Advanced smart biomaterials and constructs for hard tissue engineering and regeneration

Abstract

Hard tissue repair and regeneration cost hundreds of billions of dollars annually worldwide, and the need has substantially increased as the population has aged. Hard tissues include bone and tooth structures that contain calcium phosphate minerals. Smart biomaterial-based tissue engineering and regenerative medicine methods have the exciting potential to meet this urgent need. Smart biomaterials and constructs refer to biomaterials and constructs that possess instructive/inductive or triggering/stimulating effects on cells and tissues by engineering the material’s responsiveness to internal or external stimuli or have intelligently tailored properties and functions that can promote tissue repair and regeneration. The smart material-based approaches include smart scaffolds and stem cell constructs for bone tissue engineering; smart drug delivery systems to enhance bone regeneration; smart dental resins that respond to pH to protect tooth structures; smart pH-sensitive dental materials to selectively inhibit acid-producing bacteria; smart polymers to modulate biofilm species away from a pathogenic composition and shift towards a healthy composition; and smart materials to suppress biofilms and avoid drug resistance. These smart biomaterials can not only deliver and guide stem cells to improve tissue regeneration and deliver drugs and bioactive agents with spatially and temporarily controlled releases but can also modulate/suppress biofilms and combat infections in wound sites. The new generation of smart biomaterials provides exciting potential and is a promising opportunity to substantially enhance hard tissue engineering and regenerative medicine efficacy.

Bone repair: a new generation of smart biomaterials

Smart biomaterials that are able to instruct bone repair can overcome some of the shortcomings of bone grafting and meet the growing need for hard tissue regeneration in ageing populations. Hockin Xu at the University of Maryland in Baltimore, United States, and colleagues review recent advances in the development of smart biomaterials for repairing and regenerating damaged bones and teeth. They highlight scaffolds that closely mimic natural bone tissue and immunomodulatory biomaterials that can prevent infection and promote cell survival for guiding and enhancing bone regeneration. Furthermore, scaffolds with shape-memory capability and materials that provide tailored spatio-temporal delivery of drugs or bioactive agents in response to internal or external stimuli, hold great promise not only for bone tissue engineering but also for dentistry.

References

[1] 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

[2] Sohail M et al. Natural and synthetic polymer-based smart biomaterials for management of ulcerative colitis: a review of recent developments and future prospects. Drug Deliv. Transl. Res., 2018

[3] Khan F, Tanaka M. Designing smart biomaterials for tissue engineering. Int. J. Mol. Sci., 2018, 19:17

[4] Lendlein Andreas, Feng Yujun, Grijpma Dirk W., Zhao Yuanjin. Smart Materials. ChemPhysChem, 2018, 19 16 1938-1940

[5] Mikos AG et al. Engineering complex tissues. Tissue Eng., 2006, 12:3307-3339

[6] Mao, J. J., Vunjak-Novakovic, G., Mikos, A. G. & Atala, A. Regenerative Medicine: Translational Approaches and Tissue Engineering (Artech House, Boston and London, 2007).

[7] Cutter CS, Mehrara BJ. Bone grafts and substitutes. J. Long. Term. Eff. Med. Implants, 2006, 16:249-260

[8] United States Bone and Joint Decade. The Burden of Musculoskeletal Diseases in the United States (American Academy of Orthopaedic Surgeons, Rosemont, IL, 2008).

[9] Shi J, Qi W, Cao S. Biomimetic self-assembly of calcium phosphate templated by PNIPAAm nanogels for sustained smart drug delivery. Mater. Sci. Eng. C, 2012, 32:1299-1306

[10] Perez RA, Won JE, Knowles JC, Kim HW. Naturally and synthetic smart composite biomaterials for tissue regeneration. Adv. Drug Deliv. Rev., 2013, 65:471-496

[11] United Nations, World Population Prospects: http://esa.un.org/unpd/wpp/excel-data/population.htm (2012).

