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The gold standard of auricular reconstruction involves manual graft assembly from autologous costal cartilage. The intervention may require multiple surgical procedures and lead to donor-site morbidity, while the outcome is highly dependent on individual surgical skills. A tissue engineering approach provides the means to produce cartilage grafts of a defined shape from autologous chondrocytes. The use of autologous cells minimizes the risk of host immune response; however, factors such as biomaterial compatibility and in vitro maturation of the tissue-engineered (TE) cartilage may influence the engraftment and shape-stability of TE implants. Here, this work tests the biocompatibility of bioprinted autologous cartilage constructs in a rabbit model. The TE cartilage is produced by embedding autologous auricular chondrocytes into hyaluronan transglutaminase (HATG) based bioink, previously shown to support chondrogenesis in human auricular chondrocytes in vitro and in immunocompromised xenotransplantation models in vivo. A drastic softening and loss of cartilage markers, such as sulfated glycosaminoglycans (GAGs) and collagen type II are observed. Furthermore, fibrous encapsulation and partial degradation of the transplanted constructs are indicative of a strong host immune response to the autologous TE cartilage. The current study thus illustrates the crucial importance of immunocompetent autologous animal models for the evaluation of TE cartilage function and compatibility., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

Volumizing fillers aim to create or restore facial volume in fat layers. To provide strong tissue lifting and long-term persistence, gels are generally designed with stiff properties, characterized by a high storage modulus (G'). However, clinical evidence shows a discrepancy between high G' and good lifting capacities, especially after skin tension has been exerted on the gel. To better explore the in vivo behavior of a gel, we first evaluated the elastic moduli of five commercial volumizers (RHA 4 , JUV VOL , RES VOL , RES LYFT , and BEL VOL ) in dynamic compression mode, E'. We further developed a Projection Index score based on the rheological assessment of creep in compression to mimic skin tension-induced stress relaxation (flattening). Finally, the ability of a gel to resist enzymatic degradation was analyzed with a multidose approach. Despite similar clinical indications, volumizers exhibited distinct behaviors. RHA 4 and BEL VOL showed the highest E' values (resistance to strain), RHA 4 , JUV VOL , and RES VOL exhibited the greatest projection capacities, while JUV VOL and RHA 4 offered the largest persistence to enzymatic degradation. In this article, we introduce the use of the Projection Index to efficiently assess the ability of a gel to lift tissues, thus increasing preclinical models' efficiency and reducing the need for animal studies.

Minimally invasive hyaluronan (HA) tissue fillers are routinely employed to provide tissue projection and correct age-related skin depressions. HA fillers can advantageously be degraded by hyaluronidase (HAase) administration in case of adverse events. However, clear guidelines regarding the optimal dosage and mode of administration of HAase are missing, leaving a scientific gap for practitioners in their daily practice. In this study, we implemented a novel rheological procedure to rationally evaluate soft tissue filler degradability and optimize their degradation kinetics. TEOSYAL RHA ® filler degradation kinetics in contact with HAase was monitored in real-time by rheological time sweeps. Gels were shown to degrade as a function of enzymatic activity, HA concentration, and BDDE content, with a concomitant loss of their viscoelastic properties. We further demonstrated that repeated administration of small HAase doses improved HA degradation kinetics over large single doses. Mathematical analyses were developed to evaluate the degradation potential of an enzyme. Finally, we tuned the optimal time between injections and number of enzymatic units, maximizing degradation kinetics. In this study, we have established a scientific rationale for the degradation of HA fillers by multidose HAase administration that could serve as a basis for future clinical management of adverse events.

3D bioprinting offers an excellent opportunity to provide tissue-engineered cartilage to microtia patients. However, hydrogel-based bioinks are hindered by their dense and cell-restrictive environment, impairing tissue development and ultimately leading to mechanical failure of large scaffolds in vivo . Granular hydrogels, made of annealed microgels, offer a superior alternative to conventional bioinks, with their improved porosity and modularity. We have evaluated the ability of enzymatically crosslinked hyaluronic acid (HA) microgel bioinks to form mature cartilage in vivo . Microgel bioinks were formed by mechanically sizing bulk HA-tyramine hydrogels through meshes with aperture diameters of 40, 100 or 500 µ m. Annealing of the microgels was achieved by crosslinking residual tyramines. Secondary crosslinked scaffolds were stable in solution and showed tunable porosity from 9% to 21%. Bioinks showed excellent rheological properties and were used to print different objects. Printing precision was found to be directly correlated to microgel size. As a proof of concept, freeform reversible embedding of suspended hydrogels printing with gelation triggered directly in the bath was performed to demonstrate the versatility of the method. The granular hydrogels support the homogeneous development of mature cartilage-like tissues in vitro with mechanical stiffening up to 200 kPa after 63 d. After 6 weeks of in vivo implantation, small-diameter microgels formed stable constructs with low immunogenicity and continuous tissue maturation. Conversely, increasing the microgel size resulted in increased inflammatory response, with limited stability in vivo . This study reports the development of new microgel bioinks for cartilage tissue biofabrication and offers insights into the foreign body reaction towards porous scaffolds implantation., (Creative Commons Attribution license.)

Repairing or replacing damaged human tissues has been the ambitious goal of regenerative medicine for over 25years. One promising approach is the use of hydrated three-dimensional scaffolds, known as hydrogels, which have had good results repairing tissues in pre-clinical trials. Benefiting from breakthrough advances in the field of biology, and more particularly regarding cell/matrix interactions, these hydrogels are now designed to recapitulate some of the fundamental cues of native environments to drive the local tissue regeneration. We highlight the key parameters that are required for the development of smart and biomimetic hydrogels. We also review the wide variety of polymers, crosslinking methods, and manufacturing processes that have been developed over the years. Of particular interest is the emergence of supramolecular chemistries, allowing for the development of highly functional and reversible biohydrogels. Moreover, advances in computer assisted design and three-dimensional printing have revolutionized the production of macroporous hydrogels and allowed for more complex designs than ever before with the opportunity to develop fully reconstituted organs. Today, the field of biohydrogels for regenerative medicine is a prolific area of research with applications for most bodily tissues. On top of these applications, injectable hydrogels and macroporous hydrogels (foams) were found to be the most successful. While commonly associated with cells or biologics as drug delivery systems to increase therapeutic outcomes, they are steadily being used in the emerging fields of organs-on-chip and hydrogel-assisted cell therapy. To highlight these advances, we review some of the recent developments that have been achieved for the regeneration of tissues, focusing on the articular cartilage, bone, cardiac, and neural tissues. These biohydrogels are associated with improved cartilage and bone defects regeneration, reduced left ventricular dilation upon myocardial infarction and display promising results repairing neural lesions. Combining the benefits from each of these areas reviewed above, we envision that an injectable biohydrogel foam loaded with either stem cells or their secretome is the most promising hydrogel solution to trigger tissue regeneration. A paradigm shift is occurring where the combined efforts of fundamental and applied sciences head toward the development of hydrogels restoring tissue functions, serving as drug screening platforms or recreating complex organs., (Copyright © 2017 Elsevier B.V. All rights reserved.)