Knee osteoarthritis patients assessed during walking for ankle inversion movement discrimination sensitivity.

Background: Knee osteoarthritis (KOA) is a common musculoskeletal condition that affects dynamic balance control and increases the risk of falling during walking. However, the mechanisms underlying this are still unclear. Diminished ankle proprioception during walking has been found to be related to fear of falling in older adults, with a gender difference in incidence of falling. This study aimed to determine 1) whether ankle inversion proprioceptive acuity during walking is impaired in patients with KOA; and 2) whether there is any difference between genders. Methods: Thirty-two patients with KOA (F:M = 17:15, Median age = 52.5, BMI = 22.3 ± 3.0) and 34 healthy controls without KOA (HC) (F:M = 17:17; median age = 49.0, BMI = 22.5 ± 2.7) were recruited. In patients with KOA, ankle inversion proprioceptive acuity was measured on the affected side using the ankle inversion discrimination apparatus for walking (AIDAW), whilst HC were assessed on a randomly selected side. Two-way (2*2) analysis of variance (ANOVA) was performed to determine the main effects and interaction between gender and KOA condition. Results: Two-way ANOVA showed a significant KOA main effect (F = 26.6, p < 0.001, ƞp 2 = 0.3) whereby AIDAW scores during walking for individuals with KOA were significantly lower than those without KOA (KOA vs. HC: 0.746 ± 0.057 vs. 0.807 ± 0.035). There was neither a gender main effect nor interaction (both p > 0.05). Conclusion: Individuals with KOA demonstrated lower ankle proprioception scores during walking compared to their healthy counterparts, with a similar level of impairment in ankle proprioceptive acuity between male and female patients. A low score may contribute to an increased risk of falling in the KOA population. The current findings suggest the need for global concern about lower limb proprioception in the clinical management of KOA.

Association of the Stability Ratio With Postoperative Clinical Function and Recurrence of Instability in Patients With Anterior Shoulder Instability: A Retrospective Cohort Study.

Background: The stability ratio (SR) is used to assess the stability of the glenoid in anterior shoulder instability (ASI). However, the association between the SR and postoperative clinical function and instability recurrence after arthroscopic Bankart repair is unknown. Hypothesis: Patients with a higher SR would have better postoperative clinical scores and a lower incidence of recurrent instability than patients with a lower SR after arthroscopic Bankart repair. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 62 patients who underwent arthroscopic Bankart repair for ASI between 2013 and 2019 were enrolled. All patients had at least 2 years of follow-up data. The preoperative SR was calculated via biomechanical testing based on patient-specific 3-dimensional glenoid models, and patients were evenly divided into 2 groups: high SR (≥16.13%) and low SR (<16.13%). Baseline information (patient characteristics, clinical history, bone defect area [BDA], and SR), clinical scores at the final follow-up (Single Assessment Numerical Evaluation, Western Ontario Shoulder Index, and American Shoulder and Elbow Surgeons), and instability recurrence were compared between the 2 groups. Results: No significant differences were found in the baseline information between the high- and low-SR groups, except for the BDA (8.5% [high-SR group] vs 11.9% [low-SR group]; P = .01). No patients in the high-SR group had recurrent instability, while 6 patients (19.4%) had recurrent instability in the low-SR group (P = .02). Patients in the high-SR group had superior clinical outcomes compared with those in the low-SR group in terms of postoperative Western Ontario Shoulder Index scores (median, 205 vs 410, respectively; P = .006) and American Shoulder and Elbow Surgeons scores (median, 98.3 vs 95, respectively; P = .02). Conclusion: In the present study, the SR was significantly associated with postoperative clinical function and recurrence of instability after arthroscopic Bankart repair in patients with ASI.

The development of a novel navigation system for reverse shoulder arthroplasty and its accuracy: a phantom and cadaveric study.

