On the road to smart biomaterials for bone research: definitions, concepts, advances, and outlook

Abstract

The demand for biomaterials that promote the repair, replacement, or restoration of hard and soft tissues continues to grow as the population ages. Traditionally, smart biomaterials have been thought as those that respond to stimuli. However, the continuous evolution of the field warrants a fresh look at the concept of smartness of biomaterials. This review presents a redefinition of the term “Smart Biomaterial” and discusses recent advances in and applications of smart biomaterials for hard tissue restoration and regeneration. To clarify the use of the term “smart biomaterials”, we propose four degrees of smartness according to the level of interaction of the biomaterials with the bio-environment and the biological/cellular responses they elicit, defining these materials as inert, active, responsive, and autonomous. Then, we present an up-to-date survey of applications of smart biomaterials for hard tissues, based on the materials’ responses (external and internal stimuli) and their use as immune-modulatory biomaterials. Finally, we discuss the limitations and obstacles to the translation from basic research (bench) to clinical utilization that is required for the development of clinically relevant applications of these technologies.

References

[1] Ratner BD, Bryant SJ. Biomaterials: where we have been and where we are going. Annu. Rev. Biomed. Eng., 2004, 6:41-75

[2] Bayne SC. Dental biomaterials: where are we and where are we going? J. Dent. Educ., 2005, 69:571-585

[3] Hench LL, Thompson I. Twenty-first century challenges for biomaterials. J. R. Soc. Interface, 2010, 7:S379-S391

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

[5] Kirk, D. E. Optimal control theory: an introduction (Courier Corporation, 2012).

[6] Goguitchaichvili A, Ortega V, Archer J, Morales J, Guerrero AT. Absolute geomagnetic intensity record from pre-Columbian pottery dates elite Tlailotlacan Woman in ancient Teotihuacan. J. Archaeological Sci. Rep., 2017, 14:146-151

[7] Ferracane, J., Bertassoni, L. E. & Pfeifer, C. S. Dental Biomaterials, An Issue of Dental Clinics of North America, E-Book. Vol. 61 (Elsevier Health Sciences, 2017).

[8] Santin, M. & Phillips, G. J. Biomimetic, bioresponsive, and bioactive materials: An introduction to integrating materials with tissues (John Wiley & Sons, 2012).

[9] Melo MA, Orrego S, Weir MD, Xu HH, Arola DD. Designing multiagent dental materials for enhanced resistance to biofilm damage at the bonded interface. ACS Appl. Mater. interfaces, 2016, 8:11779-11787

[10] Yang Y et al. pH-sensitive compounds for selective inhibition of acid-producing bacteria. ACS Appl. Mater. interfaces, 2018, 10:8566-8573

[11] Wiegand A, Buchalla W, Attin T. Review on fluoride-releasing restorative materials—Fluoride release and uptake characteristics, antibacterial activity and influence on caries formation. Dent. Mater., 2007, 23:343-362

[12] Delaviz Y, Finer Y, Santerre JP. Biodegradation of resin composites and adhesives by oral bacteria and saliva: a rationale for new material designs that consider the clinical environment and treatment challenges. Dent. Mater., 2014, 30:16-32

[13] Chen F-M, Liu X. Advancing biomaterials of human origin for tissue engineering. Prog. Polym. Sci., 2016, 53:86-168

[14] Mariani, E., Lisignoli, G., Borzì, R. M. & Pulsatelli, L. Biomaterials: foreign bodies or tuners for the immune response? Int. J. Mol. Sci. 20, 636 (2019).

[15] Hench LL, Polak JM. Third-generation biomedical materials. Science, 2002, 295:1014-1017

[16] Najdanović, J., Rajković, J. & Najman, S. Biomaterials in Clinical Practice 333-360 (Springer, 2018).

[17] Drago L, Toscano M, Bottagisio M. Recent evidence on bioactive glass antimicrobial and antibiofilm activity: a mini-review. Materials, 2018, 11:326

[18] Makvandi P et al. Polymeric and inorganic nanoscopical antimicrobial fillers in dentistry. Acta Biomater., 2019, 101:69-101

[19] Matuszewska A, Jaszek M, Stefaniuk D, Ciszewski T, Matuszewski Ł. Anticancer, antioxidant, and antibacterial activities of low molecular weight bioactive subfractions isolated from cultures of wood degrading fungus Cerrena unicolor. PloS One, 2018, 13

[20] Pandey A et al. Antioxidant and antibacterial hydroxyapatite-based biocomposite for orthopedic applications. Mater. Sci. Eng., 2018, 88:13-24

[21] Jones JR. Review of bioactive glass: from Hench to hybrids. Acta Biomater, 2013, 9:4457-4486

[22] Ebara, M. et al. Smart biomaterials (Springer, 2014).

