Nanoarchitectonic Engineering of Thermal-Responsive Magnetic Nanorobot Collectives for Intracranial Aneurysm Therapy.

Stent-assisted coiling is a main treatment modality for intracranial aneurysms (IAs) in clinics, but critical challenges remain to be overcome, such as exogenous implant-induced stenosis and reliance on antiplatelet agents. Herein, an endovascular approach is reported for IA therapy without stent grafting or microcatheter shaping, enabled by active delivery of thrombin (Th) to target aneurysms using innovative phase-change material (PCM)-coated magnetite-thrombin (Fe3O4-Th@PCM) FTP nanorobots. The nanorobots are controlled by an integrated actuation system of dynamic torque-force hybrid magnetic fields. With robust intravascular navigation guided by real-time ultrasound imaging, nanorobotic collectives can effectively accumulate and retain in model aneurysms constructed in vivo, followed by controlled release of the encapsulated Th for rapid occlusion of the aneurysm upon melting the protective PCM (thermally responsive in a tunable manner) through focused magnetic hyperthermia. Complete and stable aneurysm embolization is confirmed by postoperative examination and 2-week postembolization follow-up using digital subtraction angiography (DSA), contrast-enhanced ultrasound (CEUS), and histological analysis. The safety of the embolization therapy is assessed through biocompatibility evaluation and histopathology assays. This strategy, seamlessly integrating secure drug packaging, agile magnetic actuation, and clinical interventional imaging, avoids possible exogenous implant rejection, circumvents cumbersome microcatheter shaping, and offers a promising option for IA therapy.

Synergistic Integration and Pharmacomechanical Function of Enzyme-Magnetite Nanoparticle Swarms for Low-Dose Fast Thrombolysis.

Magnetic micro-/nanoparticles are extensively explored over the past decade as active diagnostic/therapeutic agents for minimally invasive medicine. However, sufficient function integration on these miniaturized bodies toward practical applications remains challenging. This work proposes a synergistic strategy via integrating particle functionalization and bioinspired swarming, demonstrated by recombinant tissue plasminogen activator modified magnetite nanoparticles (rtPA-Fe3 O4 NPs) for fast thrombolysis in vivo with low drug dosage. The synthesized rtPA-Fe3 O4 NPs exhibit superior magnetic performance, high biocompatibility, and thrombolytic enzyme activity. Benefiting from a customized magnetic operation system designed for animal experiments and preclinical development, these agglomeration-free NPs can assemble into micro-/milli-scale swarms capable of robust maneuver and reconfigurable transformation for on-demand tasks in complex biofluids. Specifically, the spinning mode of the swarm exerts focused fluid shear stresses while rubbing on the thrombus surface, constituting a mechanical force for clot breakdown. The synergy of the NPs' inherent enzymatic effect and swarming-triggered fluid forces enables amplified efficacy of thrombolysis in an in vivo occlusion model of rabbit carotid artery, using lower drug concentration than clinical dosage. Furthermore, swarming-enhanced ultrasound signals aid in imaging-guided treatment. Therefore, the pharmacomechanical NP swarms herein represent an injectable thrombolytic tool joining advantages of intravenous drug therapy and robotic intervention.

[Examples of Professor MA Kun's treatment of infertility caused by hyperprolactinemia with kidney deficiency and blood stasis].

Hyperprolactinemia(HPRL) is one of the diseases leading to anovulatory infertility, which is a refractory gynecological disease and seriously affects female reproductive function. Professor MA Kun has summarized his experience in clinical and scientific studies for many years. And believes that kidney deficiency is the pathogenesis of HPRL and blood stasis is the dominant pathological manifestation of HPRL and can promote the progress of the disease. In view of this, Professor MA Kun took the therapy of kidney-tonifying and blood-activating as the principle for treating anovulatory infertility caused by HPRL, with soothing the liver and promoting Qi as adjuvant therapies. She has also summarized and refined the prescriptions for tonifying kidney and inducing ovulation, which have a remarkable clinical efficacy.

An assessment of how the anterior cerebral artery anatomy impacts ACoA aneurysm formation based on CFD analysis.

