The field of tissue engineering has experienced transformative advancements with the emergence of smart scaffolding systems that not only provide mechanical support but also deliver dynamic biofunctionality to actively influence cellular behavior and tissue regeneration. In this review, the term “smart” specifically refers to polymeric foams that integrate stimuli-responsive properties — such as sensitivity to mechanical, chemical, or thermal cues — with the controlled and sustained release of bioactive factors, thereby enabling dynamic modulation of the cellular microenvironment. Owing to these multifunctional characteristics, polymeric foams have become especially versatile platforms, distinguished by their highly interconnected porous architecture, tunable mechanical properties, and ease of chemical and biological functionalization. This comprehensive review consolidates recent developments in the design and fabrication of biofunctional polymeric foams tailored to deliver controlled mechanical and electrical stimulation and biochemical cues critical for directing cell fate and promoting regenerative outcomes. Foam materials are systematically categorized based on their polymeric origin and structural features, while biofunctionalization strategies—such as peptide conjugation, growth factor integration, and gene delivery—are critically analyzed. Advanced fabrication techniques enabling stimuli-responsive behavior and patient-specific customization, including 3D/4D bioprinting and supercritical fluid processing, are highlighted for their capacity to generate adaptive scaffold microenvironments. Mechanobiological interactions, especially mechanotransduction mechanisms elicited by foam elasticity and dynamic deformation, are discussed in detail, along with emerging dual-responsive systems that simultaneously deliver mechanical and biochemical stimuli. In addition, this review addresses key translational challenges, including immunocompatibility, degradation kinetics, mechanical resilience, and regulatory considerations. Based on an integrative analysis of recent studies, we propose a strategic roadmap for the rational design of next-generation adaptive, multifunctional polymeric foams with enhanced clinical utility. Ultimately, this review emphasizes the critical role of smart polymeric foams in bridging the gap between laboratory innovation and patient-centered regenerative medicine.
LutzweilerGNdreu HaliliAEngin VranaN. The overview of porous, bioactive scaffolds as instructive biomaterials for tissue regeneration and their clinical translation. Pharmaceutics2020; 12(7): 602.
2.
WanXLiuZLiL. Manipulation of stem cells fates: the master and multifaceted roles of biophysical cues of biomaterials. Adv Funct Mater2021; 31(23): 2010626.
3.
MaksoudFJVelázquez de la PazMFHannAJ, et al.Porous biomaterials for tissue engineering: a review. J Mater Chem B2022; 10(40): 8111–8165.
4.
El-HusseinyHMMadyEAEl-DakrouryWA, et al.Smart/stimuli-responsive hydrogels: state-of-the-art platforms for bone tissue engineering. Appl Mater Today2022; 29: 101560.
5.
NarkarARTongZSomanP, et al.Smart biomaterial platforms: controlling and being controlled by cells. Biomaterials2022; 283: 121450.
6.
ZhuLYuhanJYuH, et al.Decellularized extracellular matrix for remodeling bioengineering organoid's microenvironment. Small2023; 19(25): 2207752.
7.
DeyKRocaERamorinoG, et al.Progress in the mechanical modulation of cell functions in tissue engineering. Biomater Sci2020; 8(24): 7033–7081.
8.
KongYDuanJLiuF, et al.Regulation of stem cell fate using nanostructure-mediated physical signals. Chem Soc Rev2021; 50(22): 12828–12872.
9.
GoonooNBhaw-LuximonA. Piezoelectric polymeric scaffold materials as biomechanical cellular stimuli to enhance tissue regeneration. Mater Today Commun2022; 31: 103491.
10.
Abdel KhalekMAAbdelhameedAMAbdel GaberSA. The use of photoactive polymeric nanoparticles and nanofibers to generate a photodynamic-mediated antimicrobial effect, with a special emphasis on chronic wounds. Pharmaceutics2024; 16(2): 229.
11.