[23] Wu G, Li P, Feng H, Zhang X, Chu PK. Engineering and functionalization of biomaterials via surface modification. J. Mater. Chem. B, 2015, 3:2024-2042

[24] Thakur, V. K., Thakur, M. K. & Kessler, M. R. (editors) Handbook of composites from renewable materials. (Wiley, 2016).

[25] Paterlini TT et al. The role played by modified bioinspired surfaces in interfacial properties of biomaterials. Biophysical Rev., 2017, 9:683-698

[26] Bose S, Robertson SF, Bandyopadhyay A. Surface modification of biomaterials and biomedical devices using additive manufacturing. Acta Biomater, 2018, 66:6-22

[27] Morris E, Chavez M, Tan C. Dynamic biomaterials: toward engineering autonomous feedback. Curr. Opin. Biotechnol., 2016, 39:97-104

[28] Badeau, B. A. & DeForest, C. A. Programming stimuli-responsive behavior into biomaterials. Ann. Rev. Biomed. Eng. 21, 241–265 (2019).

[29] Ahmed, W., Zhai, Z. & Gao, C. Adaptive anti-bacterial biomaterial surfaces and their applications. Mater. Today Bio. 2, 100017 (2019).

[30] Tibbitt, M. W., Rodell, C. B., Burdick, J. A. & Anseth, K. S. Progress in material design for biomedical applications. Proc. Natl Acad. Sci. 112, 14444–14451, (2015).

[31] Li S, Xiao L, Deng H, Shi X, Cao Q. Remote controlled drug release from multi-functional Fe3O4/GO/Chitosan microspheres fabricated by an electrospray method. Colloids Surf. B Biointerfaces, 2017, 151:354-362

[32] He L et al. Electrochemically stimulated drug release from flexible electrodes coated electrophoretically with doxorubicin loaded reduced graphene oxide. Chem. Commun., 2017, 53:4022-4025

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

[34] Chandrawati R. Enzyme-responsive polymer hydrogels for therapeutic delivery. Exp. Biol. Med., 2016, 241:972-979

[35] Ferreira NN et al. Recent advances in smart hydrogels for biomedical applications: From self-assembly to functional approaches. Eur. Polym. J., 2018, 99:117-133

[36] Ooi H, Hafeez S, Van Blitterswijk C, Moroni L, Baker M. Hydrogels that listen to cells: a review of cell-responsive strategies in biomaterial design for tissue regeneration. Mater. Horiz., 2017, 4:1020-1040

[37] Ju X-J, Xie R, Yang L, Chu L-Y. Biodegradable ‘intelligent’materials in response to physical stimuli for biomedical applications. Expert Opin. Therap. Pat., 2009, 19:493-507

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

[39] Orrego, S. et al. Bioinspired materials with self-adaptable mechanical properties. Adv Mater. 32, e1906970 (2020).

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

[41] Kaplan, J. B. Microbial Biofilms. 203–213 (Springer, 2014).

[42] Bai X et al. Bioactive hydrogels for bone regeneration. Bioact. Mater., 2018, 3:401-417

[43] Zhao X et al. Injectable stem cell-laden photocrosslinkable microspheres fabricated using microfluidics for rapid generation of osteogenic tissue constructs. Adv. Funct. Mater., 2016, 26:2809-2819

[44] Tibbitt MW, Langer R. Living biomaterials. Acc. Chem. Res., 2017, 50:508-513

[45] Wang Y. Bioadaptability: an innovative concept for biomaterials. J. Mater. Sci. Technol., 2016, 32:801-809

[46] Sankaran S, Zhao S, Muth C, Paez J, Del Campo A. Toward light‐regulated living biomaterials. Adv. Sci., 2018, 5:1800383

[47] Morley CD et al. Quantitative characterization of 3D bioprinted structural elements under cell generated forces. Nat. Commun., 2019, 10

[48] Badeau BA, Comerford MP, Arakawa CK, Shadish JA, DeForest CA. Engineered modular biomaterial logic gates for environmentally triggered therapeutic delivery. Nat. Chem., 2018, 10:251-258

[49] Salinas CN, Anseth KS. The enhancement of chondrogenic differentiation of human mesenchymal stem cells by enzymatically regulated RGD functionalities. Biomaterials, 2008, 29:2370-2377

[50] Kriegman, S., Blackiston, D., Levin, M. & Bongard, J. A scalable pipeline for designing reconfigurable organisms. Proc. Natl. Acad. Sci. USA 117, 1853–1859 (2020).

[51] Aguado BA, Grim JC, Rosales AM, Watson-Capps JJ, Anseth KS. Engineering precision biomaterials for personalized medicine. Sci. Transl. Med., 2018, 10

[52] Eysenck, H. J. The biological basis of intelligence. Human abilities in cultural context, 87–104 (Cambridge University Press, 1988).

