Bioabsorbable radiopaque water responsive shape memory polymer-hydrogel composite device for temporary vascular occlusion in liver cancer treatment

Hepatocellular carcinoma (HCC) is the second most reason of cancer related death worldwide (approximately 800,000 deaths globally per annum). Whilst the surgery is the only curative way, only 10% of primary and metastatic liver cancer patients are eligible for resection while the remaining patients can only opt for palliative treatments such as transarterial chemo embolization (TACE). TACE treatment requires temporary embolization/blocking of hepatic artery, which accounts for 90% blood supply of tumor. Repeat sessions at six- to twelve-weeks intervals of the treatment are recommended, so patency of the hepatic artery needs to be restored before next treatment. Use of biodegradable embolic agent holds great promise for this application. Most of the embolic device available in the market are metallic. In this regard, Gelfoam is the most widely used biodegradable embolic agent for intravascular embolization, but their use is associated with some problems such as unpredictable occlusion level, non-target embolization and inaccurate placement, uncontrolled degradation, permanent occlusion (at times) etc. We have proposed biodegradable shape memory polymer-hydrogel composite as an embolic agent which will prevail over above-mentioned limitations of Gelfoam. The proposed embolic device consists of biodegradable Poly(DL-Lactide-co-Glcolide) (PLGA) filament coated with Polyethylene Glycol (PEG) hydrogel. The main objective of this research work is to understand the water induced buckling mechanism of the PEG hydrogel and to use it for making a shape memory embolic device which can be activated on contact with body fluid at body temperature to facilitate occlusion of a blood vessel. To do so, in this work shape memory characteristics of individual components poly(dl-lactide-co-glcolide) and polyethylene glycol hydrogel were investigated. PLGA evinces thermo responsive shape memory around body temperature. Different PLGA compositions with the varying amount of plasticizer and radiopaque fillers were extruded in filament form with the objective of having a filament with shape memory effect and radiopacity at body temperature. These compositions were characterized for thermal, mechanical, shape memory, and radiopacity in order to find the optimized composition. From the studies, it was found that the PLGA formulation with 2% plasticizer and 50% bismuth oxychloride exhibited the optimal properties. Mechanical and swelling characteristics of different hydrogel formulations were studied to investigate the effect of different parameters such as PEG concentration, initiator concentration, and crosslinking time. Shape memory effect and shape change effect in dry PEG hydrogel were studied individually. Buckling mechanism of the PEG hydrogel filament, synthesized using photo-crosslinking method was explored and correlated to several factors, including the extent of strain, deformation temperature, and diameter of the sample. Parameters to control buckling of the PEG hydrogel were identified and validated using theoretical modeling and experimental results. It was found that the original diameter and amount of pre-stretching are identified as two influential parameters to tailor the buckling time as confirmed by both experiments and simulation. The polymer-hydrogel composite was then fabricated using optimized formulation and conditions derived from the individual characterization results of the PLGA and PEG hydrogel. Fabricated device samples programmed for water induced shape memory using melting transition temperature of the PEG. In-vitro performance of the device was investigated using simulated flow model, with 100% occlusion being achieved within 2-3 minutes of deployment. Performance characteristics of the device such as stability in flow, degradation, cytotoxicity, hemocompatibility and shelf life were investigated. The cytotoxicity and hemocompatibility studies indicated good biocompatibility and non-hemolytic properties of the embolic plug. The shelf life studies confirmed the mechanical integrity of the device as well as no loss of shape memory properties over a period of six months. Finally, a feasibility study was conducted in- vivo in a rabbit model to investigate the ease of device deployment, device migration and extent of vessel occlusion. In-vivo studies in rabbit model evinced successful deployment of the new embolic plug using the existing method and complete occlusion at a targeted location of the vessel was achieved in less than two minutes.Doctor of Philosophy (IGS

Advanced Shape Memory Technology for Biomedical Engineering

The ability to recover to the original shape only at the presence of the right stimulus is traditionally known as the shape memory effect (SME) [1]. The materials with such a capability are technically termed shape memory materials (SMMs) [2]. Typical SMMs include shape memory alloy (SMA) and shape memory polymer (SMP, including hydrogel), while typical stimuli are temperature (thermo-responsive, both heating or cooling), chemical (chemo-responsive, including water), light (photo-responsive) and magnetic (magneto-responsive)[3]. Although SMMs have been mostly used for actuators in the past,they have been proposed for new types of sensors as well, but not so successful till today [4-7].</p

Vitrimer-Like Shape Memory Polymers: Characterization and Applications in Reshaping and Manufacturing

