Prem Sagar,Amit Handa,Gitesh Kumar,Vikas Gupta,Rinku Walia,Shivali Singla
1.Department of Mechanical Engineering, The Technological Institute of Textile & Sciences,Bhiwani,127021,India
2.Department of Mechanical Engineering, Inder Kumar Gujral Punjab Technical University,Kapurthala,144603,India
3.Department of Mechanical Engineering,Guru Jambheshwar University of Science&Technology,Hisar,125001,India
4.Department of Mechanical Engineering, Ch.Devi Lal State Institute of Engineering &Technology,Panniwala Mota,Sirsa,125077,India
5.Department of Civil Engineering, Inder Kumar Gujral Punjab Technical University, Kapurthala,144603,India
Abstract: Osteoarthritis (OA) is a regressive ailment that affects a large population of patients.The most common symptoms of OA in humans are cartilage abnormalities.Hydrogels are excellent candidates for cartilage regeneration and are widely accepted as implants.In the past few decades,numerous types of hydrogels have been synthesized to repair cartilage defects.This study highlights recent advances in hydrogel development for the treatment of cartilage defects.In addition, the detailed progression of tailored nanocomposite hydrogels is summarized, and emphasis has been placed on the mechanical properties, especially the tribological behavior of the developed nanocomposite hydrogels.
Keywords: hydrogels; cartilage defects; nanocomposites; tribological properties
Osteoarthritis (OA) is a progressive condition that causes degradation of the bone tissue and articular cartilage over time.This degradation/biodegradation mechanism of bone tissue inevitably results in irreversible destruction of articular cartilage and other joint structures.It is the most common disease in modern culture, affecting people worldwide and causing a socioeconomic burden on society.However, researchers worldwide are unable to elucidate its exact etiology.In the Western world, it has the fourth-highest impact on women's health and the eighth-highest impact on men's health[1].OA poses a significant problem for communities worldwide,especially in nations with rapidly ageing populations.Studies show that the number of people with OA is expected to rise by 50%in the next 20 years owing to the ageing of many societies[2].Although OA is more common in the elderly, it can also affect young people,particularly following joint injury.Despite the fact that it is not lethal, it significantly limits the patient's mobility,and associated pain further influences physical and mental well-being.To date, numerous medicines and therapies are currently available to overcome these underlying issues[3].However, there is no viable treatment known to date that successfully slows cartilage and bone structural degeneration or restores any of the current structural defects[4].To mitigate this grave situation, new OA treatment strategies are urgently needed.
However, novel therapeutic methods are facing challenges due to a lack of understanding of the molecular pathways involved in OA onset and development, as well as the prevalence of heterogeneous OA pathogenesis.Degenerative changes in OA joints result in gradual loss and degradation of articular cartilage, as well as structural and functional alterations in the synovium,meniscus(in the knee),and subchondral bone[5-6].Once a cartilage defect occurs, cartilage has a reduced ability to self-repair, owing to its intrinsic limited vascularity.Another known source of cartilage repair disability is the poor replicative capability of the major cell type,that is,chondrocytes in cartilage[7].In medical practice,numerous strategies have been adopted to repair the traumatic and degenerative pathology of articular cartilage, with some of them on the verge of entering clinical trials[8-9],as shown in Fig.1 and Fig.2.
Fig.1 Articular cartilage defect
Fig.2 Methods used in restoration of cartilage,whether in vivo or in vitro
Nonetheless, the growth of arthrofibrosis, scarcity of chondrocytes, lack of efficacy, symptomatic hypertrophy, disturbed fusion, delamination, graft failure, andfibrocartilage, which affect joint function, complicate the effectiveness of these methods[10-11].All of these vulnerabilities force us to urgently develop approaches to further ameliorate the current situation.
Furthermore, rather than replacing the whole joint,investigations on repairing damaged cartilage lesions are gaining traction, and new avenues are being thoroughly explored[2-4].Fig.3 shows nanocomposite hydrogels used for different types of cartilage defects.
