Smart biomaterials for skeletal aging repair and regeneration

Abstract

Skeletal aging associated with diverse age-related disorders is increasing due to unhealthy diets, stressful lifestyles, and rapid aging. Repair and regeneration of aging skeletons are a global issue. Despite the self-healing ability of bone and the availability of various treatment strategies, degenerative bone repair and regeneration face significant problems due to unbalanced bone remodeling and a lack of active treatment strategies. The development of smart materials has created opportunities for degenerative bone repair and regeneration. The smart materials are responsive to endogenous/exogenous stimuli with tailored structure and function, which can promote skeletal aging repair and regeneration. Thus, in this study, skeletal aging is recognized as the progressive state that begins from peak bone mass to pathophysiological state and disorder conditions. We have introduced and characterized skeletal aging from the perspectives of cell-matrix-microenvironment and macrostructure-function-mechanical properties, for which systemic smart drug delivery systems and local smart scaffolds are designed. The smart drug delivery systems undergo conformation change and phase transition upon stimuli to release drugs at time- and site-specific to promote aging bone repair. Smart scaffolds with versatility and mechanical strength can replace bone defects to provide a tissue repair and regeneration microenvironment. Endogenous disease microenvironments and/or external physical triggers stimulate scaffold activation, which release bioactive factors to accelerate bone regeneration. This manuscript discusses the manufacturing techniques of these smart materials and presents key challenges and future directions for clinical translation, emphasizing their potential for personalized treatment and targeted therapy of skeletal aging.

References

[1] Oeppen J, Vaupel JW. Broken limits to life expectancy. Science, 2002, 296: 1029-1031

[2] Xi JYet al.. Effects of population aging on quality of life and disease burden: a population-based study. Glob. Health Res. Policy, 2025, 10 2

[3] Chandra A, Rajawat J. Skeletal aging and osteoporosis: mechanisms and therapeutics. Int. J. Mol. Sci., 2021, 22: 3553-3578

[4] Sfeir JG, Drake MT, Khosla S, Farr JN. Skeletal aging. Mayo Clin. Proc., 2022, 97: 1194-1208

[5] Roberts Set al.. Ageing in the musculoskeletal system. Acta Orthop., 2016, 87: 15-25

[6] Gheno R, Cepparo JM, Rosca CE, Cotten A. Musculoskeletal disorders in the elderly. J. Clin. Imaging Sci., 2012, 2: 39-47

[7] Sfeir JG, Pignolo RJ. Pharmacologic interventions for fracture risk reduction in the oldest old: what is the evidence?. JBMR, 2021, 5e10538

[8] Mitchell MJet al.. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov., 2021, 20: 101-124

[9] Dilliard SA, Siegwart DJ. Passive, active and endogenous organ-targeted lipid and polymer nanoparticles for delivery of genetic drugs. Nat. Rev. Mater., 2023, 8: 282-300

[10] Lin H, Sohn J, Shen H, Langhans MT, Tuan RS. Bone marrow mesenchymal stem cells: Aging and tissue engineering applications to enhance bone healing. Biomaterials, 2019, 203: 96-110

[11] Liu HHet al.. Stem cell homing as a promising strategy for bone regeneration: focus on biomaterials. Eur. Cell. Mater., 2025, 51: 83-102

[12] Antebi B, Pelled G, Gazit D. Stem cell therapy for osteoporosis. Curr. Osteoporos. Rep., 2014, 12: 41-47

[13] Gu Zet al.. Smart biomaterials for articular cartilage repair and regeneration. Adv. Funct. Mater., 2023, 33 2212561

[14] Wei H, Cui J, Lin K, Xie J, Wang X. Recent advances in smart stimuli-responsive biomaterials for bone therapeutics and regeneration. Bone Res., 2022, 10: 17-36

[15] Chen Het al.. Cartilage-targeting and dual MMP-13/pH responsive theranostic nanoprobes for osteoarthritis imaging and precision therapy. Biomaterials, 2019, 225 119520

[16] Yang Qet al.. Targeting micromotion for mimicking natural bone healing by using NIPAM/Nb2C hydrogel. Bioact. Mater., 2024, 39: 41-58

[17] Shi Net al.. A 3D, magnetically actuated, aligned collagen fiber hydrogel platform recapitulates physical microenvironment of myoblasts for enhancing myogenesis. Small Methods, 2021, 5 e2100276

[18] Corrado A, Cici D, Rotondo C, Maruotti N, Cantatore FP. Molecular basis of bone aging. Int. J. Mol. Sci., 2020, 21: 3679-3696

[19] Sfeir JG, Drake MT, Khosla S, Farr JN. Skeletal aging. Mayo Clin. Proc., 2022, 97: 1194

[20] Veronese N, Maggi S. Epidemiology and social costs of hip fracture. Injury, 2018, 49: 1458-1460

[21] Liu E. Hip fractures: mortality, economic burden, and organisational factors for improved patient outcomes. Lancet Healthy Longev., 2023, 4: e360-e361

[22] Cosman Fet al.. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos. Int., 2014, 25: 2359-2381

[23] Fang Het al.. The mechanism of bone remodeling after bone aging. Clin. Interv. Aging, 2022, 17: 405-415

[24] Anagnostis Pet al.. New therapeutic targets for osteoporosis. Maturitas, 2019, 120: 1-6

[25] Deeks ED. Denosumab: a review in postmenopausal osteoporosis. Drugs Aging, 2018, 35: 163-173

[26] Olevsky OM, Martino S. Randomized clinical trials of raloxifene: reducing the risk of osteoporosis and breast cancer in postmenopausal women. Menopause, 2008, 15: 790-796

[27] Féron J-M, Mauprivez R. Fracture repair: general aspects and influence of osteoporosis and anti-osteoporosis treatment. Injury, 2016, 47: S10-S14

[28] Kangari P, Talaei-Khozani T, Razeghian-Jahromi I, Razmkhah M. Mesenchymal stem cells: amazing remedies for bone and cartilage defects. Stem Cell. Res. Ther., 2020, 11: 492-513

[29] Wang Zet al.. Efficacy of bone marrow–derived stem cells in strengthening osteoporotic bone in a rabbit model. Tissue Eng., 2006, 12: 1753-1761

[30] Hills RKet al.. Clinical efficacy and safety of mesenchymal stem cell transplantation for osteoarthritis treatment: a meta-analysis. PLoS One, 2017, 12 e0175449

[31] Hatzistergos KE, Blum A, Ince TA, Grichnik JM, Hare JM. What is the oncologic risk of stem cell treatment for heart disease?. Circ. Res., 2011, 108: 1300-1303

[32] Barkholt Let al.. Risk of tumorigenicity in mesenchymal stromal cell–based therapies—Bridging scientific observations and regulatory viewpoints. Cytotherapy, 2013, 15: 753-759

[33] Wang Y, Chen X, Cao W, Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat. Immunol., 2014, 15: 1009-1016

[34] Mäkelä Tet al.. Safety and biodistribution study of bone marrow–derived mesenchymal stromal cells and mononuclear cells and the impact of the administration route in an intact porcine model. Cytotherapy, 2015, 17: 392-402

[35] Zhang L, Mack R, Breslin P, Zhang J. Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches. J. Hematol. Oncol., 2020, 13: 157-179

[36] Joswig A-Jet al.. Repeated intra-articular injection of allogeneic mesenchymal stem cells causes an adverse response compared to autologous cells in the equine model. Stem Cell. Res. Ther., 2017, 8: 42-53

[37] Lazarenko OPet al.. Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. Endocrinology, 2007, 148: 2669-2680

[38] Jiang Yet al.. Gene expression analysis of major lineage-defining factors in human bone marrow cells: Effect of aging, gender, and age-related disorders. J. Orthop. Res., 2008, 26: 910-917

[39] Stolzing A, Jones E, McGonagle D, Scutt A. Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech. Ageing Dev., 2008, 129: 163-173

[40] Stenderup K. Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone, 2003, 33: 919-926

[41] Wang Het al.. Impairment of osteoblast differentiation due to proliferation-independent telomere dysfunction in mouse models of accelerated aging. Aging Cell, 2012, 11: 704-713

[42] Ma C, Yu R, Li J, Chao J, Liu P. Targeting proteostasis network in osteoporosis: Pathological mechanisms and therapeutic implications. Ageing Res. Rev., 2023, 90: 102024

[43] Kawabata Tet al.. HSP90 inhibitors diminish PDGF-BB-induced migration of osteoblasts via suppression of p44/p42 MAP kinase. Biomed. Res., 2019, 40: 169-178

