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.

Curcumin and Vitamin C dual release from Hydroxyapatite coated Ti6Al4V discs enhances in vitro biological properties.

Titanium alloys are widely used as implant materials due to their biocompatibility and superior mechanical properties for high-load-bearing applications. However, one of the major challenges is their inferior bioactivity and osseoconductivity. Hydroxyapatite is widely used as an alternative material for bone implants due to its compositional similarity to natural bone. In this study, hydroxyapatite is coated on Ti6Al4V discs to enhance its bioactivity. The coated discs are drop-casted with curcumin in the lower layer and vitamin C in the upper layer. This study aims to evaluate the effects of this dual drug delivery system on osteoblast cell proliferation, inhibition of osteoclastogenesis, chemo-preventive and infection control properties. The coating strength obtained is 22 ± 2 MPa. The release from the dual delivery system shows a 1.5-fold increase in osteoblast cell viability, a 1.5-fold reduction in osteoclast cell differentiation, a 2-fold decrease in osteosarcoma growth. The release of curcumin demonstrates a 94% antibacterial efficacy, while the release of vitamin C exhibits an efficacy of 98.6% aganist Staphylococcus aureus. This multifunctional system can be used as a potential implant for load-bearing applications.

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.

Ginger extract loaded Fe2O3/MgO-doped hydroxyapatite: Evaluation of biological properties for bone-tissue engineering.

Since antiquity, the medicinal properties of naturally sourced biomolecules such as ginger (Zingiber officinale) extract are documented in the traditional Indian and Chinese medical systems. However, limited work is performed to assess the potential of ginger extracts for bone-tissue engineering. Our work demonstrates the direct incorporation of ginger extract on iron oxide-magnesium oxide (Fe2O3 and MgO) co-doped hydroxyapatite (HA) for enhancement in the biological properties. The addition of Fe2O3 and MgO co-doping system and ginger extract with HA increases the osteoblast viability up to ~ 1.4 times at day 11. The presence of ginger extract leads to up to ~ 9 times MG-63 cell viability reduction. The co-doping does not adversely affect the release of ginger extract from the graft surface in the biological medium at pH 7.4 for up to 28 days. Assessment of antibacterial efficacy according to the modified ISO 22196: 2011 standard method indicates that the combined effects of Fe2O3, MgO, and ginger extract lead to ~ 82 % more bacterial cell reduction, compared to the control HA against S. aureus. These ginger extract-loaded artificial bone grafts with enhanced biological properties may be utilized as a localized site-specific delivery vehicle for various bone tissue engineering applications.

Extrusion 3D-printed tricalcium phosphate-polycaprolactone biocomposites for quercetin-KCl delivery in bone tissue engineering.

Critical-sized bone defects pose a significant challenge in advanced healthcare due to limited bone tissue regenerative capacity. The complex interplay of numerous overlapping variables hinders the development of multifunctional biocomposites. Phytochemicals show promise in promoting bone growth, but their dose-dependent nature and physicochemical properties halt clinical use. To develop a comprehensive solution, a 3D-printed (3DP) extrusion-based tricalcium phosphate-polycaprolactone (TCP-PCL) scaffold is augmented with quercetin and potassium chloride (KCl). This composite material demonstrates a compressive strength of 30 MPa showing promising stability for low load-bearing applications. Quercetin release from the scaffold follows a biphasic pattern that persists for up to 28 days, driven via diffusion-mediated kinetics. The incorporation of KCl allows for tunable degradation rates of scaffolds and prevents the initial rapid release. Functionalization of scaffolds facilitates the attachment and proliferation of human fetal osteoblasts (hfOB), resulting in a 2.1-fold increase in cell viability. Treated scaffolds exhibit a 3-fold reduction in osteosarcoma (MG-63) cell viability as compared to untreated substrates. Ruptured cell morphology and decreased mitochondrial membrane potential indicate the antitumorigenic potential. Scaffolds loaded with quercetin and quercetin-KCl (Q-KCl) demonstrate 76% and 89% reduction in bacterial colonies of Staphylococcus aureus, respectively. This study provides valuable insights as a promising strategy for bone tissue engineering (BTE) in orthopedic repair.