MendenhallJ. Three-dimensional biomaterials with spatiotemporal control for regenerative tissue engineering. Acc Chem Res2023; 56(11): 1313–1319.
12.
RichardsonLWilcocksonSGGuglielmiL, et al.Context-dependent TGFβ family signalling in cell fate regulation. Nat Rev Mol Cell Biol2023; 24(12): 876–894.
13.
Anupama SekarJAthiraRKLakshmiTS, et al.3D bioprinting in tissue engineering and regenerative medicine: current landscape and future prospects. In: Biomaterials in Tissue Engineering and Regenerative Medicine: From Basic Concepts to State of the Art Approaches2021, pp. 561–580.
14.
CaraccioloPCAbrahamGABattagliaES, et al.Recent progress and trends in the development of electrospun and 3D printed polymeric-based materials to overcome antimicrobial resistance (AMR). Pharmaceutics2023; 15(7): 1964.
15.
WeldemhretTGParkYTSongJI. Recent progress in surface engineering methods and advanced applications of flexible polymeric foams. Adv Colloid Interface Sci2024; 326: 103132.
16.
XuFDawsonCLambM, et al.Hydrogels for tissue engineering: addressing key design needs toward clinical translation. Front Bioeng Biotechnol2022; 10: 849831.
17.
IdumahCIOderaRSEzeaniEO, et al.Construction, characterization, properties and multifunctional applications of stimuli-responsive shape memory polymeric nanoarchitectures: a review. Polymer-Plastics Technology and Materials2023; 62(10): 1247–1272.
18.
LawACWangRChungJ, et al.Process parameter optimization for reproducible fabrication of layer porosity quality of 3D-printed tissue scaffold. J Intell Manuf2024; 35(4): 1825–1844.
19.
Bolívar-MonsalveEJAlvarezMMHosseiniS, et al.Engineering bioactive synthetic polymers for biomedical applications: a review with emphasis on tissue engineering and controlled release. Mater Adv2021; 2(14): 4447–4478.
20.
WangLChenXZengX, et al.Degradable smart composite foams for bone regeneration. Compos Sci Technol2022; 217: 109124.
21.
KumarADattaAKumarA, et al.Recent advancements and future trends in next-generation materials for biomedical applications. In: Advanced materials for biomedical applications. CRC Press, 2022, vol 13, pp. 1–19.
22.
PinaSReisRLOliveiraJM. Natural polymeric biomaterials for tissue engineering. In: Tissue Engineering Using Ceramics and Polymers. Woodhead Publishing, 2022, vol 1, pp. 75–110.
23.
ChenMJiangRDengN, et al.Natural polymer-based scaffolds for soft tissue repair. Front Bioeng Biotechnol2022; 10: 954699.
24.
TamerTMKenawyERAgwaMM, et al.Wound dressing membranes based on immobilized Anisaldehyde onto (chitosan-GA-gelatin) copolymer: in-vitro and in-vivo evaluations. Int J Biol Macromol2022; 211: 94–106.
25.
LiuWGongZChenY. Mechanically robust, superelastic and lightweight composite foam enabled by hydrogen bond cross-linking. Eur Polym J2023; 196: 112283.
26.
KrishnakumarAShedaliyaUShahK, et al.Tunable biopolymers: biomedical applications. In: Handbook of Biopolymers. Singapore: Springer Nature Singapore, 2023, vol 30, pp. 833–876.
27.
PhutanePTelangeDAgrawalS, et al.Biofunctionalization and applications of polymeric nanofibers in tissue engineering and regenerative medicine. Polymers2023; 15(5): 1202.
28.
Javid-NaderiMJBehravanJKarimi-HajishohrehN, et al.Synthetic polymers as bone engineering scaffold. Polym Adv Technol2023; 34(7): 2083–2096.
29.
ArifZUKhalidMYNorooziR, et al.Recent advances in 3D-printed polylactide and polycaprolactone-based biomaterials for tissue engineering applications. Int J Biol Macromol2022; 218: 930–968.
