Intelligent microstructure materials for diagnosis and treatment of osteoarthritis: progress and AI-enpowered future

Abstract

Osteoarthritis (OA) is a widespread joint disorder that has emerged as a significant global healthcare challenge. Over the past decade, advancements in material science and medicine have transformed the development of functional materials aimed at addressing the complex issues associated with the diagnosis and treatment of OA. This review synthesizes the latest advancements in various types of intelligent micro-structured materials and their design principles. By examining the exceptional structural characteristics of materials with unique properties such as tailored attributes, controllability, biocompatibility, and bioactivity, we emphasize the design of composite materials for precise and early intervention in OA. This is achieved through advanced imaging techniques and machine learning-based analysis, alongside the customization of micro-structured material properties to align with the biological and mechanical requirements of specific joint tissues. This review offers an in-depth analysis of the transformative potential of advanced technologies and artificial intelligence (AI) in the development of innovative solutions for OA diagnosis and therapy. It aims to inform future research and inspire the creation of next-generation smart materials with unprecedented performance, thereby enhancing our capabilities in the prevention and treatment of OA.

References

[1] Collaborators GBDO. Global, regional, and national burden of osteoarthritis, 1990-2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol., 2023, 5: e508-e522.

[2] Zhang W, Ouyang H, Dass CR, Xu J. Current research on pharmacologic and regenerative therapies for osteoarthritis. Bone Res., 2016, 4. 15040

[3] Sanchez-Lopez E, Coras R, Torres A, Lane NE, Guma M. Synovial inflammation in osteoarthritis progression. Nat. Rev. Rheumatol., 2022, 18: 258-275.

[4] Makris EA, Hadidi P, Athanasiou KA. The knee meniscus: structure-function, pathophysiology, current repair techniques, and prospects for regeneration. Biomaterials, 2011, 32: 7411-7431.

[5] Nickel JC, Iwasaki LR, Gonzalez YM, Gallo LM, Yao H. Mechanobehavior and ontogenesis of the temporomandibular joint. J. Dent. Res., 2018, 97: 1185-1192.

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

[7] Juan Z, Xing-Tong M, Xu Z, Chang-Yi L. Potential pathological and molecular mechanisms of temporomandibular joint osteoarthritis. J. Dent. Sci., 2023, 18: 959-971.

[8] Molnar, V., et al. Cytokines and chemokines involved in osteoarthritis pathogenesis. Int. J. Mol. Sci.22, 9208 (2021).

[9] Wang X, Oo WM, Linklater JM. What is the role of imaging in the clinical diagnosis of osteoarthritis and disease management?. Rheumatology, 2018, 57: iv51-iv60.

[10] Zhang W. et al.. EULAR evidence-based recommendations for the diagnosis of hand osteoarthritis: report of a task force of ESCISIT. Ann. Rheum. Dis., 2009, 68: 8-17.

[11] Zhang W. et al.. EULAR evidence-based recommendations for the diagnosis of knee osteoarthritis. Ann. Rheum. Dis., 2010, 69: 483-489.

[12] Katz JN, Brownlee SA, Jones MH. The role of arthroscopy in the management of knee osteoarthritis. Best. Pr. Res Clin. Rheumatol., 2014, 28: 143-156.

[13] Kolasinski SL. et al.. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Care Res., 2020, 72: 149-162.

[14] Madry H. Surgical therapy in osteoarthritis. Osteoarthr. Cartil., 2022, 30: 1019-1034.

[15] Saeedi T, Alotaibi HF, Prokopovich P. Polymer colloids as drug delivery systems for the treatment of arthritis. Adv. Colloid Interface Sci., 2020, 285. 102273

[16] Graham NB. Hydrogels: their future, Part I. Med Device Technol., 1998, 9: 18-22

[17] Anderson DG, Burdick JA, Langer R. Materials science. Smart biomaterials. Science, 2004, 305: 1923-1924.

[18] Montoya C. et al.. On the road to smart biomaterials for bone research: definitions, concepts, advances, and outlook. Bone Res., 2021, 9: 12.

[19] Zhang K. et al.. Advanced smart biomaterials and constructs for hard tissue engineering and regeneration. Bone Res., 2018, 6: 31.

[20] Ruoslahti E. Peptides as targeting elements and tissue penetration devices for nanoparticles. Adv. Mater., 2012, 24: 3747-3756.