PURPOSE: Reverse shoulder arthroplasty has demonstrated excellent clinical efficacy for patients with shoulder joint diseases and is increasingly in demand. Traditional surgery faces challenges such as limited exposed surfaces and a narrow field of vision, leading to a shorter prosthesis lifespan and a higher risk of complications. In this study, an optical navigation system was proposed to assist surgeons in real-time tracking of the surgical scene. METHODS: Our optical navigation system was developed using the NDI Polaris Spectra device and several open-source platforms. The first step involved using the preoperative medical image to plan screw implantation paths. Real-time tracking of the patient phantom or cadaver and the surgical instrument was achieved through registration and calibration algorithms. Surgeons were guided on drilling through visualization methods. Postoperative results were compared with the planned implantation paths, and an algorithm was introduced to correct errors caused by the incorrect beginning points. RESULTS: Experiments involved three scapula cadavers and their corresponding phantoms with identical anatomy. For each experiment, three holes were completed with drills with diameters of 3.2 mm and 8.0 mm, respectively. Comparisons between the postoperative actual screw implantation paths and the preoperative planned implantation paths revealed an entry error of 1.05 ± 0.15 mm and an angle error of 2.47 ± 0.55° for phantom experiments. For cadaver experiments, the entry error was 1.53 ± 0.22 mm, and the angle error was 4.91 ± 0.78°. CONCLUSION: Our proposed optical navigation system successfully achieved real-time tracking of the surgical site, encompassing the patient phantom or cadaver and surgical instrument, thereby aiding surgeons in achieving precise surgical outcomes. Future study will explore the integration of robots to further enhance surgical efficiency and effectiveness.

Adipose-derived stem cell-based optimization strategies for musculoskeletal regeneration: recent advances and perspectives.

Musculoskeletal disorders are the leading causes of physical disabilities worldwide. The poor self-repair capacity of musculoskeletal tissues and the absence of effective therapies have driven the development of novel bioengineering-based therapeutic approaches. Adipose-derived stem cell (ADSC)-based therapies are being explored as new regenerative strategies for the repair and regeneration of bone, cartilage, and tendon owing to the accessibility, multipotency, and active paracrine activity of ADSCs. In this review, recent advances in ADSCs and their optimization strategies, including ADSC-derived exosomes (ADSC-Exos), biomaterials, and genetic modifications, are summarized. Furthermore, the preclinical and clinical applications of ADSCs and ADSC-Exos, either alone or in combination with growth factors or biomaterials or in genetically modified forms, for bone, cartilage, and tendon regeneration are reviewed. ADSC-based optimization strategies hold promise for the management of multiple types of musculoskeletal injuries. The timely summary and highlights provided here could offer guidance for further investigations to accelerate the development and clinical application of ADSC-based therapies in musculoskeletal regeneration.

Metformin-loaded PLGA microspheres combined with an in situ-formed injectable SA/BG hydrogel alleviate rotator cuff muscle degeneration.

Rotator cuff tears are a prevalent musculoskeletal problem that affect many individuals and may result in substantial social and health-related expenses. Moreover, the muscular fat infiltration and dystrophy associated with rotator cuff tears have been persistent challenges in rotator cuff surgical repair and postoperative rehabilitation. In this study, an in situ-formed injectable sodium alginate (SA) and bioglass (BG) hydrogel consisting of poly (lactic-co-glycolic acid) (PLGA) microspheres containing metformin (SA/BG-PLGA-Met) was developed for the prevention of muscular fat infiltration and dystrophy. Metformin and silicon ions were slowly released by the combined hydrogel, resulting in long-term biological effects. Moreover, the hydrogel displayed excellent degradability and biocompatibility. Extracts of SA/BG-PLGA-Met inhibited the adipogenesis of 3T3-L1 cells and stimulated the myogenic differentiation of C2C12 cells in vitro. In a mouse model of rotator cuff degeneration, the SA/BG-PLGA-Met hydrogel inhibited fat infiltration and dystrophy of the supraspinatus muscle. Overall, the SA/BG-PLGA-Met hydrogel, as a novel biomaterial, has great clinical potential for preventing rotator cuff muscle fat infiltration and atrophy.

Injectable and Microporous Microgel-Fiber Granular Hydrogel Loaded with Bioglass and siRNA for Promoting Diabetic Wound Healing.

