Systems-level computational modeling in ischemic stroke: from cells to patients.

Ischemic stroke, a significant threat to human life and health, refers to a class of conditions where brain tissue damage is induced following decreased cerebral blood flow. The incidence of ischemic stroke has been steadily increasing globally, and its disease mechanisms are highly complex and involve a multitude of biological mechanisms at various scales from genes all the way to the human body system that can affect the stroke onset, progression, treatment, and prognosis. To complement conventional experimental research methods, computational systems biology modeling can integrate and describe the pathogenic mechanisms of ischemic stroke across multiple biological scales and help identify emergent modulatory principles that drive disease progression and recovery. In addition, by running virtual experiments and trials in computers, these models can efficiently predict and evaluate outcomes of different treatment methods and thereby assist clinical decision-making. In this review, we summarize the current research and application of systems-level computational modeling in the field of ischemic stroke from the multiscale mechanism-based, physics-based and omics-based perspectives and discuss how modeling-driven research frameworks can deliver insights for future stroke research and drug development.

Development and performance evaluation of a novel elastic bacterial nanocellulose/polyurethane small caliber artificial blood vessels.

There is an increasing demand for small-diameter blood vessels. Currently, there is no clinically available small-diameter artificial vessel. Bacterial nanocellulose (BNC) has vast potential for applications in artificial blood vessels due to its good biocompatibility. At the same time, medical polyurethane (PU) is a highly elastic polymer material widely used in artificial blood vessels. This study reports a composite small-diameter BNC/PU conduit using a non-solvent-induced phase separation method with the highly hydrophilic BNC tube as the skeleton and the hydrophobic polycarbonate PU as the filling material. The results revealed that the compliance and mechanical matching of BNC/PU tubes were higher than BNC tubes; the axial/radial mechanical strength, burst pressure, and suture strength were significantly improved; the blood compatibility and cell compatibility were also excellent. The molecular and subcutaneous embedding tests showed that the composite tubes had lighter inflammatory reactions. The results of the animal substitution experiments showed that the BNC/PU tubes kept blood flow unobstructed without tissue proliferation after implantation in rats for 9 months. Thus, the BNC/PU small-diameter vascular prosthesis had the potential for long-term patency and acted as an ideal material for small-diameter vessels.

Quantitative systems pharmacology modeling of HER2-positive metastatic breast cancer for translational efficacy evaluation and combination assessment across therapeutic modalities.

HER2-positive (HER2+) metastatic breast cancer (mBC) is highly aggressive and a major threat to human health. Despite the significant improvement in patients' prognosis given the drug development efforts during the past several decades, many clinical questions still remain to be addressed such as efficacy when combining different therapeutic modalities, best treatment sequences, interindividual variability as well as resistance and potential coping strategies. To better answer these questions, we developed a mechanistic quantitative systems pharmacology model of the pathophysiology of HER2+ mBC that was extensively calibrated and validated against multiscale data to quantitatively predict and characterize the signal transduction and preclinical tumor growth kinetics under different therapeutic interventions. Focusing on the second-line treatment for HER2+ mBC, e.g., antibody-drug conjugates (ADC), small molecule inhibitors/TKI and chemotherapy, the model accurately predicted the efficacy of various drug combinations and dosing regimens at the in vitro and in vivo levels. Sensitivity analyses and subsequent heterogeneous phenotype simulations revealed important insights into the design of new drug combinations to effectively overcome various resistance scenarios in HER2+ mBC treatments. In addition, the model predicted a better efficacy of the new TKI plus ADC combination which can potentially reduce drug dosage and toxicity, while it also shed light on the optimal treatment ordering of ADC versus TKI plus capecitabine regimens, and these findings were validated by new in vivo experiments. Our model is the first that mechanistically integrates multiple key drug modalities in HER2+ mBC research and it can serve as a high-throughput computational platform to guide future model-informed drug development and clinical translation.

Study on the Effect of Main Chain Molecular Structure on Adsorption, Dispersion, and Hydration of Polycarboxylate Superplasticizers.

Polycarboxylate ether (PCE) with different main chain structures was prepared by aqueous solution free radical polymerization using unsaturated acids containing sulfonic acid groups, acrylamide groups, and carboxyl groups and isoprenyl polyoxyethylene ether (IPEG). The molecular structure was characterized by infrared spectroscopy and gel chromatography, while adsorption, dispersion, and hydration properties were studied using a total organic carbon analyzer, rheometer, and isothermal microcalorimeter, respectively. The results show that the adsorption process of PCE on cement particles is spontaneous physical adsorption. The adsorption forces are mainly electrostatic interaction, and hydrogen bonding. The introduction of sulfonic acid groups and polycarboxylic acid groups reduces the initial adsorption amount of PCE but can accelerate the adsorption rate of PCE on cement and increase the adsorption amount at the adsorption equilibrium. The introduction of acrylamide groups in the PCE main chain is beneficial to the initial dispersion of PCE and can reduce the plastic viscosity of cement slurry. PCE can delay the hydration of cement. The introduction of acrylamide groups and dicarboxylic acid groups in the PCE main chain helps prolong the induction period of cement hydration, while the introduction of sulfonic acid groups is not conducive to its retarding effect.

