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1. Computational and experimental characterizations of the spatiotemporal activity and functional role of TGF-β in the synovial joint

   https://doi.org/10.1016/j.jbiomech.2023.111673  

   Dogru, Sedat; Dai, Zhonghao; Alba, Gabriela M.; Simone, Nicholas J.; Albro, Michael B. (July 2023, Journal of Biomechanics)

   TGF-β is a prominent anabolic signaling molecule associated with synovial joint health. Recent work has uncovered mechanochemical mechanisms that activate the latent form of TGF-β (LTGF-β) in the synovial joint-synovial fluid (SF) shearing or cartilage compression-pointing to mechanobiological phenomena, whereby enhanced TGF-β activity occurs during joint stimulation. Here, we implement computational and experimental models to better understand the role of mechanochemical-activated TGF-β (aTGF-β) in regulating the functional biosynthetic activities of synovial joint tissues. Reaction-diffusion models describe the pronounced role of extracellular chemical reactions-load-induced activation, reversible ECM-binding, and cell-mediated internalization-in modulating the spatiotemporal distribution of aTGF-β in joint tissues. Of note, aTGF-β from SF shearing predominantly acts on cells in peripheral tissue regions (superficial zone [SZ] chondrocytes and synoviocytes) and aTGF-β from cartilage compression acts on chondrocytes through all cartilage layers. Further, ECM reversible binding sites in cartilage act to modulate the temporal delivery of aTGF-β to cells, creating a dynamic where short durations of joint activity give rise to extended periods of aTGF-β exposure at moderated doses. Ex vivo tissue models were subsequently utilized to characterize the influence of physiologic aTGF-β activity regimens in regulating functional biosynthetic activities. Physiologic exposure regimens of aTGF-β in SF induce strong 4-fold to 9-fold enhancements in the secretion rate of the synovial biolubricant, PRG4, from SZ cartilage and synovium explants. Further, aTGF-β inhibition in cartilage over 1-month culture leads to a pronounced loss of GAG content (30-35% decrease) and tissue softening (60-65% EY reduction). Overall, this work advances a novel perspective on the regulation of TGF-β in the synovial joint and its role in maintaining synovial joint health. 

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2. Injectable hydrogel mediated delivery of gene-engineered adipose-derived stem cells for enhanced osteoarthritis treatment

   https://doi.org/10.1039/d1bm01122g  

   Yu, Wei; Hu, Bin; Boakye-Yiadom, Kofi Oti; Ho, William; Chen, Qijing; Xu, Xiaoyang; Zhang, Xue-Qing (November 2021, Biomaterials Science)

   Osteoarthritis (OA), a chronic and degenerative joint disease, remains a challenge in treatment due to the lack of disease-modifying therapies. As a promising therapeutic agent, adipose-derived stem cells (ADSCs) have an effective anti-inflammatory and chondroprotective paracrine effect that can be enhanced by genetic modification. Unfortunately, direct cell delivery without matrix support often results in poor viability of therapeutic cells. Herein, a hydrogel implant approach that enabled intra-articular delivery of gene-engineered ADSCs was developed for improved therapeutic outcomes in a surgically induced rat OA model. An injectable extracellular matrix (ECM)-mimicking hydrogel was prepared as the carrier for cell delivery, providing a favorable microenvironment for ADSC spreading and proliferation. The ECM-mimicking hydrogel could reduce cell death during and post injection. Additionally, ADSCs were genetically modified to overexpress transforming growth factor-β1 (TGF-β1), one of the paracrine factors that exert an anti-inflammatory and pro-anabolic effect. The gene-engineered ADSCs overexpressing TGF-β1 (T-ADSCs) had an enhanced paracrine effect on OA-like chondrocytes, which effectively decreased the expression of tumor necrosis factor-alpha and increased the expression of collagen II and aggrecan. In a surgically induced rat OA model, intra-articular injection of the T-ADSC-loaded hydrogel markedly reduced cartilage degeneration, joint inflammation, and the loss of the subchondral bone. Taken together, this study provides a potential biomaterial strategy for enhanced OA treatment by delivering the gene-engineered ADSCs within an ECM-mimicking hydrogel. 

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3. 3D Bioprinting Strategies for Articular Cartilage Tissue Engineering

   https://doi.org/10.1007/s10439-023-03236-8  

   Park, Do Young; Kim, Seon-Hwa; Park, Sang-Hyug; Jang, Ji Su; Yoo, James J.; Lee, Sang Jin (January 2023, Annals of Biomedical Engineering)

   Articular cartilage is the avascular and aneural tissue which is the primary connective tissue covering the surface of articulat- ing bone. Traumatic damage or degenerative diseases can cause articular cartilage injuries that are common in the population. As a result, the demand for new therapeutic options is continually increasing for older people and traumatic young patients. Many attempts have been made to address these clinical needs to treat articular cartilage injuries, including osteoarthritis (OA); however, regenerating highly qualified cartilage tissue remains a significant obstacle. 3D bioprinting technology combined with tissue engineering principles has been developed to create biological tissue constructs that recapitulate the anatomical, structural, and functional properties of native tissues. In addition, this cutting-edge technology can precisely place multiple cell types in a 3D tissue architecture. Thus, 3D bioprinting has rapidly become the most innovative tool for manufacturing clinically applicable bioengineered tissue constructs. This has led to increased interest in 3D bioprinting in articular cartilage tissue engineering applications. Here, we tissue engineering. 

