Drug delivery strategies through 3D-printed calcium phosphate.

3D printing has revolutionized bone tissue engineering (BTE) by enabling the fabrication of patient- or defect-specific scaffolds to enhance bone regeneration. The superior biocompatibility, customizable bioactivity, and biodegradability have enabled calcium phosphate (CaP) to gain significance as a bone graft material. 3D-printed (3DP) CaP scaffolds allow precise drug delivery due to their porous structure, adaptable structure-property relationship, dynamic chemistry, and controlled dissolution. The effectiveness of conventional scaffold-based drug delivery is hampered by initial burst release and drug loss. This review summarizes different multifunctional drug delivery approaches explored in controlling drug release, including polymer coatings, formulation integration, microporous scaffold design, chemical crosslinking, and direct extrusion printing for BTE applications. The review also outlines perspectives and future challenges in drug delivery research, paving the way for next-generation bone repair methodologies.

3D printed scaffolds with quercetin and vitamin D3 nanocarriers: In vitro cellular evaluation.

Increasing bone diseases and anomalies significantly challenge bone regeneration, necessitating the development of innovative implantable devices for effective healing. This study explores the potential of 3D-printed calcium phosphate (CaP) scaffolds functionalized with natural medicine to address this issue. Specifically, quercetin and vitamin D3 (QVD) encapsulated solid lipid nanoparticles (QVD-SLNs) are incorporated into the scaffold to enhance bone regeneration. The melt emulsification method is utilized to achieve high drug encapsulation efficiency (~98%) and controlled biphasic release kinetics. The process-structure-property performance of these systems allows more controlled release while maintaining healthy cell-material interactions. The functionalized scaffolds show ~1.3- and ~-1.6-fold increase in osteoblast cell proliferation and differentiation, respectively, as compared with the control. The treated scaffold demonstrates a reduction in osteoclastic activity as compared with the control. The QVD-SLN-loaded scaffolds show ~4.2-fold in vitro chemopreventive potential against osteosarcoma cells. Bacterial assessment with both Staphylococcus aureus and Pseudomonas aeruginosa shows a significant reduction in bacterial colony growth over the treated scaffold. These findings summarize that the release of QVD-SLNs through a 3D-printed CaP scaffold can treat various bone-related disorders for low or non-load-bearing applications.

3D Printed SiO2-Tricalcium Phosphate Scaffolds Loaded with Carvacrol Nanoparticles for Bone Tissue Engineering Application.

Bone damage resulting from trauma or aging poses challenges in clinical settings that need to be addressed using bone tissue engineering (BTE). Carvacrol (CA) possesses anti-inflammatory, anticancer, and antibacterial properties. Limited solubility and physicochemical stability restrict its biological activity, requiring a stable carrier system for delivery. Here, we investigate the utilization of a three-dimensional printed (3DP) SiO2-doped tricalcium phosphate (TCP) scaffold functionalized with carvacrol-loaded lipid nanoparticles (CA-LNPs) to improve bone health. It exhibits a negative surface charge with an entrapment efficiency of ∼97% and size ∼129 nm with polydispersity index (PDI) and zeta potential values of 0.18 and -16 mV, respectively. CA-LNPs exhibit higher and long-term release over 35 days. The CA-LNP loaded SiO2-doped TCP scaffold demonstrates improved antibacterial properties against Staphylococcus aureus and Pseudomonas aeruginosa by >90% reduction in bacterial growth. Functionalized scaffolds result in 3-fold decrease and 2-fold increase in osteosarcoma and osteoblast cell viability, respectively. These findings highlight the therapeutic potential of the CA-LNP loaded SiO2-doped TCP scaffold for bone defect treatment.

Hydroxyapatite coated titanium with curcumin and epigallocatechin gallate for orthopedic and dental applications.

