Xinzhu Gu

Biodegradable, elastomeric coatings with controlled anti-proliferative agent release for magnesium-based cardiovascular stents.

Vascular stent design continues to evolve to further improve the efficacy and minimize the risks associated with these devices. Drug-eluting coatings have been widely adopted and, more recently, biodegradable stents have been the focus of extensive evaluation. In this report, biodegradable elastomeric polyurethanes were synthesized and applied as drug-eluting coatings for a relatively new class of degradable vascular stents based on Mg. The dynamic degradation behavior, hemocompatibility and drug release were investigated for poly(carbonate urethane) urea (PCUU) and poly(ester urethane) urea (PEUU) coated magnesium alloy (AZ31) stents. Poly(lactic-co-glycolic acid) (PLGA) coated and bare stents were employed as control groups. The PCUU coating effectively slowed the Mg alloy corrosion in dynamic degradation testing compared to PEUU-coated, PLGA-coated and bare Mg alloy stents. This was confirmed by electron microscopy, energy-dispersive x-ray spectroscopy and magnesium ion release experiments. PCUU-coating of AZ31 was also associated with significantly reduced platelet adhesion in acute blood contact testing. Rat vascular smooth muscle cell (rSMC) proliferation was successfully inhibited when paclitaxel was released from pre-loaded PCUU coatings. The corrosion retardation, low thrombogenicity, drug loading capacity, and high elasticity make PCUU an attractive option for drug eluting coating on biodegradable metallic cardiovascular stents.

Heart valve scaffold fabrication: Bioinspired control of macro-scale morphology, mechanics and micro-structure

Valvular heart disease is currently treated with mechanical valves, which benefit from longevity, but are burdened by chronic anticoagulation therapy, or with bioprosthetic valves, which have reduced thromboembolic risk, but limited durability. Tissue engineered heart valves have been proposed to resolve these issues by implanting a scaffold that is replaced by endogenous growth, leaving autologous, functional leaflets that would putatively eliminate the need for anticoagulation and avoid calcification. Despite the diversity in fabrication strategies and encouraging results in large animal models, control over engineered valve structure-function remains at best partial. This study aimed to overcome these limitations by introducing double component deposition (DCD), an electrodeposition technique that employs multi-phase electrodes to dictate valve macro and microstructure and resultant function. Results in this report demonstrate the capacity of the DCD method to simultaneously control scaffold macro-scale morphology, mechanics and microstructure while producing fully assembled stent-less multi-leaflet valves composed of microscopic fibers. DCD engineered valve characterization included: leaflet thickness, biaxial properties, bending properties, and quantitative structural analysis of multi-photon and scanning electron micrographs. Quasi-static ex-vivo valve coaptation testing and dynamic organ level functional assessment in a pressure pulse duplicating device demonstrated appropriate acute valve functionality.

A novel low-profile ventriculoamniotic shunt for foetal aqueductal stenosis.

Abstract This study proposed a novel ventriculoamniotic shunt device for foetal aqueductal stenosis treatment fabricated with 3Fr or 4Fr size catheters that have a longitudinal bending stiffness with kink resistance, sufficient luminal area for cerebrospinal fluid drainage and capacity for valve integration. Computational flow dynamics studies were carried out to optimise the device design, including size of the lumen and length of the device. An in vitro pressure and flow rate measurement test circuit was constructed to assess the high pressure relieving functionality of draining cerebrospinal fluid from foetal brain. Additionally, a resistance force measurement test platform was built to quantitatively evaluate the anchor performance of various geometric designs. The valve functionality was qualitatively evaluated through the visualisation of the flow patterns in the amniotic sac with injected red coloured fluid under stereomicroscopy. These in vitro results demonstrate the feasibility of the ventriculoamniotic shunt device designed for placement in the foetal brain.

Nitro-oleic acid (NO2OA) release enhances regional angiogenesis in a rat abdominal wall defect model

Ventral hernia is often addressed surgically by the placement of prosthetic materials, either synthetic or from allogeneic and xenogeneic biologic sources. Despite advances in surgical approaches and device design, a number of postsurgical limitations remain, including hernia recurrence, mesh encapsulation, and reduced vascularity of the implanted volume. The in situ controlled release of angiogenic factors from a scaffold facilitating abdominal wall repair might address some of these issues associated with suboptimal tissue reconstruction. Furthermore, a biocomposite material that combines the favorable mechanical properties achievable with synthetic materials and the bioactivity associated with xenogeneic tissue sources would be desirable. In this report, an abdominal wall repair scaffold has been designed based on a microfibrous, elastomeric poly(ester carbonate)urethane urea matrix integrated with a hydrogel derived from decellularized porcine dermis (extracellular matrix [ECM] gel) and poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with nitro-oleic acid (NO2-OA). NO2-OA is an electrophilic fatty acid nitro-alkene derivative that, under hypoxic conditions, induces angiogenesis. This scaffold was utilized to repair a rat abdominal wall partial thickness defect, hypothesizing that the nitro-fatty acid release would facilitate increased angiogenesis at the 8-week endpoint. The quantification of neovascularization was conducted by novel methodologies to assess vessel morphology and spatial distribution. The repaired abdominal wall defects were evaluated by histopathologic methods, including quantification of the foreign body response and cellular ingrowth. The results showed that NO2-OA release was associated with significantly improved regional angiogenesis. The combined biohybrid scaffold and NO2-OA-controlled release strategy also reduced scaffold encapsulation, increased wall thickness, and enhanced cellular infiltration. More broadly, the three components of the composite scaffold design (ECM gel, polymeric fibers, and PLGA microparticles) enable the tuning of performance characteristics, including scaffold bioactivity, degradation, mechanics, and drug release profile, all decisive factors to better address current limitations in abdominal wall repair or other soft tissue augmentation procedures.

