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Chitosan: A promising polymer for cartilage repair and viscosupplementation
Abstract
Osteoarthritis (OA) is a painful, degenerative and inflammatory disease that affects the entire synovial joints. Nowadays, no cure exists, and the pharmacological treatments are limited to symptoms alleviation. There is a need for a new efficient and safe treatment. Viscosupplementation is a process that aims to restore the normal rheological properties of synovial fluid. For the past years, hyaluronic acid was usually used but this molecule has some limitations including the short residency time in joint cavity. Recently, in vitro studies have suggested that chitosan could promote the expression of cartilage matrix components and reduce inflammatory and catabolic mediator's production by chondrocytes. In vivo, chitosan prevented cartilage degradation and synovial membrane inflammation in OA induced rabbit model. Several studies have also shown that chitosan could induce chondrogenic differentiation of mesenchymal stem cells. Therefore, chitosan is an interesting polymer to design scaffold and hydrogel for cartilage lesion repair, cells transplantation, sustained drug release and viscosupplementation.
... Therefore, the development of innovative and more efficient therapeutical intervention to treat OA symptoms is of extreme clinical importance (Comblain et al. 2017). In this context, photobiomodulation (PBM), also known as lowlevel laser therapy, has also been considered a very promising therapeutic intervention for cartilage tissue engineering, mainly due to its stimulatory effect on tissue metabolism and ability of modulating the inflammatory process after an injury (Bjordal et al. 2010;Hamblin 2016). ...
... Similarly, biomaterials for articular viscosupplementation such as hyaluronic acid (HA) and chitosan (Ch) have been frequently used (Comblain et al. 2017). Chitosan is a cationic polysaccharide which is derived from naturally chitin and it has gained lots of attention due to its ability to stimulate tissue repair (Yan et al. 2014a), anti-inflammatory effects (Chung et al. 2012), and biocompatibility (Vandevord et al. 2002). ...
... Chitosan is a cationic polysaccharide which is derived from naturally chitin and it has gained lots of attention due to its ability to stimulate tissue repair (Yan et al. 2014a), anti-inflammatory effects (Chung et al. 2012), and biocompatibility (Vandevord et al. 2002). Chitosan has a number of commercial and possible biomedical applications, such as bandages to reduce bleeding, antibacterial effects, and articular viscosupplementation (Comblain et al. 2017;Dantas et al. 2011). Recently, in vitro studies have suggested that chitosan could induce the expression of cartilage matrix components (such as collagen and proteoglycans) and reduce inflammatory and catabolic mediator's production by chondrocytes (Comblain et al. 2017;Dantas et al. 2011). ...
Purpose
The aim of the present study was to investigate the tissue performance of the association of photobiomodulation (PBM) and chitosan hydrogel (Ch), using in vitro and in vivo studies, in culture of chondrocytes and in an experimental model of osteoarthritis (OA) in the knee of rats.
Methods
The chitosan hydrogel was characterized by pH, gelation time, and degradation rate. For the in vitro study, chondrocyte cells were seeded in the Ch irradiated or not with PBM to assess cell viability and proliferation after 1, 3, and 5 days. For the in vivo study, sixty Wistar rats with OA were randomly distributed: control group (CG), Ch hydrogel injection (Ch), Ch hydrogel injection associated with PBM (Ch/PBM).
Results
The characterization results revealed that Ch hydrogels can be controlled precisely by variation of the urea and urease concentrations. The in vitro findings demonstrated that Ch and Ch/PBM are biocompatible and noncytotoxic. The in vivo findings showed that PBM associated with Ch prevented articular degeneration by stimulating anabolic factor (TGF-β) and reducing catabolic factor (TNF-α) and increasing the gene related to components of the cartilage extracellular matrix.
Conclusion
In conclusion, the PBM associated with Ch can be used as a cartilage repair application.
... However, natural hydrogels that can be fabricated on a kg-scale at a low price, narrows down the library of possible candidates. Commonly used candidates are thus centred on alginate, chitosan, hyaluronic acid (HA), fibrin, and collagen/gelatin [39,42,49,[90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109]. Additional work has been performed with decellularised materials as it offers additional biological complexity and stimulation. ...
... However, natural hydrogels that can be fabricated on a kg-scale at a low price, narrows down the library of possible candidates. Commonly used candidates are thus centred on alginate, chitosan, hyaluronic acid (HA), fibrin, and collagen/gelatin [39,42,49,[90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109]. ...
Biofabrication has emerged as an attractive strategy to personalise medical care and provide new treatments for common organ damage or diseases. While it has made impactful headway in e.g., skin grafting, drug testing and cancer research purposes, its application to treat musculoskeletal tissue disorders in a clinical setting remains scarce. Albeit with several in vitro breakthroughs over the past decade, standard musculoskeletal treatments are still limited to palliative care or surgical interventions with limited long-term effects and biological functionality. To better understand this lack of translation, it is important to study connections between basic science challenges and developments with translational hurdles and evolving frameworks for this fully disruptive technology that is biofabrication. This review paper thus looks closely at the processing stage of biofabrication, specifically at the bioinks suitable for musculoskeletal tissue fabrication and their trends of usage. This includes underlying composite bioink strategies to address the shortfalls of sole biomaterials. We also review recent advances made to overcome long-standing challenges in the field of biofabrication, namely bioprinting of low-viscosity bioinks, controlled delivery of growth factors, and the fabrication of spatially graded biological and structural scaffolds to help biofabricate more clinically relevant constructs. We further explore the clinical application of biofabricated musculoskeletal structures, regulatory pathways, and challenges for clinical translation, while identifying the opportunities that currently lie closest to clinical translation. In this article, we consider the next era of biofabrication and the overarching challenges that need to be addressed to reach clinical relevance.
... Some authors have recently demonstrated that the combined use of both low MW and high MW HA provide good results in the management of patients suffering from hip OA [14]. However, since HA therapeutic activity is limited by its short biological half-life, crosslinking of the molecule [15] as well as combination with other molecules such as chitosan [16,17] have been tested in order to increase both the short-term HA therapeutic activity and/or viscoelastic properties. Chitosan, a biodegradable and biocompatible compound, was chosen for its structural similarity to glycosaminoglycans and for its chondro-protective and anti-inflammatory properties [18,19]. ...
... In particular, mid-MW HA at a concentration of 0.5 mg/mL has been shown to increase normal human chondrocyte proliferation via activation of the CD44 receptor [15]. However, residence time of HA in the joint cavity is short and it was demonstrated that its combination with other molecules such as chitosan [16,17], increased its biological half-life. Indeed, it was recently demonstrated that HA, when administrated together with CTL in a rat OA model [26], it counteracted cartilage degradation even more that HA alone. ...
The development and progression of osteoarthritis (OA) is associated with macrophage-mediated inflammation that generates a broad spectrum of cytokines and reactive oxygen species (ROS). This study investigates the effects of mid-MW hyaluronic acid (HA) in combination with a lactose-modified chitosan (CTL), on pro-inflammatory molecules and metalloproteinases (MMPs) expression, using an in vitro model of macrophage-mediated inflammation.
Methods:
To assess chondrocyte response to HA and CTL in the presence of macrophage derived inflammatory mediators, cells were exposed to the conditioned medium (CM) of U937 activated monocytes and changes in cell viability, pro-inflammatory mediators and MMPs expression or ROS generation were analysed.
Results:
CTL induced changes in chondrocyte viability that are reduced by the presence of HA. The CM of activated U937 monocytes (macrophages) significantly increased gene expression of pro-inflammatory molecules and MMPs and intracellular ROS generation in human chondrocyte cultures. HA, CTL and their combinations counteracted the oxidative damage and restored gene transcription for IL-1β, TNF-α, Gal-1, MMP-3 and MMP-13 to near baseline values.
Conclusions:
This study suggests that HA-CTL mixture attenuated macrophage-induced inflammation, inhibited MMPs expression and exhibited anti-oxidative effects. This evidence provides an initial step toward the development of an early stage OA therapeutic treatment.
... Of note, hyaluronate formulations administered via intra-articular injections are commonly used for viscosupplementation [7,8]. Chitosan is another biopolymer that has been considered for this purpose [9,10]. This popular macromolecule can be obtained from chitin via chemical [11][12][13][14] or enzymatic [15][16][17] deacetylation. ...
Chitosan and chitin are promising biopolymers used in many areas including biomedical applications, such as tissue engineering and viscosupplementation. Chitosan shares similar properties with hyaluronan, a natural component of synovial fluid, making it a good candidate for joint disease treatment. The structural and energetic consequences of intermolecular interactions are crucial for understanding the biolubrication phenomenon and other important biomedical features. However, the properties of biopolymers, including their complexation abilities, are influenced by the nature of the aqueous medium with which they interact. In this study, we employed molecular dynamics simulations to describe the effect of pH and the presence of sodium and calcium cations on the stability of molecular complexes formed by collagen type II with chitin and chitosan oligosaccharides. Based on Gibbs free energy of binding, all considered complexes are thermodynamically stable over the entire pH range. The affinity between chitosan oligosaccharide and
collagen is highly influenced by pH, while oligomeric chitin shows no pH-dependent effect on the stability of molecular assemblies with collagen. On the other hand, the presence of sodium and calcium cations has a negligible effect on the affinity of chitin and chitosan for collagen.
... Chitosan, owing to its chemical structural similarity with various GAGs such as those found in cartilage and meniscus, the predominant ECM molecules, imitates the native microenvironment for chondrocytes and meniscus cells, thus fostering chondrogenic activity and expression of cartilage-specific proteins (Chen and Cheng, 2009;Park et al., 2009;Neves et al., 2011). As a result, chitosan, with its advantageous characteristics of bioactivity, biocompatibility, and biodegradability, has emerged as a promising natural biomaterial scaffold for the repair of cartilage defects (Comblain et al., 2017). It has found wide application in TE, particularly for articular cartilage regeneration (Rodriguez-Vazquez et al., 2015;LogithKumar et al., 2016). ...
Tissue engineering represents a promising approach for impaired articular cartilage tissue regeneration. 3D printed hydrogels have become an emerging tissue engineering strategy because they closely mimic the physical and biochemical characteristics of the extracellular matrix. The formulation of hydrogel ink holds significant importance in attaining a precisely defined scaffold, which could exhibit excellent shape fidelity post-printing. Natural polysaccharide-based hydrogels are a highly promising class of scaffold biomaterials for articular cartilage regeneration in the field of material science and tissue engineering. These hydrogels are particularly advantageous due to their exceptional water absorption capacity, biodegradability, adjustable porosity, and biocompatibility, which closely resemble those of the natural extracellular matrix. This review aims to provide a comprehensive overview of the key characteristics, functions, and research progress in 3D printing technology for natural polysaccharide-based hydrogels. Specifically, this review categorizes the commonly used natural polysaccharide-based hydrogel materials in cartilage tissue engineering, and summarizes the classic literature in this area. In the end, we provide a comprehensive analysis of the challenges and potential applications of natural polysaccharide-based hydrogels in cartilage tissue engineering.
... Finally, most studies have reported that chitosan is non-toxic in the mg·L −1 range. In the field of tissue repair or regeneration, chitosan hydrogels have been evaluated in many areas, but especially for skin [14], bone [15] and cartilage [16]. The uniqueness of chitosan very likely originates from the presence of amine and N-acetyl groups that somehow resemble the carbohydrate chains of proteoglycans. ...
Type I collagen and chitosan are two of the main biological macromolecules used to design scaffolds for tissue engineering. The former has the benefits of being biocompatible and provides biochemical cues for cell adhesion, proliferation and differentiation. However, collagen hydrogels usually exhibit poor mechanical properties and are difficult to functionalize. Chitosan is also often biocompatible, but is much more versatile in terms of structure and chemistry. Although it does have important biological properties, it is not a good substrate for mammalian cells. Combining of these two biomacromolecules is therefore a strategy of choice for the preparation of interesting biomaterials. The aim of this review is to describe the different protocols available to prepare Type I collagen–chitosan hydrogels for the purpose of presenting their physical and chemical properties and highlighting the benefits of mixed hydrogels over single-macromolecule ones. A critical discussion of the literature is provided to point out the poor understanding of chitosan–type I collagen interactions, in particular due to the lack of systematic studies addressing the effect of chitosan characteristics.
... In addition to HA, alginate, chitosan, cellulose, and many other polysaccharide-based hydrogels are widely applied in hydrogel design (Comblain et al., 2017;Bhaladhare and Das, 2022;Liu et al., 2022). Alginate incorporation into constructs enhances chondrogenesis of MSCs and tensile load bearing ability (Ma et al., 2012). ...
Osteoarthritis (OA) is a kind of degenerative joint disease usually found in older adults and those who have received meniscal surgery, bringing great suffering to a number of patients worldwide. One of the major pathological features of OA is retrograde changes in the articular cartilage. Mesenchymal stromal cells (MSCs) can differentiate into chondrocytes and promote cartilage regeneration, thus having great potential for the treatment of osteoarthritis. However, improving the therapeutic effect of MSCs in the joint cavity is still an open problem. Hydrogel made of different biomaterials has been recognized as an ideal carrier for MSCs in recent years. This review focuses on the influence of the mechanical properties of hydrogels on the efficacy of MSCs in OA treatment and compares artificial materials with articular cartilage, hoping to provide a reference for further development of modified hydrogels to improve the therapeutic effect of MSCs.
