A novel hybrid design and modelling of a customised graded Ti-6Al-4V porous hip implant to reduce stress-shielding: An experimental and numerical analysis.

Stress shielding secondary to bone resorption is one of the main causes of aseptic loosening, which limits the lifespan of hip prostheses and exacerbates revision surgery rates. In order to minimise post-hip replacement stress variations, this investigation proposes a low-stiffness, porous Ti6Al4V hip prosthesis, developed through selective laser melting (SLM). The stress shielding effect and potential bone resorption properties of the porous hip implant were investigated through both in vitro quasi-physiological experimental assays, together with finite element analysis. A solid hip implant was incorporated in this investigation for contrast, as a control group. The stiffness and fatigue properties of both the solid and the porous hip implants were measured through compression tests. The safety factor of the porous hip stem under both static and dynamic loading patterns was obtained through simulation. The porous hip implant was inserted into Sawbone/PMMA cement and was loaded to 2,300 N (compression). The proposed porous hip implant demonstrated a more natural stress distribution, with reduced stress shielding (by 70%) and loss in bone mass (by 60%), when compared to a fully solid hip implant. Solid and porous hip stems had a stiffness of 2.76 kN/mm and 2.15 kN/mm respectively. Considering all daily activities, the porous hip stem had a factor of safety greater than 2. At the 2,300 N load, maximum von Mises stresses on the hip stem were observed as 112 MPa on the medial neck and 290 MPa on the distal restriction point, whereby such values remained below the endurance limit of 3D printed Ti6Al4V (375 MPa). Overall, through the strut thickness optimisation process for a Ti6Al4V porous hip stem, stress shielding and bone resorption can be reduced, therefore proposing a potential replacement for the generic solid implant.

A critical review on polydopamine surface-modified scaffolds in musculoskeletal regeneration.

Increasing concern about age-related diseases, particularly musculoskeletal injuries and orthopedic conditions, highlights the need for strategies such as tissue engineering to address them. Surface modification has been developed to create pro-healing interfaces, personalize scaffolds and provide novel medicines. Polydopamine, a mussel-inspired adhesive polymer with highly reactive functional groups that adhere to nearly all substrates, has gained attention in surface modification strategies for biomaterials. Polydopamine was primarily developed to modify surfaces, but its effectiveness has opened up promising approaches for further applications in bioengineering as carriers and nanoparticles. This review focuses on the recent discoveries of the role of polydopamine as a surface coating material, with focus on the properties that make it suitable for tackling musculoskeletal disorders. We report the evolution of using it in research, and discuss papers involving the progress of this field. The current research on the role of polydopamine in bone, cartilage, muscle, nerve, and tendon regeneration is discussed, thus giving comprehensive overview about the function of polydopamine both in-vitro and in-vivo. Finally, the report concludes presenting the critical challenges that must be addressed for the clinical translation of this biomaterial while exploring future perspectives and research opportunities in this area.

Stress Shielding and Bone Resorption of Press-Fit Polyether-Ether-Ketone (PEEK) Hip Prosthesis: A Sawbone Model Study.

Stress shielding secondary to bone resorption is one of the main causes of aseptic loosening, which limits the lifespan of the hip prostheses and increases the rates of revision surgery. This study proposes a low stiffness polyether-ether-ketone (PEEK) hip prostheses, produced by fused deposition modelling to minimize the stress difference after the hip replacement. The stress shielding effect and the potential bone resorption of the PEEK implant was investigated through both experimental tests and FE simulation. A generic Ti6Al4V implant was incorporated in this study to allow fair comparison as control group. Attributed to the low stiffness, the proposed PEEK implant showed a more natural stress distribution, less stress shielding (by 104%), and loss in bone mass (by 72%) compared with the Ti6Al4V implant. The stiffness of the Ti6Al4V and the PEEK implant were measured through compression tests to be 2.76 kN/mm and 0.276 kN/mm. The factor of safety for the PEEK implant in both static and dynamic loading scenarios were obtained through simulation. Most of the regions in the PEEK implant were tested to be safe (FoS larger than 1) in terms of representing daily activities (2300 N), while the medial neck and distal restriction point of the implant attracts large von Mises stress 82 MPa and 76 MPa, respectively, and, thus, may possibly fail during intensive activities by yield and fatigue. Overall, considering the reduction in stress shielding and bone resorption in cortical bone, PEEK could be a promising material for the patient-specific femoral implants.