Vitamin D3 Release from MgO Doped 3D Printed TCP Scaffolds for Bone Regeneration.

Regenerating bone tissue in critical-sized craniofacial bone defects remains challenging and requires the implementation of innovative bone implants with early stage osteogenesis and blood vessel formation. Vitamin D3 is incorporated into MgO-doped 3D-printed scaffolds for defect-specific and patient-specific implants in low load-bearing areas. This novel bone implant also promotes early stage osteogenesis and blood vessel development. Our results show that vitamin D3-loaded MgO-doped 3D-printed scaffolds enhance osteoblast cell proliferation 1.3-fold after being cultured for 7 days. Coculture studies on osteoblasts derived from human mesenchymal stem cells (hMSCs) and osteoclasts derived from monocytes show the upregulation of genes related to osteoblastogenesis and the downregulation of RANK-L, which is essential for osteoclastogenesis. Release of vitamin D3 also inhibits osteoclast differentiation by 1.9-fold after a 21-day culture. After 6 weeks, vitamin D3 release from MgO-doped 3D-printed scaffolds enhances the new bone formation, mineralization, and angiogenic potential. The multifunctional 3D-printed scaffolds can improve early stage osteogenesis and blood vessel formation in craniofacial bone defects.

Evaluating the in vitro wettability and coefficient of friction of a novel and contemporary reusable silicone hydrogel contact lens materials using an in vitro blink model.

PURPOSE: To evaluate the in vitro wettability and coefficient of friction of a novel amphiphilic polymeric surfactant (APS), poly(oxyethylene)-co-poly(oxybutylene) (PEO-PBO) releasing silicone hydrogel (SiHy) contact lens material (serafilcon A), compared to other reusable SiHy lens materials. METHODS: The release of fluorescently-labelled nitrobenzoxadiazole (NBD)-PEO-PBO was evaluated from serafilcon A over 7 days in a vial. The wettability and coefficient of friction of serafilcon A and three contemporary SiHy contact lens materials (senofilcon A; samfilcon A; comfilcon A) were evaluated using an in vitro blink model over their recommended wearing period; t = 0, 1, 7, 14 days for all lens types and t = 30 days for samfilcon A and comfilcon A (n = 4). Sessile drop contact angles were determined and in vitro non-invasive keratographic break-up time (NIKBUT) measurements were assessed on a blink model via the OCULUS Keratograph 5 M. The coefficient of friction was measured using a nano tribometer. RESULTS: The relative fluorescence of NBD-PEO-PBO decreased in serafilcon A by approximately 18 % after 7 days. The amount of NBD-PEO-PBO released on day 7 was 50 % less than the amount released on day 1 (6.5±1.0 vs 3.4±0.5 µg/lens). The reduction in PEO-PBO in the lens also coincided with an increase in contact angles for serafilcon A after 7 days (p < 0.05), although there were no changes in NIKBUT or coefficient of friction (p > 0.05). The other contact lens materials had stable contact angles and NIKBUT over their recommended wearing period (p > 0.05), with the exception of samfilcon A, which had an increase in contact angle after 14 days as compared to t = 0 (p < 0.05). Senofilcon A and samfilcon A also showed an increase in coefficient of friction at 14 and 30 days, respectively, compared to their blister pack values (p < 0.05). CONCLUSION: The results indicate that serafilcon A gradually depletes its reserve of PEO-PBO over 1 week, but this decrease did not significantly change the lens performance in vitro during this time frame.

Natural medicine delivery from 3D printed bone substitutes.

