Effect of Remnant-Preserving Reconstruction of Acute Anterior Cruciate Ligament Injuries in a Rabbit Model: Histological and Biomechanical Analysis

Acute anterior cruciate ligament (ACL) is a key structure that stabilizes knee joints. The objective of this research is to investigate the influence of ligament remnants preserved on the tendon-bone healing following ACL reconstruction and to examine postoperative articular cartilage degeneration in rabbit as a model animal. Sixty New Zealand rabbits are randomly divided into an ACL reconstruction without remnant preservation group (Group A; n = 30) or ACL reconstruction with remnant preservation group (Group B; n = 30). The expression of HIF-1α, VEGF, and micro vessel density (MVD) in the transplanted tendon was detected by immunohistochemical staining at week 6 and 12 after the operation. The signal intensity of the transplanted tendon was observed by MRI scanning, and the width of the bone tunnel was measured by CT scanning at week 6 and 12 after the operation. The graft biomechanics was tested 12 weeks after the operation. The JNK and MMP-13 expression levels were compared to analyze the cartilage degeneration of the knee at week 12 after the operation. The experimental results were analyzed and showed that the remnant-preserving ACL reconstruction is beneficial for bone healing of the tendon in rabbits, but ACL reconstruction with or without ligament remnants preserved will not affect knee articular cartilage degeneration post-surgery.

Restoration of the Phenotype of Dedifferentiated Rabbit Chondrocytes by Sesquiterpene Farnesol

Osteoarthritis (OA) is a joint disorder characterized by the progressive degeneration of articular cartilage. The phenotype and metabolism behavior of chondrocytes plays crucial roles in maintaining articular cartilage function. Chondrocytes dedifferentiate and lose their cartilage phenotype after successive subcultures or inflammation and synthesize collagen I and X (COL I and COL X). Farnesol, a sesquiterpene compound, has an anti-inflammatory effect and promotes collagen synthesis. However, its potent restoration effects on differentiated chondrocytes have seldom been evaluated. The presented study investigated farnesol’s effect on phenotype restoration by examining collagen and glycosaminoglycan (GAG) synthesis from dedifferentiated chondrocytes. The results indicated that chondrocytes gradually dedifferentiated through cellular morphology change, reduced expressions of COL II and SOX9, increased the expression of COL X and diminished GAG synthesis during four passages of subcultures. Pure farnesol and hyaluronan-encapsulated farnesol nanoparticles promote COL II synthesis. GAG synthesis significantly increased 2.5-fold after a farnesol treatment of dedifferentiated chondrocytes, indicating the restoration of chondrocyte functions. In addition, farnesol drastically increased the synthesis of COL II (2.5-fold) and GAG (15-fold) on interleukin-1β-induced dedifferentiated chondrocytes. A significant reduction of COL I, COL X and proinflammatory cytokine prostaglandin E2 was observed. In summary, farnesol may serve as a therapeutic agent in OA treatment.

Experimental-analytical approach to assessing mechanosensitive cartilage blood marker kinetics in healthy adults: dose-response relationship and interrelationship of nine candidate markers

Purpose: To determine the suitability of selected blood biomarkers of articular cartilage as mechanosensitive markers and to investigate the dose-response relationship between ambulatory load magnitude and marker kinetics in response to load. Methods: Serum samples were collected from 24 healthy volunteers before and at three time points after a 30-minute walking stress test performed on three test days. In each experimental session, one of three ambulatory loads was applied: 100% body weight (BW); 80%BW; 120%BW. Serum concentrations of COMP, MMP-3, MMP-9, ADAMTS-4, PRG-4, CPII, C2C and IL-6 were assessed using commercial enzyme-linked immunosorbent assays. A two-stage analytical approach was used to determine the suitability of a biomarker by testing the response to the stress test (criterion I) and the dose-response relationship between ambulatory load magnitude and biomarker kinetics (criterion II). Results. COMP, MMP-3 and IL-6 at all three time points after, MMP-9 at 30 and 60 minutes after, and ADAMTS-4 and CPII at immediately after the stress test showed an average response to load or an inter-individual variation in response to load of up to 25% of pre-test levels. The relation to load magnitude on average or an inter-individual variation in this relationship was up to 8% from load level to load level. There was a positive correlation for the slopes of the change-load relationship between COMP and MMP-3, and a negative correlation for the slopes between COMP, MMP-3 and IL-6 with MMP-9, and COMP with IL6. Conclusions: COMP, MMP-3, IL-6, MMP-9, and ADAMTS-4 warrant further investigation in the context of articular cartilage mechanosensitivity and its role in joint degeneration and OA. While COMP seems to be able to reflect a rapid response, MMP-3 seems to reflect a slightly longer lasting, but probably also more distinct response. MMP-3 showed also the strongest association with the magnitude of load.