[53] Yurish SY. Sensors: smart vs. intelligent. Sens. Transducers, 2010, 114:I

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

[55] Smart Biomaterials. Smarter medicine? EBioMedicine, 2017, 16:1-2

[56] Wang H et al. The effect of 3D-printed Ti6Al4V scaffolds with various macropore structures on osteointegration and osteogenesis: a biomechanical evaluation. J. Mech. Behav. Biomed. Mater., 2018, 88:488-496

[57] Qasim M, Chae DS, Lee NY. Advancements and frontiers in nano-based 3D and 4D scaffolds for bone and cartilage tissue engineering. Int. J. Nanomed., 2019, 14:4333-4351

[58] Pei, X. et al. Creating hierarchical porosity hydroxyapatite scaffolds with osteoinduction by three-dimensional printing and microwave sintering. Biofabrication. 9, 045008 (2017).

[59] Lee DJ et al. Effect of pore size in bone regeneration using polydopamine‐laced hydroxyapatite collagen calcium silicate scaffolds fabricated by 3D mould printing technology. Orthod. Craniofacial Res., 2019, 22:127-133

[60] Mestre, R. et al. Force modulation and adaptability of 3D-bioprinted biological actuators based on skeletal muscle tissue. Adv. Mater. Technol. 4, https://doi.org/10.1002/admt.201800631 (2019).

[61] Nicolas J et al. 3D extracellular matrix mimics: fundamental concepts and role of materials chemistry to influence stem cell fate. Biomacromolecules, 2020, 21:1968-1994

[62] Metwally S et al. Surface potential and roughness controlled cell adhesion and collagen formation in electrospun PCL fibers for bone regeneration. Mater. Des., 2020, 194:108915

[63] Collins FS, Varmus H. A new initiative on precision medicine. N. Engl. J. Med, 2015, 372:793-795

[64] Ashley EA. The precision medicine initiative: a new national effort. JAMA, 2015, 313:2119-2120

[65] Guzzi EA, Tibbitt MW. Additive manufacturing of precision biomaterials. Adv. Mater., 2020, 32:1901994

[66] Restrepo D, Naleway SE, Thomas V, Schniepp HC. Advanced manufacturing for biomaterials and biological materials, Part I. JOM, 2020, 72:1151-1153

[67] Chahal S, Kumar A, Hussian FSJ. Development of biomimetic electrospun polymeric biomaterials for bone tissue engineering. A review. J. Biomater. Sci. Polym. Ed., 2019, 30:1308-1355

[68] Zhu L, Luo D, Liu Y. Effect of the nano/microscale structure of biomaterial scaffolds on bone regeneration. Int. J. Oral. Sci., 2020, 12:6

[69] Asa’ad F et al. 3D-printed scaffolds and biomaterials: review of alveolar bone augmentation and periodontal regeneration applications. Int. J. Dent., 2016, 2016:1239842

[70] Shamsoddin E, Houshmand B, Golabgiran M. Biomaterial selection for bone augmentation in implant dentistry: A systematic review. J. Adv. Pharm. Technol. Res., 2019, 10:46-50

[71] Bock N et al. Engineering osteoblastic metastases to delineate the adaptive response of androgen-deprived prostate cancer in the bone metastatic microenvironment. Bone Res., 2019, 7:13

[72] Liu, C. et al. The effect of the fibre orientation of electrospun scaffolds on the matrix production of rabbit annulus fibrosus-derived stem cells. Bone Res. 3, 15012 (2015).

[73] Bignon A et al. Effect of micro- and macroporosity of bone substitutes on their mechanical properties and cellular response. J. Mater. Sci. Mater. Med., 2003, 14:1089-1097

[74] Zhao YN et al. Effects of pore size on the osteoconductivity and mechanical properties of calcium phosphate cement in a rabbit model. Artif. Organs, 2017, 41:199-204

[75] Jian B, Wu W, Song Y, Tan N, Ma C. Microporous elastomeric membranes fabricated with polyglycerol sebacate improved guided bone regeneration in a rabbit model. Int J. Nanomed., 2019, 14:2683-2692

[76] Gangolli RA, Devlin SM, Gerstenhaber JA, Lelkes PI, Yang M. A bilayered poly (Lactic-Co-Glycolic Acid) scaffold provides differential cues for the differentiation of dental pulp stem cells. Tissue Eng. Part A, 2019, 25:224-233

[77] Lin TH, Wang HC, Cheng WH, Hsu HC, Yeh ML. Osteochondral tissue regeneration using a tyramine-modified bilayered PLGA scaffold combined with articular chondrocytes in a porcine model. Int. J. Mol. Sci., 2019, 20:326

[78] Cohen DJ et al. Novel osteogenic Ti-6Al-4V device for restoration of dental function in patients with large bone deficiencies: design, development and implementation. Sci. Rep., 2016, 6

[79] Klymov A et al. Nanometer-grooved topography stimulates trabecular bone regeneration around a concave implant in a rat femoral medulla model. Nanomedicine, 2016, 12:2283-2290

