Enhanced osteogenic and ROS-scavenging MXene nanosheets incorporated gelatin-based nanocomposite hydrogels for critical-sized calvarial defect repair.

The healing of critical-sized bone defects is a major challenge in the field of bone tissue engineering. Gelatin-related hydrogels have emerged as a potential solution due to their desirable properties. However, their limited osteogenic, mechanical, and reactive oxygen species (ROS)-scavenging capabilities have hindered their clinical application. To overcome this issue, we developed a biofunctional gelatin-Mxene nanocomposite hydrogel. Firstly, we prepared two-dimensional (2D) Ti3C2 MXene nanosheets using a layer delamination method. Secondly, these nanosheets were incorporated into a transglutaminase (TG) enzyme-containing gallic acid-imbedded gelatin (GGA) pre-gel solution to create an injectable GGA-MXene (GM) nanocomposite hydrogel. The GM hydrogels exhibited superior compressive strength (44-75.6 kPa) and modulus (24-44.5 kPa) compared to the GGA hydrogels. Additionally, the GM hydrogel demonstrated the ability to scavenge reactive oxygen species (OH- and DPPH radicals), protecting MC3T3-E1 cells from oxidative stress. GM hydrogels were non-toxic to MC3T3-E1 cells, increased alkaline phosphatase secretion, calcium nodule formation, and upregulated osteogenic gene expressions (ALP, OCN, and RUNX2). The GM400 hydrogel was implanted in critical-sized calvarial defects in rats. Remarkably, it exhibited significant potential for promoting new bone formation. These findings indicated that GM hydrogel could be a viable candidate for future clinical applications in the treatment of critical-sized bone defects.

Shape-recovery of implanted shape-memory devices remotely triggered via image-guided ultrasound heating.

Shape-memory materials hold great potential to impart medical devices with functionalities useful during implantation, locomotion, drug delivery, and removal. However, their clinical translation is limited by a lack of non-invasive and precise methods to trigger and control the shape recovery, especially for devices implanted in deep tissues. In this study, the application of image-guided high-intensity focused ultrasound (HIFU) heating is tested. Magnetic resonance-guided HIFU triggered shape-recovery of a device made of polyurethane urea while monitoring its temperature by magnetic resonance thermometry. Deformation of the polyurethane urea in a live canine bladder (5 cm deep) is achieved with 8 seconds of ultrasound-guided HIFU with millimeter resolution energy focus. Tissue sections show no hyperthermic tissue injury. A conceptual application in ureteral stent shape-recovery reduces removal resistance. In conclusion, image-guided HIFU demonstrates deep energy penetration, safety and speed.

Epoxy silane sulfobetaine block copolymers for simple, aqueous thromboresistant coating on ambulatory assist lung devices.

Developing an ambulatory assist lung (AAL) for patients who need continuous extracorporeal membrane oxygenation has been associated with several design objectives, including the design of compact components, optimization of gas transfer efficiency, and reduced thrombogenicity. In an effort to address thrombogenicity concerns with currently utilized component biomaterials, a low molecular weight water soluble siloxane-functionalized zwitterionic sulfobetaine (SB-Si) block copolymer was coated on a full-scale AAL device set via a one pot aqueous circulation coating. All device parts including hollow fiber bundle, housing, tubing and cannular were successfully coated with increasing atomic compositions of the SB block copolymer and the coated surfaces showed a significant reduction of platelet deposition while gas exchange performance was sustained. However, water solubility of the SB-Si was unstable, and the coating method, including oxygen plasma pretreatment on the surfaces were considered inconsistent with the objective of developing a simple aqueous coating. Addressing these weaknesses, SB block copolymers were synthesized bearing epoxy or epoxy-silane groups with improved water solubility (SB-EP & SB-EP-Si) and no requirement for surface pretreatment (SB-EP-Si). An SB-EP-Si triblock copolymer showed the most robust coating capacity and stability without prior pretreatment to represent a simple aqueous circulation coating on an assembled full-scale AAL device.