[44] Dobson PFet al.. Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss. Sci. Rep., 2020, 10 11643

[45] Burr DB. Changes in bone matrix properties with aging. Bone, 2019, 120: 85-93

[46] Robinson RA. An electron-microscopic study of the crystalline inorganic component of bone and its relationship to the organic matrix. J. Bone Jt. Surg., 1952, 34: 389-476

[47] Fernández-Seara MA, Wehrli SL, Takahashi M, Wehrli FW. Water content measured by proton-deuteron exchange NMR predicts bone mineral density and mechanical properties. J. Bone Miner. Res., 2004, 19: 289-296

[48] Lee K, Seo I, Choi M, Jeong D. Roles of mitogen-activated protein kinases in osteoclast biology. Int. J. Mol. Sci., 2018, 19: 3004

[49] Zhang Yet al.. Angiogenesis changes in ovariectomized rats with osteoporosis treated with estrogen replacement therapy. Biomed. Res. Int., 2019, 2019: 1-9

[50] Tencerova Met al.. Obesity-associated hypermetabolism and accelerated senescence of bone marrow stromal stem cells suggest a potential mechanism for bone fragility. Cell Rep., 2019, 27: 2050-2062.e2056

[51] Li X, Li B, Shi Y, Wang C, Ye L. Targeting reactive oxygen species in stem cells for bone therapy. Drug Discov. Today, 2021, 26: 1226-1244

[52] Lawrence M, Goyal A, Pathak S, Ganguly P. Cellular senescence and inflammaging in the bone: pathways, genetics, anti-aging strategies and interventions. Int. J. Mol. Sci., 2024, 25: 7411-7434

[53] Aaron N, Costa S, Rosen CJ, Qiang L. The implications of bone marrow adipose tissue on inflammaging. Front. Endocrinol., 2022, 13: 853765

[54] Du Jet al.. Effects of estradiol on voltage-gated potassium channels in mouse dorsal root ganglion neurons. J. Membr. Biol., 2014, 247: 541-548

[55] Zhu Get al.. Knockout and double knockout of cathepsin K and Mmp9 reveals a novel function of Cathepsin K as a regulator of osteoclast gene expression and bone homeostasis. Int. J. Biol. Sci., 2022, 18: 5522-5538

[56] Heng BCet al.. The bioelectrical properties of bone tissue. Anim. Model Exp. Med., 2023, 6: 120-130

[57] Yang Bet al.. Recapitulating hypoxic metabolism in cartilaginous organoids via adaptive cell-matrix interactions enhances histone lactylation and cartilage regeneration. Nat. Commun., 2025, 16 2711

[58] Pignolo, R. J. Aging and bone metabolism. Compr. Physiol., 4355-4386, (2023).

[59] Khosla Set al.. Effects of sex and age on bone microstructure at the ultradistal radius: a population-based noninvasive in vivo assessment. J. Bone Miner. Res., 2006, 21: 124-131

[60] Parfitt AM. Osteonal and hemi-osteonal remodeling-the spatial and temporal framework for signal traffic in adult human bone. J. Cell. Biochem., 1994, 55: 273-286

[61] Macdonald HM, Nishiyama KK, Kang J, Hanley DA, Boyd SK. Age-related patterns of trabecular and cortical bone loss differ between sexes and skeletal sites: a population-based HR-pQCT study. J. Bone Miner. Res., 2011, 26: 50-62

[62] Peters AE, Akhtar R, Comerford EJ, Bates KT. The effect of ageing and osteoarthritis on the mechanical properties of cartilage and bone in the human knee joint. Sci. Rep., 2018, 8: 5931-5944

[63] Francis APet al.. A review on biomaterials-based scaffold: an emerging tool for bone tissue engineering. Mater. Today Commun., 2023, 34: 105124

[64] Mirzaali MJet al.. Mechanical properties of cortical bone and their relationships with age, gender, composition and microindentation properties in the elderly. Bone, 2016, 93: 196-211

[65] Frost BA, Camarero-Espinosa S, Foster EJ. Materials for the spine: anatomy, problems, and solutions. Materials, 2019, 12: 253-294

[66] Khoo BCC, Brown K, Lewis JR, Perilli E, Prince RL. Ageing effects on 3-dimensional femoral neck cross-sectional asymmetry: implications for age-related bone fragility in falling. J. Clin. Densitom., 2019, 22: 153-161

[67] DiGirolamo DJ, Clemens TL, Kousteni S. The skeleton as an endocrine organ. Nat. Rev. Rheumatol., 2012, 8: 674-683

[68] Wei Xet al.. Understanding the stony bridge between osteoporosis and vascular calcification: impact of the FGF23/Klotho axis. Oxid. Med. Cell. Longev., 2021, 2021: 7536614

[69] Nuñez-Garcia Met al.. Osteopontin regulates the cross-talk between phosphatidylcholine and cholesterol metabolism in mouse liver. J. Lipid Res., 2017, 58: 1903-1915

[70] Kondegowda NGet al.. Osteoprotegerin and denosumab stimulate human beta cell proliferation through inhibition of the receptor activator of NF-κB ligand pathway. Cell Metab., 2015, 22: 77-85

[71] Zhivodernikov IV, Kirichenko TV, Markina YV, Postnov AY, Markin AM. Molecular and cellular mechanisms of osteoporosis. Int. J. Mol. Sci., 2023, 24: 15772

[72] Yang J, Jiang T, Xu G, Liu W. Bibliometrics analysis and visualization of sarcopenia associated with osteoporosis from 2000 to 2022. J. Pain. Res., 2023, 16: 821-837

[73] Xie Yet al.. Bench-to-bedside strategies for osteoporotic fracture: From osteoimmunology to mechanosensation. Bone Res., 2019, 7: 25-38

[74] Chan JKet al.. Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response. EMBO Mol. Med., 2015, 7: 547-561

[75] Timlin Met al.. Fracture hematoma is a potent proinflammatory mediator of neutrophil function. J. Trauma, 2005, 58: 1223-1229

[76] Gibon E, Lu L, Goodman SB. Aging, inflammation, stem cells, and bone healing. Stem Cell. Res. Ther., 2016, 7: 44-51

[77] Briot K, Geusens P, Em Bultink I, Lems WF, Roux C. Inflammatory diseases and bone fragility. Osteoporos. Int., 2017, 28: 3301-3314

[78] Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet, 2019, 393: 1745-1759

[79] Yao Qet al.. Osteoarthritis: pathogenic signaling pathways and therapeutic targets. Signal Transduct. Target Ther., 2023, 8: 56-87

[80] Diekman BO, Loeser RF. Aging and the emerging role of cellular senescence in osteoarthritis. Osteoarthr. Cartil., 2024, 32: 365-371

[81] Jiang Wet al.. Mechanisms linking mitochondrial mechanotransduction and chondrocyte biology in the pathogenesis of osteoarthritis. Ageing Res. Rev., 2021, 67 101315

[82] Blaney Davidson ENet al.. Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice. J. Immunol., 2009, 182: 7937-7945

[83] van der Kraan PM, Blaney Davidson EN, van den Berg WB. A role for age-related changes in TGFβ signaling in aberrant chondrocyte differentiation and osteoarthritis. Arthritis Res. Ther., 2010, 12: 201-210

[84] Pueyo Moliner Aet al.. Restoring articular cartilage: insights from structure, composition and development. Nat. Rev. Rheumatol., 2025, 21: 291-308

[85] Montoya Cet al.. On the road to smart biomaterials for bone research: definitions, concepts, advances, and outlook. Bone Res., 2021, 9: 12-28

[86] Pérez RA, Won J-E, Knowles JC, Kim H-W. Naturally and synthetic smart composite biomaterials for tissue regeneration. Adv. Drug Del. Rev., 2013, 65: 471-496

[87] Farokhzad OC, Langer R. Impact of nanotechnology on drug delivery. ACS Nano, 2009, 3: 16-20

[88] Filipczak N, Pan J, Yalamarty SSK, Torchilin VP. Recent advancements in liposome technology. Adv. Drug Del. Rev., 2020, 156: 4-22

[89] Karimi Met al.. Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems. Chem. Soc. Rev., 2016, 45: 1457-1501

[90] Kowalski PS, Bhattacharya C, Afewerki S, Langer R. Smart Biomaterials: Recent Advances and Future Directions. ACS Biomater. Sci. Eng., 2018, 4: 3809-3817

[91] Webb BA, Chimenti M, Jacobson MP, Barber DL. Dysregulated pH: a perfect storm for cancer progression. Nat. Rev. Cancer, 2011, 11: 671-677

