3D Printing of Microenvironment‐Specific Bioinspired and Exosome‐Reinforced Hydrogel Scaffolds for Efficient Cartilage and Subchondral Bone Regeneration

Abstract

In clinical practice, repairing osteochondral defects presents a challenge due to the varying biological properties of articular cartilages and subchondral bones. Thus, elucidating how spatial microenvironment‐specific biomimetic scaffolds can be used to simultaneously regenerate osteochondral tissue is an important research topic. Herein, a novel bioinspired double‐network hydrogel scaffold produced via 3D printing with tissue‐specific decellularized extracellular matrix (dECM) and human adipose mesenchymal stem cell (MSC)‐derived exosomes is described. The bionic hydrogel scaffolds promote rat bone marrow MSC attachment, spread, migration, proliferation, and chondrogenic and osteogenic differentiation in vitro, as determined based on the sustained release of bioactive exosomes. Furthermore, the 3D‐printed microenvironment‐specific heterogeneous bilayer scaffolds efficiently accelerate the simultaneous regeneration of cartilage and subchondral bone tissues in a rat preclinical model. In conclusion, 3D dECM‐based microenvironment‐specific biomimetics encapsulated with bioactive exosomes can serve as a novel cell‐free recipe for stem cell therapy when treating injured or degenerative joints. This strategy provides a promising platform for complex zonal tissue regeneration whilst holding attractive clinical translation potential.

Functionalized 3D Hydroxyapatite Scaffold by Fusion Peptides-Mediated Small Extracellular Vesicles of Stem Cells for Bone Tissue Regeneration

“…3D printing technology is an emergent and promising technique to fabricate microporous biomaterial scaffolds with customized structures and mechanical properties. , Researchers summarized the integration of various stem cell-derived EVs into biomaterial scaffolds for bone regeneration to achieve sustained release of bioactive molecules . A 3D printing hydrogel scaffold constructed with a decellularized extracellular matrix (dECM) and human adipose mesenchymal stem cell (MSC)-derived exosomes was proven to enhance regeneration of cartilage and subchondral bone tissues in a rat preclinical model . EVs as natural nanocarriers can transmit diverse substances such as DNA, RNA, and proteins, and further efficiently regulate the behavior of recipient cells .…”

“…66 A 3D printing hydrogel scaffold constructed with a decellularized extracellular matrix (dECM) and human adipose mesenchymal stem cell (MSC)-derived exosomes was proven to enhance regeneration of cartilage and subchondral bone tissues in a rat preclinical model. 67 EVs as natural nanocarriers can transmit diverse substances such as DNA, RNA, and proteins, and further efficiently regulate the behavior of recipient cells. 68 The main finding of this paper provides evidence that bioactive extracellular vesicles associated with different scaffold types highlight the potential benefits of regenerative medicine.…”

Recent advances in composite hydrogels: synthesis, classification, and application in the treatment of bone defects

“…18). 166 The obtained hydrogel scaffold was able to mimic the spatial structure of natural bone, thus enabling the continuous release of exosomes. The combination of the two was able to provide a biomimetic microenvironment and corresponding stimuli for osteoblast adhesion and propagation, thereby accelerating cartilage regeneration.…”

Nerve Growth Factor-Preconditioned Mesenchymal Stem Cell-Derived Exosome-Functionalized 3D-Printed Hierarchical Porous Scaffolds with Neuro-Promotive Properties for Enhancing Innervated Bone Regeneration

“…15−17 Numerous researches have demonstrated that MSCs-derived exosomes (MSCs-Exos) exhibit beneficial bone regeneration effects through transporting intercellular biochemicals, and orchestrating multiple biological processes, and could avoid the risks of immune rejection and tumorigenicity from direct MSC transplantation, thus providing promising perspectives for cellfree therapy in regenerative medicine. 18,19 Furthermore, significant recent work revealed that MSCs are "environmental responsive" cells, with the bioactive components in their exosomes tunable with histological origin, physicochemical stimulation, and genetic modification. 20,21 This suggested that manipulation of exosomes to transfer desired cargoes has important implications in improving their therapeutic potential.…”

“…Mesenchymal stem cells (MSCs) have consistently been a crucial reservoir of progenitor cells in tissue engineering, and hold great therapeutic promise in preclinical and clinical studies. − Accumulating evidence have suggested that other than directly differentiate into effector cells to replace the tissue, MSCs exhibit a high paracrine activity via exosome release mechanism to regulate the surrounding microenvironment. , Exosomes are a type of nanosized membranous vesicles actively secreted by various cells, and are considered effective paracrine signal mediators by delivering bioactive molecules (including nucleic acids, proteins, and liquids) for intercellular communication and signal transduction. − Numerous researches have demonstrated that MSCs-derived exosomes (MSCs-Exos) exhibit beneficial bone regeneration effects through transporting intercellular biochemicals, and orchestrating multiple biological processes, and could avoid the risks of immune rejection and tumorigenicity from direct MSC transplantation, thus providing promising perspectives for cell-free therapy in regenerative medicine. , Furthermore, significant recent work revealed that MSCs are “environmental responsive” cells, with the bioactive components in their exosomes tunable with histological origin, physicochemical stimulation, and genetic modification. , This suggested that manipulation of exosomes to transfer desired cargoes has important implications in improving their therapeutic potential. However, how to engineer MSCs-Exos with effective neuro- and osteo-promotive effects, and further to promote innervated bone regeneration, remains elusive.…”