Injectable hydrogels find extensive application in the treatment of diabetic wound healing. However, traditional bulk hydrogels are significantly limited due to their nano-porous structure, which obstructs cell migration and tissue infiltration. Moreover, regulating inflammation and matrix metalloproteinase -9 (MMP-9) expression in diabetic wounds is crucial for enhancing wound healing. This study marks the first instance of introducing an efficient, scalable, and simple method for producing microfiber-gel granules encapsulating bioceramics powders. Utilizing this method, an injectable microporous granular microgel-fiber hydrogel (MFgel) is successfully developed by assembling microgel-fibers made from hyaluronic acid (HA) and sodium alginate (SA) loaded with small interfering RNA (siRNA) and bioglass (BG) particles. Compared to traditional hydrogels (Tgel), MFgel possesses a highly interconnected network with micron-sized pores, demonstrating favorable properties for cell adhesion and penetration in in vitro experiments. Additionally, MFgel exhibits a higher compressive modulus and superior mechanical stability. When implanted subcutaneously in mice, MFgel promotes cellular and tissue infiltration, facilitating cell proliferation. Furthermore, when applied to skin defects in diabetic rats, MFgel not only effectively regulates inflammation and suppresses MMP-9 expression but also enhances angiogenesis and collagen deposition, thereby significantly accelerating diabetic wound healing. Taken together, this hydrogel possesses great potential in diabetic wound healing applications.

Macroporous Granular Hydrogels Functionalized with Aligned Architecture and Small Extracellular Vesicles Stimulate Osteoporotic Tendon-To-Bone Healing.

Osteoporotic tendon-to-bone healing (TBH) after rotator cuff repair (RCR) is a significant orthopedic challenge. Considering the aligned architecture of the tendon, inflammatory microenvironment at the injury site, and the need for endogenous cell/tissue infiltration, there is an imminent need for an ideal scaffold to promote TBH that has aligned architecture, ability to modulate inflammation, and macroporous structure. Herein, a novel macroporous hydrogel comprising sodium alginate/hyaluronic acid/small extracellular vesicles from adipose-derived stem cells (sEVs) (MHA-sEVs) with aligned architecture and immunomodulatory ability is fabricated. When implanted subcutaneously, MHA-sEVs significantly improve cell infiltration and tissue integration through its macroporous structure. When applied to the osteoporotic RCR model, MHA-sEVs promote TBH by improving tendon repair through macroporous aligned architecture while enhancing bone regeneration by modulating inflammation. Notably, the biomechanical strength of MHA-sEVs is approximately two times higher than the control group, indicating great potential in reducing postoperative retear rates. Further cell-hydrogel interaction studies reveal that the alignment of microfiber gels in MHA-sEVs induces tenogenic differentiation of tendon-derived stem cells, while sEVs improve mitochondrial dysfunction in M1 macrophages (Mφ) and inhibit Mφ polarization toward M1 via nuclear factor-kappaB (NF-κb) signaling pathway. Taken together, MHA-sEVs provide a promising strategy for future clinical application in promoting osteoporotic TBH.

Evaluation of the Mass Balance and Metabolic Profile of Futibatinib in Healthy Participants.

Futibatinib, a selective, irreversible fibroblast growth factor receptor 1-4 inhibitor, was recently approved for FGFR2 rearrangement-positive cholangiocarcinoma. This Phase I study evaluated the mass balance and metabolic profile of 14 C-futibatinib single oral 20-mg dose in healthy participants (n = 6). Futibatinib was rapidly absorbed; median time to peak drug concentration was 1.0 hours. The mean elimination half-life in plasma was 2.3 hours for futibatinib, and 11.9 hours for total radioactivity. Mean recovery of total radioactivity was 70% of the dose, with 64% recovered in feces and 6% in urine. The major excretion route was fecal; negligible levels were excreted as parent futibatinib. Futibatinib was the most abundant plasma component, comprising 59% of circulating radioactivity (CRA). The most abundant metabolites were cysteinylglycine-conjugated futibatinib in plasma (13% CRA) and reduction of desmethyl futibatinib in feces (17% of dose). In human hepatocytes, 14 C-futibatinib metabolites included glucuronide and sulfate of desmethyl futibatinib, whose formation was inhibited by 1-aminobenzotriazole (a pan-cytochrome P450 inhibitor), and glutathione- and cysteine-conjugated futibatinib. These data indicate the primary metabolic pathways of futibatinib are O-desmethylation and glutathione conjugation, with cytochrome P450 enzyme-mediated desmethylation as the main oxidation pathway. 14 C-futibatinib was well tolerated in this Phase 1 study.

Three-Dimensional Bioprinting of a Structure-, Composition-, and Mechanics-Graded Biomimetic Scaffold Coated with Specific Decellularized Extracellular Matrix to Improve the Tendon-to-Bone Healing.

