Regenerating the cartilages of the knee or hip damaged by osteoarthritis is the ambition of a team of biologists and biomaterials specialists that we have gathered at the University of Lorraine.
Regenerating the cartilages of the knee or hip damaged by osteoarthritis is the ambition of a team of biologists and biomaterials specialists that we have gathered at the University of Lorraine. This disease, very debilitating, does not have at the moment effective drugs. As the congress of the French arthroscopy society opens in Paris on November 30th , we wish to draw attention to other avenues besides surgery – even if it was not invasive like this, practiced with miniaturized instruments .
A new line of research is to send in the joints, inside the cartilage cells, substances to repair this “buffer” protecting the bones. And this, thanks to tiny vehicles whose size is measured at the nanoscale , one billionth of a meter. Researchers have dubbed them “nanocargos”, alluding to cargo ships, themselves part of what is now called “nanomedicine”.
Our team has identified a first natural molecule beneficial for the synthesis of new cartilage, which we seek to send by “nanocargo”. The challenge is to find the model of ship that will bring it to the right place.
Osteoarthritis is a disease that affects about 10 million people in France. It will represent a cost increasingly important for the society because of the lengthening of the lifespan and the increasing number of patients. In fact, the risks increase with age, but also with overweight and sedentary lifestyle. Joint trauma is also a contributing factor. In the most severe cases, osteoarthritis results in the destruction of cartilage, which hinders mobility and causes severe pain. It may require the installation of a prosthesis, which is a heavy intervention.
Within the university, three laboratories including biologists, biomaterials engineering specialists and vectorization specialists (targeted drug transport) have come together to provide solutions in this joint disease. This is the laboratory Molecular engineering and articular physiopathology (Imopa) to which I belong, the Biomolecules Engineering Laboratory (LIBio) of the National School of Agronomy and Food Industries (ENSAIA), and the Jean Lamour Institute (IJL), research laboratory in materials science.
To better understand the problem and the way we seek to solve it, we must embark on the virtual journey that I propose to you within a joint, here that of the knee. It consists of five essential tissues: bone tissue, cartilage tissue, synovial membrane, synovial fluid, and elastic tissues such as ligaments and tendons (see Figure 1). In adulthood, cartilage is a highly specialized tissue that is neither vascularized nor innervated. His remodeling is slow and he is nourished by the synovial fluid. It contains about 2.5% of scattered cells in a dense matrix whose thickness varies according to the joints.
This cartilaginous matrix, composed mainly of collagen proteins, behaves like a buffer that prevents the bones from touching each other. It acts like a sponge holding water and crushes when pressure is applied to the joint – when walking, for example, to the knee. This matrix, negatively charged, is indeed capable of absorbing a lot of water molecules. When it is degraded, the bones touch each other and that is where the pain is felt. Because the bones are innervated.
In summary, cartilage is an elastic tissue, resistant to the biomechanical forces associated with the movements of the joint. It ensures good sliding between the bones, dampens and distributes the pressures. Its matrix is secreted by a single type of cell, the chondrocyte. And the chondrocyte, precisely, is the final destination that we seek to achieve with our nanocargos.
The chondrocyte is the factory where the cartilage matrix is made. It ensures a permanent balance between the synthesis of new cartilage and the elimination of used cartilage. If the chondrocyte does not work anymore or badly, this leads to osteoarthritis. The synthesis, incorporation and degradation of the matrix proteins are all directed by the chondrocytes.
We have been able to highlight the essential role of an ion, inorganic pyrophosphate (ePPi), in the ability of the chondrocyte to perform its work properly. The challenge now is to provide this ion in sufficient quantities to chondrocytes, in the laboratory already, and later in the cartilage of patients.
For the expedition, therefore, of these “nanomedicines”, we are currently looking for structures in which to encapsulate them. Vehicles capable, once injected into the cartilages of the knee, to cross the most formidable obstacle, crossing the matrix. Most attempts made so far by researchers with vehicles such as viruses or plasmids (DNA fragment) have indeed failed. The embedded substances were rather transferred to the tendons and the synovial membrane than in the cartilage and its chondrocytes …
Our idea, developed within the framework of the Mirabelle exploratory first aid project (Peps) set up by the university, consists in using natural nano-objects, thus biocompatible and biodegradable, that we divert for a therapeutic use. Indeed, the cells spontaneously communicate with each other via nano-vesicles (called matrix vesicles) of 200 nanometers or other even smaller structures, exosomes, of 20 nanometers. Our hypothesis is that the success of the operation will depend on their size and lipid structure. In other words, smaller vehicles will be able to cross the matrix more efficiently. As a result, we are currently using 100-nanometer vehicles (see Figure 2) from organic waste, and we plan to test smaller ones.