[12] Beazoglou T et al. Economic impact of regulating the use of amalgam restorations. Public Health Rep., 2007, 122:657-663

[13] Saunders RH, Meyerowitz C. Dental caries in older adults. Dent. Clin. North Am., 2005, 49:293-308

[14] Zaura E, ten Cate JM. Towards understanding oral health. Caries Res., 2015, 49:55-61

[15] Sakaguchi RL. Review of the current status and challenges for dental posterior restorative composites: clinical, chemistry, and physical behavior considerations. Summary of discussion from the portland composites symposium (pocos) June 17-19, 2004, oregon health and science university, portland, oregon. Dent. Mater., 2005, 21:3-6

[16] Jokstad A, Bayne S, Blunck U, Tyas M, Wilson N. Quality of dental restorations. FDI Commission Project 2-95. Int. Dent. J., 2001, 51:117-158

[17] O’Brien FJ. Biomaterials & scaffolds for tissue engineering. Mater. Today, 2005, 14:88-95

[18] Oest ME, Dupont KM, Kong HJ, Mooney DJ, Guldberg RE. Quantitative assessment of scaffold and growth factor-mediated repair of critically sized bone defects. J. Orthop. Res., 2007, 25:941-950

[19] Tatara AM, Mikos AG. Tissue engineering in orthopaedics. J. Bone Joint Surg. Am., 2016, 98:1132-1139

[20] Motamedian SR, Hosseinpour S, Ahsaie MG, Khojasteh A. Smart scaffolds in bone tissue engineering: a systematic review of literature. World J. Stem Cells, 2015, 7:657-668

[21] Kaigler D, Wang Z, Horger K, Mooney DJ, Krebsbach PH. VEGF scaffolds enhance angiogenesis and bone regeneration in irradiated osseous defects. J. Bone Miner. Res., 2006, 21:735-744

[22] Kim Hwan D., Amirthalingam Sivashanmugam, Kim Seunghyun L., Lee Seunghun S., Rangasamy Jayakumar, Hwang Nathaniel S.. Biomimetic Materials and Fabrication Approaches for Bone Tissue Engineering. Advanced Healthcare Materials, 2017, 6 23 1700612

[23] Murphy WL, McDevitt TC, Engler AJ. Materials as stem cell regulators. Nat. Mater., 2014, 13:547-557

[24] Franz S, Rammelt S, Scharnweber D, Simon JC. Immune responses to implants—a review of the implications for the design of immunomodulatory biomaterials. Biomaterials, 2011, 32:6692-6709

[25] Wu T, Yu S, Chen D, Wang Y. Bionic design, materials and performance of bone tissue scaffolds. Materials, 2017, 10:1187

[26] Mittal A, Negi P, Garkhal K, Verma S, Kumar N. Integration of porosity and bio-functionalization to form a 3D scaffold: cell culture studies and in vitro degradation. Biomed. Mater., 2010, 5:045001

[27] Shi JP et al. A porous scaffold design method for bone tissue engineering using triply periodic minimal surfaces. IEEE Access, 2018, 6:1015-1022

[28] Chung L, Maestas DR Jr, Housseau F, Elisseeff JH. Key players in the immune response to biomaterial scaffolds for regenerative medicine. Adv. Drug Deliv. Rev., 2017, 114:184-192

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

[30] Li WA et al. The effect of surface modification of mesoporous silica micro-rod scaffold on immune cell activation and infiltration. Biomaterials, 2016, 83:249-256

[31] Liu X, Ma PX. Phase separation, pore structure, and properties of nanofibrous gelatin scaffolds. Biomaterials, 2009, 30:4094-4103

[32] Liu X et al. Biomimetic nanofibrous gelatin/apatite composite scaffolds for bone tissue engineering. Biomaterials, 2009, 30:2252-2258

[33] Sachar A et al. Osteoblasts responses to three-dimensional nanofibrous gelatin scaffolds. J. Biomed. Mater. Res. A, 2012, 100:3029-3041

[34] 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

[35] Zeng D et al. Theosteoimmunomodulatory properties of MBG scaffold coated with amino functional groups. Artif. Cells Nanomed. Biotechnol., 2017, 30:1-11

[36] Chen ZT et al. Osteoimmunomodulatory properties of magnesium scaffolds coated with b-tricalcium phosphate. Biomaterials, 2014, 35:8553e8565

[37] Huang WM, Yang B, Zhao Y, Ding Z. Thermo-moisture responsive polyurethane shape-memory polymer and composites: a review. J. Mater. Chem., 2010, 20:3367-3381

[38] Buckley PR et al. Inductively heated shape memory polymer for the magnetic actuation of medical devices. IEEE Trans. Biomed. Eng., 2006, 53:2075-2083

[39] Mohr R et al. Initiation of shape-memory effect by inductive heating of magnetic nanoparticles in thermoplastic polymers. Proc. Natl Acad. Sci. USA, 2006, 103:3540-3545

[40] Lendlein A, Jiang H, Junger O, Langer R. Light-induced shape-memory polymers. Nature, 2005, 434:879-882

[41] Yakacki, C. M. & Gall, K. in Shape-Memory Polymers (Springer, Berlin, Heidelberg, 2010).

