Urethane dimethacrylate-based photopolymerizable resins for stereolithography 3D printing: A physicochemical characterisation and biocompatibility evaluation.

Vat photopolymerisation (VP) three-dimensional printing (3DP) has attracted great attention in many different fields, such as electronics, pharmaceuticals, biomedical devices and tissue engineering. Due to the low availability of biocompatible photocurable resins, its application in the healthcare sector is still limited. In this work, we formulate photocurable resins based on urethane dimethacrylate (UDMA) combined with three different difunctional methacrylic diluents named ethylene glycol dimethacrylate (EGDMA), di(ethylene glycol) dimethacrylate (DEGDMA) or tri(ethylene glycol) dimethacrylate (TEGDMA). The resins were tested for viscosity, thermal behaviour and printability. After printing, the 3D printed specimens were measured with a digital calliper in order to investigate their accuracy to the digital model and tested with FT-IR, TGA and DSC. Their mechanical properties, contact angle, water sorption and biocompatibility were also evaluated. The photopolymerizable formulations investigated in this work achieved promising properties so as to be suitable for tissue engineering and other biomedical applications.

3D printed biodegradable multifunctional implants for effective breast cancer treatment.

By carefully controlling the dose administered and the drug release rate from drug-eluting implants, safety and efficacy of the therapeutic agent dispensed can be improved. The present work focuses on the promising advantages of 3D Bioprinting process in developing two layers' implantable scaffolds. The two layers have different functions, in order to ensure a more effective and synergistic breast cancer therapy. First layer involves use of polymers such as Poly- ε-Caprolactone (PCL) and Chitosan (CS), and incorporation of 5-Fluorouracil (5-FU). The aim of the first layer is releasing the drug within 4 weeks, obtaining a prolonged and modified release. According to in vitro drug release tests performed, ∼32 % of 5-FU was released after one month, after an initial burst effect of 17.22 %. The sudden release of the drug into the body would quickly reach an effective therapeutic concentration, while the drug sustained release maintains an effective therapeutic concentration range during the administration time. The second layer is made exclusively from PCL as polymeric matrix, into which Gold Nanoparticles (AuNPs) were subsequently loaded, and its main purpose is to be radiation enhancement. The long biodegradation time of PCL would make the non-soluble scaffold an alternative to conventional chemotherapy, optimizing drug release to the specific needs of the patients.

Melt-extrusion 3D printing of resorbable levofloxacin-loaded meshes: Emerging strategy for urogynaecological applications.

Current surgical strategies for the treatment of pelvic floor dysfunctions involve the placement of a polypropylene mesh into the pelvic cavity. However, polypropylene meshes have proven to have inadequate mechanical properties and have been associated to the arising of severe complications, such as infections. Furthermore, currently employed manufacturing strategies are unable to produce compliant and customisable devices. In this work, polycaprolactone has been used to produce resorbable levofloxacin-loaded meshes in two different designs (90° and 45°) via melt-extrusion 3D printing. Drug-loaded meshes were produced using a levofloxacin concentration of 0.5% w/w. Drug loaded meshes were successfully produced with highly reproducible mechanical and physico-chemical properties. Tensile test results showed that drug-loaded 45° meshes possessed a mechanical behaviour close to that of the vaginal tissue (E ≃ 8.32 ± 1.85 MPa), even after 4 weeks of accelerated degradation. Meshes released 80% of the loaded levofloxacin in the first 3 days and were capable of producing an inhibitory effect against S. Aureus and E. coli bacterial strains with an inhibition zone equal to 12.8 ± 0.45 mm and 15.8 ± 0.45 mm respectively. Thus, the strategy adopted in this work holds great promise for the manufacturing of custom-made surgical meshes with antibacterial properties.

Development of drug loaded cardiovascular prosthesis for thrombosis prevention using 3D printing.

Cardiovascular disease (CVD) is a general term for conditions which are the leading cause of death in the world. Quick restoration of tissue perfusion is a key factor to combat these diseases and improve the quality and duration of patients' life. Revascularization techniques include angioplasty, placement of a stent, or surgical bypass grafting. For the latter technique, autologous vessels remain the best clinical option; however, many patients lack suitable autogenous due to previous operations and they are often unsuitable. Therefore, synthetic vascular grafts providing antithrombosis, neointimal hyperplasia inhibition and fast endothelialization are still needed. To address these limitations, 3D printed dipyridamole (DIP) loaded biodegradable vascular grafts were developed. Polycaprolactone (PCL) and DIP were successfully mixed without solvents and then vascular grafts were 3D printed. A mixture of high and low molecular weight PCL was used to better ensure the integration of DIP, which would offer the biological functions required above. Moreover, 3D printing technology provides the ability to fabricate structures of precise geometries from a 3D model, enabling to customize the vascular grafts' shape or size. The produced vascular grafts were fully characterized through multiple techniques and the last step was to evaluate their drug release, antiplatelet effect and cytocompatibility. The results suggested that DIP was properly mixed and integrated within the PCL matrix. Moreover, these materials can provide a sustained and linear drug release without any obvious burst release, or any faster initial release rates for 30 days. Compared to PCL alone, a clear reduced platelet deposition in all the DIP-loaded vascular grafts was evidenced. The hemolysis percentage of both materials PCL alone and PCL containing 20% DIP were lower than 4%. Moreover, PCL and 20% DIP loaded grafts were able to provide a supportive environment for cellular attachment, viability, and growth.

Poly(caprolactone)-based subcutaneous implant for sustained delivery of levothyroxine.

This work aimed to develop a subcutaneous implant for prolonged delivery of LEVO to treat hypothyroidism. This could overcome challenges with patient compliance and co-administration and could improve treatment of this condition. For this purpose, implants were produced by solvent casting mixtures of poly(caprolactone) (PCL), poly(ethylene glycol) (PEG) and LEVO sodium. These implants contained mixtures of PCL of differing molecular weight, PEG and different LEVO sodium loadings (20% or 40% w/w). SEM images confirmed that the drug was evenly dispersed throughout the implant. In vitro release rates ranging from 28.37 ± 1.19 - 78.21 ± 19.93 µg/day and 47.39 ± 8.76 - 98.92 ± 4.27 µg/day were achieved for formulations containing 20% and 40% w/w drug loading, respectively. Implants containing higher amounts of low molecular weight PCL and 40% w/w of LEVO showed release profiles governed by zero order kinetics. On the other hand, implants containing higher amounts of high molecular weight PCL showed a release mechanism governed by Fickian diffusion. Finally, two representative formulations were tested in vivo. These implants were capable of providing detectable LEVO levels in plasma during the entire duration of the experiments (4 weeks) with LEVO plasma levels ranging between 5 and 20 ng/mL.