Unmet medical needs in treating critical-size bone defects have led to the development of numerous innovative bone tissue engineering implants. Although additive manufacturing allows flexible patient-specific treatments by modifying topological properties with various materials, the development of ideal bone implants that aid new tissue regeneration and reduce post-implantation bone disorders has been limited. Natural biomolecules are gaining the attention of the health industry due to their excellent safety profiles, providing equivalent or superior performances when compared to more expensive growth factors and synthetic drugs. Supplementing additive manufacturing with natural biomolecules enables the design of novel multifunctional bone implants that provide controlled biochemical delivery for bone tissue engineering applications. Controlled release of naturally derived biomolecules from a three-dimensional (3D) printed implant may improve implant-host tissue integration, new bone formation, bone healing, and blood vessel growth. The present review introduces us to the current progress and limitations of 3D printed bone implants with drug delivery capabilities, followed by an in-depth discussion on cutting-edge technologies for incorporating natural medicinal compounds embedded within the 3D printed scaffolds or on implant surfaces, highlighting their applications in several pre- and post-implantation bone-related disorders.

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.

Micelle encapsulated curcumin and piperine-laden 3D printed calcium phosphate scaffolds enhance in vitro biological properties.

Limitations in the current clinical management of critical-sized osseous defects have driven the need for multifunctional bone constructs. The ideal bone scaffold should possess advanced microarchitecture, well-defined pore interconnectivity, and supply biological signals, which actively guide and control tissue regeneration while simultaneously preventing post-implantation complications. Here, a natural medicine-based localized drug delivery from 3D printed scaffold is presented, which offers controlled release of curcumin, piperine from nano-sized polymeric micelles, and burst release of antibacterial carvacrol from the coating endowing the scaffold with their distinct, individual biological properties. This functionalized scaffold exhibits improved osteoblast (hFOB) cell attachment, 4-folds higher hFOB proliferation, and 73% increased hFOB differentiation while simultaneously providing cytotoxicity towards osteosarcoma cells with 61% lesser viability compared to control. In vitro, early tube formation (p < 0.001) indicates that the scaffolds can modulate the endothelial cellular network, critical for faster wound healing. The scaffold also exhibits 94% enhanced antibacterial efficacy (p < 0.001) against gram-positive Staphylococcus aureus, the main causative bacteria for osteomyelitis. Together, the multifunctional scaffolds provide controlled delivery of natural biomolecules from the nano-sized micelle-loaded 3D printed matrix for significant improvement in osteoblast proliferation, endothelial formation, osteosarcoma, and bacterial inhibition, guiding better bone regeneration for post-traumatic defect repair.

Garlic extract enhances bioceramic bone scaffolds through upregulating ALP & BGLAP expression in hMSC-monocyte co-culture.

Bone homeostasis is predicated by osteoblast and osteoclast cell cycles where gene expressions are responsible for their differentiation from human mesenchymal stem cells (hMSC) and monocytes, respectively. The pro-osteogenic potential of an hMSC-monocyte co-culture can be measured through complementary DNA (mRNA synthesis) within the nucleus, known as quantitative polymerase chain reaction (qPCR). Through this technique, the effects of garlic extract (allicin) release from calcium phosphate bone scaffolds on gene expression of bone forming and bone remodeling cells was explored. Results show this complex biomaterial system enhances hMSC differentiation through the upregulation of bone-forming proteins. Osteoblastic gene markers alkaline phosphatase (ALP) and osteocalcin (BGLAP), are respectively upregulated by 3-fold and 1.6-fold by day 14. These mature osteoblasts then upregulate the receptor activator of nuclear factor-kB ligand (RANKL) which recruits osteoclast cells, as captured by a nearly 2-fold higher osteoclast expression of tartrate-resistance acid-phosphatase (ACP5). This also activates antagonist osteoprotegerin (OPG) expression in osteoblasts, decreasing osteoclast resorption potential and ACP5 expression by day 21. The pro-osteogenic environment with garlic extract release is further quantified by a 4× increase in phosphatase activity and visibly captured in immunofluorescent tagged confocal images. Also corroborated by enhanced collagen formation in a preliminary in vivo rat distal femur model, this work collectively reveals how garlic extract can enhance bioceramic scaffolds for bone tissue regenerative applications.

Porous metal implants: processing, properties, and challenges.