Fig.3 Hydrogel design for various cartilage tissue engineering
To address these issues, mesenchymal stem cells (MCS),when combined with materials such as hydrogels, are a promising strategy for preventing cartilage degradation and regenerating defective cartilage.Hydrogels possess similar collagen and cartilage-like tissue properties.They are composed of a three dimensional (3D) hydrophilic polymer network that can absorb water.They are elastomeric biomaterials that have smooth surfaces and contain a large amount of water.In recent years, various types of hydrogels have been created and employedin vitroorin vivo, with some of them being used in clinical trials.Developing high-quality hydrogels is still a major challenge for researchers.Li et al[12]summarized various potential methods for preparing hydrogels.Currently, the addition of nanoparticles to hydrogels is gaining wide attention from researchers because nanoparticles interact with polymer functional groups.The application of nanoparticles has been proving forming material composites[13-17].Mixing these nanoparticles not only provides adequate strength to hydrogels, but also significantly contributes to increasing physical properties such as porosity and swelling[18-20].The major challenge is attaining a homogenous and uniform distribution of these nanoparticles in hydrogel matrices.A number of approaches exist, such as ultrasonic irradiation,electrostatic stabilization, and coating the surfaces of nanoparticles[21-23].As hydrogels are viscoelastic, their wear characteristics are analogous to those of rubber, in which fatigue and adhesion wear are predominant[24].
As hydrogels are tissue-like materials that are kept in the cartilage, they are subject to wear.Hence, their wear and mechanical behaviors are pivotal.Hydrogels based on synthetic polymers, polysaccharides, proteins,and peptides exhibit different behaviors during wear.This study reviews the mechanical and tribological behaviors of nanocomposite hydrogels.
Arjmandi et al[25]studied the wear behavior of alginate polyacrylamide (PAM) nanocomposite hydrogels reinforced with silica and compared the results with those of unmodified hydrogels as control samples.For tribological analysis, they considered three normalloads (0.1, 0.5, and 0.7 N) with a fixed sliding velocity of 100 mm/s and a sliding distance of 1000 m.They also used three further tests with sliding speeds of 50,100,and 150 mm/s at a constant load of 0.5 N.Compared with the nanocomposite hydrogel, the major findings were that the standard unmodified hydrogel exhibited considerable deformation.However,for increased siliconnanoparticle (Si-NP) concentration within the hydrogel matrix, reduced surface deformation was observed,which further demonstrates that Si-NP had a favorable influence on the wear characteristics of the reinforced hydrogel matrix.For the highest load and test duration in the unmodified hydrogel samples, the fatigue wear was discovered to be the dominant wear mechanism,which can be attributed to the presence of surface pitting.Owing to the influence of the Si-NP on the mechanical properties of the matrix,pitting was less common in the nanocomposite hydrogels than in the control samples.Furthermore, it was observed that the adhesion wear mechanism was dominant for both unmodified and nanocomposite hydrogels.
Gaharwar et al[26]synthesized elastomeric nanocomposite hydrogels composed of poly(ethylene glycol)(PEG) and hydroxyapatite nanoparticles (nHAp).Further,to examine the mechanical characteristics of the manufactured nanocomposite hydrogels, they conducted tensile tests, rheological studies, and compression tests.Field Electron and Ion NOVA nano, scanning electron microscopy(SEM)was used to analyze the microstructure of the hydrogels,and Raman spectroscopy was performed for chemical analysis, phase, polymorphy, crystallinity,and molecular interactions.The results were analyzed and compared using a one-way analysis of variance(ANOVA).In addition, all pairwise mean comparisons were studied and tested using Tukey's method.The results show that PEG-nHAp hydrogels possess higher compressive strengths, toughness, and fracture stresses than poly(ethylene oxide) hydrogels.Because interactions between polymers and polymer nanoparticles occur with the persistent cross-linking of PEG during photopolymerization,the mechanical properties improved.PEG and nHAp nanoparticles were combined to improve the chemical, biological (in mammalian cells), and physical hydrogel qualities.