Production of novel elastic bacterial nanocellulose/polyvinyl alcohol conduits via mercerization and phase separation for small-caliber vascular grafts application.

Size and properties of tubular bacterial nanocellulose (BNC) can be regulated by controllable mercerization with thinner tube walls, better mechanical properties, and improved biocompatibility. Although mercerized BNC (MBNC) conduits have considerable potential as small-caliber vascular grafts (<6 mm), poor suture retention and lack of compliance that cannot match natural blood vessels increase the difficulty of surgery and limit potential clinical application. Polyvinyl alcohol (PVA) is a kind of hydrophilic polymer with good biocompatibility and elasticity, which can precipitate in alkaline solutions. In this study, novel elastic mercerized BNC/PVA conduits (MBP) are manufactured combining mercerization of BNC tubes with precipitation and phase separation of PVA with thinner tube wall, improved suture retention, better elasticity, good hemocompatibility and great cytocompatibility. The MBP obtained with 12.5 % PVA is selected for transplantation in a rat abdominal aorta model. For 32 weeks, normal blood flow is observed using Doppler sonographic inspection, which demonstrates long-term patency. Immunofluorescence staining results also indicate the formation of endothelium and smooth muscle layers. The results indicate the introduction of PVA, and its phase separation into mercerization of tubular BNC can endow MBP conduits with better compliance and suture retention, making it a promising candidate for blood vessel replacement.

Vascular cells responses to controlled surface structure and properties of bacterial nanocellulose artificial blood vessel after mercerization.

Therapeutic benefits of small caliber artificial blood vessels to cure cardio and cerebrovascular diseases are mainly limited by their low patency during long-term transplantation. Bacterial nanocellulose (BNC), as a natural polysaccharide mainly synthesized by a bacterium Komagataeibatacter xylinus, has shown great potential in small-caliber vascular graft applications due to its shape controllability, and furthermore its physical surface structure can be adjusted with different treatments. However, influences of physical surface structure and properties of BNC conduits on behaviors of vascular cells have not been investigated. In this work, mercerized BNC conduits (MBNC) with different surface roughness and stiffness were constructed by controlled alkali (NaOH) treatment. The changes of surface structures and properties significantly affected the behaviors of vascular cells and gene expression; meanwhile, the cell seeding density also affected the cell responses. After mercerization with NaOH concentration > 10 %, it was observed that the increased stiffness of MBNC decreased several functional gene expressions of human vascular endothelial cells, and the pathological transformation of smooth muscle cells was inhibited. This study demonstrates physical surface structure of MBNC conduits will critically regulate functions and behaviors of vascular cells and it also provides important designing parameters to improve the long-term patency of BNC-based conduits.

Preparation and Evaluation of Bacterial Nanocellulose/Hyaluronic Acid Composite Artificial Cornea for Application of Corneal Transplantation.

The treatment for corneal damage requires donor corneal transplantation, but there is a serious scarcity of donor corneas worldwide. In this study, we aimed to design a new artificial cornea with good cytocompatibility, excellent optical properties and suture resistance, and great moisturizing properties. A new bacterial nanocellulose (BNC) membrane with anisotropic mechanical properties and high light transmission was produced in a horizontal rotary drum reactor. However, as a potential material for artificial keratoplasty, the transparency and mechanical properties of the new BNC membrane were not satisfactory. Thus, hyaluronic acid (HA) was introduced in the BNC to synthesize the BNC/HA composite membrane by using 1,4-butanediol diglycidyl ether (BDDE) as the chemical cross-linking agent. The micro-morphology, light transmittance, mechanical properties, water content, moisture retention ability, and cytocompatibility of the composite membranes were further evaluated. HA was fixed in the BNC network by the ether bond, and the composite membrane was found to have excellent light transmittance (up to 95.96%). The composite membrane showed excellent mechanical properties, for instance, its tensile strength exceeded the human normal intraocular pressure (IOP) (1.33-2.80 kPa), the maximum burst pressure was about 130 kPa, 46-97 times that of the normal IOP, and its suture force was close to that of the human amniotic membrane (0.1 N). Based on the three-dimensional network scaffold of BNC and the high water absorption characteristics of HA, the artificial cornea had high water content and high moisture retention ability. The rabbit corneal stromal cells cultured in vitro showed that the artificial cornea substitute had excellent cytocompatibility. BDDE is the most frequently used cross-linker in most HA products in the current cosmetic medicine industry owing to its long-term safety records for over 15 years. Therefore, the BNC/HA composite hydrogel cross-linked with BDDE has great potential in artificial keratoplasty or ocular surface repair.

