Marie Curie research training project on Osteoarthritis

Cure To OA Right Under Our Noses

Department of Biomedicine - University of Basel
Atharva Damle

Millions of people worldwide suffer from extreme pain and difficulty in walking, which is usually caused by wear of the knee cartilage. This degenerative disorder is termed Osteoarthritis (OA). Although it affects other joints like the hands and hips, knee OA contributes to the majority of cases. The symptoms of OA are apparent in the form of pain and inflammation in the knee but the changes in the body leading to OA are significantly complex. Overcoming this complexity has posed an untreatable challenge to biomedical researchers and clinicians for decades. So far, the biological and pharmacological options are limited and have only been able to postpone cartilage degradation, but not prevent it. Hence, patients suffering from end-stage OA, where all non-surgical treatment options have failed, are prescribed for partial or total knee replacement.

The Good, the Bad and the Ugly
Imagine two lubricated mechanical gears sliding against each other. This movement is analogous to that of two bones of the knee joint covered with a lubricating cartilage surface. Applying the analogy of sliding gears to treating OA, a knee devoid of cartilage is replaced with metal components. Between these two metal components, a plastic spacer acts as a cartilage replacement. After a surgical intervention like this, it might take months to fully recover. Most patients undergoing knee replacement enjoy a pain-free life. However, there might be some problems associated with using implants for the treatment of OA.

Figure 1:  (Left) Severe osteoarthritis. (Right) Knee after a Replacement Surgery1

Implants used for knee replacement surgeries typically have a 15–20-year lifespan. Due to increased life expectancy and a sedentary lifestyle, the next generation may have to undergo multiple knee replacement surgeries. With the growing population of the world, this can put a significant socioeconomic burden. Additionally, knee replacement surgeries carry the risk of implant-associated infections and loosening, which although rare, can be challenging to manage and often require revision surgeries. To address these problems, researchers have been exploring other alternatives and are trying to move away from implants.

A Regenerative Renaissance
Along with the problems accompanying replacement surgeries, scientists have been grappling with the treatment's philosophy of simply replacing the degenerated cartilage with a foreign object instead of regenerating it. An alternative suggests using the regeneration power of your own cells (autologous) to reconstruct cartilage. Think of a lizard growing its tail back. This may sound easy, but cartilage cells of the joint or articular chondrocytes, have a poor regenerative capacity, especially where age is a limiting factor. Thus, therapies to repair knee defects based on implanting healthy autologous cartilage into the damaged area resulted in limited success.
To overcome these problems, scientists are working on utilizing the regeneration potential of Mesenchymal Stem Cells (MSCs). Simplistically speaking, MSCs are special cells that can transform into different cell types, including chondrocytes when induced by specific signals. Moreover, they help maintain and repair our connective tissues with their unparalleled regeneration capacity. Moreover, articular cartilage is developed from MSCs during human development. Various approaches have been developed to exploit their self-renewal and regenerative power for cartilage repair. These include an injection of MSCs in the knee defect, which then gets matured into cartilage by the signals provided by the surrounding environment. MSCs can be isolated from the patient and induced to form a cartilage graft by providing certain extrinsic signals in the laboratory. The generated graft can then be implanted in the knee defect of the patient. Such reconstructed cartilage from cells is termed tissue-engineered cartilage. Nevertheless, there is significant variation in the quality and reparative ability of cartilage constructed from different sources of MSCs. Although MSCs are potentially safe, it is a topic of investigation to standardize the cell source and the dosage of cells to establish a clinical procedure for cartilage regeneration

Pinocchio’s Remedy
Nasal chondrocytes (NCs) might be the most promising candidate among autologous regenerative cell sources. NCs have a higher self-renewal capacity than articular chondrocytes. Moreover, harvesting nasal cartilage is much less invasive than harvesting MSCs, with minimum damage to the nasal septum providing a standardized and reproducible source for regenerative cell therapy.