Arjmandi et al[27]studied the mechanical and tribological characteristics such as indentation, unconfined uniaxial compression, and stress relaxation of alginate-PAM nanocomposite hydrogels reinforced with silica and compared the results with those of unmodified hydrogels as control samples.These tests were performed to examine the influence of the addition of Si-NP on the elastic and viscoelastic responses of the nanocomposite hydrogels.When 4%Si-NP were added to the matrix, the elastic modulus and hardness of the reinforced hydrogel rose by 38.6% and 39.11%,respectively.This demonstrates that the Si-NP concentration has a favorable impact on the mechanical characteristics of nanocomposite hydrogels.When compared with interpenetrating polymer network (IPN)hydrogel samples, stiffness and hardness were found to be improved by 26.2% and 18.3%, respectively.Rial et al[28]added hydroxyapatite nanorods(HA)to the gelatin hydrogel (GE) network and studied properties such as viscoelasticity, continuous flow, and frequency sweeps.The outcome of the research shows that the viscosity shifts toward higher stress levels as a consequence of greater viscosity,owing to the influence of nanoparticle concentration at the plateau.In addition, a change in the surface appearance of the gels was observed, which was due to the electrostatic interactions between the ions on the nanoparticles.Furthermore, they found that particle size, particularly asymmetry, plays a pivotal role in the reaction of the material to mechanical forces.Finally, they concluded that these materials are shapeable,stretchable,and reversible(with shear thinning and thixotropy).Mostakhdemin et al[29]assessed the mechanical and tribological characteristics of acrylamide-alginate bilayer hydrogels modified via polymerization.A series of different TiO2nanoparticle loadings (0.05 wt%, 0.2 wt%, 0.4 wt%, and 0.6 wt%)were used to prepare the samples and examine the effect of TiO2nanoparticles on the mechanical properties of hydrogels.A steel ball plate with a diameter of 4 mm was used for sliding wear experiments across hydrogelsamples.A 10 N load cell was used to monitor the applied normal load and friction during the trials.Wear experiments were carried out at three distinct sliding frequencies to simulate the speeds encountered by the articular cartilage during walking, jogging, and running.For the linear reciprocating sliding wear experiments, a comparable experimental setup (Fig.4)was used.They concluded that under the highest sliding speed, hydrogel with 0.2 wt% TiO2nanoparticles has a low coefficient of friction(0.01).
Fig.4 Setup for linear reciprocating sliding wear tests
Further, they found that when contrasted with nanoreinforced hydrogels (NRHs), nanocomposite hydrogels(NCHs) show good stability in the coefficient of friction.Along with this,it was found that cracks and wear debris reveal that adhesive wear became a fatigue wear between 0.7 and 0.9 N, indicating that the wear mechanism of the hydrogels is load-dependent.Deng et al[30]found that by mimicking the hierarchical structure of natural joints,they could form artificial hierarchical joints comprising a polyacrylicacid (PAA)-PAM composite hydrogel coated on a Ti6Al4V substrate.To determine the composition and microstructure, various tests were conducted, such as SEM, X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared (FT-IR) spectroscopy.The outcome of this study reveals that, in contrast to bare Ti6Al4V, which has a dynamic friction of approximately 0.429, the hierarchical-structure material has a lower dynamic friction of approximately 0.085 with shallow wear and no appreciable fracturing on the surface.Another outcome is that PAA-PAM hydrogel is more homogeneous and compact with less porous size when compared to the PAA hydrogel.Furthermore,it was found that a double-cross-linked network stops water molecules from penetrating, resulting in a lower equilibrium water content.In addition, the presence of water molecules in the cross-linked network helps withstand normal loads,which consequently makes it difficult to compress and significantly enhances the anti-shearing and tribological characteristics.Finally, they concluded that hydrogel covering acts as a vital buffer and the lubricant Ti6Al4V substrate could withstand high impact stress.Li et al[31]fabricated PAM hydrogels with comparable stiffness and examined the correlation between friction and adhesion via atomic force microscopy(AFM).They also used AFM to determine the composition of PAM hydrogels of similar stiffness with different degrees of cross-linking degrees and polymer volume fractions.However, they concluded that adhesion increases with the polymer volume fraction,but decreases with cross-linking degree.In addition,lateral force measurements examination reveals that friction increases with polymer volume fraction but decreases with cross-linking degree.As far as friction is considered, it is mostly controlled by load and adhesion forces in the low normal force regime, and it increases dramatically with adhesion and polymer volume percentage.Furthermore, their research revealed that adhesion and friction are governed by the structure and composition of the hydrogel rather than being directly related to stiffness.Awasthi et al[32]tested the strength of PAM hydrogels (produced via the deployment of density functional theory (DFT)) when incorporated with TiO2and carbon nanotubes (CNTs) and mixed separately in a PAM matrix.Compression and needle insertion experiments were used to examine the mechanical strength of the synthesized hydrogels, and it was discovered that PAM-TiO2-CNT was stiffer (elastic modulus of 2.34 MPa) and had better compressive strength (>0.43 MPa) than PAM-TiO2and PAM-CNT.Furthermore, owing to the substantial interfacial strengthening provided by TiO2(Ti—O—C bonding with PAM), PAM-TiO2-CNT had five times greater puncture resistance than PAM.