[21] Shih PC, Lee YH, Tsou HK, Cheng-Chung Wei J. Recent targets of osteoarthritis research. Best. Pr. Res. Clin. Rheumatol., 2023, 37. 101851

[22] Xiao S, Chen L. The emerging landscape of nanotheranostic-based diagnosis and therapy for osteoarthritis. J. Control Rel., 2020, 328: 817-833.

[23] Gu, Z., et al. Smart biomaterials for articular cartilage repair and regeneration. Adv. Funct. Mater.33, https://doi.org/10.1002/adfm.202212561 (2023).

[24] Hassanzadeh P, Atyabi F, Dinarvand R. The significance of artificial intelligence in drug delivery system design. Adv. Drug Deliv. Rev., 2019, 151-152: 169-190.

[25] Han Z. et al.. Development of the design and synthesis of metal–organic frameworks (MOFs) – from large scale attempts, functional oriented modifications, to artificial intelligence (AI) predictions. Chem. Soc. Rev., 2025, 54: 367-395.

[26] Javaid M, Haleem A. Significant advancements of 4D printing in the field of orthopaedics. J. Clin. Orthop. Trauma, 2020, 11: S485-S490.

[27] Hou, X., et al. Interplay between materials and microfluidics. Nat. Rev. Mater.2, 17016 (2017).

[28] Katz JN, Arant KR, Loeser RF. Diagnosis and treatment of hip and knee osteoarthritis: a review. JAMA, 2021, 325: 568-578.

[29] Olah T. et al.. Quantifying the human subchondral trabecular bone microstructure in osteoarthritis with clinical CT. Adv. Sci., 2022, 9. e2201692

[30] Glyn-Jones S. et al.. Osteoarthritis. Lancet, 2015, 386: 376-387.

[31] Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: an update with relevance for clinical practice. Lancet, 2011, 377: 2115-2126.

[32] Lawson T, Joenathan A, Patwa A, Snyder BD, Grinstaff MW. Tantalum oxide nanoparticles for the quantitative contrast-enhanced computed tomography of ex vivo human cartilage: assessment of biochemical composition and biomechanics. ACS Nano, 2021, 15: 19175-19184.

[33] Garcia JP. et al.. Contrast enhanced computed tomography for real-time quantification of glycosaminoglycans in cartilage tissue engineered constructs. Acta Biomater., 2019, 100: 202-212.

[34] Piscaer TM. et al.. In vivo imaging of cartilage degeneration using microCT-arthrography. Osteoarthr. Cartil., 2008, 16: 1011-1017.

[35] Song G. et al.. Catalase-loaded TaOx nanoshells as bio-nanoreactors combining high-Z element and enzyme delivery for enhancing radiotherapy. Adv. Mater., 2016, 28: 7143-7148.

[36] Freedman JD, Lusic H, Snyder BD, Grinstaff MW. Tantalum oxide nanoparticles for the imaging of articular cartilage using X‐ray computed tomography: visualization of ex vivo/in vivo murine tibia and ex vivo human index finger cartilage. Angew. Chem., 2014, 126: 8546-8550.

[37] Lee N, Choi SH, Hyeon T. Nano-sized CT contrast agents. Adv. Mater., 2013, 25: 2641-2660.

[38] Saukko AEA. et al.. Dual contrast CT method enables diagnostics of cartilage injuries and degeneration using a single CT image. Ann. Biomed. Eng., 2017, 45: 2857-2866.

[39] Zhang C, Vedadghavami A, He T, Charles JF, Bajpayee AG. Cationic carrier mediated delivery of anionic contrast agents in low doses enable enhanced computed tomography imaging of cartilage for early osteoarthritis diagnosis. ACS Nano, 2023, 17: 6649-6663.

[40] Samuels J, Krasnokutsky S, Abramson SB. Osteoarthritis: a tale of three tissues. Bull. NYU Hosp. Jt Dis., 2008, 66: 244-250

[41] Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol., 2010, 6: 625-635.

[42] Eckstein F. et al.. Imaging of cartilage and bone: promises and pitfalls in clinical trials of osteoarthritis. Osteoarthr. Cartil., 2014, 22: 1516-1532.

[43] Mahmoudi M, Hofmann H, Rothen-Rutishauser B, Petri-Fink A. Assessing the in vitro and in vivo toxicity of superparamagnetic iron oxide nanoparticles. Chem. Rev., 2012, 112: 2323-2338.

[44] Sandiford L. et al.. Bisphosphonate-anchored PEGylation and radiolabeling of superparamagnetic iron oxide: long-circulating nanoparticles for in vivo multimodal (T1 MRI-SPECT) imaging. ACS Nano, 2013, 7: 500-512.

