Introduction: The shape memory effect (SME), involves the pre-programming the material into an initial shape, then into a second shape outside the body, and finally recovering the initial shape inside the body. The two materials classes that exhibit shape memory are Shape Memory Alloys (SMA) such as Nitinol and Shape Memory Polymers (SMP). In spite of the obvious advantages of the Shape Memory Effect (SME), only a few products products have actually been approved as implanted devices[1]. The SME in polymers have not been sufficiently exploited for medical applications.
We report here on a novel application of SME, using a fully biodegradable polymer system. The application is the minimally-invasive deployment of an embolic plug for enhancing localization of chemotherapeutic drugs to treat liver cancer.
Liver cancer has the second highest mortality rate worldwide and is highly prevalent in Asia. At least 70% of the liver cancer patients are inoperable and are treated with palliative Transarterial Chemoembolization (TACE) or Selective Internal Radiation Therapy (SIRT)[2],[3]. In TACE and SIRT the hepatic artery is embolized following delivery of the chemotherapeutic agents. Repeat procedures are effective, so patency of the hepatic arteries needs to be restored before the next treatment.
Concept and Methodology: The concept is a fully biodegradable radiopaque shape memory polymer-hydrogel composite which can be delivered to the target in a low profile temporary shape. Upon contact with the body fluid at target location it self-expands to the fully functional shape, giving perfect occlusion in less than two minutes.
For the gel, we used polyethylene glycol diacrylate, crosslinked via radiation. For the radio-opaque material (this component also confers mechanical strength to the composite) we evaluated bariuml sulfate, tantalum and bismuth oxychloride filled polylactide-co-glycollide, or PLGA. Results of compositional optimization and radio-opacity will be presented.
Additionally, the In-vitro performance of the device was evaluated in peristaltic flow models at different flow rates and different sizes of tubing. In particular, the kinetics and the extent of the shape-memory recovery process is crucial to the success of deployment. Approximately 90% recovery was possible with a 50% bismuth oxychloride-loaded PLGA embedded in a 7.5% PEGDA gel precursor. Additionally, we found that for this composite, recovery was started within 20 seconds and completed in under 4 minutes. The recovery is activated by the combination of water and temperature.
In-vivo performance of the device was assessed in a rabbit model for feasibility of deployment, duration and degree of occlusion. The prototype plug was delivered into the carotid arteries via a 4F or a 2.7F catheter, depending on the initial (pre-swollen) dimensions of the plug composites. Complete vascular occlusion occured within 2 minutes for all deployed plugs.
Conclusions: The results demonstrate that the SME concept works well in this application. However, it is important to balance radio-opacity with recovery of shape. A hydrogel acts as a shape-filling component, while a filler-incorporated PLGA polymer acts as a scaffold and as a radioopaque tracer in this novel composite. Both components are fully biodegradable.
References:
[1] Wong YS, Kong JF, Widjaja LK, Venkatraman S, Biomedical Applications of the shape-memory polymers: How practically useful are they? Science China Chemistry, 2014. 57 (4), 1-15.
[2] El-Serag, H.B., A.C. Mason, and C. Key,Trends in survival of patients with hepatocellular carcinoma between 1977 and 1996 in the United States. Hepatology, 2001. 33(1): p. 62-65.
[3] Llovet, J., Treatment of hepatocellular carcinoma. Current Treatment Options in Gastroenterology, 2004. 7(6): p. 431-441.