OBJECTIVE: The aim of this study was to identify independent anatomic, morphologic and hemodynamic features of the ACoA (anterior communicating artery) complex that serve as risk factors for the occurrence of ACoA aneurysms. METHODS: Fifteen consecutive patients with 15 ACoA aneurysms were included. Computational fluid dynamics (CFD) simulations based on patient-specific models were carried out using 3D time-of-flight magnetic resonance angiography (3D-TOF-MRA) images. A reverse reconstruction technique was used to generate a pre-aneurysm vessel anatomy. Geometric parameters and hemodynamic changes were compared and evaluated. RESULTS: The overall prevalence of symmetric, dysplastic, and absent A1 segments were 53.3%, 26.7%, and 20%. The mean wall shear stress (WSS) of the absent group (AG) was significantly higher than that of the symmetric group (SG) and dysplastic group (DG). The absolute mean A1 artery flow rate (410.2 ± 88 versus 439.4 ± 101 mL/min; p = .45) of the aneurysm side was similar between the SG and DG but significantly higher in the AG (528.1 ± 77 mL/min; p < .05). The A1-A2 angles of the aneurysm side showed no significant differences among the 3 groups (p = .32). However, the mean A1-A2 angle on the aneurysm side was smaller than the contralateral A1-A2 angle (101.9 ± 9.1˚ versus 120.3 ± 7.7˚; p <.05). A regression analysis demonstrated that high WSS was significantly associated with a large A1-A2 ratio (R2=0.52; p <.05). CONCLUSIONS: ACoA aneurysms are a high-WSS pathology. Severe flow impingement and the anatomic vasculature structures play a role in triggering the occurrence of ACoA aneurysms.

Mitochondrial outer membrane protein Samm50 protects against hypoxia-induced cardiac injury by interacting with Shmt2.

Cardiac remodeling is a critical process following myocardial infarction (MI), potentially leading to heart failure if untreated. The significance of mitochondrial homeostasis in MI remains insufficiently understood. Samm50 is an essential component of mitochondria. Our study aimed to investigate its role in hypoxia-induced cardiac injury and the underlying mechanisms. First, we observed that Samm50 was dynamically downregulated in mice with MI compared to the control mice. In vitro, Samm50 was also downregulated in oxygen-glucose-deprived neonatal rat cardiomyocytes and fibroblasts. Overexpression and knockdown of Samm50 mitigated and exacerbated cardiac apoptosis and fibrosis, while also improving and worsening mitochondrial homeostasis, respectively. Protein interactions with Samm50 during the protective process were identified via immune-coprecipitation/mass spectroscopy. Mechanistically, serine hydroxymethyltransferase 2 (Shmt2) interacted with Samm50, acting as a crucial element in the protective process by hindering the transfer of Bax from the cytoplasm to the mitochondria and subsequent activation of caspase-3. Inhibition of Shmt2 diminished the protective effect of Samm50 overexpression against cardiac injury. Finally, Samm50 overexpression in vivo mitigated cardiac remodeling and enhanced cardiac function in both acute and chronic MI. In conclusion, Samm50 overexpression mitigated hypoxia-induced cardiac remodeling by inhibiting apoptosis and fibrosis, with Shmt2 acting as a key regulator in this protective process. The Samm50/Shmt2 axis represents a newly discovered mitochondria-related pathway for mitigating hypoxia-induced cardiac injury.

Prediction of cerebral aneurysm rupture using a point cloud neural network.

OBJECTIVE: Accurate prediction of cerebral aneurysm (CA) rupture is of great significance. We intended to evaluate the accuracy of the point cloud neural network (PC-NN) in predicting CA rupture using MR angiography (MRA) and CT angiography (CTA) data. METHODS: 418 CAs in 411 consecutive patients confirmed by CTA (n=180) or MRA (n=238) in a single hospital were retrospectively analyzed. A PC-NN aneurysm model with/without parent artery involvement was used for CA rupture prediction and compared with ridge regression, support vector machine (SVM) and neural network (NN) models based on radiomics features. Furthermore, the performance of the trained PC-NN and radiomics-based models was prospectively evaluated in 258 CAs of 254 patients from five external centers. RESULTS: In the internal test data, the area under the curve (AUC) of the PC-NN model trained with parent artery (AUC=0.913) was significantly higher than that of the PC-NN model trained without parent artery (AUC=0.851; p=0.041) and of the ridge regression (AUC=0.803; p=0.019), SVM (AUC=0.788; p=0.013) and NN (AUC=0.805; p=0.023) radiomics-based models. Additionally, the PC-NN model trained with MRA source data achieved a higher prediction accuracy (AUC=0.936) than that trained with CTA source data (AUC=0.824; p=0.043). In external data of prospective cohort patients, the AUC of PC-NN was 0.835, significantly higher than ridge regression (0.692; p<0.001), SVM (0.701; p<0.001) and NN (0.681; p<0.001) models. CONCLUSION: PC-NNs can achieve more accurate CA rupture prediction than traditional radiomics-based models. Furthermore, the performance of the PC-NN model trained with MRA data was superior to that trained with CTA data.