Titanium and its alloy are clinically used as an implant material for load-bearing applications to treat bone defects. However, the lack of biological interaction between bone tissue and implant and the risk of infection are still critical challenges in clinical orthopedics. In the current work, we have developed a novel approach by first 1) modifying the implant surface using hydroxyapatite (HA) coating to enhance bioactivity and 2) integrating curcumin and epigallocatechin gallate (EGCG) in the coating that would induce chemopreventive and osteogenic potential and impart antibacterial properties to the implant. The study shows that curcumin and EGCG exhibit controlled and sustained release profiles in acidic and physiological environments. Curcumin and EGCG also show in vitro cytotoxicity toward osteosarcoma cells after 11 days, and the dual system shows a ~94 % reduction in bacterial growth, indicating their in vitro chemopreventive potential and antibacterial efficacy. The release of both curcumin and EGCG was found to be compatible with osteoblast cells and further promotes their growth. It shows a 3-fold enhancement in cellular viability in the dual drug-loaded implant compared to the untreated samples. These findings suggest that multifunctional HA-coated Ti6Al4V implants integrated with curcumin and EGCG could be a promising strategy for osteosarcoma inhibition and osteoblast cell growth while preventing infection.

Multi-length scale strengthening and cytocompatibility of ultra high molecular weight polyethylene bio-composites by functionalized carbon nanotube and hydroxyapatite reinforcement.

The mechanical properties, such as hardness and elastic modulus, of ultra-high molecular weight polyethylene (UHMWPE) composites for acetabular cup liner are improved by adding hydroxyapatite (HAp) and carbon nanotubes (CNT). However, the weak adhesion of HAp (H) and CNT (C) with UHMWPE (U) limits the enhancement of mechanical properties. Thus, the surface of these reinforcements is silane-treated to improve the adhesion with polymer via Si-O and C=O bonds, as evidenced from spectroscopy techniques. An increased dispersion and interfacial adhesion of functionalized HAp (fH) and CNT (fC) with the polymer matrix is confirmed by nearly two-fold increased reinforcement fraction (Rf: 0.55) of U-10 wt% fHAp-2 wt.% fCNT (U10fH2fC) in comparison to U-10 wt% HAp-2 wt.% CNT (U10H2C). Additionally, Voronoi Tessellation (VT) on SEM micrographs of U10H2C and U10fH2fC revealed the dispersion of functionalized CNTs in U10fH2fC with a center-to-center distance of 0.076 µm, which is 74% higher for unfunctionalized CNT in U10H2C. The multilength scale strengthening of the UHMWPE matrix is confirmed from atomic level modification via functionalization of fillers which effectively adhered to the polymer chain on a micro-scale level. A uniform distribution of CNTs rendered increased crystallinity (+28%) of U10fH2fC, which in turn resulted in significant improvement in bulk mechanical properties (18%, 49%, and 12% increased hardness (148.1 MPa), elastic modulus (3.51 GPa) and tensile elastic modulus (219.8 MPa), respectively) in comparison to that of U10H2C. Functionalized-HAp/CNT reinforced UHMWPE composites maintained its cytocompatibility in the MTT test and fluorescence microscopy, affirming their potential employment as acetabular cup liners for hip joint arthroplasty.

Effects of Vitamin A (Retinol) Release from Calcium Phosphate Matrices and Porous 3D Printed Scaffolds on Bone Cell Proliferation and Maturation.

Vitamin A is a fat-soluble compound widely known for vision health. Highly variable reports on its effects on bone health have necessitated further research to truly understand its role on bone cell proliferation. Retinol, one bioactive form of vitamin A, is incorporated into synthetic bone graft scaffolds for low load-bearing clinical bone treatment. The objective of this work is to understand the effects of retinol on osteoblast and osteoclast cells when embedded within calcium phosphate matrices, including interconnected porous 3D printed tricalcium phosphate scaffolds. Results show that hydrophobic retinol can be released from bone scaffolds when a combination of biodegradable polymers, polycaprolactone and polyethylene glycol, are employed as drug carriers. The release of retinol in vitro can support a 20 ± 1% increase in osteoblast (bone-forming) cell proliferation with proper cell adhesion and filopodial extensions. Osteoclast cell morphology is necrosed and torn with a reduction in proliferation at approximately 6 ± 1% when retinol is present. In addition, inhibition of osteoclastic resorption pit bays is noted using scanning electron microscopy. With the scaffolds' round pore interconnectivity facilitating retinol release, this system can provide an alternative to traditional bone grafts while additionally supporting bone healing through enhanced osteoblast cell proliferation and inhibition of osteoclast resorption activity.