[45] Panahifar A, Mahmoudi M, Doschak MR. Synthesis and in vitro evaluation of bone-seeking superparamagnetic iron oxide nanoparticles as contrast agents for imaging bone metabolic activity. ACS Appl. Mater. Interfaces, 2013, 5: 5219-5226.

[46] Rothenfluh DA, Bermudez H, O’Neil CP, Hubbell JA. Biofunctional polymer nanoparticles for intra-articular targeting and retention in cartilage. Nat. Mater., 2008, 7: 248-254.

[47] Wu J. et al.. Ultra-small superparamagnetic iron oxide nanoparticles for intra-articular targeting of cartilage in early osteoarthritis. Regen. Biomater., 2023, 10. rbad052

[48] Pi Y. et al.. Targeted delivery of non-viral vectors to cartilage in vivo using a chondrocyte-homing peptide identified by phage display. Biomaterials, 2011, 32: 6324-6332.

[49] Ouyang Z. et al.. Targeted delivery of hesperetin to cartilage attenuates osteoarthritis by bimodal imaging with Gd(2)(CO(3))(3)@PDA nanoparticles via TLR-2/NF-kappaB/Akt signaling. Biomaterials, 2019, 205: 50-63.

[50] Lin T. et al.. Carboxymethyl chitosan-assisted MnO(x) nanoparticles: Synthesis, characterization, detection and cartilage repair in early osteoarthritis. Carbohydr. Polym., 2022, 294. 119821

[51] Choi W. et al.. Recent advances in contrast-enhanced photoacoustic imaging: overcoming the physical and practical challenges. Chem. Rev., 2023, 123: 7379-7419.

[52] Shen J. et al.. Early diagnosis and treatment of osteoarthritis with a Au@PDA-WL NP nano-probe by photoacoustic imaging. J. Mater. Chem. B, 2023, 11: 5777-5785.

[53] Au MT. et al.. Nerve growth factor-targeted molecular theranostics based on molybdenum disulfide nanosheet-coated gold nanorods (MoS(2)-AuNR) for osteoarthritis pain. ACS Nano, 2021, 15: 11711-11723.

[54] Chen L. et al.. Cationic poly-l-lysine-encapsulated melanin nanoparticles as efficient photoacoustic agents targeting to glycosaminoglycans for the early diagnosis of articular cartilage degeneration in osteoarthritis. Nanoscale, 2018, 10: 13471-13484.

[55] Xiao S, Tang Y, Lin Y, Lv Z, Chen L. Tracking osteoarthritis progress through cationic nanoprobe-enhanced photoacoustic imaging of cartilage. Acta Biomater., 2020, 109: 153-162.

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

[57] Lan Q. et al.. MMP-13 enzyme and pH responsive theranostic nanoplatform for osteoarthritis. J. Nanobiotechnol., 2020, 18. 117

[58] Zhou D. et al.. MMP13-targeted siRNA-loaded micelles for diagnosis and treatment of posttraumatic osteoarthritis. Bioact. Mater., 2024, 37: 378-392

[59] Peng S. et al.. Detection of ADAMTS-4 activity using a fluorogenic peptide-conjugated Au nanoparticle probe in human knee synovial fluid. ACS Appl Mater. Interfaces, 2013, 5: 6089-6096.

[60] Liu Z. et al.. Diagnostic utility of fluorogenic peptide-conjugated Au nanoparticle probe corroborated by rabbit model of mild cartilage injury and panel of osteoarthritic patients. Am. J. Transl. Res, 2018, 10: 2277-2289

[61] Shen C. et al.. Reactive oxygen species (ROS)-responsive nanoprobe for bioimaging and targeting therapy of osteoarthritis. J. Nanobiotechnol., 2021, 19. 395

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

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

[64] Yu Q. et al.. A neutrophil cell membrane-biomimetic nanoplatform based on L-arginine nanoparticles for early osteoarthritis diagnosis and nitric oxide therapy. Nanoscale, 2022, 14: 11619-11634.

[65] Ge X. et al.. Single wavelength laser excitation ratiometric NIR-II fluorescent probe for molecule imaging in vivo. Anal. Chem., 2020, 92: 6111-6120.

[66] Lu Z. et al.. A smart hypochlorous acid fluorescent probe enabling Ibuprofen-release for osteoarthritis theranostics. Theranostics, 2024, 14: 3900-3908.