A Perfluorocarbon-Coated ZrP Cation Exchanger with Excellent Ammonium Selectivity and Chemical Stability: An Oral Sorbent for End-Stage Kidney Disease (ESKD).

An oral sorbent to remove NH4+ within the small intestine of end-stage kidney disease (ESKD) patients could reduce blood urea levels and diminish their dialysis treatment burden. But current sorbent materials like amorphous zirconium phosphate particles Zr(HPO4)2·H2O (ZrP) lack the selectivity to remove NH4+ in water solution with other competing ions. Our previous work found that a gas-permeable, hydrophobic polydimethylsiloxane (PDMS) coating on ZrP improved the material's selectivity for NH4+. However, a competing ion Ca2+ was still removed by PDMS-coated ZrP sorbent, and the permeability of the PDMS coating to Ca2+ was increased after low-pH stomach-like condition exposure. An alternative hydrophobic and gas permeable coating has been investigated─perfluorooctyltriethoxysilane (FOTS). The coating was attached in place of PDMS to a tetraethyl orthosilicate-coated ZrP surface. Surface atomic composition analysis and scanning electron microscopy observation verified the successful application of the FOTS coating. Water contact angle analysis validated the FOTS coating was hydrophobic (145.0 ± 3.2°). In vitro competing ion studies indicated the FOTS coating attached to ZrP increased NH4+ removal by 53% versus uncoated ZrP. FOTS offers complete selectivity for NH4+ over Ca2+ with similar NH4+ capacity as the previous PDMS coating. Moreover, FOTS-coated ZrP maintained NH4+ removal capacity and selectivity after the acid exposure study, indicating excellent acid resistance while NH4+ selectivity of ZrP-PDMS decreased by 72%. The results suggested that FOTS-coated ZrP is promising as an oral sorbent for ESKD patients.

In vitro and in vivo assessment of a novel ultra-flexible ventriculoamniotic shunt for treating fetal hydrocephalus.

Fetal aqueductal stenosis (AS) is one of the most common causes of congenital hydrocephalus, which increases intracranial pressure due to partial or complete obstruction of cerebrospinal fluid (CSF) flow within the ventricular system. Approximately 2-4 infants per 10,000 births develop AS, which leads to progressive hydrocephalus, which enlarges the head often necessitating delivery by cesarean section. Most babies born with AS are severely neurologically impaired and experience a lifetime of disability. Therefore, a new device technology for venticuloamniotic shunting is urgently needed and has been studied to ameliorate or prevent fetal hydrocephalus development, which can provide a significant impact on patients and their family's quality of life and on the decrease of the healthcare dollars spent for the treatment. This study has successfully validated the design of shunt devices and demonstrated the mechanical performance and valve functions. A functional prototype shunt has been fabricated and subsequently used in multiple in vitro tests to demonstrate the performance of this newly developed ventriculoamniotic shunt. The shunt contains a main silicone-nitinol composite tube, a superelastic 90° angled dual dumbbell anchor, and an ePTFE valve encased by a stainless-steel cage. The anchor will change its diameter from 1.15 mm (collapsed state) to 2.75 mm (deployed state) showing up to 1.4-fold diameter change in human body temperature. Flow rates in shunts were quantified to demonstrate the valve function in low flow rates mimicking the fetal hydrocephalus condition showing "no backflow" for the valved shunt while there is up to 15 mL/h flow through the shunt with pressure difference of 20 Pa. In vivo ovine study results show the initial successful device delivery and flow drainage with sheep model.

Developing a Selective Zirconium Phosphate Cation Exchanger to Adsorb Ammonium: Effect of a Gas-Permeable and Hydrophobic Coating.

