Advanced Hydrogel-Based Strategies for Enhanced Bone and Cartilage Regeneration: A Comprehensive Review

Abstract

Bone and cartilage tissue play multiple roles in the organism, including kinematic support, protection of organs, and hematopoiesis. Bone and, above all, cartilaginous tissues present an inherently limited capacity for self-regeneration. The increasing prevalence of disorders affecting these crucial tissues, such as bone fractures, bone metastases, osteoporosis, or osteoarthritis, underscores the urgent imperative to investigate therapeutic strategies capable of effectively addressing the challenges associated with their degeneration and damage. In this context, the emerging field of tissue engineering and regenerative medicine (TERM) has made important contributions through the development of advanced hydrogels. These crosslinked three-dimensional networks can retain substantial amounts of water, thus mimicking the natural extracellular matrix (ECM). Hydrogels exhibit exceptional biocompatibility, customizable mechanical properties, and the ability to encapsulate bioactive molecules and cells. In addition, they can be meticulously tailored to the specific needs of each patient, providing a promising alternative to conventional surgical procedures and reducing the risk of subsequent adverse reactions. However, some issues need to be addressed, such as lack of mechanical strength, inconsistent properties, and low-cell viability. This review describes the structure and regeneration of bone and cartilage tissue. Then, we present an overview of hydrogels, including their classification, synthesis, and biomedical applications. Following this, we review the most relevant and recent advanced hydrogels in TERM for bone and cartilage tissue regeneration.

Keywords: advanced hydrogels; bone regeneration; extracellular matrix (ECM); scaffolds; stem cells (SCs); tissue engineering and regenerative medicine (TERM).

Figure 1

Bone anatomy and histology. A typical large bone exhibits a distinct structural organization, comprising epiphyses at the extremities housing bone marrow and cancellous bone, a central diaphysis characterized by a robust cortical bone layer, and the transitional metaphysis region. The bone tissue comprises various cell types alongside a mineralized extracellular matrix. The organic component, constituting approximately 30% of bone composition, primarily consists of collagen type I. In contrast, the inorganic component, representing around 60% of the bone’s composition, mainly comprises hydroxyapatite crystals.

Figure 2

Bone healing process. The bone healing process comprises different phases. It begins with the formation of a hematoma and coagulation at the fracture site, followed by the recruitment of neutrophils and macrophages, together with the proliferation of fibroblasts and endothelial cells, leading to the formation of granulation tissue. Subsequently, a soft callus, characterized by a fibrocartilaginous matrix, connects the fractured bone ends. Osteoprogenitor cells of the periosteum differentiate into osteoblasts, initiating the formation of new bone around the soft callus. As fibrocartilage calcification occurs, new bone is deposited, culminating in the formation of a hard callus. Finally, bone remodeling occurs, restoring normal bone structure.

Figure 3

Classification of hydrogels according to different criteria.

Figure 4

Schematic representation of strategies for creating injectable hydrogels intended for TERM applications in cartilage and bone. Injectable hydrogels are designed to solidify in situ via chemical reactions or the induction of physical factors to repair bone or cartilage defects.