30.
AzimiHJahaniDAghamohammadiS, et al.Experimental and numerical investigation of bubble nucleation and growth in supercritical CO2-blown poly (vinyl alcohol). Korean J Chem Eng2022; 39(8): 2252–2262.
31.
AzimiHPeighambardoustSJ. Characterization and morphological study of biodegradable PVA-Gelatin/CNT composite foams prepared via high-pressure batch foaming method. J Porous Mater2023; 30(3): 751–766.
32.
BabakhaniAPeighambardoustSJGhahremani-NasabM, et al.Fabrication of biodegradable nanocomposite scaffolds with hydroxyapatite, magnetic clay, and graphene oxide for bone tissue engineering. Sci Rep2025; 15(1): 22235.
33.
BabakhaniAPeighambardoustSJOladA. Fabrication of magnetic nanocomposite scaffolds based on polyvinyl alcohol-chitosan containing hydroxyapatite and clay modified with graphene oxide: evaluation of their properties for bone tissue engineering applications. J Mech Behav Biomed Mater2024; 150: 106263.
34.
Mohammadzadeh PakdelPPeighambardoustSJ. Review on recent progress in chitosan-based hydrogels for wastewater treatment application. Carbohydr Polym2018; 201: 264–279.
35.
Hossein PanahiFPeighambardoustSJDavaranS, et al.Development and characterization of PLA-mPEG copolymer containing iron nanoparticle-coated carbon nanotubes for controlled delivery of docetaxel. Polymer2017; 117: 117–131.
36.
SetayeshmehrMEsfandiariERafieiniaM, et al.Hybrid and composite scaffolds based on extracellular matrices for cartilage tissue engineering. Tissue Eng Part B Rev2019; 25(3): 202–224.
37.
OmigbodunFTOladapoBIOsa-uwagboeN. Exploring the frontier of polylactic acid/hydroxyapatite composites in bone regeneration and their revolutionary biomedical applications–A review. J Reinforc Plast Compos2024; 6: 07316844241278045.
38.
PeighambardoustSJFakhiminajafiBMohammadzadeh PakdelP, et al.Simultaneous elimination of cationic dyes from water media by carboxymethyl cellulose-graft-poly (acrylamide)/magnetic biochar nanocomposite hydrogel adsorbent. Environ Res2025; 273: 121150.
39.
MukashevaFAdilovaLDyussenbinovA, et al.Optimizing scaffold pore size for tissue engineering: insights across various tissue types. Front Bioeng Biotechnol2024; 12: 1444986.
40.
CidonioGCostantiniMPieriniF, et al.3D printing of biphasic inks: beyond single-scale architectural control. J Mater Chem C Mater2021; 9(37): 12489–12508.
41.
BabuSAlbertinoFOmidinia AnarkoliA, et al.Controlling structure with injectable biomaterials to better mimic tissue heterogeneity and anisotropy. Adv Healthc Mater2021; 10(11): 2002221.
CarotenutoFPolitiSUl HaqA, et al.From soft to hard biomimetic materials: tuning micro/nano-architecture of scaffolds for tissue regeneration. Micromachines2022; 13(5): 780.
44.
SolaABertacchiniJD'AvellaD, et al.Development of solvent-casting particulate leaching (SCPL) polymer scaffolds as improved three-dimensional supports to mimic the bone marrow niche. Mater Sci Eng C2019; 96: 153–165.
45.
JosephBJoseCKavilSV, et al.Solvent-casting approach for design of polymer scaffolds and their multifunctional applications. Functional biomaterials: design and development for biotechnology. Pharmacology, and Biomedicine2023; 2: 371–394.
46.
SpedicatiMZosoAMortatiL, et al.Three-dimensional microfibrous scaffold with aligned topography produced via a combination of melt-extrusion additive manufacturing and porogen leaching for in vitro skeletal muscle modeling. Bioengineering2024; 11(4): 332.
47.
