A new method for computing the uniaxial modulus of articular cartilages using modified inhomogeneous triphasic model

It is well known that subtle changes in structure and tissue composition of articular cartilage can lead to its degeneration. The present paper puts forward a modified layered inhomogeneous triphasic model with four parameters based on the inhomogeneous triphasic model proposed by Narmoneva et al. Incorporating a piecewise fitting optimization criterion, the new model was used to obtain the uniaxial modulus Ha, and predict swelling pattern for the articular cartilage based on ultrasound-measured swelling strain data. The results show that the new method can be used to provide more accurate estimation on the uniaxial modulus than the inhomogeneous triphasic model with three parameters and the homogeneous mode, and predict effectively the swell- ing strains of highly nonuniform distribution of degenerated articular cartilages. This study can provide supplementary information for exploring mechanical and material properties of the cartilage, and thus be helpful for the diagnosis of osteoarthritis-related diseases.

Abnormal subchondral bone remodeling and its association with articular cartilage degradation in knees of type 2 diabetes patients

Type 2 diabetes （T2D） is associated with systemic abnormal bone remodeling and bone loss. Meanwhile, abnormal subchondral bone remodeling induces cartilage degradation, resulting in osteoarthritis （OA）. Accordingly, we investigated alterations in subchondral bone remodeling, microstructure and strength in knees from T2D patients and their association with cartilage degradation. Tibial plateaus were collected from knee OA patients undergoing total knee arthroplasty and divided into non-diabetic （n---70） and diabetes （n = 51） groups. Tibial plateaus were also collected from cadaver donors （n = 20） and used as controls. Subchondral bone microstructure was assessed using micro-computed tomography. Bone strength was evaluated by micro-finite-element analysis. Cartilage degradation was estimated using histology. The expression of tartrate-resistant acidic phosphatase （TRAP）, osterix, and osteocalcin were calculated using immunohistochemistry. Osteoarthritis Research Society International （OARSI） scores of lateral tibial plateau did not differ between non-diabetic and diabetes groups, while higher OARSI scores on medial side were detected in diabetes group. Lower bone volume fraction and trabecular number and higher structure model index were found on both sides in diabetes group. These microstructural alterations translated into lower elastic modulus in diabetes group. Moreover, diabetes group had a larger number of TRAP~ osteoclasts and lower number of Osterix~ osteoprogenitors and Osteocalcin~ osteoblasts. T2D knees are characterized by abnormal subchondral bone remodeling and microstructural and mechanical impairments, which were associated with exacerbated cartilage degradation. In regions with intact cartilage the underlying bone still had abnormal remodeling in diabetes group, suggesting that abnormal bone remodeling may contribute to the early pathogenesis of T2D-associated knee OA.

The study on the mechanical characteristics of articular cartilage in simulated microgravity

The microgravity environment of a long-term space flight may induce acute changes in an astronaut＇s musculo-skeletal systems. This study explores the effects of simulated microgravity on the mechanical characteristics of articular cartilage. Six rats underwent tail suspension for 14 days and six additional rats were kept under normal earth gravity as controls. Swelling strains were measured using high-frequency ultrasound in all cartilage samples subject to osmotic loading. Site-specific swelling strain data were used in a triphasic theoretical model of cartilage swelling to determine the uniaxial modulus of the cartilage solid matrix. No severe surface irregularities were found in the cartilage samples obtained from the control or tail-suspended groups. For the tail-suspended group, the thickness of the cartilage at a specified site, as determined by ultrasound echo, showed a minor decrease. The uniaxial modulus of articular cartilage at the specified site decreased significantly, from （6.31 ± 3.37） MPa to （5.05 ± 2.98）MPa （p 〈 0.05）. The histology- stained image of a cartilage sample also showed a reduced number of chondrocytes and decreased degree of matrix staining. These results demonstrated that the 14 d simulated microgravity induced significant effects on the mechanical characteristics of articular cartilage. This study is the first attempt to explore the effects of simulated microgravity on the mechanical characteristics of articular cartilage using an osmotic loading method and a triphasic model. The conclusions may provide reference information for manned space flights and a better understanding of the effects of microgravity on the skeletal system.

