Control and interplay of scaffold–biomolecule interactions applied to cartilage tissue engineering

Cartilage tissue engineering based on the combination of biomaterials, adult or stem cells and bioactive factors is a challenging approach for regenerative medicine with the aim of achieving the formation of a functional neotissue stable in the long term. Various 3D scaffolds have been developed to mimic the extracellular matrix environment and promote cartilage repair. In addition, bioactive factors have been extensively employed to induce and maintain the cartilage phenotype. However, the spatiotemporal control of bioactive factor release remains critical for maximizing the regenerative potential of multipotent cells, such as mesenchymal stromal cells (MSCs), and achieving efficient chondrogenesis and sustained tissue homeostasis, which are essential for the repair of hyaline cartilage. Despite advances, the effective delivery of bioactive factors is limited by challenges such as insufficient retention at the site of injury and the loss of therapeutic efficacy due to uncontrolled drug release. These limitations have prompted research on biomolecule-scaffold interactions to develop advanced delivery systems that provide sustained release and controlled bioavailability of biological factors, thereby improving therapeutic outcomes. This review focuses specifically on biomaterials (natural, hybrid and synthetic) and biomolecules (molecules, proteins, nucleic acids) of interest for cartilage engineering. Herein, we review in detail the approaches developed to maintain the biomolecules in scaffolds and control their release, based on their chemical nature and structure, through steric, non-covalent and/or covalent interactions, with a view to their application in cartilage repair.