Robert Liska

Strategies to Reduce Oxygen Inhibition in Photoinduced Polymerization

hydrogen from thiol, and as a result reinitiation occurs by a thiyl radical. While the thiol−ene reaction in Scheme 14 implies the formation of linear polymer from difunctional enes and difunctional thiols, the situation is in reality much more complicated with reactive vinyls such as acrylates. In such cases, both thiol−ene step growth and acrylate chain growth polymerization occur simultaneously, resulting in a difficultto-predict molecular architecture. Cramer and Bowman photocured resins with stoichiometric amounts of acrylate and thiol moieties and found acrylate conversion to be roughly twice that of thiol. This means that the kinetic rate constant of acrylate propagation is approximately 1.5 times that of thiol hydrogen abstraction. In the presence of air, reaction with thiol becomes preferential. Addition of multifunctional alkylthiols to diacrylates markedly improves final DBC. Degree of functionality was shown to have an effect both on cure time and on the modulus of the formed film. Higher functionality thiols are preferred since they increase reaction viscosity more quickly and hence slow diffusion of atmospheric oxygen. The gel point in thiol−ene polymerization, in both air and nitrogen, is greatly delayed relative to neat acrylate polymerization. While thiols tend to retard the rate of polymerization with both acrylates and methacrylates, the rate is increased in the case of vinyl esters and vinyl carbonates. In spite of the promise that thiols offer, odor (volatile thiols born from ester hydrolysis) and storage stability are two major obstacles to their widespread use. This second problem arises from the thermally induced addition to acrylates. Stabilization of thiol−ene formulations is addressed in multiple patents. In addition to small-molecule alkylthiols such as hexanedithiol (HDT) or pentaerythritol tetrakis-3-mercaptopropionate (TT), nonvolatile polymeric thiols such as homoand copolymers of mercaptopropylmethylsiloxane (MMSiO) have been investigated (Figure 7). Aromatic thiols have also been studied in photopolymerization due to their excellent hydrogen-donation capacity and better storage stability (Figure 7). Aromatic thiols have been used with type I photoinitiators and in place of amines with type II sensitizers. In the first case, addition of 0.1 wt % mercaptobenzoxazole (MBO) enhanced cure rate and mechanical properties of the film, while higher concentrations of thiol reduced cure rate. Since polymerizations were performed between KCl plates, the enhanced rate is explained by hydrogen transfer to early-stage peroxyl radicals formed with predissolved oxygen, while further hydrogen transfer retards propagating alkyl radicals. Type II triplet quenching of aryl thiols was found to be dependent on the sensitizer, viscosity, and hydrogen-donating capability of the monomer and on the presence of oxygen. With Scheme 13. Solvolysis of Acylphosphine Oxide in the Presence of an Amine Scheme 14. Main Reactions in Thiol−ene Copolymerization Figure 7. Commonly used thiols for reduced oxygen inhibition. Chemical Reviews Review dx.doi.org/10.1021/cr3005197 | Chem. Rev. XXXX, XXX, XXX−XXX O CQ as sensitizer, MBO and analogous mercaptobenzamidazole (MBI) allowed methacrylate polymerization rates in air comparable to those obtained with the commonly used amine DMAB. The polymerization rate achieved with mercaptobenzothiazole (MBT) was lower but could be increased by introduction of an electron-withdrawing nitro moiety to the aromatic ring. The thiazol dimer DBT increased polymerization rate in argon but not in air. MBO, MBI, and MBT were also tested in combination with ITX, where they were found to be effective in argon but inferior to DMAB in air. Poor reactivity with ITX is explained by the π, π* character of its lowest-lying triplet state, which purportedly abstracts hydrogen atoms less efficiently than the n, π* triplet of CQ. 3.4.3. Silanes. Organosilanes can play a number of different roles in radical polymerizations. On one hand, polysilanes with photocleavable Si−Si bonds can be utilized as photoinitiators, and on the other hand, silanes with Si−H bonds may be used as secondary additives to serve as hydrogen donors. In either case, a silane radical is formed that has very high reactivity toward molecular oxygen (kox ≈ 3 × 10 L·mol−1·s−1) to give a silylperoxyl radical (SiOO•). This silylperoxyl radical may rearrange to provide a new silyl radical that may then react with monomer or additional oxygen (Scheme 15). Polysilanes undergo efficient photocleavage to provide silane radicals and are reported to be less sensitive to oxygen inhibition. However, the efficiency of these macroradicals to initiate acrylate polymerization was found to be generally low. Small-molecule disilanes with pendant aromatic moieties to red-shift absorbance were synthesized by Laleveé et al. and found to have much better reactivity toward MMA. As expected, steric effects at the silane play an important role in initiation kinetics. Silanes with Si−H bonds may be utilized in type II systems and can even provide better results than amines, particularly when cured in air. Polysilanes with latent Si−H bonds along the backbone have also been investigated. These compounds can function in either of the above-mentioned roles and were shown to work very well as replacements for amines in visible light curing systems with CQ. A possible disadvantage of silanes is their sensitivity toward hydrolysis. 3.4.4. Other Hydrogen Donors. In addition to amines, thiols, and silanes, a number of hydrogen donors based on other elements have been tested as type II co-initiators and as peroxyl radical scavengers. While not the only parameter, bond dissociation energy (BDE) of the donor−H bond is a very useful metric for gauging the ability of a reagent to function as a hydrogen donor. Triphenyl derivatives of group 14 elements silicon, germanium and tin were tested for their ability to quench the excited state of benzophenone and for hydrogen donation to peroxyl radicals (Table 3). The quenching rate is highest for stannane, which is to be expected from the dissociation energy. Similar to thiols, hydrogen donors based on other chalcogens (selenium and tellurium) have been investigated in radical photopolymerization. Arylselenols are highly reactive hydrogen donors but tend to be avoided as they are also reactive vesicants. Organic derivatives of tellurium may be photodecomposed to provide initiating radicals; however, oxygen stability is limited. Thiols and selenols can both oxidize to provide dimers with photolabile S−S or Se−Se bonds. Although such compounds can be used as initiators, the ability to counter oxygen inhibition is compromised. While low-oxidation-state compounds such as phosphane tend not be appropriately stable, phosphites with a P−H bond have also been studied for oxygen inhibition. Schmitt et al. used didecylphenyl phosphite to reduce the photopolymerization time of methacrylates in open air. This phosphite may react directly with oxygen to form a phosphate or alternatively donate hydrogen to an alkylperoxyl radical. The phosphite radical formed from this latter reaction can be oxidized by a second peroxyl radical to provide a stable phosphate radical and an alkoxyl radical, which may reinitiate polymerization (Scheme 16). A variety of borane and metal hydride hydrogen donors that undergo similar reactions will be discussed in the next section. 3.5. Other Reducing Agents While hydrogen donors may also be classified as reducing agents, the term is used here to refer specifically to additives that react with either alkylperoxyl radicals or molecular oxygen by a reduction that does not involve hydrogen. The two most important classes of additives that serve this role are organic molecules based on either boron or phosphorus, where the oxidation state of boron or phosphorus is raised during the course of the reaction. A number of metallic-based additives are suggested for use as peroxyl radical reducing agents. One example is provided by Courtecuisse et al., demonstrating the use of zirconium complex Zr(TEA)4 to combat oxygen inhibition (Figure 8). Purportedly zirconium is oxidized by peroxyl radicals releasing an amine ligand as an initiating radical. Hydrolytic stability of the zirconium complex may, however, be a concern. 3.5.1. Boranes. Organoboranes are an interesting class of radical initiators that have also found some application in photocuring. An interesting feature of borane radical initiators is that most actually require oxygen as a co-initiator. While this may at first sound like a simple solution to avoid oxygen inhibition, the problem in this case is that formulations are not stable and react prematurely. The mechanisms given by Bhanu and Kishore for oxidation of alkylborane gives a number of radicals that can potentially initiate polymerization (Scheme 17). Although this scheme presents the reaction with a trialkylborane, the same radical interchange reaction has been observed with boronic esters, where Ingold measured a rate constant of 4.8 × 10 L·mol−1·s−1. Scheme 15. Reaction of Silyl Radical with Oxygen Table 3. Bond Dissociation Energy of Group 14 Triaryl Hydrides and Rate Constant for Hydrogen Donation to Benzophenone and tert-Butylperoxyl Radical hydrogen donor BDE (kcal·mol−1) kH→BP × 10 7 (L·mol−1·s−1) kH→tBuOO (L·mol−1·s−1)

