Hydroxyapatite/alginate/gellan gum inks with osteoconduction and osteogenic potential for bioprinting bone tissue analogues.

There is a growing demand for engineered bone tissues custom-designed to match the patient-specific defect size and in vitro models for studying bone diseases and/or drug screening. Herein, we propose a bioprinted bone tissue construct using SaOs-2 cells within alginate/gellan gum/hydroxyapatite inks. Different ink formulations were developed with varying hydroxyapatite content and then evaluated for viscoelasticity, printability, biomineralization properties, post-printing viability, proliferation, metabolic activity, and osteogenic phenotype of SaOs-2-encapsulated cells. Results indicate that ink formulations exhibit non-Newtonian shear-thinning behaviour, maintaining shape integrity and structural stability post-printing. Ink mineralization rates increase with the hydroxyapatite content, rendering them suitable for bone defect strategies. Post-printed cells in the developed constructs remain live, spreading, and metabolically active but do not proliferate. Osteogenic gene and protein expression, both early and late, show upregulation at day 7 relative to day 1, followed by downregulation at day 14. Lower hydroxyapatite content inks demonstrate up to fourfold upregulation in genes and proteins at most time points. Additionally, these constructs release calcium and phosphate at levels conducive to mineralization. Overall, the tissue-engineered miniaturized constructs not only meet the criteria for early-stage bone defect/fracture regeneration but also serve as a promising platform for drug screening and evaluating potential therapeutic treatments.

Inconsistency in Shoulder Arthrometers for Measuring Glenohumeral Joint Laxity: A Systematic Review.

There is no consensus on how to measure shoulder joint laxity and results reported in the literature are not well systematized for the available shoulder arthrometer devices. This systematic review aims to summarize the results of currently available shoulder arthrometers for measuring glenohumeral laxity in individuals with healthy or injured shoulders. Searches were conducted on the PubMed, EMBASE, and Web of Science databases to identify studies that measure glenohumeral laxity with arthrometer-assisted assessment. The mean and standard deviations of the laxity measurement from each study were compared based on the type of population and arthrometer used. Data were organized according to the testing characteristics. A total of 23 studies were included and comprised 1162 shoulders. Populations were divided into 401 healthy individuals, 278 athletes with asymptomatic shoulder, and 134 individuals with symptomatic shoulder. Sensors were the most used method for measuring glenohumeral laxity and stiffness. Most arthrometers applied an external force to the humeral head or superior humerus by a manual-assisted mechanism. Glenohumeral laxity and stiffness were mostly assessed in the sagittal plane. There is substantial heterogeneity in glenohumeral laxity values that is mostly related to the arthrometer used and the testing conditions. This variability can lead to inconsistent results and influence the diagnosis and treatment decision-making.

Cutting-edge advances in modeling the blood-brain barrier and tools for its reversible permeabilization for enhanced drug delivery into the brain.

The blood-brain barrier (BBB) is a sophisticated structure whose full functionality is required for maintaining the executive functions of the central nervous system (CNS). Tight control of transport across the barrier means that most drugs, particularly large size, which includes powerful biologicals, cannot reach their targets in the brain. Notwithstanding the remarkable advances in characterizing the cellular nature of the BBB and consequences of BBB dysfunction in pathology (brain metastasis, neurological diseases), it remains challenging to deliver drugs to the CNS. Herein, we outline the basic architecture and key molecular constituents of the BBB. In addition, we review the current status of approaches that are being explored to temporarily open the BBB in order to allow accumulation of therapeutics in the CNS. Undoubtedly, the major concern in field is whether it is possible to open the BBB in a meaningful way without causing negative consequences. In this context, we have also listed few other important key considerations that can improve our understanding about the dynamics of the BBB.

Childhood Brain Tumors: A Review of Strategies to Translate CNS Drug Delivery to Clinical Trials.