[67] Luo Q. et al.. A new HClO-activated “turn-off” mitochondria-targetable NIR fluorescent probe for imaging of osteoarthritis in vivo. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2022, 273. 121017

[68] Yu KH, Beam AL, Kohane IS. Artificial intelligence in healthcare. Nat. Biomed. Eng., 2018, 2: 719-731.

[69] Lin X, Zhu J, Shen J, Zhang Y, Zhu J. Advances in exosome plasmonic sensing: device integration strategies and AI-aided diagnosis. Biosens. Bioelectron., 2024, 266. 116718

[70] Haldavnekar R, Venkatakrishnan K, Tan B. Cancer stem cell derived extracellular vesicles with self-functionalized 3D nanosensor for real-time cancer diagnosis: eliminating the roadblocks in liquid biopsy. ACS Nano, 2022, 16: 12226-12243.

[71] Rong M. et al.. A superparamagnetic composite hydrogel scaffold as in vivo dynamic monitorable theranostic platform for osteoarthritis regeneration. Adv. Mater., 2024, 36. e2405641

[72] Rothbauer, M. et al. A progress report and roadmap for microphysiological systems and organ-on-a-chip technologies to be more predictive models in human (knee) osteoarthritis. Front. Bioeng. Biotechnol.10, 886360 (2022).

[73] Rothbauer M. et al.. Monitoring tissue-level remodelling during inflammatory arthritis using a three-dimensional synovium-on-a-chip with non-invasive light scattering biosensing. Lab. Chip, 2020, 20: 1461-1471.

[74] Caliva F. et al.. Studying osteoarthritis with artificial intelligence applied to magnetic resonance imaging. Nat. Rev. Rheumatol., 2022, 18: 112-121.

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

[76] Li W. et al.. Near infrared responsive gold nanorods attenuate osteoarthritis progression by targeting TRPV1. Adv. Sci., 2024, 11. e2307683

[77] Xue S. et al.. Cartilage-targeting peptide-modified dual-drug delivery nanoplatform with NIR laser response for osteoarthritis therapy. Bioact. Mater., 2021, 6: 2372-2389

[78] Luo Z-Y. et al.. Multifunctional mesoporous polydopamine near-infrared photothermal controlled release of kartogenin for cartilage repair. Mater. Des., 2023, 231. 112007

[79] Shi H. et al.. Integrating physicomechanical and biological strategies for BTE: biomaterials-induced osteogenic differentiation of MSCs. Theranostics, 2023, 13: 3245-3275.

[80] Savadipour A. et al.. Membrane stretch as the mechanism of activation of PIEZO1 ion channels in chondrocytes. Proc. Natl. Acad. Sci. USA, 2023, 120. e2221958120

[81] Hodgkinson T, Kelly DC, Curtin CM, O’Brien FJ. Mechanosignalling in cartilage: an emerging target for the treatment of osteoarthritis. Nat. Rev. Rheumatol., 2022, 18: 67-84.

[82] Mohanraj, B., et al. Mechanically-activated microcapsules for ‘on-demand’ drug delivery in dynamically loaded musculoskeletal tissues. Adv. Funct. Mater. 29, 1807909 (2019).

[83] Shubayev VI, Pisanic TR2nd, Jin S. Magnetic nanoparticles for theragnostics. Adv. Drug Deliv. Rev., 2009, 61: 467-477.

[84] Zhang M. et al.. Advanced application of stimuli-responsive drug delivery system for inflammatory arthritis treatment. Mater. Today Bio, 2022, 14. 100223

[85] Cen, X. et al. An “all-in-one” strategy to reconstruct temporomandibular joint osteoarthritic microenvironment using gamma-Fe(2)O(3)@TA@ALN nanoparticles. Small21, e2403561 (2024).

[86] Yang, L., Li, W., Zhao, Y. & Shang, L. Magnetic polysaccharide mesenchymal stem cells exosomes delivery microcarriers for synergistic therapy of osteoarthritis. ACS Nano, https://doi.org/10.1021/acsnano.4c01406 (2024).

[87] Jahanbekam S. et al.. Ultrasound-responsive hyaluronic acid hydrogel of hydrocortisone to treat osteoarthritis. Int. J. Biol. Macromol., 2023, 240. 124449

[88] Yuan, F. Z. et al. Fabrication of injectable chitosan-chondroitin sulfate hydrogel embedding kartogenin-loaded microspheres as an ultrasound-triggered drug delivery system for cartilage tissue engineering. Pharmaceutics13, 1487 (2021).