Schlichting et al[33]developed a copolymer-based injectable nanocomposite hydrogelin situthrough mineralization.Furthermore, they examined themechanical properties of the developed nanocomposite hydrogel via compressive modulus testing, shear testing,and tensile testing.The compressive modulus of nanocomposite material was found to be better:0.64 MPa as compared to 0.35 MPa for bovine cartilage.The tensile modulus of bovine cartilage was (0.9 ± 0.1) MPa,compared with (0.5 ± 0.1) MPa for bovine cartilage bonded to the mineralized material with carboxyl end groups.Asadi et al[34]fabricated a new hydrogel based on gelatin/polycaprolactone-PEG (Gel/PCEC-TGFβ1) for cartilage tissue engineering.The efficacy of the developed hydrogel was evaluated via porosity, swelling behavior,and mechanical property (compression) testing.SEM revealed that the developed hydrogels possessed interconnected porous structures.The inclusion of PCECTGFβ1 nanoparticles caused decreasing pore size of the nanocomposite hydrogel, as these nanoparticles can fill pores due to the Van der Waals forces present between them.They developed scaffolds with average pore sizes of Gel/PCEC-TGFβ1 and gel hydrogels being (140.60 ±49.69) and (263.19 ± 95.36) μm, respectively, which was in accord with earlier available reports[24].Furthermore,they found that the gel hydrogels showed a greater swelling ratio than Gel/PCEC-TGFβ1 hydrogel.The addition of PCEC nanoparticles to the hydrogel reduced the nanocomposite scaffold's swelling, as nanoparticles can act as fillers, which makes the hydrogel material denser and has a tighter network with fewer pores.In addition, they reported that owing to the availability of large pores, the gel hydrogel showed inferior mechanical properties when compared to the Gel/PCEC-TGFβ1 hydrogel.Finally,they observed that the Young's modulus of the hydrogel scaffold increased when the PCEC nanoparticles were added.Meng et al[35]used the freezing method to synthesize poly(vinyl alcohol) (PVA)/graphene oxide (GO) nanocomposite hydrogels as an artificial cartilage replacement.Furthermore, FT-IR spectrometer analysis, Raman spectrum analysis, transmission electron microscopy, X-ray diffraction (XRD) analysis, and rheological analysis (viscoelasticity) were performed to examine the superiority and performability of the developed nanocomposite hydrogel.This study suggested that properties such as mechanical strength and toughness of the composite hydrogel were improved because of the increased crystalline regions of PVA and the formation of a GO-centered second network structure.They further showed that when compared to the neat PVA hydrogel,tensile strength, elongation at break, and compressive modulus increased by up to 200%, 40%, and 100%,respectively.In addition, their summary reveals that adding merely 1.5 wt% GO to a clean PVA hydrogel results in a significant improvement in mechanical properties.Mohsen et al[36]used irradiation as an initiator to produce a crosslinked network structure in organic montmorillonite-PVA-co-polyacrylic (OMMT-PVA/AAc)nanocomposite hydrogels with varied OMMT ratios ranging from 1.3% to 15%.The effects of the clay ratio and absorbed dose on the gel fraction and swelling percentage were studied.They discovered that increasing the loaded OMMT to 15%increased the gel fraction by up to 92%, while the swelling percentage reached its maximum value with 6% nanoscale clay.The thermal stabilities of the PVA/AAc and OMMT-PVA/AAc nanocomposite hydrogels were investigated by thermogravimetric analysis (TGA), which revealed that the nanocomposite hydrogel had greater thermal stability.The bond structures of the PVA/AAc and OMMT-PVA/AAc nanocomposite hydrogels were determined by FT-IR spectral analysis.XRD was used to investigate the nanostructure of the composite as well as the degree of clay exfoliation.
