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Teaser, summary, work performed and final results

Periodic Reporting for period 1 - DN-CARTILOGEL (Design of double network polycarbonate-based hydrogels by simultaneous reactions: scaffolds for load-bearing soft tissue regeneration)


Articular cartilage (AC) is the white flexible load-bearing soft tissue able to withstand the highest loads in physically demanding areas of the body. Once it is damaged, its poor ability for self-repair induces a progressive loss of function that, ultimately, results in...


Articular cartilage (AC) is the white flexible load-bearing soft tissue able to withstand the highest loads in physically demanding areas of the body. Once it is damaged, its poor ability for self-repair induces a progressive loss of function that, ultimately, results in severe rheumatic or musculoskeletal degenerative conditions, which are leading causes of morbidity. Among them, osteoarthritis (OA) is already one of the ten most disabling diseases in developed countries. Therefore, OA contributes to functional impairment and loss of independence in the middle-aged and the elderly, and it represents an immense burden to patients, thus having a major impact on European society.
Unfortunately, the regeneration of AC is limited by its complex and unique structure and low self-repair capacity. Hence, the preventive repair of damaged AC remains a significant challenge in orthopaedic medicine, and DN-CARTILOGEL aimed at tackling this problem.
The overall goal of the project focused on developing a cell-based therapy using polymeric-based hydrogel matrices as biocompatible scaffolds to replace damaged AC or support new functional tissue formation. While commonly used hydrogel fabrication techniques have several practical limitations (i.e. time-consuming, multistep process, lack of control over the reproducibility of the mechanical properties, or high degree of heterogeneity), DN-CARTILOGEL prepared innovative hydrogels based on hydrophilic polymeric materials as versatile biofunctional platforms with improved mechanical strength, toughness and high water content. The ultimate goal covered the development of a straightforward path to design robust hydrogels able to induce the differentiation of adult mesenchymal stem cells (MSCs) into specialized cartilage-producing cells. Indeed, DN-CARTILOGEL project has achieved significant milestones for solving the aforementioned drawbacks and fulfilled the research objectives.

Work performed

The three work packages of the action covered (i) the preparation of robust and biocompatible hydrogels through the thiol-yne click chemistry approach, (ii) their exhaustive general characterizations and, finally, (iii) their bioapplication as tissue engineering scaffolds.
Firstly, polymeric precursors based on polyethylene glycol (PEG) were satisfactorily synthesized with specific side-chain and end-group functionalities and cross-linked in situ under physiologically relevant conditions (cell culture media, pH at 7.4, 37 °C). At this stage, two different hydrogel systems were developed. For the first one, the swelling properties of the hydrogels were finely tuned by varying the hydrophilic/hydrophobic ratio of the hydrogel polymeric chains (Figure 1). In doing so, we were able to slow down the degradation process of the hydrogels, which were then stable for more than 30 days, as well as retain their excellent mechanical performance for longer. For the second group, biopolymers (i.e. alginate, gelatin, chitosan, hyaluronic acid, and heparin) were also included in the chemical composition of the hydrogels (Figure 2). Specifically, the addition of alginate chains, crosslinked with calcium ions, not only rendered the hydrogels stretchable and with enhanced tensile performance, but also self-healing. Furthermore, in comparison to the PEG-only system, PEG/Alginate hydrogels exhibit much higher cell viability, suggesting they are ideal matrices for cell growth and proliferation. Overall, our strategy resulted in a simple but effective way to improve the properties of covalent synthetic hydrogel systems.
Regardless of the approach followed, hydrogels showed adequate gelation times (i.e. from 30 seconds to 10 minutes), which allowed their injectability, as well as high water content (86% - 95%) and gelation fraction values (74%-92%). In general, as a consequence of the nature of the chemistry exploited to prepare the hydrogels, all the systems tested displayed excellent mechanical properties. Results obtained in this part were extremely promising. The hydrogels prepared displayed a robust nature and mechanical features, in terms of compression strength and stiffness, which match those exhibited by native cartilage tissue.
Finally, adult stem cells were encapsulated within the different hydrogel systems, and their viability at specific time points was determined (Figure 3). All the systems tested were highly cytocompatible, which allowed for the growth and proliferation of the cells.
As specified in the action, Dr. Pérez-Madrigal has been actively disseminating the new knowledge generated by the DN-CARTILOGEL project, thus enhancing the quality and effectiveness of interactions between scientists, general media and the society. As a first action of dissemination, results have been (or will be soon) published in peer-reviewed journals to ease their diffusion among the international community of researchers, and always fulfilling the requirement of Horizon2020 to as open access [Polym. Chem. 2017, 8, 5082; Biomacromolecules 2017, 19, 1378; Biomater. Sci. 2018, Advance Article]. Also, the Dr. Pérez-Madrigal has attended several national and international symposia and conferences to ensure maximum diffusion of the action. Finally, Dr. Pérez-Madrigal has also been engaged with web-based and social media activities to disseminate the action, as well as events to outreach the general public and children. Most relevant, the fellow created a web-page dedicated to the project to maximize the diffusion of the action.

Final results

The progress achieved with the DN-CARTILOGEL action has allowed the preparation of robust and though hydrogels based on polymers and biopolymers overcoming all the existing drawbacks of currently followed strategies. In that sense, our approach – based on the thiol-yne click-chemistry - renders hydrogels in a one-step protocol, gelation taking place within minutes. Moreover, catalyst or purification steps are no longer needed, and the obtained hydrogels can be used as prepared, which enabled the 3D encapsulation of stem cells for their differentiation to cartilage-producing cells. Besides, the new methodology developed with this action results in a straightforward procedure to produce hydrogels as scaffolds for tissue engineering applications that can be easily translated to a commercial setting where biomaterials mimicking the ECM are needed. In addition to that, the action has explored other approaches to render hydrogels with additional features, such as nonswelling response, self-healing, improved stretchability and enhanced biocompatibility.
Overall, the DN-CARTILOGEL project has produced positive results, and the research undertaken within the frame of the action has advanced the current knowledge on hydrogels and their application as tissue engineering scaffolds. Although we are still on early stages, the hydrogel systems developed with the DN-CARTILOGEL project present great potential to be used in further studies (in vivo). In that sense, the implications of the action from a societal point of view rely on the fact that hydrogels have become a more clear solution to address a specific concerns raised by the medical community, like cartilage regeneration.
Therefore, it is clear that DN-CARTILOGEL has gone beyond the state of the art in different areas related to hydrogels as tissue engineering scaffolds, fact that will have a tremendous impact on healthcare and, accordingly, socio-economically as well.

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