Hyaline cartilage differentiation of fibroblasts in regeneration and regenerative medicine

Amputation injuries in mammals are typically non-regenerative, however joint regeneration is stimulated by BMP9 treatment (Yu et al., 2019) indicating the presence of latent articular chondrocyte progenitor cells. BMP9 induces a battery of chondrogenic genes in vivo, and a similar response is observed in cultures of amputation wound cells. Extended cultures of BMP9 treated cells results in differentiation of hyaline cartilage and single cell RNAseq analysis identified wound fibroblasts as BMP9 responsive. This culture model was used to identify a BMP9 responsive adult fibroblast cell line and a culture strategy was developed to engineer hyaline cartilage for engraftment into an acutely damaged joint. Transplanted hyaline cartilage survived engraftment and maintained a hyaline cartilage phenotype but did not form mature articular cartilage. In addition, individual hypertrophic chondrocytes were identified in some samples indicating that the acute joint injury site can promote osteogenic progression of engrafted hyaline cartilage. The findings identify fibroblasts as a cell source for engineering articular cartilage and establishes a novel experimental strategy that bridges the gap between regeneration biology and regenerative medicine.

Baicalein Alleviates Osteoarthritis Progression in Mice by Protecting Subchondral Bone and Suppressing Chondrocyte Apoptosis Based on Network Pharmacology

As life expectancy increases, Osteoarthritis (OA) is becoming a more frequently seen chronic joint disease. The main characteristics of OA are loss of articular cartilage, subchondral bone sclerosis, and synovial inflammation. Baicalein (Bai), a traditional Chinese medicine extracted from Scutellaria baicalensis Georgi, has been demonstrated to exert notable anti-inflammatory effects in previous studies, suggesting its potential effect in the treatment of OA. In this study, we first predicted the action targets of Bai, mapped target genes related to OA, identified potential anti-OA targets for Bai, performed gene ontology (GO) enrichment, and KEGG signaling pathway analyses of the action targets, and analyzed the molecular docking of key Bai targets. Additionally, the effect and potential mechanism of Bai against OA were verified in mouse knee OA models induced by destabilized medial meniscus (DMM) surgery. GO and KEGG analyses showed that 19 anti-OA targets were mainly involved in the response to oxidative stress, the response to hypoxia and apoptosis, and the PI3K-Akt and p53 signaling pathways. Molecular docking results indicated that BAX, BCL 2, and Caspase 3 enriched in the apoptotic signaling pathway have high binding affinity with Bai. Validation experiments showed that Bai can significantly attenuate the loss of articular cartilage (OARSI score), suppress synovial inflammation (synovitis score), and ameliorate subchondral bone resorption measured by micro-CT. In addition, Bai notably inhibited the expression of apoptosis-related proteins in articular cartilage (BAX, BCL 2, and Caspase 3). By combining network pharmacology with experimental validation, our study identifies and verifies the importance of the apoptotic signaling pathway in the treatment of OA by Bai. Bai may have promising application and potential therapeutic value in OA treatment.

Application Effect of Different Concentrations of Platelet-Rich Plasma Combined with Quadriceps Training on Cartilage Repair of Knee Osteoarthritis

We investigated the application effect of different concentrations of platelet-rich plasma (PRP) combined with quadriceps training on cartilage repair of knee osteoarthritis. Data of 37 patients with knee osteoarthritis (KOA) treated in our hospital (November 2019–February 2021) were retrospectively analyzed and the patients were divided into low concentration group (LCG) (n = 12), medium concentration group (MCG) (n = 12), and high concentration group (HCG) (n = 13) according to the order of admission. All patients received quadriceps training. Three groups above received knee injection of PRP, and the platelet concentrations were 1000–1400 × 109/L, 1400–1800 × 109/L, and 1800–2100 × 109/L, respectively. Articular cartilage thickness of the medial and lateral femur, knee joint function scores, inflammatory factor levels, and matrix metalloproteinases (MMPs) levels were compared. After treatment, compared with the MCG and HCG, articular cartilage thickness of the medial and lateral femur of the diseased side in the LCG was obviously lower ( P < 0.05 ). At 2 months after treatment (T3), compared with the HCG, articular cartilage thickness of the medial and lateral femur of the diseased side in the MCG was obviously higher ( P < 0.05 ), without remarkable difference in articular cartilage thickness of the medial and lateral femur of the healthy side among three groups ( P > 0.05 ). After treatment, compared with the LCG, knee joint function scores of the MCG and HCG were obviously better ( P < 0.001 ). Compared with the HCG, the knee function score at T3 in the MCG was obviously better ( P < 0.001 ). After treatment, compared with the LCG, inflammatory factor levels and levels of MMPs in the MCG and HCG were obviously lower ( P < 0.05 ). Compared with the HCG, inflammatory factor levels and levels of MMPs at T3 in the MCG were obviously lower ( P < 0.05 ). PRP combined with quadriceps training can accelerate cartilage repair of patients with KOA and reduce inflammatory factor levels and levels of MMPs, but the treatment effect of PRP depends on platelet concentration, with the best range of 1400–1800 × 109/L. Too high or too low platelet concentrations will affect recovery of knee function.