Study on the Microstructure of Human Articular Cartilage/Bone Interface

For improving the theory of gradient microstructure of cartilage/bone interface, human distal femurs were studied. Scanning Electron Microscope （SEM）, histological sections and MicroCT were used to observe, measure and model the micro- structure of cartilage/bone interface. The results showed that the cartilage/bone interface is in a hierarchical structure which is composed of four different tissue layers. The interlocking of hyaline cartilage and calcified cartilage and that of calcified car- tilage and subchondral bone are in the manner of＂protrusion-pore＂ with average diameter of 17.0 gm and 34.1 lam respectively. In addition, the cancellous bone under the cartilage is also formed by four layer hierarchical structure, and the adjacent layers are connected by bone trabecula in the shape of H, I and Y, forming a complex interwoven network structure. Finally, the simplified structure model of the cartilage/bone interface was proposed according to the natural articular cartilage/bone interface. The simplified model is a 4-layer gradient biomimetic structure, which corresponds to four different tissues of natural cartilage/bone interface. The results of this work would be beneficial to the design of bionic scaffold for the tissue engineering of articular cartilage/bone.

The Frictional Coefficient of Bovine Knee Articular Cartilage

The normal displacement of articular cartilage was measured under load and in sliding, and the coefficient of friction during sliding was measured using a UMT-2 Multi-Specimen Test System. The maximum normal displacement under load and the start-up frictional coefficient have similar tendency of variation with loading time. The sliding speed does not significantly influence the frictional coefficient of articular cartilage.

Functionalized Hydrogels for Articular Cartilage Tissue Engineering

Articular cartilage(AC)is an avascular and flexible connective tissue located on the bone surface in the diarthrodial joints.AC defects are common in the knees of young and physically active individuals.Because of the lack of suitable tissue-engineered artificial matrices,current therapies for AC defects,espe-cially full-thickness AC defects and osteochondral interfaces,fail to replace or regenerate damaged carti-lage adequately.With rapid research and development advancements in AC tissue engineering(ACTE),functionalized hydrogels have emerged as promising cartilage matrix substitutes because of their favor-able biomechanical properties,water content,swelling ability,cytocompatibility,biodegradability,and lubricating behaviors.They can be rationally designed and conveniently tuned to simulate the extracel-lular matrix of cartilage.This article briefly introduces the composition,structure,and function of AC and its defects,followed by a comprehensive review of the exquisite(bio)design and(bio)fabrication of func-tionalized hydrogels for AC repair.Finally,we summarize the challenges encountered in functionalized hydrogel-based strategies for ACTE both in vivo and in vitro and the future directions for clinical translation.

Effects of Structural Changes in Subchondral Bone on Articular Cartilage in a Beagle Dog Model

Objective Using MR T2-mapping and histopathologic score for articular cartilage to evaluate the effect of structural changes in subchondral bone on articular cartilage. Methods Twenty-four male Beagle dogs were randomly divided into a subchondral bone defect group （n = 12） and a bone cement group （n = 12）. Models of subchondral bone defectin the medial tibial plateau and subchondral bone filled with bone cement were constructed. In all dogs, the left knee joint was used as the experimental sideand the right knee as the sham side. The T2 value for articular cartilage at the medial tibial plateau was measured at postoperative weeks 4, 8, 16, and 24. The articular cartilage specimens were stained with hematoxylin and eosin, and evaluated using the Mankin score. Results There was a statistically significant difference （P 〈 0.05） in Mankin score between the bone defect group and the cement group at postoperative weeks 16 and 24. There was a statistically significant difference in the T2 values between the bone defect group and its sham group （P 〈 0.05） from week 8, and between the cement group and its sham group （P 〈 0.05） from week 16. There was significant difference in T2 values between the two experimental groups at postoperative week 24 （P 〈 0.01）. The T2 value for articular cartilage was positively correlated with the Mankin score （ρ = 0.758, P 〈 0.01）. Conclusion Structural changes in subchondral bone can lead to degeneration of the adjacent articular cartilage. Defects in subchondral bone cause more severe degeneration of cartilage than subchondral bone filled with cement. The T2 value for articular cartilage increases with the extent of degeneration. MR T2-mapping images and the T2 value for articular cartilage can indicate earlycartilage degeneration.