Mechanical Characterisation and Numerical Modelling of TPMS-Based Gyroid and Diamond Ti6Al4V Scaffolds for Bone Implants: An Integrated Approach for Translational Consideration.

Additive manufacturing has been used to develop a variety of scaffold designs for clinical and industrial applications. Mechanical properties (i.e., compression, tension, bending, and torsion response) of these scaffolds are significantly important for load-bearing orthopaedic implants. In this study, we designed and additively manufactured porous metallic biomaterials based on two different types of triply periodic minimal surface structures (i.e., gyroid and diamond) that mimic the mechanical properties of bone, such as porosity, stiffness, and strength. Physical and mechanical properties, including compressive, tensile, bending, and torsional stiffness and strength of the developed scaffolds, were then characterised experimentally and numerically using finite element method. Sheet thickness was constant at 300 µm, and the unit cell size was varied to generate different pore sizes and porosities. Gyroid scaffolds had a pore size in the range of 600-1200 µm and a porosity in the range of 54-72%, respectively. Corresponding values for the diamond were 900-1500 µm and 56-70%. Both structure types were validated experimentally, and a wide range of mechanical properties (including stiffness and yield strength) were predicted using the finite element method. The stiffness and strength of both structures are comparable to that of cortical bone, hence reducing the risks of scaffold failure. The results demonstrate that the developed scaffolds mimic the physical and mechanical properties of cortical bone and can be suitable for bone replacement and orthopaedic implants. However, an optimal design should be chosen based on specific performance requirements.

On the mechanical aspect of additive manufactured polyether-ether-ketone scaffold for repair of large bone defects.

Polyether-ether-ketone (PEEK) is widely used in producing prosthesis and have gained great attention for repair of large bone defect in recent years with the development of additive manufacturing. This is due to its excellent biocompatibility, good heat and chemical stability and similar mechanical properties which mimics natural bone. In this study, three replicates of rectilinear scaffolds were designed for compression, tension, three-point bending and torsion test with unit cell size of 0.8 mm, a pore size of 0.4 mm, strut thickness of 0.4 mm and nominal porosity of 50%. Stress-strain graphs were developed from experimental and finite element analysis models. Experimental Young's modulus and yield strength of the scaffolds were measured from the slop of the stress-strain graph to be 395 and 19.50 MPa respectively for compression, 427 and 6.96 MPa respectively for tension, 257 and 25.30 MPa respectively for three-point bending and 231 and 12.83 MPa respectively for torsion test. The finite element model was found to be in good agreement with the experimental results. Ductile fracture of the struct subjected to tensile strain was the main failure mode of the PEEK scaffold, which stems from the low crystallinity of additive manufacturing PEEK. The mechanical properties of porous PEEK are close to those of cancellous bone and thus are expected to be used in additive manufacturing PEEK bone implants in the future, but the lower yield strength poses a design challenge.

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.

On the Morphological Deviation in Additive Manufacturing of Porous Ti6Al4V Scaffold: A Design Consideration.

Additively manufactured Ti scaffolds have been used for bone replacement and orthopaedic applications. In these applications, both morphological and mechanical properties are important for their in vivo performance. Additively manufactured Ti6Al4V triply periodic minimal surface (TPMS) scaffolds with diamond and gyroid structures are known to have high stiffness and high osseointegration properties, respectively. However, morphological deviations between the as-designed and as-built types of these scaffolds have not been studied before. In this study, the morphological and mechanical properties of diamond and gyroid scaffolds at macro and microscales were examined. The results demonstrated that the mean printed strut thickness was greater than the designed target value. For diamond scaffolds, the deviation increased from 7.5 µm (2.5% excess) for vertical struts to 105.4 µm (35.1% excess) for horizontal struts. For the gyroid design, the corresponding deviations were larger, ranging from 12.6 µm (4.2% excess) to 198.6 µm (66.2% excess). The mean printed pore size was less than the designed target value. For diamonds, the deviation of the mean pore size from the designed value increased from 33.1 µm (-3.0% excess) for vertical struts to 92.8 µm (-8.4% excess) for horizontal struts. The corresponding deviation for gyroids was larger, ranging from 23.8 µm (-3.0% excess) to 168.7 µm (-21.1% excess). Compressive Young's modulus of the bulk sample, gyroid and diamond scaffolds was calculated to be 35.8 GPa, 6.81 GPa and 7.59 GPa, respectively, via the global compression method. The corresponding yield strength of the samples was measured to be 1012, 108 and 134 MPa. Average microhardness and Young's modulus from α and ß phases of Ti6Al4V from scaffold struts were calculated to be 4.1 GPa and 131 GPa, respectively. The extracted morphology and mechanical properties in this study could help understand the deviation between the as-design and as-built matrices, which could help develop a design compensation strategy before the fabrication of the scaffolds.