Photopolymers with tunable mechanical properties processed by laser-based high-resolution stereolithography

Stereolithography (SLA) is a widely used technique for the fabrication of prototypes and small series products. The main advantage of SLA and related solid freeform fabrication (SFF) techniques is their capability to fabricate parts with complex shapes with high resolution. Although the spectrum of available materials has been widened in recent years, there is still a lack of materials which can be processed with SLA on a routine basis. In this work, a micro-SLA (?SLA) system is presented which can shape a number of different photopolymers with resolutions down to 5 ?m in the xy-plane and 10 ?m in the z-direction. The system is capable of processing various specifically tailored photopolymers which are based on acrylate chemistry. The materials processed for this work range from hybrid sol?gel materials (ORMOCER) to photo-crosslinked elastomers and hydrogels. The elastic moduli of these materials can be tuned over several orders of magnitude and range from 0.1 MPa to 8000 MPa. The reactivity of these monomers is sufficient for achieving writing speeds up to 500 mm s?1 which is comparable to commercial SLA resins. Various test structures are presented which show the suitability of the process for fabricating parts required for applications in micro-mechanical systems as well as for applications in biomedical engineering. Using the presented system, internal channels with a diameter of 50 ?m and a length of 1500 ?m could be fabricated. It was also possible to manufacture a micro-mechanical system consisting of a fixed axe and a free spinning turbine wheel.

