3D additive manufactured composite scaffolds with antibiotic-loaded lamellar fillers for bone infection prevention and tissue regeneration

Abstract

Bone infections following open bone fracture or implant surgery remain a challenge in the orthopedics field. In order to avoid high doses of systemic drug administration, optimized local antibiotic release from scaffolds is required. 3D additive manufactured (AM) scaffolds made with biodegradable polymers are ideal to support bone healing in non-union scenarios and can be given antimicrobial properties by the incorporation of antibiotics. In this study, ciprofloxacin and gentamicin intercalated in the interlamellar spaces of magnesium aluminum layered double hydroxides (MgAl) and α-zirconium phosphates (ZrP), respectively, are dispersed within a thermoplastic polymer by melt compounding and subsequently processed via high temperature melt extrusion AM (~190 °C) into 3D scaffolds. The inorganic fillers enable a sustained antibiotics release through the polymer matrix, controlled by antibiotics counterions exchange or pH conditions. Importantly, both antibiotics retain their functionality after the manufacturing process at high temperatures, as verified by their activity against both Gram + and Gram - bacterial strains. Moreover, scaffolds loaded with filler-antibiotic do not impair human mesenchymal stromal cells osteogenic differentiation, allowing matrix mineralization and the expression of relevant osteogenic markers. Overall, these results suggest the possibility of fabricating dual functionality 3D scaffolds via high temperature melt extrusion for bone regeneration and infection prevention.

A hybrid additive manufacturing platform to create bulk and surface composition gradients on scaffolds for tissue regeneration

“…The base polymer was a random block copolymer poly(ethylene oxide terephthalate)/poly(butylene terephthalate (PEOT/PBT), comprising 300 g/mol average molecular weight PEO and a PEOT:PBT weight ratio of 55:45. The filler loadings were: (i) 45% (w/w) HA nanoparticles, hereafter denoted 45nHA; (ii) 10% (w/w) reduced graphene oxide, hereafter denoted 10rGO; (iii) 10% (w/w) zirconium phosphate lamellar filler and 10% (w/w) intercalated gentamicin, hereafter denoted 20ZrP–GTM; and (iv) 10% (w/w) magnesium–aluminum layered double hydroxide and 10% (w/w) intercalated ciprofloxacin, hereafter denoted 20LDH–CFX 20 , 21 . The first two polymeric composites were developed with the goal of improving the mechanical and bone formation ability of scaffolds, while the last two were developed to provide local antibiotic release from scaffolds after implantation, avoiding the need for systemic delivery.…”

Perspective Applications and Associated Challenges of Using Nanocellulose in Treating Bone-Related Diseases

“…Various novel approaches have been developed to treat bonerelated diseases, among which the use of nanodrugs is receiving great attention due to their broad-spectrum antimicrobial and antitumor activities. For example, the CaCO 3 , copper, silica, gold, magnesium-oxide, silver, and boron nanoparticles have been reported to effectively treat various bone-related diseases, such as multiple myeloma, rheumatoid arthritis, microbial infections, and osteoporosis (Bari et al, 2017;Hassani Besheli et al, 2017;Qadri et al, 2017;Gisbert-Garzarán et al, 2020;Cámara-Torres et al, 2021). In a study, the administration of gold nanoparticles in the ankle of rats effectively reduced collagen-induced arthritis and inhibited angiogenesis by blocking the key factors, such as vascular endothelial growth factor (VEGF), synovial fluid, and cell proliferation (Tsai et al, 2007).…”

Additive manufactured scaffolds for bone tissue engineering: physical characterization of thermoplastic composites with functional fillers

“…The MgAl-CFX and ZrP-GTM fillers were obtained from the manufacturer Prolabin & Tefarm S.r.l. and their production has been previously described [22,23]. The fillers had ~50% w/w lamellar compounds (MgAl or ZrP) and the rest antibiotic (CFX or GTM).…”

“…The fillers had ~50% w/w lamellar compounds (MgAl or ZrP) and the rest antibiotic (CFX or GTM). The compounding was done using a lab-scale Twin Screw Extruder at temperatures ranging between 140 and 150 °C, followed by die extrusion and pelletization, as described previously [22,23]. Compounding was done by the supplier Nadir S.r.l.…”

“…One mode of antibiotic loading that has been utilized is intercalation into inorganic lamellar fillers, where the active compound is held by electrostatic forces while being shielded from thermal degradation during scaffold manufacture. Examples include gentamycin intercalated in zirconium phosphate (ZrP-GTM) [22,23] and ciprofloxacin intercalated in magnesium aluminum layered double hydroxide (MgAl-CFX) [22].…”