Neuro–bone tissue engineering: emerging mechanisms, potential strategies, and current challenges

Marrella, A. et al. Engineering vascularized and innervated bone biomaterials for improved skeletal tissue regeneration. Mater. Today (Kidlington, Engl.) 21, 362–376 (2018).

Salhotra, A., Shah, H. N., Levi, B. & Longaker, M. T. Mechanisms of bone development and repair. Nat. Rev. Mol. Cell Biol. 21, 696–711 (2020).

Liu, M. et al. Injectable hydrogels for cartilage and bone tissue engineering. Bone Res. 5, 17014 (2017).

Koons, G. L., Diba, M. & Mikos, A. G. Materials design for bone-tissue engineering. Nat. Rev. Materials 5, 584–603 (2020).

Wan, Q. et al. Simultaneous regeneration of bone and nerves through materials and architectural design: are we there yet. Adv. Funct. Mater. 30, 2003542 (2020).

Qin, Q. et al. Neurovascular coupling in bone regeneration. Exp. Mol. Med. 54, 1844–1849 (2022).

Burger, M. G. et al. Robust coupling of angiogenesis and osteogenesis by VEGF-decorated matrices for bone regeneration. Acta Biomater. 149, 111–125 (2022).

Liu, S. et al. Nerves within bone and their application in tissue engineering of bone regeneration. Front. Neurol. 13, 1085560 (2022).

Gajda, M., Adriaensen, D. & Cichocki, T. Development of the innervation of long bones: expression of the growth-associated protein 43. Folia Histochem. Cytobiol. 38, 103–110 (2000).

Li, Z. et al. Fracture repair requires TrkA signaling by skeletal sensory nerves. J. Clin. Invest. 129, 5137–5150 (2019).

Tomlinson, R. E. et al. NGF-TrkA signaling by sensory nerves coordinates the vascularization and ossification of developing endochondral bone. Cell Rep. 16, 2723–2735 (2016).

Xu, J. et al. NGF-p75 signaling coordinates skeletal cell migration during bone repair. Sci. Adv. 8, eabl5716 (2022).

Tao, R. et al. Hallmarks of peripheral nerve function in bone regeneration. Bone Res. 11, 6 (2023).

Leroux, A., Paiva Dos Santos, B., Leng, J., Oliveira, H. & Amédée, J. Sensory neurons from dorsal root ganglia regulate endothelial cell function in extracellular matrix remodelling. Cell Commun. Signal. 18, 162 (2020).

Zhang, Y. & Haga, N. Skeletal complications in congenital insensitivity to pain with anhidrosis: a case series of 14 patients and review of articles published in Japanese. J. Orthop. Sci. 19, 827–831 (2014).

Zhu, S. et al. Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain. J. Clin. Invest. 129, 1076–1093 (2019).

Simon, A. & Tanaka, E. M. Limb regeneration. Wiley Interdiscip. Rev. Dev. Biol. 2, 291–300 (2013).

Gerber, T. et al. Single-cell analysis uncovers convergence of cell identities during axolotl limb regeneration. Science. 362, eaaq0681 (2018).

Cao, Z. et al. Calcineurin controls proximodistal blastema polarity in zebrafish fin regeneration. Proc. Natl. Acad. Sci. USA. 118, e2009539118 (2021).

Stocum, D. L. The role of peripheral nerves in urodele limb regeneration. Eur. J. Neurosci. 34, 908–916 (2011).

Endo, T., Bryant, S. V. & Gardiner, D. M. A stepwise model system for limb regeneration. Dev. Biol. 270, 135–145 (2004).

Kumar, A. & Brockes, J. P. Nerve dependence in tissue, organ, and appendage regeneration. Trends Neurosci. 35, 691–699 (2012).

Dolan, C. P. et al. Axonal regrowth is impaired during digit tip regeneration in mice. Dev. Biol. 445, 237–244 (2019).

Xu, Y. et al. Inferior alveolar nerve transection disturbs innate immune responses and bone healing after tooth extraction. Ann. N. Y. Acad. Sci. 1448, 52–64 (2019).

Cao, J. et al. Sensory nerves affect bone regeneration in rabbit mandibular distraction osteogenesis. Int J. Med Sci. 16, 831–837 (2019).

Felgueiras, H. P. Emerging antimicrobial and immunomodulatory fiber-based scaffolding systems for treating diabetic foot ulcers. Pharmaceutics. 15, 258 (2023).

Louiselle, A. E., Niemiec, S. M., Zgheib, C. & Liechty, K. W. Macrophage polarization and diabetic wound healing. Transl. Res. 236, 109–116 (2021).

Nowak, N. C., Menichella, D. M., Miller, R. & Paller, A. S. Cutaneous innervation in impaired diabetic wound healing. Transl. Res. 236, 87–108 (2021).

Yu, F. X. et al. The impact of sensory neuropathy and inflammation on epithelial wound healing in diabetic corneas. Prog. Retin Eye Res. 89, 101039 (2022).

Leal, E. C. et al. Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype. Am. J. Pathol. 185, 1638–1648 (2015).

Zhang, Y. et al. Role of VIP and sonic hedgehog signaling pathways in mediating epithelial wound healing, sensory nerve regeneration, and their defects in diabetic corneas. Diabetes 69, 1549–1561 (2020).

Yagi, S., Hirata, M., Miyachi, Y. & Uemoto, S. Liver Regeneration after Hepatectomy and Partial Liver Transplantation. Int. J. Mol. Sci. 21, 8414 (2020).

Miller, B. M., Oderberg, I. M. & Goessling, W. Hepatic nervous system in development, regeneration, and disease. Hepatology 74, 3513–3522 (2021).

Tanaka, K., Ohkawa, S., Nishino, T., Niijima, A. & Inoue, S. Role of the hepatic branch of the vagus nerve in liver regeneration in rats. Am. J. Physiol. 253, G439–G444 (1987).

Izumi, T. et al. Vagus-macrophage-hepatocyte link promotes post-injury liver regeneration and whole-body survival through hepatic FoxM1 activation. Nat. Commun. 9, 5300 (2018).

Mizutani, T. et al. Calcitonin gene-related peptide regulates the early phase of liver regeneration. J. Surg. Res. 183, 138–145 (2013).

Laschinger, M. et al. The CGRP receptor component RAMP1 links sensory innervation with YAP activity in the regenerating liver. FASEB J. 34, 8125–8138 (2020).

Kim, J. H. et al. Neural cell integration into 3D bioprinted skeletal muscle constructs accelerates restoration of muscle function. Nat. Commun. 11, 1025 (2020).

Lepore, E., Casola, I., Dobrowolny, G. & Musarò, A. Neuromuscular junction as an entity of nerve-muscle communication. Cells. 8(2019).

Cisterna, B. A. et al. Active acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation. Nat. Commun. 11, 1073 (2020).

Ciciliot, S. & Schiaffino, S. Regeneration of mammalian skeletal muscle. Basic mechanisms and clinical implications. Clin. Implic. Curr. Pharm. Des. 16, 906–914 (2010).

Liu, L., Dana, R. & Yin, J. Sensory neurons directly promote angiogenesis in response to inflammation via substance P signaling. FASEB J. 34, 6229–6243 (2020).

Jacobsen, N. L., Morton, A. B. & Segal, S. S. Angiogenesis precedes myogenesis during regeneration following biopsy injury of skeletal muscle. Skelet. Muscle 13, 3 (2023).

Mastorakos, P. & McGavern, D. The anatomy and immunology of vasculature in the central nervous system. Sci. Immunol. 4, eaav0492 (2019).

Bajayo, A. et al. Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual. Proc. Natl. Acad. Sci. USA. 109, 15455–15460 (2012).

Varadarajan, S. G., Hunyara, J. L., Hamilton, N. R., Kolodkin, A. L. & Huberman, A. D. Central nervous system regeneration. Cell 185, 77–94 (2022).

Xia, W. et al. Damaged brain accelerates bone healing by releasing small extracellular vesicles that target osteoprogenitors. Nat. Commun. 12, 6043 (2021).

Shehab, D., Elgazzar, A. H. & Collier, B. D. Heterotopicossification ossification. J. Nucl. Med. 43, 346–353 (2002).

Xu, Y. et al. Heterotopic ossification: Clinical features, basic researches, and mechanical stimulations. Front. Cell Dev. Biol. 10, 770931 (2022).

Shams, R. et al. The pathophysiology of osteoporosis after spinal cord injury. Int. J. Mol. Sci. 22, 3057 (2021).

Zeng, L. et al. Guidelines for management of pediatric acute hyperextension spinal cord injury. Chin. J. Traumatol. 26, 2–7 (2023).

Zhang, L. et al. Bidirectional control of parathyroid hormone and bone mass by subfornical organ. Neuron 111, 1914–1932.e6 (2023).

Huang, S. et al. Neural regulation of bone remodeling: Identifying novel neural molecules and pathways between brain and bone. J. Cell. Physiol. 234, 5466–5477 (2019).

Zhang, Z. et al. Neuro-bone tissue engineering: Multiple potential translational strategies between nerve and bone. Acta Biomater. 153, 1–12 (2022).

Elefteriou, F. Regulation of bone remodeling by the central and peripheral nervous system. Arch. Biochem. Biophys. 473, 231–236 (2008).

Dimitri, P. & Rosen, C. The central nervous system and bone metabolism: an evolving story. Calcif. Tissue Int. 100, 476–485 (2017).

Maryanovich, M., Takeishi, S. & Frenette, P. S. Neural regulation of bone and bone marrow. Cold Spring Harb Perspect Med. 8, a031344 (2018).

van Galen, K. A., Ter Horst, K. W. & Serlie, M. J. Serotonin, food intake, and obesity. Obes. Rev. 22, e13210 (2021).