In vivo evaluation of additively manufactured multi-layered scaffold for the repair of large osteochondral defects.

The repair of osteochondral defects is one of the major clinical challenges in orthopaedics. Well-established osteochondral tissue engineering methods have shown promising results for the early treatment of small defects. However, less success has been achieved for the regeneration of large defects, which is mainly due to the mechanical environment of the joint and the heterogeneous nature of the tissue. In this study, we developed a multi-layered osteochondral scaffold to match the heterogeneous nature of osteochondral tissue by harnessing additive manufacturing technologies and combining the established art laser sintering and material extrusion techniques. The developed scaffold is based on a titanium and polylactic acid matrix-reinforced collagen "sandwich" composite system. The microstructure and mechanical properties of the scaffold were examined, and its safety and efficacy in the repair of large osteochondral defects were tested in an ovine condyle model. The 12-week in vivo evaluation period revealed extensive and significantly higher bone in-growth in the multi-layered scaffold compared with the collagen-HAp scaffold, and the achieved stable mechanical fixation provided strong support to the healing of the overlying cartilage, as demonstrated by hyaline-like cartilage formation. The histological examination showed that the regenerated cartilage in the multi-layer scaffold group was superior to that formed in the control group. Chondrogenic genes such as aggrecan and collagen-II were upregulated in the scaffold and were higher than those in the control group. The findings showed the safety and efficacy of the cell-free "translation-ready" osteochondral scaffold, which has the potential to be used in a one-step surgical procedure for the treatment of large osteochondral defects. Supplementary Information: The online version contains supplementary material available at 10.1007/s42242-021-00177-w.

TiO2 Nanotopography-Driven Osteoblast Adhesion through Coulomb's Force Evolution.

Nanotopography is an effective method to regulate cells' behaviors to improve Ti orthopaedic implants' in vivo performance. However, the mechanism underlying cellular matrix-nanotopography interactions that allows the modulation of cell adhesion has remained elusive. In this study, we have developed novel nanotopographic features on Ti substrates and studied human osteoblast (HOb) adhesion on nanotopographies to reveal the interactive mechanism regulating cell adhesion and spreading. Through nanoflat, nanoconvex, and nanoconcave TiO2 nanotopographies, the evolution of Coulomb's force between the extracellular matrix and nanotopographies has been estimated and comparatively analyzed, along with the assessment of cellular responses of HOb. We show that HObs exhibited greater adhesion and spreading on nanoconvex surfaces where they formed super matured focal adhesions and an ordered actin cytoskeleton. It also demonstrated that Coulomb's force on nanoconvex features exhibits a more intense and concentrated evolution than that of nanoconcave features, which may result in a high dense distribution of fibronectin. Thus, this work is meaningful for novel Ti-based orthopaedic implants' surface designs for enhancing their in vivo performance.

Bilayered scaffold with 3D printed stiff subchondral bony compartment to provide constant mechanical support for long-term cartilage regeneration.