JiaoZDengZZhangY, et al.Fabrication magnetic composite scaffolds with multi-modal cell structure for enhanced properties using supercritical CO2 two-step depressurization foaming process. Polym Bull2024; 81(6): 5627–5652.
48.
TaberneroAGonzález-GarcinuñoÁCardeaS, et al.Supercritical carbon dioxide and biomedicine: opening the doors towards biocompatibility. Chem Eng J2022; 444: 136615.
49.
AzimiHJahaniD. The experimental and numerical relation between the solubility, diffusivity and bubble nucleation of supercritical CO2 in polystyrene via visual observation apparatus. J Supercrit Fluids2018; 139: 30–37.
50.
Aldemir DikiciB. Impact of internal phase volume on the physical, morphological and mechanical characteristics of emulsion templated scaffolds. The European Research Journal2024; 10(5): 522–532.
51.
WhitelyMRodriguez-RiveraGWaldronC, et al.Porous PolyHIPE microspheres for protein delivery from an injectable bone graft. Acta Biomater2019; 93: 169–179.
52.
BehereIVaidyaAIngavleG. Chondroitin sulfate and hyaluronic acid–based PolyHIPE scaffolds for improved osteogenesis and chondrogenesis in vitro. ACS Appl Bio Mater2024; 7(8): 5222–5236.
53.
Sengokmen-OzsozNAleemardaniMPalancaM, et al.Fabrication of hierarchically porous trabecular bone replicas via 3D printing with high internal phase emulsions (HIPEs). Biofabrication2024; 17(1): 015012.
54.
ZhangJYinZRenL, et al.Advances in 4D printed shape memory polymers: from 3D printing, smart excitation, and response to applications. Adv Mater Technol2022; 7(9): 2101568.
55.
KumarPSuryavanshiPDwivedySK, et al.Stimuli-responsive materials for 4D printing: mechanical, manufacturing, and biomedical applications. J Mol Liq2024; 16: 125553.
56.
MemicAColombaniTEggermontLJ, et al.Latest advances in cryogel technology for biomedical applications. Adv Ther2019; 2(4): 1800114.
57.
RazaviMQiaoYThakorAS. Three-dimensional cryogels for biomedical applications. J Biomed Mater Res2019; 107(12): 2736–2755.
58.
CarrieroVCDi MuzioLPetralitoS, et al.Cryogel scaffolds for tissue-engineering: advances and challenges for effective bone and cartilage regeneration. Gels2023; 9(12): 979.
59.
El-HusseinyHMMadyEAEl-DakrouryWA, et al.Smart/stimuli-responsive hydrogels: State-of-the-art platforms for bone tissue engineering. Appl Mater Today2022; 29: 101560.
60.
WeiHCuiJLinK, et al.Recent advances in smart stimuli-responsive biomaterials for bone therapeutics and regeneration. Bone Res2022; 10(1): 17.
61.
RibeiroCSilvánULanceros-MendezS (eds). Stimuli-Responsive Materials for Tissue Engineering. Hoboken (NJ): John Wiley & Sons, 2024.
62.
RamanNImranSAMAhmad Amin NoordinKB, et al.Mechanotransduction in mesenchymal stem cells (MSCs) differentiation: a review. Int J Mol Sci2022; 23(9): 4580.
63.
BakhshandehBSorboniSGRanjbarN, et al.Mechanotransduction in tissue engineering: insights into the interaction of stem cells with biomechanical cues. Exp Cell Res2023; 431(2): 113766.
64.
TiskratokWChuinsiriNLimraksasinP, et al.Extracellular matrix stiffness: mechanotransduction and mechanobiological response-driven strategies for biomedical applications targeting fibroblast inflammation. Polymers2025; 17(6): 822.
65.
ShafiqMAliOHanSB, et al.Mechanobiological strategies to enhance stem cell functionality for regenerative medicine and tissue engineering. Front Cell Dev Biol2021; 9: 747398.
66.