Brain and spinal tumors affect 1 in 1000 people by 25 years of age, and have diverse histological, biological, anatomical and dissemination characteristics. A mortality of 30-40% means the majority are cured, although two-thirds have life-long disability, linked to accumulated brain injury that is acquired prior to diagnosis, and after surgery or chemo-radiotherapy. Only four drugs have been licensed globally for brain tumors in 40 years and only one for children. Most new cancer drugs in clinical trials do not cross the blood-brain barrier (BBB). Techniques to enhance brain tumor drug delivery are explored in this review, and cover those that augment penetration of the BBB, and those that bypass the BBB. Developing appropriate delivery techniques could improve patient outcomes by ensuring efficacious drug exposure to tumors (including those that are drug-resistant), reducing systemic toxicities and targeting leptomeningeal metastases. Together, this drug delivery strategy seeks to enhance the efficacy of new drugs and enable re-evaluation of existing drugs that might have previously failed because of inadequate delivery. A literature review of repurposed drugs is reported, and a range of preclinical brain tumor models available for translational development are explored.

Electroconductive PEDOT nanoparticle integrated scaffolds for spinal cord tissue repair.

BACKGROUND: Hostile environment around the lesion site following spinal cord injury (SCI) prevents the re-establishment of neuronal tracks, thus significantly limiting the regenerative capability. Electroconductive scaffolds are emerging as a promising option for SCI repair, though currently available conductive polymers such as polymer poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) present poor biofunctionality and biocompatibility, thus limiting their effective use in SCI tissue engineering (TE) treatment strategies. METHODS: PEDOT NPs were synthesized via chemical oxidation polymerization in miniemulsion. The conductive PEDOT NPs were incorporated with gelatin and hyaluronic acid (HA) to create gel:HA:PEDOT-NPs scaffolds. Morphological analysis of both PEDOT NPs and scaffolds was conducted via SEM. Further characterisation included dielectric constant and permittivity variances mapped against morphological changes after crosslinking, Young's modulus, FTIR, DLS, swelling studies, rheology, in-vitro, and in-vivo biocompatibility studies were also conducted. RESULTS: Incorporation of PEDOT NPs increased the conductivity of scaffolds to 8.3 × 10-4 ± 8.1 × 10-5 S/cm. The compressive modulus of the scaffold was tailored to match the native spinal cord at 1.2 ± 0.2 MPa, along with controlled porosity. Rheological studies of the hydrogel showed excellent 3D shear-thinning printing capabilities and shape fidelity post-printing. In-vitro studies showed the scaffolds are cytocompatible and an in-vivo assessment in a rat SCI lesion model shows glial fibrillary acidic protein (GFAP) upregulation not directly in contact with the lesion/implantation site, with diminished astrocyte reactivity. Decreased levels of macrophage and microglia reactivity at the implant site is also observed. This positively influences the re-establishment of signals and initiation of healing mechanisms. Observation of axon migration towards the scaffold can be attributed to immunomodulatory properties of HA in the scaffold caused by a controlled inflammatory response. HA limits astrocyte activation through its CD44 receptors and therefore limits scar formation. This allows for a superior axonal migration and growth towards the targeted implantation site through the provision of a stimulating microenvironment for regeneration. CONCLUSIONS: Based on these results, the incorporation of PEDOT NPs into Gel:HA biomaterial scaffolds enhances not only the conductive capabilities of the material, but also the provision of a healing environment around lesions in SCI. Hence, gel:HA:PEDOT-NPs scaffolds are a promising TE option for stimulating regeneration for SCI.

Translation through collaboration: practice applied in BAMOS project in in vivo testing of innovative osteochondral scaffolds.

Osteoarthritis is the most common chronic degenerative joint disease, recognized by the World Health Organization as a public health problem that affects millions of people worldwide. The project Biomaterials and Additive Manufacturing: Osteochondral Scaffold (BAMOS) innovation applied to osteoarthritis, funded under the frame of the Horizon 2020 Research and Innovation Staff Exchanges (RISE) program, aims to delay or avoid the use of joint replacements by developing novel cost-effective osteochondral scaffold technology for early intervention of osteoarthritis. The multidisciplinary consortium of BAMOS, formed by international leading research centres, collaborates through research and innovation staff exchanges. The project covers all the stages of the development before the clinical trials: design of scaffolds, biomaterials development, processability under additive manufacturing, in vitro test, and in vivo test. This paper reports the translational practice adopted in the project in in vivo assessment of the osteochondral scaffolds developed.

Engineering Hydrogels for Modulation of Material-Cell Interactions.