Porous and functionally graded materials have seen extensive applications in modern biomedical devices-allowing for improved site-specific performance; their appreciable mechanical, corrosive, and biocompatible properties are highly sought after for lightweight and high-strength load-bearing orthopedic and dental implants. Examples of such porous materials are metals, ceramics, and polymers. Although, easy to manufacture and lightweight, porous polymers do not inherently exhibit the required mechanical strength for hard tissue repair or replacement. Alternatively, porous ceramics are brittle and do not possess the required fatigue resistance. On the other hand, porous biocompatible metals have shown tailorable strength, fatigue resistance, and toughness. Thereby, a significant interest in investigating the manufacturing challenges of porous metals has taken place in recent years. Past research has shown that once the advantages of porous metallic structures in the orthopedic implant industry have been realized, their biological and biomechanical compatibility-with the host bone-has been followed up with extensive methodical research. Various manufacturing methods for porous or functionally graded metals are discussed and compared in this review, specifically, how the manufacturing process influences microstructure, graded composition, porosity, biocompatibility, and mechanical properties. Most of the studies discussed in this review are related to porous structures for bone implant applications; however, the understanding of these investigations may also be extended to other devices beyond the biomedical field.

Multifunctional polydopamine - Zn2+-curcumin coated additively manufactured ceramic bone grafts with enhanced biological properties.

The lack of site-specific chemotherapeutic agents after osteosarcoma surgeries often induces severe side effects. We propose the utilization of curcumin as an alternative natural chemo-preventive drug for tumor-specific delivery systems with 3D printed tricalcium phosphate (TCP) based artificial bone grafts. The poor bioavailability and hydrophobic nature of curcumin restrict its clinical use. We have used polydopamine (PDA) coating with Zn2+ functionalization to enhance the curcumin release in the biological medium. The obtained PDA-Zn2+ complex is characterized by X-ray photoelectron spectroscopy (XPS). The presence of PDA-Zn2+ coating leads to ~2 times enhancement in curcumin release. We have computationally predicted and validated the optimized surface composition by a novel multi-objective optimization method. The experimental validation of the predicted compositions indicates that the PDA-Zn2+ coated curcumin immobilized delivery system leads to a ~12 folds decrease in osteosarcoma viability on day 11 as compared to only TCP. The osteoblast viability shows ~1.4 folds enhancement. The designed surface shows the highest ~90 % antibacterial efficacy against gram-positive and gram-negative bacteria. This unique strategy of curcumin delivery with PDA-Zn2+ coating is expected to find application in low-load bearing critical-sized tumor-resection sites.

In vivo and In vitro properties evaluation of curcumin loaded MgO doped 3D printed TCP scaffolds.

The lack of site-specific chemotherapeutic agents to treat bone malignancy throws a significant challenge in the design of a delivery vehicle. The major scientific question posed in this study is, can we utilize curcumin-loaded magnesium oxide (MgO) doped 3D printed tricalcium phosphate (TCP) bone grafts as a localized delivery system that improves early stage in vivo osseointegration and in vitro chemoprevention, antibacterial properties? We have utilized curcumin as an alternative natural chemopreventive agent for bone cancer-specific delivery after direct incorporation on the 3D printed tricalcium phosphate (TCP) bone grafts. The addition of MgO as a dopant to TCP leads to ∼1.3 times enhancement in compressive strength. The designed drug delivery system shows up to ∼22% curcumin release in a physiological pH of 7.4 after 30 days. The presence of curcumin leads to up to ∼8.5 times reduction in osteosarcoma viability. In vitro results indicate that these scaffolds significantly enhance bone-forming osteoblast cells while reducing the bone-resorbing osteoclast cells. The in vivo rat distal femur model surgery followed by histological assessment with H&E, vWF, and Movat pentachrome staining results show that the designed scaffolds lead to new bone formation (up to ∼2.5 times higher than the control) after successful implantation. The presence of MgO and curcumin results in up to ∼71% antibacterial efficacy against osteomyelitis causing S. aureus. These 3D printed osteogenic and chemopreventive scaffolds can be utilized in patient-specific low load-bearing defect sites.