Healing of a damaged tendon-to-bone enthesis occurs through the formation of fibrovascular scar tissue with greatly compromised histological and biomechanical properties instead of the regeneration of a new enthesis due to the lack of graded tissue-engineering zones in the interface during the healing process. In the present study, a structure-, composition-, and mechanics-graded biomimetic scaffold (GBS) coated with specific decellularized extracellular matrix (dECM) (GBS-E) aimed to enhance its cellular differentiation inducibilities was fabricated using a three-dimensional (3-D) bioprinting technique. In vitro cellular differentiation studies showed that from the tendon-engineering zone to the bone-engineering zone in the GBS, the tenogenic differentiation inducibility decreased in correspondence with an increase in the osteogenic differentiation inducibility. The chondrogenic differentiation inducibility peaked in the middle, which was in consistent with the graded cellular phenotypes observed in a native tendon-to-bone enthesis, while specific dECM coating from the tendon-engineering zone to the bone-engineering zone (tendon-, cartilage-, and bone-derived dECM, respectively) further enhanced its cellular differentiation inducibilities (GBS-E). In a rabbit rotator cuff tear model, histological analysis showed that the GBS-E group exhibited well-graded tendon-to-bone differentiated properties in the repaired interface that was similar to a native tendon-to-bone enthesis at 16 weeks. Moreover, the biomechanical properties in the GBS-E group were also significantly higher than those in other groups at 16 weeks. Therefore, our findings suggested a promising tissue-engineering strategy for the regeneration of a complex enthesis using a three-dimensional bioprinting technique.

Cryopreserved Adipose-Derived Stem Cell Sheets: An Off-the-Shelf Scaffold for Augmenting Tendon-to-Bone Healing in a Rabbit Model of Chronic Rotator Cuff Tear.

BACKGROUND: Adipose-derived stem cell (ADSC) sheets have been shown to promote tendon-to-bone healing. However, conventional laboratory preparation methods for ADSC sheets are time-consuming and risky, which precludes their diverse clinical applications. PURPOSE: To explore the utility of off-the-shelf cryopreserved ADSC sheets (c-ADSC sheets) for rotator cuff tendon-to-bone healing. STUDY DESIGN: Controlled laboratory study. METHODS: The ADSC sheets were cryopreserved and thawed for live/dead double staining, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, scanning electron microscopy observation, and biomechanical testing. Clone formation, proliferative capacity, and multilineage differentiation of ADSCs within the c-ADSC sheets were assayed to explore the effect of cryopreservation on stem cell properties. A total of 67 rabbits were randomly divided into 4 groups: normal group (without supraspinatus tendon tears; n = 7), control group (repair alone; n = 20), fresh ADSC (f-ADSC) sheet group (repair; n = 20), and c-ADSC sheet group (repair; n = 20). Rabbit bilateral supraspinatus tendon tears were induced to establish a chronic rotator cuff tear model. Gross observation, micro-computed tomography analysis, histological or immunohistochemical tests, and biomechanical tests were conducted at 6 and 12 weeks after repair. RESULTS: No significant impairment was seen in the cell viability, morphology, and mechanical properties of c-ADSC sheets when compared with f-ADSC sheets. The stem cell properties of ADSC sheets also were preserved by cryopreservation. At 6 and 12 weeks after the repair, the f-ADSC and c-ADSC sheet groups showed superior bone regeneration, higher histological scores, larger fibrocartilage areas, more mature collagen, and better biomechanical results compared with the control group. No obvious difference was seen between the f-ADSC and c-ADSC sheet groups in terms of bone regeneration, histological score, fibrocartilage formation, and biomechanical tests. CONCLUSION: c-ADSC sheets, an off-the-shelf scaffold with a high potential for clinical translational application, can effectively promote rotator cuff tendon-to-bone healing. CLINICAL RELEVANCE: Programmed cryopreservation of ADSC sheets is an efficient off-the-shelf scaffold for rotator cuff tendon-to-bone healing.

Evaluation of the Cytochrome P450 3A and P-glycoprotein Drug-Drug Interaction Potential of Futibatinib.