[80] Hu D et al. The combined effects of nanotopography and Sr ion for enhanced osteogenic activity of bone marrow mesenchymal stem cells (BMSCs). J. Biomater. Appl., 2017, 31:1135-1147

[81] Mahapatra C et al. Differential chondro- and osteo-stimulation in three-dimensional porous scaffolds with different topological surfaces provides a design strategy for biphasic osteochondral engineering. J. Tissue Eng., 2019, 10:2041731419826433

[82] Chen G, Dong C, Yang L, Lv Y. 3D scaffolds with different stiffness but the same microstructure for bone tissue engineering. ACS Appl Mater. Interfaces, 2015, 7:15790-15802

[83] Qu T et al. Complete pulpodentin complex regeneration by modulating the stiffness of biomimetic matrix. Acta biomaterialia, 2015, 16:60-70

[84] Tan S, Fang JY, Yang Z, Nimni ME, Han B. The synergetic effect of hydrogel stiffness and growth factor on osteogenic differentiation. Biomaterials, 2014, 35:5294-5306

[85] Zigon-Branc, S. et al. Impact of hydrogel stiffness on differentiation of human adipose-derived stem cell microspheroids. Tissue Eng Part A, 25, 1369–1380 (2019).

[86] Chen J et al. Collagen/heparin coating on titanium surface improves the biocompatibility of titanium applied as a blood-contacting biomaterial. J. Biomed. Mater. Res A, 2010, 95:341-349

[87] Goenka S, Sant V, Sant S. Graphene-based nanomaterials for drug delivery and tissue engineering. J. Control Release, 2014, 173:75-88

[88] Kim, J. W. et al. The effect of reduced graphene oxide-coated biphasic calcium phosphate bone graft material on osteogenesis. Int. J. Mol. Sci. 18, 1725 (2017).

[89] Sasayama, S., Hara, T., Tanaka, T., Honda, Y. & Baba, S. Osteogenesis of multipotent progenitor cells using the epigallocatechin gallate-modified gelatin sponge scaffold in the rat congenital Cleft-Jaw model. Int. J. Mol. Sci. 19, 3803 (2018).

[90] De Luca I et al. Positively charged polymers modulate the fate of human mesenchymal stromal cells via ephrinB2/EphB4 signaling. Stem Cell Res., 2016, 17:248-255

[91] Hao L et al. Surface chemistry from wettability and charge for the control of mesenchymal stem cell fate through self-assembled monolayers. Colloids Surf. B Biointerfaces, 2016, 148:549-556

[92] Raic A et al. Potential of electrospun cationic BSA fibers to guide osteogenic MSC differentiation via surface charge and fibrous topography. Sci. Rep., 2019, 9

[93] Samanta SK et al. Metallic ion doped tri-calcium phosphate ceramics: Effect of dynamic loading on in vivo bone regeneration. J. Mech. Behav. Biomed. Mater., 2019, 96:227-235

[94] Vieira, S. et al. Self-mineralizing Ca-enriched methacrylated gellan gum beads for bone tissue engineering. Acta Biomater. 93, 74–85 (2019).

[95] Xin X et al. Delivery vehicle of muscle-derived irisin based on silk/calcium silicate/sodium alginate composite scaffold for bone regeneration. Int J. Nanomed., 2019, 14:1451-1467

[96] Balagangadharan K, Trivedi R, Vairamani M, Selvamurugan N. Sinapic acid-loaded chitosan nanoparticles in polycaprolactone electrospun fibers for bone regeneration in vitro and in vivo. Carbohydr. Polym., 2019, 216:1-16

[97] Jalili NA, Jaiswal MK, Peak CW, Cross LM, Gaharwar AK. Injectable nanoengineered stimuli-responsive hydrogels for on-demand and localized therapeutic delivery. Nanoscale, 2017, 9:15379-15389

[98] Martínez-Carmona M, Lozano D, Colilla M, Vallet-Regí M. Lectin-conjugated pH-responsive mesoporous silica nanoparticles for targeted bone cancer treatment. Acta Biomater., 2018, 65:393-404

[99] Feng S et al. Engineering of bone-and CD44-dual-targeting redox-sensitive liposomes for the treatment of orthotopic osteosarcoma. ACS Appl. Mater. interfaces, 2019, 11:7357-7368

[100] Shahriari, M. et al. Enzyme responsive drug delivery systems in cancer treatment. J. Control. Release 308, 172–189 (2019).

