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

Periodic Reporting for period 1 - ADMAIORA (ADvanced nanocomposite MAterIals fOr in situ treatment and ultRAsound-mediated management of osteoarthritis)

Reporting period: 2019-01-01 to 2020-07-31

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 first reporting Period, the Consortium successfully worked on the definition of clinical, biological and technical specifications, which drove the subsequent project research efforts. Then, a series of hydrogel formulations was developed and evaluated, with the aim to assess the most promising polymeric matrix to host nanoparticles and stem cells. The most promising solutions, at the end of the first reporting Period, resulted mathacrylated gellan gum and VitroGel. Still in WP3, graphene oxide, reduced graphene oxide, carbon nanotubes and piezoelectric nanomaterials (BaTiO3 nanoparticles, ZnO nnowires and KNN-LTS nanoparticles) were successfully produced. In WP4, two different platforms for controlled ultrasound stimulation were successfully produced (leading also to a patent filing) and validated in vitro. Appropriate models for future translation in vivo also started to be approached. In WP5, a preliminary version of the wearable brace was achieved. Interesting results were obtained on the procesing of raw radiofrequency ultrasound data, which allowed discriminating (through a non-invasive technique) different biochemical compositions of tissue-mimicking materials. In WP5 two versions of a handheld bioprinting tool were also pursued, with the development of prototypes and with the filing of one patent. Still in WP5, a preliminary version of the App and Internet-of-Things architecture were developed. In WP6 the optimal conditions for the culture and chondrogenic differentiation of adipose tissue-derived stem cells were set. Cell encapsulation in VitroGel materials was also assessed. Finally, preliminary results on the biophysical ultrasound stimulation of immune cells (macrophages), with the aim to promote anti-inflammatory phenomena, were obtained. The overall ADMAIORA therapeutic paradigm was protected through a PCT patent application, thus to maximize future exploitation opportunities.
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 year, 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. At the moment, the Consortium produced interesting publishable results mainly in the fields of biomaterials development and testing, non-invasive monitoring of biochemical characteristics through ultrasound and biophysical stimulation of cells. The potential impact of the project is enormous and concerns mainly citizens’ health and quality of life and OA cost reduction for different European healthcare systems.The preliminary results achieved by the Consortium in the first Reporting Period confirm such a high potential.