Minimally invasive transcatheter embolization is a common nonsurgical procedure in interventional radiology used for the deliberate occlusion of blood vessels for the treatment of diseased or injured vasculature. One of the most commonly used embolic agents for clinical practice are microspheres. They come with different materials (i.e., PVA and trisacryl gelatin) in a variety of sizes (50 - 1200 ��m), which can be strategically selected to treat various conditions ranging from arteriovenous malformations to hypervascular tumors, Accurate particle size is crucial for localized targeted embolization since the delivery of microspheres is driven by blood flow and their movement and accumulation in vivo is size-dependent. Limitations of marketed microspheres include danger of being washed away, no intrinsic radiopacity for visualization on X-ray, and lack of therapeutics. Despite the similar morphologies microspherical embolic agents, their physical and mechanical properties vary due to differences in their chemical composition and manufacturing processes, which in turn influence microsphere and tissue interactions and clinical outcomes. No systemic platform has been developed to investigate the correlation between these properties and embolic outcomes. More importantly, clinicians have no technology for estimating the trajectory of emboli and as such significant uncertainty exists in embolization treatment. Microsphere transportation to undesired vessels will cause off-target embolization and damage to healthy tissue. The precise prediction of particle-flow behavior and the particle-vessel distribution is difficult even for experienced physicians because this is essentially a fluid-driven transport problem that has not been systemically investigated and validated. In this proposal, we will develop, for the first time, a two-way interactive biomaterial-computational platform that will 1) offer rational design of multifunctional microspheres, 2) accurately guide the transcatheter location for microsphere deployment, and 3) predict microsphere in vivo trajectory and their aggregation in the vasculature to maximize embolic success for personalized therapies. In Aim 1, we will develop microspheres with controllable sizes and tunable properties for effective embolization. In Aim 2, we will develop computational fluid dynamics (CFD) models integrated with biomaterial design to maximize emboli transport to desired locations. Lastly in Aim 3, we will demonstrate predictive capability using in-vitro vasculature and adaptive framework using patient specific physical models. Successful completion of this study shows that the versatile biomaterial-computational platform can maximize the delivery of embolic microspheres under random injection of emboli within the luminal cross-section (current practice) or complete delivery under informed injection with tracking the catheter. This pilot study will set the stage for further guided in vivo testing in large animal studies using clinically relevant models (porcine liver models). We envision that this innovative technology can be applied to liquid embolic agents, and also be widely disseminated to the treatment of diverse vascular conditions, such as prostate hyperplasia, liver tumor, and fibroids, for translation to patient-specific therapy.

Arteriovenous malformation (AVM) is an abnormal connection between an artery and vein that bypasses the normal capillary circulation, resulting in a tangle of vessels called a nidus. The malformation results in excessive stress on the venous wall, and can cause the rupturing of overstressed veins. Brain AVMs are particularly concerning since brain hemorrhage has the most severe complications, including seizures and neurologic deficits. The mortality rate after brain AVM rupture ranges from 12%-66.7%, and 23%-40% of survivors have significant disability. Furthermore, localized inflammation is found to be responsible for brain AVM progression and rupture. Anti-inflammatory drug therapy may, therefore, be a possibility to stabilize brain AVMs. Current treatment for brain AVMs includes microsurgery, embolization and radiosurgery. In embolization, which is the focus of this work, liquid embolic agents are delivered through catheters to embolize upstream or within the AVM shunt, aiming to return venous pressure to normal. The main challenge in embolizing AVMs stems from the difficulty involved with adequately penetrating the dense, tortuous and low resistance nidus. Proximal occlusion leads to the development of collateral vessels, promoting angiogenesis. Therefore, blockage of both nidus and the feeding arteries is essential for successful embolization. Current FDA approved embolic systems for brain AVM embolization include Onyx and n-butyl cyanoacrylate. Both are liquid embolic agents that undergo liquid-solid transition once in contact of blood. They are intended to travel distally from the site of release to penetrate fine vasculature. Despite clinical availability, both liquids have significant drawbacks and cannot serve as curative treatment of AVM. Limitations include toxicity from organic solvents, difficulty in delivery, danger of being washed away, lack of universality to block wide range of vasculature sizes, no intrinsic radiopacity for visualization on X-ray, and lack of therapeutics. In this proposal, we will develop gel embolic agent as a minimally invasive platform that is biocompatible, imageable, durable, hemostatic and anti-inflammatory to embolize and stabilize AVMs. We posit that gel embolic agents containing natural crosslinker, genipin, will 1) offer flexibility to penetrate different AVM geometries/sizes, 2) enhance mechanical robustness of the clot-gel system in embolized AVMs to prevent migration, and 3) serve as an anti-inflammatory therapy for AVM stabilization. In Aim 1, we will develop different gel compositions for effective embolization. In Aim 2, we will evaluate the gel���s mechanical properties, injectability and in vitro occlusion ability to optimize occlusion capability. Lastly in Aim 3, we will study the biological properties of the gels in vitro using relevant cell lines for biosafety evaluation and therapeutic characterization. Successful completion of this study will show that therapeutic gel embolic agents can be used safely and occlude effectively with therapeutic characteristics. This pilot study will set the stage for further in vivo testing in large animal studies using clinically relevant AVM models. We envision that this embolization platform can be widely disseminated to other applications, such as venous hypertension, aneurysms, and tumor embolization.