[101] Kamaly N, Yameen B, Wu J, Farokhzad OC. Degradable controlled-release polymers and polymeric nanoparticles: mechanisms of controlling drug release. Chem. Rev., 2016, 116:2602-2663

[102] Saghazadeh S et al. Drug delivery systems and materials for wound healing applications. Adv. Drug Deliv. Rev., 2018, 127:138-166

[103] Aoki K, Saito N. Biodegradable polymers as drug delivery systems for bone regeneration. Pharmaceutics, 2020, 12:95

[104] Singh G, Singh RP, Jolly SS. Customized hydroxyapatites for bone-tissue engineering and drug delivery applications: a review. J. Sol.-Gel Sci. Technol., 2020, 94:505-530

[105] Zhang, Y. et al. Advancements in hydrogel-based drug sustained release systems for bone tissue engineering. Front. Pharmacol. 11, 622 (2020).

[106] Ihlefeld, J. F. Ferroelectricity in Doped Hafnium Oxide: Materials, Properties and Devices 1–24 (Elsevier, 2019).

[107] Messerli MA, Graham DM. Extracellular electrical fields direct wound healing and regeneration. Biol. Bull., 2011, 221:79-92

[108] Minary-Jolandan M, Yu MF. Nanoscale characterization of isolated individual type I collagen fibrils: polarization and piezoelectricity. Nanotechnology, 2009, 20:085706

[109] Fukada E. History and recent progress in piezoelectric polymers. IEEE Trans. Ultrason Ferroelectr. Freq. Control, 2000, 47:1277-1290

[110] Mirzaei, A. et al. Comparison of osteogenic differentiation potential of induced pluripotent stem cells on 2D and 3D polyvinylidene fluoride scaffolds. J. Cell Physiol. 234, 17854–17862 (2019).

[111] Kitsara, M. et al. Permanently hydrophilic, piezoelectric PVDF nanofibrous scaffolds promoting unaided electromechanical stimulation on osteoblasts. Nanoscale. 11, 8906–8917 (2019).

[112] Saburi E et al. In vitro osteogenic differentiation potential of the human induced pluripotent stem cells augments when grown on Graphene oxide-modified nanofibers. Gene, 2019, 696:72-79

[113] Jeong, H. G., Han, Y. S., Jung, K. H. & Kim, Y. J. Poly(vinylidene fluoride) composite nanofibers containing polyhedral oligomeric silsesquioxane(-)epigallocatechin gallate conjugate for bone tissue regeneration. Nanomaterials 9, 184 (2019).

[114] Damaraju SM et al. Three-dimensional piezoelectric fibrous scaffolds selectively promote mesenchymal stem cell differentiation. Biomaterials, 2017, 149:51-62

[115] Zhang C et al. Modulating surface potential by controlling the beta phase content in poly(vinylidene fluoridetrifluoroethylene) membranes enhances bone regeneration. Adv. Health. Mater., 2018, 7

[116] Chen, W. et al. Fabrication of biocompatible potassium sodium niobate piezoelectric ceramic as an electroactive implant. Materials 10, 345 (2017).

[117] Yu P et al. Bone-inspired spatially specific piezoelectricity induces bone regeneration. Theranostics, 2017, 7:3387-3397

[118] Kim EC et al. Effects of moderate intensity static magnetic fields on osteoclastic differentiation in mouse bone marrow cells. Bioelectromagnetics, 2018, 39:394-404

[119] Suryani L et al. Effects of electromagnetic field on proliferation, differentiation, and mineralization of MC3T3 Cells. Tissue Eng. Part C. Methods, 2019, 25:114-125

[120] Singh, N., Jenkins, G. J., Asadi, R. & Doak, S. H. Potential toxicity of superparamagnetic iron oxide nanoparticles (SPION). Nano Rev. 2010, 1 (2010).

[121] Singh RK et al. Potential of magnetic nanofiber scaffolds with mechanical and biological properties applicable for bone regeneration. PLoS One, 2014, 9

[122] Zhao Y et al. Magnetic bioinspired micro/nanostructured composite scaffold for bone regeneration. Colloids Surf. B Biointerfaces, 2019, 174:70-79

[123] Zhang N, Lock J, Sallee A, Liu H. Magnetic nanocomposite hydrogel for potential cartilage tissue engineering: synthesis, characterization, and cytocompatibility with bone marrow derived mesenchymal stem cells. ACS Appl Mater. Interfaces, 2015, 7:20987-20998

[124] Zhuang J, Lin S, Dong L, Cheng K, Weng W. Magnetically actuated mechanical stimuli on Fe3O4/mineralized collagen coatings to enhance osteogenic differentiation of the MC3T3-E1 cells. Acta Biomater., 2018, 71:49-60

[125] Silva ED et al. Multifunctional magnetic-responsive hydrogels to engineer tendon-to-bone interface. Nanomedicine, 2018, 14:2375-2385

[126] Meng J et al. Super-paramagnetic responsive nanofibrous scaffolds under static magnetic field enhance osteogenesis for bone repair in vivo. Sci. Rep., 2013, 3

[127] Zhu Y et al. Dynamic protein corona influences immune-modulating osteogenesis in magnetic nanoparticle (MNP)-infiltrated bone regeneration scaffolds in vivo. Nanoscale, 2019, 11:6817-6827