Futibatinib, a selective, irreversible fibroblast growth factor receptor 1-4 inhibitor, is being investigated for tumors harboring FGFR aberrations and was recently approved for the treatment of FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma. In vitro studies identified cytochrome P450 (CYP) 3A as the major CYP isoform in futibatinib metabolism and indicated that futibatinib is likely a P-glycoprotein (P-gp) substrate and inhibitor. Futibatinib also showed time-dependent inhibition of CYP3A in vitro. Phase I studies investigated the drug-drug interactions of futibatinib with itraconazole (a dual P-gp and strong CYP3A inhibitor), rifampin (a dual P-gp and strong CYP3A inducer), or midazolam (a sensitive CYP3A substrate) in healthy adult participants. Compared with futibatinib alone, coadministration of futibatinib with itraconazole increased futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 51% and 41%, respectively, and coadministration of futibatinib with rifampin lowered futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 53% and 64%, respectively. Coadministration of midazolam with futibatinib had no effect on midazolam pharmacokinetics compared with midazolam administered alone. These findings suggest that concomitant use of dual P-gp and strong CYP3A inhibitors/inducers with futibatinib should be avoided, but futibatinib can be concomitantly administered with other drugs metabolized by CYP3A. Drug-drug interaction studies with P-gp-specific substrates and inhibitors are planned.

Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma.

BACKGROUND: Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors. METHODS: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. RESULTS: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment. CONCLUSIONS: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).

Arthroscopic Autologous Iliac Crest Grafting Results in Similar Outcomes and Low Recurrence Compared to Remplissage Plus Bankart Repair for Anterior Shoulder Instability With Bipolar Bone Defects.

PURPOSE: To compare the functional outcomes, range of motion (ROM), recurrence rates, and complication rates of arthroscopic autologous iliac crest grafting (AICG) and Remplissage plus Bankart repair (RB) for anterior shoulder instability with bipolar bone defects. METHODS: This study enrolled patients undergoing arthroscopic AICG or RB with 13.5-25% glenoid bone defect combined with Hill-Sachs lesion between January 2013 and April 2020, who had a minimum 2-year follow-up. Patient-reported outcomes were evaluated by Subjective Shoulder Value (SSV), Oxford Shoulder Instability Score (OSIS), Rowe score, Constant score, and visual analog scale (VAS) for pain. Active ROM, return to sports, recurrence, self-reported apprehension, and complications were recorded. RESULTS: This study included 60 patients, including 28 AICG (Group A) and 32 RB (Group R). Mean glenoid bone defect was similar (17.7% ± 3.1% vs 16.6% ± 2.4%; P = .122). Both groups showed significant postoperative improvement in Rowe score, SSV, OSIS, and Constant score. No significant difference was found in postoperative Rowe Score (87.7 vs 85.2; P = .198). A total of 20/28 (71.4%) patients in Group A versus 26/32 (81.3%) patients in Group R met the Patient Acceptable Symptomatic State determined by VAS pain score (P = .370). Both groups showed high return-to-sports rates (67.8% vs 71.8%; P = .735) and slightly decreased ROM. There were two cases of recurrence in Group A versus one in Group R (P = .594). Group R had insignificantly higher positive self-reported apprehension rate (40.6% vs 17.9%; P = .055). CONCLUSIONS: For anterior shoulder instability with bipolar bone defects, both arthroscopic AICG and RB can result in satisfactory clinical outcomes, good postoperative ROM, and low recurrence and complication rates. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Effect of Futibatinib on Cardiac Repolarization: Results of a Randomized, Controlled, Double-Blind, QT/QTc, Phase 1 Study in Healthy Subjects.

Futibatinib, a fibroblast growth factor receptor (FGFR) 1-4 inhibitor, is being investigated for FGFR-aberrant tumors. A 4-period, crossover, phase 1 thorough QT/QTc study compared effects on Fridericia heart rate-corrected QT (QTcF) interval of single doses of futibatinib 20 and 80 mg (therapeutic and supratherapeutic doses, respectively), placebo, and moxifloxacin (positive control) in healthy subjects. The study objective was to assess the time-matched difference in change from baseline in QTcF (ddQTcF) between futibatinib and placebo. In addition, changes from baseline in QTcF and other electrocardiogram (ECG) parameters, pharmacokinetics, ECG morphology, and safety were assessed. Forty-eight subjects were randomized. ddQTcF upper limits of 2-sided 90%CIs remained <10 milliseconds (clinical threshold) for both futibatinib doses at all time points (range, 2.0-4.5 milliseconds). Assay sensitivity was demonstrated by lower limits of 2-sided 97.5%CIs of the dQTcF difference between moxifloxacin and placebo of >5 milliseconds. Futibatinib exposure increased in a dose-dependent manner, and no significant relationship was detected between plasma futibatinib concentration and ddQTcF. There were no significant effects on heart rate, other ECG parameters, or ECG morphology. No serious adverse events occurred. Futibatinib did not prolong QTcF or affect other cardiac measures at therapeutic or supratherapeutic doses.