[89] Fukamachi T. et al.. Acidic environments enhance the inhibitory effect of statins on proliferation of synovial cells. Int. Immunopharmacol., 2013, 17: 148-153.

[90] Tao W, Wang J, Parak WJ, Farokhzad OC, Shi J. Nanobuffering of pH-responsive polymers: a known but sometimes overlooked phenomenon and its biological applications. ACS Nano, 2019, 13: 4876-4882.

[91] Tajik E, Vaezi Z, Tabarsa M, Hekmat A, Naderi-Manesh H. Grafting of sinapic acid onto glucosamine nanoparticle as a potential therapeutic drug with enhanced anti-inflammatory activities in osteoarthritis treatment. Int. J. Biol. Macromol., 2023, 253. 127454

[92] Wang Z. et al.. Injectable regenerated silk fibroin micro/nanosphere with enhanced permeability and stability for osteoarthritis therapy. Small, 2024, 20. e2405049

[93] Xiong H. et al.. Biodegradable hollow-structured nanozymes modulate phenotypic polarization of macrophages and relieve hypoxia for treatment of osteoarthritis. Small, 2022, 18. e2203240

[94] Majumder J, Minko T. Multifunctional and stimuli-responsive nanocarriers for targeted therapeutic delivery. Expert Opin. Drug Deliv., 2021, 18: 205-227.

[95] Joshi N. et al.. Towards an arthritis flare-responsive drug delivery system. Nat. Commun., 2018, 9. 1275

[96] Zhou T. et al.. Hypoxia and matrix metalloproteinase 13-responsive hydrogel microspheres alleviate osteoarthritis progression in vivo. Small, 2024, 20. e2308599

[97] 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.

[98] Vanparijs N, Nuhn L, De Geest BG. Transiently thermoresponsive polymers and their applications in biomedicine. Chem. Soc. Rev., 2017, 46: 1193-1239.

[99] 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.

[100] Guan H. et al.. Toughness and thermoresponsive hydrogel for sandwich smart window with adaptive solar modulation and energy saving. ACS Appl Mater. Interfaces, 2024, 16: 52997-53006.

[101] Shen J, Abu-Amer Y, O’Keefe RJ, McAlinden A. Inflammation and epigenetic regulation in osteoarthritis. Connect Tissue Res., 2017, 58: 49-63.

[102] Lee JB, Shin YM, Kim WS, Kim SY, Sung HJ. ROS-responsive biomaterial design for medical applications. Adv. Exp. Med. Biol., 2018, 1064: 237-251.

[103] Liang J, Liu B. ROS-responsive drug delivery systems. Bioeng. Transl. Med., 2016, 1: 239-251.

[104] Li H. et al.. Reprogramming macrophage polarization, depleting ROS by astaxanthin and thioketal-containing polymers delivering rapamycin for osteoarthritis treatment. Adv. Sci., 2024, 11. e2305363

[105] Municoy, S. et al. Stimuli-responsive materials for tissue engineering and drug delivery. Int. J. Mol. Sci.21, 4724 (2020).

[106] Chan A, Orme RP, Fricker RA, Roach P. Remote and local control of stimuli responsive materials for therapeutic applications. Adv. Drug Deliv. Rev., 2013, 65: 497-514.

[107] Chorsi MT. et al.. Piezoelectric biomaterials for sensors and actuators. Adv. Mater., 2019, 31. e1802084

[108] Liu Y. et al.. Exercise-induced piezoelectric stimulation for cartilage regeneration in rabbits. Sci. Transl. Med., 2022, 14. eabi7282

[109] Qin, W. et al. Neurovascularization inhibiting dual responsive hydrogel for alleviating the progression of osteoarthritis. Nat. Commun.16, 1390 (2025).

[110] Zhang, H., et al. Lubricating and dual-responsive injectable hydrogels formulated from ZIF-8 facilitate osteoarthritis treatment by remodeling the microenvironment. Small21, e2407885 (2024).

[111] Vinikoor T. et al.. Injectable and biodegradable piezoelectric hydrogel for osteoarthritis treatment. Nat. Commun., 2023, 14. 6257

[112] Deng C. et al.. Sophisticated magneto-mechanical actuation promotes in situ stem cell assembly and chondrogenesis for treating osteoarthritis. ACS Nano, 2023, 17: 21690-21707.

[113] Rabani E, Reichman DR, Geissler PL, Brus LE. Drying-mediated self-assembly of nanoparticles. Nature, 2003, 426: 271-274.