A sorbent with a high enough capacity for NH4+ could serve as an oral binder to lower urea levels in end-stage kidney disease (ESKD) patients. A hydrogen-loaded cation exchanger such as zirconium phosphate Zr(HPO4)2·H2O (ZrP) is a promising candidate for this application. However, the NH4+ binding selectivity versus other ions must be improved. Here, we have developed a gas-permeable and hydrophobic surface coating on an amorphous form of ZrP using tetraethyl orthosilicate and methoxy-terminated polydimethylsiloxane. The hydrophobic coating serves as a barrier to ions in water solution from reaching the ion-exchanger's surface. Meanwhile, its gas-permeable nature allows for gaseous ammonia transfer to the cation exchanger. In vitro studies were designed to replicate the small intestine's expected ion concentrations and exposure time to the sorbent. The effectiveness of the coating was measured with NH4+ and Ca2+ solutions and uncoated ZrP as the negative control. X-ray photoelectron spectroscopy and scanning electron microscopy measurements show that the coating successfully modifies the surface of the cation exchanger─ZrP. Water contact angle studies indicate that coated ZrP is hydrophobic with an angle of (149.8 ± 2.5°). Simulated small intestine solution studies show that the coated ZrP will bind 94% (±11%) more NH4+ than uncoated ZrP in the presence of Ca2+. Meanwhile, Ca2+ binding decreases by 64% (±6%). The nearly fourfold increase in NH4+ selectivity can be attributed to the gas-permeable and hydrophobic coating applied on the ZrP surface. This work suggests a novel pathway to develop a selective cation exchanger for treating ESKD patients.

PDMS-Zwitterionic Hybrid for Facile, Antifouling Microfluidic Device Fabrication.

Poly(dimethylsiloxane) (PDMS) has been used in a wide range of biomedical devices and medical research due to its biostability, cytocompatibility, gas permeability, and optical properties. Yet, some properties of PDMS create critical limitations, particularly fouling through protein and cell adhesion. In this study, a diallyl-terminated sulfobetaine (SB-diallyl) molecule was synthesized and then directly mixed with a commercial PDMS base (Sylgard 184) and curing agent to produce a zwitterionic group-bearing PDMS (PDMS-SB) hybrid that does not require a complex or an additional surface modification process for the desired end product. In vitro examination of antifouling behavior following exposure to fresh ovine blood showed a significant reduction in platelet deposition for the PDMS-SB hybrid surface compared to that of a PDMS control (p < 0.05, n = 5). The manufacturability via soft lithography using the synthesized polymers was found to be comparable to that for unmodified PDMS. Bonding via O2 plasma treatment was confirmed, and the strength was measured and again found to be comparable to the control. PDMS-SB microfluidic devices were successfully fabricated and showed improved blood compatibility that could reduce channel occlusion due to clot formation relative to PDMS control devices. Further, gas (CO2) transfer through a PDMS-SB hybrid membrane was also tested with a proof-of-concept microchannel device and shown to be comparable to that through the PDMS control.

Fully implantable batteryless soft platforms with printed nanomaterial-based arterial stiffness sensors for wireless continuous monitoring of restenosis in real time.

Atherosclerosis is a common cause of coronary artery disease and a significant factor in broader cardiovascular diseases, the leading cause of death. While implantation of a stent is a prevalent treatment of coronary artery disease, a frequent complication is restenosis, where the stented artery narrows and stiffens. Although early detection of restenosis can be achieved by continuous monitoring, no available device offers such capability without surgeries. Here, we report a fully implantable soft electronic system without batteries and circuits, which still enables continuous wireless monitoring of restenosis in real-time with a set of nanomembrane strain sensors in an electronic stent. The low-profile system requires minimal invasive implantation to deploy the sensors into a blood vessel through catheterization. The entirely printed, nanomaterial-based set of soft membrane strain sensors utilizes a sliding mechanism to offer enhanced sensitivity and detection of low strain while unobtrusively integrating with an inductive stent for passive wireless sensing. The performance of the soft sensor platform is demonstrated by wireless monitoring of restenosis in an artery model and an ex-vivo study in a coronary artery of ovine hearts. The capacitive sensor-based artery implantation system offers unique advantages in wireless, real-time monitoring of stent treatments and arterial health for cardiovascular disease.