Hydrogels are a recurrent platform for Tissue Engineering (TE) strategies. Their versatility and the variety of available methods for tuning their properties highly contribute to hydrogels' success. As a result, the design of advanced hydrogels has been thoroughly studied, in the quest for better solutions not only for drugs- and cell-based therapies but also for more fundamental studies. The wide variety of sources, crosslinking strategies, and functionalization methods, and mostly the resemblance of hydrogels to the natural extracellular matrix, makes these three dimensional hydrated structures an excellent tool for TE approaches. The state-of-the-art information regarding hydrogel design, processing methods, and the influence of different hydrogel formulations on the final cell-biomaterial interactions are overviewed herein.

Methacrylated Gellan Gum/Poly-l-lysine Polyelectrolyte Complex Beads for Cell-Based Therapies.

Cell encapsulation strategies using hydrogel beads have been considered as an alternative to immunosuppression in cell-based therapies. They rely on layer-by-layer (LbL) deposition of polymers to tune beads' permeability, creating a physical barrier to the host immune system. However, the LbL approach can also create diffusion barriers, hampering the flow of essential nutrients and therapeutic cell products. In this work, the polyelectrolyte complex (PEC) methodology was used to circumvent the drawbacks of the LbL strategy by inducing hydrogel bead formation through the interaction of anionic methacrylated gellan gum (GG-MA) with cationic poly-l-lysine (PLL). The interfacial complexation between both polymers resulted in beads with a cell-friendly GG-MA hydrogel core surrounded by a PEC semipermeable membrane. The beads showed great in vitro stability over time, a semi-permeable behavior, and supported human adipose-derived stem cell encapsulation. Additionally, and regarding immune recognition, the in vitro and in vivo studies pointed out that the hydrogel beads behave as an immunocompatible system. Overall, the engineered beads showed great potential for hydrogel-mediated cell therapies, when immunoprotection is required, as when treating different metabolic disorders.

Engineering bioinks for 3D bioprinting.

In recent years, three-dimensional (3D) bioprinting has attracted wide research interest in biomedical engineering and clinical applications. This technology allows for unparalleled architecture control, adaptability and repeatability that can overcome the limits of conventional biofabrication techniques. Along with the emergence of a variety of 3D bioprinting methods, bioinks have also come a long way. From their first developments to support bioprinting requirements, they are now engineered to specific injury sites requirements to mimic native tissue characteristics and to support biofunctionality. Current strategies involve the use of bioinks loaded with cells and biomolecules of interest, without altering their functions, to deliverin situthe elements required to enhance healing/regeneration. The current research and trends in bioink development for 3D bioprinting purposes is overviewed herein.

Cartilage Restoration of Patellofemoral Lesions: A Systematic Review.

PURPOSE: This study aimed to systematically analyze the postoperative clinical, functional, and imaging outcomes, complications, reoperations, and failures following patellofemoral cartilage restoration surgery. METHODS: This review was conducted according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PubMed, EMBASE, and Cochrane Library databases were searched up to August 31, 2018, to identify clinical studies that assessed surgical outcomes of patellofemoral cartilage restoration surgery. The Methodological Index for Non-Randomized Studies (MINORS) was used to assess study quality. RESULTS: Forty-two studies were included comprising 1,311 knees (mean age of 33.7 years and 56% males) and 1,309 patellofemoral defects (891 patella, 254 trochlear, 95 bipolar, and 69 multiple defects, including the patella or trochlea) at a mean follow-up of 59.2 months. Restoration techniques included autologous chondrocyte implantation (56%), particulated juvenile allograft cartilage (12%), autologous matrix-induced chondrogenesis (9%), osteochondral autologous transplantation (9%), and osteochondral allograft transplantation (7%). Significant improvement in at least one score was present in almost all studies and these surpassed the minimal clinically important difference threshold. There was a weighted 19%, 35%, and 6% rate of reported complications, reoperations, and failures, respectively. Concomitant patellofemoral surgery (51% of patients) mostly did not lead to statistically different postoperative outcomes. CONCLUSION: Numerous patellofemoral restoration techniques result in significant functional improvement with a low rate of failure. No definitive conclusions could be made to determine the best surgical technique since comparative studies on this topic are rare, and treatment choice should be made according to specific patient and defect characteristics. LEVEL OF EVIDENCE: Level IV, systematic review of level II to IV studies.

Advances in 3D neural, vascular and neurovascular models for drug testing and regenerative medicine.