[128] Sajesh KM et al. Magnetic 3D scaffold: a theranostic tool for tissue regeneration and non-invasive imaging in vivo. Nanomedicine, 2019, 18:179-188

[129] Huang W et al. Shape memory materials. Mater. Today, 2010, 13:54-61

[130] Xiong JY, Li YC, Wang XJ, Hodgson PD, Wen CE. Titanium-nickel shape memory alloy foams for bone tissue engineering. J. Mech. Behav. Biomed. Mater., 2008, 1:269-273

[131] Kujala S et al. Bone modeling controlled by a nickel–titanium shape memory alloy intramedullary nail. Biomaterials, 2002, 23:2535-2543

[132] Xie R et al. Self-fitting shape memory polymer foam inducing bone regeneration: a rabbit femoral defect study. Biochim Biophys. Acta Gen. Subj., 2018, 1862:936-945

[133] Yamauchi K et al. The effect of decortication for periosteal expansion osteogenesis using shape memory alloy mesh device. Clin. Implant Dent. Relat. Res., 2015, 17:e376-e384

[134] Yamauchi K et al. Timed-release system for periosteal expansion osteogenesis using NiTi mesh and absorbable material in the rabbit calvaria. J. Craniomaxillofac Surg., 2016, 44:1366-1372

[135] Muller CW et al. A novel shape memory plate osteosynthesis for noninvasive modulation of fixation stiffness in a rabbit tibia osteotomy model. Biomed. Res Int., 2015, 2015:652940

[136] Tong H et al. Trans-sutural distraction osteogenesis for midfacial hypoplasia in growing patients with cleft lip and palate: clinical outcomes and analysis of skeletal changes. Plast. Reconstr. Surg., 2015, 136:144-155

[137] Cheung JPY et al. A randomized double-blinded clinical trial to evaluate the safety and efficacy of a novel superelastic nickel-titanium spinal rod in adolescent idiopathic scoliosis: 5-year follow-up. Eur. Spine J., 2018, 27:327-339

[138] Zhang D et al. A bioactive “self-fitting” shape memory polymer scaffold with potential to treat cranio-maxillo facial bone defects. Acta Biomater., 2014, 10:4597-4605

[139] Kai D et al. Elastic poly(epsilon-caprolactone)-polydimethylsiloxane copolymer fibers with shape memory effect for bone tissue engineering. Biomed. Mater., 2016, 11:015007

[140] Tseng LF et al. Osteogenic capacity of human adipose-derived stem cells is preserved following triggering of shape memory scaffolds. Tissue Eng. Part A, 2016, 22:1026-1035

[141] Baker RM, Tseng LF, Iannolo MT, Oest ME, Henderson JH. Self-deploying shape memory polymer scaffolds for grafting and stabilizing complex bone defects: A mouse femoral segmental defect study. Biomaterials, 2016, 76:388-398

[142] Jiang LB et al. Shape-memory collagen scaffold for enhanced cartilage regeneration: native collagen versus denatured collagen. Osteoarthr. Cartil., 2018, 26:1389-1399

[143] Li J, Mooney DJ. Designing hydrogels for controlled drug delivery. Nat. Rev. Mater., 2016, 1:1-17

[144] Ren Z et al. Effective bone regeneration using thermosensitive poly(N-Isopropylacrylamide) grafted gelatin as injectable carrier for bone mesenchymal stem cells. ACS Appl Mater. Interfaces, 2015, 7:19006-19015

[145] Liao HT, Chen CT, Chen JP. Osteogenic differentiation and ectopic bone formation of canine bone marrow-derived mesenchymal stem cells in injectable thermo-responsive polymer hydrogel. Tissue Eng. Part C. Methods, 2011, 17:1139-1149

[146] Liao, H. T., Tsai, M. J., Brahmayya, M. & Chen, J. P. Bone regeneration using adipose-derived stem cells in injectable thermo-gelling hydrogel scaffold containing platelet-rich plasma and biphasic calcium phosphate. Int. J. Mol. Sci. 19, 2537 (2018).

