Unveiling Regional Variations in Articular Cartilage Mechanics Affected by Osteoarthritis

doi:10.21203/rs.3.rs-3548104/v1

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Unveiling Regional Variations in Articular Cartilage Mechanics Affected by Osteoarthritis

https://doi.org/10.21203/rs.3.rs-3548104/v1

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Due to its biofunction, the mechanics of articular cartilage (AC) is a vital index concerning the lesion of AC, and there are many studies on the relationship between the mechanics of AC and lesions of AC. It is expected that the variation of mechanics of AC can be used as an early diagnosis index of osteoarthritis (OA) or other lesions of AC. In clinical observation, the degradation of AC is region-specific, therefore, to further achieve this goal, the mechanics of AC under different stages of OA at different regions, i.e., medial distal femoral condyle, lateral distal femoral condyle, medial posterior femoral condyle, and lateral posterior femoral condyle, were systematically measured using the deep indentation technique in this study. The results demonstrated that the mechanics of AC in the four regions follow the same trend with the development of OA. Interestingly, the elastic modulus of AC at the stage of OA3 is the smallest among the last three stages of OA. The discovery of this inflection point at the stage of OA3 holds promise for improving our understanding and therapy for OA in the future. This study also highlights the need for future research to focus on the impact of location on the mechanics of AC.

Articular cartilage

Osteoarthritis

Elastic modulus

Inflection point

Osteoarthritis (OA) is one of the most prevalent musculoskeletal conditions, affecting up to 303 million people globally in 2017, and this number is increasing due to an aging population and the obesity pandemic¹. Unfortunately, OA remains a progressive, irreversible, and incurable condition². Therefore, it is essential to understand the prevalence, incidence, and modifiable risk factors of OA to provide effective prevention and treatment in the early stages³. From a structural perspective, the degradation of articular cartilage (AC) is a hallmark feature of OA⁴. It is well-known that AC protects the joint by distributing applied loads, thus preventing potentially damaging stress concentrations and providing a low-friction bearing surface for free joint movement⁵.

AC has evolved into a remarkable and inhomogeneous tissue with a heterogeneous composition to precisely fulfill its biological function. This structural tissue consists primarily of water (60–85%), a solid matrix of collagen (15–22%) and proteoglycan (PG, 4–7%), and chondrocytes (3–5%)⁶. Collagen, in addition to water, is the largest component of AC, followed by proteoglycan. Each component has its own biological functions and mechanics. For example, the collagen network serves as the structural framework of AC and is the primary source of tensile and shear strength, while proteoglycan has a significant net negative charge that draws water into the tissue and imparts AC with considerable compressive strength. The synergy of each component gives AC excellent mechanical properties. Conversely, any variation in any component of the outstanding system can lead to AC damage, and impede AC from exerting its normal function in the body^{7, 8}. In addition, the mechanical properties of AC will also be altered due to its component variation⁹.

Given the biological function of AC and its relationship with OA, the mechanics of AC and its components have also been extensively investigated in the context of OA development^{10, 11}. Although quite a number of previous studies have concluded that the mechanics of AC is closely related to the advancement of OA, the relationship between the mechanics of AC and the development of OA remains controversial. For instance, Stolz et al. found that the mechanics of AC decreased with the advancement of OA¹², while Wang et al. demonstrated that the mechanics of AC increased from healthy cartilage to mildly worn cartilage and then decreased as OA reached the severe condition¹³. However, Rybka et al. argued that the increasing grade of OA was not correlated with the decrease or increase of the mechanical properties of AC¹⁴. As previously mentioned¹⁵, AC is an inhomogeneous tissue, and its mechanical properties mostly depend on its components. Additionally, different regions of AC are exposed to different magnitudes of forces. Therefore, it is crucial to consider fully the regional differences of AC when investigating the mechanics of AC, especially the AC with OA.

To clearly differentiate the morphology and weight-bearing characteristics of the femoral condyle, it is commonly divided into four areas: the medial distal femoral condyle (MDC), lateral distal femoral condyle (LDC), medial posterior femoral condyle (MPC), and lateral posterior femoral condyle (LPC)¹⁶. Moreover, to systematically understand the relationship between the mechanics of AC and the development of OA, the elastic modulus of the entire AC from the OA knee patient was divided into four distinct regions and explored through depth-sensing indentation. The results demonstrated that the mechanics of AC in all four regions exhibited a consistent trend with the progression of OA, with an inflection point observed at stage 3 of OA. This inflection point represents a significant discovery in the relationship between the mechanics of AC and OA, providing valuable insights for future understanding and treatment of the condition. Furthermore, this study highlights the importance of investigating the influence of location on the mechanics of AC in future research.

