Polyphenolic materials are a class of fascinating and versatile bioinspired materials for biointerfacial engineering. In particular, due to the presence of active chemical groups, a series of unique physicochemical properties become accessible and tunable of the as-prepared polyphenolic platforms, which could delicately regulate the cell activities via cell-material contact-dependent interactions. More interestingly, polyphenols could also affect the cell behaviors via cell-material contact-independent manner, which arise due to their intrinsically functional characteristics (e.g., antioxidant and photothermal behaviors). As such, a comprehensive understanding on the relationship between material properties and desired biomedical applications, as well as the underlying mechanism at the cellular and molecular level would provide material design principles and accelerate the lab-to-clinic translation of polyphenolic platforms. In this review, we firstly give a brief overview of cell hallmarks governed by surrounding cues, followed by the introduction of polyphenolic material engineering strategies. Subsequently, a detailed discussion on cell-polyphenols contact-dependent interfacial interaction and contact-independent interaction was also carefully provided. Lastly, their biomedical applications were elaborated. We believe that this review could provide guidances for the rational material design of multifunctional polyphenols and extend their application window.

Versatile polyphenolic platforms in regulating cell biology.

Tissue repair after trauma and infection has always been a difficult problem in regenerative medicine. Hydrogels have become one of the most important scaffolds for tissue engineering due to their biocompatibility, biodegradability and water solubility. Especially, the stiffness of hydrogels is a key factor, which influence the morphology of mesenchymal stem cells (MSCs) and their differentiation. The researches on this point are meaningful to the field of tissue engineering. Herein, this review focus on the design of hydrogels with different stiffness and their effects on the behavior of MSCs. In addition, the effect of hydrogel stiffness on the phenotype of macrophages is introduced, and then the relationship between the phenotype changes of macrophages on inflammatory response and tissue repair is discussed. Finally, the future application of hydrogels with a certain stiffness in regenerative medicine and tissue engineering has been prospected.

/pdf/a-review-on-the-design-of-hydrogels-with-different-stiffness-1qxuoefz.pdf

A Review on the Design of Hydrogels With Different Stiffness and Their Effects on Tissue Repair

Articular cartilage serves as a low-friction, load-bearing tissue without the support with blood vessels, lymphatics and nerves, making its repair a big challenge. Transforming growth factor-beta 3 (TGF-β3), a vital member of the highly conserved TGF-β superfamily, plays a versatile role in cartilage physiology and pathology. TGF-β3 influences the whole life cycle of chondrocytes and mediates a series of cellular responses, including cell survival, proliferation, migration, and differentiation. Since TGF-β3 is involved in maintaining the balance between chondrogenic differentiation and chondrocyte hypertrophy, its regulatory role is especially important to cartilage development. Increased TGF-β3 plays a dual role: in healthy tissues, it can facilitate chondrocyte viability, but in osteoarthritic chondrocytes, it can accelerate the progression of disease. Recently, TGF-β3 has been recognized as a potential therapeutic target for osteoarthritis (OA) owing to its protective effect, which it confers by enhancing the recruitment of autologous mesenchymal stem cells (MSCs) to damaged cartilage. However, the biological mechanism of TGF-β3 action in cartilage development and OA is not well understood. In this review, we systematically summarize recent progress in the research on TGF-β3 in cartilage physiology and pathology, providing up-to-date strategies for cartilage repair and preventive treatment. 

https://www.nature.com/articles/s41413-022-00239-4.pdf

The role of TGF-beta3 in cartilage development and osteoarthritis

Hydrogel platform with tunable stiffness based on magnetic nanoparticles cross-linked GelMA for cartilage regeneration and its intrinsic biomechanism.

Abstract Microenvironmental biophysical factors play a fundamental role in controlling cell behaviors including cell morphology, proliferation, adhesion and differentiation, and even determining the cell fate. Cells are able to actively sense the surrounding mechanical microenvironment and change their cellular morphology to adapt to it. Although cell morphological changes have been considered to be the first and most important step in the interaction between cells and their mechanical microenvironment, their regulatory network is not completely clear. In the current study, we generated silicon-based elastomer polydimethylsiloxane (PDMS) substrates with stiff (15:1, PDMS elastomer vs. curing agent) and soft (45:1) stiffnesses, which showed the Young’s moduli of ~450 kPa and 46 kPa, respectively, and elucidated a new path in cytoskeleton re-organization in chondrocytes in response to changed substrate stiffnesses by characterizing the axis shift from the secreted extracellular protein laminin β1, focal adhesion complex protein FAK to microfilament bundling. We first showed the cellular cytoskeleton changes in chondrocytes by characterizing the cell spreading area and cellular synapses. We then found the changes of secreted extracellular linkage protein, laminin β1, and focal adhesion complex protein, FAK, in chondrocytes in response to different substrate stiffnesses. These two proteins were shown to be directly interacted by Co-IP and colocalization. We next showed that impact of FAK on the cytoskeleton organization by showing the changes of microfilament bundles and found the potential intermediate regulators. Taking together, this modulation axis of laminin β1-FAK-microfilament could enlarge our understanding about the interdependence among mechanosensing, mechanotransduction, and cytoskeleton re-organization. 