An analytical poroelastic model for laboratorial mechanical testing of the articular cartilage (AC)

The articular cartilage （AC） can be seen as a biphasic poroelastic material. The cartilage deformation under compression mainly leads to an interstitial fluid flow in the porous solid phase. In this paper, an analytical poroelastic model for the AC under laboratorial mechanical testing is developed. The solutions of interstitial fluid pressure and velocity are obtained. The results show the following facts. （i） Both the pressure and fluid velocity amplitudes are proportional to the strain loading amplitude. （ii） Both the amplitudes of pore fluid pressure and velocity in the AC depend more on the loading amplitude than on the frequency. Thus, in order to obtain the considerable fluid stimulus for the AC cell responses, the most effective way is to increase the loading amplitude rather than the frequency. （iii） Both the interstitiM fluid pressure and velocity are strongly affected by permeability variations. This model can be used in experimental tests of the parameters of AC or other poroelastic materials, and in research of mechanotransduction and injury mechanism involved interstitial fluid flow.

Comparative study on identi¯cation of healthy and osteoarthritic articular cartilages by fourier transform infrared imaging and chemometrics methods

Two discriminant methods,partial least squares-discriminant analysis(PLS-DA)and Fisher's discriminant analysis(FDA),were combined with Fourier transform infrared imaging(FTIRI)to differentiate healthy and osteoarthritic articular cartilage in a canine model.Osteoarthritic cartilage had been developed for up to two years after the anterior cruciate ligament(ACL)transection in one knee.Cartilage specimens were sectioned into 10μm thickness for FTIRI.A PLS-DA model was developed after spectral pre-processing.All IR spectra extracted from FTIR images were calculated by PLS-DA with the discriminant accuracy of 90%.Prior to FDA,principal component analysis(PCA)was performed to decompose the IR spectral matrix into informative princi pal component matrices.Based on the different discriminant mechanism,the discriminant accuracy(96%)of PCA-FDA with high convenience was higher than that of PLS-DA.No healthy cartilage sample was mis assigned by these two methods.The above mentioned suggested that both integrated technologies of FTIRI-PLS-DA and,especially,FTIRI-PCA-FDA could become a promising tool for the discrimination of healthy and osteoarthritic cartilage specimen as well as the diagnosis of cartilage lesion at microscopic level.The results of the study would be helpful for better understanding the pathology of osteoarthritics.

The effect of spinal cord injury on the expression of TGF-β and TNF-α in rat articular cartilage

Objective： To observe the expression of TGF-β and TNF-α in the spinal cord injured rat model and discuss the significance of the articular cartilage metabolism. Methods： 36 SD female rats were randomly divided into 2 groups： Rats models of spinal cord injury were implemented by Allen method. T10 laminectomy was performed in the control group. Both groups of rats were killed respectively in 1w, 3w and 6w. Hematoxylin-eosin stain was given to each slice in the model group and control group. Immunohistochemical stain was applied by using ABC method in the expression of TGF-β and TNF-α. Those expressed level were performed in image analysis and statistics process. Results： TGF-β and TNF-α were mainly distributed on the surface layer of the articular cartilage, with a weak expression in control group. The expression of TNF-α in the model group was more significant than that in the control group in the lw, and still remained an evident difference with that in control group until the 6w（P 〈 0.05）. TGF-β expression of the model group had no remarkable difference with the control group in the lw （P 〉 0.05） and prominently became stronger at 6w（P 〈 0.05）. Conclusion： The expression of TNF-α occurred early in the development of spinal cord injury, and the expression of TGF-β became stronger with the revival of spinal neural function. Both expressions were strengthened in articular cartilage in the 3rd week.

