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ADvanced nanocomposite MAterIals fOr in situ treatment and ultRAsound-mediated management of osteoarthritis

Periodic Reporting for period 2 - ADMAIORA (ADvanced nanocomposite MAterIals fOr in situ treatment and ultRAsound-mediated management of osteoarthritis)

Reporting period: 2020-08-01 to 2022-01-31

GENERAL INFORMATION
ADMAIORA (ADvanced nanocomposite MAterIals fOr in situ treatment and ultRAsound-mediated management of osteoarthritis) is a research project funded under the Horizon 2020 EU Framework Programme (Call: H2020-NMBP-TR-IND-2018, Research and Innovation action), coordinated by Prof. Leonardo Ricotti at the Scuola Superiore Sant’Anna (Pisa, Italy).

WHAT IS OSTEOARTHRITIS?
Osteoarthritis (OA) is a major burden that affects ~ 40 million of EU citizens, with enormous direct and indirect costs for the European healthcare systems. This disease involves the degeneration of cartilage and other joint structures and is one of the most common causes of pain and disability in middle-aged and elderly people. Over the next decade, the number of people affected by OA is expected to double due to population ageing and increased rate of obesity (a risk factor for OA), resulting in a significant burden at the society level. According to the United Nations, by 2050, 130 million people will suffer from OA worldwide, of whom 40 million will be severely disabled by the disease. This represents an issue that is largely unsolved, at present.

THE PROJECT
ADMAIORA aims, in the long-term, at increasing the healthy and active lifespan of people affected by OA, by considerably slowing down or even stopping the degeneration process, thus delaying by several years or even avoiding surgical interventions for total joint replacement.
To make this challenging objective a reality, the project partners will collaborate in the investigation of nanotechnologies, advanced materials, remotely physical stimulation, advanced manufacturing, wearable devices and cloud platforms into a unique workflow. ADMAIORA will explore the potential of smart nanocomposite materials and stem cells, in synergy with external physical stimuli (based on low-intensity ultrasound), for stopping the degeneration of cartilage during OA at early stages. Within the project time-frame (4 years), the target is to demonstrate the ground-breaking potential of such a regenerative approach, at a preclinical level.
ADMAIORA will contribute to keep EU a leader in high-impact and high-level research in the biomedical field. In addition, the project outcomes are expected to dramatically improve patients’ quality of life and their healthy and active lifespan in the long-term, thus promoting healthy and active ageing, which is a priority of the European Commission. This would also imply to considerably reduce the financial burden on European healthcare systems, related to OA. Finally, the project efforts are also expected to generate new market opportunities in different niches, such as surgical/arthroscopic tools, biomaterials and cells for tissue regeneration, ultrasonic technologies and Internet-of-Things frameworks.

OBJECTIVES
Overall, ADMAIORA will target a ground-breaking paradigm that may revolutionize OA treatment. Within the project time-frame (4 years) the target is to achieve a 60% reduction of degeneration in OA animal models treated with the ADMAIORA technologies, with respect to control (untreated) ones, after 4 weeks, and a 90% reduction after 3 months. To achieve this ambitious objective the Consortium will evolve and merge technologies that already showed a high potential as experimental proof of concepts and will bring them at a preclinical level.
The ADMAIORA Consortium will develop biosynthetic hydrogels embedded with carbon-based nanomaterials, conferring higher mechanical and lubrication properties, and piezoelectric nanoparticles enabling responsivity to remote wireless ultrasound waves. Stem cells derived from autologous adipose tissue, which already demonstrated anti-inflammatory and regenerative properties, will be entrapped in the hydrogels. Materials and cells will be delivered in situ through an innovative handheld 3D bioprinter, embedded in an arthroscopic tool. A custom brace will be designed and equipped with ultrasound probes for both monitoring the joint status and stimulating the implanted piezoelectric nanobiomaterial. A dedicated App will allow a direct connection between patient and physician in an Internet of Things framework.
At the end of the second Reporting Period, the Consortium made a selection of the most promising material formulations (VitroGel and gellan gum) among those tested, as well as the most suitable nanomaterial candidates for being integrated within the hydrogels (barium titanate nanoparticles and graphene oxide nanoflakes). This allowed speeding up the efforts and getting good results on the different work packages, keeping the project timeline on time. VitroGel-based and gellan-gum-based nanocomposite hydrogels were developed and characterized, proving their suitability for the ADMAIORA application. WP4 has been completed effectively and on time, with the development of software simulations that will allow translating the optimal ultrasound dose found in vitro into the in-vivo scenario. In WP5, different technologies were developed: three wearable brace solutions for facilitating an objective US-based diagnosis, a brace for stimulating the target area, a wearable bracelet to monitor patient's activities, a balance board to record balance-related performance, etc. Furtehrmore, the development of the two versions of handheld bioprinter were evolved and characterized and are close to be finalized. One of them was also tested on a human cadaver, with good results obtained. The activities of WP6 demonstrated exciting results, which validated the high-risk hypothesis on which ADMAIORA was grounded (a boost in chondrogenesis due to the combination of piezoelectric nanomaterials and ultrasound waves). This evidence, confirmed by several independent experiments, are expected to generate a high impact factor paper and to pave the way to in vivo tests. The activities covered in WP7 and WP8 have been carried out successfully. Deviations from Annex I and Annex II have been minor and have been managed timely. The use of resources is in line with the expected one. The project impact is not downgraded, but on the contrary, it confirms to be very high, at both scientific and clinical/commercial levels. At the end of the second Reporting Period, the Consortium has filed 4 patents and published 14 journal papers, 5 papers in conference proceedings and 11 conference abstracts.
ADMAIORA proposes a ground-breaking ambitious approach that goes well beyond the current state-of-the-art concerning articular cartilage healing/regeneration. We expect that the Consortium, at the end of the 4 years, will be able to demonstrate for the first time on animal models the efficacy of this new paradigm, which aims to be a game-changing approach in the field of osteoarthritis treatment. The updated results obtained by the Consortium in the second Reporting Period confirm the potential of the proposed approached, especially thanks to exciting in vitro results, which confirmed an important boost in chondrogenesis due to the combination of piezoelectric nanomaterials and ultrasound waves. This represents a considerable jump ahead in the field and paves the way to in vivo tests, planned in the 3rd Period. The 4 patents filed by the Consortium also guarantee a good portfolio of IP-protected technologies, which maximize their possible future exploitation. The potential impact of the project confirms to be very large.
Graphical representation of implanted nanocomposite materials, ultrasound waves and wearable devices