[92] Dou Cet al.. Bone-targeted pH-responsive cerium nanoparticles for anabolic therapy in osteoporosis. Bioact. Mater., 2021, 6: 4697-4706

[93] Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature, 2003, 423: 337-342

[94] Wang Zet al.. Stimuli-sensitive nanotherapies for the treatment of osteoarthritis. Macromol. Biosci., 2021, 21 2100280

[95] Yang Xet al.. Novel one-pot strategy for fabrication of a pH-Responsive bone-targeted drug self-frame delivery system for treatment of osteoporosis. Mater. Today Bio., 2023, 20 100688

[96] Newman Het al.. pH-Sensitive nanocarrier assisted delivery of adenosine to treat osteoporotic bone loss. Biomater. Sci., 2022, 10: 5340-5355

[97] Zerrillo Let al.. pH-responsive poly(lactide-co-glycolide) nanoparticles containing near-infrared dye for visualization and hyaluronic acid for treatment of osteoarthritis. J. Control. Release, 2019, 309: 265-276

[98] Sun Cet al.. ROS-initiated chemiluminescence-driven payload release from macrocycle-based Azo-containing polymer nanocapsules. J. Mater. Chem. B, 2020, 8: 8878-8883

[99] Cerqueni G, Scalzone A, Licini C, Gentile P, Mattioli-Belmonte M. Insights into oxidative stress in bone tissue and novel challenges for biomaterials. Mater. Sci. Eng. C. Mater. Biol. Appl., 2021, 130: 112433

[100] Hayyan M, Hashim MA, AlNashef IM. Superoxide ion: generation and chemical implications. Chem. Rev., 2016, 116: 3029-3085

[101] Pei Pet al.. ROS-sensitive thioketal-linked polyphosphoester-doxorubicin conjugate for precise phototriggered locoregional chemotherapy. Biomaterials, 2019, 188: 74-82

[102] Li Jet al.. Photoinduced PEG deshielding from ROS-sensitive linkage-bridged block copolymer-based nanocarriers for on-demand drug delivery. Biomaterials, 2018, 170: 147-155

[103] Gao F, Xiong Z. Reactive oxygen species responsive polymers for drug delivery systems. Front. Chem., 2021, 9: 649048

[104] Napoli A, Valentini M, Tirelli N, Müller M, Hubbell JA. Oxidation-responsive polymeric vesicles. Nat. Mater., 2004, 3: 183-189

[105] Ren Xet al.. Reactive oxygen species (ROS)-responsive biomaterials for the treatment of bone-related diseases. Front. Bioeng. Biotechnol., 2022, 9 820468

[106] Wu Zet al.. ROS-reactive PMS/PC drug delivery system improves new bone formation under diabetic conditions by promoting angiogenesis-osteogenesis coupling via down-regulating NOX2-ROS signalling axis. Biomaterials, 2022, 291 121900

[107] Lui YSet al.. 4D printing and stimuli-responsive materials in biomedical aspects. Acta Biomater., 2019, 92: 19-36

[108] Galuska SP, Geyer R, Gerardy-Schahn R, Mühlenhoff M, Geyer H. Enzyme-dependent variations in the polysialylation of the neural cell adhesion molecule (NCAM) in vivo. J. Biol. Chem., 2008, 283: 17-28

[109] Qu Met al.. Stimuli-responsive delivery of growth factors for tissue engineering. Adv. Healthc. Mater., 2020, 9 e1901714

[110] Arrighi Iet al.. Bone healing induced by local delivery of an engineered parathyroid hormone prodrug. Biomaterials, 2009, 30: 1763-1771

[111] Patterson J, Hubbell JA. Enhanced proteolytic degradation of molecularly engineered PEG hydrogels in response to MMP-1 and MMP-2. Biomaterials, 2010, 31: 7836-7845

[112] Chen, W. et al. Smart hydrogels for bone reconstruction via modulating the microenvironment. Research6, 0089.

[113] Chen Yet al.. Bone-targeted nanoparticle drug delivery system: an emerging strategy for bone-related disease. Front. Pharmacol., 2022, 13: 909408

[114] Qi Het al.. Systemic administration of enzyme-responsive growth factor nanocapsules for promoting bone repair. Biomater. Sci., 2019, 7: 1675-1685

[115] Xiao Bet al.. Advancing bone-targeted drug delivery: leveraging biological factors and nanoparticle designs to improve therapeutic efficacy. ACS Biomater. Sci. Eng., 2024, 10: 2224-2234

[116] Lu Y, Aimetti AA, Langer R, Gu Z. Bioresponsive materials. Nat. Rev. Mater., 2016, 2: 16075

[117] Li Met al.. Microenvironment-responsive nanocarriers for targeted bone disease therapy. Nano Today, 2023, 50 101838

[118] Polat S, Burak Eral H. Elucidating the role of hyaluronic acid in the structure and morphology of calcium oxalate crystals. Adv. Powder Technol., 2021, 32: 3650-3659

[119] Jing Pet al.. A biocompatible adenine-based metal–organic framework for Ca2+ responsive drug delivery. Mater. Lett., 2023, 349 134812

[120] Fan Det al.. Phosphate ion-responsive and calcium peroxide-based nanomedicine for bone-targeted treatment of breast cancer bone metastasis. Adv. Healthc. Mater., 2024, 13: 202402216

[121] Xiong Yet al.. The role of the immune microenvironment in bone, cartilage, and soft tissue regeneration: from mechanism to therapeutic opportunity. Mil. Med. Res., 2022, 9: 65

[122] Tsukasaki M, Takayanagi H. Osteoimmunology: evolving concepts in bone–immune interactions in health and disease. Nat. Rev. Immunol., 2019, 19: 626-642

[123] Salhotra A, Shah HN, Levi B, Longaker MT. Mechanisms of bone development and repair. Nat. Rev. Mol. Cell Biol., 2020, 21: 696-711

[124] Kondo N, Kuroda T, Kobayashi D. Cytokine networks in the pathogenesis of rheumatoid arthritis. Int. J. Mol. Sci., 2021, 22: 10922

[125] van den Bosch MHJ, Blom AB, van der Kraan PM. Inflammation in osteoarthritis: Our view on its presence and involvement in disease development over the years. Osteoarthr. Cartil., 2024, 32: 355-364

[126] Xiao Bet al.. Bone-targeted nanoparticle drug delivery system-mediated macrophage modulation for enhanced fracture healing. Small, 2024, 20 e2305336

[127] Jin Pet al.. Nitric oxide nanosensors for predicting the development of osteoarthritis in rat model. ACS Appl. Mater. Interfaces, 2017, 9: 25128-25137

[128] Tang Let al.. Poly(N-isopropylacrylamide)-based smart hydrogels: Design, properties and applications. Prog. Mater. Sci., 2021, 115: 100702

[129] Poh S, Lin JB, Panitch A. Release of anti-inflammatory peptides from thermosensitive nanoparticles with degradable cross-links suppresses pro-inflammatory cytokine production. Biomacromolecules, 2015, 16: 1191-1200

[130] Kang ML, Kim JE, Im GI. Thermoresponsive nanospheres with independent dual drug release profiles for the treatment of osteoarthritis. Acta Biomater., 2016, 39: 65-78

[131] Municoy Set al.. Stimuli-responsive materials for tissue engineering and drug delivery. Int. J. Mol. Sci., 2020, 21: 4724-4763

[132] Wu S, Butt HJ. Near-infrared-sensitive materials based on upconverting nanoparticles. Adv. Mater., 2015, 28: 1208-1226

[133] Escudero JSBet al.. Photobiomodulation therapy (PBMT) in bone repair: a systematic review. Injury, 2019, 50: 1853-1867

[134] Linsley CS, Wu BM. Recent advances in light-responsive on-demand drug-delivery systems. Ther. Deliv., 2017, 8: 89-107

[135] Wang Xet al.. Near-infrared light-triggered drug delivery system based on black phosphorus for in vivo bone regeneration. Biomaterials, 2018, 179: 164-174

[136] Yang YYet al.. Natural chlorogenic acid planted nanohybrids with steerable hyperthermia for osteosarcoma suppression and bone regeneration. Adv. Healthc. Mater., 2023, 12 2300325

[137] Han Xet al.. Ultrasound-responsive smart composite biomaterials in tissue repair. Nano Today, 2023, 49 101804

[138] Qian X, Zheng Y, Chen Y. Micro/Nanoparticle-Augmented Sonodynamic Therapy (SDT): Breaking the Depth Shallow of Photoactivation. Adv. Mater., 2016, 28: 8097-8129