Chemicals

Ethylenediaminetetraacetic acid (EDTA) was purchased from Sigma-Aldrich (Shanghai, China). Benzamidine hydrochloride, N-ethyl maleimide and phenylmethylsulfonyl fluoride were purchased from China National Pharmaceutical Reagents Co. Ltd. (Shanghai, China). Sterile 1× Phosphate-Buffered Saline (PBS, pH 7.4) and double antibodies (penicillin and streptomycin) was purchased from Tiangen Biotech (Beijing, China) Co., Ltd., China. The other chemical reagents were purchased from from Shengong Bioengineering Co., Ltd. (Shanghai, China). All chemicals were directly used as received without further purification, unless otherwise stated. The water used in the study was 18.2 MΩ cm deionized water (DI water).

Sample Preparation and Histopathological Review

This research is approved and supervised by the Institutional Ethics Review Committee of Zhujiang Hospital (trial register number: 2017-GJGBK-001). The experiments also followed approved guidelines and regulations. The AC used in this study was retrieved from total knee arthroplasty disposals. Twenty-one volunteers participated and signed informed consent forms. Patients who met the criteria of OA according to the American College of Rheumatology, aged more than 50 years old, with Kellgren-Lawrence grade 3–4 were included. Exclusion criteria was as follows: (1) autoimmune disease; (2) rheumatoid arthritis; (3) knee infection and (4) participants considered inappropriate in the clinical trial. The AC used in this study was retrieved from total knee arthroplasty disposals.

Two experienced pathologists, respectively, performed a routine histopathological evaluation of each section based on the Osteoarthritis Research Society International (OARSI) osteoarthritis cartilage assessment system and the Kellgren-Lawrence Classification System^17–19, and the results were reviewed to achieve consensus. However, if there is a different assessment for one sample, the sample will be re-reviewed by the other pathologist to reach a consensus and determine the final pathological grade.

After obtaining the samples, it was immediately divided into two parts, one for hematoxylin-eosin (HE) staining, and the other (obtained AC with subchondral bone) was kept in anti-degradation solution (2 mM ethylenediaminetetraacetic acid, 5 mM benzamidine hydrochloride, 10 mM ethyl maleimide, 1 mM phenylmethylsulfonyl fluoride, and 1% Double antibodies (penicillin and streptomycin) were dissolved in 1L of PBS buffer) and stored at -80 ^oC for mechanical measurement.

HE Staining and Histopathological Review

The obtained samples of condyles were fixed in 4% polymethyl alcohol, and decalcified with Rapid Bone Decalcifier (American Master Tech Inc., Lodi, CA, USA) for 48 h, and then embedded with paraffin. The fixed samples were sagittally cut into slices with a thickness of about 8 µm. All the cutting samples were stained with HE.

Magnetic resonance imaging (MRI) and image analysis

The commercial 3.0 T MRI scanner (Philips Healthcare, Eindhoven, Netherlands) was employed to obtain the MRI image preoperatively. Three sagittal MR images were acquired including fat-suppressed (FS) proton density-weighted imaging (PDWI) sequence, T2 mapping sequence, and T1ρ mapping sequence. All sagittal images were obtained without oblique angulation, parallel to the magnetic static field (B0). The acquisition parameters for the sagittal T2 mapping sequence were consistent with the methods previously described²⁰: repetition time = 1000 ms, echo time = 0 ms, optional locking time = 9.5/19.1/28.6/38.1/47.6/57.2/66.7/76.2 ms, slice thickness = 4 mm, slice thickness = 0.5 mm, scanning layers = 20 layers, field of view = 160 mm, matrix size = 320 × 256, excitation times = 1, scanning time = 8 min 46 s.

Regions of interest (ROIs) of different cartilages were outlined. Condyles were divided into ROI parts to match the histology images (HE stain): The c-line of the condyle (Whiteside’s line) was drawn during surgery for surgery consideration. The ROIs of histopathology were selected by the R-line of histopathology was drawn parallel to the c-line. P-distance was applied to determine the interval between the c-line and the R-line. The ROI was obtained and marked by the surgeon during surgery. Then the Whiteside’s line was drawn in MRI image and set as a reference line. Using c-line as a reference line and applying p-distance, histological sections of interest can be marked in MRI images. Through the above method, the histological slices were matched with ROIs of MRI. This method could refer to our previous research²¹.