... Although numerous preclinical and clinical studies evaluating the efficacy and safety of HA have demonstrated that it is an effective treatment for knee OA, its rapid clearance and short residence time in the joint vicinity limit its application (Foti et al., 2011). Presently, preclinical research focuses on evaluating new strategies and molecules that can prevent or delay cartilage degeneration and prolong chondroprotective effects (Comblain et al., 2017). ...
Osteoarthritis is a debilitating, progressive joint disease linked to lower quality of life and higher health care costs. This study compared hyaluronic acid-chitosan nanoparticle encapsulation to hyaluronic-acid monotherapy in a rat model of knee osteoarthritis. Four groups of 40 adult male albino rats were designed. Group (Gp) I: control; Gp II (osteoarthritis model): intra-articular injection of monoiodoacetate; Gp III (hyaluronic acid-treated): intra-articular injections of hyaluronic-acid on days 14 and 21 after monoiodoacetate injection; and Gp IV (hyaluronic acid-chitosan nanoparticle-treated): intra-articular injections of hyaluronic acid-chitosan nanoparticle on days 14 and 21 after monoiodoacetate injection. After 28 days, knee joints were examined using H&E, Safranin O, and immunohistochemistry for nuclear factor kappa beta (NF-κB), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase (MMP)-13. Quantification for gene expression of collagen-II, aggrecan, and micro-RNA-140; ELISA for interleukin (IL)-1β and IL-8; and western blotting for IKBα and NF-κB was estimated. Osteoarthritis-knee joints showed a severe cartilage damage and synovial inflammation with increased NF-κB, iNOS, and MMP-13 immunostaining, decreased miR-140, collagen II, and aggrecan levels, and increased inflammatory markers’ gene expressions. The hyaluronic acid-chitosan nanoparticle significantly improved knee joint structure and reduced inflammatory cytokines compared to hyaluronic acid monotherapy. Intra-articular injection of hyaluronic acid-chitosan nanoparticle encapsulation revealed a significant improvement in the knee joint structure compared to hyaluronic-acid in a rat model of osteoarthritis.
... In matrix enriched with chitosan, a homogeneous distribution was detected, as well as direct contact between the polymer chains and chondrocytes. It has been observed that chondrocyte homeostasis could be restored after 4 weeks of encapsulation in chitosan matrix (Comblain et al., 2017). ...
Tissue engineering represents a potential approach to improve cartilage mending, where an artificial 3D extracellular matrix (ECM) is essential to generate new tissues. Native ECMs can be effectively mimicked by electrospun nanofiber membranes, specially using natural sourced polymers.In this work, chitosan (CS)-based systems (CS and CS/Hyaluronan (HA)) are transformed, by electrospinning, into biocompatible and biodegradable nanofibrous mats adapted for chondrocyte (CHCT) development. CS materials are claimed to favor cell adhesion and growth, providing the microenvironment adequate for CHCT phenotype preservation. No current procedures for cartilage renovation have successfully achieved long-lasting cartilage regeneration.Homogeneous CS, HA, and CS/HA polyelectrolyte complex solutions are prepared using formic acid mixtures as solvent. Stability of the complex is improved by thermal treatment at 120°C. After treatment, material crystallization and amide bond formation are related to modifications of physicochemical properties.Enabling electrospinning, polyethylene oxide (PEO) is incorporated to the CS and HA solutions. The PEO content in the blend is set at 30 % and electrospun CS/PEO and CS/HA/PEO fibers are obtained, with diameters ranging between 100-200 nm. Several collector types allow the production of nanofibrous mats with a visible fiber arrangement depending on the collector structure. Patterned fiber mats are produced and applied for CHCT culture and cell morphology observation.Atomic force microscopy measurements between single CHCT and CS film and fibers, help to compare adhesion strength as a function of substrate topography. The cell-substrate adhesive force is found slightly higher in the case of CS film compared to the mat. Nevertheless, adhesion is more efficient on the mats, considering a lower effective contact area (support porosity ~40%).For cell culture, the importance of CS fiber stabilization is highlighted. Cell proliferation tests, performed on CS fiber mats, revealed that fiber mats lead to higher proliferation rates compared to casted films.Topography of electrospun CS nanofiber membranes could impact cell colonization patterns. Cell alignment in certain zones of aligned fiber samples is detected. In the same way, concentration of cells is observed on zones of the mat more fiber densely charged.When comparing CHCT development on CS and CS/HA substrates, it is found that cell confluency is achieved earlier on CS/HA than on CS fibers. Cell development could be improved by the presence of HA in the support, as a natural component of the ECM, favoring cell adhesion. In both cases, high CHCT viability (>90%) is detected.Regarding cell morphology, primary CHCT maintain an oval shape in cartilage. This form is also observed for CHCT on CS and CS/HA fibrous mats. On the contrary, cells spread during monolayer cultures on flat surfaces such as films and Petri dish. Morphology preservation could indicate native cell characteristics maintaining.As an alternative for cell/substrate implantation, the feasibility of intra-articular injections of cell/fiber suspensions is studied. Proliferation profiles differ significatively from CS fiber mats, mainly attributed to the limited available surface for cell development on the fiber suspension in contrast with the continuous mat. However, since some patients do not fit for surgery, the injectable approach could become a viable treatment for cartilage regeneration.In conclusion, electrospinning process optimization and material characterization allowed the use of stable nanofiber mats for CHCT development in pursuit of tissue repair applications. Compatibility of CS-based fiber mats is confirmed and substrate efficiency compared as a function of material topography.Considering the promising results herein obtained, CS and CS/HA nanofibrous mats can be considered as potential scaffolds maintaining adequate proliferation profiles and native cell shape.
... Drug delivery systems incorporating HA present an alternative method to extend functional residence time in vivo, as well as allow a controlled release [11,77,[81][82][83][84][85][86]. Other biomaterials that show promising features in the development of viscosupplementation components are based on cellulose hydrogels [17,87,88], xanthan gum [89], biolubricants [90], or chitosan-based interpenetrating polymer networks (IPNs) to restore cartilage mechanical properties (Figure 1) [91][92][93][94][95]. gum, chitosan, as well as biolubricants. ...
Osteoarthritis is a high-prevalence joint disease characterized by the degradation of cartilage, subchondral bone thickening, and synovitis. Due to the inability of cartilage to self-repair, regenerative medicine strategies have become highly relevant in the management of osteoarthritis. Despite the great advances in medical and pharmaceutical sciences, current therapies stay unfulfilled, due to the inability of cartilage to repair itself. Additionally, the multifactorial etiology of the disease, including endogenous genetic dysfunctions and exogenous factors in many cases, also limits the formation of new cartilage extracellular matrix or impairs the regular recruiting of chondroprogenitor cells. Hence, current strategies for osteoarthritis management involve not only analgesics, anti-inflammatory drugs, and/or viscosupplementation but also polymeric biomaterials that are able to drive native cells to heal and repair the damaged cartilage. This review updates the most relevant research on osteoarthritis management that employs polymeric biomaterials capable of restoring the viscoelastic properties of cartilage, reducing the symptomatology, and favoring adequate cartilage regeneration properties.
... Chitosan (CS) is a polysaccharide whose structure is highly similar to glycosaminoglycans that make up articular cartilage, so it has been frequently used in the development of hydrogels for intra-articular application. In addition, CS is a cationic, biocompatible, biodegradable polymer with marked mucoadhesive properties that are very useful for anchoring to surrounding tissue [2,23,24]. CS can also form gels by interacting with some salts such as phosphates, specifically with disodium β-glycerophosphate (BGP), to form thermosensitive hydrogels [25,26]. This system has also been extensively studied in the formation of injectable scaffolds for controlled release and tissue engineering. ...
The intra-articular administration of drugs has attracted great interest in recent decades for the treatment of osteoarthritis. The use of modified drugs has also attracted interest in recent years because their intra-articular administration has demonstrated encouraging results. The objective of this work was to prepare injectable-thermosensitive hydrogels for the intra-articular administration of Etanercept (ETA), an inhibitor of tumor necrosis factor-α. Hydrogels were prepared from the physical mixture of chitosan and Pluronic F127 with β-glycerolphosphate (BGP). Adding β-glycerolphosphate to the system reduced the gelation time and also modified the morphology of the resulting material. In vitro studies were carried out to determine the cytocompatibility of the prepared hydrogels for the human chondrocyte line C28/I2. The in vitro release study showed that the incorporation of BGP into the system markedly modified the release of ETA. In the in vivo studies, it was verified that the hydrogels remained inside the implantation site in the joint until the end of the study. Furthermore, ETA was highly concentrated in the blood of the study mice 48 h after the loaded material was injected. Histological investigation of osteoarthritic knees showed that the material promotes cartilage recovery in osteoarthritic mice. The results demonstrate the potential of ETA-loaded injectable hydrogels for the localized treatment of joints.
... Its similarity with glycosaminoglycan and hyaluronic acid makes chitosan an interesting option for cartilage repair [126]. Moreover, chitosan is a polymer that shows great potential for viscosupplementation, which, according to Comblain et al., "is a process that aims to restore the normal rheological properties of synovial fluid" [127]. Hyaluronic acid, which is frequently used for viscosupplementation, has the disadvantage of remaining in the joint cavity for a short period. ...
The continuous advances in surgical procedures require continuous research regarding materials with surgical applications. Biopolymers are widely studied since they usually provide a biocompatible, biodegradable, and non-toxic material. Among them, chitosan is a promising material for the development of formulations and devices with surgical applications due to its intrinsic bacteriostatic, fungistatic, hemostatic, and analgesic properties. A wide range of products has been manufactured with this polymer, including scaffolds, sponges, hydrogels, meshes, membranes, sutures, fibers, and nanoparticles. The growing interest of researchers in the use of chitosan-based materials for tissue regeneration is obvious due to extensive research in the application of chitosan for the regeneration of bone, nervous tissue, cartilage, and soft tissues. Chitosan can serve as a substance for the administration of cell-growth promoters, as well as a support for cellular growth. Another interesting application of chitosan is hemostasis control, with remarkable results in studies comparing the use of chitosan-based dressings with traditional cotton gauzes. In addition, chitosan-based or chitosan-coated surgical materials provide the formulation with antimicrobial activity that has been highly appreciated not only in dressings but also for surgical sutures or meshes.
... It also improves chondrocyte homeostasis. [35,36] Collagen fibril 3 BioMed Research International obtained from cadaveric tissues, but the autogenic tissue can provide better mechanical stability and biocompatibility. Although articular cartilage is located in an immunologically privileged position, the immune response is still a major concern with the osteochondral transfer technique [49]. ...
There is a clear clinical need for efficient cartilage healing strategies for treating cartilage defects which burdens millions of patients physically and financially. Different strategies including microfracture technique, osteochondral transfer, and scaffold-based treatments have been suggested for curing cartilage injuries. Although some improvements have been achieved in several facets, current treatments are still less than satisfactory. Recently, different hydrogel-based biomaterials have been suggested as a therapeutic candidate for cartilage tissue regeneration due to their biocompatibility, high water content, and tunability. Specifically, magnetic hydrogels are becoming more attractive due to their smart response to magnetic fields remotely. We seek to outline the context-specific regenerative potential of magnetic hydrogels for cartilage tissue repair. In this review, first, we explained conventional techniques for cartilage repair and then compared them with new scaffold-based approaches. We illustrated various hydrogels used for cartilage regeneration by highlighting the magnetic hydrogels. Also, we gathered in vitro and in vivo studies of how magnetic hydrogels promote chondrogenesis as well as studied the biological mechanism which is responsible for cartilage repair due to the application of magnetic hydrogel.
... Furthermore, these three characteristics are difficult to achieve using traditional tissue engineering scaffolds. For example, the mechanical strength of natural biomaterials (collagen [12], alginate [13], chitosan [14], gelatin [15], and silk [16]) are mismatched with those of native cartilage. Compared to natural biomaterials, some synthetic materials (such as polylactic acid (PLA) [17], polylactide-co-glycolide (PLGA) [18], and polycaprolactone (PCL) [19]) have ideal mechanical properties. ...
Objective
The treatment of cartilage lesions has always been a difficult problem. Although cartilage tissue engineering provides alternative treatment options for cartilage lesions, biodegradable tissue engineering scaffolds have limitations.
Methods
In this study, we constructed a porous PEEK scaffold via 3D printing, surface-engineered with concentrated sulfuric acid for 15 s (SPK-15), 30 s (SPK-30), and 60 s (SPK-60). We systematically evaluated the physical and chemical characteristics and biofunctionalities of the scaffolds, and then evaluated the macrophage polarization modulating ability and anti-inflammatory effects of the sulfonated PEEK, and observed the cartilage-protective effect of SPK using a co-culture study. We further evaluated the repair effect of PEEK and SPK by implanting the prosthetic scaffold into a cartilage defect in a rabbit model.
Results
Compared to the PEEK, SPK-15 and SPK-60 scaffolds, SPK-30 has a good micro/nanostructure, appropriate biomechanical properties (compressive modulus, 43 ± 5 MPa; Shaw hardness, 20.6 ± 1.3 HD; close to native cartilage, 30 ± 8 MPa, 17.8 ± 0.8 HD), and superior biofunctionalities. Compared to PEEK, sulfonated PEEK can favor macrophage polarization to the M2 phenotype, which increases anti-inflammatory cytokine secretion. Furthermore, SPK can also prevent macrophage-induced cartilage degeneration. The in-vivo animal experiment demonstrates that SPK can favor new tissue ingrowth and integration, prevent peri-scaffold cartilage degeneration and patellar cartilage degeneration, inhibit inflammatory cytokine secretion, and promote cartilage function restoration.