An Elastomeric Polymer Matrix, PEUU-Tac, Delivers Bioactive Tacrolimus Transdurally to the CNS in Rat

Central nervous system (CNS) neurons fail to regrow injured axons, often resulting in permanently lost neurologic function. Tacrolimus is an FDA-approved immunosuppressive drug with known neuroprotective and neuroregenerative properties in the CNS. However, tacrolimus is typically administered systemically and blood levels required to effectively treat CNS injuries can lead to lethal, off-target organ toxicity. Thus, delivering tacrolimus locally to CNS tissues may provide therapeutic control over tacrolimus levels in CNS tissues while minimizing off-target toxicity. Herein we show an electrospun poly(ester urethane) urea and tacrolimus elastomeric matrix (PEUU-Tac) can deliver tacrolimus trans-durally to CNS tissues. In an acute CNS ischemia model in rat, the optic nerve (ON) was clamped for 10s and then PEUU-Tac was used as an ON wrap and sutured around the injury site. Tacrolimus was detected in PEUU-Tac wrapped ONs at 24 h and 14 days, without significant increases in tacrolimus blood levels. Similar to systemically administered tacrolimus, PEUU-Tac locally decreased glial fibrillary acidic protein (GFAP) at the injury site and increased growth associated protein-43 (GAP-43) expression in ischemic ONs from the globe to the chiasm, consistent with decreased astrogliosis and increased retinal ganglion cell (RGC) axon growth signaling pathways. These initial results suggest PEUU-Tac is a biocompatible elastic matrix that delivers bioactive tacrolimus trans-durally to CNS tissues without significantly increasing tacrolimus blood levels and off-target toxicity.

A retrievable rescue stent graft and radiofrequency positioning for rapid control of noncompressible hemorrhage.

BACKGROUND Noncompressible hemorrhage of the torso remains a challenging surgical dilemma. Stent graft repair requires endovascular expertise, imaging, and inventory that are not available within the critical window of massive hemorrhage. We developed a retrievable stent graft for rapid hemorrhage. We further investigated a radiofrequency (RF) positioning approach as a possible alternative to the logistics of fluoroscopy. METHODS A retrievable stent graft was constructed with a novel “petal and stem” design from nitinol and covered with a sleeve of electrospun polyurethane. The stent graft was tested using an in vitro model of simulated hemorrhage. Next, the stent graft was examined in vivo using a porcine model of noncompressible hemorrhage. The stent was examined for hemorrhage control in a porcine model of either aortic or caval injury. An RF reader was assembled from an Arduino processor while RF tags were affixed to the ends of the stent graft. Detection accuracy of a handheld RF wand for an RF tag was quantified both in vitro and through tissue. RESULTS The retrievable RESCUEstent graft was deployed within minutes and rapidly controlled traumatic hemorrhage angiographically in both aortic injury (n = 3) and caval injury (n = 2). Stent grafts were easily recaptured in both models in under 15 seconds. The LED light of a handheld RF detector illuminated when positioned directly over an RF tag. The RF detection approach revealed positioning accuracy to within 1 cm of the intended target, despite tissue interference. CONCLUSION This study demonstrates the rapid deployment and retrieval of a RESCUE stent graft as well as the ability to tamponade injuries of the aorta and cava. In addition, this study demonstrates the feasibility of RF tags to guide stent placement through tissue. More rigorous models are needed to define the effectiveness of this approach in the setting of vascular injury and shock.

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.

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.

A novel compartmentalised stent graft to isolate the perfusion of the abdominal organs.

Abstract Donation after cardiac death has been adopted to address the critical shortage of donor organs for transplant. Recovery of these organs is hindered by low blood flow that leads to permanent organ injury. We propose a novel approach to isolate the perfusion of the abdominal organs from the systemic malperfusion of the dying donor. We reasoned that this design could improve blood flow to organs without open surgery, while respecting the ethical principle that cardiac stress not be increased during organ recovery. Conditions within the stent were analysed using a computational fluid dynamics (CFD) method and validated on two prototypes in vitro. The hydrodynamic pressure drop across the stent was measured as 0.14–0.22 mmHg, which is a negligible influence. Device placement studies were also conducted on swine model fluoroscopically. All these results demonstrated the feasibility of rapidly isolating the perfusion to abdominal organs using a compartmentalised stent graft design.