Mechanical measurements

To thaw the frozen AC, the samples were kept for 10h at -20 ^oC, 4 ^oC, and room temperature sequentially. The AC used for the mechanical measurements was harvested using a round punch with a diameter of 10 mm, and then the prepared sample was fixed on the holder for the mechanical measurement using 3M quick-drying glue (AD119, 3M, USA). Noted: the glue was adsorbed to the interface between the subchondral bone of the sample and the holder. Then, the prepared samples were immediately used in the mechanical measurements.

The micro-mechanical properties of AC were measured by depth-sensing indentation. A Nano Indenter G200 (Keysight Technologies, Inc., Santa Rosa, CA, USA) equipment with a standard Berkovich indenter was adopted, whose elastic modulus is 1140 GPa and Poisson's ratio is 0.07. The holder with the prepared sample was fixed in a homemade sealed cell that was filled with PBS solution. The AC sample and tip are in PBS solution to simulate its mechanical properties like the natural state in the body.

The detailed instrumentation of the indentation measurement can be found elsewhere^{22, 23}. In brief, an indentation test started with the indenter tip approaching the surface with an approach velocity of 20 nm/s. The contact point was determined by setting a setpoint of 2 µN, which means that when the indenter approached, the instrument would judge to reach the sample surface when a value of 2 µN was reached and then start loading at the velocity of 50 nm/s. At the maximum penetration depth of 3000 nm, the load on the indenter was held constant for 60 s. Then, to reduce the viscous effect of AC on its calculation of elastic modulus, the indenter was withdrawn from the surface of the sample at a high velocity of 300 nm/s and then be held at a relatively low load for evaluating the effect of thermal drift. The insert shown in Fig. 1 is the designed loading and unloading scheme. To ensure the reproduction of the results, more than 100 points were selected randomly on each sample to carry out the indentation measurements. The distance between the indentation points on the sample is 50 µm to prevent possible strain field interactions among these indentations.

To obtain a more realistic elastic modulus of the sample, the contact zero point of the load-displacement curve was examined and corrected is it is necessary. 50–95% of the unloading segment of each load-displacement curve was analyzed using Oliver-Pharr model²⁴. The relationship between the reduced modulus for the indenter-specimen system (E_r) and slope (S) of the linear stage in the upper part of the unloading curve (Fig. 1) is²⁵:

$${E_r}=\frac{{S\sqrt \pi }}{{2\sqrt {{A_c}} }}$$

where A_C is the contact area between the tip and the sample. The shape of Berkovich tip, which has a three-sided pyramid with a face angle of 65.3°, used in indentation testing is usually described by area function. The projected contact area Ac as a function of contact depth h_c can be described as the following Eq. 2⁶:

$${A_c} \approx {C_0}h_{c}^{2}+{C_1}h_{c}^{{}}+{C_2}h_{c}^{{\frac{1}{2}}}+{C_3}h_{c}^{{\frac{1}{4}}}+....+{C_8}h_{c}^{{\frac{1}{{128}}}}$$

here h_c is the contact indentation depth and the coefficients C₀, C₁, …, C₈ are determined by fitting experimental data. For an ideal Berkovich tip, C₀ is 24.5 and the other coefficients are equal to 0.

The elastic modulus of the sample can be described as the following Eq. 2⁵:

$$\frac{1}{{{E_r}}}=\frac{{1 - \lambda _{{sample}}^{2}}}{{{E_{sample}}}}+\frac{{1 - \lambda _{{indenter}}^{2}}}{{{E_{indenter}}}}$$

where, λ is the Poisson's ratio for the tested specimen and the indenter, respectively. Given to the fact that the elastic modulus of the indenter (E_indenter, 1140 GPa) is much larger than that of the sample (E_sample). Thus, the above equation can be transformed into:

$${E_{sample}} \approx {E_r}(1 - \lambda _{{sample}}^{2})$$

here, the Poisson's ratio of the AC (λ_sample) was considered to be 0.5, according to the statement of Lewis et. al.²⁷ and Mow et. al²⁸..