[139] Moonga SS, Qin Y-X. MC3T3 infiltration and proliferation in bovine trabecular scaffold regulated by dynamic flow bioreactor and augmented by low-intensity pulsed ultrasound. J. Orthop. Transl., 2018, 14: 16-22

[140] Haqiqullah C, Shakib Z, Nasratullah Z, Sherzad A, Adil A. Basics of ultrasound and its use in medicine: a review article. J. Res. Appl. Sci. Biotechnol., 2024, 3: 22-27

[141] Sotoudehbagha P, Flores AC, Hartmann T, Pattilachan T, Razavi M. Bone-targeted ultrasound-responsive nanobubbles for siRNA delivery to treat osteoporosis in mice. Biomater. Adv., 2025, 166: 214078

[142] Ma Bet al.. Piezoelectric nylon-11 nanoparticles with ultrasound assistance for high-efficiency promotion of stem cell osteogenic differentiation. J. Mater. Chem., 2019, 7: 1847-1854

[143] Frith JEet al.. Mechanically-sensitive miRNAs bias human mesenchymal stem cell fate via mTOR signalling. Nat. Commun., 2018, 9: 257-269

[144] Weyts FAA, Bosmans B, Niesing R, Leeuwen JPTM, Weinans H. Mechanical control of human osteoblast apoptosis and proliferation in relation to differentiation. Calcif. Tissue Int., 2003, 72: 505-512

[145] Panciera T, Azzolin L, Cordenonsi M, Piccolo S. Mechanobiology of YAP and TAZ in physiology and disease. Nat. Rev. Mol. Cell Biol., 2017, 18: 758-770

[146] Shen H, Larsen MB, Roessler AG, Zimmerman PM, Boydston AJ. Mechanochemical release of N-heterocyclic carbenes from flex-activated mechanophores. Angew. Chem. Int. Ed., 2021, 60: 13559-13563

[147] Mohanraj Bet al.. Mechanically activated microcapsules for “on-demand” drug delivery in dynamically loaded musculoskeletal tissues. Adv. Funct. Mater., 2019, 29 1807909

[148] Zhao Yet al.. Magnetic bioinspired micro/nanostructured composite scaffold for bone regeneration. Colloid Surf. B, 2019, 174: 70-79

[149] Chen Zet al.. Synthesis, functionalization, and nanomedical applications of functional magnetic nanoparticles. Chin. Chem. Lett., 2018, 29: 1601-1608

[150] Cao Zet al.. Effect of nanoheat stimulation mediated by magnetic nanocomposite hydrogel on the osteogenic differentiation of mesenchymal stem cells. Sci. China Life Sci., 2018, 61: 448-456

[151] Zhu Yet al.. Magnetic mesoporous bioactive glass scaffolds: preparation, physicochemistry and biological properties. J. Mat. Chem. B, 2013, 1: 1279

[152] Wang Yet al.. Magnesium–magnetic field synergy enhances mouse bone marrow mesenchymal stem cell differentiation into osteoblasts via the MAGT1 channel. J. Nanomater., 2022, 2022 3273077

[153] Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater., 2013, 12: 991-1003

[154] Jia Yet al.. Regeneration of large bone defects using mesoporous silica coated magnetic nanoparticles during distraction osteogenesis. Nanomedicine, 2019, 21 102040

[155] Montha W, Maneeprakorn W, Tang IM, Pon-On W. Hyperthermia evaluation and drug/protein-controlled release using alternating magnetic field stimuli-responsive Mn–Zn ferrite composite particles. RSC Adv., 2020, 10: 40206-40214

[156] Zhao Cet al.. Structural transformative antioxidants for dual-responsive anti-inflammatory delivery and photoacoustic inflammation imaging. Angew. Chem. Int. Ed. Engl., 2021, 60: 14458-14466

[157] Li Jet al.. Dual-responsive nanoparticles targeting bone microenvironment for synergistic chemoimmunotherapy of osteosarcoma by remodeling immune microenvironment. Nano Today, 2023, 50 101877

[158] Ruan Jet al.. A smart ROS/NIR dual-responsive melanin delivery platform for photoacoustic imaging-guided osteoarthritis therapy. Appl. Mater. Today, 2021, 25 101216

[159] Liu Net al.. A pH and near-infrared light dual-responsive drug delivery system based on TiO₂ nanotube arrays modified with polydopamine and Fe³⁺. J. Drug Deliv. Sci. Technol., 2024, 99 106003

[160] Cheng Xet al.. Fabrication of multifunctional triple-responsive platform based on CuS-capped periodic mesoporous organosilica nanoparticles for chemo-photothermal therapy. Int. J. Nanomed., 2018, 13: 3661-3677

[161] Al Bostami RD, Abuwatfa WH, Husseini GA. Recent advances in nanoparticle-based co-delivery systems for cancer therapy. Nanomaterials, 2022, 12: 2672

[162] Giordano Fet al.. Nanodelivery systems face challenges and limitations in bone diseases management. Adv. Ther., 2021, 4 2100152

[163] Gaharwar AK, Singh I, Khademhosseini A. Engineered biomaterials for in situ tissue regeneration. Nat. Rev. Mater., 2020, 5: 686-705

[164] Pina Set al.. Scaffolding strategies for tissue engineering and regenerative medicine applications. Materials, 2019, 12: 1824-1866

[165] Chen Set al.. Tuning surface properties of bone biomaterials to manipulate osteoblastic cell adhesion and the signaling pathways for the enhancement of early osseointegration. Colloid Surf. B, 2018, 164: 58-69

[166] Wang Xet al.. Recent strategies and advances in hydrogel-based delivery platforms for bone regeneration. Nano-Micro Lett., 2025, 17 73

[167] Gotman I. Characteristics of metals used in implants. J. Endourol., 1997, 11: 383-389

[168] Babuska Vet al.. Evaluating the osseointegration of nanostructured titanium implants in animal models: Current experimental methods and perspectives (Review). Biointerphases, 2016, 11 030801

[169] Chocholata P, Kulda V, Babuska V. Fabrication of scaffolds for bone-tissue regeneration. Materials, 2019, 12: 568-593

[170] Holzapfel BMet al.. How smart do biomaterials need to be? A translational science and clinical point of view. Adv. Drug Del. Rev., 2013, 65: 581-603

[171] Babuska Vet al.. Comparison of fibroblast and osteoblast response to cultivation on titanium implants with different grain sizes. J. Nanomater., 2015, 2015: 1-9

[172] Xu Jet al.. An adaptive biodegradable zinc alloy with bidirectional regulation of bone homeostasis for treating fractures and aged bone defects. Bioact. Mater., 2024, 38: 207-224

[173] Wilson J, Pigott GH, Schoen FJ, Hench LL. Toxicology and biocompatibility of bioglasses. J. Biomed. Mater. Res., 2004, 15: 805-817

[174] Turnbull Get al.. 3D bioactive composite scaffolds for bone tissue engineering. Bioact. Mater., 2018, 3: 278-314

[175] Kattimani VS, Kondaka S, Lingamaneni KP. Hydroxyapatite—past, present, and future in bone regeneration. Bone Tissue Regen. Insights, 2016, 7: 9-19

[176] Kirillova Aet al.. Fabrication of biomedical scaffolds using biodegradable polymers. Chem. Rev., 2021, 121: 11238-11304

[177] Stevens MM. Biomaterials for bone tissue engineering. Mater. Today, 2008, 11: 18-25

[178] Chen Let al.. Cationized decalcified bone matrix for infected bone defect treatment. BME Front., 2024, 5 0066

[179] Lee CH, Singla A, Lee Y. Biomedical applications of collagen. Int. J. Pharm., 2001, 221: 1-22

[180] Bartlett Wet al.. Autologous chondrocyte implantation at the knee using a bilayer collagen membrane with bone graft—a preliminary report. J. Bone Jt. Surg. Br., 2005, 87b: 330-332

[181] Asti A, Gioglio L. Natural and synthetic biodegradable polymers: different scaffolds for cell expansion and tissue formation. Int. J. Artif. Organs, 2018, 37: 187-205

[182] Dawson E, Mapili G, Erickson K, Taqvi S, Roy K. Biomaterials for stem cell differentiation. Adv. Drug Del. Rev., 2008, 60: 215-228

[183] Rezwan K, Chen QZ, Blaker JJ, Boccaccini AR. Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering. Biomaterials, 2006, 27: 3413-3431