Transferrin-targeted iridium nanoagglomerates with multi-enzyme activities for cerebral ischemia-reperfusion injury therapy.

Cerebral ischemia-reperfusion injury (CIRI) is a complex pathological condition with high mortality. In particular, reperfusion can stimulate overproduction of reactive oxygen species (ROS) and activation of inflammation, causing severe secondary injuries to the brain. Despite tremendous efforts, it remains urgent to rationally design antioxidative agents with straightforward and efficient ROS scavenging capability. Herein, a potent antioxidative agent was explored based on iridium oxide nano-agglomerates (Tf-IrO2 NAs) via the facile transferrin (Tf)-templated biomineralization approach, and innovatively applied to treat CIRI. Containing some small-size IrO2 aggregates, these NAs possess intrinsic hydroxyl radicals (•OH)-scavenging ability and multifarious enzyme activities, such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Moreover, they also showed improved blood-brain barrier (BBB) penetration and enhanced accumulation in the ischemic brain via Tf receptor-mediated transcytosis. Therefore, Tf-IrO2 NAs achieved robust in vitro anti-inflammatory and cytoprotection effects against oxidative stress. Importantly, mice were effectively protected against CIRI by enhanced ROS scavenging activity in vivo, and the therapeutic mechanism was systematically verified. These findings broaden the idea of expanding Ir-based NAs as potent antioxidative agents to treat CIRI and other ROS-mediated diseases. STATEMENT OF SIGNIFICANCE: (1) The ROS-scavenging activities of IrO2 are demonstrated comprehensively, which enriched the family of nano-antioxidants. (2) The engineering Tf-IrO2 nano-agglomerates present unique multifarious enzyme activities and simultaneous transferrin targeting and BBB crossing ability for cerebral ischemia-reperfusion injury therapy. (3) This work may open an avenue to enable the use of IrO2 to alleviate ROS-mediated inflammatory and brain injury diseases.

Efficacy of Diffusion-Weighted Imaging in Neoadjuvant Chemotherapy for Osteosarcoma: A Systematic Review and Meta-Analysis.

RATIONALE AND OBJECTIVES: Diffusion-weighted imaging (DWI) is a noninvasive imaging technique that reflects the diffusion movement of water molecules through apparent diffusion coefficient (ADC) values. The role of DWI in predicting the histological response to neoadjuvant chemotherapy in osteosarcoma is being increasingly researched, and a systematic review and meta-analysis of this topic is urgently required to help determine the potential diagnostic value of DWI. MATERIALS AND METHODS: The present meta-analysis included 13 studies (303 patients). We divided the target population into good responders and poor responders based on tumor necrosis on histological biopsy (≥90%, good responders). The mean ADC values and ADC ratio were extracted and/or calculated for the two groups. RESULTS: The mean difference in ADC values before and after neoadjuvant chemotherapy was significantly higher in good responders than in poor responders (mean difference, 0.33; 95% confidence interval [CI], 0.18-0.49; p< 0.0001), and significant heterogeneity was present among the 10 studies that reported these values (I2 = 66%, p< 0.05). The ADC ratio was also significantly higher in good responders than in poor responders (mean difference, 28.34; 95% CI, 1.83-54.85; p = 0.04), and significant heterogeneity in ADC ratio was present among 7 studies (I2 = 97%, p< 0.05). CONCLUSION: The mean differences in ADC values and ADC ratios before and after neoadjuvant chemotherapy for osteosarcoma were significantly higher in good responders than in poor responders.

Diagnostic Performance of MRA for UnrupturedAneurysms at the Distal ICA.