The finite element analysis of articular cartilage fiber-reinforced composite model under rolling load

Articular cartilage is a layer of low-friction,load-bearing soft hydrated tissue covering bone-ends in diarthrosis,which plays an important role in spreading the load,reducing the joint contact stress,joint friction and wear during exercise.The vital mechanical function

Engineered biochemical cues of regenerative biomaterials to enhance endogenous stem/progenitor cells(ESPCs)-mediated articular cartilage repair

As a highly specialized shock-absorbing connective tissue,articular cartilage(AC)has very limited self-repair capacity after traumatic injuries,posing a heavy socioeconomic burden.Common clinical therapies for small-to medium-size focal AC defects are well-developed endogenous repair and cell-based strategies,including microfracture,mosaicplasty,autologous chondrocyte implantation(ACI),and matrix-induced ACI(MACI).However,these treatments frequently result in mechanically inferior fibrocartilage,low cost-effectiveness,donor site morbidity,and short-term durability.It prompts an urgent need for innovative approaches to pattern a pro-regenerative microenvironment and yield hyaline-like cartilage with similar biomechanical and biochemical properties as healthy native AC.Acellular regenerative biomaterials can create a favorable local environment for AC repair without causing relevant regulatory and scientific concerns from cell-based treatments.A deeper understanding of the mechanism of endogenous cartilage healing is furthering the(bio)design and application of these scaffolds.Currently,the utilization of regenerative biomaterials to magnify the repairing effect of joint-resident endogenous stem/progenitor cells(ESPCs)presents an evolving improvement for cartilage repair.This review starts by briefly summarizing the current understanding of endogenous AC repair and the vital roles of ESPCs and chemoattractants for cartilage regeneration.Then several intrinsic hurdles for regenerative biomaterials-based AC repair are discussed.The recent advances in novel(bio)design and application regarding regenerative biomaterials with favorable biochemical cues to provide an instructive extracellular microenvironment and to guide the ESPCs(e.g.adhesion,migration,proliferation,differentiation,matrix production,and remodeling)for cartilage repair are summarized.Finally,this review outlines the future directions of engineering the next-generation regenerative biomaterials toward ultimate clinical translation.

Advancing drug delivery to articular cartilage:From single to multiple strategies

Articular cartilage(AC) injuries often lead to cartilage degeneration and may ultimately result in osteoarthritis(OA) due to the limited self-repair ability. To date, numerous intra-articular delivery systems carrying various therapeutic agents have been developed to improve therapeutic localization and retention, optimize controlled drug release profiles and target different pathological processes. Due to the complex and multifactorial characteristics of cartilage injury pathology and heterogeneity of the cartilage structure deposited within a dense matrix, delivery systems loaded with a single therapeutic agent are hindered from reaching multiple targets in a spatiotemporal matched manner and thus fail to mimic the natural processes of biosynthesis, compromising the goal of full cartilage regeneration. Emerging evidence highlights the importance of sequential delivery strategies targeting multiple pathological processes. In this review, we first summarize the current status and progress achieved in single-drug delivery strategies for the treatment of AC diseases. Subsequently, we focus mainly on advances in multiple drug delivery applications, including sequential release formulations targeting various pathological processes, synergistic targeting of the same pathological process, the spatial distribution in multiple tissues, and heterogeneous regeneration. We hope that this review will inspire the rational design of intraarticular drug delivery systems(DDSs) in the future.

Quantitative T2 mapping evaluation for articular cartilage lesions in a rabbit model of anterior cruciate ligament transection osteoarthritis

Background Quantitative T2 mapping has been a widely used method for the evaluation, of pathological cartilage properties, and the histological assessment system of osteoarthritis in the rabbit has been published recently. The aim of the study was to investigate the effectiveness of quantitative T2 mapping evaluation for articular cartilage lesions of a rabbit model of anterior cruciate liaament transection （ACLTI osteoarthritis.

Influence of synovia constituents on tribological behaviors of articular cartilage

The extremely low friction and minimal wear in natural synovial joints appear to be established by effective lubrication mechanisms based on appropriate combination of articular cartilage and synovial fluid.The complex structure of cartilage composed of collagen and proteoglycan with high water content contributes to high load-carrying capacity as biphasic materials and the various constituents of synovial fluid play important roles in various lubrication mechanisms.However,the detailed differences in functions of the intact and damaged cartilage tissues,and the interaction or synergistic action of synovia constituents with articular cartilage have not yet been clarified.In this study,to examine the roles of synovia constituents and the importance of cartilage surface conditions,the changes in friction were observed in the reciprocating tests of intact and damaged articular cartilage specimens against glass plate lubricated with lubricants containing phospholipid,protein and/or hyaluronic acid as main constituents in synovial fluid.The effectiveness of lubricant constituents and the influence of cartilage surface conditions on friction are discussed.In addition,the protectiveness by synovia constituents for intact articular cartilage surfaces is evaluated.