A poly-l-lysine-bonded TEMPO-oxidized bacterial nanocellulose-based antibacterial dressing for infected wound treatment.

Oxidized bacterial nanocellulose (O-BNC) is a favorable material to subdue bacterial infection because of the carboxylate content that not only has a weak antibacterial activity but also is capable of bonding electrostatically to polycationic antibacterial agents. In this study, the 2,2,6,6-Tetramethylpiperidinyloxy radical (TEMPO)-mediated oxidation of BNC was optimized to achieve high carboxylate content while retaining an acceptable tensile profile. To develop an O-BNC-based functional wound dressing, ε-poly-l-lysine (PLL) was then covalently bonded with O-BNC via 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS) reaction after homogeneous distribution by ultrasonication. The antibacterial activity of the obtained wound dressing was significantly higher (p < 0.05), and no toxicity was observed. The infected full-thickness wounds of rats were healed faster (p < 0.05) covered by the dressing due to less inflammation, faster blood vessel proliferation, and epidermal layer formation. The material is an effective and promising functional dressing for the treatment of infected wounds.

Adjuvant Radiotherapy After Minimally Invasive Surgery in Patients With Stage IA1-IIA1 Cervical Cancer.

To estimate whether adjuvant radiotherapy is necessary for patients with stage IA1-IIA1 cervical cancer after laparoscopic hysterectomy, 221 patients were retrospectively analyzed. Sixty-two of them were treated with laparoscopic hysterectomy and adjuvant radiotherapy (group A), 115 underwent open surgery (group B) and 44 received laparoscopic hysterectomy alone (group C). Results showed that the 3-year local recurrence-free survival (LRFS) rates of group A, B and C were 98.4%, 97.4% and 86.4%, respectively. The LRFS rates of group A and B surpassed C (A vs. B, p=0.634; A vs. C, p=0.011; B vs. C, p=0.006). The inter-group differences of 3-year overall survival (OS) and distant metastasis free survival (DMFS) were not statistically significant. In subgroup analysis of stage IB disease, the 3-year LRFS rates of group A, B and C were 100%, 98.8% and 83.1%, the 3-year OS rates of group A, B and C were 100%, 98.9% and 91.5%, respectively. The 3-year LRFS and OS rates of group A and B were significantly superior to group C (p<0.05). Our findings suggest that adjuvant radiotherapy can reduce the risk of recurrence for women with early-stage cervical cancer after laparoscopic hysterectomy and bring survival benefits for patients with stage IB disease.

Implantation of air-dried bacterial nanocellulose conduits in a small-caliber vascular prosthesis rabbit model.

There are no small-caliber (<6 mm) vascular prostheses so far commercially available around the globe. Bacterial nanocellulose (BNC) is considered a promising material for small-caliber artificial blood vessel applications. Although BNC hydrogel-like (BNC-Gel) materials possess a 3D network structure, facilitating nutrient exchange when used as vascular prostheses, they are difficult to suture during surgery due to their softness. Furthermore, a water content greater than 99% prevents the material from convenient methods of preservation and transport. Air-drying the BNC (BNC-Dry) would solve these problems. The comparative morphology, mechanical properties, hemocompatibility, and cytocompatibility of the BNC-Gel and BNC-Dry conduits of 3 mm in diameter were recorded in the present study, the results indicating that the mechanical properties, hemocompatibility, and cytocompatibility of BNC-Dry conduits were superior to conduits of BNC-Gel. Forty-six days after replacement of the carotid artery in New Zealand white rabbits, the BNC-Dry conduits remained patent. Composite blood vessels composed of cellulose and autologous tissue were harvested for immunohistochemistry and immunofluorescence staining. Sections demonstrated that the outer walls of the conduits were wrapped with autologous tissue. Contractile smooth muscle cells (SMCs) were observed on the outer surface of the conduit, similar to that observed in natural blood vessels. BNC-Dry conduits exhibited excellent performance and possessed properties convenient for surgical applications as small-diameter blood vessels.

Improved Performance of Bacterial Nanocellulose Conduits by the Introduction of Silk Fibroin Nanoparticles and Heparin for Small-Caliber Vascular Graft Applications.