Conclusion
The present study confirmed that the 3D printed porous sulfonated PEEK scaffold could promote cartilage functional repair, and suggests a new promising strategy for treating cartilage defects with a functional prosthesis that spontaneously inhibits nearby cartilage degeneration.
Translational potential of this article
In the present study, we propose a new cartilage repair strategy based on a porous, non-biodegradable polyetheretherketone (PEEK) scaffold, which may bring up a new treatment route for elderly patients with cartilage lesions in the future.
... These GAG-analogous structures are also involved in the synthesis of chondroitin sulfate, HA, and collagen type II [88]. Therefore, chitosan, especially in the form of a hydrogel [89], can simulate the ECM of articular cartilage and promote cartilage formation as a natural scaffold for repairing cartilage defects [90]. These unique properties of the chitosan scaffold are related to the size and orientation of the chitosan pores [85]. ...
The aim of this narrative review was to present research investigating chitosan, including its general characteristics, properties, and medical and dental applications, and finally to present the current state of knowledge regarding the efficacy of chitosan in the treatment of temporomandibular disorders (TMDs) based on the literature. The PICO approach was used for the literature search strategy. The PubMed database was analyzed with the following keywords: (“chitosan”[MeSH Terms] OR “chitosan”[All Fields] OR “chitosans”[All Fields] OR “chitosan s”[All Fields] OR “chitosane”[All Fields]) AND (“temporomandibular joint”[MeSH Terms] OR (“tem-poromandibular”[All Fields] AND “joint”[All Fields]) OR “temporomandibular joint”[All Fields] OR (“temporomandibular”[All Fields] AND “joints”[All Fields]) OR “temporo-mandibular joints”[All Fields]). After screening 8 results, 5 studies were included in this review. Chitosan presents many biological properties and therefore it can be widely used in several branches of medicine and dentistry. Chitosan promotes wound healing, helps to control bleeding, and is used in wound dressings, such as sutures and artificial skin. Apart from its antibacterial property, chitosan has many other properties, such as antifungal, mucoadhesive, anti-inflammatory, analgesic, antioxidant, antihyperglycemic, and antitumoral properties. Further clinical studies assessing the efficacy of chitosan in the treatment of TMD are required. According to only one clinical study, chitosan was effective in the treatment of TMD; however, better clinical results were obtained with platelet-rich plasma.
... Partial deacetylation of chitin makes chitosan, unlike chitin, water soluble in a week acid media and extend its application in medicine [129]. Chitosan has also attracted attention due to its biocompatibility, biodegradability, antibacterial properties, ability to be sterilized, therefore, be used in tissue engineering as cells carrier and deliverer to the tissue [36,130,131]. In addition, chitosan has similar structure as glycosaminoglycans and it is believed to be able to induce or support chondrogenesis [132]. ...
Osteoarthritis (OA) is a long-term chronic joint disease characterized by the deterioration of bones and cartilage, which results in rubbing of bones which causes joint stiffness, pain, and restriction of movement. Tissue engineering strategies for repairing damaged and diseased cartilage tissue have been widely studied with various types of stem cells, chondrocytes, and extracellular matrices being on the lead of new discoveries. The application of natural or synthetic compound-based scaffolds for the improvement of chondrogenic differentiation efficiency and cartilage tissue engineering is of great interest in regenerative medicine. However, the properties of such constructs under conditions of mechanical load, which is one of the most important factors for the successful cartilage regeneration and functioning in vivo is poorly understood. In this review, we have primarily focused on natural compounds, particularly extracellular matrix macromolecule-based scaffolds and their combinations for the chondrogenic differentiation of stem cells and chondrocytes. We also discuss different mechanical forces and compression models that are used for In Vitro studies to improve chondrogenic differentiation. Summary of provided mechanical stimulation models In Vitro reviews the current state of the cartilage tissue regeneration technologies and to the potential for more efficient application of cell- and scaffold-based technologies for osteoarthritis or other cartilage disorders.
... Recently, in vitro studies have suggested that chitosan could promote cartilage-specific protein expression and reduce inflammatory and catabolic mediator production by chondrocytes [21]. Moreover, chitosan prevented cartilage degradation and synovial membrane inflammation in a rabbit model with induced OA [22,23]. The poly (3-hydroxybutyrate; PHB) represents natural or synthetic biodegradable and hydrophobic biopolymer, whereas the hydroxybutyric acid is a degradation product found in the body similar to glycolic acid and lactic acid as a normal metabolite [24]. ...
Biopolymer composites allow the creation of an optimal environment for the regeneration of chondral and osteochondral defects of articular cartilage, where natural regeneration potential is limited. In this experimental study, we used the sheep animal model for the creation of knee cartilage defects. In the medial part of the trochlea and on the medial condyle of the femur, we created artificial defects (6 × 3 mm2) with microfractures. In four experimental sheep, both defects were subsequently filled with the porous acellular polyhydroxybutyrate/chitosan (PHB/CHIT)-based implant. Two sheep had untreated defects. We evaluated the quality of the newly formed tissue in the femoral trochlea defect site using imaging (X-ray, Computer Tomography (CT), Magnetic Resonance Imaging (MRI)), macroscopic, and histological methods. Macroscopically, the surface of the treated regenerate corresponded to the niveau of the surrounding cartilage. X-ray examination 6 months after the implantation confirmed the restoration of the contour in the subchondral calcified layer and the advanced rate of bone tissue integration. The CT scan revealed a low regenerative potential in the bone zone of the defect compared to the cartilage zone. The percentage change in cartilage density at the defect site was not significantly different to the reference area (0.06–6.4%). MRI examination revealed that the healing osteochondral defect was comparable to the intact cartilage signal on the surface of the defect. Hyaline-like cartilage was observed in most of the treated animals, except for one, where the defect was repaired with fibrocartilage. Thus, the acellular, chitosan-based biomaterial is a promising biopolymer composite for the treatment of chondral and osteochondral defects of traumatic character. It has potential for further clinical testing in the orthopedic field, primarily with the combination of supporting factors.
... As an example, chitosan is a natural polymer that is structurally similar to the native cartilage tissue. Chitosanalginate, chitosan-gelatin, and chitosan-silk fibroin were successfully applied as cartilage scaffolds [222,223]. An amphiphilic block copolymer composed of hydrophobic polyesters and a blocked hydrophilic polymer was developed. ...
The tissue engineering of hard organs and tissues containing cartilage, teeth, and bones is a widely used and rapidly progressing field. One of the main features of hard organs and tissues is the mineralization of their extracellular matrices (ECM) to enable them to withstand pressure and weight. Recently, a variety of printing strategies have been developed to facilitate hard organ and tissue regeneration. Fundamentals in three-dimensional (3D) printing techniques are rapid prototyping, additive manufacturing, and layered built-up and solid-free construction. This strategy promises to replicate the multifaceted architecture of natural tissues. Nowadays, 3D bioprinting techniques have proved their potential applications in tissue engineering to construct transplantable hard organs/tissues including bone and cartilage. Though, 3D bioprinting methods still have some uncertainties to fabricate 3D hard organs/tissues. In the present review, most advanced technical improvements, experiments, and future outlooks of hard tissue engineering are discussed, as well as their relevant additive manufacturing techniques.
... New treatments that prevent bony bar formation and repair the growth plate cartilage could restore long bone growth, prevent growth abnormalities, and improve patient outcomes. Given that chitosan-based biomaterials have been shown to enhance chondrogenesis of cultured cells, and promote repair of articular cartilage defects, chitosan microgels could be an effective treatment for growth plate injuries 4,[12][13][14][15][16] . ...
The growth plate is a cartilage tissue near the ends of children’s long bones and is responsible for bone growth. Injury to the growth plate can result in the formation of a ‘bony bar’ which can span the growth plate and result in bone growth abnormalities in children. Biomaterials such as chitosan microgels could be a potential treatment for growth plate injuries due to their chondrogenic properties, which can be enhanced through loading with biologics. They are commonly fabricated via an emulsion method, which involves solvent rinses that are cytotoxic. Here, we present a high throughput, non-cytotoxic, non-emulsion-based method to fabricate chitosan–genipin microgels. Chitosan was crosslinked with genipin to form a hydrogel network, and then pressed through a syringe filter using mesh with various pore sizes to produce a range of microgel particle sizes. The microgels were then loaded with chemokines and growth factors and their release was studied in vitro. To assess the applicability of the microgels for growth plate cartilage regeneration, they were injected into a rat growth plate injury. They led to increased cartilage repair tissue and were fully degraded by 28 days in vivo. This work demonstrates that chitosan microgels can be fabricated without solvent rinses and demonstrates their potential for the treatment of growth plate injuries.
... Several previous studies have shown that chitosan has a chondroprotective function and could enhance chondrocyte proliferation, increase the expression level of cartilage matrix components and inhibit inflammatory and catabolic mediators after IA injection in OA models [12,13]. Moreover, chitosan is prone to inhibiting cartilage degradation and synovial membrane inflammation [14]. ...
Background
Pain and cartilage destruction caused by osteoarthritis (OA) is a major challenge in clinical treatment. Traditional intra-articular injection of hyaluronic acid (HA) can relieve the disease, but limited by the difficulty of long-term maintenance of efficacy.
Methods
In this study, an injectable and self-healing hydrogel was synthesized by in situ crosslinking of N -carboxyethyl chitosan ( N -chitosan), adipic acid dihydrazide (ADH), and hyaluronic acid–aldehyde (HA-ALD).
Results
This supramolecular hydrogel sustains good biocompatibility for chondrocytes. Intra-articular injection of this novel hydrogel can significantly alleviate the local inflammation microenvironment in knee joints, through inhibiting the inflammatory cytokines (such as TNF-α, IL-1β, IL-6 and IL-17) in the synovial fluid and cartilage at 2- and even 12-weeks post-injection. Histological and behavioral test indicated that hydrogel injection protected cartilage destruction and relieved pain in OA rats, in comparison to HA injection.
Conclusion
This kind of novel hydrogel, which is superior to the traditional HA injection, reveals a great potential for the treatment of OA.
... CH, as the only natural cationic polysaccharide, can be crosslinked with many anionic polymers; at the same time, its structure is similar to that of GAG, so CH has attracted considerable interest [101]. In addition, modified CH hydrogel can provide a good chondrogenic or osteogenic environment for cells, making it an excellent choice for mimicking the zonal structures of cartilage [102]. For example, Mellati et al. used CH and poly(N-isopropylacrylamide) to make temperature-sensitive hydrogels with different microstrip widths for the culture of MSCs. ...
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.
... 17 Chitosan is one of the most widely investigated polymers for regenerative medicine, in particular for cartilage regeneration because it displays structural properties that are similar to natural glycosaminoglycans. [18][19][20] Chitosan promotes the expression of cartilage matrix compounds and reduces production of inflammatory and catabolic mediators by chondrocytes. 21 A chitosan gel has been combined with microfracture to stabilize the blood clot and factors obtained from bone marrow stimulation, resulting in superior cartilage repair compared with microfracture alone up to 5 years postoperatively. ...
Objective:
To determine the ability of three implants to enhance the healing of osteochondral defects: (1) a biphasic construct composed of calcium phosphate (CaP) and chitosan/cellulosic polymer, (2) a titanium-polyurethane implant, and (3) an osteochondral autograft.
Study design:
Experimental study.
Animals:
Ten adult female sheep.
Methods:
In five sheep, an 8-mm diameter osteochondral defect was created on the medial femoral condyle of a stifle and filled with a synthetic titanium-polyurethane implant. In five sheep, a similar defect was filled with an osteochondral autograft, and the donor site was filled with a biphasic construct combining CaP granules and a chitosan/cellulosic polymer. Sheep were monitored daily for lameness. Stifle radiographs and MRI were evaluated at 20 weeks, prior to animals being humanely killed. Surgical sites were evaluated with histology, microcomputed tomography, and scanning electron microscopy.
Results:
Clinical outcomes were satisfactory regardless of the tested biomaterials. All implants appeared in place on imaging studies. Osteointegration of prosthetic implants varied between sites, with limited ingrowth of new bone into the titanium structure. Autografts and biphasic constructs were consistently well integrated in subchondral bone. All autografts except one contained a cartilage surface, and all biphasic constructs except one partially restored hyaline cartilage surface.
Conclusion:
Biphasic constructs supported hyaline cartilage and subchondral bone regeneration, although restoration of the articular cartilage was incomplete.
Clinical impact:
Biphasic constructs may provide an alternative treatment for osteochondral defects, offering a less invasive approach compared with autologous grafts and eliminating the requirement for a prosthetic implant.
... Moreover, in this condition it was observed a strong expression of the key chondrogenic genes such as COL2A1, SOX9 or ACAN and the deposition of collagen type II, whilst collagen type I deposition was not observed. These results are consistent with recent publications on cartilage regeneration using bone marrow hMSCs with self-assembling peptides such as RAD16-I or KLD12 [37,60] and either mono-or copolymeric hydrogels of polyethylene glycol (PEG) [61,62], chitosan [63,64], agarose [65,66] and alginate [67][68][69]. In addition, although a strong COL10A1 gene expression in PCL/RAD biocomposites was observed, no translation of this gene to the collagen type X protein was observed, avoiding hypertrophic processes described in previous work [70][71][72]. ...