PURPOSE: Unruptured intracranial aneurysms (UIAs) at the distal internal carotid artery (ICA) (segments C5-C7) are difficult to accurately display on computed tomography angiography (CTA) due to the influences of bone structures and vessel curvature. We investigated the utility of three-dimensional time-of-flight magnetic resonance angiography (3D-TOF-MRA) at 3.0­T for the detection of morphologic features compared to digital subtraction angiography (DSA). METHODS: This retrospective study included 2398 patients between January 2015 and May 2020 who underwent 3D-TOF-MRA and DSA within 3 months. Morphologic features including aneurysm size, neck width, shape and relation to adjacent arteries and other diagnostic parameters were recorded. Three observers blinded to the clinical and DSA results independently analyzed MRA data sets. The statistical difference of each aneurysm-specific variable was performed using χ2-tests and multivariate logistic regression analysis. RESULTS: A total of 551 aneurysms in 514 patients were confirmed at the distal ICA by DSA. Patient-based, aneurysm-based and location-based evaluations with 3D-TOF-MRA yielded high diagnostic accuracy in the detection of target UIAs. The accuracy of displayed morphologic features was 94.9% for size, 97.2% for neck width, 92.6% for shape, and 96.4% for relationship to adjacent vessels. Multivariate logistic regression showed that tiny (P < 0.001) or giant (P = 0.039) size and a lobulated shape (P = 0.006) significantly affected the morphologic assessment on 3D-TOF-MRA. CONCLUSION: Three-dimensional TOF-MRA can accurately depict and display morphologic features of distal ICA UIAs. Tiny or giant-sized distal ICA aneurysms and with lobulation tend to carry a great risk of misdiagnosis in morphologic assessments.

Roles of inflammation in the natural history of intracranial saccular aneurysms.

Aneurysmal subarachnoid hemorrhage is caused by intracranial aneurysm (IA) rupture and results in high rates of mortality and morbidity. Factors contributing to IA generation, growth and rupture can involve genetics, injury, hemodynamics, environmental factors, and inflammation, in which inflammatory factors are believed to play central roles in the whole natural history. Inflammatory reactions that contribute to IA development may involve synthesis of many functional proteins and expression of genes induced by changes of blood flow, external stimuli such as smoking, internal balance such as hormonal status changes, and blood pressure. Meanwhile, inflammatory reactions itself can evoke inflammatory cytokines release and aggregation such as MMPs, MCP-1, TNF-α and ZO-1, directly or indirectly promoting aneurysm growth and rupture. However, the details of these inflammatory reactions and their action on inflammatory chemokines are still unknown. Moreover, some agents with the function of anti-inflammation, lipid-lowering, antihypertension or inflammatory factor inhibition may have the potential benefit to reduce the risk of aneurysm development or rupture in a group of population despite the underlying mechanism remains unclear. Consequently, we reviewed the potential inflammatory responses and their mechanisms contributing to aneurysm development and rupture and sought intervention targets that may prevent IA rupture or generation.

Guiding Drug Through Interrupted Bloodstream for Potentiated Thrombolysis by C-Shaped Magnetic Actuation System In Vivo.

Fast and effective thrombolysis using tissue plasminogen activator (tPA) is limited by the poor delivery efficiency of thrombolytic drugs, which is induced by an interrupted bloodstream and delayed recanalization. Existing magnetic micro/nanodrug-loaded robots used for targeted thrombotic therapy are limited by the complexity of the clinical verification of nanodrugs and the limited space of magnetic actuation systems. Herein, a general drug delivery strategy based on mass transportation theory for thrombolysis is presented, and an open space C-shaped magnetic actuation system with laser location and ultrasound imaging navigation for in vivo evaluation is developed. tPA can be guided through an interrupted bloodstream to the thrombi by the locomotion of magnetic nanoparticle swarms (MNSs), thereby improving the thrombolysis efficacy. Notably, this strategy is able to quickly establish a life channel to achieve time-critical recanalization, which is typically inaccessible using native tPA. Both in vitro and in vivo thrombolysis experiments demonstrate that the thrombus lysis efficacy significantly increases after the application of the MNS under a rotating magnetic field. This study provides an anticipated C-shaped magnetic actuation system for in vivo validation and also presents a clinically feasible drug delivery strategy for targeted thrombolytic therapy with minimal systemic tPA exposure.

The contribution of wall shear stress insult to the growth of small unruptured cerebral aneurysms in longitudinal 3D-TOF-MRA.