Chabbi-Achengli, Y. et al. Decreased osteoclastogenesis in serotonin-deficient mice. Proc. Natl. Acad. Sci. USA. 109, 2567–2572 (2012).

Nam, S. S. et al. Serotonin inhibits osteoblast differentiation and bone regeneration in rats. J. Periodontol. 87, 461–469 (2016).

Yun, H. M., Park, K. R., Hong, J. T. & Kim, E. C. Peripheral serotonin-mediated system suppresses bone development and regeneration via serotonin 6 G-protein-coupled receptor. Sci. Rep. 6, 30985 (2016).

Yadav, V. K. et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135, 825–837 (2008).

Kode, A. et al. FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin. J. Clin. Invest. 122, 3490–3503 (2012).

Yadav, V. K. et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 138, 976–989 (2009).

Kumar, M., Wadhwa, R., Kothari, P., Trivedi, R. & Vohora, D. Differential effects of serotonin reuptake inhibitors fluoxetine and escitalopram on bone markers and microarchitecture in Wistar rats. Eur. J. Pharmacol. 825, 57–62 (2018).

Durham, E., Zhang, Y., LaRue, A., Bradshaw, A. & Cray, J. Selective serotonin reuptake inhibitors (SSRI) affect murine bone lineage cells. Life Sci. 255, 117827 (2020).

Ferretti, G. et al. An increase in Semaphorin 3A biases the axonal direction and induces an aberrant dendritic arborization in an in vitro model of human neural progenitor differentiation. Cell Biosci. 12, 182 (2022).

Hayashi, M. et al. Osteoprotection by semaphorin 3A. Nature 485, 69–74 (2012).

Kim, B. J. & Koh, J. M. Coupling factors involved in preserving bone balance. Cell. Mol. Life Sci. 76, 1243–1253 (2019).

Fukuda, T. et al. Sema3A regulates bone-mass accrual through sensory innervations. Nature 497, 490–493 (2013).

Li, Z. et al. The role of semaphorin 3A in bone remodeling. Front. Cell Neurosci. 11, 40 (2017).

Sun, S. et al. No pain, no gain? The effects of pain-promoting neuropeptides and neurotrophins on fracture healing. Bone 131, 115109 (2020).

Pezet, S. & McMahon, S. B. Neurotrophins: mediators and modulators of pain. Annu. Rev. Neurosci. 29, 507–538 (2006).

Su, Y. W. et al. Roles of neurotrophins in skeletal tissue formation and healing. J. Cell. Physiol. 233, 2133–2145 (2018).

Ida-Yonemochi, H., Yamada, Y., Yoshikawa, H. & Seo, K. Locally produced BDNF promotes sclerotic change in alveolar bone after nerve injury. PLoS One 12, e0169201 (2017).

Liu, Q., Lei, L., Yu, T., Jiang, T. & Kang, Y. Effect of brain-derived neurotrophic factor on the neurogenesis and osteogenesis in bone engineering. Tissue Eng. Part A 24, 1283–1292 (2018).

Zhang, Z., Hu, P., Wang, Z., Qiu, X. & Chen, Y. BDNF promoted osteoblast migration and fracture healing by up-regulating integrin β1 via TrkB-mediated ERK1/2 and AKT. Signal. J. Cell. Mol. Med. 24, 10792–10802 (2020).

Ai, L. S. et al. Inhibition of BDNF in multiple myeloma blocks osteoclastogenesis via down-regulated stroma-derived RANKL expression both in vitro and in vivo. PLoS One 7, e46287 (2012).

Wan, Q. Q. et al. Crosstalk between Bone and Nerves within Bone. Adv. Sci. (Weinh). 8, 2003390 (2021).

Elefteriou, F. Impact of the autonomic nervous system on the skeleton. Physiol. Rev. 98, 1083–1112 (2018).

Kang, H. W. et al. A 3D bioprinting system to produce human-scale tissue constructs with structural integrity. Nat. Biotechnol. 34, 312–319 (2016).

Li, J., Kreicbergs, A., Bergström, J., Stark, A. & Ahmed, M. Site-specific CGRP innervation coincides with bone formation during fracture healing and modeling: A study in rat angulated tibia. J. Orthop. Res. 25, 1204–1212 (2007).

Li, J., Ahmad, T., Spetea, M., Ahmed, M. & Kreicbergs, A. Bone reinnervation after fracture: a study in the rat. J. Bone Miner. Res. 16, 1505–1510 (2001).

Pagani, F. et al. Sympathectomy alters bone architecture in adult growing rats. J. Cell. Biochem. 104, 2155–2164 (2008).

Elefteriou, F. et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434, 514–520 (2005).

Burt-Pichat, B. et al. Dramatic decrease of innervation density in bone after ovariectomy. Endocrinology 146, 503–510 (2005).

Mano, T., Nishimura, N. & Iwase, S. Sympathetic neural influence on bone metabolism in microgravity (Review). Acta Physiol. Hung. 97, 354–361 (2010).

Vignaux, G., Ndong, J. D., Perrien, D. S. & Elefteriou, F. Inner ear vestibular signals regulate bone remodeling via the sympathetic nervous system. J. Bone Miner. Res. 30, 1103–1111 (2015).

Matteoli, M. et al. Differential effect of alpha-latrotoxin on exocytosis from small synaptic vesicles and from large dense-core vesicles containing calcitonin gene-related peptide at the frog neuromuscular junction. Proc. Natl. Acad. Sci. USA 85, 7366–7370 (1988).

Zhang, Y. et al. Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats. Nat. Med. 22, 1160–1169 (2016).

Zhou, R., Yuan, Z., Liu, J. & Liu, J. Calcitonin gene-related peptide promotes the expression of osteoblastic genes and activates the WNT signal transduction pathway in bone marrow stromal stem cells. Mol. Med. Rep. 13, 4689–4696 (2016).

Li, H. et al. Corrigendum: CGRP regulates the age-related switch between osteoblast and adipocyte differentiation. Front. Cell Dev. Biol. 9, 715740 (2021).

Assefa, F. The role of sensory and sympathetic nerves in craniofacial bone regeneration. Neuropeptides 99, 102328 (2023).

Wang, L. et al. Calcitonin-gene-related peptide stimulates stromal cell osteogenic differentiation and inhibits RANKL induced NF-kappaB activation, osteoclastogenesis and bone resorption. Bone 46, 1369–1379 (2010).

He, H. et al. CGRP may regulate bone metabolism through stimulating osteoblast differentiation and inhibiting osteoclast formation. Mol. Med. Rep. 13, 3977–3984 (2016).

Gaete, P. S., Lillo, M. A., Puebla, M., Poblete, I. & Figueroa, X. F. CGRP signalling inhibits NO production through pannexin-1 channel activation in endothelial cells. Sci. Rep. 9, 7932 (2019).

Li, Y. et al. Biodegradable magnesium combined with distraction osteogenesis synergistically stimulates bone tissue regeneration via CGRP-FAK-VEGF signaling axis. Biomaterials 275, 120984 (2021).

Mi, J. et al. Implantable electrical stimulation at dorsal root ganglions accelerates osteoporotic fracture healing via calcitonin gene-related peptide. Adv. Sci. (Weinh.) 9, e2103005 (2022).

Niedermair, T., Straub, R. H., Brochhausen, C. & Gr„ssel, S. Impact of the sensory and sympathetic nervous system on fracture healing in ovariectomized mice. Int. J. Mol. Sci. 21, 405 (2020).

Yuan, Y. et al. Deficiency of calcitonin gene-related peptide affects macrophage polarization in osseointegration. Front. Physiol. 11, 733 (2020).

Duan, J. X. et al. Calcitonin gene-related peptide exerts anti-inflammatory property through regulating murine macrophages polarization in vitro. Mol. Immunol. 91, 105–113 (2017).

Yuan, K. et al. Sensory nerves promote corneal inflammation resolution via CGRP mediated transformation of macrophages to the M2 phenotype through the PI3K/AKT signaling pathway. Int. Immunopharmacol. 102, 108426 (2022).

Harrison, S. & Geppetti, P. Substance p. Int. J. Biochem. Cell Biol. 33, 555-576 (2001).

Liu, D., Jiang, L. S., Dai, L. Y. & Substance, P. and its receptors in bone metabolism. Neuropeptides 41, 271–283 (2007).

Mei, G. et al. Substance P activates the Wnt signal transduction pathway and enhances the differentiation of mouse preosteoblastic MC3T3-E1 cells. Int. J. Mol. Sci. 15, 6224–6240 (2014).

Geng, W. et al. Substance P enhances BMSC osteogenic differentiation via autophagic activation. Mol. Med. Rep. 20, 664–670 (2019).

Adamus, M. A. & Dabrowski, Z. J. Effect of the neuropeptide substance P on the rat bone marrow-derived osteogenic cells in vitro. J. Cell. Biochem. 81, 499–506 (2001).

Zhang, Y. et al. Systemic injection of substance P promotes murine calvarial repair through mobilizing endogenous mesenchymal stem cells. Sci. Rep. 8, 12996 (2018).

Liu, H. J. et al. Substance P promotes the proliferation, but inhibits differentiation and mineralization of osteoblasts from rats with spinal cord injury via RANKL/OPG system. PLoS One 11, e0165063 (2016).

Guo, X. et al. Clinical guidelines for neurorestorative therapies in spinal cord injury (2021 China version). J. Neurorestoratol. 9, 31–49 (2021).

Mori, T. et al. Substance P regulates the function of rabbit cultured osteoclast; increase of intracellular free calcium concentration and enhancement of bone resorption. Biochem. Biophys. Res. Commun. 262, 418–422 (1999).

Wang, L. et al. Substance P stimulates bone marrow stromal cell osteogenic activity, osteoclast differentiation, and resorption activity in vitro. Bone 45, 309–320 (2009).