Chen et al[37]fabricated poly(styrene-acrylic acid) (P(S-AA)) core-shell nanoparticles (NPs) with numerous carboxyl groups on their surface, and reported their enhancement to hydrophobic-associated hydrogels.The toughness, ductility, and self-healing properties of the developed hydrogels were examined.In this study,P(SAA) core-shell NPs with numerous carboxyl groups on their surfaces were used to create a type of resistant hydroxyapatite gel.The hydrogen bonding connections between the amide groups of the PAM chains and the dual physical cross-linking carboxyl groups in coreshell NPs and hydrophobic tangling modified hyaluronic acid gels are endowed not only with good mechanicalproperties but also chains.Excellent self-healing and reconstruction abilities were observed.In addition, the mechanical strength and self-healing efficiency of the system could be improved.
Holyoak et al[38]formed a four-arm maleimidefunctionalized PEG (PEG-4MAL) hydrogel incorporated with fluorescent fluorescein isothiocyanate (FITC)polystyrene nanoparticles.The results showed excellent mechanical properties, relieving stress and protecting the knee joint cartilage.Various hydrogel materials for cartilage tissue engineering are presented in Table 1.
Table 1 Different hydrogels for cartilage tissue engineering
In this manuscript,we have reviewed recent developments in the synthesis of hydrogel materials for cartilage tissue engineering and reviewed the mechanical behavior of these hydrogels when exposed to articular cartilage repair.We present a summary of hydrogel structures,the bulk of which operate as scaffolds for cell growth.Poly(vinyl alcohol) (PVA) and poly(ethylene glycol) (PEG) are synthetic polymers that are physiologically neutral and therefore have no significant impact on cells.Here, we provide some proposals regarding the synthesis of hydrogels for articular cartilage tissue engineering:(1) synthetic polymers and silk-related materials may be ideal candidates if a mechanically robust scaffold is required; (2) proteins such as collagen and gelatin improve cell adhesion; for cartilage defects in osteoarthritis (OA) it has been observed, nanocomposite artificial cartilage hydrogels are promising candidates that can act as tough and lubricated hydrogels.For articular cartilage repair, artificial cartilage can be injectedin vivoto the defect sites or as a replacement for the whole cartilage.Nanocomposite-based artificial cartilage hydrogel materials with superior qualities to genuine cartilage might be created and manufactured in the future.As stem cells from synovial fluids is most often not able to adhere with cells and are incapable of allowing cartilage to self-repair, we conclude from above studies that hydrogels with sufficient mechanical strength and good stem cell adhesion qualities are promising cartilage repair materials.Many of the aforementioned development methodologies for various types of hydrogel scaffolds demonstrate the potential of such materials for the treatment of various OA cartilage deformities.With recent advancements in stem cell therapy, combining the benefits of both treatments could provide extremely effective solutions for patients with OA.
The tribological properties of the novel nanocomposite artificial cartilage hydrogels were considered.Many studies have shown that nanocomposite hydrogels are vital materials because they possess a solid and stable networks with minimum fluctuations when compared with non-reinforced hydrogels.In addition to the above nanocomposites,hydrogels demonstrated lower values of wear and wear volume/wear rate than nanocomposite hydrogels.In addition, scanning electron microscopy images reveal that hydrogels without reinforcement show large cracks, which means that these hydrogel materials cannot withstand large wear forces and consequently lead to a worn-out lubricant layer.