KongYDuanJLiuF, et al.Regulation of stem cell fate using nanostructure-mediated physical signals. Chem Soc Rev2021; 50(22): 12828–12872.
67.
XuHHaoSZhouJ. Magnetically actuated scaffolds to enhance tissue regeneration. In: Nanotechnology in Regenerative Medicine and Drug Delivery Therapy, 2020, pp. 1–38.
68.
MarovičNBanIMaverU, et al.Magnetic nanoparticles in 3D-printed scaffolds for biomedical applications. Nanotechnol Rev2023; 12(1): 20220570.
69.
SantosLFSilvaASManoJF. Magnetic-based strategies for regenerative medicine and tissue engineering. Adv Healthc Mater2023; 12(25): 2300605.
70.
ShiMBaiLXuM, et al.Magnetically induced anisotropic conductive in situ hydrogel for skeletal muscle regeneration by promoting cell alignment and myogenic differentiation. Chem Eng J2024; 484: 149019.
71.
ParamshettiSAngolkarMAl FateaseA, et al.Revolutionizing drug delivery and therapeutics: the biomedical applications of conductive polymers and composites-based systems. Pharmaceutics2023; 15(4): 1204.
72.
CostaCMCardosoVFMartinsP, et al.Smart and multifunctional materials based on electroactive poly(vinylidene fluoride): recent advances and opportunities in sensors, actuators, energy, environmental, and biomedical applications. Chem Rev2023; 123(19): 11392–11487.
73.
Peñas-NúñezSJMecerreyesDCriado-GonzalezM. Recent advances and developments in injectable conductive polymer gels for bioelectronics. ACS Appl Bio Mater2024; 7(12): 7944–7964.
74.
XuXLiuYFuW, et al.Poly(N-isopropylacrylamide)-based thermoresponsive composite hydrogels for biomedical applications. Polymers2020; 12(3): 580.
75.
TanRYHLeeCSPichikaMR, et al.PH responsive polyurethane for the advancement of biomedical and drug delivery. Polymers2022; 14(9): 1672.
76.
WangMGaoBWangX, et al.Enzyme-responsive strategy as a prospective cue to construct intelligent biomaterials for disease diagnosis and therapy. Biomater Sci2022; 10(8): 1883–1903.
77.
MunicoySAlvarez EchazuMIAntezanaPE, et al.Stimuli-responsive materials for tissue engineering and drug delivery. Int J Mol Sci2020; 21(13): 4724.
78.
AmirthalingamSRajendranAKMoonYG, et al.Stimuli-responsive dynamic hydrogels: design, properties and tissue engineering applications. Mater Horiz2023; 10(9): 3325–3350.
79.
Echeverria MolinaMIMalollariKGKomvopoulosK. Design challenges in polymeric scaffolds for tissue engineering. Front Bioeng Biotechnol2021; 9: 617141.
80.
AmaniHAlipourMShahriariE, et al.Immunomodulatory biomaterials: tailoring surface properties to mitigate foreign body reaction and enhance tissue regeneration. Adv Healthc Mater2024; 13(29): 2401253.
81.
BatoolFÖzçelikHStutzC, et al.Modulation of immune-inflammatory responses through surface modifications of biomaterials to promote bone healing and regeneration. J Tissue Eng2021; 12: 20417314211041428.
CrosbyCOSternBKalkunteN, et al.Interpenetrating polymer network hydrogels as bioactive scaffolds for tissue engineering. Rev Chem Eng2022; 38(3): 347–361.
84.
PercivalKMPaulVHusseiniGA. Recent advancements in bone tissue engineering: integrating smart scaffold technologies and bio-responsive systems for enhanced regeneration. Int J Mol Sci2024; 25(11): 6012.
85.
LiangJ-PAccollaRPJiangK, et al.Controlled release of anti-inflammatory and proangiogenic factors from macroporous scaffolds. Tissue Eng Part A2021; 27(19–20): 1275–1289.
86.