Clinical trials continue to fall short regarding drugs to effectively treat brain-affecting diseases. Although there are many causes of these shortcomings, the most relevant are the inability of most therapeutic agents to cross the blood-brain barrier (BBB) and the failure to translate effects from animal models to patients. In this review, we analyze the most recent developments in BBB, neural, and neurovascular models, analyzing their impact on the drug development process by considering their quantitative and phenotypical characterization. We offer a perspective of the state-of-the-art of the models that could revolutionize the pharmaceutical industry.

Marine collagen-chitosan-fucoidan cryogels as cell-laden biocomposites envisaging tissue engineering.

The combination of marine origin biopolymers for tissue engineering (TE) applications is of high interest, due to their similarities with the proteins and polysaccharides present in the extracellular matrix of different human tissues. This manuscript reports on innovative collagen-chitosan-fucoidan cryogels formed by the simultaneous blending of these three marine polymers in a chemical-free crosslinking approach. The physicochemical characterization of marine biopolymers comprised FTIR, amino acid analysis, circular dichroism and SDS-PAGE, and suggested that the jellyfish collagen used in the cryogels was not denatured (preserved the triple helical structure) and had similarities with type II collagen. The chitosan presented a high deacetylation degree (90.1%) that can strongly influence the polymer physicochemical properties and biomaterial formation. By its turn, rheology, and SEM studies confirmed that these novel cryogels present interesting properties for TE purposes, such as effective blending of biopolymers without visible material segregation, mechanical stability (strong viscoelastic character), as well as adequate porosity to support cell proliferation and exchange of nutrients and waste products. Additionally, in vitro cellular assessments of all cryogel formulations revealed a non-cytotoxic behavior. The MTS test, live/dead assay and cell morphology assessment (phalloidin DAPI) showed that cryogels can provide a proper microenvironment for cell culturing, supporting cell viability and promoting cell proliferation. Overall, the obtained results suggest that the novel collagen-chitosan-fucoidan cryogels herein presented are promising scaffolds envisaging tissue engineering purposes, as both acellular biomaterials or cell-laden cryogels.

Methacrylated gellan gum and hyaluronic acid hydrogel blends for image-guided neurointerventions.

Cell-based therapies delivered via intrathecal injection are considered as one of the most promising solutions for the treatment of amyotrophic lateral sclerosis (ALS). Herein, injectable manganese-based biocompatible hydrogel blends were developed, that can allow image-guided cell delivery. The hydrogels can also provide physical support for cells during injection, and at the intrathecal space after transplantation, while assuring cell survival. In this regard, different formulations of methacrylated gellan gum/hyaluronic acid hydrogel blends (GG-MA/HA) were considered as a vehicle for cell delivery. The hydrogels blends were supplemented with paramagnetic Mn2+ to allow a real-time monitorization of hydrogel deposition via T1-weighted magnetic resonance imaging (MRI). The developed hydrogels were easily extruded and formed a stable fiber upon injection into the cerebrospinal fluid. Hydrogels prepared with a 75 : 25 GG-MA to HA ratio supplemented with MnCl2 at 0.1 mM showed controlled hydrogel degradation, suitable permeability, and a distinct MRI signal in vitro and in vivo. Additionally, human-derived adipose stem cells encapsulated in 75 : 25 GG-MA/HA hydrogels remained viable for up to 14 days of culture in vitro. Therefore, the engineered hydrogels can be an excellent tool for injectable image-guided cell delivery approaches.

Osteochondral scaffolds for early treatment of cartilage defects in osteoarthritic joints: from bench to clinic.

Osteoarthritis is a degenerative joint disease, typified by the loss in the quality of cartilage and bone at the interface of a synovial joint, resulting in pain, stiffness and reduced mobility. The current surgical treatment for advanced stages of the disease is joint replacement, where the non-surgical therapeutic options or less invasive surgical treatments are no longer effective. These are major surgical procedures which have a substantial impact on patients' quality of life and lifetime risk of requiring revision surgery. Treatments using regenerative methods such as tissue engineering methods have been established and are promising for the early treatment of cartilage degeneration in osteoarthritis joints. In this approach, 3-dimensional scaffolds (with or without cells) are employed to provide support for tissue growth. However, none of the currently available tissue engineering and regenerative medicine products promotes satisfactory durable regeneration of large cartilage defects. Herein, we discuss the current regenerative treatment options for cartilage and osteochondral (cartilage and underlying subchondral bone) defects in the articulating joints. We further identify the main hurdles in osteochondral scaffold development for achieving satisfactory and durable regeneration of osteochondral tissues. The evolution of the osteochondral scaffolds - from monophasic to multiphasic constructs - is overviewed and the osteochondral scaffolds that have progressed to clinical trials are examined with respect to their clinical performances and their potential impact on the clinical practices. Development of an osteochondral scaffold which bridges the gap between small defect treatment and joint replacement is still a grand challenge. Such scaffold could be used for early treatment of cartilage and osteochondral defects at early stage of osteoarthritis and could either negate or delay the need for joint replacements.