Polymers for 3D Printing and Customized Additive Manufacturing

Additive manufacturing (AM) alias 3D printing translates computer-aided design (CAD) virtual 3D models into physical objects. By digital slicing of CAD, 3D scan, or tomography data, AM builds objects layer by layer without the need for molds or machining. AM enables decentralized fabrication of customized objects on demand by exploiting digital information storage and retrieval via the Internet. The ongoing transition from rapid prototyping to rapid manufacturing prompts new challenges for mechanical engineers and materials scientists alike. Because polymers are by far the most utilized class of materials for AM, this Review focuses on polymer processing and the development of polymers and advanced polymer systems specifically for AM. AM techniques covered include vat photopolymerization (stereolithography), powder bed fusion (SLS), material and binder jetting (inkjet and aerosol 3D printing), sheet lamination (LOM), extrusion (FDM, 3D dispensing, 3D fiber deposition, and 3D plotting), and 3D bioprinting. The range of polymers used in AM encompasses thermoplastics, thermosets, elastomers, hydrogels, functional polymers, polymer blends, composites, and biological systems. Aspects of polymer design, additives, and processing parameters as they relate to enhancing build speed and improving accuracy, functionality, surface finish, stability, mechanical properties, and porosity are addressed. Selected applications demonstrate how polymer-based AM is being exploited in lightweight engineering, architecture, food processing, optics, energy technology, dentistry, drug delivery, and personalized medicine. Unparalleled by metals and ceramics, polymer-based AM plays a key role in the emerging AM of advanced multifunctional and multimaterial systems including living biological systems as well as life-like synthetic systems.

Engineering 3D cell-culture matrices: multiphoton processing technologies for biological and tissue engineering applications

Cells respond to topographical, mechanical and biochemical characteristics of the surrounding environment. Capability to reconstruct these factors individually, and also acting in accord, would facilitate systematic investigations of a multitude of related biological and tissue engineering questions. The subject of the present review is a group of technologies allowing realization of customized cell-culture matrices. These methods utilize photochemistry induced by multiphoton absorption and are carried out using essentially identical equipment. Fabrication of 2D microstructured substrates, complex 3D scaffolds, containing actively induced topographies, and immobilization of biomolecules in a spatially defined manner was demonstrated with these techniques. The reviewed reports indicate that multiphoton processing is a promising technology platform for the development of standard biomimetic microenvironments for 3D cell culture.

Laser Photofabrication of Cell-Containing Hydrogel Constructs

The two-photon polymerization (2PP) of photosensitive gelatin in the presence of living cells is reported. The 2PP technique is based on the localized cross-linking of photopolymers induced by femtosecond laser pulses. The availability of water-soluble photoinitiators (PI) suitable for 2PP is crucial for applying this method to cell-containing materials. Novel PIs developed by our group allow 2PP of formulations with up to 80% cell culture medium. The cytocompatibility of these PIs was evaluated by an MTT assay. The results of cell encapsulation by 2PP show the occurrence of cell damage within the laser-exposed regions. However, some cells located in the immediate vicinity and even within the 2PP-produced structures remain viable and can further proliferate. The control experiments demonstrate that the laser radiation itself does not damage the cells at the parameters used for 2PP. On the basis of these findings and the reports by other groups, we conclude that such localized cell damage is of a chemical origin and can be attributed to reactive species generated during 2PP. The viable cells trapped within the 2PP structures but not exposed to laser radiation continued to proliferate. The live/dead staining after 3 weeks revealed viable cells occupying most of the space available within the 3D hydrogel constructs. While some of the questions raised by this study remain open, the presented results indicate the general practicability of 2PP for 3D processing of cell-containing materials. The potential applications of this highly versatile approach span from precise engineering of 3D tissue models to the fabrication of cellular microarrays.

