3.1.2. Anti-Inflammatory and Antibiotics

Since any bone loss such as that following trauma, bone diseases and surgery, potentially provides suitable conditions for the onset of chronic infections or biofilm, it is highly desired the realization of anti-inflammatory and antibiotic-eluting scaffolds for sustained release without side effect in osteointegration, osteogenesis and osteoconduction processes. Dexamethasone loaded mesoporous CaSiO3/calcium sulfate hemihydrate (MCS/CSH) cement scaffolds have been realized by 3D printing. Compared to the tissue culture plates control, MCS/CSH scaffolds exhibited a good in vitro OCT-1 cells response, an extra balanced degradation rate and capacities to slowly release the uploaded drug in targeted sites [79].

3DP high porosity dual-drug delivery layered MBG/sodium-alginate (SA)–SA scaffolds were successfully fabricated enriching the printing step with SA cross-linking. They resulted able to stimulate proliferation and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells, furthermore, bovine serum albumin (BSA) and ibuprofen were successfully loaded in SA layer and the MBG of MBG/SA layer, respectively, resulting in a quite fast BSA release due to the macroporous network of SA, and in a constant release of ibuprofen due to the retention effect of the mesoporous channels of MBG [80].

It is well-known that inflammation phenomena thwart bone regeneration in transplanted loci and the local effect of short-term corticosteroid administration increase the effectiveness of bone tissue engineering [81]. Dexamethasone-loaded polydopamine-functionalized MBG was incorporated into polyglycolic acid/poly-1-lactic acid (PGPL) to fabricate a 3D mesoporous scaffold via laser additive manufacturing able to stimulate cell differentiation, biomineralization [82]. Loaded dexamethasone electrospun fibrous scaffolds of PCL-gelatin, incorporating MBG nanoparticles (MBGn), were presented excellent valid 3D platforms for bone tissue engineering [83].

In the case of dexamethasone-loaded 3DP strontium-containing MBG scaffolds the mesoporous matrix with enhanced mechanical strength to ensure grea<sup>t</sup> bone-growing bioactivity together with marked drug delivery capability [84]. 3DP scaffolds realized by using MBG and concentrated alginate pastes efficiently delivered dexamethasone in an in vitro test with human bone marrow-derived mesenchymal stem cells thanks to their matrix characterized by a well-ordered network of nano-channels and micro and macro-pores [85]. Poly(1,8-octanediol-*co*-citrate) and β-tricalcium phosphate (β-Ca3(PO4)2), together with ibuprofen-loaded SiO2 were made-up by micro-droplet jetting 3DP technique. Their hierarchically macro/mesoporous extremely interconnected pore matrix made them a valid antimicrobial bioengineered solution for bone regeneration [86,87].

The antimicrobials local application usually provides higher drug delivery than those attained with the intravenous application [88,89] and many 3DP macro/meso-porous composite sca ffolds, are at the moment used to support a reproducible safe a better and well-regulated in situ antibiotics delivery. Some doxorubicin-loaded 3DP magnetic Fe3O4 nanoparticles containing mesoporous bioactive glass/polycaprolactone composite sca ffolds enhanced osteogenic activity also assured sustained local anticancer delivery coupled with magnetic hyperthermia treatment [90].

Multidrug-loaded sca ffold undoubtedly improves the applicability of 3D rapid prototype implants to ward o ff biofilm growth and drug resistance. Antibiotics are usually locally delivered via PMMA bone cement spacers [91,92] compatible with a restricted number of antibiotics and characterized by having low release profiles. Mesoporous bioactive glass/metal-organic framework and macro/meso-porous composite bioactive ceramics bound with poly (3-hydroxybutyrate-*co*-3-hydroxyhexanoate) sca ffolds loaded with high dosages of isoniazid and/or rifampin, anti- tuberculosis drugs, had good biocompatibility and bioactivity when tested for long-term therapy after osteoarticular tuberculosis debridement surgery. Hierarchical 3DP multidrug sca ffolds built with nanocomposite bioceramic and PVA were coated of gelatin-glutaraldehyde (Gel-Glu). Levofloxacin was loaded into the mesopores of the bioceramic part, vancomycin was packed into the biopolymer portion while rifampin in the external layer of Gel-Glu. The early delivery of rifampin followed by a sustained release of vancomycin and levofloxacin, represented an excellent and encouraging alternative for bone infection managemen<sup>t</sup> [93]. 3DP rifampin- and vancomycin-loaded calcium phosphate sca ffolds, used in a mouse model implant-associated staphylococcus aureus bone infection, proved that the concomitant local delivery of rifampin and vancomycin significantly improves the outcomes of the implant compared to PMMA spacers which cannot carry rifampin [94]. Gelatine and Si-doped hydroxyapatite porous 3D sca ffolds were successfully loaded with vancomycin since they were rapidly prototyped fabricated at room temperature and apart from by increasing in vitro pre-osteoblastic MC3T3-E1 cell di fferentiation they also inhibit bacterial growth [95].

## 3.1.3. Metallic Ions and Trace Elements

Recently, many metallic ions such as zinc, copper, silver, cerium, strontium and cobalt, were combined with bioactive glasses to improve osteogenesis and angiogenesis [96–98]. Silver, among all, is the one that stands out for its strong antibacterial qualities. Silver/graphene oxide homogeneous nanocomposites were modified on 3DP β-tricalcium phosphate bioceramic sca ffolds leading to a bifunctional sca ffold with, just test in vitro, antibacterial and osteogenic activity were realized and in vitro tested [99].

In addition to the direct e ffect that a drug-loaded on a sca ffold can have at the implantation site, several authors highlighted that also the integration of trace elements such as strontium, zinc, magnesium, calcium, copper, boron and cerium in 3DP mesoporous bioactive glass sca ffolds enhance in vitro and in vivo osteogenic and di fferentiation activity [100–102].
