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Biocompatibility of photopolymers for additive manufacturing

  • Stefan Leonhardt EMAIL logo , Martin Klare , Maurice Scheer , Theresa Fischer , Burghard Cordes and Markus Eblenkamp
Published/Copyright: September 30, 2016
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Current Directions in Biomedical Engineering
From the journal Current Directions in Biomedical Engineering Volume 2 Issue 1

Abstract

To establish photopolymers for the production of class II or class III medical products by additive manufacturing it is essential to know which components of photopolymeric systems, consisting of monomers, photoinitiators and additives, are the determining factors on their biocompatible properties. In this study the leachable substances of a cured photopolymeric system were eluted and identified by HPLC-MS detection. In addition the cured photopolymer was testes for cytotoxicity and genotoxicity according to DIN EN ISO 10993 for long time applications. The results showed that uncured residual monomers are the determining factor on the biocompatible properties of the photopolymeric system. Strategies to reduce these residual monomers in the cured photopolymer are presented.

Keywords: additive manufacturing; biocompatibility; digital light processing; monomers; patient individual medical products; photopolymeric system

1 Introduction

Additive manufacturing (AM) allows the production of three-dimensional (3D) objects layer by layer, based on a digital model [1], [2]. These models can be designed by using a CAD software or 3d imaging data (e.g. CT, MRI or three dimensional X-ray diagnostics) [3]. Regarding medical applications AM offers the great option to produce patient individual medical devices [4].

Until now the production of class II or class III medical devices by AM has mostly been realized by manufacturing metal alloy implants. However, since also polymers are widely used nowadays for class II or class III medical devices, there is a need to establish polymeric based AM methods for these applications.

A promising polymeric AM method is digital light processing (DLP) which is based on the selective exposer of a photopolymeric system. DLP is especially characterized by high speed, good resolution, and high surface quality [5]. However, so far the use of this technology for long time medical applications is not established yet because there have been very few studies on the biocompatible properties of the photopolymeric systems. Zhu et al. showed in their study that many photopolymers (Watershed 11122XC, Dreve Fototec 7150 Clear, VisiJet SL Clear and Form 1 Clear resin) are not biocompatible as they appear to leach toxic substances [6], [7].

Photopolymeric systems basically consists of three components [8]:

  • Monomers: long-chain molecules, which ensure the required mechanical properties

  • Photoinitiators: molecules, which split into radicals after energy input and thus induce the curing reaction

  • Additives: e.g. UV-stabilisators to prevent uncontrolled curing reactions

To establish photopolymers for production of class II or class III medical products the biocompatibility of the material must be ensured. In this study a highly promising photopolymeric system is evaluated regarding its biocompatible properties.

2 Material and methods

2.1 Additive manufacturing of specimens

According to DIN EN ISO 10993 specimens (50 mm × 10 mm × 1 mm) for the creation of eluates for HPLC-MS detection, for cytotoxicity tests and for genotoxicity tests were manufactured (layer thickness 100 μm) using a DLP-printer (FAB-12, pro3dure medical GmbH) and GR-10 (pro3dure medical GmbH) as a photopolymeric system. After the printing process the specimens were cleaned with a 70% isopropanol solution in an ultrasonic bath for 15 min and hardened in an UV-light-chamber for 7 min.

2.2 HPLC-MS detection

To detect leachable substances from the cured specimens, three specimens were stored each in 50 ml water at 37°C for 7 days. As a reference, pure non-cured photopolymer monomers, photoinitiators and UV-stabilisators were dissolved each in deionized water. The extract and the reference solutions were analysed by HPLC-MS (Agilent Technologies Deutschland GmbH). A chromatography column type C-18 with the dimensions 3 μm × 2.1 mm × 125 mm was used.

2.3 Cytotoxicity testing

Cytotoxicity tests were performed with a cell line of fibroblasts (Hs27) and a Cell Counting Kit-8 (Dojindo, CCK-8) according to DIN EN ISO 10993-5 (Tests for in vitro cytotoxicity). DMEM was used as extraction medium. The extraction time was 3, 7, 14 and 30 days. According to the norm a reduction of the viability of cells by 30% is considered as a cytotoxic effect.

