Effect of TiC Nanoparticles on a Zn-Al-Cu System for Biodegradable Cardiovascular Stent Applications.

Despite being a weaker metal, zinc has become an increasingly popular candidate for biodegradable implant applications due to its suitable corrosion rate and biocompatibility. Previous studies have experimented with various alloy elements to improve the overall mechanical performance of pure Zn without compromising the corrosion performance and biocompatibility; however, the thermal stability of biodegradable Zn alloys has not been widely studied. In this study, TiC nanoparticles were introduced for the first time to a Zn-Al-Cu system. After hot rolling, TiC nanoparticles were uniformly distributed in the Zn matrix and effectively enabled phase control during solidification. The Zn-Cu phase, which was elongated and sharp in the reference alloy, became globular in the nanocomposite. The strength of the alloy, after introducing TiC nanoparticles, increased by 31% from 259.7 to 340.3 MPa, while its ductility remained high at 49.2% elongation to failure. Fatigue performance also improved greatly by adding TiC nanoparticles, increasing the fatigue limit by 47.6% from 44.7 to 66 MPa. Furthermore, TiC nanoparticles displayed excellent phase control capability during body-temperature aging. Without TiC restriction, Zn-Cu phases evolved into dendritic morphologies, and the Al-rich eutectic grew thicker at grain boundaries. However, both Zn-Cu and Al-rich eutectic phases remained relatively unchanged in shape and size in the nanocomposite. A combination of exceptional tensile properties, improved fatigue performance, better long-term stability with a suitable corrosion rate, and excellent biocompatibility makes this new Zn-Al-Cu-TiC material a promising candidate for biodegradable stents and other biodegradable applications.

Experimental study on novel biodegradable Zn-Fe-Si alloys.

Bioabsorbable metals are increasingly attracting attention for their potential use as materials for degradable implant devices. Zinc (Zn) alloys have shown great promises due to their good biocompatibility and favorable degradation rate. However, it has been difficult to maintain an appropriate balance among strength, ductility, biocompatibility, and corrosion rate for Zn alloys historically. In this study, the microstructure, chemical composition, mechanical properties, biocompatibility, and corrosion rate of a new ternary zinc-iron-silicon (Zn-Fe-Si) alloy system was studied as a novel material for potential biodegradable implant applications. The results demonstrated that the in situ formed Fe-Si intermetallic phases enhanced the mechanical strength of the material while maintaining a favorable ductility. With Fe-Si reinforcements, the microhardness of the Zn alloys was enhanced by up to 43%. The tensile strength was increased by up to 76% while elongation to failure remained above 30%. Indirect cytotoxicity testing showed the Zn-Fe-Si system had good biocompatibility. Immersion testing revealed the corrosion rate of Zn-Fe-Si system was not statistically different from pure Zn. To understand the underlying phase formation mechanism, the reaction process in this ternary system during the processing was also studied via phase evolution and Gibbs free energy analysis. The results suggest the Zn-Fe-Si ternary system is a promising new material for bioabsorbable metallic medical devices.

Functionalizing Fibrin Hydrogels with Thermally Responsive Oligonucleotide Tethers for On-Demand Delivery.

There are a limited number of stimuli-responsive biomaterials that are capable of delivering customizable dosages of a therapeutic at a specific location and time. This is especially true in tissue engineering and regenerative medicine applications, where it may be desirable for the stimuli-responsive biomaterial to also serve as a scaffolding material. Therefore, the purpose of this study was to engineer a traditionally non-stimuli responsive scaffold biomaterial to be thermally responsive so it could be used for on-demand drug delivery applications. Fibrin hydrogels are frequently used for tissue engineering and regenerative medicine applications, and they were functionalized with thermally labile oligonucleotide tethers using peptides from substrates for factor XIII (FXIII). The alpha 2-plasmin inhibitor peptide had the greatest incorporation efficiency out of the FXIII substrate peptides studied, and conjugates of the peptide and oligonucleotide tethers were successfully incorporated into fibrin hydrogels via enzymatic activity. Single-strand complement oligo with either a fluorophore model drug or platelet-derived growth factor-BB (PDGF-BB) could be released on demand via temperature increases. These results demonstrate a strategy that can be used to functionalize traditionally non-stimuli responsive biomaterials suitable for on-demand drug delivery systems (DDS).

Zn-Mg-WC Nanocomposites for Bioresorbable Cardiovascular Stents: Microstructure, Mechanical Properties, Fatigue, Shelf Life, and Corrosion.

Zinc (Zn) and Zn alloys have been studied as potential materials for bioresorbable stents (BRSs) in the last decade due to their favorable biodegradability and biocompatibility. However, most Zn alloys lack the necessary combination of strength, ductility, fatigue resistance, corrosion rate (CR), and thermal stability needed for such applications. In this study, nanoparticles made of tungsten carbide (WC) were successfully incorporated into Zn alloyed with 0.5 wt % magnesium (Mg) and evaluated for their suitability for BRS applications. Specifically, the resulting Zn-0.5Mg-WC nanocomposite's microstructure, mechanical properties, in vitro CR, and thermal stability were evaluated. The Zn-0.5Mg-WC nanocomposite had excellent mechanical strength [ultimate tensile strength (UTS) > 250 MPa], elongation to failure (>30%), and a suitable in vitro CR (∼0.02 mm/y) for this clinical application. Moreover, the Zn-0.5Mg-WC nanocomposite survived 10 million cycles of tensile loading (stress ratio, R = 0.053) when the maximum stress was 80% of the yield stress. Its ductility was also retained during a 90-day thermal stability study, indicating an excellent shelf life. Stent prototypes were fabricated using this composition and were successfully deployed during bench testing without fracture. These results show that the Zn-0.5Mg-WC nanocomposite is a promising material for BRS applications. In vivo studies are underway to validate both biocompatibility, stent function, and degradation.