Improving Biocompatibility for Next Generation of Metallic Implants.

The increasing need for joint replacement surgeries, musculoskeletal repairs, and orthodontics worldwide prompts emerging technologies to evolve with healthcare's changing landscape. Metallic orthopaedic materials have a shared application history with the aerospace industry, making them only partly efficient in the biomedical domain. However, suitability of metallic materials in bone tissue replacements and regenerative therapies remains unchallenged due to their superior mechanical properties, eventhough they are not perfectly biocompatible. Therefore, exploring ways to improve biocompatibility is the most critical step toward designing the next generation of metallic biomaterials. This review discusses methods of improving biocompatibility of metals used in biomedical devices using surface modification, bulk modification, and incorporation of biologics. Our investigation spans multiple length scales, from bulk metals to the effect of microporosities, surface nanoarchitecture, and biomolecules such as DNA incorporation for enhanced biological response in metallic materials. We examine recent technologies such as 3D printing in alloy design and storing surface charge on nanoarchitecture surfaces, metal-on-metal, and ceramic-on-metal coatings to present a coherent and comprehensive understanding of the subject. Finally, we consider the advantages and challenges of metallic biomaterials and identify future directions.

In vitro biological evaluation of epigallocatechin gallate (EGCG) release from three-dimensional printed (3DP) calcium phosphate bone scaffolds.

Three-dimensional printed (3DP) tricalcium phosphate (TCP) scaffolds can guide bone regeneration, especially for patient-specific defect repair applications in low-load bearing sites. Epigallocatechin gallate (EGCG), a green tea compound, has gained attention as a safer alternative treatment for bone disorders. The 3DP TCP scaffold is designed for localized EGCG delivery, which can enhance in vitro osteogenic ability, anti-osteoclastogenic activity, vascularization formation, and chemoprevention. In the cocultures of human bone marrow-derived mesenchymal stem cells (hMSCs) and monocytes (THP-1), EGCG release enhances osteogenic differentiation of hMSCs at day 16 compared to the control; this is indicated by a 2.8- and 4.0-fold upregulation of Runt-related transcription factor 2 (Runx2) and bone gamma-carboxyglutamic acid-containing protein (BGLAP), the early and late osteoblast differentiation marker expressions. However, EGCG significantly downregulates the receptor activator of nuclear factor-κB ligand (RANKL) expression by 7.0-fold, indicating that EGCG suppresses RANKL-induced osteoclast maturation. EGCG also stimulates endothelial tube formation at as early as 3 hours when human umbilical vein endothelial cells (HUVECs) grow on Matrigel. It reduces human osteosarcoma MG-63 cell viability by 66% compared to the control at day 11. An in vitro release kinetics study demonstrates that EGCG shows a ∼64% release within a day followed by a sustained release in the physiological environment (pH 7.4) because its phenolic hydroxyl groups are easily deprotonated at physiological pH. These findings contribute to developing a multifunctional scaffold for the treatment of low load-bearing patient-specific bone defects after trauma and tumor excision.

In vivo biocompatibility of SrO and MgO doped brushite cements.

The addition of dopants in biomaterials has emerged as a critical regulator of bone formation and regeneration due to their imminent role in the biological process. The present work evaluated the role of strontium (Sr) and magnesium (Mg) dopants in brushite cement (BrC) on in vivo bone healing performance in a rabbit model. Pure, 1 wt% SrO (Sr-BrC), 1 wt% MgO (Mg-BrC), and a binary composition of 1.0 wt% SrO + 1.0 wt% MgO (Sr + Mg-BrC) BrCs were implanted into critical-sized tibial defects in rabbits for up to 4 months. The in vivo bone healing of three doped and pure BrC samples was examined and compared using sequential radiological examination, histological evaluations, and fluorochrome labeling studies. The results indicated excellent osseous tissue formation for Sr-BrC and Sr + Mg-BrC and moderate bone regeneration for Mg-BrC compared to pure BrC. Our findings indicated that adding small amounts of SrO, MgO, and binary dopants to the BrC can significantly influence new bone formation for bone tissue engineering.