Degenerative cartilage pathologies are nowadays a major problem for the world population. Factors such as age, genetics or obesity can predispose people to suffer from articular cartilage degeneration, which involves severe pain, loss of mobility and consequently, a loss of quality of life. Current strategies in medicine are focused on the partial or total replacement of affected joints, physiotherapy and analgesics that do not address the underlying pathology. In an attempt to find an alternative therapy to restore or repair articular cartilage functions, the use of bioengineered tissues is proposed. In this study we present a three-dimensional (3D) bioengineered platform combining a 3D printed polycaprolactone (PCL) macrostructure with RAD16-I, a soft nanofibrous self-assembling peptide, as a suitable microenvironment for human mesenchymal stem cells’ (hMSC) proliferation and differentiation into chondrocytes. This 3D bioengineered platform allows for long-term hMSC culture resulting in chondrogenic differentiation and has mechanical properties resembling native articular cartilage. These promising results suggest that this approach could be potentially used in articular cartilage repair and regeneration.
... Indeed, chitosan shows all the properties of an ideal contact lens; including gas permeability, optical clarity, optical correction, biocompatibility and mechanical stability [81]. Chitosan is also used for the repair of articular cartilage [82]. ...
The mechanotransduction is the process by which cells sense mechanical stimuli such as elasticity, viscosity, and nanotopography of extracellular matrix and translate them into biochemical signals. The mechanotransduction regulates several aspects of the cell behavior, including migration, proliferation, and differentiation in a time-dependent manner. Several reports have indicated that cell behavior and fate are not transmitted by a single signal, but rather by an intricate network of many signals operating on different length and timescales that determine cell fate. Since cell biology and biomaterial technology are fundamentals in cell-based regenerative therapies, comprehending the interaction between cells and biomaterials may allow the design of new biomaterials for clinical therapeutic applications in tissue regeneration. In this work, we present the most relevant mechanism by which the biomechanical properties of extracellular matrix (ECM) influence cell reprogramming, with particular attention on the new technologies and materials engineering, in which are taken into account not only the biochemical and biophysical signals patterns but also the factor time.
... CH is a hydrophilic cationic polymer of D-glucosamine and N-acetyl-D-glucosamine units derived from shellfish chitin protein, and it is able to accelerate wound healing by activating and modulating inflammatory cells (neutrophils, macrophages, and fibroblasts) and supporting adhesion and cells proliferation (Levengood & Zhang, 2014). CH polymer was cross-linked with substances in order to optimize resistance and elasticity (Comblain, Rocasalbas, Gauthier, & Henrotin, 2017). Moreover, it possesses certain intriguing characteristics such as high surface-volume ratio, great porosity on surface, possibility to obtain small pore size, ability to control biodegradation processes, and improved mechanical properties (Rodriguez-Vazquez et al., 2015) Mesenchymal stem cells (MSCs) represent an attractive cell source for cartilage tissue engineering, thanks to their immunomodulatory property and self-renewing and high proliferative capability (Jayasuriya, Chen, Liu, & Chen, 2016;Manferdini et al., 2013;Maumus et al., 2013). ...
Cartilage tissue engineering remains problematic since no systems are able to induce signals that contribute to native cartilage structure formation. Therefore, we tested the potentiality of gelatin‐polyethylene glycol scaffolds containing three different concentrations of chitosan (CH) (0%, 8% and 16%) on chondrogenic differentiation of human platelet lysate (HPL)‐expanded human bone marrow mesenchymal stromal cells (hBM‐MSCs). Typical chondrogenic (SOX9, collagen type 2 and aggrecan), hypertrophic (collagen type 10) and fibrotic (collagen type 1) markers were evaluated at gene and protein level at day 1, 28 and 48. We demonstrated that 16% CH scaffold had the highest percentage of relaxation with the fastest relaxation rate. In particular, 16% CH scaffold, combined with chondrogenic factor TGFβ3, was more efficient in inducing hBM‐MSCs chondrogenic differentiation compared to 0% or 8% scaffolds. Collagen type 2, SOX9 and aggrecan showed the same expression in all scaffolds, while collagen type 10 and collagen type 1 markers were efficiently down‐modulated only in 16% CH. We demonstrated that using HPL chronically during hBM‐MSCs chondrogenic differentiation, the chondrogenic, hypertrophic and fibrotic markers were significantly decreased. Our data demonstrate that only a high concentration of CH, combined with TGFβ3, creates an environment capable of guiding in vitro hBM‐MSCs towards a phenotypically stable chondrogenesis.
... 12 Nowadays, preclinical research is focusing on the evaluation of new treatments and molecules able to prevent or delay cartilage degradation. [14][15] In this contest, chitosan seems to be an interesting candidate. Chitosan, a partially deacetylated derivative from chitin, composed of D-gucosamine and N-acetylglucosamine, is structurally similar to glycosaminoglycans. ...
Among conventional osteoarthritis (OA) treatments, intra‐articular (i.a) viscosupplementation with hyaluronic acid (HA) is used to restore joint viscoelasticity. However, the rapid clearance and elimination of HA may limit its application. The aim of this study was to verify the improved efficacy of HA within the joint, using a lactose‐modified chitosan (chitlac) as a potentially chondroprotective additive.
Four weeks after induction of experimental OA by destabilization of the medial meniscus (DMM), 12‐week‐old Sprague Dawley male rats (n = 30), received once a week, for three weeks, i.a injections of i) HA associated to chitlac (ARTY‐DUO®), ii) HA and iii) sodium chloride (NaCl). Five animals for each group were euthanized 4 weeks after the first i.a injection, while the remaining 5 were euthanized 8 weeks after the first i.a injection. The restoration of physiological joint microenvironment was tested by histology, histomorphometry, immunohistochemistry and microtomography (micro‐CT).
At 4 and even more at 8 weeks, histological analysis showed a significant decrease in OARSI and Mankin scores, with weaker matrix metalloproteinase (MMP)‐3, MMP‐13 and Galectin‐3 in ARTY‐DUO® group versus NaCl and HA groups. A reduction in Galectin‐1 and a stronger Collagen II staining was seen in both ARTY‐DUO® and HA versus NaCl. A reduction in Kreen‐modified score, for synovium inflammation, was observed in the ARTY‐DUO® group. Micro‐CT measurements did not shown significant differences between the groups.
The present results show that i.a ARTY‐DUO® injections produce a significant improvement in knee articular cartilage degeneration and synovium inflammation in a rat model of DMM‐induced OA. This article is protected by copyright. All rights reserved
... It has been suggested that chitosan inhibits fibroplasia in wound healing, and promotes tissue growth and differentiation in vitro (5,6). Notably, chitosan has anti-inflammatory and anti-oxidative properties (7)(8)(9). ...
Chitosan is a linear polysaccharide that is made by treating the chitin shells of shrimp and crustaceans with an alkaline substance, for example sodium hydroxide. Due to its unique physical and chemical properties, chitosan has a wide range of applications in the medical field. Currently, there are no effective treatments for liver fibrosis; therefore, the aim of the present study was to investigate the therapeutic effect of chitosan in a CCl4‑induced hepatic fibrosis (HF) rat model. The serum levels of aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) were measured by ELISA. Collagen (COL) 3 and α‑smooth muscle actin (SMA) expression levels in the rat liver were detected by reverse transcription‑semiquantitative polymerase chain reaction and western blotting, respectively. The results demonstrated that treatment with chitosan significantly improved HF, by decreasing the serum levels of AST, ALT, and ALP; improving liver histology; and decreasing the expression levels of COL3 and α‑SMA. Chitosan may offer an alternative approach for the clinical treatment of HF.
The impairment of articular cartilage due to traumatic incidents or osteoarthritis has posed significant challenges for healthcare practitioners, researchers, and individuals suffering from these conditions. Due to the absence of an approved treatment strategy for the complete restoration of cartilage defects to their native state, the tissue condition often deteriorates over time, leading to osteoarthritic (OA). However, recent advancements in the field of regenerative medicine have unveiled promising prospects through the utilization of injectable hydrogels. This versatile class of biomaterials, characterized by their ability to emulate the characteristics of native articular cartilage, offers the distinct advantage of minimally invasive administration directly to the site of damage. These hydrogels can also serve as ideal delivery vehicles for a diverse range of bioactive agents, including growth factors, anti-inflammatory drugs, steroids, and cells. The controlled release of such biologically active molecules from hydrogel scaffolds can accelerate cartilage healing, stimulate chondrogenesis, and modulate the inflammatory microenvironment to halt osteoarthritic progression.
The present review aims to describe the methods used to design injectable hydrogels, expound upon their applications as delivery vehicles of biologically active molecules, and provide an update on recent advances in leveraging these delivery systems to foster articular cartilage regeneration.
Development of biomimetic constructs for cartilage tissue regeneration has become an increasing field of interest in today’s biomedical research. Both, synthetic and natural compound-based scaffolds are being used for biomimetic construct formation, and their mix, with polylactic acid (PLA), poly(ethylene glycol) (PEG), etc., being on the lead of most commonly used synthetic materials and cartilage extracellular matrix (ECM) proteins, such as collagens, hyaluronic acid (HA), glycosaminoglycans (GAGs), and proteoglycans, are the most popular ones for developing natural scaffolds/hydrogels for cartilage tissue engineering purposes. Most important properties for both types of scaffolds include fluid absorption, piezoelectric properties, surface parameters, porosity, electrical conductance, stiffness, and wettability. Synthetic materials are mostly favorable for their stiffness and mechanical stability, while natural molecules are advantageous for mimicking the in vivo environment, stimulating cell differentiation processes and possessing biodegradability. In order to achieve the highest biomimicry of a construct to be used for regenerative purposes of cartilage tissue, optimal conditions of scaffold synthesis and its application techniques should be optimized. To date, no effective scaffold system exists, which would overcome every difficulty, and challenges of developing a qualitative construct remain high. However, a number of studies demonstrated promising results of using different kinds of scaffolds, suggesting their potential application for clinical trials. This chapter deals with synthetic, natural, and their mixed scaffolds, as well as their properties and functions for stimulating cellular responses for cartilage regeneration purposes. We observe scaffolds’ basic chemical/biological properties, their effects on chondrogenic differentiation, and physical stimuli, such as mechanical and electrical stimulations. We assume this chapter will bring novel insights for early and advanced scaffold developers and will help indicate the most important properties of a scaffold system required for cartilage tissue regeneration.KeywordsCartilageBiomimetic scaffoldsSynthetic scaffoldsNatural scaffoldsMechanical/electrical stimulation
Combining biomacromolecules with green chemistry principles and clean technologies has proven to be an effective approach for drug delivery, providing a prolonged and sustained release of the encapsulated material. The current study investigates the potential of cholinium caffeate (Ch[Caffeate]), a phenolic-based biocompatible ionic liquid (Bio-IL) entrapped in alginate/acemannan beads, as a drug delivery system able to reduce local joint inflammation on osteoarthritis (OA) treatment. The synthesized Bio-IL has antioxidant and anti-inflammatory actions that, combined with biopolymers as 3D architectures, promote the entrapment and sustainable release of the bioactive molecules over time. The physicochemical and morphological characterization of the beads (ALC, ALAC0,5, ALAC1, and ALAC3, containing 0, 0.5, 1, and 3 %(w/v) of Ch[Caffeate], respectively) revealed a porous and interconnected structure, with medium pore sizes ranging from 209.16 to 221.30 μm, with a high swelling ability (up 2400 %). Ch[Caffeate] significantly improved the antioxidant activities of the constructs by 95 % and 97 % for ALAC1 and ALAC3, respectively, when compared to ALA (56 %). Besides, the structures provided the environment for ATDC5 cell proliferation, and cartilage-like ECM formation, supported by the increased GAGs in ALAC1 and ALAC3 formulations after 21 days. Further, the ability to block the secretion of pro-inflammatory cytokines (TNF-α and IL-6), from differentiated THP-1 was evidenced by ChAL-Ch[Caffeate] beads. These outcomes suggest that the established strategy based on using natural and bioactive macromolecules to develop 3D constructs has great potential to be used as therapeutic tools for patients with OA.
The key to regenerative medicine is in situ regeneration of lesion cells, so as to achieve lesion repair and regeneration. However, the complex environment of the joint cavity where cartilage is located leads to poor efficacy of traditional therapies to promote cartilage repair and regeneration. Development of hydrogel microspheres offers an attractive solution for regenerative medicine aimed at cartilage repair to address these limitations. Hydrogel microspheres have the potential of injectable and multi-functional transformation, which can effectively regulate the pathophysiological changes of cells and extracellular matrix at the site of cartilage injury. This review summarizes the application of various functional modified hydrogel microspheres in cartilage repair and regeneration. The common techniques and biomaterials used to prepare hydrogel microspheres are first briefly introduced. In particular, the microfluidic technology is highlighted in detail. Besides, the construction strategies of hydrogel microspheres with different functions and their mechanisms to promote cartilage repair and regeneration are further presented. Finally, the problems and challenges of hydrogel microspheres for cartilage repair are summarized.