Month-long Respiratory Support by a Wearable Pumping Artificial Lung in an Ovine Model.

BACKGROUND: A wearable artificial lung could improve lung transplantation outcomes by easing implementation of physical rehabilitation during long-term pretransplant respiratory support. The Modular Extracorporeal Lung Assist System (ModELAS) is a compact pumping artificial lung currently under development. This study evaluated the long-term in vivo performance of the ModELAS during venovenous support in awake sheep. Feedback from early trials and computational fluid dynamic analysis guided device design optimization along the way. METHODS: The ModELAS was connected to healthy sheep via a dual-lumen cannula in the jugular vein. Sheep were housed in a fixed-tether pen while wearing the device in a holster during support. Targeted blood flow rate and support duration were 2-2.5 L/min and 28-30 days, respectively. Anticoagulation was maintained via systemic heparin. Device pumping and gas exchange performance and hematologic indicators of sheep physiology were measured throughout support. RESULTS: Computational fluid dynamic-guided design modifications successfully decreased pump thrombogenicity from initial designs. For the optimized design, 4 of 5 trials advancing past early perioperative and cannula-related complications lasted the full month of support. Blood flow rate and CO2 removal in these trials were 2.1 ± 0.3 L/min and 139 ± 15 mL/min, respectively, and were stable during support. One trial ended after 22 days of support due to intradevice thrombosis. Support was well tolerated by the sheep with no signs of hemolysis or device-related organ impairment. CONCLUSIONS: These results demonstrate the ability of the ModELAS to provide safe month-long support without consistent deterioration of pumping or gas exchange capabilities.

In vivo testing of the low-flow CO2 removal application of a compact, platform respiratory device.

BACKGROUND: Non-invasive and lung-protective ventilation techniques may improve outcomes for patients with an acute exacerbation of chronic obstructive pulmonary disease or moderate acute respiratory distress syndrome by reducing airway pressures. These less invasive techniques can fail due to hypercapnia and require transitioning patients to invasive mechanical ventilation. Extracorporeal CO2 removal devices remove CO2 independent of the lungs thereby controlling the hypercapnia and permitting non-invasive or lung-protective ventilation techniques. We are developing the Modular Extracorporeal Lung Assist System as a platform technology capable of providing three levels of respiratory assist: adult and pediatric full respiratory support and adult low-flow CO2 removal. The objective of this study was to evaluate the in vivo performance of our device to achieve low-flow CO2 removal. METHODS: The Modular Extracorporeal Lung Assist System was connected to 6 healthy sheep via a 15.5 Fr dual-lumen catheter placed in the external jugular vein. The animals were recovered and tethered within a pen while supported by the device for 7 days. The pump speed was set to achieve a targeted blood flow of 500 mL/min. The extracorporeal CO2 removal rate was measured daily at a sweep gas independent regime. Hematological parameters were measured pre-operatively and regularly throughout the study. Histopathological samples of the end organs were taken at the end of each study. RESULTS: All animals survived the surgery and generally tolerated the device well. One animal required early termination due to a pulmonary embolism. Intra-device thrombus formation occurred in a single animal due to improper anticoagulation. The average CO2 removal rate (normalized to an inlet pCO2 of 45 mmHg) was 75.6 ± 4.7 mL/min and did not significantly change over the course of the study (p > 0.05). No signs of consistent hemolysis or end organ damage were observed. CONCLUSION: These in vivo results indicate positive performance of the Modular Extracorporeal Lung Assist System as a low-flow CO2 removal device.

A biostable, anti-fouling zwitterionic polyurethane-urea based on PDMS for use in blood-contacting medical devices.