[114] Xu W. et al.. 3D printing-enabled nanoparticle alignment: a review of mechanisms and applications. Small, 2021, 17. e2100817

[115] Hu X. et al.. Novel 3D printed shape-memory PLLA-TMC/GA-TMC scaffolds for bone tissue engineering with the improved mechanical properties and degradability. Chin. Chem. Lett., 2023, 34. 107451

[116] Park, J., Wetzel, I., Dreau, D. & Cho, H. 3D miniaturization of human organs for drug discovery. Adv. Healthc. Mater.7, https://doi.org/10.1002/adhm.201700551 (2018).

[117] Luo Y, Wei X, Huang P. 3D bioprinting of hydrogel-based biomimetic microenvironments. J. Biomed. Mater. Res. B Appl. Biomater., 2019, 107: 1695-1705.

[118] Yu H. et al.. Stimulus-responsive hydrogels as drug delivery systems for inflammation targeted therapy. Adv. Sci., 2024, 11. e2306152

[119] Ding G. et al.. Sustained-drug-release, strong, and anti-swelling water-lipid biphasic hydrogels prepared via digital light processing 3D printing for protection against osteoarthritis: demonstration in a porcine model. Adv. Health. Mater., 2023, 12. e2203236

[120] Zhang H, Huang J, Alahdal M. Exosomes loaded with chondrogenic stimuli agents combined with 3D bioprinting hydrogel in the treatment of osteoarthritis and cartilage degeneration. Biomed. Pharmacother., 2023, 168. 115715

[121] Zhang, W., Kuss, M., Yan, Y. & Shi, W. Dynamic alginate hydrogel as an antioxidative bioink for bioprinting. Gels9, 312 (2023).

[122] Majumder, N., et al. Assessing the advantages of 3D bioprinting and 3D spheroids in deciphering the osteoarthritis healing mechanism using human chondrocytes and polarized macrophages. Biomed. Mater.19, https://doi.org/10.1088/1748-605X/ad1d18 (2024).

[123] Buckwalter JA. Articular cartilage: injuries and potential for healing. J. Orthop. Sports Phys. Ther., 1998, 28: 192-202.

[124] Nguyen, L. T. et al. Review of prospects of biological fluid biomarkers in osteoarthritis. Int. J. Mol. Sci. 18, 601 (2017).

[125] Koons GL, Diba M, Mikos AG. Materials design for bone-tissue engineering. Nat. Rev. Mater., 2020, 5: 584-603.

[126] Wei W, Dai H. Articular cartilage and osteochondral tissue engineering techniques: Recent advances and challenges. Bioact. Mater., 2021, 6: 4830-4855

[127] Chen Y. et al.. 3D bioprinted xanthan hydrogels with dual antioxidant and chondrogenic functions for post-traumatic cartilage regeneration. ACS Biomater. Sci. Eng., 2024, 10: 1661-1675.

[128] Li Q. et al.. 3D printed silk-gelatin hydrogel scaffold with different porous structure and cell seeding strategy for cartilage regeneration. Bioact. Mater., 2021, 6: 3396-3410

[129] Lee J, Lee S, Huh SJ, Kang BJ, Shin H. Directed regeneration of osteochondral tissue by hierarchical assembly of spatially organized composite spheroids. Adv. Sci., 2022, 9. e2103525

[130] Liang Q, Ma Y, Yao X, Wei W. Advanced 3D-printing bioinks for articular cartilage repair. Int. J. Bioprint, 2022, 8: 511.

[131] Guo T, Lembong J, Zhang LG, Fisher JP. Three-dimensional printing articular cartilage: recapitulating the complexity of native tissue. Tissue Eng. Part B Rev., 2017, 23: 225-236.

[132] Xue JX. et al.. Chondrogenic differentiation of bone marrow-derived mesenchymal stem cells induced by acellular cartilage sheets. Biomaterials, 2012, 33: 5832-5840.

[133] Liu Y. et al.. 3D-bioprinted BMSC-laden biomimetic multiphasic scaffolds for efficient repair of osteochondral defects in an osteoarthritic rat model. Biomaterials, 2021, 279. 121216

[134] Ryu, J. et al. Evaluation of three-dimensional bioprinted human cartilage powder combined with micronized subcutaneous adipose tissues for the repair of osteochondral defects in beagle dogs. Int. J. Mol. Sci. 23, 2743 (2022).

[135] Mandal A, Chatterjee K. 4D printing for biomedical applications. J. Mater. Chem. B, 2024, 12: 2985-3005.

