Young Investigator Award

Nevena Paunovic

ETH Zurich, Switzerland
Title:”Development of Biomedical Inks for Light-Based 3D Printing of Biodegradable  Non-Vascular Stents”
Supervisors: Prof. Dr. Jean-Christophe Leroux and Prof. Dr. André R.Studart

Abstract PhD thesis

3D printing in combination with medical imaging represents a powerful tool for the manufacturing of affordable patient-specific medical devices. Among the different 3D printing techniques, digital light processing (DLP) stands out due to its ability to rapidly produce high-resolution objects with smooth surfaces. However, the formulation of biomedical inks for DLP is challenging, which limits the scope of devices that can be fabricated by this technique. Therefore, novel DLP-compatible inks are sought-after to produce elastic, strong and biodegradable medical devices such as non-vascular stents.

This thesis describes several strategies to achieve this goal. The approaches for introducing therapeutic and shape-memory functions are also proposed. A library of polyester-based copolymers was synthesized and used to formulate inks, which were further proved suitable for DLP printing of medical devices, in particular airway stents.

The developed dual-polymer ink strategy proved successful in DLP printing of biodegradable elastomers with tuneable mechanical properties. It was accomplished by mixing high (ca. 15,000 g mol⁻¹) and low (< 1000 g mol⁻¹) molecular weight (MW) poly(D,L-lactide-co-ε-caprolactone) methacrylates in the same ink. High MW component provided cleavable groups and flexible chains required for degradability and elasticity, respectively. On the other hand, low MW photopolymer reduced viscosity of the inks, which is essential for high resolution printing. It also provided strength to the printed objects by increasing crosslinking density. The inks based on linear high MW and 4-arm low MW photopolymer enabled DLP printing of elastomers with mechanical properties comparable to those of silicone used for prototyping devices in biomedicine (Sylgard^TM-184) with tailorable biodegradability as an additional asset. Another pair of photopolymers, comprising 4‑arm high MW and linear low MW constituent, also allowed for printing of materials with tuneable elastomeric properties and biodegradability. Notably, the ink with 25 wt% of low MW photopolymer enabled to manufacture human-sized airway stents exhibiting an elasticity comparable to that of the state-of-the-art silicone stent. Besides the properties of photopolymers, the mechanical performance of a stent is determined by its radius and wall thickness. Simulations provided a guideline for selecting the thickness to achieve application-imposed stiffness of a stent with patient-specific radius. In vivo studies in healthy rabbits confirmed the biocompatibility of the DLP printed customized stents, and showed that the latter stayed in place for 7 weeks, after which they became radiographically invisible.

Besides biocompatibility, suitable mechanical properties and biodegradability, a therapeutic function is also a valuable asset to non-vascular stents. This thesis reports DLP printed composite material based on PEGylated gold nanorods (AuNRs) and 9000 g mol⁻¹ poly(D,L-lactide-co-ε-caprolactone) methacrylate with equimolar ratio of monomers that could be applied for photothermal therapy. The material demonstrated robust near infrared (NIR) light responsiveness, which allowed rapid and stable photothermal performance and led to the irradiation time-dependent cell death in vitro. Moreover, an increase in MW of photopolymer to 15,000 g mol⁻¹ and proportion of ε-caprolactone to 90 mol% enabled the manufacturing of devices with shape-memory properties. AuNRs were further functionalized with a ligand having a composition similar to the photopolymer in order to prevent aggregation of the colloid within the ink. NIR light‑triggerable shape transformation was illustrated by deploying a DLP printed stent ex vivo.

In addition to NIR light responsive devices, drug-eluting shape-memory stents based on 15,000 g mol⁻¹ poly(D,L-lactide-co-trimethylene carbonate) methacrylates that self-open at body temperature were also developed in this thesis. The stents prepared from 70−90 mol% D,L-lactide photopolymer recovered their functional shape at 37 °C in 1−3.5 min, respectively. Furthermore, the stents could release the model drugs levofloxacin (antibiotic) and nintedanib (antifibrotic agent) in a sustained fashion. The drug release kinetics could be tuned by varying the molar ratio of monomers in photopolymer’s composition, exhibited by faster release of levofloxacin from the polymer network with higher content of D,L-lactide.

The results presented in this thesis provide the basis for the rapid and highly precise manufacturing of personalized multifunctional therapeutic devices displaying elasticity, degradability, shape-memory and therapeutic functions.

Céline Jaudoin

University of Paris-Saclay, France
Title:”Characterization and evaluation of hybrid systems composed of hyaluronic acid and liposomes for the transtympanic administration of an antioxidant for cochlear implantation”
Supervisors: Prof. Amélie Bochot and Prof. Florence Agnely (University of Paris-Saclay)

Abstract PhD thesis

Nowadays, patients suffering from deafness with residual hearing could benefit from cochlear implantation. However, the insertion of this device can damage cochlear structures and induce an oxidative stress harmful for sensory cells. To protect the inner ear from this trauma, this thesis describes the encapsulation of an antioxidant, N-acetyl-L-cysteine (NAC), in a formulation adapted for transtympanic injection. For this purpose, we developed hybrid systems composed of liposomes dispersed in a hyaluronic acid network. A physicochemical study of these systems by small-angle neutron scattering and of liposome release by Transwell^® diffusion cell was performed.

It showed the impact of liposome surface and size on the microstructure of these hybrid systems and on release mechanisms. Then, NAC encapsulation in liposomes was optimized to avoid its degradation in N,N’diacetyl-L-cystine (DiNAC) and comply with transtympanic injection criteria. In guinea pigs, the liposomal gel allowed NAC release in the inner ear fluids for 15 days. Nevertheless, an unexpected ototoxicity was observed in both implanted and non-implanted animals. DiNAC was quantified in the inner ear in higher proportion than NAC. The production of glutathione and its oxidized form was not stimulated.