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Recent advances in bone tissue engineering have shown promise for bone repair post osteosarcoma excision. However, conflicting research on mesenchymal stem cells (MSCs) has raised concerns about their potential to either promote or inhibit tumor cell proliferation. It is necessary to thoroughly understand the interactions between MSCs and tumor cells. Most previous studies only focused on the interactions between cells within the tumor tissues. It has been challenging to develop an in vitro model of osteosarcoma excision sites replicating the complexity of the bone microenvironment and cell distribution. In this work, we designed and fabricated modular bioceramic scaffolds to assemble into a co-culture model. Because of the bone-like composition and mechanical property, tricalcium phosphate bioceramic could mimic the bone microenvironment and recapitulate the cell-extracellular matrix interaction. Moreover, the properties for easy assembly enabled the modular units to mimic the spatial distribution of cells in the osteosarcoma excision site. Under this co-culture model, MSCs showed a noticeable tumor-stimulating effect with a potential risk of tumor recurrence. In addition, tumor cells also could inhibit the osteogenic ability of MSCs. To undermine the stimulating effects of MSCs on tumor cells, we present the methods of pre-differentiated MSCs, which had lower expression of IL-8 and higher expression of osteogenic proteins. Both in vitro and in vivo studies confirm that pre-differentiated MSCs could maintain high osteogenic capacity without promoting tumor growth, offering a promising approach for MSCs' application in bone regeneration. Overall, 3D modular scaffolds provide a valuable tool for constructing hard tissue in vitro models. Bone tissue engineering using mesenchymal stem cells (MSCs) and biomaterials has shown promise for bone repair post osteosarcoma excision. However, conflicting researches on MSCs have raised concerns about their potential to either promote or inhibit tumor cell proliferation. It remains challenges to develop in vitro models to investigate cell interactions, especially of osteosarcoma with high hardness and special composition of bone tissue. In this work, modular bioceramic scaffolds were fabricated and assembled to co-culture models. The interactions between MSCs and MG-63 were manifested as tumor-stimulating and osteogenesis-inhibiting, which means potential risk of tumor recurrence. To undermine the stimulating effect, pre-differentiation method was proposed to maintain high osteogenic capacity without tumor-stimulating, offering a promising approach for MSCs' application in bone regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • The optimized modular reinforced scaffold with enhanced mechanical properties is designed. • The optimization significantly improves the mechanical properties of the scaffold. • The optimization of the module is based on the defect shape. • The finite element model of customized alveolar bone defect is developed. • This kind of scaffold can be useful for treatment of critical-sized defects. A modular reinforced bone scaffold with enhanced mechanical properties has recently been developed by our group. It includes: 1) A load-bearing module: a skeleton which is made of a slowly degradable material, undertaking mechanical necessities of the scaffold, and 2) A bio-reactive module: a porous and biodegradable component undertaking biological necessities of the scaffold. The load-bearing module is placed into the bio-reactive module to reinforce it. This paper is dedicated to optimizing the load-bearing module for a certain customized alveolar bone defect. More specifically, a 3D-printed skeleton, made of polycaprolactone (PCL), is optimized based on the boundary conditions of the defect shape using the finite element method (FEM) to minimize the weight (to minimize the amount of PCL) and maximize the mechanical properties and porosity of the skeleton. Gelatin foam has been incorporated into the optimized skeleton through the aminolysis process to form the bio-reactive module. The mechanical characterization confirmed that the optimized load-bearing module has a bridge-like shape and can significantly improve the mechanical properties of the scaffold. Also, in vitro studies showed that the fabricated scaffold can improve cell proliferation and osteogenesis. This kind of scaffold can be useful for the treatment of critical-sized defects. [ABSTRACT FROM AUTHOR]

Abstract: This research focused on developing a modular poly(ethylene glycol) (PEG) scaffold, assembled from PEG microgels and collagen I, to provide an environment to decouple the chemical and mechanical cues within a three-dimensional scaffold. We first characterized the microgel fabrication process, examining the size, polydispersity, swelling ratio, mesh size and storage modulus of the polymer particles. The resulting microgels had a low polydispersity index, PDI=1.08, and a diameter of ∼1.6μm. The mesh size of the microgels, calculated from the swelling ratio, was 47.53Å. Modular hydrogels (modugels) were then formed by compacting N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride/N-hydroxysuccinimidyl group-activated microgels with PEG–4arm-amine and 0, 1, 10, or 100μgml−1 collagen. The stiffness (G ∗) of the modugels was not significantly altered with the addition of collagen, allowing for modification of the chemical environment independent from the mechanical properties of the scaffold. PC12 cell aggregation increased in modugels as collagen concentrations increased and cell viability in modugels was improved over bulk PEG hydrogels. Overall, these results indicate that further exploration of modular scaffolds formed from microgels could allow for a better understanding of the relationship between the chemical and mechanical properties and cellular behavior. [Copyright &y& Elsevier]

Abstract: Modular, bioactive, macroporous scaffolds were formed by crosslinking poly(ethylene glycol) (PEG) microspheres around living cells. Hydrogel microspheres were produced from reactive PEG derivatives in aqueous sodium sulfate solutions without the use of surfactants or copolymers. Microspheres were formed following thermally induced phase separation if the gel point was reached prior to extensive coarsening of the PEG-rich domains. Three types of PEG microspheres with different functionalities were used to form scaffolds: one type provided mechanical support, the second type provided controlled delivery of the angiogenesis-promoting molecule, sphingosine 1-phosphate (S1P) and the third type served as a slowly dissolving non-cytotoxic porogen. Scaffolds were formed by centrifuging microspheres in the presence of HepG2 hepatoma cells, resulting in a homogenous distribution of cells. During overnight incubation at 37°C, the microspheres reacted with serum proteins in cell culture medium to stabilize the scaffolds. Within 2days in culture, macropores formed due to the dissolution of the porogenic PEG microspheres, without affecting cell viability. Gradients in porosity were produced by varying the buoyancy of the porogenic microspheres. Conjugated RGD cell adhesion peptides and the delivery of S1P promoted endothelial cell infiltration through macropores in the scaffolds. The scaffolds presented here differ from previous hydrogel scaffolds in that: (i) cells are not encapsulated in hydrogel; (ii) macropores form in the presence of cells; and (iii) scaffold properties are controlled by the modular assembly of different microspheres that perform distinct functions. [Copyright &y& Elsevier]