Offley, S. C. et al. Capsaicin-sensitive sensory neurons contribute to the maintenance of trabecular bone integrity. J. Bone Miner. Res. 20, 257–267 (2005).

Um, J., Yu, J., Dubon, M. J. & Park, K. S. Substance P and thiorphan synergically enhance angiogenesis in wound healing. Tissue Eng. Regen. Med. 13, 149–154 (2016).

Um, J., Yu, J. & Park, K. S. Substance P accelerates wound healing in type 2 diabetic mice through endothelial progenitor cell mobilization and Yes-associated protein activation. Mol. Med Rep. 15, 3035–3040 (2017).

Hong, J. Y. et al. Self-assembling peptide gels promote angiogenesis and functional recovery after spinal cord injury in rats. J. Tissue Eng. 13, 20417314221086491 (2022).

Jiang, M. H. et al. Substance P induces M2-type macrophages after spinal cord injury. Neuroreport 23, 786–792 (2012).

Liu, S. et al. Somatotopic organization and intensity dependence in driving distinct NPY-expressing sympathetic pathways by electroacupuncture. Neuron 108, 436–450.e7 (2020).

Vähätalo, L. H., Ruohonen, S. T., Ailanen, L. & Savontaus, E. Neuropeptide Y in noradrenergic neurons induces obesity in transgenic mouse models. Neuropeptides 55, 31–37 (2016).

Xie, W. et al. Neuropeptide Y1 receptor antagonist promotes osteoporosis and microdamage repair and enhances osteogenic differentiation of bone marrow stem cells via cAMP/PKA/CREB pathway. Aging (Albany NY) 12, 8120–8136 (2020).

Lee, N. J. et al. Critical role for Y1 receptors in mesenchymal progenitor cell differentiation and osteoblast activity. J. Bone Miner. Res. 25, 1736–1747 (2010).

Zhang, Y. et al. Neuronal induction of bone-fat imbalance through osteocyte neuropeptide Y. Adv. Sci. (Weinh.) 8, e2100808 (2021).

Long, H., Ahmed, M., Ackermann, P., Stark, A. & Li, J. Neuropeptide Y innervation during fracture healing and remodeling. A study of angulated tibial fractures in the rat. Acta Orthop. 81, 639–646 (2010).

Wu, J. et al. Neuropeptide Y enhances proliferation and prevents apoptosis in rat bone marrow stromal cells in association with activation of the Wnt/β-catenin pathway in vitro. Stem Cell Res. 21, 74–84 (2017).

Baldock, P. A. et al. Neuropeptide y attenuates stress-induced bone loss through suppression of noradrenaline circuits. J. Bone Miner. Res. 29, 2238–2249 (2014).

Gu, X. C., Zhang, X. B., Hu, B., Zi, Y. & Li, M. Neuropeptide Y accelerates post-fracture bone healing by promoting osteogenesis of mesenchymal stem cells. Neuropeptides 60, 61–66 (2016).

Sousa, D. M. et al. Neuropeptide Y modulates fracture healing through Y1 receptor signaling. J. Orthop. Res. 31, 1570–1578 (2013).

Liu, S. et al. Neuropeptide Y stimulates osteoblastic differentiation and VEGF expression of bone marrow mesenchymal stem cells related to canonical Wnt signaling activating in vitro. Neuropeptides 56, 105–113 (2016).

Shi, L. et al. Function study of vasoactive intestinal peptide on chick embryonic bone development. Neuropeptides 83, 102077 (2020).

Moody, T. W., Nuche-Berenguer, B. & Jensen, R. T. Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer. Curr. Opin. Endocrinol. Diabetes Obes. 23, 38–47 (2016).

Shi, L. et al. Vasoactive intestinal peptide stimulates bone marrow-mesenchymal stem cells osteogenesis differentiation by activating Wnt/β-catenin signaling pathway and promotes rat skull defect repair. Stem Cells Dev. 29, 655–666 (2020).

Liu, X. et al. Postmenopausal osteoporosis is associated with the regulation of SP, CGRP, VIP, and NPY. Biomed. Pharmacother. 104, 742–750 (2018).

Shi, L. et al. Vasoactive intestinal peptide promotes fracture healing in sympathectomized mice. Calcif. Tissue Int. 109, 55–65 (2021).

Eger, M. et al. Therapeutic potential of vasoactive intestinal peptide and its derivative stearyl-norleucine-VIP in inflammation-induced osteolysis. Front. Pharm. 12, 638128 (2021).

Valdehita, A., Carmena, M. J., Collado, B., Prieto, J. C. & Bajo, A. M. Vasoactive intestinal peptide (VIP) increases vascular endothelial growth factor (VEGF) expression and secretion in human breast cancer cells. Regul. Pept. 144, 101–108 (2007).

Kanemitsu, M. et al. Role of vasoactive intestinal peptide in the progression of osteoarthritis through bone sclerosis and angiogenesis in subchondral bone. J. Orthop. Sci. 25, 897–906 (2020).

Wang, Y. et al. In-situ-generated vasoactive intestinal peptide loaded microspheres in mussel-inspired polycaprolactone nanosheets creating spatiotemporal releasing microenvironment to promote wound healing and angiogenesis. ACS Appl. Mater. Interfaces 8, 7411–7421 (2016).

Ivanov, E., Akhmetshina, M., Erdiakov, A. & Gavrilova, S. Sympathetic system in wound healing: Multistage control in normal and diabetic skin. Int. J. Mol. Sci. 24, 2045 (2023).

Khosla, S. et al. Sympathetic β1-adrenergic signaling contributes to regulation of human bone metabolism. J. Clin. Invest. 128, 4832–4842 (2018).

Karsenty, G. & Khosla, S. The crosstalk between bone remodeling and energy metabolism: A translational perspective. Cell Metab. 34, 805–817 (2022).

Hedderich, J. et al. Norepinephrine inhibits the proliferation of human bone marrow-derived mesenchymal stem cells via β2-adrenoceptor-mediated ERK1/2 and PKA phosphorylation. Int. J. Mol. Sci. 21, 3924 (2020).

Ma, Y. et al. 2-Adrenergic receptor signaling in osteoblasts contributes to the catabolic effect of glucocorticoids on bone. Endocrinology 152, 1412–1422 (2011).

Yao, Q. et al. Beta-adrenergic signaling affect osteoclastogenesis via osteocytic MLO-Y4 cells’ RANKL production. Biochem. Biophys. Res. Commun. 488, 634–640 (2017).

Chen, H. et al. Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis. Nat. Commun. 10, 181 (2019).

Wu, H. et al. Blockade of adrenergic β-receptor activation through local delivery of propranolol from a 3D collagen/polyvinyl alcohol/hydroxyapatite scaffold promotes bone repair in vivo. Cell Prolif. 53, e12725 (2020).

Haffner-Luntzer, M. et al. Chronic psychosocial stress compromises the immune response and endochondral ossification during bone fracture healing via β-AR signaling. Proc. Natl. Acad. Sci. USA 116, 8615–8622 (2019).

Sato, T. et al. Functional role of acetylcholine and the expression of cholinergic receptors and components in osteoblasts. FEBS Lett. 584, 817–824 (2010).

Huang, Q., Liao, C., Ge, F., Ao, J. & Liu, T. Acetylcholine bidirectionally regulates learning and memory. J. Neurorestoratol. 10, 100002 (2022).

Mandl, P. et al. Nicotinic acetylcholine receptors modulate osteoclastogenesis. Arthritis Res. Ther. 18, 63 (2016).

Negishi-Koga, T. & Takayanagi, H. Ca²⁺-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol. Rev. 231, 241–256 (2009).

Ternes, S. et al. Impact of acetylcholine and nicotine on human osteoclastogenesis in vitro. Int. Immunopharmacol. 29, 215–221 (2015).

Spieker, J., Ackermann, A., Salfelder, A., Vogel-Höpker, A. & Layer, P. G. Acetylcholinesterase regulates skeletal in ovo development of chicken limbs by ACh-dependent and -independent mechanisms. PLoS One 11, e0161675 (2016).

Lv, X., Gao, F. & Cao, X. Skeletal interoception in bone homeostasis and pain. Cell Metab. 34, 1914–1931 (2022).

Zhang, Y. Y. et al. Microsomal prostaglandin E2 synthase-1 and its inhibitors: Molecular mechanisms and therapeutic significance. Pharmacol. Res. 175, 105977 (2022).

Lisowska, B., Kosson, D. & Domaracka, K. Positives and negatives of nonsteroidal anti-inflammatory drugs in bone healing: the effects of these drugs on bone repair. Drug Des. Devel. Ther. 12, 1809–1814 (2018).

Hu, B. et al. Sensory nerves regulate mesenchymal stromal cell lineage commitment by tuning sympathetic tones. J. Clin. Invest. 130, 3483–3498 (2020).

Xue, P. et al. PGE2/EP4 skeleton interoception activity reduces vertebral endplate porosity and spinal pain with low-dose celecoxib. Bone Res. 9, 36 (2021).

Qiao, W. et al. Divalent metal cations stimulate skeleton interoception for new bone formation in mouse injury models. Nat. Commun. 13, 535 (2022).

Rousseaud, A., Moriceau, S., Ramos-Brossier, M. & Oury, F. Bone-brain crosstalk and potential associated diseases. Horm. Mol. Biol. Clin. Investig. 28, 69–83 (2016).

Pinho-Ribeiro, F. A., Verri, W. A. Jr & Chiu, I. M. Nociceptor Sensory Neuron-Immune Interactions in Pain and Inflammation. Trends Immunol. 38, 5–19 (2017).

Baral, P., Udit, S. & Chiu, I. M. Pain and immunity: implications for host defence. Nat. Rev. Immunol. 19, 433–447 (2019).

Gordon, T. Peripheral nerve regeneration and muscle reinnervation. Int. J. Mol. Sci. 21, 8652 (2020).