Polydimethylsiloxane (PDMS) is commonly used in medical devices because it is non-toxic and stable against oxidative stress. Relatively high blood platelet adhesion and the need for chemical crosslinking through curing, however, limit its utility. In this research, a biostable PDMS-based polyurethane-urea bearing zwitterion sulfobetaine (PDMS-SB-UU) was synthesized for potential use in the fabrication or coating of blood-contacting devices, such as a conduits, artificial lungs, and microfluidic devices. The chemical structure and physical properties of synthesized PDMS-SB-UU were confirmed by 1H-nuclear magnetic resonance (1H-NMR), X-ray diffraction (XRD), and uniaxial stress-strain curve. In vitro stability of PDMS-SB-UU was confirmed against lipase and 30% H2O2 for 8 weeks, and PDMS-SB-UU demonstrated significantly higher resistance to fibrinogen adsorption and platelet deposition compared to control PDMS. Moreover, PDMS-SB-UU showed a lack of hemolysis and cytotoxicity with whole ovine blood and rat vascular smooth muscle cells (rSMCs), respectively. The PDMS-SB-UU was successfully processed into small-diameter (0.80 ± 0.05 mm) conduits by electrospinning and coated onto PDMS- and polypropylene-based blood-contacting biomaterials due to its unique physicochemical characteristics from its soft- and hard- segments.

Blending Polymer Labile Elements at Differing Scales to Affect Degradation Profiles in Heart Valve Scaffolds.

After more than 22 years of research challenges and innovation, the heart valve tissue engineering paradigm still attracts attention as an approach to overcome limitations which exist with clinically utilized mechanical or bioprosthetic heart valves. Despite encouraging results, delayed translation can be attributed to limited knowledge on the concurrent mechanisms of biomaterial degradation in vivo, host inflammatory response, cell recruitment, and de novo tissue elaboration. This study aimed to reduce this gap by evaluating three alternative levels at which lability could be incorporated into candidate polyurethane materials electroprocessed into a valve scaffold. Specifically, polyester and polycarbonate labile soft segment diols were reacted into thermoplastic elastomeric polyurethane ureas that formed scaffolds where (1) a single polyurethane containing both of the two diols in the polymer backbone was synthesized and processed, (2) two polyurethanes were physically blended, one with exclusively polycarbonate and one with exclusively polyester diols, followed by processing of the blend, and (3) the two polyurethane types were concurrently processed to form individual fiber populations in a valve scaffold. The resulting valve scaffolds were characterized in terms of their mechanics before and after exposure to varying periods of pulsatile flow in an enzymatic (lipase) buffer solution. The results showed that valve scaffolds made from the first type of polymer and processing combination experienced more extensive degradation. This approach, although demonstrated with polyurethane scaffolds, can generally be translated to investigate biomaterial approaches where labile elements are introduced at different structural levels to alter degradation properties while largely preserving the overall chemical composition and initial mechanical behavior.

In Vivo 5 Day Animal Studies of a Compact, Wearable Pumping Artificial Lung.

Recent studies show improved outcomes in ambulated lung failure patients. Ambulation still remains a challenge in these patients. This necessitates development of more compact and less cumbersome respiratory support specifically designed to be wearable. The Paracorporeal Ambulatory Assist Lung (PAAL) is being designed for providing ambulatory support in lung failure patients during bridge to transplant or recovery. We previously published in vitro and acute in vivo results of the PAAL. This study further evaluates the PAAL for 5 days. Five-day in vivo studies with the PAAL were conducted in 50-60 kg sheep after heparinization (activated clotting time range: 190-250 s) and cannulation with a 27 Fr. Avalon Elite dual-lumen cannula. The animals were able to move freely in a stanchion while device flow, resistance, and hemodynamics were recorded hourly. Oxygenation and hemolysis were measured daily. Platelet activation, blood chemistry, and comprehensive blood counts are reported for preoperatively, on POD 0, and POD 5. Three animals survived for 5 days. No study termination resulted from device failure. One animal was terminated on POD 0 and one animal was terminated at POD 3. The device was operated between 1.93 and 2.15 L/min. Blood left the device 100% oxygenated. Plasma-free hemoglobin ranged 10.8-14.5 mg/dl. CD62-P expression was under 10%. Minimal thrombus was seen in devices at explant. Chronic use of the PAAL in awake sheep is promising based on our study. There were no device-related complications over the study course. This study represents the next step in our pathway to eventual clinical translation.