[136] Sheikh A, Abourehab MAS, Kesharwani P. The clinical significance of 4D printing. Drug Discov. Today, 2023, 28. 103391

[137] Yarali E. et al.. 4D printing for biomedical applications. Adv. Mater., 2024, 36. e2402301

[138] Gazzaniga A. et al.. Towards 4D printing in pharmaceutics. Int J. Pharm. X, 2023, 5100171

[139] Diaz-Payno PJ. et al.. Swelling-dependent shape-based transformation of a human mesenchymal stromal cells-laden 4D bioprinted construct for cartilage tissue engineering. Adv. Health. Mater., 2023, 12. e2201891

[140] Hippler M. et al.. Controlling the shape of 3D microstructures by temperature and light. Nat. Commun., 2019, 10. 232

[141] van Manen, T., Janbaz, S., Jansen, K. M. B. & Zadpoor, A. A. 4D printing of reconfigurable metamaterials and devices. Commun. Mater.2, https://doi.org/10.1038/s43246-021-00165-8 (2021).

[142] Wang Y. et al.. Emerging 4D printing strategies for next-generation tissue regeneration and medical devices. Adv. Mater., 2022, 34. e2109198

[143] Couto, M., et al. Neuro-immunomodulatory potential of nanoenabled 4D bioprinted microtissue for cartilage tissue engineering. Adv. Healthc. Mater.14, e2400496 (2024).

[144] Whitesides GM. The origins and the future of microfluidics. Nature, 2006, 442: 368-373.

[145] Ingber DE. Is it time for reviewer 3 to request human organ chip experiments instead of animal validation studies?. Adv. Sci., 2020, 7. 2002030

[146] Pandey, C. M. et al. Microfluidics based point-of-care diagnostics. Biotechnol. J.13, https://doi.org/10.1002/biot.201700047 (2018).

[147] Zhao CX. Multiphase flow microfluidics for the production of single or multiple emulsions for drug delivery. Adv. Drug Deliv. Rev., 2013, 65: 1420-1446.

[148] Salehi, S., Brambilla, S., Rasponi, M., Lopa, S. & Moretti, M. Development of a microfluidic vascularized osteochondral model as a drug testing platform for osteoarthritis. Adv. Healthc. Mater.13, e2402350 (2024).

[149] Zou Z, Luo X, Chen Z, Zhang YS, Wen C. Emerging microfluidics-enabled platforms for osteoarthritis management: from benchtop to bedside. Theranostics, 2022, 12: 891-909.

[150] Shang L, Cheng Y, Zhao Y. Emerging droplet microfluidics. Chem. Rev., 2017, 117: 7964-8040.

[151] Li W, Greener J, Voicu D, Kumacheva E. Multiple modular microfluidic (M3) reactors for the synthesis of polymer particles. Lab Chip, 2009, 9: 2715-2721.

[152] Han Z. et al.. Nanofat functionalized injectable super-lubricating microfluidic microspheres for treatment of osteoarthritis. Biomaterials, 2022, 285. 121545

[153] Yang J. et al.. Ball-bearing-inspired polyampholyte-modified microspheres as bio-lubricants attenuate osteoarthritis. Small, 2020, 16. e2004519

[154] Li X. et al.. Living and injectable porous hydrogel microsphere with paracrine activity for cartilage regeneration. Small, 2023, 19. e2207211

[155] Yang L, Sun L, Zhang H, Bian F, Zhao Y. Ice-inspired lubricated drug delivery particles from microfluidic electrospray for osteoarthritis treatment. ACS Nano, 2021, 15: 20600-20606.

[156] Hou J. et al.. Zwitterion-lubricated hydrogel microspheres encapsulated with metformin ameliorate age-associated osteoarthritis. Adv. Sci., 2024, 11. e2402477

[157] Yao Y, Wei G, Deng L, Cui W. Visualizable and lubricating hydrogel microspheres via nanoPOSS for cartilage regeneration. Adv. Sci., 2023, 10. e2207438

[158] Lei Y. et al.. Injectable hydrogel microspheres with self-renewable hydration layers alleviate osteoarthritis. Sci. Adv., 2022, 8. eabl6449

[159] Yang L, Li W, Zhao Y, Wang Y, Shang L. Stem cell recruitment polypeptide hydrogel microcarriers with exosome delivery for osteoarthritis treatment. J. Nanobiotechnol., 2024, 22. 512

[160] Yu M. et al.. Deep learning large-scale drug discovery and repurposing. Nat. Comput Sci., 2024, 4: 600-614.