OBJECTIVE: Aneurysm growth is a risk factor for rupture, however the detailed mechanism remains unclear. The present study was performed to identify whether hemodynamic insult could prompt small unruptured aneurysms to grow. METHODS: Six pairs of unruptured small (<5 mm) cerebral aneurysms from patients followed with longitudinally three-dimensional MR imaging were selected and divided into an angiographic confirmed enlarged group (with >50% volume increase; n = 6) and an angiographic stable group (with ±10% volume changes; n = 6). Patient-specific computational fluid dynamic models were created and run under pulsatile flow conditions. Reverse reconstruction technique was used to simulate the status of before aneurysm generation. Relevant hemodynamic variables were calculated and compared between the two groups. RESULTS: In the enlarged group, wall shear stress (WSS) decreased from aneurysm neck to dome, whereas WSS at the aneurysm neck (58.68 ± 34.45 Pa) and body (52.68 ± 46.37 Pa) was significantly higher than the stable group (neck: 36.83 ± 18.20 Pa and body: 30.77 ± 18.85 Pa) (P < .05). WSS decreased at the neck, body, and dome and flow patent became stable after aneurysm growth (P < .05). Reverse reconstruction revealed an elevated WSS at the site of aneurysm formation compared with other sites in the parent artery, and WSS at the formation site significantly decreased after aneurysm growth and further enlargement (P < .05). CONCLUSION: Local elevated WSS to the arterial wall contributed to cerebral aneurysm generation, whereas turbulent flow patterns and elevated WSS at the aneurysm neck and body worked together to result in further growth of small aneurysms.

An electrospun fiber-covered stent with programmable dual drug release for endothelialization acceleration and lumen stenosis prevention.

Aneurysmal subarachnoid hemorrhage (SAH) causes high rates of mortality and morbidity. A covered stent is an effective endovascular treatment for complicated aneurysms intractable to endovascular coiling and surgical clipping. However, in-stent restenosis and delayed endothelialization are the main challenges contributing to its safety. In this study, we designed a biofunctional stent covered with dual drug-loaded electrospun fibers to achieve programmed vascular endothelial growth factor (VEGF) and paclitaxel (PTX) release for the early promotion of stent endothelialization and long-term inhibition of stenosis caused by smooth muscle hyperplasia. By encapsulating PTX-loaded mesoporous silica nanoparticles (MSNs) within electrospun polylactic acid (PLA) fibers, the release period of PTX was effectively extended. Furthermore, VEGF was conjugated onto the surface of the membrane by reacting with polydopamine (PDA) for quick release. The in vitro drug release profile revealed the sustained release of PTX, which persisted for 63 days without early burst release, while up to 87.05% of VEGF was rapidly released within 3 days. After 6 days of incubation, cell experiments demonstrated that the dual drug-loaded scaffold effectively prompted endothelial cell proliferation (488% vs. 386% in the control group, P = 0.001) and inhibited the proliferation of smooth muscle cells (SMCs) using the 21-day extracts (155% vs. 303% in the control group, P = 0.039). Animal studies showed that compared to bare stents, the drug-loaded covered stents improved the immediate- and mid-term complete aneurysm occlusion rates (P < 0.05). The drug-loaded covered stents also showed earlier endothelialization promotion and better lumen restenosis than normal covered stents (0% vs. 25%, P = 0.29) for 12 weeks. Overall, a programmed dual drug-loaded scaffold that effectively occluded the aneurysm sac was developed in this study, and the discrete release of VEGF and PTX promoted endothelialization and prevented in-stent stenosis. This study provided a new method to improve the biosafety of implanted covered stents for the treatment of intracranial aneurysms. STATEMENT OF SIGNIFICANCE: Aneurysmal subarachnoid hemorrhage (SAH) is one of the most common hemorrhage stroke resulted in a nearly 40% mortality and 33% morbidity due to sudden rupture of an intracranial aneurysm. Endovascular coil embolism is a popular treatment for aneurysm but this technique run high risk of bleeding, mass effect, low complete occlusion rate and higher recanalization rate due to its operation conducted within aneurysm sac. A bio-functional membrane knitted by dual-drug loaded electrospun fibers covered on a stent was designed to realize programed vascular endothelial growth factor and paclitaxel release for the early promotion of vascular endothelium and long-term inhibition of stenosis caused by smooth muscle hyperplasia. This study provides new method to improve the biosafety of covered stent insertion for the treatment of intracranial aneurysms.