2.4 Genotoxicity testing

To investigate the genotoxicity, respectively the mutagenicity, a Salmonella typhimurium reverse mutation test (Ames test) with extracts of the cured photopolymer was performed according to DIN EN ISO 10993-3 (Tests for genotoxicity, carcinogenicity and reproductive toxicity). The extraction medium was DMSO and the extraction times were 3, 7, 14, and 30 days. The used bacteria strain was Salmonella typhimurium TA 18 (Tinova Biochem GmbH). 2-nitrofluorene (2NF) was used as a positive control.

3 Results

3.1 Leachable substances

The upper part of Figure 1 shows the mass spectrum of the extracted solution. In the lower part the exact mass numbers of the highest peak of the mass spectrum can be seen in detail. Figure 2 shows the mass numbers of the reference solution with the pure photopolymer monomers.

Figure 1: Upper part: Characteristic of the mass spectrum of the extracted solution. Lower part: Mass spectrum of the highest peak in detail.
Figure 1:

Upper part: Characteristic of the mass spectrum of the extracted solution. Lower part: Mass spectrum of the highest peak in detail.

Figure 2: Mass spectrum of the reference solution with pure photopolymer monomers.
Figure 2:

Mass spectrum of the reference solution with pure photopolymer monomers.

Due to the accordance of the mass numbers it could be proofed that the main component of the leachable substances are the monomers.

3.2 Cytotoxicity testing

The cytotoxicity tests showed that extracts of the cured photopolymer reduces the viability of cells by 20%, 26% and 29% after 3, 7 and 14 days of elution time (see Figure 3). Only after 30 days of elution time the cell viability is reduced by 45% and thus drops below the cytotoxicity level.

Figure 3: Cytotoxicity tests showed that the cured photopolymer induces no cytotoxic effect for usage up to 14 days. For usage up to 30 days a minor cytotoxic effect could be observed (n = 3).
Figure 3:

Cytotoxicity tests showed that the cured photopolymer induces no cytotoxic effect for usage up to 14 days. For usage up to 30 days a minor cytotoxic effect could be observed (n = 3).

3.3 Genotoxicity of the photopolymer

As widely used in literature a 2-3 fold increase of bacteria growth of the probe compared to the negative control was chosen as a cut-off between mutagenic and non-mutagenic response [9]. The tested photopolymer eluates showed no genotoxic effect up to an elution time of 30 days (see Figure 4).

Figure 4: Genotoxicity tests showed that the cured photopolymer causes no genotoxic effect for elution times up to 30 days (n = 3).
Figure 4:

Genotoxicity tests showed that the cured photopolymer causes no genotoxic effect for elution times up to 30 days (n = 3).

4 Discussion

This study showed that the main component of the leachable substances out of the cured photopolymer are by far non-cured residual monomers, which therefore might have the greatest influence on the biocompatibility of the photopolymeric system. However, cytotoxicity tests showed that the cured photopolymer anyway can be considered as non-cytotoxic for elution times up to 14 days. For elution times of 30 days the photopolymer showed a minor cytotoxic effect, which might be caused by reaching a critical concentration of residual monomers. One option to further improve the biocompatibility is a post-processing of the cured photopolymer, like extraction of residual photopolymer monomers with supercritical CO2. Another approach to reduce the amount of leachable substances would be the chemical modification of the chain length of the photopolymer monomers to reduce water uptake and therefore the dissolving of substances.

Genotoxicity tests revealed that there are no indications for mutagenic effects of the cured photopolymer.