Enterocutaneous fistula (ECF), a pathologic connection between the gastrointestinal tract and the skin, can profoundly impact the quality of life of the patient. ECFs are referred to as surgical tragedies in the literature, as up to 85% are the result of intraabdominal surgical complications. Despite advances in surgical techniques and postoperative management, ECFs still account for significant mortality of 15-20%. Only 20-30% of ECFs close spontaneously, while the remaining requires interventions that simply do not work; these include fibrin glue, endoscopic clips or fistula plugs, which are prone to dislodgement and recurring sepsis. No successful treatment of ECF exists today; high discharge, infection, and chronic inflammation lead to high failure and recurrence rates. The prevalence, complexity, and inability to effectively treat many ECFs demand the development of a novel bioengineering therapeutic approach. Main challenges associated with intervention of ECF include device migration and infection. To overcome these hurdles, we are developing a bioengineered material that is mechanically stable, antimicrobial and pro-regenerative, aiming to accelerate healing of ECF. Our preliminary work includes fabrication of a malleable nanocomposite gel embolic agent consists of nanoclay (antimicrobial), alginate (for tissue regeneration) and genipin crosslinker (for enhanced mechanical stability and anti-inflammation). Our initial studies will focus on harnessing physical and biological properties of the gel embolic agent by rheometry, mechanical testing and bioactivity assays. These results will pave the road for future animal studies where we will create relevant ECF model in vivo to investigate the material��������s embolic efficacy and therapeutic effect.

To respond to the CHHE program������������������s focus on emerging contaminants and pulmonary health, we propose to study the adhesive and mechanical interactions between nanoparticles and alveolar epithelial cells using atomic force microscopy (AFM) and theoretical modeling. For this one-year project, we would specifically focus on the role of pulmonary surfactant on the adhesive interaction on nanoparticle uptake from mechanics perspective to predict particle entry kinetics. Pulmonary surfactant is a sub-micrometer thick fluid layer that presents on the surface of alveolar lumen. Therefore, it is the first place that inhaled nanoparticles come in to contact prior to any interaction with epithelial cells. The role of surfactant in the adhesion interactions is lacking and the understanding of the interfacial mechanics can be considered in predictive assessment of nanoparticle toxicity or drug nanocarrier uptake. Specifically, AFM tips will be functionalized with selected nanoparticles and mixed with model surfactants. The adhesive interactions will be investigated on varying contact parameters, including indentation depth, frequency and contact time. The measure adhesion will then be fed into a modified nanoparticle entry model that we have developed previously to predict the wrapping time and entry kinetics. This combined experimental and theoretical approach would also serve as a platform on the rational design of drugs or engineered particles for pulmonary health.

Liver cancer is the sixth cause of cancer related deaths in the US. Chemotherapy for liver cancer has many challenges; low bioavailability of the drug at the tumor site accounts for a major obstacle, which may finally lead to low treatment efficacy, high relapse rate, and poor survival especially at advanced stages of the cancer. The pronounced collateral toxicity to non-cancerous liver and systemic side-effects further significantly impairs patients��� quality of life and limits overall efficacy. Transarterial embolization (TAE) using microspherical embolic agents, overcomes some of the challenges of systemic therapy. In this procedure, polyvinyl alcohol (PVA) beads allows for targeted treatment of tumors; here, microcatheters are used to navigate to the arterial supply of tumors and the beads are infused to block the blood supply. This approach aims to ���starve��� the lesion by depriving it of oxygen and nutrients, thereby triggering ischemic injury and shrinkage of the tumor. However, precise spatiotemporal control of the embolic material remains a challenge due large and often irregular shapes of the particles leading to their proximal aggregation and preventing deeper penetration into tumor, sedimentation, and explosive. In addition, the embolization efficiency of the particles is relatively low as the large-sized particles cannot be readily delivered into downstream microvasculature to achieve localized chemotherapy. Other issues associated with the embolic microspheres include unintended ischemia due to non-target embolization in to healthy tissues.To control embolization and better manage cytotoxicity, we aim at designing a biocompatible, shear-thinning gel embolic agent (GEA), which can be delivered by a catheter to liver lesions and solidify upon reaching the target. Promising in vitro and in vivo performance of GEAs in endovascular embolization have encouraged us to develop a transformative technology for liver cancer treatment by using an improved TAE procedure, which integrates the concept of embolization and a universal injectable GEAs that can be loaded with anti-cancer drugs such as doxorubicin. Through tuning the composition of the different components and their combinatory properties, the GEA can be delivered to fill the multi-scale downstream microvasculature at the site of liver cancer.