[42] Langer R, Tirrell DA. Designing materials for biology and medicine. Nature, 2004, 428:487-492

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

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

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

[46] Miao S, Zhu W, Castro NJ, Leng J, Zhang LG. Four-dimensional printing hierarchy scaffolds with highly biocompatible smart polymers for tissue engineering applications. Tissue Eng. Part C Methods, 2016, 22:952-963

[47] Hendrikson WJ et al. Towards 4D printed scaffolds for tissue engineering: exploiting 3D shape memory polymers to deliver time-controlled stimulus on cultured cells. Biofabrication, 2017, 9:031001

[48] Markx GH. The use of electric fields in tissue engineering. Organogenesis, 2008, 4:11-17

[49] Singh, J., Rani, S., Rohini & Parida, A. Generation of piezoelectricity from the human body. 2014 Annual International Conference on Emerging Research Areas: Magnetics, Machines and Drives (AICERA/iCMMD) (2014).

[50] Ribeiro C et al. Enhanced proliferation of pre-osteoblastic cells by dynamic piezoelectric stimulation. RSC Adv., 2012, 2:11504-11509

[51] Dubey, A. K., Balani, K. & Basu, B. in Nanomedicine: Technologies and Applications 537–570 (Woodhead Publishing Ltd, 2012).

[52] Rajabi AH, Jaffe M, Arinzeh TL. Piezoelectric materials for tissue regeneration: A review. Acta Biomater., 2015, 24:12-23

[53] More N, Kapusetti G. Piezoelectric material—a promising approach for bone and cartilage regeneration. Med. Hypotheses, 2017, 108:10-16

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

[55] Augustine R et al. Electrospun poly(vinylidene fluoride-trifluoroethylene)/zinc oxide nanocomposite tissue engineering scaffolds with enhanced cell adhesion and blood vessel formation. Nano Res., 2017, 10:3358-3376

[56] Tang Y et al. Fabrication and in vitro biological properties of piezoelectric bioceramics for bone regeneration. Sci. Rep., 2017, 7

[57] Sun G, Mao JJ. Engineering dextran-based scaffolds for drug delivery and tissue repair. Nanomedicine (Lond.), 2012, 7:1771-1184

[58] Samorezov JE, Alsberg E. Spatial regulation of controlled bioactive factor delivery for bone tissue engineering. Adv. Drug Deliv. Rev., 2015, 84:45-67

[59] Lee EJ et al. Application of materials as medical devices with localized drug delivery capabilities for enhanced wound repair. Prog. Mater. Sci., 2017, 89:392-410

[60] Kretlow JD, Hacker MC, Klouda L, Ma BB, Mikos AG. Synthesis and characterization of dual stimuli responsive macromers based on poly(N-isopropylacrylamide) and poly(vinylphosphonic acid). Biomacromolecules, 2010, 11:797-805

[61] Safari J, Zarnegar Z. Advanced drug delivery systems: nanotechnology of health design. A review. J. Saudi Chem. Soc., 2014, 18:85-99

[62] Liu D, Yang F, Xiong F, Gu N. The smart drug delivery system and its clinical potential. Theranostics, 2016, 6:1306-1323

[63] Kelley EG, Albert JN, Sullivan MO, Epps TH 3rd. Stimuli-responsive copolymer solution and surface assemblies for biomedical applications. Chem. Soc. Rev., 2013, 42:7057-7071

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

[65] Gu Z. Introduction to special issue on “Responsive Materials and Systems: Toward Smart and Precision Medications”. Bioeng. Transl. Med., 2016, 1:235-236

