A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from induced pluripotent stem cells committed to mesenchymal, endothelial, and hematopoietic lineages. These 3D structures capture key features of human bone marrow—stroma, lumen-forming sinusoids, and myeloid cells including proplatelet-forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ stimulation and engraftment with myelofibrosis but not healthy donor–derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow–like milieu. This enabling technology is likely to accelerate the discovery and prioritization of novel targets for bone marrow disorders and blood cancers. Significance: We present a human bone marrow organoid that supports the growth of primary cells from patients with myeloid and lymphoid blood cancers. This model allows for mechanistic studies of blood cancers in the context of their microenvironment and provides a much-needed ex vivo tool for the prioritization of new therapeutics. See related commentary by Derecka and Crispino, p. 263. This article is highlighted in the In This Issue feature, p. 247

Inorganic sol-gel solutions were electrospun to produce the first bioactive three-dimensional (3-D) scaffolds for bone tissue regeneration with a structure like cotton-wool (or cotton candy). This flexible 3-D fibrous structure is ideal for packing into complex defects. It also has large inter-fiber spaces to promote vascularization, penetration of cells and transport of nutrients throughout the scaffold. The 3-D fibrous structure was obtained by electrospinning, where the applied electric field and the instabilities exert tremendous force on the spinning jet, which is required to be viscoelastic to prevent jet break up. Previously, polymer binding agents were used with inorganic solutions to produce electrospun composite two-dimensional fibermats, requiring calcination to remove the polymer. This study presents novel reaction and processing conditions for producing a viscoelastic inorganic sol-gel solution that results in fibers by the entanglement of the intermolecularly overlapped nanosilica species in the solution, eliminating the need for a binder. Three-dimensional cotton-wool-like structures were only produced when solutions containing calcium nitrate were used, suggesting that the charge of the Ca(2+) ions had a significant effect. The resulting bioactive silica fibers had a narrow diameter range of 0.5-2μm and were nanoporous. A hydroxycarbonate apatite layer was formed on the fibers within the first 12h of soaking in simulated body fluid. MC3T3-E1 preosteoblast cells cultured on the fibers showed no adverse cytotoxic effect and they were observed to attach to and spread in the material.

Advances in bioprinting have enabled the fabrication of complex tissue constructs with high speed and resolution. However, there remains significant structural and biological complexity within tissues that bioprinting is unable to recapitulate. Bone, for example, has a hierarchical organization ranging from the molecular to whole organ level. Current bioprinting techniques and the materials employed have imposed limits on the scale, speed, and resolution that can be achieved, rendering the technique unable to reproduce the structural hierarchies and cell–matrix interactions that are observed in bone. The shift toward biomimetic approaches in bone tissue engineering, where hydrogels provide biophysical and biochemical cues to encapsulated cells, is a promising approach to enhancing the biological function and development of tissues for in vitro modeling. A major focus in bioprinting of bone tissue for in vitro modeling is creating dynamic microenvironmental niches to support, stimulate, and direct the cellular processes for bone formation and remodeling. Hydrogels are ideal materials for imitating the extracellular matrix since they can be engineered to present various cues whilst allowing bioprinting. Here, recent advances in hydrogels and 3D bioprinting toward creating a microenvironmental niche that is conducive to tissue engineering of in vitro models of bone are reviewed.

Bone grafts are commonly used to regenerate bone in defect sites resulting from disease or trauma but there is clinical need for artificial materials that will be readily available and reduce pain and recovery time for the patient. Current artificial bone graft materials include bioactive ceramics and glasses, which are too brittle for bone defects that experience cyclic load. The synthesis of a new nanocomposite material is described that has the potential of being a tough off-the-shelf artificial bone graft that can regenerate a bone defect and have enough flexibility to press-fit into place. The poly(γ-glutamic acid)/bioactive silica hybrid material with composition 40 wt% organic and 60 wt% bioactive inorganic (composition 70 mol% SiO₂ and 30 mol% CaO) was synthesised using a sol–gel route. The potential advantage of a hybrid material over conventional composites is the molecular scale interactions between the bioactive inorganic and the tough degradable organic. The organic and inorganic chains were covalently cross-linked using an organosilane that has an organic functionality to bond to poly(γ-glutamic acid) (γ-PGA) and an alkoxysilane group that condenses with the inorganic phase. The covalent cross-linking (class II hybrid) is required to control the dissolution and improve mechanical properties of the material. The two key variables, the concentration of cross-linking agent and the addition of calcium, were investigated by ²⁹Si solid-state NMR and electron microscopy. The hybrid materials were bioactive in simulated body fluid (SBF) with a hydroxy carbonate apatite (HCA) layer detected after immersion for 72 h. The hybrid material favours cell attachment and is not cytotoxic as demonstrated by culture of the osteosarcoma cell line SaOs-2 on the material for 4 days.