BACKGROUND/OBJECTIVE: We seek to figure out the effect of stable and powerful mechanical microenvironment provided by Ti alloy as a part of subchondral bone scaffold on long-term cartilage regeneration.Methods: we developed a bilayered osteochondral scaffold based on the assumption that a stiff subchondral bony compartment would provide stable mechanical support for cartilage regeneration and enhance subchondral bone regeneration. The subchondral bony compartment was prepared from 3D printed Ti alloy, and the cartilage compartment was created from a freeze-dried collagen sponge, which was reinforced by poly-lactic-co-glycolic acid (PLGA). RESULTS: In vitro evaluations confirmed the biocompatibility of the scaffold materials, while in vivo evaluations demonstrated that the mechanical support provided by 3D printed Ti alloy layer plays an important role in the long-term regeneration of cartilage by accelerating osteochondral formation and its integration with the adjacent host tissue in osteochondral defect model at rabbit femoral trochlea after 24 weeks. CONCLUSION: Mechanical support provided by 3D printing Ti alloy promotes cartilage regeneration by promoting subchondral bone regeneration and providing mechanical support platform for cartilage synergistically. TRANSLATIONAL POTENTIAL STATEMENT: The raw materials used in our double-layer osteochondral scaffolds are all FDA approved materials for clinical use. 3D printed titanium alloy scaffolds can promote bone regeneration and provide mechanical support for cartilage regeneration, which is very suitable for clinical scenes of osteochondral defects. In fact, we are conducting clinical trials based on our scaffolds. We believe that in the near future, the scaffold we designed and developed can be formally applied in clinical practice.

Sheep condyle model evaluation of bone marrow cell concentrate combined with a scaffold for repair of large osteochondral defects.

AIMS: Minimally manipulated cells, such as autologous bone marrow concentrates (BMC), have been investigated in orthopaedics as both a primary therapeutic and augmentation to existing restoration procedures. However, the efficacy of BMC in combination with tissue engineering is still unclear. In this study, we aimed to determine whether the addition of BMC to an osteochondral scaffold is safe and can improve the repair of large osteochondral defects when compared to the scaffold alone. METHODS: The ovine femoral condyle model was used. Bone marrow was aspirated, concentrated, and used intraoperatively with a collagen/hydroxyapatite scaffold to fill the osteochondral defects (n = 6). Tissue regeneration was then assessed versus the scaffold-only group (n = 6). Histological staining of cartilage with alcian blue and safranin-O, changes in chondrogenic gene expression, microCT, peripheral quantitative CT (pQCT), and force-plate gait analyses were performed. Lymph nodes and blood were analyzed for safety. RESULTS: The results six months postoperatively showed that there were no significant differences in bone regrowth and mineral density between BMC-treated animals and controls. A significant upregulation of messenger RNA (mRNA) for types I and II collagens in the BMC group was observed, but there were no differences in the formation of hyaline-like cartilage between the groups. A trend towards reduced sulphated glycosaminoglycans (sGAG) breakdown was detected in the BMC group but this was not statistically significant. Functional weightbearing was not affected by the inclusion of BMC. CONCLUSION: Our results indicated that the addition of BMC to scaffold is safe and has some potentially beneficial effects on osteochondral-tissue regeneration, but not on the functional endpoint of orthopaedic interest. Cite this article: Bone Joint Res 2021;10(10):677-689.

Determination of an Initial Stage of the Bone Tissue Ingrowth Into Titanium Matrix by Cell Adhesion Model.

For achieving early intervention treatment to help patients delay or avoid joint replacement surgery, a personalized scaffold should be designed coupling the effects of mechanical, fluid mechanical, chemical, and biological factors on tissue regeneration, which results in time- and cost-consuming trial-and-error analyses to investigate the in vivo test and related experimental tests. To optimize the fluid mechanical and material properties to predict osteogenesis and cartilage regeneration for the in vivo and clinical trial, a simulation approach is developed for scaffold design, which is composed of a volume of a fluid model for simulating the bone marrow filling process of the bone marrow and air, as well as a discrete phase model and a cell impingement model for tracking cell movement during bone marrow fillings. The bone marrow is treated as a non-Newtonian fluid, rather than a Newtonian fluid, because of its viscoelastic property. The simulation results indicated that the biofunctional bionic scaffold with a dense layer to prevent the bone marrow flow to the cartilage layer and synovia to flow into the trabecular bone area guarantee good osteogenesis and cartilage regeneration, which leads to high-accuracy in vivo tests in sheep . This approach not only predicts the final bioperformance of the scaffold but also could optimize the scaffold structure and materials by their biochemical, biological, and biomechanical properties.