Figure 2: Advantages and Potential Regenerative Applications of Nasal Chondrocytes3

Owing to these advantages, NCs have already been used in the clinic for the repair of focal defects of the knee. As the name suggests, these defects are the result of wear of cartilage in specific regions, unlike OA where the symptoms are more severe. NCs can be isolated from a small piece of nasal cartilage and multiplied. They are then seeded onto a membrane, which acts as a frame for the cartilage to form around it to obtain a Nasal Tissue Engineered Cartilage (N-TEC) graft. The N-TEC graft is trimmed to the defect size, placed into the defect, and sutured to the surrounding cartilage4.
Hypothetically, a similar strategy can be adopted to treat Osteoarthritis. In a case representative study published by our group5, two young patients suffering from OA scheduled to undergo knee replacement surgery were successfully treated with N-TEC. Considering that the majority of people with osteoarthritis are older and have advanced OA, this may not be feasible. In such a scenario, NCs will have to be primed to survive the harsh inflammatory environment to further their clinical application.
Upcoming innovative approaches have allowed for enhancing the innate properties of autologous cells by editing the genetic code of cells. Such enhanced cells have been implanted in patients for the treatment of multiple malignancies. Likewise, NCs can be genetically altered to sustain and mitigate the harsh inflammatory environment typical of end-stage OA. A promising strategy of the near future may involve implanting an N-TEC graft comprising such enhanced cells.

In conclusion, the use of NCs for regenerative therapy in OA presents a promising avenue for research and development. While the concept has shown positive results in treating focal cartilage defects, further studies are needed to validate its effectiveness and safety for a wider range of OA cases. If successful, this approach could offer a less invasive and more sustainable solution for individuals suffering from end-stage osteoarthritis.

(1) Total Knee Replacement - OrthoInfo - AAOS. https://www.orthoinfo.org/en/treatment/total-knee-replacement/ (accessed 2024-01-08).
(2) Carneiro, D. de C.; de Araújo, L. T.; Santos, G. C.; Damasceno, P. K. F.; Vieira, J. L.; dos Santos, R. R.; Barbosa, J. D. V.; Soares, M. B. P. Clinical Trials with Mesenchymal Stem Cell Therapies for Osteoarthritis: Challenges in the Regeneration of Articular Cartilage. Int. J. Mol. Sci. 2023, 24 (12), 9939. https://doi.org/10.3390/ijms24129939.
(3) Pelttari, K.; Mumme, M.; Barbero, A.; Martin, I. Nasal Chondrocytes as a Neural Crest-Derived Cell Source for Regenerative Medicine. Curr. Opin. Biotechnol. 2017, 47, 1–6. https://doi.org/10.1016/j.copbio.2017.05.007.
(4) Mumme, M.; Barbero, A.; Miot, S.; Wixmerten, A.; Feliciano, S.; Wolf, F.; Asnaghi, A. M.; Baumhoer, D.; Bieri, O.; Kretzschmar, M.; Pagenstert, G.; Haug, M.; Schaefer, D. J.; Martin, I.; Jakob, M. Nasal Chondrocyte-Based Engineered Autologous Cartilage Tissue for Repair of Articular Cartilage Defects: An Observational First-in-Human Trial. The Lancet 2016, 388 (10055), 1985–1994. https://doi.org/10.1016/S0140-6736(16)31658-0.
(5) Acevedo Rua, L.; Mumme, M.; Manferdini, C.; Darwiche, S.; Khalil, A.; Hilpert, M.; Buchner, D. A.; Lisignoli, G.; Occhetta, P.; von Rechenberg, B.; Haug, M.; Schaefer, D. J.; Jakob, M.; Caplan, A.; Martin, I.; Barbero, A.; Pelttari, K. Engineered Nasal Cartilage for the Repair of Osteoarthritic Knee Cartilage Defects. Sci. Transl. Med. 2021, 13 (609), eaaz4499. https://doi.org/10.1126/scitranslmed.aaz4499.