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User-centred smart nanobiomaterial-based 3D matrices for chondral repair

Periodic Reporting for period 1 - RESTORE (User-centred smart nanobiomaterial-based 3D matrices for chondral repair)

Reporting period: 2019-01-01 to 2020-06-30

Injury to articular cartilage is recognised as a cause of significant joint morbidity. The initially small focal chondral lesions gradually increase not only in circumference (perimeter) but also in length and commonly result in the development of osteoarthritis (OA), eventually leading to progressive total joint destruction. The most recent report of the Osteoarthritis Research Society International estimated that OA affects 242 million people globally. In Europe, it has been reported that the average total annual costs of OA per patient ranges from €1,330 to €10,4522. These facts clearly support the need for efforts to take on the challenge to repair even minor articular cartilage injuries or lesions. The RESTORE project addresses this clinical need by developing an effective approach to treat knee chondral lesions. The RESTORE concept is to realize a new generation of smart nanoenabled 3D matrices able to fit into complex lesion geometry, modulate undesirable biological events, and remotely control, stimulate and monitor cartilage repair. To create smart and functional 3D matrices, RESTORE is developing (i) nanobiomaterial-based nanocarriers to modulate undesirable biological threats, (ii) stimuli-responsive nanobiomaterials tuned via external physical stimulus, and (iii) non-invasive wearable and wireless device for remote stimulus and regeneration monitoring. The nanobiomaterials are planned to be integrated into cutting-edge 3D matrices that meet the needs of severe and mild chondral lesions.
During the first 18 months, the RESTORE consortium focused on producing the building blocks and tools required to develop the smart 3D matrices able to repair cartilage lesions. The main results achieved are:
I. Standard Operating Procedures (SOPs) for RESTORE nanobiomaterial safety assessment were developed.
II. The first groups of nanomaterials that will be incorporated in the 3D matrices (COPLA® Scaffold and bioprinted cartilage) were synthetized and characterized following the SOPs: a) nanoparticles that can carry pharmacologically active drugs to fight undesirable threats such as inflammation cartilage tissue degradation and infection and b) nanomaterials (stimuli-responsive nanomaterials) that are able to activate cartilage cells via remote stimulation were synthesized and characterized.
III. Stimuli-responsive nanomaterials and nanocarriers have been incorporated in initial experiments into COPLA Scaffolds. Improvement and thorough characterization are ongoing.
IV. The first prototypes of platforms where the stimuli-responsive nanomaterials can be tested in vitro with cartilage cells were designed and delivered.
V. The bioink that will serve for cartilage tissue bioprinting was improved to make it more suitable for cartilage cells. It was also incorporated with the developed nanoparticles. The enhanced bioink was tested to bioprint human cartilage tissue.
VI. The bioprinting platform for human cartilage printing is improved by upgrading print heads and the software.
VII. The first version of the patient-specific anatomical models for condyle lesion database was created and uploaded.

The dissemination and communication activities of the project have also been carried out. For the first reporting period, we aimed to create project visibility and disseminate the project among academic researchers in nanomedicine, biomaterials and regenerative medicine, the orthopaedic community as well as the general public.
The RESTORE website ( had 3,372 views, 680 visitors and 18 posts, fulfilling the yearly goal. A second version of the website was launched on M15 and a Twitter account was launched at M16.
RESTORE scientific results have been presented in several scientific events such as congresses, workshops, displays/fairs, etc. As planned, 1 press release was published at the beginning of the project.
Progress beyond the state of the art:

During the first 18 months of the project, the following progress beyond the state of the art were achieved:
I. The tri-combinatory delivery system to fight inflammation, bacterial infection and cartilage degradation has been prepared.
II. The first prototype of the in vitro stimulation testing platform was delivered and ready to be tested.
III. The database of patient-specific anatomical models for condyle lesions has been created, and part of the data has already been uploaded.
VI. Reliable data on the safety of some of RESTORE’s 3D matrices building blocks were obtained.

Expected results until the end of the project:
I. Functional nanocarriers capable of mitigating inflammation, inhibit cartilage ECM degradation and hinder bacterial growth.
II. Stimuli-responsive nanobiomaterial tuned to physical stimulus.
III. Viable 3D bioprinted human cartilage microtissues from patient-specific anatomical models.
IV. Nanoenabled 3D matrices for efficient chondral lesion repair.
V. Device to stimulate and monitor cartilage regeneration.
VI. Reliable data on the safety of RESTORE’s nanoenabled solutions.

Potential impact:
Patients suffering from knee chondral lesions have reduced quality of life. By using the solutions developed in RESTORE, patients either young or aged, can be rehabilitated and regain an active life in shorter times (reducing the absenteeism of working patients). Relative to traditional approaches (chemical and biologic), cell-based products combined with nanocarriers are considered to be expensive to manufacture. However, RESTORE tailored nanocarriers hold great potential to reduce treatment's costs, as the dosage of bioactive molecules will decrease from milligrams to nanograms, with less side effects. The stimuli-responsive nanobiomaterials do not represent a significant increase in the final nanoenabled solution, since their manufacturing costs are low. The integration of the developed smart nanobiomaterials to the 3D matrices is planned with regard to minimising additional manufacturing costs and, therefore, providing an affordable nanoenabled solution. Its application by orthopaedic surgeons in hospitals or specialised clinics is expected to improve patient quality of life and will ease the burden from the social and health systems and from the families and societies. Finally, the use of SOPs accepted by regulatory bodies from an early stage of product development will ease the translation from lab to clinic and contribute to results directly useable in regulatory documentation at a later stage. Also, the focus on sterile production processes by continuous sterility and endotoxin testing will contribute to an accelerated scale-up production and translation from lab to product.