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4. Quantification of Cartilage Poroelastic Material Properties Via Analysis of Loading-Induced Cell Death

   https://doi.org/10.1115/1.4065194  

   Kotelsky, Alexander; Carrier, Joseph S; Buckley, Mark R (August 2024, Journal of Biomechanical Engineering)

   Abstract Articular cartilage (AC) is a load-bearing tissue that covers long bones in synovial joints. The biphasic/poroelastic mechanical properties of AC help it to protect joints by distributing loads, absorbing impact forces, and reducing friction. Unfortunately, alterations in these mechanical properties adversely impact cartilage function and precede joint degeneration in the form of osteoarthritis (OA). Thus, understanding what factors regulate the poroelastic mechanical properties of cartilage is of great scientific and clinical interest. Transgenic mouse models provide a valuable platform to delineate how specific genes contribute to cartilage mechanical properties. However, the poroelastic mechanical properties of murine articular cartilage are challenging to measure due to its small size (thickness ∼ 50 microns). In the current study, our objective was to test whether the poroelastic mechanical properties of murine articular cartilage can be determined based solely on time-dependent cell death measurements under constant loading conditions. We hypothesized that in murine articular cartilage subjected to constant, sub-impact loading from an incongruent surface, cell death area and tissue strain are closely correlated. We further hypothesized that the relationship between cell death area and tissue strain can be used—in combination with inverse finite element modeling—to compute poroelastic mechanical properties. To test these hypotheses, murine cartilage-on-bone explants from different anatomical locations were subjected to constant loading conditions by an incongruent surface in a custom device. Cell death area increased over time and scaled linearly with strain, which rose in magnitude over time due to poroelastic creep. Thus, we were able to infer tissue strain from cell death area measurements. Moreover, using tissue strain values inferred from cell death area measurements, we applied an inverse finite element modeling procedure to compute poroelastic material properties and acquired data consistent with previous studies. Collectively, our findings demonstrate in the key role poroelastic creep plays in mediating cell survival in mechanically loaded cartilage and verify that cell death area can be used as a surrogate measure of tissue strain that enables determination of murine cartilage mechanical properties. 

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5. Surface-immobilized fibronectin conformation drives synovial fluid adsorption and film formation

   https://doi.org/10.1101/2025.04.27.650860  

   Ahmed, Syeda Tajin; Honey, Ummay; Vitkova, Lenka; Jaramillo_Pinto, Diego R; Flores, Warren; Lunny, Katelyn L; Cutter, Kaleb A; Wen, Yidan; De_France, Kevin; Andresen_Eguiluz, Roberto C (April 2025, bioRxiv)

   ABSTRACT The articular cartilage extracellular matrix (ECM) is a complex network of biomolecules that includes fibronectin (FN). FN acts as an extracellular glue, controlling the assembly of other macromolecular constituents to the ECM. However, how FN participates in the binding and retention of synovial fluid components, the natural lubricant of articulated joints, to form a wear-protecting and lubricating film has not been established. This study reports on the role of FN and its molecular conformation in mediating macromolecular assembly of synovial fluid ad-layers. FN films as precursor films on functionalized surfaces, a model of FN’s articular cartilage surface, adsorbed and retained different amounts of synovial fluid (SF). FN conformational changes were induced by depositing FN at pH 7 (extended state) or at pH 4 (unfolded state) on self-assembled monolayers on gold-coated quartz crystals, followed by adsorption of diluted SF (25%) onto FN precursor films. Mass density, thin film compliance, surface morphologies, and adsorbed FN films’ secondary and tertiary structures reveal pH-induced differences. FN films deposited at pH 4 were thicker, more rigid, showed a more homogeneous morphology, and had alteredα-helix andβ-sheet content, compared to FN films deposited at pH 7. FN precursor films deposited at pH 7 adsorbed and retained more synovial fluid than those at pH 4, revealing the importance of FN conformation at the articular cartilage surface to bind and maintain a thin lubricating and wear protective layer of synovial fluid constituents. This knowledge will enable a better understanding of the molecular regulation of articular cartilage-SF interface homeostasis and joint pathophysiology and identify molecular interactions and synergies between the articular cartilage ECM and SF to reveal the complexity of joint biotribology. 

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