[66] Kondiah Pariksha, Choonara Yahya, Kondiah Pierre, Marimuthu Thashree, Kumar Pradeep, du Toit Lisa, Pillay Viness. A Review of Injectable Polymeric Hydrogel Systems for Application in Bone Tissue Engineering. Molecules, 2016, 21 11 1580

[67] Mohd Amin MC, Ahmad N, Pandey M, Jue Xin C. Stimuli-responsive bacterial cellulose-g-poly(acrylic acid-co-acrylamide) hydrogels for oral controlled release drug delivery. Drug Dev. Ind. Pharm., 2014, 40:1340-1349

[68] Ashley GW, Henise J, Reid R, Santi DV. Hydrogel drug delivery system with predictable and tunable drug release and degradation rates. Proc. Natl Acad. Sci. USA, 2013, 110:2318-2323

[69] Horev B et al. pH-activated nanoparticles for controlled topical delivery of farnesol to disrupt oral biofilm virulence. ACS Nano, 2015, 9:2390-2404

[70] Li F, Zhu Y, Wang Y. Dual-responsive drug delivery system with real time tunable release behavior. Micro. Mesopor. Mater., 2014, 200:46-51

[71] Suri SS, Fenniri H, Singh B. Nanotechnology-based drug delivery systems. J. Occup. Med. Toxicol., 2007, 2

[72] Singh R, Lillard JW. Nanoparticle-based targeted drug delivery. Exp. Mol. Pathol., 2009, 86:215-223

[73] van Rijt S, Habibovic P. Enhancing regenerative approaches with nanoparticles. J. R. Soc. Interface, 2017, 14:20170093

[74] Bharti C, Nagaich U, Pal AK, Gulati N. Mesoporous silica nanoparticles in target drug delivery system: a review. Int. J. Pharm. Investig., 2015, 5:124-133

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

[76] Karimi, M., Mirshekari, H., Aliakbari, M., Sahandi-Zangabad, P. & Michael, R. H. Smart mesoporous silica nanoparticles for controlled-release drug delivery. Nanotechnol. Rev. 195, (2015). https://doi.org/10.1515/ntrev-2015-0057.

[77] Luo Z et al. Time-responsive osteogenic niche of stem cells: a sequentially triggered, dual-peptide loaded, alginate hybrid system for promoting cell activity and osteo-differentiation. Biomaterials, 2018, 163:25-42

[78] Pellowe A, Gonzalez A. Extracellular matrix biomimicry for the creation of investigational and therapeutic devices. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol., 2016, 8:5-22

[79] Ma PX. Biomimetic materials for tissue engineering. Adv. Drug Deliv. Rev., 2008, 60:184-198

[80] Tsiapalis D, De Pieri A, Biggs M, Pandit A, Zeugolis DI. Biomimetic bioactive biomaterials: the next generation of implantable devices. ACS Biomater. Sci. Eng., 2017, 3:1172-1174

[81] Fernandez-Yague MA et al. Biomimetic approaches in bone tissue engineering: Integrating biological and physicomechanical strategies. Adv. Drug Deliv. Rev., 2015, 84:1-29

[82] Sant S, Hancock MJ, Donnelly JP, Iyer D, Khademhosseini A. Biomimetic gradient hydrogels for tissue engineering. Can. J. Chem. Eng., 2010, 88:899-911

[83] Sheikhpour M, Barani L, Kasaeian A. Biomimetics in drug delivery systems: a critical review. J. Control Release, 2017, 253:97-109

[84] Lee N, Robinson J, Lu H. Biomimetic strategies for engineering composite tissues. Curr. Opin. Biotechnol., 2016, 40:64-74

[85] Phipps MC, Monte F, Mehta M, Kim HKW. Intraosseous delivery of bone morphogenic protein-2 using a self-assembling peptide hydrogel. Biomacromolecules, 2016, 17:2329-2336

[86] Feng C et al. Lotus root-like biomimetic materials for cell delivery and tissue regeneration. Adv. Sci., 2017, 4:1700401

[87] Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet, 2005, 366:1809

[88] Monsarrat P et al. Concise review: mesenchymal stromal cells used for periodontal regeneration: a systematic review. Stem Cells Transl. Med., 2014, 3:768-774