/pdf/microenvironmental-stiffness-mediates-cytoskeleton-re-22tb0gb4.pdf

Microenvironmental stiffness mediates cytoskeleton re-organization in chondrocytes through laminin-FAK mechanotransduction

Transforming growth factor-beta2 (TGF-β2) is recognized as a versatile cytokine that plays a vital role in regulation of joint development, homeostasis, and diseases, but its role as a biological mechanism is understood far less than that of its counterpart, TGF-β1. Cartilage as a load-resisting structure in vertebrates however displays a fragile performance when any tissue disturbance occurs, due to its lack of blood vessels, nerves, and lymphatics. Recent reports have indicated that TGF-β2 is involved in the physiological processes of chondrocytes such as proliferation, differentiation, migration, and apoptosis, and the pathological progress of cartilage such as osteoarthritis (OA) and rheumatoid arthritis (RA). TGF-β2 also shows its potent capacity in the repair of cartilage defects by recruiting autologous mesenchymal stem cells and promoting secretion of other growth factor clusters. In addition, some pioneering studies have already considered it as a potential target in the treatment of OA and RA. This article aims to summarize the current progress of TGF-β2 in cartilage development and diseases, which might provide new cues for remodelling of cartilage defect and intervention of cartilage diseases.

The role of TGF-β2 in cartilage development and diseases.

The exquisite cartilage architecture maintains an orderly dynamic equilibrium as a result of the interplay between chondrocyte functions and the unique extracellular matrix (ECM) microenvironment. Numerous studies have demonstrated that extracellular cues, including topological, mechanical, and biochemical properties of the underlying substrates, dictate the chondrocyte behaviors. Consequently, developing advanced biomaterials with the desired characteristics which could achieve the biointerface between cells and the surrounded matrix close to the physiological conditions becomes a great hotspot in bioengineering. However, how the substrate stiffness influences the intercellular communication among chondrocytes is still poorly reported. We used polydimethylsiloxane with varied stiffnesses as a cell culture substrate to elucidate a novel cell-to-cell communication in a collective of chondrocytes. First, morphological images collected using scanning electron microscopy revealed that the tunable substrate stiffnesses directed the changes in intercellular links among chondrocytes. Next, fibronectin, which played a vital role in the connection of ECM components or linkage of ECM to chondrocytes, was shown to be gathered along cell-cell contact areas and was changed with the tunable substrate stiffnesses. Furthermore, transmembrane junctional proteins including connexin 43 (Cx43) and pannexin 1 (Panx1), which are responsible for gap junction formation in cell-to-cell communication, were mediated by the tunable substrate stiffnesses. Finally, through a scrape loading/dye transfer assay, we revealed cell-to-cell communication changes in a living chondrocyte population in response to the tunable substrate stiffnesses via cell-to-cell fluorescent molecule transport. Taken together, this novel cell-to-cell communication regulated by biomaterial stiffness could help us to increase the understanding of cell behaviors under biomechanical control and may ultimately lead to refining cell-based cartilage tissue engineering.

Biomaterial Stiffness Guides Cross-talk between Chondrocytes: Implications for a Novel Cellular Response in Cartilage Tissue Engineering.

Osteocytes are the main sensitive cells in bone remodeling due to their potent functional cell processes from the mineralized bone matrix to the bone surface and the bone marrow. Neighboring osteocytes communicate with each other by these cell processes to achieve molecular exchange through gap junction channels. Platelet-derived growth factor-AA (PDGF-AA) has been reported to enhance bone tissue remodeling by promoting cell proliferation, migration, and autocrine secretion in osteoid cell linage. However, the effect of PDGF-AA on intercellular communication between osteocytes is still unclear. In the present study, we elucidated that PDGF-AA could enhance the formation of dendritic processes of osteocytes and the gap junctional intercellular communication by promoting the expression of connexin43 (Cx43). This modulation process was mainly dependent on the activation of phosphorylation of Akt protein by phosphatidylinositol 3-kinase (PI3K)/Akt (also known as protein kinase B, PKB) signaling. Inhibition of PI3K/Akt signaling decreased the Cx43 expression induced by PDGF-AA. These results establish a bridge between PDGF-AA and cell-cell communication in osteocytes, which could help us understand the molecular exchange between bone cells and fracture healing.

http://academic.oup.com/abbs/advance-article-pdf/doi/10.1093/abbs/gmab136/40472604/gmab136.pdf

PDGF-AA promotes cell-to-cell communication in osteocytes through PI3K/Akt signaling pathway.

TGF-β2 increases cell-cell communication in chondrocytes via p-Smad3 signalling

Osteocytes are the main sensitive and responsive cells for mechanical stimuli in bone. The connexin family enables them to communicate with each other via forming functional gap junctions. However, how osteoporosis-impaired extracellular mechanical property modulates gap junction intercellular communication in osteocytes remains elusive. In this study, we established an ovariectomy (OVX)-induced osteoporosis mouse model in vivo and a polydimethylsiloxane (PDMS)-based cell culture substrate model in vitro to explore the influence of extracellular matrix (ECM) stiffness on cell-to-cell communication in osteocytes. Firstly, we established an OVX-induced osteoporosis mouse model by characterizing the changes in radiography, morphology and histochemistry of femurs. Our results showed that osteoporosis decreased the bone matrix stiffness together with the changes including the loss of osteocytes and the decrease of protein markers. Meanwhile, the dendritic process interconnection and channel-forming protein, Cx43, were reduced in osteoporosis mice. Next we mimicked ECM stiffness changes in vitro by using PDMS substrates at ratios 1:5 for normal stiffness and 1:45 for osteoporosis stiffness. Our results showed that the decreased ECM stiffness reduced the number of dendritic processes in a single cell and gap junctions between adjacent osteocytes. We further detected the decreased expression of Cx43, in the substrate with decreased stiffness. Finally, we found that gap junction-based intercellular communication was reduced in living osteocytes in the substrate with decreased stiffness. This study demonstrates the correlation between ECM mechanical property and cell-to-cell communication in osteocytes and might pave the way for further exploration of osteoporosis in terms of biomechanics.

Osteoporosis-decreased extracellular matrix stiffness impairs connexin 43-mediated gap junction intercellular communication in osteocytes

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