Curcumin and resveratrol delivery from multi-functionalized calcium phosphate scaffold enhances biological properties.

Natural medicinal compounds (NMCs) can assist effectively in treating bone disorders. NMC release kinetics from a ceramic bone tissue engineering scaffold can be tailored. However, inferior physicochemical properties halt their therapeutic applications and need a carrier system for delivery. We developed a multi-functionalized scaffold to understand the effect of curcumin (Cur) and resveratrol (Rsv) on in vitro biological properties. Polycaprolactone (PCL) nanoparticles encapsulated resveratrol in the polymeric matrix. Nanoparticles showed a hydrodynamic diameter of about 180 nm, - 16 mV zeta potential, and up to ~65 % encapsulation efficiency. Scaffolds made of zinc-doped tricalcium phosphate (Zn-TCP) were coated with curcumin followed by either resveratrol (Cur-Rsv) or resveratrol nanoparticles (Cur-Rsv-NP). NMC-loaded scaffolds exhibited a biphasic release pattern over 60 days. Solubility and hydrophobic-hydrophilic interactions affected the NMC release profile. Resveratrol showed rapid release as compared to curcumin. The treated scaffold increased the cell viability of human fetal osteoblast (hFOB) by 1.8-fold as compared to the control. It exhibited a 6-fold increase in cytotoxicity toward osteosarcoma (MG-63) cells as compared to the untreated scaffold. NMCs loaded scaffold effectively inhibited Staphylococcus aureus from colonizing over the scaffold. Zinc doping enhanced osteoblast growth and prevented bacterial colony formation. Such design principle provided a direction for developing multi-functionalized calcium phosphate (CaP) scaffolds against bone diseases for orthopedic applications.

Fabrication and Characterization of an Enzyme-Triggered, Therapeutic-Releasing Hydrogel Bandage Contact Lens Material.

PURPOSE: The purpose of this study was to develop an enzyme-triggered, therapeutic-releasing bandage contact lens material using a unique gelatin methacrylate formulation (GelMA+). METHODS: Two GelMA+ formulations, 20% w/v, and 30% w/v concentrations, were prepared through UV polymerization. The physical properties of the material, including porosity, tensile strain, and swelling ratio, were characterized. The enzymatic degradation of the material was assessed in the presence of matrix metalloproteinase-9 (MMP-9) at concentrations ranging from 0 to 300 µg/mL. Cell viability, cell growth, and cytotoxicity on the GelMA+ gels were evaluated using the AlamarBlueTM assay and the LIVE/DEADTM Viability/Cytotoxicity kit staining with immortalized human corneal epithelial cells over 5 days. For drug release analysis, the 30% w/v gels were loaded with 3 µg of bovine lactoferrin (BLF) as a model drug, and its release was examined over 5 days under various MMP-9 concentrations. RESULTS: The 30% w/v GelMA+ demonstrated higher crosslinking density, increased tensile strength, smaller pore size, and lower swelling ratio (p < 0.05). In contrast, the 20% w/v GelMA+ degraded at a significantly faster rate (p < 0.001), reaching almost complete degradation within 48 h in the presence of 300 µg/mL of MMP-9. No signs of cytotoxic effects were observed in the live/dead staining assay for either concentration after 5 days. However, the 30% w/v GelMA+ exhibited significantly higher cell viability (p < 0.05). The 30% w/v GelMA+ demonstrated sustained release of the BLF over 5 days. The release rate of BLF increased significantly with higher concentrations of MMP-9 (p < 0.001), corresponding to the degradation rate of the gels. DISCUSSION: The release of BLF from GelMA+ gels was driven by a combination of diffusion and degradation of the material by MMP-9 enzymes. This work demonstrated that a GelMA+-based material that releases a therapeutic agent can be triggered by enzymes found in the tear fluid.