Photo-sensitive hydrogels for three-dimensional laser microfabrication in the presence of whole organisms

Abstract. Hydrogels are polymeric materials with water contents similar to that of soft tissues. Due to their biomimetic properties, they have been extensively used in various biomedical applications including cell encapsulation for tissue engineering. The utilization of photopolymers provides a possibility for the temporal and spatial controlling of hydrogel cross-links. We produced three-dimensional (3-D) hydrogel scaffolds by means of the two-photon polymerization (2PP) technique. Using a highly efficient water-soluble initiator, photopolymers with up to 80 wt.% water were processed with high precision and reproducibility at a writing speed of 10  mm/s. The biocompatibility of the applied materials was verified using Caenorhabditis elegans as living test organisms. Furthermore, these living organisms were successfully embedded within a 200×200×35 μm3 hydrogel scaffold. As most biologic tissues exhibit a window of transparency at the wavelength of the applied femtosecond laser, it is suggested that 2PP is promising for an in situ approach. Our results demonstrate the feasibility of and potential for bio-fabricating 3-D tissue constructs in the micrometre-range via near-infrared lasers in direct contact with a living organism.

Initiation efficiency and cytotoxicity of novel water-soluble two-photon photoinitiators for direct 3D microfabrication of hydrogels

The lack of efficient water-soluble two-photon absorption (TPA) photoinitiators has been a critical obstruction for three dimensional hydrogel microfabrications with high water load by two-photon induced polymerization (TPIP). In this paper, a series of cyclic benzylidene ketone-based two-photon initiators, containing carboxylic acid sodium salts to improve water solubility, were synthesized via classical aldol condensation reactions. The cytotoxicity of cyclopentanone-based photoinitiators is as low as that of the well-known biocompatible photoinitiator Irgacure 2959 as assessed in the dark with MG63 cell line. In z-scan measurement, the TPA cross sections of the investigated initiators are only moderate in water, while the TPA values for hydrophobic analogues measured in chloroform were much higher. All novel initiators exhibited broad processing windows in TPIP tests using hydrophilic photopolymers with up to 50 wt% of water. Impressively, microfabrication of hydrogels with excellent precision was possible at a writing speed as high as 100 mm s−1.

Fabrication and moulding of cellular materials by rapid prototyping

Many biological materials (e.g. wood, cork, bone, etc) are based on cellular designs, since cellular architectures offer the possibility to optimise the properties (stiffness, density, strength, etc) of a structure according to the environmental conditions the structure is exposed to. By using rapid prototyping, it is possible to fabricate cellular materials on a similar size scale as in natural material-structures. By using appropriate moulding techniques, these structures can be fabricated out of a wide variety of materials (polymers, ceramics, composites). In this work, several RP techniques are investigated regarding their suitability for the fabrication of cellular solids. The main focus is on using direct light projection (stereolithography) in combination with gelcasting as moulding technique. Besides using commercial light-sensitive resins, a class of newly developed water-soluble resins has been evaluated regarding its usability as sacrificial mould material.

Acylgermanes: Photoinitiators and Sources for Ge-Centered Radicals. Insights into their Reactivity

Acylgermanes have been shown to act as efficient photoinitiators. In this investigation we show how dibenzoyldiethylgermane 1 reacts upon photoexcitation. Our real-time investigation utilizes femto- and nanosecond transient absorption, time-resolved EPR (50 ns), photo-chemically induced dynamic nuclear polarization, DFT calculations, and GC-MS analysis. The benzoyldiethylgermyl radical G• is formed via the triplet state of parent 1. On the nanosecond time scale this radical can recombine or undergo hydrogen-transfer reactions. Radical G• reacts with butyl acrylate at a rate of 1.2 ± 0.1 × 10(8) and 3.2 ± 0.2 × 10(8) M(-1) s(-1), in toluene and acetonitrile, respectively. This is ~1 order of magnitude faster than related phosphorus-based radicals. The initial germyl and benzoyl radicals undergo follow-up reactions leading to oligomers comprising Ge-O bonds. LC-NMR analysis of photocured mixtures containing 1 and the sterically hindered acrylate 3,3-dimethyl-2-methylenebutanoate reveals that the products formed in the course of a polymerization are consistent with the intermediates established at short time scales.

Evaluation of Biocompatible Photopolymers I: Photoreactivity and Mechanical Properties of Reactive Diluents

Important characteristics of bone replacement materials are to support the attachment, growth, and differentiation of osteogenic cells. A second important characteristic of the material is that it can be photopolymerized, which allows the material to be applied to rapid prototyping that enables us to fabricate scaffolds in nearly any shape and structure. In these investigations, reactivity and biocompatibility of different types of commercially available acrylates and photoinitiators were determined. Cell viability was related to the functional groups in the monomers present, e.g., oligoethyleneglycol, urethane‐, hydroxy‐ or carboxy groups. It was found that polymers obtained from acrylates with urethane units, most dialkylacrylamide and especially trimethylolpropane triacrylate gave outstanding biocompatibility. Mechanical testing proved to have significantly better performance (stiffness, strength) than many known thermoplastic biopolymers.