[184] Pai S, Hebbar A, Selvaraj S. A critical look at challenges and future scopes of bioactive compounds and their incorporations in the food, energy, and pharmaceutical sector. Environ. Sci. Pollut. Res. Int., 2022, 29: 35518-35541

[185] Zhang Het al.. Cellular-scale matrix stiffness gradient at soft-hard tissue interfaces regulates immunophenotype of mesenchymal stem cells. Adv. Funct. Mater., 2024, 34 2309676

[186] Shi Net al.. Matrix nonlinear viscoelasticity regulates skeletal myogenesis through MRTF nuclear localization and nuclear mechanotransduction. Small, 2024, 20 2305218

[187] Chan BP, Leong KW. Scaffolding in tissue engineering: general approaches and tissue-specific considerations. Eur. Spine J., 2008, 17: 467-479

[188] Rehman Met al.. A comparative bio-mechanical performance assessment of additively manufactured bone scaffolds using different beta Ti alloys and Gyroid based cellular structure. J. Mater. Res. Technol., 2025, 35: 1565-1585

[189] Liu Yet al.. Shape memory alloy-based probe for measuring elastic modulus in biological tissues in the kPa–GPa range. Device, 2025, 3 100899

[190] Miri Zet al.. Review on the strategies to improve the mechanical strength of highly porous bone bioceramic scaffolds. J. Eur. Ceram. Soc., 2024, 44: 23-42

[191] Li C-Let al.. Bimodal grain structures and tensile properties of a biomedical Co–20Cr–15W–10Ni alloy with different pre-strains. Rare Met, 2021, 40: 20-30

[192] Ma Yet al.. Viscoelastic cell microenvironment: hydrogel-based strategy for recapitulating dynamic ECM mechanics. Adv. Funct. Mater., 2021, 31: 2100848

[193] Lin Det al.. A viscoelastic PEGylated poly(glycerol sebacate)-based bilayer scaffold for cartilage regeneration in full-thickness osteochondral defect. Biomaterials, 2020, 253 120095

[194] Karageorgiou V, Kaplan D. Porosity of 3D biomaterial scaffolds and osteogenesis. Biomaterials, 2005, 26: 5474-5491

[195] Iviglia G, Kargozar S, Baino F. Biomaterials, current strategies, and novel nano-technological approaches for periodontal regeneration. J. Funct. Biomater., 2019, 10: 3-39

[196] Liu Jet al.. Pre-vascularization in fibrin Gel/PLGA microsphere scaffolds designed for bone regeneration. NPG Asia Mater., 2018, 10: 827-839

[197] Abbasi N, Abdal-hay A, Hamlet S, Graham E, Ivanovski S. Effects of gradient and offset architectures on the mechanical and biological properties of 3-D melt electrowritten (MEW) scaffolds. ACS Biomater. Sci. Eng., 2019, 5: 3448-3461

[198] Abbasi N, Hamlet S, Love RM, Nguyen N-T. Porous scaffolds for bone regeneration. J. Sci. -Adv. Mater. Dev., 2020, 5: 1-9

[199] Boccaccio A, Uva AE, Fiorentino M, Lamberti L, Monno G. A Mechanobiology-based algorithm to optimize the microstructure geometry of bone tissue scaffolds. Int. J. Biol. Sci., 2016, 12: 1-17

[200] Li Yet al.. Advanced biomimetic design strategies for porous structures promoting bone integration with additive-manufactured Ti6Al4V scaffolds. J. Mater. Res. Technol., 2024, 32: 1901-1915

[201] Pfau MR, Grunlan MA. Smart scaffolds: shape memory polymers (SMPs) in tissue engineering. J. Mater. Chem. B, 2021, 9: 4287-4297

[202] Montgomery Met al.. Flexible shape-memory scaffold for minimally invasive delivery of functional tissues. Nat. Mater., 2017, 16: 1038-1046

[203] An J, Teoh JEM, Suntornnond R, Chua CK. Design and 3D printing of scaffolds and tissues. Engineering, 2015, 1: 261-268

[204] Liu Xet al.. Delivery of growth factors using a smart porous nanocomposite scaffold to repair a mandibular bone defect. Biomacromolecules, 2014, 15: 1019-1030

[205] Burkersroda FV, Schedl L, Göpferich A. Why degradable polymers undergo surface erosion or bulk erosion. Biomaterials, 2002, 23: 4221-4231

[206] Konan S, Haddad FS. A clinical review of bioabsorbable interference screws and their adverse effects in anterior cruciate ligament reconstruction surgery. Knee, 2009, 16: 6-13

[207] Tsai PF, Richards K, Tatom I. The association between knee temperature and pain in elders with osteoarthritis of the knee: a pilot study. J. Adv. Nurs., 2003, 42: 373-381

[208] Saleh TA, Fadillah G, Ciptawati E. Smart advanced responsive materials, synthesis methods and classifications: from lab to applications. J. Polym. Res., 2021, 28: 197-212

[209] Xue Net al.. A horn peptide-thermoresponsive hydrogel for angiogenesis and bone regeneration. Adv. Healthc. Mater., 2024, 13: 202304400

[210] Lv Zet al.. A MgFe-LDH nanosheet-incorporated smart thermo-responsive hydrogel with controllable growth factor releasing capability for bone regeneration. Adv. Mater., 2023, 35 e2206545

[211] Krishna AS, Radhakumary C, Sreenivasan K. Calcium ion modulates protein release from chitosan-hyaluronic acid poly electrolyte gel. Polym. Eng. Sci., 2015, 55: 2089-2097

[212] Zhang J, Liu L, Wang L, Zhu W, Wang H. pH responsive zwitterionic-to-cationic transition for safe self-defensive antibacterial application. J. Mater. Chem. B, 2020, 8: 8908-8913

[213] Li Ket al.. Calcium-mineralized polypeptide nanoparticle for intracellular drug delivery in osteosarcoma chemotherapy. Bioact. Mater., 2020, 5: 721-731

[214] Gisbert-Garzarán M, Manzano M, Vallet-Regí M. Mesoporous silica nanoparticles for the treatment of complex bone diseases: bone cancer, bone infection and osteoporosis. Pharmaceutics, 2020, 12: 83-111

[215] Lin Xet al.. Smart nanosacrificial layer on the bone surface prevents osteoporosis through acid–base neutralization regulated biocascade effects. J. Am. Chem. Soc., 2020, 142: 17543-17556

[216] Deng Yet al.. Bacteria-triggered pH-responsive osteopotentiating coating on 3D-printed polyetheretherketone scaffolds for infective bone defect repair. Ind. Eng. Chem. Res., 2020, 59: 12123-12135

[217] Lyu Yet al.. Molecular tautomerism-induced formation of supramolecular hydrogel for mRNA enrichment and delivery. Cell Biomater., 2025, 1 100124

[218] Yao Yet al.. Reactive oxygen species (ROS)-responsive biomaterials mediate tissue microenvironments and tissue regeneration. J. Mater. Chem. B, 2019, 7: 5019-5037

[219] Wu Xet al.. A cell-free ROS-responsive hydrogel/oriented poly(lactide-co-glycolide) hybrid scaffold for reducing inflammation and restoring full-thickness cartilage defects in vivo. Biomed. Mater., 2021, 16: 064101

[220] Xu Yet al.. ROS-responsive hydrogel delivering METRNL enhances bone regeneration via dual stem cell homing and vasculogenesis activation. Adv. Healthc. Mater., 2025, 14 e2500060

[221] Hu Q, Katti PS, Gu Z. Enzyme-responsive nanomaterials for controlled drug delivery. Nanoscale, 2014, 6: 12273-12286

[222] Badeau BA, DeForest CA. Programming stimuli-responsive behavior into biomaterials. Annu. Rev. Biomed. Eng., 2019, 21: 241-265

[223] Fischer NGet al.. Antimicrobial and enzyme-responsive multi-peptide surfaces for bone-anchored devices. Mater. Sci. Eng. C. Mater. Biol. Appl., 2021, 125 112108

[224] Liu Xet al.. Bone enzyme-responsive biodegradable poly(propylene fumarate) and polycaprolactone polyphosphoester dendrimer cross-linked via click chemistry for bone tissue engineering. Biomacromolecules, 2025, 26: 835-847

[225] Liu Let al.. The synergistic promotion of osseointegration by nanostructure design and silicon substitution of hydroxyapatite coatings in a diabetic model. J. Mater. Chem. B, 2020, 8: 2754-2767

[226] Chen Zet al.. Osteoimmunomodulation for the development of advanced bone biomaterials. Mater. Today, 2016, 19: 304-321