Statistical analysis

Data are expressed as mean ± SD. For the calculation of significance, the one-way ANOVA with a posthoc test of Tukey was used. Statistical significance was considered at p < 0.05. All analyses were performed with Graphpad Prism (version: 5.01, GraphPad Software Inc., CA, USA)

Anthropometric information of osteoarthritic patients

Table 1 summarizes the anthropometric characteristics of the patients who participated in this study. The evaluation of knee radiographs, using the Osteoarthritis Research Society International criteria and the Kellgren-Lawrence Classification System^17–19, showed that none of the patients were graded 0. However, it should be noted that not all of the four regions (MDC, LDC, MPC, and LPC) of the AC had all four stages of OA, due to the samples being harvested from disposals after total knee arthroplasty (see Table 1).

Table 1

Anthropometric information of the osteoarthritic patients.
General Information		Range	Mean
Gender (male/female)		\	2/19
Age (year)		52–77	67.6±5.86
Affected Knee Joint (Right/Left)		\	12/9
Height (m)		1.45–1.68	1.57±0.053
Weight (kg)		45–66	57.7±7.91
BMI (kg/m²)		26.31–41.25	36±5.07
Histological Grade	MDC	2–4	\
	LDC	2–4
	MPC	1–4
	LPC	1–3

T2 mapping images

To have a visualized preview of the development of OA and the variation of the component of AC, MIR was employed to obtain the MRI image of the samples. Figure 4 shows the T2 mapping images and the corresponding histopathology for AC with OA. The results demonstrated that: (1) In grade I OA, proteoglycans are initially depleted, and the collagen matrix begins to break down; (2) In grade II OA, proteoglycans become severely depleted, and the collagen fibers are broken into segments. (3) In grade III OA, the number of proteoglycans and collagen matrix is greatly reduced, forming a soft layer. (4) In grade IV OA, the cartilage is almost depleted.

Elastic modulus of AC at different stage of OA

The MIR results demonstrated that the structure and morphology of AC have changed with the development of OA. Therefore, it can be expected that the mechanical properties of AC should also vary with the development of OA. To find out the variation, the depth-sensing indentation technique was employed to investigate the elastic modulus of AC at different stages of OA. Figure 2 displays the elastic modulus of the AC in the four different regions under different stages of OA. It can be found that the elastic modulus of AC in the hydrated state ranged from 1-100 MPa, which is in consistent with previous studies¹⁴.

The elastic modulus of the AC in all four regions shows a similar variation with the progression of OA (Fig. 2). It can be found that the elastic modulus of AC with OA stage 1 is higher than that with OA stage 2 (Fig. 1D). With the development of OA, the elastic modulus of AC with OA stage 3 is the lowest among the OA stage 2 to 4 (Fig. 1). In addition, the elastic modulus is the highest for AC with OA stage 4. However, it is still very interesting to observe a significant inflection point of elastic

modulus of AC during the progression of OA at OA3 stage, which might be helpful in further understand the pathology of OA.

To quantificationally confirm the mechanics of AC in the four regions, we also compared their elastic modulus under different stages of OA (Fig. 5). It can be found that the elastic modulus of AC among the four regions exhibited statistically significant differences (p < 0.05).

Based on the depth-sensing indentation tests results, it can be found that the elastic modulus of AC is largely dependent on the OA’s development. Moreover, It should be noted that the elastic modulus measured from all four regions of AC exhibit the same trend with OA progresses, although they are exposed to different levels of mechanical loading. However, the absolute value of measured elastic modulus at different regions does vary from each other, which should be due to the fact that the progression of OA at different regions is different due to the uneven loading-bearing on AC.

As stated in introduction, the variations of the content or interactions of AC should change its mechanical properties^{7, 8}. Therefore, to find out the reasons for the variation of the mechanics for AC with the development of OA, it is reasonable to further speculate on the composition of AC and the process of OA. Although the origin of OA is still not entirely clear, it is widely accepted that the degraded composition of AC differs at various stages of OA. In the early stages of OA, for example, the primary change is the loss of glycosaminoglycan, followed by alterations in collagen structures^{29, 30}. Moreover, collagen fibril orientation in the superficial AC also changed significantly in the early OA (Fig. 3), while a significant reduction in collagen content only occurs in the advanced stages of OA³¹. Due to the degradation of components are different at the different stages of OA, thus the variation of the mechanical properties for AC is different with the development of OA. The collagen network, for instance, serves as the structural framework of AC and it is the principal source of tensile and shear strength³², while the proteoglycans confer considerable compressive strength to AC due to their significant net negative charge³³. Thus, the various changes in composition that occur at different stages of OA lead to different variations in the AC’s mechanical behavior.