Biofabrication Strategies for Musculoskeletal Disorders: Evolution towards Clinical Applications.

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.

Substitution for In Vitro and In Vivo Tests: Computational Models from Cell Attachment to Tissue Regeneration.

To get an optimal product of orthopaedic implant or regenerative medicine needs to follow trial-and-error analyses to investigate suitable product's material, structure, mechanical properites etc. The whole process from in vivo tests to clinical trials is expensive and time-consuming. Computational model is seen as a useful analysis tool to make the product development. A series of models for simulating tissue engineering process from cell attachment to tissue regeneration are reviewed. The challenging is that models for simulating tissue engineering processes are developed separately. From cell to tissue regeneration, it would go through blood injection after moving out the defect; to cell disperse and attach on the scaffold; to proliferation, migration and differentiation; and to the final part-becoming mature tissues. This paper reviewed models that related to tissue engineering process, aiming to provide an opportunity for researchers to develop a mature model for whole tissue engineering process. This article focuses on the model analysis methods of cell adhesion, nutrient transport and cell proliferation, differentiation and migration in tissue engineering. In cell adhesion model, one of the most accurate method is to use discrete phase model to govern cell movement and use Stanton-Rutland model for simulating cell attachment. As for nutrient transport model, numerical model coupling with volume of fluid model and species transport model together is suitable for predicting nutrient transport process. For cell proliferation, differentiation and migration, finite element method with random-walk algorithm is one the most advanced way to simulate these processes. Most of the model analysis methods require further experiments to verify the accuracy and effectiveness. Due to the lack of technology to detect the rate of nutrient diffusion, there are especially few researches on model analysis methods in the area of blood coagulation. Therefore, there is still a lot of work to be done in the research of the whole process model method of tissue engineering. In the future, the numerical model would be seen as an optimal way to investigate tissue engineering products bioperformance and also enable to optimize the parameters and material types of the tissue engineering products.

Design and performance evaluation of additively manufactured composite lattice structures of commercially pure Ti (CP-Ti).

Ti alloys with lattice structures are garnering more and more attention in the field of bone repair or regeneration due to their superior structural, mechanical, and biological properties. In this study, six types of composite lattice structures with different strut radius that consist of simple cubic (structure A), body-centered cubic (structure B), and edge-centered cubic (structure C) unit cells are designed. The designed structures are firstly simulated and analysed by the finite element (FE) method. Commercially pure Ti (CP-Ti) lattice structures with optimized unit cells and strut radius are then fabricated by selective laser melting (SLM), and the dimensions, microtopography, and mechanical properties are characterised. The results show that among the six types of composite lattice structures, combined BA, CA, and CB structures exhibit smaller maximum von-Mises stress, indicating that these structures have higher strength. Based on the fitting curves of stress/specific surface area versus strut radius, the optimized strut radius of BA, CA, and CB structures is 0.28, 0.23, and 0.30 mm respectively. Their corresponding compressive yield strength and compressive modulus are 42.28, 30.11, and 176.96 MPa, and 4.13, 2.16, and 7.84 GPa, respectively. The CP-Ti with CB unit structure presents a similar strength and compressive modulus to the cortical bone, which makes it a potential candidate for subchondral bone restorations.

Nano-Modified Titanium Implant Materials: A Way Toward Improved Antibacterial Properties.

Titanium and its alloys have superb biocompatibility, low elastic modulus, and favorable corrosion resistance. These exceptional properties lead to its wide use as a medical implant material. Titanium itself does not have antibacterial properties, so bacteria can gather and adhere to its surface resulting in infection issues. The infection is among the main reasons for implant failure in orthopedic surgeries. Nano-modification, as one of the good options, has the potential to induce different degrees of antibacterial effect on the surface of implant materials. At the same time, the nano-modification procedure and the produced nanostructures should not adversely affect the osteogenic activity, and it should simultaneously lead to favorable antibacterial properties on the surface of the implant. This article scrutinizes and deals with the surface nano-modification of titanium implant materials from three aspects: nanostructures formation procedures, nanomaterials loading, and nano-morphology. In this regard, the research progress on the antibacterial properties of various surface nano-modification of titanium implant materials and the related procedures are introduced, and the new trends will be discussed in order to improve the related materials and methods.