Intra-articular administration of anti-inflammatory drugs is a strategy that allows localized action on damaged articular cartilage and reduces the side effects associated with systemic drug administration. The objective of this work is to prepare injectable thermosensitive hydrogels for the long-term application of dexamethasone. The hydrogels were prepared by mixing chitosan (CS) and Pluronic-F127 (PF) physically. In addition, tripolyphosphate (TPP) was used as a crosslinking agent. Chitosan added to the mix increased the gel time compared to the pluronic gel alone. The incorporation of TPP into the material modified the morphology of the hydrogels formed. Subsequently, MTS and Live/Dead® experiments were performed to investigate the toxicity of hydrogels against human chondrocytes. The in vitro releases of dexamethasone (DMT) from CS-PF and CS-PF-TPP gels had an initial burst and took more time than that from the PF hydrogel. In vivo studies showed that hydrogels retained the fluorescent compound longer in the joint than when administered in PBS alone. These results suggest that the CS-PF and CS-PF-TPP hydrogels loaded with DMT could be a promising drug delivery platform for the treatment of osteoarthritis.
Chitosan is a modified natural carbohydrate polymer derived from chitin that occurs in many natural sources. It has a diverse range of applications in medical and pharmaceutical sciences. Its primary and permitted use is biomaterial in medical devices. Chitosan and its derivatives also find utility in pharmaceuticals as an excipient, drug carrier, or therapeutic agent. The USFDA has approved chitosan usage as a biomaterial but not for pharmaceutical use, primarily because of the concerns over its source, purity, and immunogenicity. A large number of clinical studies are underway on chitosan-based materials/ products because of their diverse applications. Herein, we analyze clinical studies to understand their clinical usage portfolio. Our analysis shows that >100 clinical studies are underway to investigate the safety/efficacy of chitosan or its biomaterials/ nanoparticles, comprising ~95% interventional and ~ 5% observational studies. The regulatory considerations that limit the use of chitosan in pharmaceuticals are also deliberated.
Teaser
Clinical Trials of Chitosan.
Knee osteoarthritis (KOA) refers to a common disease in orthopaedics, whereas effective treatments have been rarely developed. As indicated from existing studies, chondrocyte death, extracellular matrix degradation and subchondral bone injury are recognized as the pathological basis of KOA. The present study aimed to determine the therapeutic effect of decellularized extracellular matrix-chitosan (dECM-CS) compound on KOA. In this study, rat knee cartilage was decellularized, and a satisfactory decellularized extracellular matrix was developed. As suggested from the in vitro experiments, the rat chondrocytes co-cultured with allogeneic dECM grew effectively. According to the results of the alamar blue detection, dECM did not adversely affect the viability of rat chondrocytes, and dECM could up-regulate the genes related to the cartilage synthesis and metabolism. As reported from the animal experiments, dECM-CS compound could protect cartilage, alleviate knee joint pain in rats, significantly delay the progress of KOA in rats, and achieve high drug safety. In brief, dECM-CS compound shows a good therapeutic effect on KOA.
Osteoarthritis (OA) is a serious chronic and degenerative disease that increasingly occurs in the aged population. Its current clinical treatments are limited to symptom relief and cannot regenerate cartilage. Although a better understanding of OA pathophysiology has been facilitating the development of novel therapeutic regimen, delivery of therapeutics to target sites with minimal invasiveness, high retention, and minimal side effects remains a challenge. Biocompatible hydrogels have been recognized to be highly promising for controlled delivery and release of therapeutics and biologics for tissue repair. In this review, the current approaches and the challenges in OA treatment, and unique properties of injectable natural polymer hydrogels as delivery system to overcome the challenges are presented. The common methods for fabrication of injectable polysaccharide‐based hydrogels and the effects of their composition and properties on the OA treatment are detailed. The strategies of the use of hydrogels for loading and release cargos are also covered. Finally, recent efforts on the development of injectable polysaccharide‐based hydrogels for OA treatment are highlighted, and their current limitations are discussed. This article provides an overview of advances in polysaccharide hydrogels for treatment of knee osteoarthritis (KOA). The structures and unique properties of commonly used polysaccharides, hydrogel formation mechanisms, drug loading, and release strategies are detailed. The recent progress in applications of polysaccharides hydrogels in KOA repair, and the current limitations and future prospects of this technology are discussed.
Rheumatoid arthritis (RA) results in increased rate of mortality in millions of people worldwide. Research utilizing Tin oxide - Chitosan- Polyethylene glycol Carvacrol (SCP-CAR) nanocomposites has gained increased attention because of its multipotent properties and application in diverse fields including medicinal preparations. The aim of the investigation was to synthesize and to examine the anti-arthritic ability of SCP-CAR nanocomposites against CFA -induced RA in rats. Arthritis induction was done by injecting 0.1 ml of Complete Freund’s adjuvant (CFA) intradermally. Body weight, weight of organs, hind paw volumes and arthritis score was assessed and the levels of inflammatory modulators such as IL-6, IL-1β, IL-10, TNF-α, PGE2 and COX-2 was examined using assay kits. Lipid peroxidation status, antioxidant enzyme activities and levels of liver function enzymes were evaluated using standard procedures. Histopathological changes observed in hind limb of experimental animals were viewed under microscope using H& E staining. The SCP-CAR nanocomposites treated arthritic animals showed increased bodyweight and reduced hind paw volume, organ weight and arthritis score together with elevated antioxidants status and depleted proinflammatory cytokines. Histopathological observation also showed reduction in bone destruction and penetration of inflammatory cells following treatment with SCP-CAR nanocomposites. Thus, together the findings depict the anti-arthritic and anti-inflammatory potential of SCP-CAR nanocomposites suggesting that it could be used as potent therapeutic agent to treat animals against arthritis induced by CFA.
The current study was undertaken to investigate the hepatoprotective potential of nanostructured oligochitosan (NOC) against the synergistic toxic effects of -irradiation exposure and carbon tetrachloride (CCl4) intoxication in male rats. Adult male rats were allocated into eight groups; control, NOC-administered, -irradiated, CCl4-intoxicated, NOC-pretreated -irradiated, NOC-pretreated CCl4-intoxicated, -irradiated and CCl4-intoxicated, NOC-pretreated CCl4-intoxicated and -irradiated. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) results demonstrated that the oligochitosan prepared by exposure to gamma irradiation was in the range of nanoparticles. A synergistic hepatotoxic effect was demonstrated following the exposure of rats to -irradiation and CCl4 intoxication, along with the induction of oxidative stress, inflammation and apoptosis. NOC was able to protect the hepatocytes from the combined toxic insults through suppressing lipid and protein oxidations, maintaining hepatic functions, downregulating the expression of some inflammatory genes, including nuclear factor kappa B (NF-B) and interleukin 1 beta (IL-1β), as well as enhancing the expression of the antiapoptotic Bcl2 gene and suppressing the proapoptotic Bax gene expression. Histological findings of liver tissues verified the biochemical and molecular data. The study clarified some of the molecular mechanisms by which NOC protects the liver against the synergistic toxic effect of -irradiation and CCl4.
Articular cartilage has limited regeneration capacity because of its acellular and avascular nature. Although tissue engineering has been shown to be life‐saving, reforming cartilage zones required by the appropriate tissue functions are challenging. Herein, the need is addressed by designing and producing a nano‐engineered structure mimicking the superficial zone (SZ) of articular cartilage. The substrate is based on silk with good mechanical properties in conjunction with nano‐topographical and biochemical cues. Nanopillar arrays are produced on the silk surface to regulate the stem cell morphology rendering them with a flattened ellipsoidal shape that is similar to that of chondrocytes in the SZ of natural cartilage. The cell interactions are enhanced by nitrogen ion implantation and the biomolecule, kartogenin (KGN), is loaded to promote chondrogenesis of the stem cells and furthermore, a thermosensitive chitosan hydrogel is formed on the nanopatterned silk to produce rheological properties similar to those of a synovial fluid. Based on the in vitro results and mechanical properties, it is a desirable implantable smart structure mimicking the cartilage SZ with the ability of continuous drug release for cartilage regeneration.
Background
An autoimmune ailment rheumatoid arthritis (RA) where body’s defense system is violated by damaging its own joints. In RA treatment strategies, attempts had been made for oral, topical and parenteral formulations with different drugs, but none of the formulation could be regarded as perfect dosage form. In the current review, meticulous discussion has been done for the suitability of novel topical formulation in treatment of RA. Moreover emphasize has been made on activities of biodegradable polymers such as hyaluronic acid, lecithin, pluronic acid, chitosan, human serum albumin (HSA) and poly lactide glycolic acid (PLGA) as well as their role in the management of RA.
Objective
To apprehend the role of polymeric materials in developing ideal topical drug delivery system which can bestow targeted delivery, enhanced penetration of drug, improved stability of the formulation and improved PKPD profile of the drugs. These polymers possess twinfold functions, primarily by increasing the skin penetration and secondarily by improving the joint mobility and cartilage regeneration. Furthermore, biocompatibility and biodegradbility are the features which amplifies the use of aforementioned polymers.
Results
Significant role of all the polymers in improving the conditions of bones and joints suffering from rheumatoid arthritis, has been demonstrated by various studies.
The adult articular cartilage has poor intrinsic healing capacity due to its avascular, aneural, and lymphatic nature. As such, the repair of cartilage defects in patient’s knees presents a great challenge to the orthopedic surgeon. If left untreated, cartilage defects can lead to osteoarthritis (OA) resulting in chronic pain and disability. In recent years, the use of tissue engineering (TE) strategies and advances in biochemical and biomechanical properties of cartilage scaffolds have led to the development of a more functional cartilage repair tissue. This chapter will highlight the characteristic features of a successful cartilage scaffold and review the scaffolds that are currently being investigated for clinical used.
Transplantation of chondrogenic stem cells is a promising strategy for cartilage repair, but requires improvements in cell sourcing, maintenance, and chondrogenic differentiation efficiency. We examined whether gelatin honeycomb scaffolds can enhance the proliferation, viability, and chondrogenic capability of human umbilical cord mesenchymal stem cells (HUCMSCs) compared to standard plate cultures. In addition, the survival and phenotypic stability of HUCMSC‐derived chondrocytes in a scaffold were evaluated in mice over 6 weeks post‐transplantation. Survival and proliferation rates of HUCMSCs were comparable between scaffold and plate culture. Scaffold culture in a chondrogenic differentiation medium induced more stable expression of the key hyaline cartilage genes COL2A1 and ACAN and the production of the respective proteins type II collagen and aggrecan as well as glycosaminoglycan. These HUCMSC‐differentiated chondrocytes also stably expressed cartilage genes and proteins in the scaffold 6 weeks after transplantation into non‐obese diabetic/severe combined immunodeficient mice. These findings indicate that honeycomb‐like gelatin scaffolds can promote the survival and chondrogenic differentiation of HUCMSCs to form hyaline‐like cartilage.
A high number of sport injuries result in damage to articular cartilage, a tissue type with poor self-healing capacity. Articular cartilage tissue is a sophisticated hydrogel, which contains 80% water and possesses strong mechanical properties. For this reason, synthetic hydrogels are thought to be an optimal material for cartilage regeneration. In the last decade, more than 2,000 research papers pertaining to “hydrogel and cartilage” have been published. Due to its biomimetic properties and user-friendly nature, especially in the field of minimal invasive surgery, intelligent injectable hydrogel have gradually become a focal point in cartilage research in recent years. In this review, we systematically summarize current “state-of-the-art” manufacture technologies of injectable hydrogels including ion-induced, thermo-induced, non-induced chemical, and light-induced crosslinking. We also review current strategies for designing intelligent injectable hydrogels, such as component-based, mechanical property-based and structure-based intelligent design to simulate the natural articular cartilage. Lastly, the applications of intelligent injectable hydrogels for cartilage regeneration are presented, and their outlooks for future clinical translation is dicussed.
A hybrid hydrogel combining collagen and chitosan (Ch) and human amniotic membranes (AM) were produced. To produce hybrid hydrogels, a fixed concentration of chitosan (2%) was used, adding AM as a booster at the concentrations of 2.5, 5.0. and 10.0% (w/w). DSC curves showed the denaturation of collagen. The swelling capacity of hydrogels ranged between 333 ± 19% and 368 ± 28%. The groups Ch-1.0 mg/mL and Ch-2.0 mg/mL had an elastic modulus 27% higher than the other groups.
Objective:
This study aimed to optimize the preparation of carboxymethyl chitosan/sodium alginate (CMCS/OSA) compound hydrogels. This study also aimed to investigate the applicability of the hydrogels in cartilage tissue engi-neering.
Methods:
Three groups of CMCS/OSA composite hydrogels with amino-to-aldehyde ratios of 2∶1, 1∶1 and 1∶2 were prepared. The microstructure, physical properties, and cell biocompatibility of the three groups of CMCS/OSA com-posite hydrogels were evaluated. Samples were subjected to scanning electron microscopy, rheological test, adhesion tension test, swelling rate test, and cell experiments to identify the CMCS/OSA composite hydrogel with the cross-linking degree that can meet the requirements for scaffolds in cartilage tissue engineering.
Results:
The experimental results showed that the CMCS/OSA hydrogel with a amine-to-aldhyde ratio of 1∶1 had good porosity, suitable gelling time, strong adhesive force, stable swelling rate, and good cellular biocompatibility.
Conclusions:
The CMCS/OSA compound hydrogel prepared with a 1∶1 ratio of amino and aldehyde groups has potential applications in cartilage tissue engineering.