[89] Khosla S, Westendorf JJ, Mödder UI. Concise review: insights from normal bone remodeling and stem cell-based therapies for bone repair. Stem Cells, 2010, 28:2124

[90] Chen FM et al. A review on endogenous regenerative technology in periodontal regenerative medicine. Biomaterials, 2010, 31:7892

[91] Zhu B et al. Jawbone microenvironment promotes periodontium regeneration by regulating the function of periodontal ligament stem cells. Sci. Rep., 2017, 7

[92] Subramaniam S, Fang YH, Sivasubramanian S, Lin FH, Lin CP. Hydroxyapatite-calcium sulfate-hyaluronic acid composite encapsulated with collagenase as bone substitute for alveolar bone regeneration. Biomaterials, 2016, 74:99-108

[93] Dan H et al. The influence of cellular source on periodontal regeneration using calcium phosphate coated polycaprolactone scaffold supported cell sheets. Biomaterials, 2014, 35:113-122

[94] Bhattarai G, Poudel SB, Kook SH, Lee JC. Anti-inflammatory, anti-osteoclastic, and antioxidant activities of genistein protect against alveolar bone loss and periodontal tissue degradation in a mouse model of periodontitis. J. Biomed. Mater. Res. A, 2017, 105:2510-2521

[95] Bhattarai G, Poudel SB, Kook SH, Lee JC. Resveratrol prevents alveolar bone loss in an experimental rat model of periodontitis. Acta Biomater., 2016, 29:398-408

[96] Chang PC, Chien LY, Ye Y, Kao MJ. Irradiation by light-emitting diode light as an adjunct to facilitate healing of experimental periodontitis in vivo. J. Periodontal Res., 2013, 48:135-143

[97] Xue J et al. Fabrication of drug-loaded anti-infective guided tissue regeneration membrane with adjustable biodegradation property. Colloids Surf. B Biointerfaces, 2015, 135:846-854

[98] Chu C, Deng J, Sun X, Qu Y, Man Y. Collagen membrane and immune response in guided bone regeneration: recent progress and perspectives. Tissue Eng. Part B Rev., 2017, 23:421-435

[99] 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 2018

[100] Zhu Y et al. Bone regeneration with micro/nano hybrid-structured biphasic calcium phosphate bioceramics at segmental bone defect and the induced immunoregulation of MSCs. Biomaterials, 2017, 147:133-144

[101] Nivedhitha Sundaram M, Sowmya S, Deepthi S, Bumgardener JD, Jayakumar R. Bilayered construct for simultaneous regeneration of alveolar bone and periodontal ligament. J. Biomed. Mater. Res. B Appl. Biomater., 2016, 104:761-770

[102] Yousefi AM, Hoque ME, Prasad RG, Uth N. Current strategies in multiphasic scaffold design for osteochondral tissue engineering: A review. J. Biomed. Mater. Res. A, 2015, 103:2460-2481

[103] Wu X et al. Electrospun fibrous scaffolds combined with nanoscale hydroxyapatite induce osteogenic differentiation of human periodontal ligament cells. Int. J. Nanomed., 2014, 9:4135-4143

[104] Lee CH et al. Three-dimensional printed multiphase scaffolds for regeneration of periodontium complex. Tissue Eng. A, 2014, 20:1342-1351

[105] Costa PF et al. Advanced tissue engineering scaffold design for regeneration of the complex hierarchical periodontal structure. J. Clin. Periodontol., 2014, 41:283-294

[106] Vaquette C et al. A biphasic scaffold design combined with cell sheet technology for simultaneous regeneration of alveolar bone/periodontal ligament complex. Biomaterials, 2012, 33:5560-5573

[107] Carlo Reis EC et al. Periodontal regeneration using a bilayered PLGA/calcium phosphate construct. Biomaterials, 2011, 32:9244-9253

[108] Han P, Ivanovski S, Crawford R, Xiao Y. Activation of the canonical Wnt signaling pathway induces cementum regeneration. J. Bone Miner. Res., 2015, 30:1160-1174

[109] Needleman IG, Worthington HV, Giedrys-Leeper E, Tucker RJ. Guided tissue regeneration for periodontal infra-bony defects. Cochrane Database Syst. Rev., 2006, 2006:Cd001724

