Additive Manufacturing of PE/Fluorouracil Waffles for Implantable Drug Delivery in Bone Cancer Treatment
Abstract
In this study, implantable polyethylene/fluorouracil waffles were additively manufactured by selective laser sintering using different laser energy densities. SEM-EDS revealed a porous morphology for both PE and PE/FU waffles. High dispersion of fluorouracil particles were observed in samples prepared under different conditions. The PE/FU waffles manufactured at 5W had the highest flexural modulus, probably due to better PE particle coalescence, higher sinter degree and the dispersion of FU particles in the co-continuous porous PE matrix. The PE/FU waffles showed an initial burst as well as a rapid drug released, which are desirable characteristics for cancer treatment. This profile provides a high initial concentration of the drug in the cancer cells and a subsequent controlled release sustaining levels of the chemotherapeutic agent in the region of the bone tumor.
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Introduction
Additive Manufacturing, also known as 3D printing, enables the fast processing of three-dimensional devices from different materials and blends. This technology is also known for overcoming geometry limitations that are characteristic of conventional manufacturing techniques and it is able to produce more complex architectures. Selective laser sintering (SLS) is a type of Additive Manufacturing that creates objects, layer by layer, through the processing of powder materials using infrared laser beams. [1-3]. The microstructures of samples prepared via SLS depend on the process parameters (laser power, scan speed and spot diameter of the laser beam, and bed temperature) and the properties of the powder. For example, the particle shape and size distribution influence the powder packing density, while the melting flow behavior and the thermal stability determine the laser power and scan speed [4-10]. In recent years, SLS has demonstrated its potential in the biomedical field, for applications in bone tissue engineering, and for manufacturing drug delivery devices (DDDs) [5-10].
Cancer is a public health concern worldwide and causes more than 600,000 deaths per year, only in the United States. The conventional approach to treat this disease includes tumor removal followed by chemotherapy or radiotherapy. However, resection surgery is not always an alternative, as observed in some cases of colon cancer metastases in which only 3.5-6.4% of the patients are eligible for tumor removal. Furthermore, current drugs used in the systemic treatments are not specific to cancer cells and end up causing toxicity to healthy cells and tissues [11-13]. Under this scenario, intratumoral drug delivery devices have emerged as a powerful strategy for localized treatment of solid tumors, promising to substantially improve the therapeutic outcomes for several kinds of cancer. This technology allows for controlled and sustained release of the drug into the solid tumors or in the resection cavities, which results in a safer and more effective strategy [14-16].
Bone cancer usually occurs in mature/old people, except osteosarcoma, which is typically diagnosed in young people (10–20 years old) and rarely in old people [17], in the extremity of the long bones, especially in the femur [18]. There are 45 main types of primary bone tumor, the most important being osteosarcoma (35.1% of the primary bone tumors), followed by chondrosarcoma, Ewing’s sarcoma, and chondroma. By sex, males are more exposed to bone cancer (4% incidence in males compared to 3% in females)[18]. The implantation of drug delivery systems at the tumor site led to a reduction in dose of the antitumor agent, and consequently the risk of systemic toxicity decreased drastically compared with conventional systemic administration. Itokazu et al developed some drug-delivery systems and proved that porosity and pore size influenced the release rate of both antitumor agents [19]. The improved contact of antitumor agents with tumoral cells is expected to reduce the recurrence and metastasis of cancer [20].
Conclusion
This study demonstrated additive manufacturing of PE/FU waffles through SLS with great efficiency. SEM-EDS revealed the presence of small fluorouracil particles dispersed over the surface and throughout the porous PE matrix for the PE/FU waffles processed under 3W and 5W. The main peaks in the FTIR and NIR spectra for the PE/FU waffles were the same as those observed in the spectra for the pure PE waffles. However, the presence of the drug was confirmed by peaks at 600 cm-1 and at 2330 nm, which were associated with C-F bond of the fluorouracil compound. The PE/FU waffles prepared using the higher laser power (5 W) had a higher flexural modulus, probably due to better coalescence of the PE particles, a higher sinter degree and a good dispersion of FU particles throughout the co-continuous porous PE matrix. The PE/FU waffles initially showed a rapid drug released due to the hydrophilic character of fluorouracil. This is a desirable characteristic to provide a high initial concentration of the drug locally in the cancer cells following implantation. The slow and controlled release of the drug presented subsequently by the PE/FU waffles is important to sustain appropriate levels of the chemotherapeutic agent in the region of the tumor; thus demonstrating a significant potential to improve bone cancer treatments.