[147] Kim MH, Kim BS, Park H, Lee J, Park WH. Injectable methylcellulose hydrogel containing calcium phosphate nanoparticles for bone regeneration. Int J. Biol. Macromol., 2018, 109:57-64

[148] Igwe JC, Mikael PE, Nukavarapu SP. Design, fabrication and in vitro evaluation of a novel polymer-hydrogel hybrid scaffold for bone tissue engineering. J. Tissue Eng. Regen. Med, 2014, 8:131-142

[149] Kim HK et al. Injectable in situ-forming pH/thermo-sensitive hydrogel for bone tissue engineering. Tissue Eng. Part A, 2009, 15:923-933

[150] Zhao C et al. A pH-triggered, self-assembled, and bioprintable hybrid hydrogel scaffold for mesenchymal stem cell based bone tissue engineering. ACS Appl. Mater. Interfaces, 2019, 11:8749-8762

[151] Jiang SH et al. Electrospun nanofiber reinforced composites: a review. Polym. Chem., 2018, 9:2685-2720

[152] Wang L et al. Multifunctional stimuli responsive polymer-gated iron and gold-embedded silica nano golf balls: nanoshuttles for targeted on-demand theranostics. Bone Res., 2017, 5:1-14

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

[154] Ulijn RV. Enzyme-responsive materials: a new class of smart biomaterials. J. Mater. Chem., 2006, 16:2217-2225

[155] Zhang X, Li Y, Chen YE, Chen J, Ma PX. Cell-free 3D scaffold with two-stage delivery of miRNA-26a to regenerate critical-sized bone defects. Nat. Commun., 2016, 7:1-15

[156] Zhang J et al. Bio-responsive smart polymers and biomedical applications. J. Phys.: Mater., 2019, 2:032004

[157] Zelzer M, Todd SJ, Hirst AR, McDonald TO, Ulijn RV. Enzyme responsive materials: design strategies and future developments. Biomater. Sci., 2013, 1:11-39

[158] Asha, A. B., Srinivas, S., Hao, X. & Narain, R. Smart Polymers and their Applications (Second Edition) (eds Maria Rosa Aguilar & Julio San Román) 155–189 (Woodhead Publishing, 2019).

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

[160] Zhou Y et al. Injectable extracellular vesicle-released self-assembling peptide nanofiber hydrogel as an enhanced cell-free therapy for tissue regeneration. J. Control. Release, 2019, 316:93-104

[161] Li N et al. An enzyme-responsive membrane for antibiotic drug release and local periodontal treatment. Colloids Surf. B Biointerfaces, 2019, 183:110454

[162] Ulijn RV et al. Bioresponsive hydrogels. Mater. Today, 2007, 10:40-48

[163] Xiao Y, Gong T, Jiang Y, Bao C, Zhou S. Controlled delivery of recombinant human bone morphogenetic protein-2 by using glucose-sensitive core–shell nanofibers to repair the mandible defects in diabetic rats. J. Mater. Chem. B, 2019, 7:4347-4360

[164] Yu J, Zhang Y, Yan J, Kahkoska AR, Gu Z. Advances in bioresponsive closed-loop drug delivery systems. Int. J. Pharmaceutics, 2018, 544:350-357

[165] Boskey AL, Coleman R. Aging and bone. J. Dent. Res., 2010, 89:1333-1348

[166] Kim S et al. Chitosan–lysozyme conjugates for enzyme-triggered hydrogel degradation in tissue engineering applications. ACS Appl. Mater. Interfaces, 2018, 10:41138-41145

[167] Yang J, Yang Y, Kawazoe N, Chen G. Encapsulation of individual living cells with enzyme responsive polymer nanoshell. Biomaterials, 2019, 197:317-326

[168] Ding Y et al. A dual-functional implant with an enzyme-responsive effect for bacterial infection therapy and tissue regeneration. Biomater. Sci., 2020, 8:1840-1854

[169] Jahan K, Manickam G, Tabrizian M, Murshed M. In vitro and in vivo investigation of osteogenic properties of self-contained phosphate-releasing injectable purine-crosslinked chitosan-hydroxyapatite constructs. Sci. Rep., 2020, 10

[170] Yu Y, Ran Q, Shen X, Zheng H, Cai K. Enzyme responsive titanium substrates with antibacterial property and osteo/angio-genic differentiation potentials. Colloids Surf. B: Biointerfaces, 2020, 185:110592

[171] Lee J, Byun H, Madhurakkat Perikamana SK, Lee S, Shin H. Current advances in immunomodulatory biomaterials for bone regeneration. Adv. Health. Mater., 2019, 8

[172] Xue DT et al. Immunomodulatory properties of graphene oxide for osteogenesis and angiogenesis. Int. J. Nanomed., 2018, 13:5799-5810

[173] Alhamdi JR et al. Controlled M1-to-M2 transition of aged macrophages by calcium phosphate coatings. Biomaterials, 2019, 196:90-99

[174] Lu X et al. Improved osteogenesis of boron incorporated calcium silicate coatings via immunomodulatory effects. J. Biomed. Mater. Res. Part A, 2019, 107:12-24

[175] Wu RX et al. Modulating macrophage responses to promote tissue regeneration by changing the formulation of bone extracellular matrix from filler particles to gel bioscaffolds. Mater. Sci. Eng. C. Mater. Biol. Appl., 2019, 101:330-340

[176] Zhang W et al. Strontium-substituted submicrometer bioactive glasses modulate macrophage responses for improved bone regeneration. Acs Appl. Mater. Interfaces, 2016, 8:30747-30758

[177] Spiller KL et al. Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds. Biomaterials, 2015, 37:194-207

[178] Liu W et al. A surface-engineered polyetheretherketone biomaterial implant with direct and immunoregulatory antibacterial activity against methicillin-resistant Staphylococcus aureus. Biomaterials, 2019, 208:8-20

[179] Liu, W. et al. Zinc-modified sulfonated polyetheretherketone surface with immunomodulatory function for guiding cell fate and bone regeneration. Adv. Sci. 5, 1800749 (2018).