Active wrinkles to drive self-cleaning: A strategy for anti-thrombotic surfaces for vascular grafts.

The inner surfaces of arteries and veins are naturally anti-thrombogenic, whereas synthetic materials placed in blood contact commonly experience thrombotic deposition that can lead to device failure or clinical complications. Presented here is a bioinspired strategy for self-cleaning anti-thrombotic surfaces using actuating surface topography. As a first test, wrinkled polydimethylsiloxane planar surfaces are constructed that can repeatedly transition between smooth and wrinkled states. When placed in contact with blood, these surfaces display markedly less platelet deposition than control samples. Second, for the specific application of prosthetic vascular grafts, the potential of using pulse pressure, i.e. the continual variation of blood pressure between systole and diastole, to drive topographic actuation was investigated. Soft cylindrical tubes with a luminal surface that transitioned between smooth and wrinkled states were constructed. Upon exposure to blood under continual pressure pulsation, these cylindrical tubes also showed reduced platelet deposition versus control samples under the same fluctuating pressure conditions. In both planar and cylindrical cases, significant reductions in thrombotic deposition were observed, even when the wrinkles had wavelengths of several tens of µm, far larger than individual platelets. We speculate that the observed thrombo-resistance behavior is attributable to a biofilm delamination process in which the bending energy within the biofilm overcomes interfacial adhesion. This novel strategy to reduce thrombotic deposition may be applicable to several types of medical devices placed into the circulatory system, particularly vascular grafts.

Biodegradable Zwitterionic Polymer Coatings for Magnesium Alloy Stents.

Degradable metallic stents, most commonly composed of Mg-based alloys, are of interest as an alternative to traditional metallic stents for application in cardiac and peripheral vasculature. Two major design challenges with such stents are control of the corrosion rate and acute presentation of a nonthrombogenic surface to passing blood. In this study, several types of sulfobetaine (SB)-bearing biodegradable polyurethanes were developed and assessed as physical, chemical, and combination-type coatings for a model degradable Mg alloy, AZ31. For physical coatings, poly(ester sulfobetaine)urethane ureas, PESBUUs were synthesized using variable monomers that allowed the incorporation of a varying extent of carboxyl groups. Introduction of the carboxyl groups was associated with faster polymer degradation time. Simple physical coating of PESBUUs reduced macro- and microscopic thrombogenic deposition together with good stability of the coating attachment compared to a control coating of polylactic- co-glycolic acid. For PESBUUs incorporating carboxyl groups (PESBUUs-COOH), these groups could be converted to siloxane groups (PESBUUs-Si), thus creating polymers that could be surface reacted with the oxidized or phytic acid treated AZ31 surface. Chemical (silanization) attachment of these polymers reduced underlying alloy corrosion rates, but following the salination reaction with physical coating most reduced corrosion rates and protected the surface better from the consequences of oxidation occurring under the coating, such as blistering. The application of a multilayered coating approach using a sulfobetaine-based biodegradable elastomer thus offers options for degradable metallic stent design where thromboresistance is desired in combination with a means to control both polymeric coating degradation rates and underlying alloy corrosion rates.

Comparison of endothelial cell attachment on surfaces of biodegradable polymer-coated magnesium alloys in a microfluidic environment.