The aim of this study is to review developments in glycosaminoglycan and proteoglycan research relevant to cartilage repair biology and in particular the treatment of osteoarthritis (OA). Glycosaminoglycans decorate a diverse range of extracellular matrix and cell associated proteoglycans conveying structural organization and physico‐chemical properties to tissues. They play key roles mediating cellular interactions with bioactive growth factors, cytokines, and morphogenetic proteins, and structural fibrillar collagens, cell interactive and extracellular matrix proteoglycans, and glycoproteins which define tissue function. Proteoglycan degradation detrimentally affects tissue functional properties. Therapeutic strategies have been developed to counter these degenerative changes. Neo‐proteoglycans prepared from chondroitin sulfate or hyaluronan and hyaluronan or collagen‐binding peptides emulate the interactive, water imbibing, weight bearing, and surface lubricative properties of native proteoglycans. Many neo‐proteoglycans outperform native proteoglycans in terms of water imbibition, matrix stabilization, and resistance to proteolytic degradation. The biospecificity of recombinant proteoglycans however, provides precise attachment to native target molecules. Visco‐supplements augmented with growth factors/therapeutic cells, hyaluronan, and lubricin (orthobiologicals) have the capacity to lubricate and protect cartilage, control inflammation, and promote cartilage repair and regeneration of early cartilage lesions and may represent a more effective therapeutic approach to the treatment of mild to moderate OA and deserve further study. Type 1 collagen resists shear forces generated from dynamic joint loading, versican immobilizes the hyaluronan on the cartilage surface, a synergy with lubricin provides joint lubrication.
Purpose: Scaffold-free cartilage tissue engineering circumvents issues with scaffold seeding, potential toxicity response, and impaired host integration. However, precisely controlling and maintaining a scaffold-free construct shape have been challenging. We explored the feasibility of microneedle arrays to print tissue using cellular microspheroids as building blocks.
Materials and Methods: Human embryonic-derived mesenchymal stem cells or infrapatellar fat pad mesenchymal stem cells were used to create microspheroids of 500 µm in diameter, which were assembled on microneedle arrays in a predefined arrangement using a robotic system under computer vision. Microspheroids on microneedles were cultured to permit fusion into a tissue construct. Infrapatellar fat pad mesenchymal stem cell constructs were either implanted into chondral defects created in human osteoarthritic cartilage explants or maintained on the microneedle array for 3 weeks. Embryonic-derived mesenchymal stem cell constructs were designed to be press-fit into 3 mm subchondral defects in New Zealand White rabbits and maintained for up to 8 weeks to assess retention, early tissue repair, and more mature cartilage regeneration.
Results: Microspheroids of both cell types fused together in culture to form neotissues of predefined shape and size. Infrapatellar fat pad mesenchymal stem cell neotissues expressed high levels of chondrogenic genes and integrated with the surrounding osteoarthritic host cartilage. Embryonic-derived mesenchymal stem cell constructs generated chondrogenic neotissue in vivo as early as 2 weeks and more mature tissue by 8 weeks with increased glycosaminoglycan deposition.
Conclusions: We constructed defined scaffold-free shapes by bioprinting and fusing microspheroids. Proof of concept was shown in the repair of ex vivo osteoarthritic human cartilage and in vivo rabbit osteochondral (OC) defects.
Small molecules loaded into biological materials present a promising strategy for stimulating endogenous repair mechanisms for in situ skin regeneration. Lithium can modulate various biologic processes, promoting proliferation, angiogenesis, and decreasing inflammation. However, its role in skin repair is rarely reported. In this study, we loaded lithium chloride (LiCl) into the chitosan (CHI) hydrogel and develop a sterile and biocompatible sponge scaffold through freeze-drying. In-vitro assessment demonstrated that the CHI-LiCl composite scaffolds (CLiS) possessed favorable cytocompatibility, swelling and biodegradation. We created full-thickness skin wounds in male C57BL/c mice to evaluate the healing capacity of CLiS. Compared with the wounds of control and CHI scaffold (CS) groups, the wounds in the CLiS-treated group showed reduced inflammation, improved angiogenesis, accelerated re-epithelialization, sustained high expression of β-catenin with a small amount of regenerated hair follicles. Therefore, CLiS may be a promising therapeutic dressing for skin wound repair and regeneration.
The repair of tissue defects after injury is of significant clinical and research importance. A variety of chitosan‐based hydrogels have been investigated and applied to address this problem. By using different synthetic methods, the hydrogels exhibit distinct physical properties, including porosity, adhesion, and stiffness. These properties are considered important factors affecting cell proliferation and tissue regeneration. Meanwhile, drug delivery and cell delivery are the two main strategies to improve the therapeutic effects of chitosan‐based hydrogels, but the choices of cells or drugs are quite varied and largely depend on the specificity of the treated tissues. The present review summarizes the physicochemical properties of chitosan‐based hydrogels and their influences on cells, and lists specific ways to promote the tissue regeneration in different systems of the human body. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018, 135, 47235.
Matrix-induced autologous chondrocyte implantation (MACI) is an established technique to treat articular cartilage defects in the knee. Traditionally, the chondral graft is harvested arthroscopically and then implanted via an open or mini-open technique. However, an arthroscopic implantation technique carries with it the potential for reduced pain, improved rehabilitation, and reduced arthrofibrosis. The arthroscopic implantation first involves a standard arthroscopic biopsy followed by cell culture and seeding onto a collagen membrane. The implantation procedure itself is performed 6–8 weeks later. A standard arthroscopy is performed and the defect is debrided to stable vertical walls using curettes and arthroscopic shavers. All irrigation fluid is subsequently evacuated such that the rest of the procedure is performed as a dry arthroscopy. The defect is sized using a graduated probe. If required, a template may be cut out of the supplied membrane. A wide-bore valveless cannula, inserted through the working portal, permits the repeated atraumatic passage of the prepared membrane. The probe is used to position the graft and check for size. A definitive graft is then cut and placed in the knee. Fibrin glue is applied to the base of the defect, the membrane is positioned, and an embolectomy or indwelling catheter balloon is inflated to apply even pressure to the graft while the glue sets. A validated, accelerated rehabilitation program is recommended, with full weight-bearing at 8-week post-procedure. Results using this technique have shown this to be a safe, reliable, and reproducible procedure with good clinical and radiological outcomes at the 5-year follow-up.
Osteoarthritis (OA) is the biggest unmet medical need among the many musculoskeletal conditions and the most common form of arthritis. It is a major cause of disability and impaired quality of life in the elderly. We review several ambitious but failed attempts to develop joint structure-modifying treatments for OA. Insights gleaned from these attempts suggest that these failures arose from unrealistic hypotheses, sub-optimal selection of patient populations or drug dose, and/or inadequate sensitivity of the trial endpoints. The long list of failures has prompted a paradigm shift in OA drug development with redirection of attention to: 1) consideration of the benefits of localized vs systemic pharmacological agents, as indicated by the increasing number of intra-articularly administered compounds entering clinical development; 2) recognition of OA as a complex disease with multiple phenotypes, that may each require somewhat different approaches for optimizing treatment; and 3) trial enhancements based on guidance regarding biomarkers provided by regulatory agencies, such as the Food and Drug Administration, that could be harnessed to help turn failures into successes.
Using tissue engineering techniques, an artificial osteochondral construct was successfully fabricated to treat large osteochondral defects. In this study, porcine cancellous bones and chitosan/gelatin hydrogel scaffolds were used as substitutes to mimic bone and cartilage, respectively. The porosity and distribution of pore size in porcine bone was measured and the degradation ratio and swelling ratio for chitosan/gelatin hydrogel scaffolds was also determined in vitro. Surface morphology was analyzed with the scanning electron microscope (SEM). The physicochemical properties and the composition were tested by using an infrared instrument. A double layer composite scaffold was constructed via seeding adipose-derived stem cells (ADSCs) induced to chondrocytes and osteoblasts, followed by inoculation in cancellous bones and hydrogel scaffolds. Cell proliferation was assessed through Dead/Live staining and cellular activity was analyzed with IpWin5 software. Cell growth, adhesion and formation of extracellular matrix in composite scaffolds blank cancellous bones or hydrogel scaffolds were also analyzed. SEM analysis revealed a super porous internal structure of cancellous bone scaffolds and pore size was measured at an average of 410 ± 59 μm while porosity was recorded at 70.6 ± 1.7 %. In the hydrogel scaffold, the average pore size was measured at 117 ± 21 μm and the porosity and swelling rate were recorded at 83.4 ± 0.8 % and 362.0 ± 2.4 %, respectively. Furthermore, the remaining hydrogel weighed 80.76 ± 1.6 % of the original dry weight after hydration in PBS for 6 weeks. In summary, the cancellous bone and hydrogel composite scaffold is a promising biomaterial which shows an essential physical performance and strength with excellent osteochondral tissue interaction in situ. ADSCs are a suitable cell source for osteochondral composite reconstruction. Moreover, the bi-layered scaffold significantly enhanced cell proliferation compared to the cells seeded on either single scaffold. Therefore, a bi-layered composite scaffold is an appropriate candidate for fabrication of osteochondral tissue.
While many tissue-engineered constructs aim to treat cartilage defects, most involve chondrocyte or stem cell seeding on scaffolds. The clinical application of cell-based techniques is limited due to the cost of maintaining cellular constructs on the shelf, potential immune response to allogeneic cell lines, and autologous chondrocyte sources requiring biopsy from already diseased or injured, scarce tissue. An acellular scaffold that can induce endogenous influx and homogeneous distribution of native stem cells from bone marrow holds great promise for cartilage regeneration. This study aims to develop such an acellular scaffold using designed, channeled architecture that simultaneously models the native zones of articular cartilage and subchondral bone. Highly porous, hydrophilic chitosan-alginate (Ch-Al) scaffolds were fabricated in three-dimensionally printed (3DP) molds designed to create millimeter scale macro-channels. Different polymer preform casting techniques were employed to produce scaffolds from both negative and positive 3DP molds. Macro-channeled scaffolds improved cell suspension distribution and uptake overly randomly porous scaffolds, with a wicking volumetric flow rate of 445.6 ± 30.3 mm(3) s(-1) for aqueous solutions and 177 ± 16 mm(3) s(-1) for blood. Additionally, directional freezing was applied to Ch-Al scaffolds, resulting in lamellar pores measuring 300 μm and 50 μm on the long and short axes, thus creating micrometer scale micro-channels. After directionally freezing Ch-Al solution cast in 3DP molds, the combined macro- and micro-channeled scaffold architecture enhanced cell suspension uptake beyond either macro- or micro-channels alone, reaching a volumetric flow rate of 1782.1 ± 48 mm(3) s(-1) for aqueous solutions and 440.9 ± 0.5 mm(3) s(-1) for blood. By combining 3DP and directional freezing, we can control the micro- and macro-architecture of Ch-Al to drastically improve cell influx into and distribution within the scaffold, while achieving porous zones that mimic articular cartilage zonal architecture. In future applications, precisely controlled micro- and macro-channels have the potential to assist immediate endogenous bone marrow uptake, stimulate chondrogenesis, and encourage vascularization of bone in an osteochondral scaffold.
This in vitro study investigated the metabolism of human osteoarthritic (OA) chondrocytes encapsulated in a spherical matrix enriched of chitosan. Human OA chondrocytes were encapsulated and cultured for 28 days either in chitosan-alginate beads or in alginate beads. The beads were formed by slowly passing dropwise either the chitosan 0.6%-alginate 1.2% or the alginate 1.2% solution through a syringe into a 102 mM CaCl2 solution. Beads were analyzed histologically after 28 days. Interleukin (IL)-6 and -8, prostaglandin (PG) E2, matrix metalloproteinases (MMPs), hyaluronan and aggrecan were quantified directly in the culture supernatant by specific ELISA and nitric oxide (NO) by using a colorimetric method based on the Griess reaction. Hematoxylin and eosin staining showed that chitosan was homogeneously distributed through the matrix and was in direct contact with chondrocytes. The production of IL-6, IL-8 and MMP-3 by chondrocytes significantly decreased in chitosan-alginate beads compared to alginate beads. PGE2 and NO decreased also significantly but only during the first three days of culture. Hyaluronan and aggrecan production tended to increase in chitosan-alginate beads after 28 days of culture. Chitosan-alginate beads reduced the production of inflammatory and catabolic mediators by OA chondrocytes and tended to stimulate the synthesis of cartilage matrix components. These particular effects indicate that chitosan-alginate beads are an interesting scaffold for chondrocytes encapsulation before transplantation to repair cartilage defects.
Unlabelled:
Articular cartilage defects have been addressed using microfracture, abrasion chondroplasty, or osteochondral grafting, but these strategies do not generate tissue that adequately recapitulates native cartilage. During the past 25 years, promising new strategies using assorted scaffolds and cell sources to induce chondrocyte expansion have emerged. We reviewed the evolution of autologous chondrocyte implantation and compared it to other cartilage repair techniques.
Methods:
We searched PubMed from 1949 to 2014 for the keywords "autologous chondrocyte implantation" (ACI) and "cartilage repair" in clinical trials, meta-analyses, and review articles. We analyzed these articles, their bibliographies, our experience, and cartilage regeneration textbooks.
Results:
Microfracture, abrasion chondroplasty, osteochondral grafting, ACI, and autologous matrix-induced chondrogenesis are distinguishable by cell source (including chondrocytes and stem cells) and associated scaffolds (natural or synthetic, hydrogels or membranes). ACI seems to be as good as, if not better than, microfracture for repairing large chondral defects in a young patient's knee as evaluated by multiple clinical indices and the quality of regenerated tissue.
Conclusion:
Although there is not enough evidence to determine the best repair technique, ACI is the most established cell-based treatment for full-thickness chondral defects in young patients.