Evaluation of Potential Food Effects and Drug Interactions With Lansoprazole in Healthy Adult Volunteers Receiving Futibatinib.

Futibatinib, an oral, irreversible fibroblast growth factor receptor (FGFR) 1-4 inhibitor, is being evaluated for FGFR-aberrant tumors. Two open-label phase 1 studies evaluated the effects of high-fat, high-calorie food and concomitant proton pump inhibitors (PPIs; lansoprazole) on single-dose futibatinib (20 mg) pharmacokinetics and safety in healthy adults. In the food effect study (N  =  17), subjects received futibatinib under fed and fasted conditions, separated by a 7-day washout. In the PPI study (N  =  20), subjects received futibatinib alone, underwent a 2-day washout, and then received lansoprazole 60 mg once daily for 5 days, with futibatinib also administered on day 5. Under fed versus fasted conditions, futibatinib bioavailability was 11.2% lower (area under the plasma concentration-time curve from time 0 to infinity geometric mean ratio 88.8%; 90% confidence interval, 79.8%-98.9%), and median time to maximum plasma concentration was significantly delayed (4.0 vs 1.5 hours; P < .0001). There were no significant differences in futibatinib exposure between futibatinib plus lansoprazole and futibatinib alone. No serious adverse events occurred in either study. These findings suggest that food and PPIs are unlikely to have clinically meaningful impacts on futibatinib bioavailability. Thus, futibatinib may be used with or without food and concomitantly with acid-reducing agents.

Measurement of the Balance Stability Angle to Predict the Stability Ratio in Patients With Recurrent Anterior Shoulder Dislocation: A Novel Computed Tomography-Based Protocol.

Background: The stability ratio (SR) is an important biomechanical parameter for evaluating glenoid stability in patients with recurrent anterior shoulder dislocation (RASD), and it cannot be practically and conveniently measured in clinical scenarios. Purpose: To investigate a novel computed tomography (CT)-based protocol to estimate the SR efficiently. Study Design: Descriptive laboratory study. Methods: A total of 102 patients with RASD were included. Demographic information, CT scans, and bone defect area (BDA) were collected. The new protocol, based on balance stability angle (BSA) measurements on CT, was conducted to estimate the SR (SRCT) by 2 surgeons independently. Biomechanical testing was then performed on patient-specific 3-dimensional (3D)-printed glenoid models to calculate the SR (SR3Dprint), which was used to (1) analyze the reliability of SRCT and (2) examine if the BDA could predict SR3Dprint. To validate whether the 3D-printed glenoid could reflect the actual biomechanical properties of the shoulder, the SR from 5 cadaveric glenoid specimens (SRcadaver) was also calculated and compared with that from the 3D-printed glenoid (SR3Dprint) under 6 osteotomy conditions. Linear regression and intraclass correlation coefficients (ICCs) were used for statistical analysis. Results: The interrater reliability of SRCT measurements was high (ICC = 0.95). SRCT was highly correlated with SR3Dprint (R 2 = 0.86; ICC = 0.92). The mean BDA was 11.44% ± 6.72% by the linear ratio method, with a weak correlation with SR3Dprint (R 2 = 0.31; ICC = -0.46). The cadaveric validation experiment indicated that SRcadaver was highly correlated with SR3Dprint (R 2 = 0.86; ICC = 0.77). Conclusion: Results indicated that (1) the proposed CT-based protocol of obtaining BSA measurements is promising for the SR estimation in patients with RASD, (2) the BDA was not an effective parameter to predict the biomechanical SR, and (3) the 3D-printed glenoid could reflect the biomechanical properties of cadaveric shoulders regarding the SR estimation. Clinical Relevance: Traditional BDA measurements cannot accurately reflect the biomechanical stability of the glenoid. The newly proposed CT-based protocol is practical for surgeons to estimate the SR.

In Situ-Forming Fibrin Gel Encapsulation of MSC-Exosomes for Partial-Thickness Rotator Cuff Tears in a Rabbit Model: Effectiveness Shown in Preventing Tear Progression and Promoting Healing.