Yang, S. et al. Self-assembling peptide hydrogels functionalized with LN- and BDNF- mimicking epitopes synergistically enhance peripheral nerve regeneration. Theranostics 10, 8227–8249 (2020).

Chartier, S. R. et al. Exuberant sprouting of sensory and sympathetic nerve fibers in nonhealed bone fractures and the generation and maintenance of chronic skeletal pain. Pain 155, 2323–2336 (2014).

Asaumi, K., Nakanishi, T., Asahara, H., Inoue, H. & Takigawa, M. Expression of neurotrophins and their receptors (TRK) during fracture healing. Bone 26, 625–633 (2000).

Ding, W. G. et al. Changes of substance P during fracture healing in ovariectomized mice. Regul. Pept. 159, 28–34 (2010).

Kilian, O. et al. BDNF and its TrkB receptor in human fracture healing. Ann. Anat. 196, 286–295 (2014).

Lin, Y. et al. Decreased expression of semaphorin3A/neuropilin-1 signaling axis in apical periodontitis. Biomed. Res. Int. 2017, 8724503 (2017).

Tang, P. et al. NPY and CGRP inhibitor influence on ERK pathway and macrophage aggregation during fracture healing. Cell. Physiol. Biochem. 41, 1457–1467 (2017).

Appelt, J. et al. The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing. EBioMedicine 59, 102970 (2020).

Lim, J. E., Chung, E. & Son, Y. A neuropeptide, Substance-P, directly induces tissue-repairing M2 like macrophages by activating the PI3K/Akt/mTOR pathway even in the presence of IFNγ. Sci. Rep. 7, 9417 (2017).

Schmidt, A. H. Autologous bone graft: is it still the gold standard. Injury 52, S18–18S22 (2021).

Hofmann, A. et al. Autologous Iliac bone graft compared with biphasic hydroxyapatite and calcium sulfate cement for the treatment of bone defects in tibial plateau fractures: A prospective, randomized, open-label, multicenter study. J. Bone Jt. Surg. Am. 102, 179–193 (2020).

Tournier, P. et al. An extrudable partially demineralized allogeneic bone paste exhibits a similar bone healing capacity as the “Gold Standard” bone graft. Front. Bioeng. Biotechnol. 9, 658853 (2021).

Steijvers, E., Ghei, A. & Xia, Z. Manufacturing artificial bone allografts: a perspective. Biomater. Transl. 3, 65–80 (2022).

Bharadwaz, A. & Jayasuriya, A. C. Recent trends in the application of widely used natural and synthetic polymer nanocomposites in bone tissue regeneration. Mater. Sci. Eng. C. Mater. Biol. Appl. 110, 110698 (2020).

Borkowski, L. et al. Fluorapatite ceramics for bone tissue regeneration: Synthesis, characterization and assessment of biomedical potential. Mater. Sci. Eng. C. Mater. Biol. Appl. 116, 111211 (2020).

Guo, L. et al. The role of natural polymers in bone tissue engineering. J. Control Release 338, 571–582 (2021).

Kang, Y. et al. Exosome-functionalized magnesium-organic framework-based scaffolds with osteogenic, angiogenic and anti-inflammatory properties for accelerated bone regeneration. Bioact. Mater. 18, 26–41 (2022).

Rao, F. et al. Aligned chitosan nanofiber hydrogel grafted with peptides mimicking bioactive brain-derived neurotrophic factor and vascular endothelial growth factor repair long-distance sciatic nerve defects in rats. Theranostics 10, 1590–1603 (2020).

Fitzpatrick, V. et al. Functionalized 3D-printed silk-hydroxyapatite scaffolds for enhanced bone regeneration with innervation and vascularization. Biomaterials 276, 120995 (2021).

Toosi, S. et al. Bioactive glass-collagen/poly (glycolic acid) scaffold nanoparticles exhibit improved biological properties and enhance osteogenic lineage differentiation of mesenchymal stem cells. Front. Bioeng. Biotechnol. 10, 963996 (2022).

Lei, L. et al. Injectable colloidal hydrogel with mesoporous silica nanoparticles for sustained co-release of microRNA-222 and aspirin to achieve innervated bone regeneration in rat mandibular defects. J. Mater. Chem. B 7, 2722–2735 (2019).

Li, Y. et al. Artificial PGA/collagen-based bilayer conduit in short gap interposition setting provides comparable regenerative potential to direct suture. Plast. Reconstr. Surg. Glob. Open 11, e4875 (2023).

Dos Santos, B. P. et al. Development of a cell-free and growth factor-free hydrogel capable of inducing angiogenesis and innervation after subcutaneous implantation. Acta Biomater. 99, 154–167 (2019).

Ardhani, R., Ana, I. D. & Tabata, Y. Gelatin hydrogel membrane containing carbonate hydroxyapatite for nerve regeneration scaffold. J. Biomed. Mater. Res. A 108, 2491–2503 (2020).

Yan, X. et al. PDLLA/β-TCP/HA/CHS/NGF sustained-release conduits for peripheral nerve regeneration. J. Wuhan. Univ. Technol. Mater. Sci. Ed. 36, 600–606 (2021).

Wu, H. et al. Dynamic degradation patterns of porous polycaprolactone/β-tricalcium phosphate composites orchestrate macrophage responses and immunoregulatory bone regeneration. Bioact. Mater. 21, 595–611 (2023).

Qi, X. et al. Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats. Int. J. Biol. Sci. 12, 836–849 (2016).

Liu, T., Li, B., Chen, G., Ye, X. & Zhang, Y. Nano tantalum-coated 3D printed porous polylactic acid/beta-tricalcium phosphate scaffolds with enhanced biological properties for guided bone regeneration. Int. J. Biol. Macromol. 221, 371–380 (2022).

Xu, Y. et al. Stratified-structural hydrogel incorporated with magnesium-ion-modified black phosphorus nanosheets for promoting neuro-vascularized bone regeneration. Bioact. Mater. 16, 271–284 (2022).

Jing, X. et al. Photosensitive and conductive hydrogel induced innerved bone regeneration for infected bone defect repair. Adv. Health. Mater. 12, e2201349 (2023).

Ye, B., Wu, B., Su, Y., Sun, T. & Guo, X. Recent advances in the application of natural and synthetic polymer-based scaffolds in musculoskeletal regeneration. Polymers. 14(2022).

Ma, Q. L. et al. Improved implant osseointegration of a nanostructured titanium surface via mediation of macrophage polarization. Biomaterials 35, 9853–9867 (2014).

Li, J. et al. Valence state manipulation of cerium oxide nanoparticles on a titanium surface for modulating cell fate and bone formation. Adv. Sci. (Weinh.) 5, 1700678 (2018).

Kohno, Y. et al. Treating titanium particle-induced inflammation with genetically modified NF-κB sensing IL-4 secreting or preconditioned mesenchymal stem cells in vitro. ACS Biomater. Sci. Eng. 5, 3032–3038 (2019).

Arthur, A. & Gronthos, S. Clinical application of bone marrow mesenchymal stem/stromal cells to repair skeletal tissue. Int. J. Mol. Sci. 21(2020).

Cai, X. X., Luo, E. & Yuan, Q. Interaction between Schwann cells and osteoblasts in vitro. Int. J. Oral. Sci. 2, 74–81 (2010).

Zhang, H. et al. Calcium silicate nanowires-containing multicellular bioinks for 3D bioprinting of neural-bone constructs. Nano Today 46, 101584 (2022).

Wu, Y. et al. Pre-implanted sensory nerve could enhance the neurotization in tissue-engineered bone graft. Tissue Eng. Part A 21, 2241–2249 (2015).

Wang, S. et al. BMSC-derived extracellular matrix better optimizes the microenvironment to support nerve regeneration. Biomaterials 280, 121251 (2022).

Raoofi, A. et al. Bone marrow mesenchymal stem cell condition medium loaded on PCL nanofibrous scaffold promoted nerve regeneration after sciatic nerve transection in male rats. Neurotox. Res. 39, 1470–1486 (2021).

Jessen, K. R. & Mirsky, R. The repair Schwann cell and its function in regenerating nerves. J. Physiol. (Lond.). 594, 3521–3531 (2016).

Schlosshauer, B., Müller, E., Schröder, B., Planck, H. & Müller, H. W. Rat Schwann cells in bioresorbable nerve guides to promote and accelerate axonal regeneration. Brain Res. 963, 321–326 (2003).

Keilhoff, G., Goihl, A., Langnäse, K., Fansa, H. & Wolf, G. Transdifferentiation of mesenchymal stem cells into Schwann cell-like myelinating cells. Eur. J. Cell Biol. 85, 11–24 (2006).

Jones, R. E. et al. Skeletal stem cell-schwann cell circuitry in mandibular repair. Cell Rep. 28, 2757–2766.e5 (2019).

Wang, D. et al. Schwann cell-derived EVs facilitate dental pulp regeneration through endogenous stem cell recruitment via SDF-1/CXCR4 axis. Acta Biomater. 140, 610–624 (2022).

Zhang, X. et al. Schwann cells promote prevascularization and osteogenesis of tissue-engineered bone via bone marrow mesenchymal stem cell-derived endothelial cells. Stem Cell Res. Ther. 12, 382 (2021).

Filipowska, J., Tomaszewski, K. A., Niedźwiedzki, Ł., Walocha, J. A. & Niedźwiedzki, T. The role of vasculature in bone development, regeneration and proper systemic functioning. Angiogenesis 20,291–302 (2017).

Lu, J. et al. Synergistic effects of dual-presenting VEGF- and BDNF-mimetic peptide epitopes from self-assembling peptide hydrogels on peripheral nerve regeneration. Nanoscale 11, 19943–19958 (2019).