Polymeric coatings can provide temporary stability to bioresorbable metallic stents at the initial stage of deployment by alleviating rapid degradation and providing better interaction with surrounding vasculature. To understand this interfacing biocompatibility, this study explored the endothelial-cytocompatibility of polymer-coated magnesium (Mg) alloys under static and dynamic conditions compared to that of non-coated Mg alloy surfaces. Poly (carbonate urethane) urea (PCUU) and poly (lactic-co-glycolic acid) (PLGA) were coated on Mg alloys (WE43, AZ31, ZWEKL, ZWEKC) and 316L stainless steel (316L SS, control sample), which were embedded into a microfluidic device to simulate a vascular environment with dynamic flow. The results from attachment and viability tests showed that more cells were attached on the polymer-coated Mg alloys than on non-coated Mg alloys in both static and dynamic conditions. In particular, the attachment and viability on PCUU-coated surfaces were significantly higher than that of PLGA-coated surfaces of WE43 and ZWEKC in both static and dynamic conditions, and of AZ31 in dynamic conditions (P<0.05). The elementary distribution map showed that there were relatively higher Carbon weight percentages and lower Mg weight percentages on PCUU-coated alloys than PLGA-coated alloys. Various levels of pittings were observed underneath the polymer coatings, and the pittings were more severe on the surface of Mg alloys that corroded rapidly. Polymer coatings are recommended to be applied on Mg alloys with relatively low corrosion rates, or after pre-stabilizing the substrate. PCUU-coating has more selective potential to enhance the biocompatibility and mitigate the endothelium damage of Mg alloy stenting.

Stretchable, Implantable, Nanostructured Flow-Diverter System for Quantification of Intra-aneurysmal Hemodynamics.

Random weakening of an intracranial blood vessel results in abnormal blood flow into an aneurysmal sac. Recent advancements show that an implantable flow diverter, integrated with a medical stent, enables a highly effective treatment of cerebral aneurysms by guiding blood flow into the normal vessel path. None of such treatment systems, however, offers post-treatment monitoring to assess the progress of sac occlusion. Therefore, physicians rely heavily on either angiography or magnetic resonance imaging. Both methods require a dedicated facility with sophisticated equipment settings and time-consuming, cumbersome procedures. In this paper, we introduce an implantable, stretchable, nanostructured flow-sensor system for quantification of intra-aneurysmal hemodynamics. The open-mesh membrane device is capable of effective implantation in complex neurovascular vessels with extreme stretchability (500% radial stretching) and bendability (180° with 0.75 mm radius of curvature) for monitoring of the treatment progress. A collection of quantitative mechanics, fluid dynamics, and experimental studies establish the fundamental aspects of design criteria for a highly compliant, implantable device. Hemocompatibility study using fresh ovine blood captures the device feasibility for long-term insertion in a blood vessel, showing less platelet deposition compared to that in existing implantable materials. In vitro demonstrations of three types of flow sensors show quantification of intra-aneurysmal blood flow in a pig aorta and the capability of observation of aneurysm treatment with a great sensitivity (detection limit as small as 0.032 m/s). Overall, this work describes a mechanically soft flow-diverter system that offers an effective treatment of aneurysms with an active monitoring of intra-aneurysmal hemodynamics.

Hybrid scaffolds of Mg alloy mesh reinforced polymer/extracellular matrix composite for critical-sized calvarial defect reconstruction.