BACKGROUND: Current nonoperative treatments for partial-thickness rotator cuff tears (PTRCTs) have limited effectiveness in preventing tear progression or promoting tendon healing. This study aimed to establish a rabbit model using in situ-forming fibrin gel containing adipose stem cell-derived exosomes (ASC-Exos/fibrin) to treat PTRCTs. METHODS: Fifty-six rabbits (112 shoulders) were included in this study and assigned to 4 groups: the control group (32 shoulders; PTRCTs without treatment), the fibrin group (32 shoulders; PTRCTs treated with fibrin gel), the ASC-Exo/fibrin group (32 shoulders; PTRCTs treated with ASC-Exos/fibrin), and the sham group (16 shoulders; sham surgery). Bilateral, 50%-thickness, bursal-side PTRCTs of 1 mm (depth) × 3 mm (width) × 5 mm (length) on the supraspinatus tendon were established by a number-11 scalpel blade, with accuracy of the measurement ensured by a digital vernier caliper. At 6 and 12 weeks postoperatively, gross observation, measurement of the thickness of residual supraspinatus tendons, and histological and biomechanical analyses were performed to analyze tendon repair. RESULTS: At 12 weeks postoperatively, the tendon thickness in the ASC-Exos/fibrin group (mean and standard deviation, 1.63 ± 0.19 mm) was significantly greater than in the control group (0.85 ± 0.09 mm) (p < 0.0001) and fibrin group (1.16 ± 0.17 mm) (p < 0.0001). The histological score in the ASC-Exos/fibrin group (6.25 ± 0.53) was significantly better than in the control group (11.38 ± 0.72) (p < 0.0001) and fibrin group (9.00 ± 0.54) (p < 0.0001). Overall, immunohistochemical staining of types-I and III collagen and biomechanical testing also showed ASC-Exos/fibrin to be more effective in repairing PTRCTs than fibrin alone and no treatment. CONCLUSIONS: Local administration of in situ-forming ASC-Exos/fibrin effectively facilitated the healing of bursal-side PTRCTs in rabbits. This approach may be a candidate for the nonoperative management of PTRCTs. CLINICAL RELEVANCE: Ultrasound-guided injection of ASC-Exos/fibrin may be a novel nonoperative strategy to treat PTRCTs.

Automatic surgical planning based on bone density assessment and path integral in cone space for reverse shoulder arthroplasty.

PURPOSE: Reverse shoulder arthroplasty (RSA) is an effective surgery for severe shoulder joint diseases. Traditionally, the preoperative planning procedure of RSA is manually conducted by experienced surgeons, resulting in prolonged operating time and unreliable drilling paths of the prosthetic fixation screws. In this study, an automatic surgical planning algorithm for RSA was proposed to compute the optimal path of screw implantation. METHODS: Firstly, a cone-shaped space containing alternative paths for each screw is generated using geometric parameters. Then, the volume constraint is applied to automatically remove inappropriate paths outside the bone boundary. Subsequently, the integral of grayscale value of the CT is used to evaluate the bone density and to compute the optimal solution. An automatic surgical planning software for RSA was also developed with the aforementioned algorithms. RESULTS: Twenty-four clinical cases were used for preoperative planning to evaluate the accuracy and efficiency of the system. Results demonstrated that the angles among the prosthetic fixation screws were all within constraint angle(45°), and the stability rate of the planned prosthesis was 94.92%. The average time for the automatic planning algorithm was 4.39 s, and 83.96 s for the whole procedure. Repetitive experiments were also conducted to demonstrate the robustness of our system, and the variance of the stability coefficient was 0.027%. CONCLUSIONS: In contrast to the cumbersome manual planning of the existing methods for RSA, our method requires only simple interaction operations. It enables efficient and precise automatic preoperative planning to simulate the ideal placement of the long prosthetic screws for the long-term stability of the prosthesis. In the future, it will have great clinical application prospects in RSA.

The prevalence and parameters of fabella and its association with medial meniscal tear in China: a retrospective study of 1011 knees.