Muangsanit, P., Roberton, V., Costa, E. & Phillips, J. B. Engineered aligned endothelial cell structures in tethered collagen hydrogels promote peripheral nerve regeneration. Acta Biomater. 126, 224–237 (2021).

Meng, D. H. et al. Endothelial cells promote the proliferation and migration of Schwann cells. Ann. Transl. Med. 10, 78 (2022).

Qin, C. et al. Cell-laden scaffolds for vascular-innervated bone regeneration. Adv Healthc. Mater. 12, e2201923 (2023).

Oliveira, É. R. et al. Advances in growth factor delivery for bone tissue engineering. Int. J. Mol. Sci. 22(2021).

Legrand, J. & Martino, M. M. Growth factor and cytokine delivery systems for wound healing. Cold Spring Harb. Perspect Biol. 14(2022).

Seims, K. B., Hunt, N. K. & Chow, L. W. Strategies to control or mimic growth factor activity for bone, cartilage, and osteochondral tissue engineering. Bioconjug. Chem. 32, 861–878 (2021).

Wu, M., Chen, G. & Li, Y. P. TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 4, 16009 (2016).

Liu, X. et al. Immunopolarization-regulated 3D printed-electrospun fibrous scaffolds for bone regeneration. Biomaterials 276, 121037 (2021).

Chai, S. et al. Injectable photo-crosslinked bioactive BMSCs-BMP2-GelMA scaffolds for bone defect repair. Front. Bioeng. Biotechnol. 10, 875363 (2022).

Pulkkinen, H. H. et al. BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF. Angiogenesis 24, 129–144 (2021).

Gillman, C. E. & Jayasuriya, A. C. FDA-approved bone grafts and bone graft substitute devices in bone regeneration. Mater. Sci. Eng. C. Mater. Biol. Appl. 130, 112466 (2021).

Nicoletti, V. G., Pajer, K., Calcagno, D., Pajenda, G. & Nógrádi, A. The role of metals in the neuroregenerative action of BDNF, GDNF, NGF and other neurotrophic factors. Biomolecules. 12(2022).

Lien, B. V. et al. Enhancing peripheral nerve regeneration with neurotrophic factors and bioengineered scaffolds: A basic science and clinical perspective. J. Peripher. Nerv. Syst. 25, 320–334 (2020).

Idrisova, K. F. et al. Application of neurotrophic and proangiogenic factors as therapy after peripheral nervous system injury. Neural Regen. Res. 17, 1240–1247 (2022).

Zhou, G. et al. Nanofibrous nerve conduits with nerve growth factors and bone marrow stromal cells pre-cultured in bioreactors for peripheral nerve regeneration. ACS Appl. Mater. Interfaces 12, 16168–16177 (2020).

Carvalho, C. R. et al. Engineering silk fibroin-based nerve conduit with neurotrophic factors for proximal protection after peripheral nerve injury. Adv. Health. Mater. 10, e2000753 (2021).

Escobar, A., Reis, R. L. & Oliveira, J. M. Nanoparticles for neurotrophic factor delivery in nerve guidance conduits for peripheral nerve repair. Nanomed. (Lond.) 17, 477–494 (2022).

Safari, B., Davaran, S. & Aghanejad, A. Osteogenic potential of the growth factors and bioactive molecules in bone regeneration. Int. J. Biol. Macromol. 175, 544–557 (2021).

James, A. W. et al. A review of the clinical side effects of bone morphogenetic protein-2. Tissue Eng. Part B Rev. 22, 284–297 (2016).

Hashimoto, K. et al. In vivo dynamic analysis of BMP-2-induced ectopic bone formation. Sci. Rep. 10, 4751 (2020).

Gabarin, N. et al. Mitogenic G(i) protein-MAP kinase signaling cascade in MC3T3-E1 osteogenic cells: activation by C-terminal pentapeptide of osteogenic growth peptide [OGP(10-14)] and attenuation of activation by cAMP. J. Cell. Biochem. 81, 594–603 (2001).

Kim, H. K. et al. Osteogenesis induced by a bone forming peptide from the prodomain region of BMP-7. Biomaterials 33, 7057–7063 (2012).

Sun, T. et al. Loading of BMP-2-related peptide onto three-dimensional nano-hydroxyapatite scaffolds accelerates mineralization in critical-sized cranial bone defects. J. Tissue Eng. Regen. Med. 12, 864–877 (2018).

Li, A. et al. Nanohydroxyapatite/polyamide 66 crosslinked with QK and BMP-2-derived peptide prevented femur nonunion in rats. J. Mater. Chem. B 9, 2249–2265 (2021).

Li, C. et al. Polydopamine-modified chitin conduits with sustained release of bioactive peptides enhance peripheral nerve regeneration in rats. Neural Regen. Res. 17, 2544–2550 (2022).

Zhu, L. et al. Noncovalent bonding of RGD and YIGSR to an electrospun Poly(ε-Caprolactone) conduit through peptide self-assembly to synergistically promote sciatic nerve regeneration in rats. Adv. Healthc. Mater. 6(2017). https://doi.org/10.1002/adhm.201600860

Balmayor, E. R. Targeted delivery as key for the success of small osteoinductive molecules. Adv. Drug Deliv. Rev. 94, 13–27 (2015).

Lo, K. W. Effects on bone regeneration of single-dose treatment with osteogenic small molecules. Drug Discov. Today 27, 1538–1544 (2022).

Kato, S., Sangadala, S., Tomita, K., Titus, L. & Boden, S. D. A synthetic compound that potentiates bone morphogenetic protein-2-induced transdifferentiation of myoblasts into the osteoblastic phenotype. Mol. Cell. Biochem. 349, 97–106 (2011).

Wong, E. et al. A novel low-molecular-weight compound enhances ectopic bone formation and fracture repair. J. Bone Jt. Surg. Am. 95, 454–461 (2013).

Chamani, S. et al. The role of statins in the differentiation and function of bone cells. Eur. J. Clin. Invest. 51, e13534 (2021).

Zhang, Y. et al. Facile fabrication of a biocompatible composite gel with sustained release of aspirin for bone regeneration. Bioact. Mater. 11, 130–139 (2022).

Raeisossadati, R. et al. Small molecule GSK-J1 affects differentiation of specific neuronal subtypes in developing rat retina. Mol. Neurobiol. 56, 1972–1983 (2019).

Yang, Y. et al. Small molecules combined with collagen hydrogel direct neurogenesis and migration of neural stem cells after spinal cord injury. Biomaterials 269, 120479 (2021).

Labroo, P. et al. Controlled delivery of FK506 to improve nerve regeneration. Shock 46, 154–159 (2016).

Sidorova, Y. A. et al. A novel small molecule GDNF receptor RET agonist, BT13, promotes neurite growth from sensory neurons in vitro and attenuates experimental neuropathy in the rat. Front. Pharm. 8, 365 (2017).

Au, N. et al. Clinically relevant small-molecule promotes nerve repair and visual function recovery. NPJ Regen. Med. 7, 50 (2022).

Cui, Z. et al. LM22B-10 promotes corneal nerve regeneration through in vitro 3D co-culture model and in vivo corneal injury model. Acta Biomater. 146, 159–176 (2022).

Li, S. et al. Inhibition of sympathetic activation by delivering calcium channel blockers from a 3D printed scaffold to promote bone defect repair. Adv. Health. Mater. 11, e2200785 (2022).

Guo, S. & He, C. Bioprinted scaffold remodels the neuromodulatory microenvironment for enhancing bone regeneration. Adv. Funct. Mater. 2304172 (2023).

Shirley, J. L., de Jong, Y. P., Terhorst, C. & Herzog, R. W. Immune responses to viral gene therapy vectors. Mol. Ther. 28, 709–722 (2020).

Cai, Y. et al. Enhanced osteoarthritis therapy by nanoengineered mesenchymal stem cells using biomimetic CuS nanoparticles loaded with plasmid DNA encoding TGF-β1. Bioact. Mater. 19, 444–457 (2023).

Li, J. et al. BMP-2 plasmid DNA-loaded chitosan films - A new strategy for bone engineering. J. Craniomaxillofac Surg. 45, 2084–2091 (2017).

Fang, Z. et al. Enhancement of sciatic nerve regeneration with dual delivery of vascular endothelial growth factor and nerve growth factor genes. J. Nanobiotechnol. 18, 46 (2020).

Zha, Y. et al. Progenitor cell-derived exosomes endowed with VEGF plasmids enhance osteogenic induction and vascular remodeling in large segmental bone defects. Theranostics 11, 397–409 (2021).

Masgutov, R. et al. Angiogenesis and nerve regeneration induced by local administration of plasmid pBud-coVEGF165-coFGF2 into the intact rat sciatic nerve. Neural Regen. Res 16, 1882–1889 (2021).

Remy, M. T. et al. Plasmid encoding miRNA-200c delivered by CaCO3-based nanoparticles enhances rat alveolar bone formation. Nanomed. (Lond.) 17, 1339–1354 (2022).

Pan, T. et al. MicroRNA-activated hydrogel scaffold generated by 3D printing accelerates bone regeneration. Bioact. Mater. 10, 1–14 (2022).

Manaka, T. et al. Local delivery of siRNA using a biodegradable polymer application to enhance BMP-induced bone formation. Biomaterials 32, 9642–9648 (2011).

Zhang, Y., Wei, L., Miron, R. J., Shi, B. & Bian, Z. Bone scaffolds loaded with siRNA-Semaphorin4d for the treatment of osteoporosis related bone defects. Sci. Rep. 6, 26925 (2016).

Wang, Y., Zhang, S. & Benoit, D. Degradable poly(ethylene glycol) (PEG)-based hydrogels for spatiotemporal control of siRNA/nanoparticle delivery. J. Control Release 287, 58–66 (2018).

Baker, L. et al. Fidgetin-like 2 negatively regulates axonal growth and can be targeted to promote functional nerve regeneration. JCI Insight. 6(2021).

