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Scientific Unit
Abstract Optogenetics and photonic technologies are changing the future of medicine. To implement light-based therapies in the clinic, patient-friendly devices that can deliver light inside the body while offering tunable properties and compatibility with soft tissues are needed. Here extrusion printing of degradable, hydrogel-based optical waveguides with optical losses as low as 0.1 dB cm−1 at visible wavelengths is described. Core-only and core-cladding fibers are printed at room temperature from polyethylene glycol (PEG)-based and PEG/Pluronic precursors, and cured by in situ photopolymerization. The obtained waveguides are flexible, with mechanical properties tunable within a tissue-compatible range. Degradation times are also tunable by adjusting the molar mass of the diacrylate gel precursors, which are synthesized by linking PEG diacrylate (PEGDA) with varying proportions of DL-dithiothreitol (DTT). The printed waveguides are used to activate photochemical and optogenetic processes in close-to-physiological environments. Light-triggered migration of cells in a photoresponsive 3D hydrogel and drug release from an optogenetically-engineered living material by delivering light across >5 cm of muscle tissue are demonstrated. These results quantify the in vitro performance, and reflect the potential of the printed degradable fibers for in vivo and clinical applications.
Hydrogel biomaterials for wound care dressing and tissue gluing need to adhere to tissue and on-demand disappear. Advanced tissue adhesives also envision the encapsulation of therapeutic drugs or cells to promote the healing process. The design of hydrogels with all these functionalities is challenging. In this PhD, hydrogels that fulfil several of the previous properties for wound dressing at reasonable chemical complexity is presented. These hydrogels can be formed in situ and encapsulate cells, they can adhere to tissue and detach after use by light exposure at cytocompatible doses. The developed photodegradable hydrogels are based on 4-star PEG end-catechol precursors for crosslinking, and intercalate photocleavable o-nitrobenzyl groups in their structure. These gels can form at mild oxidative conditions and encapsulate cells or microparticles. UV-vis light exposure (λ= 365 or 405 nm) photocleavables the nitrobenzyl moiety and promotes degradation. This can occur at cytocompatible doses, and enables on-demand detachment from tissue and release of the encapsulated materials or cells. These biomaterials are interesting for the development of advanced tissue adhesives and cell therapies, by expanding the range of functionality of existing choices.
In this paper we explore the printability of reversible networks formed by catechol functionalized PEG solutions and metal cations (Al3+, Fe3+ or V3+). The printability and shape fidelity were dependent on the ink composition (metal ion type, pH, PEG molecular weight) and printing parameters (extrusion pressure and printing speed). The relaxation time, recovery rate and viscosity of the inks were analyzed in rheology studies and correlated with thermodynamic and ligand exchange kinetic constants of the dynamic bonds and the printing performance (i.e. shape fidelity of the printed structures). The relevance of the relaxation time and ligand exchange kinetics for printability was demonstrated. Cells seeded on the materials crosslinked with Al3+, Fe3+ ions were viable and revealed well-spread morphologies during 7 day culture, indicating the potential of the formulations to be used as inks for cell encapsulation. The proposed dynamic ink design offers significant flexibility for 3D bioprinting, and enables straightforward adjustment of the printable formulation to meet application-specific needs.
Hydrogels for wound management and tissue gluing have to adhere to tissue for a given time scale and then disappear, either by removal from the skin or by slow degradation in applications inside the body. Advanced wound management materials also envision the encapsulation of therapeutic drugs or cells to support the natural healing process. The design of hydrogels that can fulfill all these properties with minimal chemical complexity, a stringent condition to favor transfer into a real medical device, is challenging. Herein, we present a hydrogel design with moderate structural complexity that fulfills a number of relevant properties for wound dressing: it can form in situ and encapsulate cells, it can adhere to tissue, and it can be degraded on demand by light exposure under cytocompatible conditions. The hydrogels are based on starPEG macromers terminated with catechol groups as crosslinking units and contain intercalated photocleavable triazole nitrobenzyl groups. Hydrogels are formed under mild conditions (HEPES buffer with 9-18 mM of sodium periodate as oxidant) and are compatible with encapsulated cells. Upon light-irradiation, the cleavage of the nitrobenzyl group mediates depolymerization, which enables on-demand release of cells or debonding from tissue. The molecular design and obtained properties are interesting for the development of advanced wound dressings and cell therapies, and expand the range of functionality of current alternatives.
The permeability of the Human Trabecular Meshwork (HTM) regulates eye pressure via a porosity gradient across its thickness modulated by stacked layers of matrix fibrils and cells. Changes in HTM porosity are associated with increases in intraocular pressure and the progress of diseases like glaucoma. Engineered HTMs could help to understand the structure-function relation in natural tissues, and lead to new regenerative solutions. Here, melt electrowriting (MEW) is explored as a biofabrication technique to produce fibrillar, porous scaffolds that mimic the multilayer, gradient structure of native HTM. Poly(caprolactone) constructs with a height of 125-500 μm and fiber diameters of 10-12 μm are printed. Scaffolds with a tensile modulus between 5.6 and 13 MPa, and a static compression modulus in the range of 6-360 kPa are obtained by varying the scaffolds design, i.e., density and orientation of the fibers and number of stacked layers. Primary HTM cells attach to the scaffolds, proliferate, and form a confluent layer within 8-14 days, depending on the scaffold design. High cell viability and cell morphology close to that in the native tissue are observed. The present work demonstrates the utility of MEW to reconstruct complex morphological features of natural tissues.Competing Interest StatementThe authors have declared no competing interest.
The permeability of the human trabecular meshwork (HTM) regulates eye pressure via a porosity gradient across its thickness modulated by stacked layers of matrix fibrils and cells. Changes in HTM porosity are associated with increases in intraocular pressure and the progress of diseases such as glaucoma. Engineered HTMs could help to understand the structure–function relation in natural tissues and lead to new regenerative solutions. Here, melt electrowriting (MEW) is explored as a biofabrication technique to produce fibrillar, porous scaffolds that mimic the multilayer, gradient structure of native HTM. Poly(caprolactone) constructs with a height of 125–500 μm and fiber diameters of 10 –12 μm are printed. Scaffolds with a tensile modulus between 5.6 and 13 MPa and a static compression modulus in the range of 6 –360 kPa are obtained by varying the scaffold design, that is, the density and orientation of the fibers and number of stacked layers. Primary HTM cells attach to the scaffolds, proliferate, and form a confluent layer within 8–14 days, depending on the scaffold design. High cell viability and cell morphology close to that in the native tissue are observed. The present work demonstrates the utility of MEW for reconstructing complex morphological features of natural tissues.