[161] Yang X, Wang Y, Byrne R, Schneider G, Yang S. Concepts of artificial intelligence for computer-assisted drug discovery. Chem. Rev., 2019, 119: 10520-10594.

[162] Zhou T, Song Z, Sundmacher K. Big data creates new opportunities for materials research: a review on methods and applications of machine learning for materials design. Engineering, 2019, 5: 1017-1026.

[163] Wang, Y. et al. Nature-inspired micropatterns. Nat. Rev. Method Prime3, https://doi.org/10.1038/s43586-023-00251-w (2023).

[164] Elgendy HA. et al.. Atorvastatin loaded lecithin-coated zein nanoparticles based thermogel for the intra-articular management of osteoarthritis: in-silico, in-vitro, and in-vivo studies. J. Pharm. Investig., 2024, 54: 497-518.

[165] Bagherpour, R., Bagherpour, G. & Mohammadi, P. Application of artificial intelligence in tissue engineering. Tissue Eng. Part B Rev.31, 31−43 (2024).

[166] Diaz-Rodriguez P, Marino C, Vazquez JA, Caeiro-Rey JR, Landin M. Targeting joint inflammation for osteoarthritis management through stimulus-sensitive hyaluronic acid based intra-articular hydrogels. Mater. Sci. Eng. C. Mater. Biol. Appl., 2021, 128. 112254

[167] Jeong CG. et al.. Screening of hyaluronic acid-poly(ethylene glycol) composite hydrogels to support intervertebral disc cell biosynthesis using artificial neural network analysis. Acta Biomater., 2014, 10: 3421-3430.

[168] Okesola BO. et al.. De novo design of functional coassembling organic-inorganic hydrogels for hierarchical mineralization and neovascularization. ACS Nano, 2021, 15: 11202-11217.

[169] Go, G. et al. Human adipose-derived mesenchymal stem cell-based medical microrobot system for knee cartilage regeneration in vivo. Sci. Robot. 5, eaay6626 (2020).

[170] Li M, Zhao P, Wang J, Zhang X, Li J. Functional antimicrobial peptide-loaded 3D scaffolds for infected bone defect treatment with AI and multidimensional printing. Mater. Horiz., 2025, 12: 20-36.

[171] DeJulius CR. et al.. Engineering approaches for RNA-based and cell-based osteoarthritis therapies. Nat. Rev. Rheumatol., 2024, 20: 81-100.

[172] Zheng Z. et al.. Shaping the water-harvesting behavior of metal–organic frameworks aided by fine-tuned GPT models. J. Am. Chem. Soc., 2023, 145: 28284-28295.

[173] Kang, Y. & Kim, J. ChatMOF: an artificial intelligence system for predicting and generating metal-organic frameworks using large language models. Nat. Commun.15, 4705 (2024).

[174] Zhu X, Li Y, Gu N. Application of artificial intelligence in the exploration and optimization of biomedical nanomaterials. Nano Biomed. Eng., 2023, 15: 342-353.

[175] Krichen, M. Generative adversarial networks. 1–7, https://doi.org/10.1109/icccnt56998.2023.10306417 (2023).

[176] Kingma, D. P. & Welling, M. Auto-encoding variational Bayes. CoRRhttps://arxiv.org/abs/1312.6114 (2013).

[177] Merchant A. et al.. Scaling deep learning for materials discovery. Nature, 2023, 624: 80-85.

[178] Liu L. et al.. Artificial intelligence-powered microfluidics for nanomedicine and materials synthesis. Nanoscale, 2021, 13: 19352-19366.

[179] Han S, Wu J. Artificial intelligence (AI) meets biomaterials and biomedicine. Smart Mater. Med., 2024, 5: 251-255

[180] Walters RK, Gale EM, Barnoud J, Glowacki DR, Mulholland AJ. The emerging potential of interactive virtual reality in drug discovery. Expert Opin. Drug Discov., 2022, 17: 685-698.

[181] Fang J. et al.. Machine learning accelerates the materials discovery. Mater. Today Commun., 2022, 33. 104900

Funding

National Natural Science Foundation of China (National Science Foundation of China)(82270995)

Zhejiang Science Foundation for Distinguished Young Scholars (LR24H140001) National Key Research and Development Program of China (No. 2023YFC2509200） The Science and Technology Department of the State Administration of Traditional Chinese Medicine and the Zhejiang Provincial Administration of Traditional Chinese Medicine jointly established the Science and Technology Plan (GZY-ZJ-KJ-24086)

RIGHTS & PERMISSIONS

The Author(s)