[110] Xue J et al. Drug loaded homogeneous electrospun PCL/gelatin hybrid nanofiber structures for anti-infective tissue regeneration membranes. Biomaterials, 2014, 35:9395-9405

[111] Cheng CF, Wu KM, Chen YT, Hung SL. Bacterial adhesion to antibiotic-loaded guided tissue regeneration membranes—a scanning electron microscopy study. J. Formos. Med. Assoc., 2015, 114:35-45

[112] Cheng CF et al. Bacterial penetration through antibiotic-loaded guided tissue regeneration membranes. J. Periodontol., 2009, 80:1471-1478

[113] Basile MA et al. Functionalized PCL/HA nanocomposites as microporous membranes for bone regeneration. Mater. Sci. Eng. C Mater. Biol. Appl., 2015, 48:457-468

[114] Xu C, Lei C, Meng L, Wang C, Song Y. Chitosan as a barrier membrane material in periodontal tissue regeneration. J. Biomed. Mater. Res. B Appl. Biomater., 2012, 100:1435-1443

[115] Xu S et al. Preparation and in vitro biological evaluation of octacalcium phosphate/bioactive glass-chitosan/alginate composite membranes potential for bone guided regeneration. J. Nanosci. Nanotechnol., 2016, 16:5577-5585

[116] Li W, Ding Y, Yu S, Yao Q, Boccaccini AR. Multifunctional chitosan-45S5 bioactive glass-poly(3-hydroxybutyrate-co-3-hydroxyvalerate) microsphere composite membranes for guided tissue/bone regeneration. ACS Appl. Mater. Interfaces, 2015, 7:20845-20854

[117] Di Benedetto A, Gigante I, Colucci S, Grano M. Periodontal disease: linking the primary inflammation to bone loss. Clin. Dev. Immunol., 2013, 2013:503754

[118] Sima C, Glogauer M. Macrophage subsets and osteoimmunology: tuning of the immunological recognition and effector systems that maintain alveolar bone. Periodontol. 2000, 2013, 63:80-101

[119] Gao, X. et al. Immunomodulatory role of stem cells from human exfoliated deciduous teeth on periodontal regeneration. Tissue Eng. Part A https://doi.org/10.1089/ten (2018).

[120] Requicha JF et al. A tissue engineering approach for periodontal regeneration based on a biodegradable double-layer scaffold and adipose-derived stem cells. Tissue Eng. Part A, 2014, 20:2483-2492

[121] Sowmya S., Mony Ullas, Jayachandran P., Reshma S., Kumar R. Arun, Arzate H., Nair Shantikumar V., Jayakumar R.. Tri-Layered Nanocomposite Hydrogel Scaffold for the Concurrent Regeneration of Cementum, Periodontal Ligament, and Alveolar Bone. Advanced Healthcare Materials, 2017, 6 7 1601251

[122] Van Houte J. Role of micro-organisms in caries etiology. J. Dent. Res., 1994, 73:v672-v681

[123] Featherstone JDB. The continuum of dental caries—evidence for a dynamic disease process. J. Dent. Res., 2004, 83:C39-C42

[124] Deng DM, ten Cate JM. Demineralization of dentin by Streptococcus mutans biofilms grown in the constant depth film fermentor. Caries Res., 2004, 38:54-61

[125] Totiam P, Gonzalez-Cabezas C, Fontana MR, Zero DT. A new in vitro model to study the relationship of gap size and secondary caries. Caries Res., 2007, 41:467-473

[126] Thylstrup, A. & Fejerskov, O. Textbook of Cariology (Munksgaard, Copenhagen, Denmark, 1986).

[127] Dawes C. What is the critical pH and why does a tooth dissolve in acid? J. Can. Dent. Assoc., 2003, 69:722-724

[128] Weir MD et al. Effect of calcium phosphate nanocomposite on in vitro remineralization of human dentin lesions. Dent. Mater., 2017, 33:1033-1044

[129] Xu HH, Moreau JL, Sun L, Chow LC. Nanocomposite containing amorphous calcium phosphate nanoparticles for caries inhibition. Dent. Mater., 2011, 27:762-769

[130] Weir MD, Chow LC, Xu HH. Remineralization of demineralized enamel via calcium phosphate nanocomposite. J. Dent. Res., 2012, 91:979-984