Moreover, the arrangement of components in AC is also altered by OA³⁴. In healthy AC, three structurally distinct zones can be distinguished based on the predominant orientations of collagen fibers^{9, 35} (Fig. 3): (i) the superficial zone (10–20% of overall thickness) where the fibers run parallel to the joint surface, (ii) the transitional zone (40–60%) with randomly oriented fibers, and (iii) the radial zone (30%) where the fibers are almost perpendicular to the AC. As OA progresses, disorganized collagen fibrils in the superficial and deep zones of AC are observed³⁶. Consequently, the second possible reason for the variation of AC mechanics with the development of OA is that (Fig. 4): (1) The degradation of the intact structure of proteoglycans collagen matrix of AC occurred in grade I OA will lead the collagen fiber to directly contact with the indentor. (2) For the grade II OA, proteoglycans become severely depleted, and the collagen fibers are broken into segments. Therefore, more collagen segments are under the indentor, resulting in a higher elastic modulus at this grade than at grade I. (3) With the further development of OA (grade III), the formation of the soft layer resulting from the degradation of proteoglycans and collagen matrix results in a lower elastic modulus. (4) In grade IV OA, due to the almost depletion of cartilage, the obtained elastic modulus may represent that of the subchondral bone, which has a higher elastic modulus than AC.

It should be noted that identifying the sequence of damage to the AC composition during the OA process remains a challenge. However, this study provides a potential pathway for addressing this challenge. The results suggested that the mechanics of the four regions of AC follow a similar trend with the development of OA, despite their differing mechanics under the same stage of OA. Thus, it is reasonable to inspect the variation of the mechanics for each component of AC under different stage of OA, and to establish the relationships between OA and the damaged composition of AC during the OA process.

As OA advances, the elastic modulus of AC becomes more diffuse, likely due to the varying degree of AC damage in different stages of OA. As a biological tissue, the biomechanical function of AC is influenced by its composition, including water content and concentrations of collagen, proteoglycans, and hyaluronate, as well as interactions between these components. As OA progresses, the integrity of AC is compromised, and the degree of damage varies even in the same location and stage of OA due to different forces acting on different regions of the knee joint. Consequently, the biomechanics of damaged AC exhibit a larger dispersion in the same OA grade (Fig. 2).

The mechanics of AC are influenced by both its composition and morphology, one factor is not recommended. The present study systematically investigated the relationship between the mechanics of the entire AC, divided into four regions (MDC, LDC, MPC, and LPC), and advancement of OA. This study found that the mechanics of AC in all four regions follow the same trend with the progression of OA, and the elastic modulus of AC with OA stage 3 is lowest among the OA stage 2 to 4. This result demonstrates that the mechanics of AC depend on its damage degree during the OA process, which is due to the varying composition of AC at different stages of OA.

The regional differences in the mechanical properties of AC with OA highlight the significance of this study. The identification of an inflection point in this study underscores the importance of studying the relationship between AC mechanics and OA based on the location on AC, and a more detailed division would yield more accurate results.

The findings of this study shed new light on our understanding of OA, provide a potential avenue for future therapies, and highlight the importance of location in investigating the mechanics of AC. By examining the mechanics of AC in different regions, this study provides more detailed information than previous studies. While the underlying mechanism of OA still requires further investigation, we believe that studying the mechanics of AC at the microscopic level will help unravel its mysteries.

Declaration of conflicting interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This study is financially supported by National Key Research and Development Program of China Grants (Project No. 2019YFA0906004), Natural Science Foundation of Hunan Province [Project No. 2021JJ41076]. the National Foundation of Science and Technology (Project No. 11872200, 32201484), Guangdong Provincial Key Laboratory of Advanced Biomaterials (Project No.2022B1212010003), Shenzhen Science and Technology Innovation Committee (Project No. KCXFZ20211020174805009, JSGG20200225151916021).

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No competing interests reported.

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Unveiling Regional Variations in Articular Cartilage Mechanics Affected by Osteoarthritis

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Abstract

Figures

Introduction

Materials and Methods

Chemicals

Sample Preparation and Histopathological Review

HE Staining and Histopathological Review

Magnetic resonance imaging (MRI) and image analysis

Mechanical measurements

Statistical analysis

Results

Anthropometric information of osteoarthritic patients

T2 mapping images

Elastic modulus of AC at different stage of OA

Discussion

Conclusion

Declarations

References

Additional Declarations

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