patch on the activity of rabbit tenocytes in vitro and on the repair of chronic rotator cuff tears associated with degenerative changes in vivo. STUDY DESIGN: Controlled laboratory study. METHODS: The MSC-Exos loaded patch was fabricated using a dynamic wet-spinning system. In the in vitro studies, the proliferation and migration activities of tenocytes were evaluated by culturing tenocytes with saline, a fiber-aligned patch, or an MSC-Exos loaded patch. In the in vivo studies, a rabbit model of chronic rotator cuff tear was established and directly repaired, repaired with fiber-aligned patch augmentation (RFPA group), and repaired with MSC-Exos loaded patch augmentation (REPA group). Histological and biomechanical analyses were performed at 4, 8, and 12 weeks after surgery. RESULTS: An MSC-Exos loaded patch with inner aligned fibers, a loose microstructure, and reliable initial strength was fabricated using a dynamic wet-spinning system. The MSC-Exos loaded patch significantly promoted tenocyte proliferation and migration activities in vitro. In vivo, the REPA group exhibited significantly higher tendon maturing scores at 8 and 12 weeks after surgery compared with both the control and the RFPA groups. Fatty infiltration was significantly reduced in the REPA group at 4, 8, and 12 weeks compared with both the control and the RFPA groups. Biomechanical properties, including load to failure and stress, were also significantly improved at 12 weeks in the REPA group compared with both the control and the RFPA groups. CONCLUSION: Results in the present study suggested that an MSC-Exos loaded patch was able to enhance the repair of a chronic rotator cuff tear by providing mechanical support and minimizing degeneration. CLINICAL RELEVANCE: This work supported the idea that loading bioactive MSC-Exos into a traditionally designed rotator cuff patch might exert a better effect on the repair of chronic rotator cuff tears than augmented patch repair alone.

The Plug-Type Patch Results in Immediate and Postoperative Advantages in Graft-to-Bone Integration for Bridging Massive Rotator Cuff Tears in a Chronic Rabbit Model.

BACKGROUND: Various patches have been used to bridge massive rotator cuff tears (MRCTs) by reconnecting the cuff tendons to the humeral head, but the outcomes continue to be suboptimal. Notably, the graft-bone junction is a vulnerable site for failure, which requires optimization in patch design and techniques to enhance initial and postoperative fixation strength at the graft-bone interface. HYPOTHESIS: The plug-type patch (Plug-Pat) through intratunnel fixation would optimize mechanical characteristics in initial graft-to-bone fixation and subsequently improve postoperative biomechanical and histological properties in graft-to-bone healing when compared with the routine rectangular patch (Rect-Pat). STUDY DESIGN: Controlled laboratory study. METHODS: A total of 60 mature male New Zealand White rabbits underwent acute rotator cuff defects to create chronic models with MRCTs. The fascia lata autograft was then harvested to prepare a Plug-Pat, which was distally rooted in the bone tunnel and proximally sutured to native tendons in a horizontal mattress fashion to reconnect the humeral head and cuff tendons. The control group was repaired with a routine Rect-Pat that was secured onto the bone surface for graft-bone fixation. After surgery, the cuff-graft-bone complexes of rabbits in both groups were harvested immediately (0 weeks) for time-zero initial fixation strength and refreshed contact area assessment, and at 6 or 12 weeks for postoperative biomechanical and histological evaluation. RESULTS: The Plug-Pat significantly enhanced initial fixation strength in comparison with the Rect-Pat (mean ± SD; failure load, 36.79 ± 4.53 N vs 24.15 ± 2.76 N; P < .001) and decreased failure at the graft-bone interface of the construct at 0 weeks, with a significantly increased refreshed bone bed contact area (52.63 ± 2.97 mm2 vs 18.28 ± 1.60 mm2; P < .001) between the graft and bone. At 6 and 12 weeks postoperatively, the Plug-Pat similarly resulted in greater failure load (43.15 ± 4.53 N vs 33.74 ± 2.58 N at 6 weeks; P = .001; 76.65 ± 5.04 N vs 58.17 ± 5.06 N at 12 weeks; P < .001) and stiffness (10.77 ± 2.67 N/mm vs 8.43 ± 0.86 N/mm at 6 weeks; P = .066; 16.98 ± 2.47 N/mm vs 13.21 ± 1.66 N/mm at 12 weeks; P = .011), with less specimen failure at the graft-bone interface than the Rect-Pat. In histological analyses, the Plug-Pat had a higher postoperative graft-bone integration score than the Rect-Pat, showing a more mature intratunnel healing interface with fibrocartilage tidemark formation, improved collagen properties, and more oriented cells when compared with those at the surface healing interface in the Rect-Pat. CONCLUSION: The Plug-Pat enhanced initial fixation strength and enlarged the refreshed contact area for graft-bone connection at time zero and subsequently improved postoperative biomechanical properties and graft-bone integration at the graft-bone healing interface when compared with the Rect-Pat. CLINICAL RELEVANCE: The Plug-Pat using intratunnel fixation may be a promising strategy for patch design to optimize its initial and postoperative graft-bone connection for bridging reconstruction of MRCTs.