Mesenchymal stromal cell-based therapy for cartilage regeneration in knee osteoarthritis

Osteoarthritis, as a degenerative disease, is a common problem and results in high socioeconomic costs and rates of disability. The most commonly affected joint is the knee and characterized by progressive destruction of articular cartilage, loss of extracellular matrix, and progressive inflammation. Mesenchymal stromal cell (MSC)-based therapy has been explored as a new regenerative treatment for knee osteoarthritis in recent years. However, the detailed functions of MSC-based therapy and related mechanism, especially of cartilage regeneration, have not been explained. Hence, this review summarized how to choose, authenticate, and culture different origins of MSCs and derived exosomes. Moreover, clinical application and the latest mechanistical findings of MSC-based therapy in cartilage regeneration were also demonstrated.

The clinical potential of articular cartilage-derived progenitor cells: a systematic review

Over the past two decades, evidence has emerged for the existence of a distinct population of endogenous progenitor cells in adult articular cartilage, predominantly referred to as articular cartilage-derived progenitor cells (ACPCs). This progenitor population can be isolated from articular cartilage of a broad range of species, including human, equine, and bovine cartilage. In vitro, ACPCs possess mesenchymal stromal cell (MSC)-like characteristics, such as colony forming potential, extensive proliferation, and multilineage potential. Contrary to bone marrow-derived MSCs, ACPCs exhibit no signs of hypertrophic differentiation and therefore hold potential for cartilage repair. As no unique cell marker or marker set has been established to specifically identify ACPCs, isolation and characterization protocols vary greatly. This systematic review summarizes the state-of-the-art research on this promising cell type for use in cartilage repair therapies. It provides an overview of the available literature on endogenous progenitor cells in adult articular cartilage and specifically compares identification of these cell populations in healthy and osteoarthritic (OA) cartilage, isolation procedures, in vitro characterization, and advantages over other cell types used for cartilage repair. The methods for the systematic review were prospectively registered in PROSPERO (CRD42020184775).

Application of Embedded Smart Wearable Device Monitoring in Joint Cartilage Injury and Rehabilitation Training

Joint injuries cause varying degrees of damage to joint cartilage. The purpose of this paper is to study the application of embedded smart wearable device monitoring in articular cartilage injury and rehabilitation training. This paper studies what an embedded system is and what a smart wearable device is and also introduces the rehabilitation training method of articular cartilage injury. We cited an embedded matching cost algorithm and an improved AD-Census. The joint cartilage damage and rehabilitation training are monitored. Finally, we introduced the types of smart wearable devices and different types of application fields. The results of this paper show that, after an articular cartilage injury, the joint function significantly recovers using the staged exercise rehabilitation training based on embedded smart wearable device monitoring. We concluded that, from 2013 to 2020, smart wearable devices are very promising in the medical field. In 2020, the value will reach 20 million US dollars.

Injectable “nano-micron” combined gene-hydrogel microspheres for local treatment of osteoarthritis

Sustained and controllable local gene therapy is a potential method for treating osteoarthritis (OA) through the delivery of therapeutic microRNAs (miRNAs) to targeted cells. However, direct injection of crude miRNAs for local gene therapy is limited due to its inadequate transfection efficiency, easy inactivation, and short half-life. Here, a multifunctional gene vector, arginine, histidine, and phenylalanine-modified generation 5 polyamidoamine (named G5-AHP), was employed to form G5-AHP/miR-140 nanoparticles by forming a complex with microRNA-140 (miR-140). Then, the nanoparticles were entrapped in hydrogel microspheres (MSs) to construct a “nano-micron” combined gene hydrogel to alleviate the degradation of articular cartilage. Monodisperse gelatin methacryloyl hydrogel MSs were produced under ultraviolet light using one-step innovative microfluidic technology. Evenly dispersed MSs showed better injectability in sustainable and matrix metalloproteinases (MMPs)-responsive degradation methods for local gene delivery. The G5-AHP/miR-140 nanoparticles released from the MSs exhibited high gene transfection efficacy and long-term bioactivity, facilitated endocytosis, and thus maintained the metabolic balance of cartilage matrix by promoting the expression of type II collagen and inhibiting the expression of a disintegrin and metalloproteinase with thrombospondin motifs-5 and MMP13 in chondrocytes. After injection of the “nano-micron” combined gene hydrogel into the articular cavity of the OA model, the gene hydrogel increased G5-AHP/miR-140 nanoparticle retention, prevented articular cartilage degeneration, and reduced osteophyte formation in a surgically induced mouse model of OA. The present study provides a novel cell-free approach to alleviate the progression of OA that shows potential for locally injected gene delivery systems.