Characteristics of novel Ti-10Mo-xCu alloy by powder metallurgy for potential biomedical implant applications.

When biomaterials are implanted in the human body, the surfaces of the implants become favorable sites for microbial adhesion and biofilm formation, causing peri-implant infection which frequently results in the failure of prosthetics and revision surgery. Ti-Mo alloy is one of the commonly used implant materials for load-bearing bone replacement, and the prevention of infection of Ti-Mo implants is therefore crucial. In this study, bacterial inhibitory copper (Cu) was added to Ti-Mo matrix to develop a novel Ti-Mo-Cu alloy with bacterial inhibitory property. The effects of Cu content on microstructure, tensile properties, cytocompatibility, and bacterial inhibitory ability of Ti-Mo-Cu alloy were systematically investigated. Results revealed that Ti-10Mo-1Cu alloy consisted of α and ß phases, while there were a few Ti2Cu intermetallic compounds existed for Ti-10Mo-3Cu and Ti-10Mo-5Cu alloys, in addition to α and ß phases. The tensile strength of Ti-10Mo-xCu alloy increased with Cu content while elongation decreased. Ti-10Mo-3Cu alloy exhibited an optimal tensile strength of 1098.1 MPa and elongation of 5.2%. Cytocompatibility study indicated that none of the Ti-10Mo-xCu alloys had a negative effect on MC3T3-E1 cell proliferation. Bacterial inhibitory rates against S. aureus and E. coli increased with the increase in Cu content of Ti-10Mo-xCu alloy, within the ranges of 20-60% and 15-50%, respectively. Taken together, this study suggests that Ti-10Mo-3Cu alloy with high strength, acceptable elongation, excellent cytocompatibility, and the bacterial inhibitory property is a promising candidate for biomedical implant applications.

Cell Seeding Process Experiment and Simulation on Three-Dimensional Polyhedron and Cross-Link Design Scaffolds.

Cell attachment to a scaffold is a significant step toward successful tissue engineering. Cell seeding is the first stage of cell attachment, and its efficiency and distribution can affect the final biological performance of the scaffold. One of the contributing factors to maximize cell seeding efficiency and consequently cell attachment is the design of the scaffold. In this study, we investigated the optimum scaffold structure using two designs - truncated octahedron (TO) structure and cubic structure - for cell attachment. A simulation approach, by ANSYS Fluent coupling the volume of fluid (VOF) model, discrete phase model (DPM), and cell impingement model (CIM), was developed for cell seeding process in scaffold, and the results were validated with in vitro cell culture assays. Our observations suggest that both designs showed a gradual lateral variation of attached cells, and live cell movements are extremely slow by diffusion only while dead cells cannot move without external force. The simulation approaches supply a more accurate model to simulate cell adhesion for three-dimensional structures. As the initial stages of cell attachment in vivo are hard to observe, this novel method provides an opportunity to predict cell distribution, thereby helping to optimize scaffold structures. As tissue formation is highly related to cell distribution, this model may help researchers predict the effect of applied scaffold and reduce the number of animal testing.

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.

Osteochondral tissue coculture: An in vitro and in silico approach.

Osteochondral tissue engineering aims to regenerate functional tissue-mimicking physiological properties of injured cartilage and its subchondral bone. Given the distinct structural and biochemical difference between bone and cartilage, bilayered scaffolds, and bioreactors are commonly employed. We present an osteochondral culture system which cocultured ATDC5 and MC3T3-E1 cells on an additive manufactured bilayered scaffold in a dual-chamber perfusion bioreactor. Also, finite element models (FEM) based on the microcomputed tomography image of the manufactured scaffold as well as on the computer-aided design (CAD) were constructed; the microenvironment inside the two FEM was studied and compared. In vitro results showed that the coculture system supported osteochondral tissue growth in terms of cell viability, proliferation, distribution, and attachment. In silico results showed that the CAD and the actual manufactured scaffold had significant differences in the flow velocity, differentiation media mixing in the bioreactor and fluid-induced shear stress experienced by the cells. This system was shown to have the desired microenvironment for osteochondral tissue engineering and it can potentially be used as an inexpensive tool for testing newly developed pharmaceutical products for osteochondral defects.