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1. Introduction the tissue-engineered bone implants and the host bone
tissues by improving the osteogenic microenvironment for
Bone defect repair and healing is a meticulously osteoblast differentiation, infiltration, and metabolism. 1,11,12
orchestrated physiological process that features a Similarly, neural development and nerve invasion also
complex interplay of diverse cells and signaling molecules happen in skeleton formation processes, providing
facilitating bone formation and wound healing. Such an an ossification cue for activating osteogenic signaling
intricate process involves many cell types and signaling pathways and guiding osteoblast lineage progression. 13-17
molecules orchestrated in specific transduction pathways, Therefore, the interplay between bone and neural as well
a complexity that, without proper understanding, leads as vascular tissues attaches paramount importance to
to failed attempts to develop optimal therapies and bone development and regeneration. While extensive
unsatisfactory repair outcomes in clinical practices. researches have been conducted on vascularized bone
Nowadays, autologous bone transplantation, as a gold- regeneration, studies about the interaction between neural
standard clinical treatment, has been widely employed for development and osteogenesis processes, particularly
bone regeneration but is limited by the low bone donor innervated bone regeneration, remain relatively nascent
availability and high infection risk, thereby resulting in and underdeveloped.
a lower success rate of transplantation than 90% in the
majority of reported cases. Especially when the size This review article illustrates the necessity and
1-3
of a lesion surpasses the innate regenerative capacity of challenges associated with constructing innervated bone
bone tissues, the process of bone repair is often impeded, organoids from the view of nerve–bone crosstalk. With
leading to delayed healing and demand for the exploration a focus on innervated bone regeneration, this article first
of novel methods, with osteoinductive biomaterials and details interaction mechanisms between neurogenesis
bone organoids emerging as novelty interventions at this and skeleton development and summarizes several major
juncture. 4 strategies for developing bioactive materials and tissue-
engineered bone organoids that osteogenesis could be
Emerging as a promising avenue for refractory bone enhanced by early neurogenesis through those approaches.
defect repair, bone organoids have been proposed and As displayed in Figure 1, the article is structured
constructed from a three-dimensional (3D) culture of stem around three primary aspects: (1) the interaction
cells and their spheroids, exhibiting differentiation capability mechanisms of the nerve–bone crosstalk within the
toward diverse osteochondral lineages. Several studies have osteogenic microenvironment for bone regeneration;
developed different hydrogel matrixes for culturing stem (2) diverse strategies for biomaterials to improve the
cell-derived spheroids, such as induced pluripotent stem osteogenic microenvironment with early innervation,
cells and bone marrow-derived mesenchymal stem cells
(BMSCs), which form bone-like organoids that present
robust osteogenesis capacity through intramembranous
ossification or endochondral ossification processes.
5,6
To better fulfill their osteogenic functions, the stem cell-
derived bone organoids should experience homing,
migration, and orchestrating bone integration in the host,
regulated by intracellular or extracellular biochemical
factors and biophysical cues similar to those of natural bone
microenvironment. Recent years have witnessed a surge in
7
studies surrounding biomaterials that deliver osteogenesis
cues into stem cells to activate or inhibit intracellular
signal pathways. 4,8,9 Therefore, it is of vital importance to
find out the biomaterial design principles and biological
mechanisms for bone organoid culture and osteogenesis
microenvironment remodeling, but it has been still not
fully understood up to now.
The bone microstructure is a well-assembled
architecture, whereas the osteogenic microenvironment is a
certainly complex system characterized not only by various
cell lineages and signaling factors but also by dense vascular
and neural networks that collectively maintain bone Figure 1. Schematic illustration of nerve–bone crosstalk mechanisms,
integrity and homeostasis. Previous studies implied that biomaterial design strategies, and fabrication approaches for bone
9,10
vascularization is a key regulator for the integration between organoid development and innervated bone regeneration.

Volume 1 Issue 1 (2025) 2 doi: 10.36922/OR8294