Microfracture, the standard of care, is recognized to be an incomplete solution for cartilage damage. BST-CarGel, a chitosan-based medical device, is mixed with autologous whole blood and is applied to a microfractured cartilage lesion in which it physically stabilizes the clot and guides and enhances marrow-derived repair. An international, multicenter, randomized controlled trial was conducted to evaluate BST-CarGel treatment compared with microfracture alone in the repair of cartilage lesions in the knee.
Eighty patients between the ages of eighteen and fifty-five years with a single, symptomatic focal lesion on the femoral condyles were randomized to BST-CarGel and microfracture treatment (n = 41) or microfracture treatment alone (n = 39). The primary end points of repair tissue quantity and quality at twelve months were assessed by quantitative three-dimensional magnetic resonance imaging measuring the degree of lesion filling and T2 relaxation time with use of standardized one and twelve-month posttreatment scans. The secondary end point at twelve months was clinical benefit determined with the Western Ontario and McMaster Universities Osteoarthritis Index. The tertiary end point was quality of life determined by the Short Form-36. Safety was assessed through the recording of adverse events.
Patient baseline characteristics were similar in the two groups, although baseline lesion areas were slightly larger on quantitative magnetic resonance imaging for the BST-CarGel group compared with the microfracture group. Blinded quantitative magnetic resonance imaging analysis demonstrated that, at twelve months, when compared with microfracture treatment alone, BST-CarGel treatment met both primary end points by achieving statistical superiority for greater lesion filling (p = 0.011) and more hyaline cartilage-like T2 values (p = 0.033). The lesion filling values were 92.8% ± 2.0% for the BST-CarGel treatment group and 85.2% ± 2.1% for the microfracture treatment group, and the mean T2 values were 70.5 ± 4.5 ms for the BST-CarGel treatment group and 85.0 ± 4.9 ms for the microfracture treatment group. Western Ontario and McMaster Universities Osteoarthritis Index subscales for pain, stiffness, and function yielded equivalent improvement for both groups at twelve months, which were significant (p < 0.0001) from baseline. Treatment safety profiles were considered comparable.
At twelve months, BST-CarGel treatment resulted in greater lesion filling and superior repair tissue quality compared with microfracture treatment alone. Clinical benefit was equivalent between groups at twelve months, and safety was similar.
Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
As medical advances lengthen average life expectancy, osteoarthritis (OA) will become a larger public health problem - not only because it is a manifestation of aging but also because it usually takes many years to reach clinical relevance. OA is already one of the ten most disabling diseases in industrialized countries. The huge financial burden emphasizes the acute need for new and more effective treatments for articular cartilage defects, especially since there are few disease modifying drugs or treatments for OA. There is no cure for OA and the management of OA is largely palliative, focusing on the alleviation of symptoms. Recent longitudinal non-controlled trials suggest that autologous chondrocyte transplantation techniques, which are indicated for young people with traumatic cartilage defects, could also be used in degenerative defects of elderly people with OA. This report discusses this therapeutic opportunity in view of some recently published data.
To update the EULAR recommendations for management of knee osteoarthritis (OA) by an evidence based medicine and expert opinion approach.
The literature search and guidelines were restricted to treatments for knee OA pertaining to clinical and/or radiological OA of any compartment of the knee. Papers for combined treatment of knee and other types of OA were excluded. Medline and Embase were searched using a combination of subject headings and key words. Searches for those treatments previously investigated were conducted for January 1999 to February 2002 and for those treatments not previously investigated for 1966 to February 2002. The level of evidence found for each treatment was documented. Quality scores were determined for each paper, an effect size comparing the treatment with placebo was calculated, where possible, and a toxicity profile was determined for each treatment modality.
497 new publications were identified by the search. Of these, 103 were intervention trials and included in the overall analysis, and 33 treatment modalities were identified. Previously identified publications which were not exclusively knee OA in the initial analysis were rejected. In total, 545 publications were included. Based on the results of the literature search and expert opinion, 10 recommendations for the treatment of knee OA were devised using a five stage Delphi technique. Based on expert opinion, a further set of 10 items was identified by a five stage Delphi technique as important for future research.
The updated recommendations support some of the previous propositions published in 2000 but also include modified statements and new propositions. Although a large number of treatment options for knee OA exist, the evidence based format of the EULAR Recommendations continues to identify key clinical questions that currently are unanswered.
Providing a controllable and definable three-dimensional (3D) microenvironment for chondrogenic differentiation of mesenchymal stem cells (MSCs) remains a great challenge for cartilage tissue engineering. In this work, poly (N-isopropylacrylamide) (PNIPAAm) polymers with the degrees of polymerization of 100 and 400 (NI100 and NI400) were prepared and the polymer solutions were introduced into the pre-prepared chitosan porous scaffolds (CS) to form hybrids (CSNI100 and CSNI400, respectively). SEM images indicated that the PNIPAAm gel partially occupied chitosan pores while the interconnected porous structure of chitosan was preserved. MSCs were incorporated within the hybrid and cell proliferation and chondrogenic differentiation were monitored. After seven-day incubation of the cell-laden constructs in a growth medium, the cell viability in CSNI100 and CSNI400 were 54% and 108% higher than that in CS alone, respectively. Glycosaminoglycan and total collagen contents increased 2.6 and 2.5 folds after 28-day culture of cell-laden CSNI400 in the chondrogenic medium. These results suggest that the hybrid structure composed of the chitosan porous scaffold and the well-defined PNIPAAm hydrogel, in particular CSNI400, is suitable for 3D stem cell culture and cartilage tissue engineering. This article is protected by copyright. All rights reserved.
Critical-sized bone defects treated with biomaterials offer an efficient alternative to traditional methods involving surgical reconstruction, allografts, and metal implants. Chitosan, a natural biopolymer is widely studied for bone regeneration applications owing to its tunable chemical and biological properties. However, the potential of chitosan to repair bone defects is limited due to its water insolubility, faster in vivo depolymerization, hemo-incompatibility, and weak antimicrobial property. Functionalization of chitosan structure through various chemical modifications provides a solution to these limitations. In this review, current trends of using chitosan as a composite with other polymers and ceramics, and its modifications such as quaternization, carboxyalkylation, hydroxylation, phosphorylation, sulfation and copolymerization in bone tissue engineering are elaborated.
Unlabelled:
Dual drug delivery of drugs with different therapeutic effects in a single system is an effective way to treat a disease. One of the main challenges in dual drug delivery is to control the release behavior of each drug independently. In this study, we devised thermo-responsive polymeric nanospheres that can provide simultaneous and independent dual drug delivery in the response to temperature change. The nanospheres based on chitosan oligosaccharide conjugated pluronic F127 grafting carboxyl group were synthesized to deliver kartogenin (KGN) and diclofenac (DCF) in a single system. To achieve the dual drug release, KGN was covalently cross-linked to the outer part of the nanosphere, and DCF was loaded into the inner core of the nanosphere. The nanospheres demonstrated immediate release of DCF and sustained release of KGN, which were independently controlled by temperature change. The nanospheres treated with cold temperature effectively suppressed lipopolysaccharide-induced inflammation in chondrocytes and macrophage-like cells. The nanospheres also induced chondrogenic differentiation of mesenchymal stem cells, which was further enhanced by cold shock treatment. Bioluminescence of the fluorescence-labeled nanospheres was significantly increased after cold treatment in vivo. The nanospheres suppressed the progression of osteoarthritis in treated rats, which was further enhanced by cold treatment. The nanospheres also reduced cyclooxygenase-2 expression in the serum and synovial membrane of treated rats, which were further decreased with cold treatment. These results suggest that the thermo-responsive nanospheres provide dual-function therapeutics possessing anti-inflammatory and chondroprotective effects which can be enhanced by cold treatment.
Statement of significance:
We developed thermo-responsive nanospheres that can provide a useful dual-function of suppressing the inflammation and promoting chondrogenesis in the treatment of osteoarthritis. For a dual delivery system to be effective, the release behavior of each drug should be independently controlled to optimize their desired therapeutic effects. We employed rapid release of diclofenac for acute anti-inflammatory effects, and sustained release of kartogenin, a newly found molecule, for chondrogenic effects in this polymeric nanospheres. This nanosphere demonstrated immediate release of diclofenac and sustained release of kartogenin, which were independently controlled by temperature change. The effectiveness of this system to subside inflammation and regenerate cartilage in osteoarthritis was successful demonstrated through in vitro and in vivo experiments in this study. We think that this study will add a new concept to current body of knowledge in the field of drug delivery and treatment of osteoarthritis.
Silk fibroin/chitosan blend has been reported to be an attractive biomaterial that provides a 3D porous structure with controllable pore size and mechanical property suitable for tissue engineering applications. However there is no systematic study for optimizing the ratio of silk fibroin(SF) and chitosan (CS) which seems to influence the scaffold property to a great extent. The present research, therefore, investigates the effect of blend ratio of SF and CS on scaffold property and establish the optimum value of blend ratio. Among the various blends, the scaffolds with blend ratio of SF/CS(80:20) was found to be superior. The scaffold possesses pore size in the range 71-210 μm and porosity of 82.2 ± 1.3%. The compressive strength of the scaffold was measured as 190 ±0.2 kPa. The cell supportive property of the scaffold in terms of cell attachment, cell viability and proliferation was confirmed by cell culture study using mesenchymal stem cells derived from umbilical cord blood. Furthermore, the assessment of glycosaminoglycan (GAG) secretion on the scaffolds indicates its potentiality towards cartilage tissue regeneration.
Osteoarthritis (OA) is a degenerative disorder of the joint, principally occurring during aging, and characterized by a focal degradation of cartilage. It is the most prevalent rheumatic disease in industrialized countries and represents the second cause of disability in France. However, the etiology of OA remains unclear. There is only one cell type found in cartilage, chondrocyte, which is responsible for its repair and the synthesis of the elements of the extra-cellular matrix. A dysfunction of these cells results in an imbalance between repair and degradation in cartilage, leading to its destruction. Recently, a link between OA and metabolic syndrome (MetS) has been suggested, introducing a notion of metabolic OA, and a new vision of the disease. MetS is characterized by a cluster of factors (insulin resistance, hypertension, dyslipidemia, visceral obesity), although there is still no clear definition of it. During the 20(th) century, MetS dramatically increased with changes in population lifestyle, becoming a major health issue in industrialized countries. MetS concerns 10 to 30% of the worldwide population, but is prevalent in 59% of OA patients. Patients with both OA and MetS have more severe symptoms, occurring sooner than in the general population. Indeed, OA is generally a disease concerning the population over 65 years old, but with an associated MetS the target population is around 50 years old. In this review, we will focus on common factors in OA and MetS, such as hypertension, obesity, dyslipidemia, mitochondrial dysfunction and hyperglycemia, linking one disease to the other.
Articular cartilage has a limited healing capacity that complicates the treatment of joint injuries and osteoarthritis. Newer repair strategies have focused on the use of cells and biomaterials to promote cartilage regeneration. In the present study, we developed and characterized bioinspired materials designed to mimic the composition of the cartilage extracellular matrix. Chondroitin sulfate (CS) and chitosan (CH) were used to form physically cross-linked macromolecular polyelectrolyte complexes (PEC) without the use of additional crosslinkers. A single-step water-in-oil emulsification process was used to either directly embed mesenchymal stem cells (MSC) in PEC particles created with a various concentrations of CS and CH, or to co-embed MSC with PEC in agarose-based microbeads. Direct embedding of MSC in PEC resulted in high cell viability but irregular and large particles. Co-embedding of PEC particles with MSC in agarose (Ag) resulted in uniform microbeads 80-90 μm in diameter that maintained high cell viability over three weeks in culture. Increased serum content resulted in more uniform PEC distribution within the microbead matrix, and both high and low CS:CH ratios resulted in more homogeneous microbeads than 1:1 formulations. Under chondrogenic conditions, expression of sulfated GAG and collagen Type II was increased in 10:1 CS:CH PEC-Ag microbeads compared to pure Ag beads, indicating a chondrogenic influence of the PEC component. Such PEC-Ag microbeads may have utility in the directed differentiation and delivery of progenitor cell populations for cartilage repair.
Analgesics, including opioids, steroidal and nonsteroidal anti-inflammatory drugs, aspirin, acetaminophen, antiepileptics, and serotonin-norepinephrine reuptake inhibitors, are medications commonly used to treat many forms of pain. However, all of these agents may have significant adverse side effects. Adverse effects may occasionally be inseparable from desired effects. Side effects are often dose dependent and time dependent. It is critical that the prescribing practitioner and the dispensing pharmacist provide a thorough, understandable review of the potential side effects to all patients before these drugs are administered. Proper monitoring and follow-up during therapy are crucial.
To develop concise, up-to-date, patient-focused, evidence-based, expert consensus guidelines for the management of knee osteoarthritis, intended to inform patients, physicians, and allied health care professionals worldwide.