The challenge of developing scaffolds to reconstruct critical-sized calvarial defects without the addition of high levels of exogenous growth factor remains relevant. Both osteogenic regenerative efficacy and suitable mechanical properties for the temporary scaffold system are of importance. In this study, a Mg alloy mesh reinforced polymer/demineralized bone matrix (DBM) hybrid scaffold was designed where the hybrid scaffold was fabricated by a concurrent electrospinning/electrospraying of poly(lactic-co-glycolic acid) (PLGA) polymer and DBM suspended in hyaluronic acid (HA). The Mg alloy mesh significantly increased the flexural strength and modulus of PLGA/DBM hybrid scaffold. In vitro results demonstrated that the Mg alloy mesh reinforced PLGA/DBM hybrid scaffold (Mg-PLGA@HA&DBM) exhibited a stronger ability to promote the proliferation of bone marrow stem cells (BMSCs) and induce BMSC osteogenic differentiation compared with control scaffolding materials lacking critical components. In vivo osteogenesis studies were performed in a rat critical-sized calvarial defect model and incorporated a variety of histological stains and immunohistochemical staining of osteocalcin. At 12 weeks, the rat model data showed that the degree of bone repair for the Mg-PLGA@HA&DBM scaffold was significantly greater than for those scaffolds lacking one or more of the principal components. Although complete defect filling was not achieved, the improved mechanical properties, promotion of BMSC proliferation and induction of BMSC osteogenic differentiation, and improved promotion of bone repair in the rat critical-sized calvarial defect model make Mg alloy mesh reinforced PLGA/DBM hybrid scaffold an attractive option for the repair of critical-sized bone defects where the addition of exogenous isolated growth factors is not employed.

Development of zwitterionic sulfobetaine block copolymer conjugation strategies for reduced platelet deposition in respiratory assist devices.

Respiratory assist devices, that utilize ∼2 m2 of hollow fiber membranes (HFMs) to achieve desired gas transfer rates, have been limited in their adoption due to such blood biocompatibility limitations. This study reports two techniques for the functionalization and subsequent conjugation of zwitterionic sulfobetaine (SB) block copolymers to polymethylpentene (PMP) HFM surfaces with the intention of reducing thrombus formation in respiratory assist devices. Amine or hydroxyl functionalization of PMP HFMs (PMP-A or PMP-H) was accomplished using plasma-enhanced chemical vapor deposition. The generated functional groups were conjugated to low molecular weight SB block copolymers with N-hydroxysuccinimide ester or siloxane groups (SBNHS or SBNHSi) that were synthesized using reversible addition fragmentation chain transfer polymerization. The modified HFMs (PMP-A-SBNHS or PMP-H-SBNHSi) showed 80-95% reduction in platelet deposition from whole ovine blood, stability under the fluid shear of anticipated operating conditions, and uninhibited gas exchange performance relative to non-modified HFMs (PMP-C). Additionally, the functionalization and SBNHSi conjugation technique was shown to reduce platelet deposition on polycarbonate and poly(vinyl chloride), two other materials commonly found in extracorporeal circuits. The observed thromboresistance and stability of the SB modified surfaces, without degradation of HFM gas transfer performance, indicate that this approach is promising for longer term pre-clinical testing in respiratory assist devices and may ultimately allow for the reduction of anticoagulation levels in patients being supported for extended periods. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2681-2692, 2018.

Orthogonally Functionalizable Polyurethane with Subsequent Modification with Heparin and Endothelium-Inducing Peptide Aiming for Vascular Reconstruction.

Surface coimmobilization modifications of blood-contacting devices with both antithrombogenic moieties and endothelium-inducing biomolecules may create a synergistic effect to improve their performance. However, it is difficult to perform covalent dual-functionalization with both biomolecules on the surface of normally used synthetic polymeric substrates. Herein, we developed and characterized an orthogonally functionalizable polymer, biodegradable elastic poly(ester urethane)urea with disulfide and amino groups (PUSN), which was further fabricated into electropun fibrous scaffolds and surface modified with heparin and endothelial progenitor cells (EPC) recruiting peptide (TPS). The modification effects were assessed through platelet adhesion, EPC, and HUVEC proliferation. Results showed the dual modified PUSN scaffolds demonstrated a synergistic effect of reduced platelet deposition and improved EPC proliferation in vitro study, and demonstrated their potential application in small diameter vascular regeneration.