5 Conclusion

In conclusion this study identified residual monomers as the presumable highest influence factor on the biocompatible properties of the photopolymeric system. Cytotoxicity tests revealed that the photopolymeric system GR-10 showed an only minor cytotoxic effect for very long elution times of 30 days, while for commonly used extraction times of up to 7 days no cytotoxic effect could be detected. A mutagenic effect could not be observed. Therefore, GR-10 must be considered as a promising material for the production of class II or class III medical products on the basis of polymeric additive manufacturing, especially against the background that the release of residual monomers can be further reduced by simple to apply post-processing methods.

Acknowledgement

The project is supported by the AiF Arbeitsgemeinschaft industrieller Forschungsvereinigungen “Otto von Guericke” e.V., based on a decision by the Deutscher Bundestag.

Author’s Statement

Research funding: The author state no funding involved. Conflict of interest: Authors state no conflict of interest. Material and Methods: Informed consent: Informed consent has been obtained from all individuals included in this study. Ethical approval: The research related to human use complies with all the relevant national regulations, institutional policies and was performed in accordance with the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee.

References

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Published Online: 2016-9-30
Published in Print: 2016-9-1

©2016 Stefan Leonhardt et al., licensee De Gruyter.

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

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https://doi.org/10.1515/cdbme-2016-0028
Keywords for this article
additive manufacturing; biocompatibility; digital light processing; monomers; patient individual medical products; photopolymeric system
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  123. Plasma treatment on novel carbon fiber reinforced PEEK cages to enhance bioactivity
  124. Wear of a total intervertebral disc prosthesis
  125. Digital health and digital biomarkers – enabling value chains on health data
  126. Usability in the lifecycle of medical software development
  127. Influence of different test gases in a non-destructive 100% quality control system for medical devices
  128. Device development guided by user satisfaction survey on auricular vagus nerve stimulation
  129. Empirical assessment of the time course of innovation in biomedical engineering: first results of a comparative approach
  130. Effect of left atrial hypertrophy on P-wave morphology in a computational model
  131. Simulation of intracardiac electrograms around acute ablation lesions
  132. Parametrization of activation based cardiac electrophysiology models using bidomain model simulations
  133. Assessment of nasal resistance using computational fluid dynamics
  134. Resistance in a non-linear autoregressive model of pulmonary mechanics
  135. Inspiratory and expiratory elastance in a non-linear autoregressive model of pulmonary mechanics
  136. Determination of regional lung function in cystic fibrosis using electrical impedance tomography
  137. Development of parietal bone surrogates for parietal graft lift training
  138. Numerical simulation of mechanically stimulated bone remodelling
  139. Conversion of engineering stresses to Cauchy stresses in tensile and compression tests of thermoplastic polymers
  140. Numerical examinations of simplified spondylodesis models concerning energy absorption in magnetic resonance imaging
  141. Principle study on the signal connection at transabdominal fetal pulse oximetry
  142. Influence of Siluron® insertion on model drug distribution in the simulated vitreous body
  143. Evaluating different approaches to identify a three parameter gas exchange model
  144. Effects of fibrosis on the extracellular potential based on 3D reconstructions from histological sections of heart tissue
  145. From imaging to hemodynamics – how reconstruction kernels influence the blood flow predictions in intracranial aneurysms
  146. Flow optimised design of a novel point-of-care diagnostic device for the detection of disease specific biomarkers
  147. Improved FPGA controlled artificial vascular system for plethysmographic measurements
  148. Minimally spaced electrode positions for multi-functional chest sensors: ECG and respiratory signal estimation
  149. Automated detection of alveolar arches for nasoalveolar molding in cleft lip and palate treatment
  150. Control scheme selection in human-machine- interfaces by analysis of activity signals
  151. Event-based sampling for reducing communication load in realtime human motion analysis by wireless inertial sensor networks
  152. Automatic pairing of inertial sensors to lower limb segments – a plug-and-play approach
  153. Contactless respiratory monitoring system for magnetic resonance imaging applications using a laser range sensor
  154. Interactive monitoring system for visual respiratory biofeedback
  155. Development of a low-cost senor based aid for visually impaired people
  156. Patient assistive system for the shoulder joint
  157. A passive beating heart setup for interventional cardiology training
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