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.

Fig. 1

Smart immunomodulatory microspheres (NHG-MS) accelerated bone regeneration in diabetes mellitus (DM). µ-CT at 4 weeks confirmed that bone regeneration was impaired by diabetes. However, IL4-loaded NHG-MS restored the bone regeneration to the healthy non-diabetic level. The defect was filled with new bone in the healthy non-diabetic control (a, b) and the IL4-loaded NHG-MS DM (g, h). In contrast, only half of the defect was filled with new bone in the DM (c, d) and DM + NHG-MS (e, f). i The ratio of bone volume to total volume (BV/TV) of the non-diabetic group was twice that of the DM group. IL4-loaded NHG-MS in DM rats increased the BV/TV ratio to 0.44, twofold that of the NHG-MS group (0.23). (**P < 0.01). (Adapted from ref. , with permission.)

Fig. 2

BMP2-loaded shape-memory scaffold promoted bone formation: a–c HE staining; d–g Masson staining; and h quantification. The defect in the control (no scaffold) was full of granulation tissues (a). There was more neonatal bone in defects in the scaffold group (b, e). BMP2-loaded scaffold group (c, f) had the greatest amounts of new bone and mature bone. g High magnification Masson staining showed many multinuclear cells. h BMP2-loaded scaffold group had the greatest new bone percentage based on quantitative analysis (*P < 0.05). (Adapted from ref. , with permission.)

Fig. 3

Smart dual-peptide alginate nanoscale drug delivery (pep@MSNs-RA) promoted bone mineralization. a Hydrogels (UA, RA, pep-RA and pep@MSNs-RA) encapsulated with hMSCs were subcutaneously implanted in nude mice. b hMSC-loaded gels following removal from mice at 2 and 4 weeks after surgery. c µ-CT reconstruction at 2 and 4 weeks. Little mineralization occurred in the groups at 2 weeks. At 4 weeks, RA, pep-RA and pep@MSNs-RA exhibited mineralization; substantially more mineralized bone tissues were identified in the pep@MSNs-RA group. d ARS staining. Minerals occurred in the hMSC-loaded groups (RA, pep-RA and pep@MSNs-RA), while no mineral occurred in UA (**P < 0.01). (Adapted from ref. , with permission.)

Fig. 4

Smart dental composites for caries inhibition. a Composites with calcium (Ca) ion release. The phosphate (P) ion release had a similar trend. Ion release substantially increased at a cariogenic pH 4 when these ions were most needed to combat caries. There was little release at a neutral pH to preserve the ion reservoir. b Remineralization. Dentin lesions without composite had substantial mineral loss. Dentin lesions restored with commercial composite had little remineralization. The smart composites caused successful remineralization. (Adapted from ref. , with permission.)

Fig. 5

Effect of smart resins on neutralizing biofilm acids and increasing the pH to avoid tooth decay. The adhesive resin contained MPC, DMAHDM and NACP from 0 to 40%. A dental plaque microcosm biofilm model was used with human saliva as inoculum. The pH of the biofilm medium with resin that contained 30 and 40% NACP was at pH 6 or greater. The pH of the biofilm medium with commercial adhesive was cariogenic at approximately pH 4, which could demineralize the tooth structures. (Adapted from ref. , with permission.)

Fig. 6

Smart pH-sensitive material for selective inhibition of acid-producing bacteria. a pH-sensitive, reversible spectroscopic properties and assembly behaviour of Azo-QPS-C16. The schematic shows the assembly and disassembly between Azo-QPS-C16 and its nano-sized aggregates, mediated by pH switch or addition of base/acid, for reversible control of the antibacterial activity. Acid-enhanced the antibacterial behaviours of Azo-QPS-C16, with E. coli growth curves after treatment with different concentrations of Azo-QPS-C16 at b pH 4.1 and c pH 7.9. d MBC values of Azo-QPS-C16 against E. coli and S. mutans at different pH values. (Adapted from ref. , with permission.)

Fig. 7

Smart composite to shift species in biofilms towards a healthy composition. Three-species biofilms (S. mutans, S. sanguinis and S. gordonii) were grown on composites for 48 and 72 h. The commercial composite was Heliomolar (Ivoclar). The DMAHDM wt% was varied in the experimental composite from 0 to 3%. The cariogenic S. mutans had overwhelming proportions for the commercial control and 0% DMAHDM group. With increasing DMAHDM wt%, the proportion of S. mutans sharply decreased, whereas S. sanguinis or S. gordonii achieved a predominant proportion. Values with dissimilar letters are significantly different (P < 0.05). (Adapted from ref. , with permission.)

Fig. 8

Smart inhibition of bacteria without inducing drug resistance. a Minimal inhibitory concentration (MIC). Twenty passages were tested, and each passage used the surviving bacteria from the previous passage as inoculum. A twofold increase in MIC occurred for DMADDM and CHX, indicating drug resistance. However, DMAHDM had no drug resistance. b From 1 to 20 passages, S. gordonii biofilm CFU on DMAHDM resin maintained a 4 log reduction over that without DMAHDM, showing the same sensitivity with no drug resistance. In b, bars with dissimilar letters are significantly different from each other (P < 0.05). (Adapted from ref. , with permission.)