Introduction

Biomaterials are widely used within clinical cartilage restoration procedures and many formulations, ranging from naturally derived to fully synthetic and from soft hydrogels to hard polymers and ceramics, are currently evaluated. Biomaterial scaffolds can act as a delivery vehicle of cells and biological cues. In addition, they can provide temporal mechanical stability to aid short-term functional restoration.

This approach follows the classic principles of tissue engineering where the newly formed tissue gradually replaces the function of the (degrading) scaffolding structures. However, new data confirming old insights with respect to the inability of the collagen network, which is essential for the mechanical resilience of the cartilage tissue, to restore itself may put us back to the drawing board.

Content

Biomaterials can successfully guide and steer behavior of cells and facilitate the differentiation towards the chondrogenic lineage. A wide array of materials have been proposed and investigated¹. For example, hydrogel-based materials provide a hydrated stable environment for chondrocytes to deposit an extracellular matrix that is rich in proteoglycans and collagen type II. Scaffolds derived from natural materials, such as cartilage extracellular matrix, can also provide specific biological cues to enhance matrix deposition. Synthetic thermoplastic polymers on the other hand can provide temporal mechanical stability. Driven by the complexity of the osteochondral unit, combined structures have been developed that also address the specific needs of the osteal and chondral regions. Moreover, advanced biofabrication technologies allow for the processing of a combination of multiple materials, biological cues and cells in a layer-by-layer fashion. This can assist in reproducing both the zonal organization of cartilage and the gradual transition from resilient cartilage towards the subchondral bone in biofabricated osteochondral grafts². Mechanical characteristics, including the smoothness and low friction that are hallmarks of the articular surface, can be tuned with multi-head or hybrid printers by controlling the spatial patterning of printed structures. Moreover, these fabrication technologies can yield patient-specific implants due to their use of digital medical images. Nevertheless, current regenerative biomaterial-based approaches are based on the classic principle of tissue engineering in which the newly formed tissue gradually takes over the function of the (degrading) scaffolding structure^3,4.

The specific biomechanical characteristicsof the articular cartilage are provided by the combination of the arcade-like architecture of the extracellular collagen network and the interspersed hydrophilic proteoglycan aggregates. The constitution of these “Benninghoff” arcade structures⁵depends on the remodeling of the deposited collagen type II fibers. It has, however, recently been shown that the collagen within the articular cartilage is, once damaged, not reconstituted to any degree in mature individuals⁶, confirming centuries-old observations⁷.Thus, the classic tissue engineering paradigm does not hold for articular cartilage.

For this reason, a paradigm shift is necessary in the field of regenerative medicine of articular cartilage and our attempts at long-term cartilage restoration will have to be redirected. Principally, there are two ways to achieve such a paradigm shift: either by recreating the tissue’s homeostatic and (epi)genetic environment as present in at the early stages of life, in which remodeling of the collagen network is still possible, or by adopting Nature’s approach in the mature individual, i.e.by creating a life-long persisting, immutable structural component of articular cartilage. Both ways face considerable challenges before they can become reality.

References

1. Hutmacher.Scaffolds in tissue engineering bone and cartilage(2000). Biomat 21(24):2529-43

2. De Ruijeret al. Simultaneous Micropatterning of Fibrous Meshes and Bioinks for the Fabrication of Living Tissue Constructs (2019). Adv Healthc Mat 8(7):e1800418

3. Langer & Vacanti. Tissue engineering (1993).Science260:920

4. Londono and Badylak. Biologic scaffolds for regenerative medicine: mechanisms of in vivo remodeling(2015). Ann Biomed Eng 43(3):577-92

5. Benninghoff. Form un Bau der Gelenkknorpel in ihren Beziehungen zur Funktion. II. Der Aufbau des Gelenkknorpels in seinen Bezeihungen zur Funktion(1925). Zeit Zellforsch und Mikroskop Anat 2:783-862.

6. Heinemeieret al. Radiocarbon dating reveals minimal collagen turnover in both healthy and osteoarthritic human cartilage (2016).Sci Transl Med 8(346):346ra90

7. Hunter, Roy Soc London, Phil Trans, 1743. 9:267

Acknowledgments

The authors would like to gratefully acknowledge funding from the European Research Council under grant agreement 647426 (3D-JOINT), Dutch Arthritis Foundation (LLP-12 and LLP-22), and the partners of ‘Regenerative Medicine Crossing Borders’ (RegMed XB), powered by Health~Holland, Top Sector Life Sciences & Health.