Page 35 - OR-1-1

Regrettably, the general properties of biomaterials often various trace elements to construct a more appropriate
present significant differences in neuronal and osteoblast microenvironment for enhanced osteogenic differentiation
development. For example, neuronal differentiation is and bone development.
feasible when a soft biomaterial matrix with stiffness lower
than 1 kPa is used, whereas osteoblast differentiation often 3.2. Releasing neurotrophic factors from
happens on the stiff biomaterial surface with rigidity much biomaterials
higher than 10 kPa. To optimize the outcome of bone In comparison with the bioactive inorganic mineral
96
regeneration, the crosstalk between innervation and bone scaffolds, the loading and controlled release of NGFs seem
development should be enhanced by introducing additional to be a more common and efficient osteogenesis cue for the
neurotrophic cues for biomaterial advancement. Within this osteoinductive biomaterials through the early neurogenesis
section, several major approaches to orchestration between process. Stimulating the release of neurotrophic factors
neurogenesis and osteogenesis processes, mainly including from biomaterials represents a key approach in the field of
bioactive inorganic mineral scaffold, neurotrophic factor innervated bone regeneration research. As a well-studied
release, and neural cell-derived exosome conjugation, are neurotrophic factor mentioned above, the NGF has been
listed as follows and described according to the recent widely discovered in the skeleton system containing bone
advances. marrow, periosteum, trabecula, and cortical bone, 104,105
and has been incorporated in silk fibroin scaffolds with
3.1. Bioactive inorganic minerals sustained release of NGF for improving peripheric neural
Bone tissues are naturally mineralized architectures cell adhesion, axonal growth in the Haversian canal, and
assembled by oriented collagen fibers and inorganic mineral activation of osteogenetic signaling pathways such as MEK/
crystals. Thus, the maintenance of bone metabolism, ERK pathway. 106,107 Previous studies have demonstrated that
robustness, and homeostasis partially depends on the the cocktail combination of BMP-2 and NGF significantly
content and crystallinity of the inorganic minerals. Among accelerated bone healing with increased expression in
all the natural minerals in skeleton systems, calcium osteoblast differentiation and, more importantly, better
phosphate (CaP) crystals are the most common; therefore, maintained the balance between osteoblasts and osteoclasts
CaP-based inorganic minerals such as hydroxyapatite, for inhibiting excessive ossification compared with those
tricalcium phosphate (TCP), brushite, and bioactive glass outcomes with the administration of single factor. 108,109
have been chosen as artificial bone biomaterials applied By a similar signaling pathway to that of the NGF, the
in bone tissue engineering. 97,98 Benefited from abundant BDNF also showed the ability to facilitate osteogenesis and
chelation spaces of phosphate anions, some trace elements bone formation both in vitro and in vivo, as evidenced by
with neuromodulation and osteoinductive activities, obvious upregulation in osteogenesis marker osteocalcin
including Mg , Zn , and Cu , could be introduced into and various neurogenesis markers containing microtubule-
2+
2+
2+
the crystal lattice of the CaP-based minerals (Figure 3), associated protein 2, glial fibrillary acidic protein, neural/
for developing the novel osteoinductive scaffolds and glial antigen 2, and β-tubulin III. To further enhance the
90
tissue-engineered bone organoids. Once released innervation and vascularization within the osteogenesis
99
from the scaffolds, these bioactive cations diffuse into microenvironment, the bioactive inorganic minerals
the intracellular space of osteocytes and are involved in mentioned above have been employed to load and
the intracellular signaling pathways related to sensory sustainably release the neurotrophic factors with a delayed
nerve activation and osteogenesis functions. Whitlockite half-life period in the host. For example, our group has
(Ca Mg (HPO ) (PO ) ), for instance, is a bioactive developed the Laponite nanosheets abundant in Mg as a
2+
18
4 2
2
4 12
mineral in human bone constitutions, with the stimulus of vehicle for NGF delivery and found that the NGF-Laponite
Mg element to SC migration and the release of NGF, BDNF, complex obviously improves the osteogenic activity of
and VEGF. 100,101 It is also evidenced by Huang et al. 102 that BMSCs by stimulating CGRP secretion of sensory neurons
the sustained release of Mg from scaffolds significantly and enhancing communication between the BMSCs and
2+
110
promotes early innervation, vascularization as well as bone sensory neurons (Figure 4). Moreover, we have analyzed
wound healing in a rat femoral condyle defect. Moreover, the major mechanism of the crosstalk between innervation
the addition of the Zn element to the whitlockite further and osteogenesis processes, indicating that the CGRP-
facilitates the rapid innervation within the bone regeneration mediated nerve–bone crosstalk would be a potential
process by promoting neural cell adhesion, SC migration, approach for facilitating innervated bone regeneration.
and paracrine, possibly benefiting from the activation of
sensory nerves and the inhibition of sympathetic activity. 3.3. Exosome-mediated regeneration of innervated
103
In light of the advantages of the bioactive inorganic bone
minerals in innervated bone regeneration, the tissue- As evidenced in the previous section, SCs, pivotal glial
engineered bone organoid matrixes can be modified by cells of the peripheral nerves in the skeleton system, are
Volume 1 Issue 1 (2025) 7 doi: 10.36922/OR8294