Thirteen experts from relevant medical disciplines (primary care, rheumatology, orthopedics, physical therapy, physical medicine and rehabilitation, and evidence-based medicine), three continents and ten countries (USA, UK, France, Netherlands, Belgium, Sweden, Denmark, Australia, Japan, and Canada) and a patient representative comprised the Osteoarthritis Guidelines Development Group (OAGDG). Based on previous OA guidelines and a systematic review of the osteoarthritis (OA) literature, twenty-nine treatment modalities were considered for recommendation. Evidence published subsequent to the 2010 OARSI guidelines was based on a systematic review conducted by the OARSI evidence team at Tufts Medical Center, Boston, USA. Medline, EMBASE, Google Scholar, Web of Science, and the Cochrane Central Register of Controlled Trials were initially searched in first quarter 2012 and last searched in March 2013. Included evidence was assessed for quality using AMSTAR criteria, and published criticism of included evidence was also considered. To provide recommendations for individuals with a range of health profiles and OA burden, treatment recommendations were stratified into four clinical subphenotypes. Consensus recommendations were produced using the Rand/UCLA Appropriateness method and Delphi voting process. Treatments were recommended as Appropriate, Uncertain, or Not Appropriate, for each of four clinical subphenotypes and accompanied by 1-10 risk and benefit scores.
Appropriate treatment modalities for all individuals with knee OA included biomechanical interventions, intra-articular corticosteroids, exercise (land-based and water-based), self-management and education, strength training, and weight management. Treatments appropriate for specific clinical subphenotypes included acetaminophen (paracetamol), balneotherapy, capsaicin, cane (walking stick), duloxetine, oral NSAIDs (COX-2 selective and non-selective), and topical NSAIDs. Treatments of uncertain appropriateness for specific clinical subphenotypes included acupuncture, avocado soybean unsaponfiables, chondroitin, crutches, diacerein, glucosamine, intra-articular hyaluronic acid, opioids (oral and transdermal), rosehip, transcutaneous electrical nerve stimulation, and ultrasound. Treatments voted not appropriate included risedronate and electrotherapy (neuromuscular electrical stimulation).
These evidence-based consensus recommendations provide guidance to patients and practitioners on treatments applicable to all individuals with knee OA, as well as therapies that can be considered according to individualized patient needs and preferences.
Purpose
Although a number of osteoarthritis (OA) management guidelines exist, uptake has been suboptimal. Our aim was to review and critically evaluate existing OA management guidelines to better understand potential issues and barriers.
Methods
A systematic review of the literature in MEDLINE published from January 1, 2000 to April 1, 2013 was performed and supplemented by bibliographic reviews, following PRISMA guidelines and a written protocol. Following initial title and abstract screening, 2 authors independently reviewed full text articles; a third settled disagreements. Two independent reviewers extracted data into a standardized form. Two authors independently assessed guideline quality using the AGREE II instrument; 3 generated summary recommendations based on the extracted guideline data.
Results
Sixteen articles were included in the final review. There was broad agreement on recommendations by the various organizations. For non-pharmacologic modalities, education/self-management, exercise, weight loss if overweight, walking aids as indicated, and thermal modalities were widely recommended. For appropriate patients, joint replacement was recommended; arthroscopy with debridement was not recommended for symptomatic knee OA. Pharmacologic modalities most recommended included acetaminophen/paracetamol (1st line) and NSAIDs (topical or oral, 2nd line). Intra-articular corticosteroids were generally recommended for hip and knee OA. Controversy remains about the use of acupuncture, knee braces, heel wedges, intra-articular hyaluronans, and glucosamine/chondroitin.
Conclusions
The relative agreement on many OA management recommendations across organizations indicates a problem with dissemination and implementation rather than a lack of quality guidelines. Future efforts should focus on optimizing implementation in primary care settings, where the majority of OA care occurs.
Objective:
This study aimed to evaluate the structural benefit of a new biomaterial composed of alginate-chitosan (AC) beads dispersed in a hydrogel (H) derived from chitosan on the development of osteoarthritis (OA) in rabbit.
Design:
OA was induced by the surgical transection of the anterior cruciate ligament in rabbits. Animals received a single intra-articular injection (900 μl) of AC beads in H hydrogel, H hydrogel alone or saline a week after surgery. OA development was followed by X-rays. Blood samples were collected throughout the study to measure biological markers (Prostaglandins E2 - PGE2 and C reactive protein - CRP). Macroscopic observation and histological evaluation of articular cartilage and synovial membrane were performed 6 weeks after surgery.
Results:
AC beads in H hydrogel prevented from the development of OA based on the reduction of the Kellgren & Lawrence (K&L) score. It also significantly reduced the histological score of cartilage lesion severity. This effect was homogenous on every joint compartment. It was due to a significant effect on cartilage structure and cellularity scores. The injection of AC beads in H hydrogel also tended to reduce the synovial membrane inflammation. No significant variation of biological markers was noted.
Conclusions:
The present pilot study provides interesting and promising results for the use of AC beads in H hydrogel in animal. It indeed prevented the development of OA cartilage lesions without inflammatory signs. The potencies of this biomaterial to protect OA joint should be further documented. It could then represent a new alternative for viscosupplementation in human OA management.
Epidemiologic and clinical research in osteoarthritis (OA) continues to focus on analytic and descriptive epidemiology, and the role of both nonpharmacologic and pharmacologic therapies in the management of OA, respectively. A systematic literature review was conducted using PubMed for the period between September 1, 2011 and March 31, 2012. Selected articles in these areas are discussed in this narrative review article.
Rabbit bone marrow-derived mesenchymal stem cells (MSCs) were stably transfected with the TGF-β1 gene in monolayer culture using Lipofectamine 2000. After transfection, the expression of cartilage-specific extracellular matrix was upregulated, whereas matrix metalloproteinases 1 and 3 (MMP 1 and 3) protein expressions and enzymatic activities were downregulated. Autologous MSCs modified with the TGF-β1 gene were seeded into chitosan scaffolds to construct gene-modified cartilage, which was then implanted into the full-thickness articular cartilage defects of rabbits’ knees. Twelve weeks after implantation, the defects were filled with regenerated hyaline-like cartilage tissue as confirmed by the positive immunohistochemical staining of collagen type II and intense toluidine blue staining of proteoglycan. Our findings suggest that the repair of cartilage defects can be enhanced by TGF-β1 gene-modified-tissue engineering of cartilage on the basis of a strategy using MSCs, chitosan, and liposomal transfection.
Despite over two decades of research on cartilage tissue engineering, very few products have moved from bench to bedside and effective therapy remains lacking. This review discusses recent progress in developing novel strategies for engineering cartilage tissues with long-term functionality. Specifically we focus on the following aspects including identifying promising cell sources, designing 3D scaffolds with dynamic and spatially patterned cues to guide desired cellular processes, mimicking zonal organization, integrating with host tissue, and monitoring cell fate and tissue regeneration in situ.
Symptomatic articular cartilage lesions have gained attention and clinical interest in recent years and can be difficult to treat. Historically, various biologic surgical treatment options have yielded inconsistent results because of the inferior biomechanical properties associated with a variable healing response. Improving technology and surgical advances has generated considerable research in cartilage resurfacing and optimizing hyaline tissue restoration. Biologic innovation and tissue engineering in cartilage repair have used matrix scaffolds, autologous and allogenic chondrocytes, cartilage grafts, growth factors, stem cells, and genetic engineering. Numerous evolving technologies and surgical approaches have been introduced into the clinical setting. This review will discuss the basic science, surgical techniques, and clinical outcomes of novel synthetic materials and scaffolds for articular cartilage repair.
The aim of this work is to study the effects of chitosan on rat knee cartilages. 0.2 ml of 0.1% chitosan solution pH = 6.9 were injected inside rat knees articular cavity. One, three and six weeks after injection, histological and histomorphometric studies were performed on undecalcified samples embedded in polymethylmetacrylate. Results show that after 1 and 6 weeks: (i) chitosan slows significantly (P < 0.005) the decrease in epiphyseal cartilage thicknesses and (ii) increases significantly articular cartilage chondrocyte densities (P < 0.002). However chitosan solution induces a proliferation of fibrous tissue with abundant fibroblasts, fibrocytes and monocytes inside the joint and this proliferation is still present after 6 weeks. This study suggests that chitosan could act on the growth of epiphyseal cartilage and wound healing of articular cartilage.
To review the basic scientific status of repair in articular cartilage tissue and to assess the efficiency of current clinical therapies instigated for the treatment of structural lesions generated therein as a result of trauma or during the course of various diseases, notably osteoarthritis (OA). Current scientific trends and possible directions for the future will also be discussed.
A systematic and critical analysis is undertaken, beginning with a description of the spontaneous repair responses in different types of lesion. Surgical interventions aimed at inducing repair without the use of active biologics will then be considered, followed by those involving active biologics and those drawing on autogenic and allogeneic tissue transplantation principles. Cell transplantation approaches, in particular novel tissue engineering concepts, will be critically presented. These will include growth-factor-based biological treatments and gene transfection protocols. A number of technical problems associated with repair interventions, such as tissue integration, tissue retention and the role of mechanical factors, will also be analysed.
A critical analysis of the literature reveals the existence of many novel and very promising biologically-based approaches for the induction of articular cartilage repair, the vast majority of which are still at an experimental phase of development. But prospective, double-blinded clinical trials comparing currently practiced surgical treatments have, unfortunately, not been undertaken.
The existence of many new and encouraging biological approaches to cartilage repair justifies the future investment of time and money in this research area, particularly given the extremely high socio-economic importance of such therapeutic strategies in the prevention and treatment of these common joint diseases and traumas. Clinical epidemiological and prospective trials are, moreover, urgently needed for an objective, scientific appraisal of current therapies and future novel approaches.
To develop concise, patient-focussed, up to date, evidence-based, expert consensus recommendations for the management of hip and knee osteoarthritis (OA), which are adaptable and designed to assist physicians and allied health care professionals in general and specialist practise throughout the world.
Sixteen experts from four medical disciplines (primary care, rheumatology, orthopaedics and evidence-based medicine), two continents and six countries (USA, UK, France, Netherlands, Sweden and Canada) formed the guidelines development team. A systematic review of existing guidelines for the management of hip and knee OA published between 1945 and January 2006 was undertaken using the validated appraisal of guidelines research and evaluation (AGREE) instrument. A core set of management modalities was generated based on the agreement between guidelines. Evidence before 2002 was based on a systematic review conducted by European League Against Rheumatism and evidence after 2002 was updated using MEDLINE, EMBASE, CINAHL, AMED, the Cochrane Library and HTA reports. The quality of evidence was evaluated, and where possible, effect size (ES), number needed to treat, relative risk or odds ratio and cost per quality-adjusted life years gained were estimated. Consensus recommendations were produced following a Delphi exercise and the strength of recommendation (SOR) for propositions relating to each modality was determined using a visual analogue scale.
Twenty-three treatment guidelines for the management of hip and knee OA were identified from the literature search, including six opinion-based, five evidence-based and 12 based on both expert opinion and research evidence. Twenty out of 51 treatment modalities addressed by these guidelines were universally recommended. ES for pain relief varied from treatment to treatment. Overall there was no statistically significant difference between non-pharmacological therapies [0.25, 95% confidence interval (CI) 0.16, 0.34] and pharmacological therapies (ES=0.39, 95% CI 0.31, 0.47). Following feedback from Osteoarthritis Research International members on the draft guidelines and six Delphi rounds consensus was reached on 25 carefully worded recommendations. Optimal management of patients with OA hip or knee requires a combination of non-pharmacological and pharmacological modalities of therapy. Recommendations cover the use of 12 non-pharmacological modalities: education and self-management, regular telephone contact, referral to a physical therapist, aerobic, muscle strengthening and water-based exercises, weight reduction, walking aids, knee braces, footwear and insoles, thermal modalities, transcutaneous electrical nerve stimulation and acupuncture. Eight recommendations cover pharmacological modalities of treatment including acetaminophen, cyclooxygenase-2 (COX-2) non-selective and selective oral non-steroidal anti-inflammatory drugs (NSAIDs), topical NSAIDs and capsaicin, intra-articular injections of corticosteroids and hyaluronates, glucosamine and/or chondroitin sulphate for symptom relief; glucosamine sulphate, chondroitin sulphate and diacerein for possible structure-modifying effects and the use of opioid analgesics for the treatment of refractory pain. There are recommendations covering five surgical modalities: total joint replacements, unicompartmental knee replacement, osteotomy and joint preserving surgical procedures; joint lavage and arthroscopic debridement in knee OA, and joint fusion as a salvage procedure when joint replacement had failed. Strengths of recommendation and 95% CIs are provided.
Twenty-five carefully worded recommendations have been generated based on a critical appraisal of existing guidelines, a systematic review of research evidence and the consensus opinions of an international, multidisciplinary group of experts. The recommendations may be adapted for use in different countries or regions according to the availability of treatment modalities and SOR for each modality of therapy. These recommendations will be revised regularly following systematic review of new research evidence as this becomes available.
Chitosan supports the expression of extracellular matrix proteins in human osteoblasts and chondrocytes
- Lahiji
A. Lahiji, A. Sohrabi, D.S. Hungerford and C.G. Frondoza, Chitosan supports the expression of extracellular matrix proteins in human osteoblasts and chondrocytes, J. Biomed. Mater. Res. 51 (2000), 586-595. doi:10.1002/1097-4636(20000915)51:4<586::AID-JBM6>3.0.CO;2-S.
Physical properties imparted by genipin to chitosan for tissue regeneration with human stem cells: A review
- Muzzarelli
R.A. Muzzarelli, M. El Mehtedi, C. Bottegoni and A. Gigante, Physical properties imparted by genipin to chitosan for tissue regeneration with human stem cells: A review, Int. J. Biol. Macromol. 93 (2016), 1366-1381. doi:10.1016/j.ijbiomac.
2016.03.075.