[227] Loi Fet al.. Inflammation, fracture and bone repair. Bone, 2016, 86: 119-130

[228] Schmidt-Bleek Ket al.. Initial immune reaction and angiogenesis in bone healing. J. Tissue Eng. Regen. Med., 2014, 8: 120-130

[229] Niu Y, Wang Z, Shi Y, Dong L, Wang C. Modulating macrophage activities to promote endogenous bone regeneration: Biological mechanisms and engineering approaches. Bioact. Mater., 2021, 6: 244-261

[230] Tan Jet al.. Osteoimmunomodulatory effects of biomaterial modification strategies on macrophage polarization and bone regeneration. Regen. Biomater., 2020, 7: 233-245

[231] Lee J, Byun H, Madhurakkat Perikamana SK, Lee S, Shin H. Current advances in immunomodulatory biomaterials for bone regeneration. Adv. Healthc. Mater., 2018, 8: 1801106

[232] Ou Qet al.. Nanosilver-incorporated halloysite nanotubes/gelatin methacrylate hybrid hydrogel with osteoimmunomodulatory and antibacterial activity for bone regeneration. Chem. Eng. J., 2020, 382 123019

[233] Sadowska JM, Ginebra M-P. Inflammation and biomaterials: role of the immune response in bone regeneration by inorganic scaffolds. J. Mater. Chem. B, 2020, 8: 9404-9427

[234] Garash R, Bajpai A, Marcinkiewicz BM, Spiller KL. Drug delivery strategies to control macrophages for tissue repair and regeneration. Exp. Biol. Med., 2016, 241: 1054-1063

[235] Chen Zet al.. Osteoimmunomodulatory properties of magnesium scaffolds coated with β-tricalcium phosphate. Biomaterials, 2014, 35: 8553-8565

[236] Yang Cet al.. Stimulation of osteogenesis and angiogenesis by micro/nano hierarchical hydroxyapatite via macrophage immunomodulation. Nanoscale, 2019, 11: 17699-17708

[237] Sun Bet al.. Bioactive composite hydrogel with effects of robust promoting osteogenesis and immunomodulation for osteoporotic bone regeneration. Chem. Eng. J., 2023, 476 146743

[238] Chen Zet al.. Tuning chemistry and topography of nanoengineered surfaces to manipulate immune response for bone regeneration applications. ACS Nano, 2017, 11: 4494-4506

[239] Hu Z, Ma C, Rong X, Zou S, Liu X. Immunomodulatory ECM-like microspheres for accelerated bone regeneration in diabetes mellitus. ACS Appl. Mater. Interfaces, 2018, 10: 2377-2390

[240] Pal R, Prasad TN, Bhadada SK. Bone fragility in type 2 diabetes mellitus: a lot left to explore. Nat. Rev. Endocrinol., 2022, 18: 651-651

[241] Cojocaru K-Aet al.. Mitochondrial dysfunction, oxidative stress, and therapeutic strategies in diabetes, obesity, and cardiovascular disease. Antioxidants, 2023, 12: 658-677

[242] Shen Yet al.. Targeting RORα in macrophages to boost diabetic bone regeneration. Cell Prolif., 2023, 56 e13474

[243] Wang Let al.. A blood glucose fluctuation-responsive delivery system promotes bone regeneration and the repair function of Smpd3-reprogrammed BMSC-derived exosomes. Int. J. Oral. Sci., 2024, 16: 65-80

[244] Liu Zet al.. Smart glucose-responsive hydrogel with ROS scavenging and homeostasis regulating properties for diabetic bone regeneration. Chem. Eng. J., 2024, 497 154433

[245] Lee HP, Gaharwar AK. Light-responsive inorganic biomaterials for biomedical applications. Adv. Sci., 2020, 7: 202000863

[246] Zhou Wet al.. 4D-printed dynamic materials in biomedical applications: chemistry, challenges, and their future perspectives in the clinical sector. J. Med. Chem., 2020, 63: 8003-8024

[247] Wells CMet al.. Stimuli-responsive drug release from smart polymers. J. Funct. Biomater., 2019, 10: 34-54

[248] Zhang Y, Fang C, Zhang S, Campbell RE, Serpe MJ. Controlled osteogenic differentiation of human mesenchymal stem cells using dexamethasone-loaded light-responsive microgels. ACS Appl. Mater. Interfaces, 2021, 13: 7051-7059

[249] Qinyuan Det al.. 3D-printed near-infrared-light-responsive on-demand drug-delivery scaffold for bone regeneration. Biomater. Adv., 2024, 159 213804

[250] Han Bet al.. The advance of ultrasound-enabled diagnostics and therapeutics. J. Control. Release, 2024, 375: 1-19

[251] He Yet al.. Remote control of the recruitment and capture of endogenous stem cells by ultrasound for in situ repair of bone defects. Bioact. Mater., 2023, 21: 223-238

[252] Jia Wet al.. Low-intensity pulsed ultrasound responsive scaffold promotes intramembranous and endochondral ossification via ultrasonic, thermal, and electrical stimulation. ACS Nano, 2025, 19: 4422-4439

[253] Tanasa Eet al.. Impact of the magnetic field on 3T3-E1 preosteoblasts inside SMART silk fibroin-based scaffolds decorated with magnetic nanoparticles. Mater. Sci. Eng. C. Mater. Biol. Appl., 2020, 110 110714

[254] Tang Bet al.. Enhanced cellular osteogenic differentiation on CoFe2O4/P(VDF-TrFE) nanocomposite coatings under static magnetic field. Colloid Surf. B, 2021, 198 111473

[255] Madani SZM, Reisch A, Roxbury D, Kennedy SM. A magnetically responsive hydrogel system for controlling the timing of bone progenitor recruitment and differentiation factor deliveries. ACS Biomater. Sci. Eng., 2020, 6: 1522-1534

[256] Marycz Ket al.. Iron oxides nanoparticles (IOs) exposed to magnetic field promote expression of osteogenic markers in osteoblasts through integrin alpha-3 (INTa-3) activation, inhibits osteoclasts activity and exerts anti-inflammatory action. J. Nanobiotechnol., 2020, 18: 33-57

[257] Przekora A. Current trends in fabrication of biomaterials for bone and cartilage regeneration: materials modifications and biophysical stimulations. Int. J. Mol. Sci., 2019, 20: 435-452

[258] Liang HFet al.. Biomimetic structural protein based magnetic responsive scaffold for enhancing bone regeneration by physical stimulation on intracellular calcium homeostasis. Adv. Healthc. Mater., 2023, 12 2301724

[259] Polley Cet al.. 3D printing of piezoelectric barium titanate-hydroxyapatite scaffolds with interconnected porosity for bone tissue engineering. Materials, 2020, 13: 1773

[260] Jacob J, More N, Kalia K, Kapusetti G. Piezoelectric smart biomaterials for bone and cartilage tissue engineering. Inflamm. Regen., 2018, 38: 2-13

[261] Ferrigno Bet al.. Bioactive polymeric materials and electrical stimulation strategies for musculoskeletal tissue repair and regeneration. Bioact. Mater., 2020, 5: 468-485

[262] Prasad NS, Varma KBR. Dielectric, structural and ferroelectric properties of strontium borate glasses containing nanocrystalline bismuth vanadate. J. Mater. Chem., 2001, 11: 1912-1918

[263] Zhang Set al.. Piezoelectric hydrogel with self-powered biomechanical stimulation enhances bone regeneration. Acta Biomater., 2025, 195: 117-133

[264] Leppik L, Oliveira KMC, Bhavsar MB, Barker JH. Electrical stimulation in bone tissue engineering treatments. Eur. J. Trauma Emerg. Surg., 2020, 46: 231-244

[265] Aleem ISet al.. Efficacy of electrical stimulators for bone healing: a meta-analysis of randomized sham-controlled trials. Sci. Rep., 2016, 6 31724

[266] Zhao C, Lin K, Wang X. Maintenance and modulation of stem cells stemness based on biomaterial designing via chemical and physical signals. Appl. Mater. Today, 2020, 19: 100614

[267] Wang Jet al.. High-glucose/high-cholesterol diet in zebrafish evokes diabetic and affective pathogenesis: The role of peripheral and central inflammation, microglia and apoptosis. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2020, 96: 109752

[268] Yan Het al.. An electrically and magnetically responsive nanocomposite of GdPO4·H2O/P3HT/PLGA with electrical stimulation for synergistically enhancing the proliferation and differentiation of pre-osteoblasts. N. J. Chem., 2019, 43: 17315-17326