Meniscal allograft transplants and new scaffolding techniques.

Clinical management of meniscal injuries has changed radically in recent years. We have moved from the model of systematic tissue removal (meniscectomy) to understanding the need to preserve the tissue.Based on the increased knowledge of the basic science of meniscal functions and their role in joint homeostasis, meniscus preservation and/or repair, whenever indicated and possible, are currently the guidelines for management.However, when repair is no longer possible or when facing the fact of the previous partial, subtotal or total loss of the meniscus, meniscus replacement has proved its clinical value. Nevertheless, meniscectomy remains amongst the most frequent orthopaedic procedures.Meniscus replacement is currently possible by means of meniscal allograft transplantation (MAT) which provides replacement of the whole meniscus with or without bone plugs/slots. Partial replacement has been achieved by means of meniscal scaffolds (mainly collagen or polyurethane-based). Despite the favourable clinical outcomes, it is still debatable whether MAT is capable of preventing progression to osteoarthritis. Moreover, current scaffolds have shown some fundamental limitations, such as the fact that the newly formed tissue may be different from the native fibrocartilage of the meniscus.Regenerative tissue engineering strategies have been used in an attempt to provide a new generation of meniscal implants, either for partial or total replacement. The goal is to provide biomaterials (acellular or cell-seeded constructs) which provide the biomechanical properties but also the biological features to replace the loss of native tissue. Moreover, these approaches include possibilities for patient-specific implants of correct size and shape, as well as advanced strategies combining cells, bioactive agents, hydrogels or gene therapy.Herein, the clinical evidence and tips concerning MAT, currently available meniscus scaffolds and future perspectives are discussed. Cite this article: EFORT Open Rev 2019;4 DOI: 10.1302/2058-5241.4.180103.

Scaffolding Strategies for Tissue Engineering and Regenerative Medicine Applications.

During the past two decades, tissue engineering and the regenerative medicine field have invested in the regeneration and reconstruction of pathologically altered tissues, such as cartilage, bone, skin, heart valves, nerves and tendons, and many others. The 3D structured scaffolds and hydrogels alone or combined with bioactive molecules or genes and cells are able to guide the development of functional engineered tissues, and provide mechanical support during in vivo implantation. Naturally derived and synthetic polymers, bioresorbable inorganic materials, and respective hybrids, and decellularized tissue have been considered as scaffolding biomaterials, owing to their boosted structural, mechanical, and biological properties. A diversity of biomaterials, current treatment strategies, and emergent technologies used for 3D scaffolds and hydrogel processing, and the tissue-specific considerations for scaffolding for Tissue engineering (TE) purposes are herein highlighted and discussed in depth. The newest procedures focusing on the 3D behavior and multi-cellular interactions of native tissues for further use for in vitro model processing are also outlined. Completed and ongoing preclinical research trials for TE applications using scaffolds and hydrogels, challenges, and future prospects of research in the regenerative medicine field are also presented.

Advances in bioinks and in vivo imaging of biomaterials for CNS applications.