Bacterial nanocellulose (BNC) is a promising material for small-caliber artificial blood vessels, although promoting its anticoagulant properties with more rapid endothelialization would improve long-term patency. Silk fibroin nanoparticles (SFNP) were introduced into the luminal wall surface of BNC conduits both with and without heparin (Hep) through pressurization followed by fixation. Hep was introduced in two ways: (1) embedded within SF nanoparticles to form SF-HepNPs for construction of the BNC-SF-HepNP conduit and (2) chemically grafted onto BNC and BNC-SFNP to form BNC-Hep and BNC-SFNP-Hep conduits. Fourier transform infrared spectroscopy confirmed the formation of SF-HepNPs, although they did not incorporate into the fibrillar network due to their large size. Hep was successfully grafted onto BNC and BNC-SFNP, verified by toluidine blue staining. The hemocompatibility and cytocompatibility of the five samples (BNC, BNC-SFNP, BNC-SF-HepNP, BNC-Hep, and BNC-SFNP-Hep conduits) were compared in vitro. The heparinized BNC-Hep and BNC-SFNP-Hep conduits improved the anticoagulant properties, and BNC-SFNP-Hep promoted human umbilical vein endothelial cell proliferation but also controlled excessive human arterial smooth muscle cell proliferation, assisting rapid endothelialization and improving lumen patency. No significant inflammatory reaction or material degradation was observed after subcutaneous implantation for 4 weeks. Autogenous tissues were observed around the conduits, and cells infiltrated into the edges of all samples, the BNC-SFNP conduit causing the deepest infiltration, providing an appropriate microenvironment for angiogenesis when used in small-caliber blood vessel applications. Few inflammatory cells were found around the BNC-Hep and BNC-SFNP-Hep conduits. Thus, the anticoagulant properties of the BNC-SFNP-Hep conduit and its stimulation of endothelialization suggest that it has great potential in clinical applications as a small-caliber artificial blood vessel.

Carbon quantum dot-functionalized aerogels for NO2 gas sensing.

Silica aerogels functionalized with strongly fluorescent carbon quantum dots were first prepared and used for simple, sensitive, and selective sensing of NO2 gas. In the presence of ethanol, homemade silica aerogels with a large specific surface area of 801.17 m(2)/g were functionalized with branched polyethylenimine-capped quantum dots (BPEI-CQDs) with fluorescence quantum yield higher than 40%. The prepared porous CQD-aerogel hybrid material could maintain its excellent fluorescence (FL) activity in its solid state. The FL of CQD-aerogel hybrid material could be selectively and sensitively quenched by NO2 gas, suggesting a promising application of the new FL-functionalized aerogels in gas sensing.

Graphene quantum dot as a green and facile sensor for free chlorine in drinking water.

Free chlorine was found to be able to destroy the passivated surface of the graphene quantum dots (GQDs) obtained by pyrolyzing citric acid, resulting in significant quenching of their fluorescence (FL) signal. After optimizing some experimental conditions (including response time, concentration of GQDs, and pH value of solution), a green and facile sensing system has been developed for the detection of free residual chlorine in water based on FL quenching of GQDs. The sensing system exhibits many advantages, such as short response time, excellent selectivity, wide linear response range, and high sensitivity. The linear response range of free chlorine (R(2) = 0.992) was from 0.05 to 10 µM. The detection limit (S/N = 3) was as low as 0.05 µM, which is much lower than that of the most widely used N-N-diethyl-p-phenylenediamine (DPD) colorimetric method. This sensing system was finally used to detect free residual chlorine in local tap water samples. The result agreed well with that by the DPD colorimetric method, suggesting the potential application of this new, green, sensitive, and facile sensing system in drinking water quality monitoring.

Polyamine-functionalized carbon quantum dots as fluorescent probes for selective and sensitive detection of copper ions.

A novel sensing system has been designed for Cu(2+) ion detection based on the quenched fluorescence (FL) signal of branched poly(ethylenimine) (BPEI)-functionalized carbon quantum dots (CQDs). Cu(2+) ions can be captured by the amino groups of the BPEI-CQDs to form an absorbent complex at the surface of CQDs, resulting in a strong quenching of the CQDs' FL via an inner filter effect. Herein, we have demonstrated that this facile methodology can offer a rapid, reliable, and selective detection of Cu(2+) with a detection limit as low as 6 nM and a dynamic range from 10 to 1100 nM. Furthermore, the detection results for Cu(2+) ions in a river water sample obtained by this sensing system agreed well with that by inductively couple plasma mass spectrometry, suggesting the potential application of this sensing system.