Exosome-Laden Hydrogels as Promising Carriers for Oral and Bone Tissue Engineering: Insight into Cell-Free Drug Delivery

Abstract

Mineralization is a key biological process that is required for the development and repair of tissues such as teeth, bone and cartilage. Exosomes (Exo) are a subset of extracellular vesicles (~50-150 nm) that are secreted by cells and contain genetic material, proteins, lipids, nucleic acids, and other biological substances that have been extensively researched for bone and oral tissue regeneration. However, Exo-free biomaterials or exosome treatments exhibit poor bioavailability and lack controlled release mechanisms at the target site during tissue regeneration. By encapsulating the Exos into biomaterials like hydrogels, these disadvantages can be mitigated. Several tissue engineering approaches, such as those for wound healing processes in diabetes mellitus, treatment of osteoarthritis (OA) and cartilage degeneration, repair of intervertebral disc degeneration, and cardiovascular diseases, etc., have been exploited to deliver exosomes containing a variety of therapeutic and diagnostic cargos to target tissues. Despite the significant efficacy of Exo-laden hydrogels, their use in mineralized tissues, such as oral and bone tissue, is very sparse. This review aims to explore and summarize the literature related to the therapeutic potential of hydrogel-encapsulated exosomes for bone and oral tissue engineering and provides insight and practical procedures for the development of future clinical techniques.

Keywords: biomaterials; bone tissue engineering; exosomes; hydrogels; mineralized tissues; oral tissue engineering; regenerative medicine.

Figure 5

(A) Demonstrated use of secreted exosomes for dental tissue regeneration and as biomarkers for periodontitis and dental caries (Reprinted from [56] with permission from Elsevier). (B) The development of chitosan hydrogel loaded with exosomes derived from dental pulp stem cells to aid in healing periodontal tissues damaged by periodontitis (Reprinted from [71]).

Figure 6

(A) Illustration of the bone, showing the cellular distribution and overall structure. Osteoprogenitors are abundant in the bone marrow and periosteum and play important roles in bone repair. In addition, a considerable degree of vascularization is seen in the periosteal and intramedullary canals of the bone (Adapted from [76]). (B) Steps for the implantation of biomaterial-loaded scaffolds for bone tissue engineering. Mesenchymal cells are isolated from the donor, cultured in vitro to differentiate into osteoblasts, and then loaded onto scaffolds that contain growth factors, polymers, biomaterials, nanoparticles, etc., prior to implantation. Following their implantation, the scaffolds could promote bone healing and regeneration (Adapted from [81]).

Figure 9

(A) Schematic illustration of uMSCEXO isolation for HA-Gel embedding and nHP scaffold printing to heal the critical-size cranial defect in rats by promoting angiogenesis (Reprinted with permission from [117]). (B). Schematic illustration of the isolation and characterization of hucMSC-derived exosomes and synthesis of CHA/SF/GCS/DF-PEG hydrogel with exosomes for testing in Sprague–Dawley rats with an induced femoral condyle defect (Reprinted from [119]).

Figure 10

A rationale for the design of exosome-laden hydrogels. (A) Fabrication of GelMA with subsequent hPDLF-Exo embedding and hydrogelation via photo-crosslinking. (B) Application of GelMA (right) and GelMA/hPDLFs-Exo (left) hydrogels into calvarial defects in a rat model (Reprinted from [123] with permission from Elsevier). (C) Schematic illustration of photoinduced imine crosslinking (PIC) hydrogel integrated with human induced pluripotent stem cells (hiPSC) derived exosomes for cartilage regeneration (Adapted from [126]).

Figure 1

Schematic illustration of exosome-laden hydrogels for bone and oral tissue engineering.

Figure 2

Drug delivery in tissue engineering applications for dental, oral, and craniofacial regeneration. In situ formation of injectable matrices or preshaped implants can be used to provide growth factors or other bioactive molecules for the regeneration of teeth, periodontal tissues, temporomandibular joints, cranial sutures, salivary glands and calvarial bone (Adapted from [31]).

Figure 3

Clinical and therapeutic applications of oral tissue engineering in dentistry (Adapted from [28]).

Figure 4

Applications of engineered hydrogels for oral tissue regeneration (Adapted from [42]).

Figure 7

Applications of hydrogels in bone tissue engineering (Adapted from [88]).

Figure 8

Illustration of cell-derived exosomes with cargo during bone and cartilage regeneration (Adapted from [107]).