Mondal, J. et al. Hybrid exosomes, exosome-like nanovesicles and engineered exosomes for therapeutic applications. J. Control Release 353, 1127–1149 (2023).

Kar, R. et al. Exosome-based smart drug delivery tool for cancer theranostics. ACS Biomater. Sci. Eng. 9, 577–594 (2023).

Hao, Z. et al. A multifunctional neuromodulation platform utilizing Schwann cell-derived exosomes orchestrates bone microenvironment via immunomodulation, angiogenesis and osteogenesis. Bioact. Mater. 23, 206–222 (2023).

Su, Y. et al. Aptamer engineering exosomes loaded on biomimetic periosteum to promote angiogenesis and bone regeneration by targeting injured nerves via JNK3 MAPK pathway. Mater. Today Bio. 16, 100434 (2022).

Wu, Z. et al. Schwann cell-derived exosomes promote bone regeneration and repair by enhancing the biological activity of porous Ti6Al4V scaffolds. Biochem. Biophys. Res. Commun. 531, 559–565 (2020).

Wang, T. et al. Bioprinted constructs that simulate nerve–bone crosstalk to improve microenvironment for bone repair. Bioact. Mater. 27, 377–393 (2023).

Li, W. et al. Tissue-engineered bone immobilized with human adipose stem cells-derived exosomes promotes bone regeneration. ACS Appl. Mater. interfaces 10, 5240–5254 (2018).

Zhang, Y. et al. A tailored bioactive 3D porous poly(lactic-acid)-exosome scaffold with osteo-immunomodulatory and osteogenic differentiation properties. J. Biol. Eng. 16, 22 (2022).

Liu, K. et al. Macrophage-derived exosomes promote bone mesenchymal stem cells towards osteoblastic fate through microRNA-21a-5p. Front. Bioeng. Biotechnol. 9, 801432 (2021).

Liu, A. et al. Macrophage-derived small extracellular vesicles promote biomimetic mineralized collagen-mediated endogenous bone regeneration. Int. J. Oral. Sci. 12, 33 (2020).

Lopez-Verrilli, M. A., Picou, F. & Court, F. A. Schwann cell-derived exosomes enhance axonal regeneration in the peripheral nervous system. Glia 61, 1795–1806 (2013).

Zhao, J. et al. Dose-effect relationship and molecular mechanism by which BMSC-derived exosomes promote peripheral nerve regeneration after crush injury. Stem Cell Res. Ther. 11, 360 (2020).

Jalilian, E. et al. Bone marrow mesenchymal stromal cells in a 3D system produce higher concentration of extracellular vesicles (EVs) with increased complexity and enhanced neuronal growth properties. Stem Cell Res. Ther. 13, 425 (2022).

Hervera, A. et al. Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons. Nat. Cell Biol. 20, 307–319 (2018).

Cerri, F. et al. Peripheral nerve morphogenesis induced by scaffold micropatterning. Biomaterials 35, 4035–4045 (2014).

Ravoor, J., Thangavel, M. & Elsen S, R. Comprehensive review on design and manufacturing of bio-scaffolds for bone reconstruction. ACS Appl. Bio. Mater. 4, 8129–8158 (2021).

Huebsch, N. et al. Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate. Nat. Mater. 9, 518–526 (2010).

Liu, Z. et al. Low-stiffness hydrogels promote peripheral nerve regeneration through the rapid release of exosomes. Front. Bioeng. Biotechnol. 10, 922570 (2022).

Rosso, G. et al. Matrix stiffness mechanosensing modulates the expression and distribution of transcription factors in Schwann cells. Bioeng. Transl. Med. 7, e10257 (2022).

Saha, K. et al. Substrate modulus directs neural stem cell behavior. Biophys. J. 95, 4426–4438 (2008).

Pathak, M. M. et al. Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells. Proc. Natl. Acad. Sci. USA 111, 16148–16153 (2014).

Liang, Y. et al. Impact of hydrogel stiffness on the induced neural stem cells modulation. Ann. Transl. Med. 9, 1784 (2021).

Brunetti, V. et al. Neurons sense nanoscale roughness with nanometer sensitivity. Proc. Natl. Acad. Sci. USA 107, 6264–6269 (2010).

Luo, J. et al. The influence of nanotopography on cell behaviour through interactions with the extracellular matrix - A review. Bioact. Mater. 15, 145–159 (2022).

Jia, Y. et al. Nanofiber arrangement regulates peripheral nerve regeneration through differential modulation of macrophage phenotypes. Acta Biomater. 83, 291–301 (2019).

Dong, X. et al. Aligned microfiber-induced macrophage polarization to guide schwann-cell-enabled peripheral nerve regeneration. Biomaterials 272, 120767 (2021).

Dong, X. et al. Oriented nanofibrous P(MMD-co-LA)/Deferoxamine nerve scaffold facilitates peripheral nerve regeneration by regulating macrophage phenotype and revascularization. Biomaterials 280, 121288 (2022).

Hu, X. et al. A novel scaffold with longitudinally oriented microchannels promotes peripheral nerve regeneration. Tissue Eng. Part A 15, 3297–3308 (2009).

Milos, F., Belu, A., Mayer, D., Maybeck, V. & Offenhäusser, A. Polymer nanopillars induce increased paxillin adhesion assembly and promote axon growth in primary cortical neurons. Adv. Biol. 5, 2000248 (2021).

Li, Q. et al. Micropatterned photothermal double-layer periosteum with angiogenesis-neurogenesis coupling effect for bone regeneration. Mater. Today Bio. 18, 100536 (2023).

Johansson, F., Kanje, M., Eriksson, C. & Wallman, L. Guidance of neurons on porous patterned silicon: is pore size important. Phys. Status Solidi (c.) 2, 3258–3262 (2005).

Gentile, F. et al. Differential cell adhesion on mesoporous silicon substrates. ACS Appl. Mater. interfaces 4, 2903–2911 (2012).

Li, Y., Hoffman, M. D. & Benoit, D. Matrix metalloproteinase (MMP)-degradable tissue engineered periosteum coordinates allograft healing via early stage recruitment and support of host neurovasculature. Biomaterials 268, 120535 (2021).

Zhang, M. et al. 3D printing of tree-like scaffolds for innervated bone regeneration. Addit. Manuf. 54, 102721 (2022).

Zhang, M. et al. 3D printing of Haversian bone-mimicking scaffolds for multicellular delivery in bone regeneration. Sci. Adv. 6, eaaz6725 (2020).

Wang, X. et al. Mimicking bone matrix through coaxial electrospinning of core-shell nanofibrous scaffold for improving neurogenesis bone regeneration. Biomater. Adv. 145, 213246 (2023).

Zhang, Z. et al. Engineered sensory nerve guides self-adaptive bone healing via NGF-TrkA signaling pathway. Adv. Sci. (Weinh), e2206155 (2023).

Jimbo, R. et al. The effect of brain-derived neurotrophic factor on periodontal furcation defects. PLoS One 9, e84845 (2014).

Jimbo, R. et al. Regeneration of the cementum and periodontal ligament using local BDNF delivery in class Ⅱ furcation defects. J. Biomed. Mater. Res. Part B Appl. Biomater. 106, 1611–1617 (2018).

Ramalho, I. et al. Periodontal tissue regeneration using brain-derived neurotrophic factor delivered by collagen sponge. Tissue Eng. Part A 25, 1072–1083 (2019).

Liao, J. et al. Peptide-modified bone repair materials: factors influencing osteogenic activity. J. Biomed. Mater. Res. A 107, 1491–1512 (2019).

Liang, T. et al. Drug-loading three-dimensional scaffolds based on hydroxyapatite-sodium alginate for bone regeneration. J. Biomed. Mater. Res. A 109, 219–231 (2021).

Wallach, S. Effects of magnesium on skeletal metabolism. Magn. Trace Elem. 9, 1–14 (1990).

Baker, A. et al. Effect of dietary copper intakes on biochemical markers of bone metabolism in healthy adult males. Eur. J. Clin. Nutr. 53, 408–412 (1999).

Bari, A. et al. Copper-containing mesoporous bioactive glass nanoparticles as multifunctional agent for bone regeneration. Acta Biomater. 55, 493–504 (2017).

Liu, Y. et al. Biodegradable metal-derived magnesium and sodium enhances bone regeneration by angiogenesis aided osteogenesis and regulated biological apatite formation. Chem. Eng. J. 410, 127616 (2021).

Zhao, Y. et al. Construction of macroporous magnesium phosphate-based bone cement with sustained drug release. Mater. Des. 200, 109466 (2021).

Chakraborty Banerjee, P., Al-Saadi, S., Choudhary, L., Harandi, S. E. & Singh, R. Magnesium implants: prospects and challenges. Materials (Basel), (2019).

Zhang, D. et al. Targeting local osteogenic and ancillary cells by mechanobiologically optimized magnesium scaffolds for orbital bone reconstruction in canines. ACS Appl. Mater. interfaces 12, 27889–27904 (2020).

Li, W. et al. Bioprinted constructs that mimic the ossification center microenvironment for targeted innervation in bone regeneration. Adv. Funct. Mater. 32, 2109871 (2022).

Götz, W., Tobiasch, E., Witzleben, S. & Schulze, M. Effects of silicon compounds on biomineralization, osteogenesis, and hard tissue formation. Pharmaceutics. 11(2019).

Zhou, X., Zhang, N., Mankoci, S. & Sahai, N. Silicates in orthopedics and bone tissue engineering materials. J. Biomed. Mater. Res. A 105, 2090–2102 (2017).

Ma, Y. X. et al. Silicified collagen scaffold induces semaphorin 3A secretion by sensory nerves to improve in-situ bone regeneration. Bioact. Mater. 9, 475–490 (2022).