[269] Zhou Tet al.. A Mussel-inspired persistent ros-scavenging, electroactive, and osteoinductive scaffold based on electrochemical-driven in situ nanoassembly. Small, 2019, 15 1805440

[270] Li Jet al.. Targeting endogenous hydrogen peroxide at bone defects promotes bone repair. Adv. Funct. Mater., 2022, 32 2111208

[271] Lu J-W, Yang F, Ke Q-F, Xie X-T, Guo Y-P. Magnetic nanoparticles modified-porous scaffolds for bone regeneration and photothermal therapy against tumors. Nanomed. Nanotechnol. Biol. Med., 2018, 14: 811-822

[272] Ma Het al.. 3D printing of high-strength bioscaffolds for the synergistic treatment of bone cancer. NPG Asia Mater., 2018, 10: 31-44

[273] Zhao S, Li Y, Dai L, Cheng B. Ultrasound-responsive piezoelectric hydrogels accelerate bone defect repair by regulating mitochondrial OXPHOS via activating AKT/GSK3β/β-catenin signaling axis. Chem. Eng. J., 2025, 522: 168176

[274] Yang Aet al.. Integrating fluorescence and magnetic resonance imaging in biocompatible scaffold for real-time bone repair monitoring and assessment. Adv. Healthc. Mater., 2024, 13 2302687

[275] Dayanandan APet al.. Emerging nano-scale delivery systems for the treatment of osteoporosis. Biomater. Res., 2023, 27: 68-93

[276] Jiann Chong ET, Ng JW, Lee P-C. Classification and medical applications of biomaterials–a mini review. BIO Integr., 2023, 4: 54-61

[277] Yadav S, Sharma AK, Kumar P. Nanoscale self-assembly for therapeutic delivery. Front. Bioeng. Biotechnol., 2020, 8: 127-151

[278] Zhang Xet al.. The entropy-controlled strategy in self-assembling systems. Chem. Soc. Rev., 2023, 52: 6806-6837

[279] Lepeltier E, Bourgaux C, Couvreur P. Nanoprecipitation and the “Ouzo effect”: Application to drug delivery devices. Adv. Drug Del. Rev., 2014, 71: 86-97

[280] Liu Yet al.. Formulation of nanoparticles using mixing-induced nanoprecipitation for drug delivery. Ind. Eng. Chem. Res., 2019, 59: 4134-4149

[281] Sarode A, Annapragada A, Guo J, Mitragotri S. Layered self-assemblies for controlled drug delivery: a translational overview. Biomaterials, 2020, 242: 119929

[282] Bangham AD, De Gier J, Greville GD. Osmotic properties and water permeability of phospholipid liquid crystals. Chem. Phys. Lipids, 1967, 1: 225-246

[283] Lombardo D, Kiselev MA. Methods of liposomes preparation: formation and control factors of versatile nanocarriers for biomedical and nanomedicine application. Pharmaceutics, 2022, 14: 543-592

[284] William B, Noémie P, Brigitte E, Géraldine P. Supercritical fluid methods: An alternative to conventional methods to prepare liposomes. Chem. Eng. J., 2020, 383: 123106

[285] Kasana, R., Rathore, P., Shashikumar, U. & Chawla, S. Nanoceramics: fabrication, properties, and applications. Indust. Applicat. Nanoceram. 19-36, (2024).

[286] Altammar KA. A review on nanoparticles: characteristics, synthesis, applications, and challenges. Front. Microbiol., 2023, 14: 1155622

[287] Sreekanth TVMet al.. Ultra-sonication-assisted silver nanoparticles using Panax ginseng root extract and their anti-cancer and antiviral activities. J. Photochem. Photobiol. B: Biol., 2018, 188: 6-11

[288] Chandrakala V, Aruna V, Angajala G. Review on metal nanoparticles as nanocarriers: current challenges and perspectives in drug delivery systems. Emergent Mater., 2022, 5: 1593-1615

[289] Mohammadi Zerankeshi M, Bakhshi R, Alizadeh R. Polymer/metal composite 3D porous bone tissue engineering scaffolds fabricated by additive manufacturing techniques: A review. Bioprinting, 2022, 25 e00191

[290] Song Wet al.. Additive manufacturing of degradable metallic scaffolds for material-structure-driven diabetic maxillofacial bone regeneration. Bioact. Mater., 2024, 36: 413-426

[291] Chakka LRJ, Chede LS, Bashetty SR, Maniruzzaman M. Functional scaffolds and methods for bone tissue engineering applications. Biofunct. Mater., 2025, 3: 1-15

[292] Shah FAet al.. Long-term osseointegration of 3D printed CoCr constructs with an interconnected open-pore architecture prepared by electron beam melting. Acta Biomater., 2016, 36: 296-309

[293] Zhao B, Wang H, Qiao N, Wang C, Hu M. Corrosion resistance characteristics of a Ti-6Al-4V alloy scaffold that is fabricated by electron beam melting and selective laser melting for implantation in vivo. Mater. Sci. Eng. C. Mater. Biol. Appl., 2017, 70: 832-841

[294] Guo Yet al.. Study of bone regeneration and osteointegration effect of a novel selective laser-melted titanium-tantalum-niobium-zirconium alloy scaffold. ACS Biomater. Sci. Eng., 2019, 5: 6463-6473

[295] Carluccio Det al.. Additively manufactured iron-manganese for biodegradable porous load-bearing bone scaffold applications. Acta Biomater., 2020, 103: 346-360

[296] Shuai Cet al.. Positive feedback effects of Mg on the hydrolysis of poly-l-lactic acid (PLLA): Promoted degradation of PLLA scaffolds. Polym. Test., 2018, 68: 27-33

[297] Zhou Z, Lennon A, Buchanan F, McCarthy HO, Dunne N. Binder jetting additive manufacturing of hydroxyapatite powders: effects of adhesives on geometrical accuracy and green compressive strength. Addit. Manuf., 2020, 36: 101645

[298] Liu Zet al.. Additive manufacturing of hydroxyapatite bone scaffolds via digital light processing and in vitro compatibility. Ceram. Int., 2019, 45: 11079-11086

[299] Wang J-C, Dommati H, Hsieh S-J. Review of additive manufacturing methods for high-performance ceramic materials. Int. J. Adv. Manuf. Tech., 2019, 103: 2627-2647

[300] Chen Zet al.. 3D printing of ceramics: a review. J. Eur. Ceram. Soc., 2019, 39: 661-687

[301] Ogier, R., Knecht, W., & Schwab, M. E. Translating academic discovery to patients’ benefit: is academia ready to assume its key role? Swiss Acad. Commun. 1-43, (2019).

[302] Duda GNet al.. Changing the mindset in life sciences toward translation: a consensus. Sci. Transl. Med., 2014, 6: 12-18

[303] Gehr S, Garner CC. Rescuing the lost in translation. Cell, 2016, 165: 765-770

[304] Salthouse D, Novakovic K, Hilkens CMU, Ferreira AM. Interplay between biomaterials and the immune system: challenges and opportunities in regenerative medicine. Acta Biomater., 2023, 155: 1-18

[305] Sicari BMet al.. The effect of source animal age upon the in vivo remodeling characteristics of an extracellular matrix scaffold. Biomaterials, 2012, 33: 5524-5533

[306] Karwowski Wet al.. Grand challenges in industrial and systems engineering. Int. J. Prod. Res., 2025, 63: 1538-1583

[307] Taeihagh A, Ramesh M, Howlett M. Assessing the regulatory challenges of emerging disruptive technologies. Regul. Gov., 2021, 15: 1009-1019

[308] Moriarty TF, Grainger DW, Richards RG. Challenges in linking preclinical anti-microbial research strategies with clinical outcomes for device-associated infections. Eur. Cell. Mater., 2014, 28: 112-128

[309] Parrish MC, Tan YJ, Grimes KV, Mochly-Rosen D. Surviving in the valley of death: opportunities and challenges in translating academic drug discoveries. Annu. Rev. Pharmacol. Toxicol., 2019, 59: 405-421

[310] Coller BS, Califf RM. Traversing the valley of death: a guide to assessing prospects for translational success. Sci. Transl. Med., 2009, 1: 9-20

[311] Bridgham, K., Chandawarkar, A., Darrach, H. and Sacks, J. M. How to overcome the valley of death from basic science to clinical trials. 213-220 (2019).