BACKGROUND: Fabella is a sesamoid bone of knee that has potential biomechanical function. We aimed to examine the fabellar prevalence and parameters in Chinese population and test the hypothesis that fabellar presence and morphology were associated with meniscus tear or ligament injury. METHODS: A total of 1011 knee magnetic resonance imaging scans from 979 patients with knee pain were analyzed retrospectively. The exclusion criteria are postsurgical scans, difficulty in fabella discrimination, conditions not suitable for measurement, and unsatisfied image. The fabellar presence and its parameters (length, width and thickness) were documented. The association between fabellar presence and meniscus tear or ligament injury were assessed by chi-square test, in all knees and subgroups (age, gender, side, lesion part). The correlation of fabellar presence and parameters with advancing age was assessed by Spearman correlation analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to investigate whether factors related with meniscus tear or ligament injury. Diagnostic performance of risk factors was assessed by receiver operating characteristic (ROC) analysis. RESULTS: The overall prevalence of fabellae was 39.8% (402/1011 knees) and increased with the increasing age (r = 0.237, P < 0.001). The size of the fabellae differed according to genders, age, and presence of articulating grooves. Fabella presented more often in knees with medial meniscus (MM) tears (66.7% vs 33.8%; P < 0.001) with a multivariate OR of 2.960 (95% CI, 1.853-3.903). The association remained in all tear parts (anterior, middle, and posterior), and in younger (age < 50 years) and older patients (age ≥ 50 years). Age, fabellar length, width, length/thickness ratio and width/thickness ratio yielded an area under the ROC curve (AUC) of 0.604-0.766 to predict an MM tear. In combination with age, fabellar width and length/thickness ratio, the AUC was improved 0.791 (95% CI, 0.744-0.837), with a sensitivity of 73.0% and a specificity of 74.6%. CONCLUSION: The presence of fabellae, increased fabellar length and width as well as flatter fabellar morphology, are significantly associated with an increased risk for MM tear. These findings might aid clinicians in identifying patients at risk for a MM tear and informing them.

The recombinant human fibroblast growth factor-18 (sprifermin) improves tendon-to-bone healing by promoting chondrogenesis in a rat rotator cuff repair model.

BACKGROUND: Rotator cuff healing is improved by reconstructing the fibrocartilaginous structure of the tendon-to-bone enthesis. Fibroblast growth factor (FGF)-18 (sprifermin) is a well-known growth factor that improves articular cartilage repair via its anabolic effect. This study aimed to investigate the effect of recombinant human FGF-18 (rhFGF-18) on the chondrogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) in vitro and tendon-to-bone healing in a rat model of rotator cuff repair. METHODS: Histological and reverse transcription-quantitative real-time polymerase chain reaction analyses of chondral pellets cultured with different concentrations of rhFGF-18 were performed. Bilateral detachment and repair of the supraspinatus tendon were performed on rats. The rats were administered 0.2 mL of sodium alginate (SA) hydrogel with (rhFGF-18/SA group, n = 12) or without (SA group, n = 12) 20 µg of rhFGF-18 into the repaired side. The simple repair group (n = 12) served as a control. At 4 and 8 weeks after surgery, histological analysis and biomechanical tests were performed. RESULTS: After chondrogenesis induction, compared with the control group, 10 ng/mL of rhFGF-18 increased pellet volume significantly (P = .002), with improved histological staining. It was noted that 10 ng/mL of rhFGF-18 upregulated the mRNA expression (relative ratio to control) of aggrecan (2.59 ± 0.29, P < .001), SRY-box transcription factor 9 (1.88 ± 0.05, P < .001), and type II collagen (1.46 ± 0.18, P = .009). At 4 and 8 weeks after surgery, more fibrocartilage and cartilaginous extracellular matrix was observed in rhFGF-18/SA-treated rats. The semiquantitative data from picrosirius red staining test were 31.1 ± 4.5 vs. 61.2 ± 4.1 at 4 weeks (P < .001) and 61.5 ± 2.8 vs. 80.5 ± 10.5 at 8 weeks (P = .002) (control vs. rhFGF-18/SA). Ultimate failure load (25.42 ± 3.61 N vs. 18.87 ± 2.71 N at 4 weeks and 28.63 ± 5.22 N vs. 22.15 ± 3.11 N at 8 weeks; P = .006 and P = .03, respectively) and stiffness (18.49 ± 1.38 N/mm vs. 14.48 ± 2.01 N/mm at 8 weeks, P = .01) were higher in the rhFGF-18/SA group than in the control group. CONCLUSION: rhFGF-18 promoted chondrogenesis in the hBMSCs in vitro. rhFGF-18/SA improved tendon-to-bone healing in the rats by promoting regeneration of the fibrocartilage enthesis. rhFGF-18 (sprifermin) may be beneficial in improving tendon-to-bone healing after rotator cuff repair.