Khare, D., Basu, B. & Dubey, A. K. Electrical stimulation and piezoelectric biomaterials for bone tissue engineering applications. Biomaterials 258, 120280 (2020).

Marsudi, M. A. et al. Conductive polymeric-based electroactive scaffolds for tissue engineering applications: current progress and challenges from biomaterials and manufacturing perspectives. Int. J. Mol. Sci. 22(2021).

Xia, F., Wang, H., Hwang, J. C. M., Neto, A. H. C. & Yang, L. Black phosphorus and its isoelectronic materials. Nat. Rev. Physics 1, 306–317 (2019).

Jing, X., Xiong, Z., Lin, Z. & Sun, T. The application of black phosphorus nanomaterials in bone tissue engineering. Pharmaceutics. 14(2022).

Su, Y. et al. Endogenous electric field-coupled PD@BP biomimetic periosteum promotes bone regeneration through sensory nerve via fanconi anemia signaling pathway. Adv. Healthc. Mater. e2203027 (2023).

Xu, C. et al. Black‐phosphorus‐incorporated hydrogel as a conductive and biodegradable platform for enhancement of the neural differentiation of mesenchymal stem cells. Adv. Funct. Mater. 30, 2000177 (2020).

Li, S. et al. Injectable thermosensitive black phosphorus nanosheet- and doxorubicin-loaded hydrogel for synergistic bone tumor photothermal-chemotherapy and osteogenesis enhancement. Int. J. Biol. Macromol. 239, 124209 (2023).

Ma, S. et al. Calcium phosphate bone cements incorporated with black phosphorus nanosheets enhanced osteogenesis. ACS Biomater. Sci. Eng. 9, 292–302 (2023).

Borges, M. et al. Recent advances of polypyrrole conducting polymer film for biomedical application: Toward a viable platform for cell-microbial interactions. Adv. Colloid Interface Sci. 314, 102860 (2023).

Chen, J., Yu, M., Guo, B., Ma, P. X. & Yin, Z. Conductive nanofibrous composite scaffolds based on in-situ formed polyaniline nanoparticle and polylactide for bone regeneration. J. Colloid Interface Sci. 514, 517–527 (2018).

Flores-Sánchez, M. G. et al. Effect of a plasma synthesized polypyrrole coverage on polylactic acid/hydroxyapatite scaffolds for bone tissue engineering. J. Biomed. Mater. Res. A 109, 2199–2211 (2021).

Vishnoi, T., Singh, A., Teotia, A. K. & Kumar, A. Chitosan-gelatin-polypyrrole cryogel matrix for stem cell differentiation into neural lineage and sciatic nerve regeneration in peripheral nerve injury model. ACS Biomater. Sci. Eng. 5, 3007–3021 (2019).

Wu, C. et al. Antioxidative and conductive nanoparticles-embedded cell niche for neural differentiation and spinal cord injury repair. ACS Appl. Mater. Interfaces. (2021).

Beygisangchin, M., Abdul Rashid, S., Shafie, S., Sadrolhosseini, A. R. & Lim, H. N. Preparations, properties, and applications of polyaniline and polyaniline thin films-a review. Polymers (2021).

Wang, Q. et al. Direct current stimulation for improved osteogenesis of MC3T3 cells using mineralized conductive polyaniline. ACS Biomater. Sci. Eng. 7, 852–861 (2021).

Kim, H. J. et al. Fabrication of nanocomposites complexed with gold nanoparticles on polyaniline and application to their nerve regeneration. ACS Appl. Mater. interfaces 12, 30750–30760 (2020).

Deng, P., Chen, F., Zhang, H., Chen, Y. & Zhou, J. Multifunctional double-layer composite hydrogel conduit based on chitosan for peripheral nerve repairing. Adv. Health. Mater. 11, e2200115 (2022).

Eivazzadeh-Keihan, R. et al. Carbon based nanomaterials for tissue engineering of bone: Building new bone on small black scaffolds: a review. J. Adv. Res. 18, 185–201 (2019).

Li, Y. et al. Polydopamine-mediated graphene oxide and nanohydroxyapatite-incorporated conductive scaffold with an immunomodulatory ability accelerates periodontal bone regeneration in diabetes. Bioact. Mater. 18, 213–227 (2022).

Zhang, X. et al. 3D printed reduced graphene oxide-GelMA hybrid hydrogel scaffolds for potential neuralized bone regeneration. J. Mater. Chem. B 11, 1288–1301 (2023).

Zhao, Y. N. et al. Electrodeposition of chitosan/graphene oxide conduit to enhance peripheral nerve regeneration. Neural Regen. Res. 18, 207–212 (2023).

Pi, W. et al. Polydopamine-coated polycaprolactone/carbon nanotube fibrous scaffolds loaded with brain-derived neurotrophic factor for peripheral nerve regeneration. Biofabrication. 14(2022).

Cao, Y. et al. 3D printed-electrospun PCL/hydroxyapatite/MWCNTs scaffolds for the repair of subchondral bone. Regen. Biomater. 10, rbac104 (2023).

Battiston, K. G., Cheung, J. W., Jain, D. & Santerre, J. P. Biomaterials in co-culture systems: towards optimizing tissue integration and cell signaling within scaffolds. Biomaterials 35, 4465–4476 (2014).

Yoo, J., Jung, Y., Char, K. & Jang, Y. Advances in cell coculture membranes recapitulating in vivo microenvironments. Trends Biotechnol. 41, 214–227 (2023).

Xu, Y. et al. A silk fibroin/collagen nerve scaffold seeded with a co-culture of schwann cells and adipose-derived stem cells for sciatic nerve regeneration. PLoS One 11, e0147184 (2016).

Resch, A. et al. Co-culturing human adipose derived stem cells and schwann cells on spider silk-a new approach as prerequisite for enhanced nerve regeneration. Int. J. Mol. Sci. 20(2018).

Zheng, T. et al. Co-culture of Schwann cells and endothelial cells for synergistically regulating dorsal root ganglion behavior on chitosan-based anisotropic topology for peripheral nerve regeneration. Burns Trauma. 10, tkac030 (2022).

Li, Y., Men, Y., Wang, B., Chen, X. & Yu, Z. Co-transplantation of Schwann cells and neural stem cells in the laminin-chitosan-PLGA nerve conduit to repair the injured recurrent laryngeal nerve in SD rats. J. Mater. Sci. Mater. Med. 31, 99 (2020).

Santos, M. I., Unger, R. E., Sousa, R. A., Reis, R. L. & Kirkpatrick, C. J. Crosstalk between osteoblasts and endothelial cells co-cultured on a polycaprolactone-starch scaffold and the in vitro development of vascularization. Biomaterials 30, 4407–4415 (2009).

Chen, W. et al. Angiogenic and osteogenic regeneration in rats via calcium phosphate scaffold and endothelial cell co-culture with human bone marrow mesenchymal stem cells (MSCs), human umbilical cord MSCs, human induced pluripotent stem cell-derived MSCs and human embryonic stem cell-derived MSCs. J. Tissue Eng. Regen. Med. 12, 191–203 (2018).

Carvalho, M. S. et al. Co-culture cell-derived extracellular matrix loaded electrospun microfibrous scaffolds for bone tissue engineering. Mater. Sci. Eng. C. Mater. Biol. Appl. 99, 479–490 (2019).

Yang, Y. et al. Magnesium-based whitlockite bone mineral promotes neural and osteogenic activities. ACS Biomater. Sci. Eng. 6, 5785–5796 (2020).

Iaquinta, M. R. et al. Adult stem cells for bone regeneration and repair. Front. Cell Dev. Biol. 7, 268 (2019).

Liu, Y., Chan, J. K. & Teoh, S. H. Review of vascularised bone tissue-engineering strategies with a focus on co-culture systems. J. Tissue Eng. Regen. Med. 9, 85–105 (2015).

Russell, F. A., King, R., Smillie, S. J., Kodji, X. & Brain, S. D. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol. Rev. 94, 1099–1142 (2014).

Jiang, Y. et al. Neuronal TRPV1-CGRP axis regulates bone defect repair through Hippo signaling pathway. Cell. Signal. 109, 110779 (2023).

Ferrigno, B. et al. Bioactive polymeric materials and electrical stimulation strategies for musculoskeletal tissue repair and regeneration. Bioact. Mater. 5, 468–485 (2020).

Khalifeh, J. M. et al. Electrical stimulation and bone Healing: A review of current technology and clinical applications. IEEE Rev. Biomed. Eng. 11, 217–232 (2018).

Wang, J., Wang, H., Mo, X. & Wang, H. Reduced graphene oxide-encapsulated microfiber patterns enable controllable formation of neuronal-like networks. Adv. Mater. Weinh. 32, e2004555 (2020).

Lau, Y. C., Qian, X., Po, K. T., Li, L. M. & Guo, X. Electrical stimulation at the dorsal root ganglion preserves trabecular bone mass and microarchitecture of the tibia in hindlimb-unloaded rats. Osteoporos. Int. 26, 481–488 (2015).

Jiang, Y. X., Gong, P. & Zhang, L. [A review of mechanisms by which low-intensity pulsed ultrasound affects bone regeneration]. Hua Xi Kou Qiang Yi Xue Za Zhi 38, 571–575 (2020).

Yang, M. H., Lim, K. T., Choung, P. H., Cho, C. S. & Chung, J. H. Application of ultrasound stimulation in bone tissue engineering. Int. J. Stem Cells 3, 74–79 (2010).

Jiang, W. et al. Low-intensity pulsed ultrasound treatment improved the rate of autograft peripheral nerve regeneration in rat. Sci. Rep. 6, 22773 (2016).

Lam, W. L., Guo, X., Leung, K. S. & Kwong, K. S. The role of the sensory nerve response in ultrasound accelerated fracture repair. J. Bone Jt. Surg. Br. 94, 1433–1438 (2012).