[312] Barr SH, Baker T, Markham SK, Kingon AI. Bridging the valley of death: lessons learned from 14 years of commercialization of technology education. Acad. Manag. Learn. Edu., 2009, 8: 370-388

[313] Gillman CE, Jayasuriya AC. FDA-approved bone grafts and bone graft substitute devices in bone regeneration. Mater. Sci. Eng. C., Mater. Biol. Appl., 2021, 130: 112466

[314] Arnold PMet al.. i-Factor™ bone graft vs autograft in anterior cervical discectomy and fusion: 2-year follow-up of the randomized single-blinded food and drug administration investigational device exemption study. Neurosurgery, 2018, 83: 377-384

[315] Reis RL. Materiobiology-driven engineering for next-generation organoids. Organoid Res., 2025, 1: 025210018

[316] Gu, X. Artificial intelligent for biomaterials and tissue engineering. J. Intell. Med. n/a, 249, (2025).

[317] Mazumdar H, Khondakar KR, Das S, Halder A, Kaushik A. Artificial intelligence for personalized nanomedicine; from material selection to patient outcomes. Expert Opin. Drug Deliv., 2025, 22: 85-108

[318] Yang Cet al.. Non-invasive monitoring of in vivo bone regeneration based on alkaline phosphatase-responsive scaffolds. Chem. Eng. J., 2021, 408 127959

[319] Jiang Yet al.. Wireless, closed-loop, smart bandage with integrated sensors and stimulators for advanced wound care and accelerated healing. Nat. Biotechnol., 2023, 41: 652-662

[320] Ding Het al.. Preparation and application of pH-responsive drug delivery systems. J. Control. Release, 2022, 348: 206-238

[321] Mollazadeh S, Mackiewicz M, Yazdimamaghani M. Recent advances in the redox-responsive drug delivery nanoplatforms: a chemical structure and physical property perspective. Mater. Sci. Eng. C. Mater. Biol. Appl., 2021, 118: 111536

[322] Kapalatiya H, Madav Y, Tambe VS, Wairkar S. Enzyme-responsive smart nanocarriers for targeted chemotherapy: an overview. Drug Deliv. Transl. Res., 2022, 12: 1293-1305

[323] Rudko M, Urbaniak T, Musiał W. Recent Developments in Ion-Sensitive Systems for Pharmaceutical Applications. Polym. (Basel), 2021, 13: 1641

[324] Karimi Met al.. Temperature-responsive smart nanocarriers for delivery of therapeutic agents: applications and recent advances. ACS Appl. Mater. Interfaces, 2016, 8: 21107-21133

[325] Yang Yet al.. Photoresponsive drug delivery systems: challenges and progress. Adv. Funct. Mater., 2024, 34: 2402975

[326] Wei P, Cornel EJ, Du J. Ultrasound-responsive polymer-based drug delivery systems. Drug Deliv. Transl. Res., 2021, 11: 1323-1339

[327] Ma Pet al.. Recent advances in mechanical force-responsive drug delivery systems. Nanoscale Adv., 2022, 4: 3462-3478

[328] Aslam Het al.. Current and future perspectives of multifunctional magnetic nanoparticles based controlled drug delivery systems. J. Drug Deliv. Sci. Technol., 2022, 67 102946

[329] Guleria S, Chopra L. Temperature responsive hydrogels for biomedical applications. Mater. Today Proc., 2023, 92: 356-363

[330] Min KH, Kim DH, Kim KH, Seo JH, Pack SP. Biomimetic scaffolds of calcium-based materials for bone regeneration. Biomimetics, 2024, 9: 511

[331] Zarur M, Seijo-Rabina A, Goyanes A, Concheiro A, Alvarez-Lorenzo C. pH-responsive scaffolds for tissue regeneration: in vivo performance. Acta Biomater., 2023, 168: 22-41

[332] Griffin DRet al.. Activating an adaptive immune response from a hydrogel scaffold imparts regenerative wound healing. Nat. Mater., 2021, 20: 560-569

[333] Rege NK, Phillips NFB, Weiss MA. Development of glucose-responsive ‘smart’ insulin systems. Curr. Opin. Endocrinol. Diab. Obes., 2017, 24: 267-278

[334] Lee HP, Gaharwar AK. Light-responsive inorganic biomaterials for biomedical applications. Adv. Sci., 2020, 7: 2000863

[335] Ake Bet al.. Ultrasound-responsive smart biomaterials for bone tissue engineering. J. Mater. Chem. B, 2025, 13: 4527-4543

[336] Almeida ACet al.. Magnetic-responsive materials tailored to enhance the cascade of bone regeneration and immune response. Mater. Des., 2025, 251 113645

[337] Mirghaffari Met al.. Electro-spun piezoelectric PLLA smart composites as a scaffold on bone fracture: a review. Regen. Ther., 2025, 28: 591-605

[338] Ding S, Anton N, Vandamme TF, Serra CA. Microfluidic nanoprecipitation systems for preparing pure drug or polymeric drug loaded nanoparticles: an overview. Expert Opin. Drug Deliv., 2016, 13: 1447-1460

[339] Wang Y, Angelatos AS, Caruso F. Template synthesis of nanostructured materials via layer-by-layer assembly. Chem. Mater., 2007, 20: 848-858

[340] Thabet Y, Elsabahy M, Eissa NG. Methods for preparation of niosomes: a focus on thin-film hydration method. Methods, 2022, 199: 9-15

[341] Duong V-A, Nguyen T-T-L, Maeng H-J. Preparation of solid lipid nanoparticles and nanostructured lipid carriers for drug delivery and the effects of preparation parameters of solvent injection method. Molecules, 2020, 25: 4781-4817

[342] Lei Qet al.. Sol–gel-based advanced porous silica materials for biomedical applications. Adv. Funct. Mater., 2020, 30 1909539

[343] Rahmani M, Mirzaee O, Tajally M, Loghman-Estarki MR. A comparative study of synthesis and spark plasma sintering of YAG nano powders by different co-precipitation methods. Ceram. Int., 2018, 44: 10035-10046

[344] Abid Net al.. Synthesis of nanomaterials using various top-down and bottom-up approaches, influencing factors, advantages, and disadvantages: a review. Adv. Colloid Interface Sci., 2022, 300: 102597

[345] Wang C, Yu D. Comparison of electron beam melting fabrication of irregularity porous Ti-6Al-4V and Ti-24Nb-4Zr-8Sn titanium alloy Scaffolds: cytocompatibility and osteogenesis. Clin. Oral. Implants Res., 2020, 31: 110-110

[346] Carluccio D, Demir AG, Bermingham MJ, Dargusch MS. Challenges and opportunities in the selective laser melting of biodegradable metals for load-bearing bone scaffold applications. Metall. Mater. Trans., 2020, 51: 3311-3334

[347] Song Y, Ghafari Y, Asefnejad A, Toghraie D. An overview of selective laser sintering 3D printing technology for biomedical and sports device applications: Processes, materials, and applications. Opt. Laser Technol., 2024, 171: 110459

[348] Marques A, Miranda G, Silva F, Pinto P, Carvalho Ó. Review on current limits and potentialities of technologies for biomedical ceramic scaffolds production. J. Biomed. Mater. Res. B Appl. Biomater., 2020, 109: 377-393

[349] Zhang Fet al.. Digital light processing of β-tricalcium phosphate bioceramic scaffolds with controllable porous structures for patient specific craniomaxillofacial bone reconstruction. Mater. Des., 2022, 216 110558

[350] Varma MV, Kandasubramanian B, Ibrahim SM. 3D printed scaffolds for biomedical applications. Mater. Chem. Phys., 2020, 255: 123642

[351] Cano-Vicent Aet al.. Fused deposition modelling: current status, methodology, applications and future prospects. Addit. Manuf., 2021, 47: 102378

[352] Schappo H, Giry K, Salmoria G, Damia C, Hotza D. Polymer/calcium phosphate biocomposites manufactured by selective laser sintering: an overview. Prog. Addit. Manuf., 2022, 8: 285-301

Funding

National Natural Science Foundation of China (National Science Foundation of China)(82422045)

The National Key Research and Development Program of China is a significant national initiative aimed at promoting innovation-driven development and enhancing China's technological capabilities. And the research was supported by one project from this funder (2024YFC2418800).The Capital’s Funds for Health Improvement and Research Program, managed by the Beijing Municipal Health Commission, is a significant initiative aimed at promoting medical research and healthcare advancements in Beijing. This program provides financial support for us to conduct health-related research project (2024-2-5052).

China Postdoctoral Science Foundation(XJ2021051)

The National Key Research and Development Program of China is a significant national initiative aimed at promoting innovation-driven development and enhancing China's technological capabilities. And the research was supported by one project from this funder (2022YFC2504300).

RIGHTS & PERMISSIONS

The Author(s)