[131] Melo MAS, Weir MD, Rodrigues LK, Xu HH. Novel calcium phosphate nanocomposite with caries-inhibition in a human in situ model. Dent. Mater., 2013, 29:231-240

[132] Xie XJ et al. Novel dental adhesive with triple benefits of calcium phosphate recharge, protein-repellent and antibacterial functions. Dent. Mater., 2017, 33:553-563

[133] Nizet V et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature, 2001, 414:454-457

[134] Li L et al. Design and characterization of an acid-activated antimicrobial peptide. Chem. Biol. Drug Des., 2010, 75:127-132

[135] Yang, Y. et al. pH-sensitive compounds for selective inhibition of acid-producing bacteria. ACS Appl. Mater. Interfaces 10.1021/acsami. 8b01089 (2018).

[136] Imazato S et al. An in vivo evaluation of bonding ability of comprehensive antibacterial adhesive system incorporating MDPB. Dent. Mater., 2007, 23:170-176

[137] Imazato S. Bioactive restorative materials with antibacterial effects: new dimension of innovation in restorative dentistry. Dent. Mater. J., 2009, 28:11-19

[138] Imazato S et al. Therapeutic polymers for dental adhesives: loading resins with bio-active components. Dent. Mater., 2014, 30:97-104

[139] Beyth N et al. Polyethyleneimine nanoparticles incorporated into resin composite cause cell death and trigger biofilm stress in vivo. Proc. Natl Acad. Sci. USA, 2014, 107:22038-22043

[140] Li F et al. Effects of a dental adhesive incorporating antibacterial monomer on the growth, adherence and membrane integrity of Streptococcus mutans. J. Dent., 2009, 37:289-296

[141] Cheng L et al. Dental plaque microcosm biofilm behavior on calcium phosphate nanocomposite with quaternary ammonium. Dent. Mater., 2012, 28:853-862

[142] Li F, Weir MD, Xu HH. Effects of quaternary ammonium chain length on antibacterial bonding agents. J. Dent. Res., 2013, 92:932-938

[143] Zhou H et al. Dental plaque microcosm response to bonding agents containing quaternary ammonium methacrylates with different chain lengths and charge densities. J. Dent., 2013, 41:1122-1131

[144] Marsh PD, Head DA, Devine DA. Dental plaque as a biofilm and a microbial community-Implications for treatment. J. Oral Biosci., 2015, 57:185-191

[145] Zhang K et al. Effect of antibacterial dental adhesive on multispecies biofilms formation. J. Dent. Res., 2015, 94:622-629

[146] Wang, H. H. et al. Novel dental composite with capability to suppress cariogenic species and promote non-cariogenic species in oral biofilms. Mater. Sci. Eng. C Mater. Biol. Appl. (2018, accepted for publication).

[147] Hegstad K et al. Does the wide use of quaternary ammonium compounds enhance the selection and spread of antimicrobial resistance and thus threaten our health? Microb. Drug Resist., 2010, 16:91-104

[148] Ioannou CJ, Hanlon GW, Denyer SP. Action of disinfectant quaternary ammonium compounds against Staphylococcus aureus. Antimicrob. Agents Chemother., 2007, 51:296-306

[149] Bragg R et al. Bacterial resistance to quaternary ammonium compounds (QAC) disinfectants. Adv. Exp. Med. Biol., 2014, 808:1-13

[150] Kitagawa H et al. Evolution of resistance to cationic biocides in Streptococcus mutans and Enterococcus faecalis. J. Dent., 2016, 47:18-22

[151] Wang SP et al. Do quaternary ammonium monomers induce drug resistance in cariogenic, endodontic and periodontal bacterial species? Dent. Mater., 2017, 33:1127-1138

[152] Wang SP et al. Drug resistance of oral bacteria to new antibacterial dental monomer dimethylaminohexadecyl methacrylate. Sci. Rep., 2018, 8

[153] Zhou H et al. Three-dimensional biofilm evaluation on bonding agents containing quaternary ammonium methacrylates with different chain lengths. Int. J. Oral Sci., 2014, 6:77-86

[154] Zhang N et al. Orthodontic cement with protein-repellent and antibacterial properties and the release of calcium and phosphate ions. J. Dent., 2016, 50:51-59

Funding

U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR)(R01DE17974)