Reher, P., Harris, M., Whiteman, M., Hai, H. K. & Meghji, S. Ultrasound stimulates nitric oxide and prostaglandin E2 production by human osteoblasts. Bone 31, 236–241 (2002).

Tang, C. H. et al. Ultrasound stimulates cyclooxygenase-2 expression and increases bone formation through integrin, focal adhesion kinase, phosphatidylinositol 3-kinase, and Akt pathway in osteoblasts. Mol. Pharmacol. 69, 2047–2057 (2006).

McCarthy, C. & Camci-Unal, G. Low intensity pulsed ultrasound for bone tissue engineering. Micromachines (Basel). 12(2021).

Mao, X. et al. Nerve ECM and PLA-PCL based electrospun bilayer nerve conduit for nerve regeneration. Front. Bioeng. Biotechnol. 11, 1103435 (2023).

Wang, X. et al. A novel decellularized matrix of Wnt signaling-activated osteocytes accelerates the repair of critical-sized parietal bone defects with osteoclastogenesis, angiogenesis, and neurogenesis. Bioact. Mater. 21, 110–128 (2023).

Halperin-Sternfeld, M. et al. Immunomodulatory fibrous hyaluronic acid-Fmoc-diphenylalanine-based hydrogel induces bone regeneration. J. Clin. Periodontol. 50, 200–219 (2023).

Yang, J. et al. A hyaluronic acid granular hydrogel nerve guidance conduit promotes regeneration and functional recovery of injured sciatic nerves in rats. Neural Regen. Res. 18, 657–663 (2023).

Jafarimanesh, M. A. et al. Sustained release of valproic acid loaded on chitosan nanoparticles within hybrid of alginate/chitosan hydrogel with/without stem cells in regeneration of spinal cord injury. Prog Biomater. (2023).

Zheng, A. et al. Promoting lacunar bone regeneration with an injectable hydrogel adaptive to the microenvironment. Bioact. Mater. 21, 403–421 (2023).

Cheng, D. et al. Strontium ion-functionalized nano-hydroxyapatite/chitosan composite microspheres promote osteogenesis and angiogenesis for bone regeneration. ACS Appl. Mater. Interfaces. (2023).

Sow, W. T. et al. Freeze-casted keratin matrix as an organic binder to integrate hydroxyapatite and BMP2 for enhanced cranial bone regeneration. Adv. Healthc. Mater. e2201886 (2022).

Qin, H. J. et al. Artificial nerve graft constructed by coculture of activated Schwann cells and human hair keratin for repair of peripheral nerve defects. Neural Regen. Res. 18, 1118–1123 (2023).

Gao, X. et al. Nerve growth factor-laden anisotropic silk nanofiber hydrogels to regulate neuronal/astroglial differentiation for scarless spinal cord repair. ACS Appl. Mater. interfaces 14, 3701–3715 (2022).

Wang, X. et al. Chitosan/silk fibroin composite bilayer PCL nanofibrous mats for bone regeneration with enhanced antibacterial properties and improved osteogenic potential. Int. J. Biol. Macromol. 230, 123265 (2023).

Ma, J. et al. Collagen modified anisotropic PLA scaffold as a base for peripheral nerve regeneration. Macromol. Biosci. 22, e2200119 (2022).

Li, J. et al. Dual-Nozzle 3D printed nano-hydroxyapatite scaffold loaded with vancomycin sustained-release microspheres for enhancing bone regeneration. Int. J. Nanomed. 18, 307–322 (2023).

Manto, K. M. et al. Erythropoietin-PLGA-PEG as a local treatment to promote functional recovery and neurovascular regeneration after peripheral nerve injury. J. Nanobiotechnol. 20, 461 (2022).

Wei, J. et al. Sequential dual-biofactor release from the scaffold of mesoporous HA microspheres and PLGA matrix for boosting endogenous bone regeneration. Adv Healthc. Mater. e2300624 (2023).

Yao, Z. et al. Magnesium-encapsulated injectable hydrogel and 3D-engineered polycaprolactone conduit facilitate peripheral nerve regeneration. Adv. Sci. (Weinh.) 9, e2202102 (2022).

Kang, D. et al. FeS2-incorporated 3D PCL scaffold improves new bone formation and neovascularization in a rat calvarial defect model. Int. J. Bioprint 9, 636 (2023).

Zhang, S. et al. Porous nerve guidance conduits reinforced with braided composite structures of silk/magnesium filaments for peripheral nerve repair. Acta Biomater. 134, 116–130 (2021).

Xia, Y. et al. 3D-printed dual-ion chronological release functional platform reconstructs neuro-vascularization network for critical-sized bone defect regeneration. Chem. Eng. J. 465, 143015 (2023).

Li, R. X. et al. Highly bioactive peptide-HA photo-crosslinking hydrogel for sustained promoting bone regeneration. Chem. Eng. J. 415, 129015 (2021).

Jiang, Y. et al. Low-intensity pulsed ultrasound improves osseointegration of dental implant in mice by inducing local neuronal production of αCGRP. Arch. Oral. Biol. 115, 104736 (2020).

Liu, X., Zou, D., Hu, Y., He, Y. & Lu, J. Research progress of low-intensity pulsed ultrasound in the repair of peripheral nerve injury. Tissue Eng. Part B Rev. (2023).

Ye, J., Huang, B. & Gong, P. Nerve growth factor-chondroitin sulfate/hydroxyapatite-coating composite implant induces early osseointegration and nerve regeneration of peri-implant tissues in Beagle dogs. J. Orthop. Surg. Res. 16, 51 (2021).

Eap, S. et al. Nanofibers implant functionalized by neural growth factor as a strategy to innervate a bioengineered tooth. Adv. Health. Mater. 3, 386–391 (2014).

Ye, J. & Gong, P. NGF-CS/HA-coating composite titanium facilitates the differentiation of bone marrow mesenchymal stem cells into osteoblast and neural cells. Biochem. Biophys. Res. Commun. 531, 290–296 (2020).

Kauschke, V. et al. Effects of a pasty bone cement containing brain-derived neurotrophic factor-functionalized mesoporous bioactive glass particles on metaphyseal healing in a new murine osteoporotic fracture model. Int. J. Mol. Sci. 19(2018).

Takeda, K. et al. Characteristics of high-molecular-weight hyaluronic acid as a brain-derived neurotrophic factor scaffold in periodontal tissue regeneration. Tissue Eng. Part A 17, 955–967 (2011).

Li, Y. et al. Bio-Oss^® modified by calcitonin gene-related peptide promotes osteogenesis in vitro. Exp. Ther. Med. 14, 4001–4008 (2017).

Yu, X. et al. CGRP gene-modified rBMSCs show better osteogenic differentiation capacity in vitro. J. Mol. Histol. 49, 357–367 (2018).

Yu, X. et al. Calcitonin gene related peptide gene-modified rat bone mesenchymal stem cells are effective seed cells in tissue engineering to repair skull defects. Histol. Histopathol. 34, 1229–1241 (2019).

Lv, T. et al. Novel calcitonin gene-related peptide/chitosan-strontium-calcium phosphate cement: Enhanced proliferation of human umbilical vein endothelial cells in vitro. J. Biomed. Mater. Res. Part B Appl. Biomater. 107, 19–28 (2019).

Luo, J. et al. CGRP-loaded porous microspheres protect BMSCs for alveolar bone regeneration in the periodontitis microenvironment. Adv. Healthc. Mater. 12, e2301366 (2023).

Chen, J. et al. Gelatin microspheres containing calcitonin gene-related peptide or substance P repair bone defects in osteoporotic rabbits. Biotechnol. Lett. 39, 465–472 (2017).

Lotz, E. M., Berger, M. B., Boyan, B. D. & Schwartz, Z. Regulation of mesenchymal stem cell differentiation on microstructured titanium surfaces by semaphorin 3A. Bone 134, 115260 (2020).

Kim, S. H., Kim, J. E., Kim, S. H. & Jung, Y. Substance P/dexamethasone-encapsulated PLGA scaffold fabricated using supercritical fluid process for calvarial bone regeneration. J. Tissue Eng. Regen. Med. 11, 3469–3480 (2017).

Amirthalingam, S. et al. Addition of lactoferrin and substance P in a chitin/PLGA-CaSO4 hydrogel for regeneration of calvarial bone defects. Mater. Sci. Eng. C. Mater. Biol. Appl. 126, 112172 (2021).

Mu, C. et al. Substance P-embedded multilayer on titanium substrates promotes local osseointegration via MSC recruitment. J. Mater. Chem. B 8, 1212–1222 (2020).

Chen, D. et al. Nacre-mimetic hydroxyapatite/chitosan/gelatin layered scaffolds modifying substance P for subchondral bone regeneration. Carbohydr. Polym. 291, 119575 (2022).

Noh, S. S. et al. A dual delivery of substance P and bone morphogenetic protein-2 for mesenchymal stem cell recruitment and bone regeneration. Tissue Eng. Part A 21, 1275–1287 (2015).

Wang, T. et al. Substance P incorporation in calcium phosphate cement for dental alveolar bone defect restoration. Mater. Sci. Eng. C. Mater. Biol. Appl. 69, 546–553 (2016).

La, W. G. et al. Delivery of bone morphogenetic protein-2 and substance P using graphene oxide for bone regeneration. Int. J. Nanomed. 9, 107–116 (2014).

Kim, S. H. et al. Self-assembling peptide nanofibers coupled with neuropeptide substance P for bone tissue engineering. Tissue Eng. Part A 21, 1237–1246 (2015).

Ji, H. et al. Programmed core-shell electrospun nanofibers to sequentially regulate osteogenesis-osteoclastogenesis balance for promoting immediate implant osseointegration. Acta Biomater. 135, 274–288 (2021).