Nanoparticle–Cartilage Interaction: Pathology-Based Intra-articular Drug Delivery for Osteoarthritis Therapy

Osteoarthritis is the most prevalent chronic and debilitating joint disease,resulting in huge medical and socioeconomic burdens.Intra-articular administration of agents is clinically used for pain management.However,the effectiveness is inapparent caused by the rapid clearance of agents.To overcome this issue,nanoparticles as delivery systems hold considerable promise for local control of the pharmacokinetics of therapeutic agents.Given the therapeutic programs are inseparable from pathological progress of osteoarthritis,an ideal delivery system should allow the release of therapeutic agents upon specific features of disorders.In this review,we firstly introduce the pathological features of osteoarthritis and the design concept for accurate localization within cartilage for sustained drug release.Then,we review the interactions of nanoparticles with cartilage microenvironment and the rational design.Furthermore,we highlight advances in the therapeutic schemes according to the pathology signals.Finally,armed with an updated understanding of the pathological mechanisms,we place an emphasis on the development of“smart”bioresponsive and multiple modality nanoparticles on the near horizon to interact with the pathological signals.We anticipate that the exploration of nanoparticles by balancing the efficacy,safety,and complexity will lay down a solid foundation tangible for clinical translation.

Advances and prospects in biomimetic multilayered scaffolds for articular cartilage regeneration

Due to the sophisticated hierarchical structure and limited reparability of articular cartilage(AC),the ideal regeneration of AC defects has been a major challenge in the field of regenerative medicine.As defects progress,they often extend from the cartilage layer to the subchondral bone and ultimately lead to osteoarthritis.Tissue engineering techniques bring new hope for AC regeneration.To meet the regenerative requirements of the heterogeneous and layered structure of native AC tissue,a substantial number of multilayered biomimetic scaffolds have been studied.Ideal multilayered scaffolds should generate zone-specific functional tissue similar to native AC tissue.This review focuses on the current status of multilayered scaffolds developed for AC defect repair,including design strategies based on the degree of defect severity and the zone-specific characteristics of AC tissue,the selection and composition of biomaterials,and techniques for design and manufacturing.The challenges and future perspectives of biomimetic multilayered scaffold strategies for AC regeneration are also discussed.

Hierarchical macro-microporous WPU-ECM scaffolds combined with Microfracture Promote in Situ Articular Cartilage Regeneration in Rabbits

Tissue engineering provides a promising avenue for treating cartilage defects.However,great challenges remain in the development of structurally and functionally optimized scaffolds for cartilage repair and regeneration.In this study,decellularized cartilage extracellular matrix(ECM)and waterborne polyurethane(WPU)were employed to construct WPU and WPU-ECM scaffolds by water-based 3D printing using low-temperature deposition manufacturing(LDM)system,which combines rapid deposition manufacturing with phase separation techniques.The scaffolds successfully achieved hierarchical macro-microporous structures.After adding ECM,WPU scaffolds were markedly optimized in terms of porosity,hydrophilia and bioactive components.Moreover,the optimized WPU-ECM scaffolds were found to be more suitable for cell distribution,adhesion,and proliferation than the WPU scaffolds.Most importantly,the WPU-ECM scaffold could facilitate the production of glycosaminoglycan(GAG)and collagen and the upregulation of cartilage-specific genes.These results indicated that the WPU-ECM scaffold with hierarchical macro-microporous structures could recreate a favorable microenvironment for cell adhesion,proliferation,differentiation,and ECM production.In vivo studies further revealed that the hierarchical macro-microporous WPU-ECM scaffold combined with the microfracture procedure successfully regenerated hyaline cartilage in a rabbit model.Six months after implantation,the repaired cartilage showed a similar histological structure and mechanical performance to that of normal cartilage.In conclusion,the hierarchical macro-microporous WPU-ECM scaffold may be a promising candidate for cartilage tissue engineering applications in the future.