[180] Gao LL et al. Dual-inflammatory cytokines on TiO2 nanotube-coated surfaces used for regulating macrophage polarization in bone implants. J. Biomed. Mater. Res. Part A, 2018, 106:1878-1886

[181] Li, X. Z. et al. Effects of titanium surface roughness on the mediation of osteogenesis via modulating the immune response of macrophages. Biomed. Mater. 13, 045013 (2018).

[182] Cockerill I et al. Micro-/nanotopography on bioresorbable zinc dictates cytocompatibility, bone cell differentiation, and macrophage polarization. Nano Lett., 2020, 20:4594-4602

[183] Li M et al. Macrophage polarization plays roles in bone formation instructed by calcium phosphate ceramics. J. Mater. Chem. B, 2020, 8:1863-1877

[184] Wang J et al. Nanostructured titanium regulates osseointegration via influencing macrophage polarization in the osteogenic environment. Int. J. Nanomed., 2018, 13:4029-4043

[185] Shayan M et al. Nanopatterned bulk metallic glass-based biomaterials modulate macrophage polarization. Acta Biomater., 2018, 75:427-438

[186] Pan, H. H. et al. Immunomodulation effect of a hierarchical macropore/nanosurface on osteogenesis and angiogenesis. Biomed. Mater. 12, 045006 (2017).

[187] Liu Y et al. Acetylsalicylic acid treatment improves differentiation and immunomodulation of SHED. J. Dent. Res., 2015, 94:209-218

[188] Sun JL et al. Intrafibrillar silicified collagen scaffold modulates monocyte to promote cell homing, angiogenesis and bone regeneration. Biomaterials, 2017, 113:203-216

[189] Ogier, R., Knecht, W. & Schwab, M. E. Translating academic discovery to patients’ benefit: is academia ready to assume its key role? Swiss Acad. Commun. 14, https://doi.org/10.5281/zenodo.1494980 (2019).

[190] National Science Board. Science and Engineering Indicators 2018. Chapter 8: Invention, Knowledge Transfer, and Innovation.NSB-2018-1. Alexandria, VA: National Science Foundation. Available at https://www.nsf.gov/statistics/indicators/ (2018).

[191] Huggett B. Reinventing tech transfer. Nat. Biotechnol., 2014, 32:1184–1191

[192] Duda GN et al. Changing the mindset in life sciences to-ward translation: a consensus. Sci. Transl. Med., 2014, 6:264cm12

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

[194] Biomaterials Market by Type of Materials (Metallic, Ceramic, Polymers, Natural) & By Application (Cardiovascular, Orthopedic, Dental, Plastic Surgery, Wound Healing, Neurological disorders, Tissue Engineering, Ophthalmology) - Global Forecast to 2024. Exclusive Report by MarketsandMarkets™. Bloomberg https://www.marketsandmarkets.com/Market-Reports/biomaterials-393.html (2019).

[195] Buwalda SJ et al. Hydrogels in a historical perspective: from simple networks to smart materials. J. Control. Release, 2014, 190:254-273

[196] Butlet D. Translational research: crossing the value of death. Nature, 2008, 453:840-842

[197] Levin LA, Behar-Cohen F. The academic–industrial complexity: failure to launch. Trends Pharmacol. Sci., 2017, 38:1052-1060

[198] Freedman S, Mullane K. The academic–industrial complex: navigating the translational and cultural divide. Drug Discov. Today, 2017, 22:976-993

[199] Schwartz J, Macomber C. So, you think you have an idea: a practical risk reduction-conceptual model for academic translational research. Bioengineering, 2017, 4:29

[200] Moriarty T, Grainger D, Richards R. Challenges in linking preclinical anti-microbial research strategies with clinical outcomes for device-associated infections. Eur. Cell Mater., 2014, 28:112-128

[201] 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

[202] Coller, B. S. & Califf, R. M. Traversing the valley of death: a guide to assessing prospects for translational success. Sci. Transl. Med. 1, 10cm9 (2009).

[203] Bridgham, K., Chandawarkar, A., Darrach, H. & Sacks, J. M. How to Overcome the Valley of Death from Basic Science to Clinical Trials in: Regenerative medicine and plastic surgery (Dominik, D. D. and Shiffman, M. A. eds.), pp 213–220 (Springer, 2019).

[204] 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. Educ., 2009, 8:370-388