ChambreLParkerRNAllardyceBJ, et al.Tunable biodegradable silk-based memory foams with controlled release of antibiotics. ACS Appl Bio Mater2020; 3(4): 2466–2472.
87.
BritoJAndrianovAKSukhishviliSA. Factors controlling degradation of biologically relevant synthetic polymers in solution and solid state. ACS Appl Bio Mater2022; 5(11): 5057–5076.
88.
ZhouQLiuQWangY, et al.Bridging smart nanosystems with clinically relevant models and advanced imaging for precision drug delivery. Adv Sci2024; 11(14): 2308659.
89.
YounesHMKadavilHIsmailHM, et al.Overview of tissue engineering and drug delivery applications of reactive electrospinning and crosslinking techniques of polymeric nanofibers with highlights on their biocompatibility testing and regulatory aspects. Pharmaceutics2023; 16(1): 32.
90.
HerczegCKSongJ. Sterilization of polymeric implants: challenges and opportunities. ACS Appl Bio Mater2022; 5(11): 5077–5088.
91.
GhelichPKazemzadeh-NarbatMNajafabadiAH, et al.(Bio)manufactured solutions for treatment of bone defects with emphasis on US-FDA regulatory science perspective. Adv Nanobiomed Res2022; 2(4): 2100073.
92.
SuhagD. Regulatory and ethical considerations. In: Handbook of Biomaterials for Medical Applications. Volume 2: Applications. Singapore: Springer Nature Singapore, 2024, pp. 355–372.
93.
BeheshtizadehNGharibshahianMPazhouhniaZ, et al.Commercialization and regulation of regenerative medicine products: promises, advances and challenges. Biomed Pharmacother2022; 153: 113431.
94.
AnjuMSRajDKMadathilBK, et al. Intelligent biomaterials for tissue engineering and biomedical applications: current landscape and future prospects. Biomaterials in Tissue Engineering and Regenerative Medicine: From Basic Concepts to State of the Art Approaches. springer, 2021, pp. 535–560.
95.
KantarosAGanetsosT. From static to dynamic: smart materials pioneering additive manufacturing in regenerative medicine. Int J Mol Sci2023; 24(21): 15748.
96.
WangYCuiHEsworthyT, et al.Emerging 4D printing strategies for next-generation tissue regeneration and medical devices. Adv Mater2022; 34(20): 2109198.
97.
ChenAWangWMaoZ, et al.Multimaterial 3D and 4D bioprinting of heterogenous constructs for tissue engineering. Adv Mater2024; 36(34): 2307686.
98.
KongXZhengTWangZ, et al.Remote actuation and on-demand activation of biomaterials pre-incorporated with physical cues for bone repair. Theranostics2024; 14(11): 4438–4461.
99.
RahmanMDipTMNurMG, et al.Nanomaterial-integrated 3D biofabricated structures for advanced biomedical applications. Macromol Mater Eng2025; 310: 2500083.
100.
TamirTSTeferiFBHuaX, et al. A review of advances in 3D and 4D bioprinting: toward mass individualization paradigm. J Intell Manuf. 2024; 35: 1–30.
101.
KennedySMAmudhanK. 4D Bioprinting for personalized medicine, innovations in implant fabrication and regenerative therapies. Polym Plast Technol Mater. 2025; 64: 1–26.
102.
AlexYShanmugamRSalunkheS, et al.Advancement of additive manufacturing technology in the development of personalized in vivo and in vitro prosthetic implants. Rev Adv Mater Sci2025; 64(1): 20250109.
103.
MohantoSBhuniaASultanaR, et al.Marine-derived biomaterials: an ignored building block in regenerative medicine and tissue engineering applications. In: Handbook of Research in Marine Pharmaceutics. Apple Academic Press, 2025, pp. 239–297.
104.
FanovichMADi MaioESalernoA. Current trend and new opportunities for multifunctional bio-scaffold fabrication via high-pressure foaming. J Funct Biomater2023; 14(9): 480.