Due to increasing life expectancy incidence of neurological disorders is rapidly rising, thus adding urgency to develop effective strategies for treatment. Stem cell-based therapies were considered highly promising and while progress in this field is evident, outcomes of clinical trials are rather disappointing. Suboptimal engraftment, poor cell survival and uncontrolled differentiation may be the reasons behind dismal results. Clearly, new direction is needed and we postulate that with recent progress in biomaterials and bioprinting, regenerative approaches for neurological applications may be finally successful. The use of biomaterials aids engraftment of stem cells, protects them from harmful microenvironment and importantly, it facilitates the incorporation of cell-supporting molecules. The biomaterials used in bioprinting (the bioinks) form a scaffold for embedding the cells/biomolecules of interest, but also could be exploited as a source of endogenous contrast or supplemented with contrast agents for imaging. Additionally, bioprinting enables patient-specific customization with shape/size tailored for actual needs. In stroke or traumatic brain injury for example lesions are localized and focal, and usually progress with significant loss of tissue volume creating space that could be filled with artificial tissue using bioprinting modalities. The value of imaging for bioprinting technology is advantageous on many levels including design of custom shapes scaffolds based on anatomical 3D scans, assessment of performance and integration after scaffold implantation, or to learn about the degradation over time. In this review, we focus on bioprinting technology describing different printing techniques and properties of biomaterials in the context of requirements for neurological applications. We also discuss the need for in vivo imaging of implanted materials and tissue constructs reviewing applicable imaging modalities and type of information they can provide. STATEMENT OF SIGNIFICANCE: Current stem cell-based regenerative strategies for neurological diseases are ineffective due to inaccurate engraftment, low cell viability and suboptimal differentiation. Bioprinting and embedding stem cells within biomaterials at high precision, including building complex multi-material and multi-cell type composites may bring a breakthrough in this field. We provide here comprehensive review of bioinks, bioprinting techniques applicable to application for neurological disorders. Appreciating importance of longitudinal monitoring of implanted scaffolds, we discuss advantages of various imaging modalities available and suitable for imaging biomaterials in the central nervous system. Our goal is to inspire new experimental approaches combining imaging, biomaterials/bioinks, advanced manufacturing and tissue engineering approaches, and stimulate interest in image-guided therapies based on bioprinting.

Tunable Enzymatically Cross-Linked Silk Fibroin Tubular Conduits for Guided Tissue Regeneration.

Hollow tubular conduits (TCs) with tunable architecture and biological properties are in great need for modulating cell functions and drug delivery in guided tissue regeneration. Here, a new methodology to produce enzymatically cross-linked silk fibroin TCs is described, which takes advantage of the tyrosine groups present in silk structure that are known to allow the formation of a covalently cross-linked hydrogel. Three different processing methods are used as a final step to modulate the properties of the silk-based TCs. This approach allows to virtually adjust any characteristic of the final TCs. The final microstructure ranges from a nonporous to a highly porous network, allowing the TCs to be selectively porous to 4 kDa molecules, but not to human skin fibroblasts. Mechanical properties are dependent both on the processing method and thickness of the TCs. Bioactivity is observed after 30 days of immersion in simulated body fluid only for the TCs submitted to a drying processing method (50 °C). The in vivo study performed in mice demonstrates the good biocompatibility of the TCs. The enzymatically cross-linked silk fibroin TCs are versatile and have adjustable characteristics that can be exploited in a variety of biomedical applications, particularly in guidance of peripheral nerve regeneration.

Emerging Concepts in Treating Cartilage, Osteochondral Defects, and Osteoarthritis of the Knee and Ankle.

The management and treatment of cartilage lesions, osteochondral defects, and osteoarthritis remain a challenge in orthopedics. Moreover, these entities have different behaviors in different joints, such as the knee and the ankle, which have inherent differences in function, biology, and biomechanics. There has been a huge development on the conservative treatment (new technologies including orthobiologics) as well as on the surgical approach. Some surgical development upraises from technical improvements including advanced arthroscopic techniques but also from increased knowledge arriving from basic science research and tissue engineering and regenerative medicine approaches. This work addresses the state of the art concerning basic science comparing the knee and ankle as well as current options for treatment. Furthermore, the most promising research developments promising new options for the future are discussed.

Advances for Treatment of Knee OC Defects.

Osteochondral (OC) defects are prevalent among young adults and are notorious for being unable to heal. Although they are traumatic in nature, they often develop silently. Detection of many OC defects is challenging, despite the criticality of early care. Current repair approaches face limitations and cannot provide regenerative or long-standing solution. Clinicians and researchers are working together in order to develop approaches that can regenerate the damaged tissues and protect the joint from developing osteoarthritis. The current concepts of tissue engineering and regenerative medicine, which have brought many promising applications to OC management, are overviewed herein. We will also review the types of stem cells that aim to provide sustainable cell sources overcoming the limitation of autologous chondrocyte-based applications. The various scaffolding materials that can be used as extracellular matrix mimetic and having functional properties similar to the OC unit are also discussed.