The shape memory effect (SME) refers to the ability of a material to recover its original shape, but only in the presence of a right stimulus. Most polymers, either thermo-plastic or thermoset, can have the SME, although the actual shape memory performance varies according to the exact material and how the material is processed. Vitrimer, which is between thermoset and thermo-plastic, is featured by the reversible cross-linking. Vitrimer-like shape memory polymers (SMPs) combine the vitrimer-like behavior (associated with dissociative covalent adaptable networks) and SME, and can be utilized to achieve many novel functions that are difficult to be realized by conventional polymers. In the first part of this paper, a commercial polymer is used to demonstrate how to characterize the vitrimer-like behavior based on the heating-responsive SME. In the second part, a series of cases are presented to reveal the potential applications of vitrimer-like SMPs and their composites. It is concluded that the vitrimer-like feature not only enables many new ways in reshaping polymers, but also can bring forward new approaches in manufacturing, such as, rapid 3D printing in solid state on space/air/sea missions

Vitrimer-like shape memory polymers : characterization and applications in reshaping and manufacturing

The shape memory effect (SME) refers to the ability of a material to recover its original shape, but only in the presence of a right stimulus. Most polymers, either thermo-plastic or thermoset, can have the SME, although the actual shape memory performance varies according to the exact material and how the material is processed. Vitrimer, which is between thermoset and thermo-plastic, is featured by the reversible cross-linking. Vitrimer-like shape memory polymers (SMPs) combine the vitrimer-like behavior (associated with dissociative covalent adaptable networks) and SME, and can be utilized to achieve many novel functions that are difficult to be realized by conventional polymers. In the first part of this paper, a commercial polymer is used to demonstrate how to characterize the vitrimer-like behavior based on the heating-responsive SME. In the second part, a series of cases are presented to reveal the potential applications of vitrimer-like SMPs and their composites. It is concluded that the vitrimer-like feature not only enables many new ways in reshaping polymers, but also can bring forward new approaches in manufacturing, such as, rapid 3D printing in solid state on space/air/sea missions.Published versio

A brief review of the shape memory phenomena in polymers and their typical sensor applications

In this brief review, an introduction of the underlying mechanisms for the shape memory effect (SME) and various shape memory phenomena in polymers is presented first. After that, a summary of typical applications in sensors based on either heating or wetting activated shape recovery using largely commercial engineering polymers, which are programmed by means of in-plane pre-deformation (load applied in the length/width direction) or out-of-plane pre-deformation (load applied in the thickness direction), is presented. As demonstrated by a number of examples, many low-cost engineering polymers are well suited to, for instance, anti-counterfeit and over-heating/wetting monitoring applications via visual sensation and/or tactual sensation, and many existing technologies and products (e.g., holography, 3D printing, nano-imprinting, electro-spinning, lenticular lens, Fresnel lens, QR/bar code, Moiré pattern, FRID, structural coloring, etc.) can be integrated with the shape memory feature.Published versio

Shape memory/change effect in a double network nanocomposite tough hydrogel

In this paper, we present a systematic investigation on the shape memory/change effect in a double network nanocomposite tough hydrogel. Water-content dependency of the response of this hydrogel to heating and wetting by water is confirmed. Since this hydrogel is tough (even after being fully wetted in water) and has a relatively lower swelling ratio, apart from conventional shape memory/change effect as in ordinary hydrogels, additional features have been realized. These features include heating induced shape memory effect utilizing the absorbed water as the transition component, mechano-responsive shape change effect after water wetting and water-induced shape memory effect. (C) 2014 Elsevier Ltd. All rights reserved

A bilayer swellable drug-eluting ureteric stent : localized drug delivery to treat urothelial diseases

A bilayer swellable drug-eluting ureteric stent (BSDEUS) is engineered and implemented, as a sustained drug delivery platform technology that enhances localized drug delivery to the highly impermeable urothelium, for the treatment of urothelial diseases such as strictures and carcinomas. On deployment, the device swells to co-apt with the ureteric wall and ensure drug availability to these tissues. BSDEUS consists of a stent spray-coated with a polymeric drug containing polylactic acid-cocaprolactone (PLC) layer which is overlaid by a swellable polyethylene glycol diacrylate (PEGDA) based hydrogel. In-vitro quantification of released drug demonstrated a tunable time-profile, indicating sustained delivery over 1-month. The PEGDA hydrogel overlayer enhanced drug release and transport into explanted porcine ureteric tissues ex-vivo, under a simulated dynamic fluid flow. A preliminary pilot invivo feasibility study, in a porcine model, demonstrated that the swollen hydrogel co-apts with the urothelium and thus enables localized drug delivery to the target tissue section. Kidney functions remained unaffected and device did not result in either hydronephrosis or systemic toxicity. This successful engineering of a bilayer coated stent prototype, demonstrates its feasibility, thus offering a unique solution for drug-based urological therapy.ASTAR (Agency for Sci., Tech. and Research, S’pore)MOE (Min. of Education, S’pore)NMRC (Natl Medical Research Council, S’pore)Accepted versio