Binder Jetting of Custom Silicone Powder for Direct Three-Dimensional Printing of Maxillofacial Prostheses.

Recent advances in digital workflow have transformed clinician's ability to offer patient-specific devices for medical and dental applications. However, the digital workflow of patient-specific maxillofacial prostheses (MFP) remains incomplete, and several steps in the manufacturing process are still labor-intensive and are costly in both time and resources. Despite the high demand for direct digital MFP manufacturing, three-dimensional (3D) printing of colored silicone MFP is limited by the processing routes of medical-grade silicones and biocompatible elastomers. In this study, a binder jetting 3D printing process with polyvinyl butyral (PVB)-coated silicone powder was developed for direct 3D printing of MFP. Nanosilica-treated silicone powder was spray dried with PVB by controlling the Ohnesorge number and processing parameters. After printing, the interconnected pores were infused with silicone and hexamethyldisiloxane (HMDS) by pressure-vacuum sequential infiltration to produce the final parts. Particle size, coating composition, surface treatment, and infusion conditions influenced the mechanical properties of the 3D-printed preform, and of the final infiltrated structure. In addition to demonstrating the feasibility of using silicone powder-based 3D printing for MFP, these results can be used to inform the modifications required to accommodate the manufacturing of other biocompatible elastomeric materials.

Novel Zinc / Tungsten Carbide Nanocomposite as Bioabsorbable Implant.

There is a lack of bioabsorbable materials with adequate mechanical strength suitable for implant applications that provide temporary support while tissue integrity is restored, especially for pediatric applications. Bioabsorbable metals have emerged as an attractive choice due to their combination of strength, ductility, and biocompatibility in vivo. Zinc has shown great promise as a bioabsorbable metal, but the weak mechanical properties of pure zinc limit its application as an implant material. This study investigates zinc-tungsten carbide (Zn-WC) nanocomposite as a novel material for bioabsorbable metallic implants. Ultrasound-assisted powder compaction was used to fabricate Zn-WC nanocomposites. This study includes the material characterization of microstructure, microhardness, and degradability. Results showed that tungsten carbide nanoparticles enhanced the mechanical properties of Zn, and maintained the favorable corrosion rate of pure Zn. These results encourage further investigation of Zn-WC nanocomposites for biomedical applications with the ultimate goal of creating safe and efficacious bioabsorbable metallic implants for many clinical applications.

Highly Ductile Zn-2Fe-WC Nanocomposite as Biodegradable Material.

Zinc (Zn) has been widely investigated as a biodegradable metal for orthopedic implants and vascular stents due to its ideal corrosion in vivo and biocompatibility. However, pure Zn lacks adequate mechanical properties for load-bearing applications. Alloying elements, such as iron (Fe), have been shown to improve the strength significantly, but at the cost of compromised ductility and corrosion rate. In this study, tungsten carbide (WC) nanoparticles were incorporated into the Zn-2Fe alloy system for strengthening, microstructure modification, and ductility enhancement. Thermally stable WC nanoparticles modified the intermetallic ζ-FeZn13 interface morphology from faceted to non-faceted. Consequently, WC nanoparticles simultaneously enhance mechanical strength and ductility while maintaining a reasonable corrosion rate. Overall, this novel Zn-Fe-WC nanocomposite could be used as biodegradable material for biomedical applications where pure Zn is inadequate.

Evaluation of a shape memory implant abutment system: An up to 6-month pilot clinical study.

STATEMENT OF PROBLEM: Screw- and cement-based retention mechanisms are used to attach prostheses to dental implants; however, each approach can lead to clinical complications such as crown fracturing or peri-implantitis. A novel abutment and prosthesis retention system has been engineered to achieve the esthetics and retention force of cement-based fixation while maintaining the retrievability of screw-retained restorations. PURPOSE: The purpose of this pilot clinical study was to evaluate the effectiveness of this innovative retention system on posterior tooth restorations. MATERIAL AND METHODS: This clinical study, with up to 6 months of follow-up, included 8 participants with posterior osseointegrated implants who met the eligibility criteria to receive the abutment and shape memory sleeve. Radiographs were used to evaluate crown seating. Crown stability was measured using the Periotest, and occlusal analysis was performed using the Tekscan system and shimstock. Peri-implant health was evaluated by probing, and the plaque and gingival indices were recorded. In addition, patient-reported outcomes were recorded. RESULTS: Minimal differences were observed between baseline and endpoint assessment of the plaque and gingival indices, probing depth, and proximal and occlusal contacts. There were no patient-reported problems or complaints about discomfort. The overall peri-implant health remained unchanged from the baseline evaluations for all participants. Proximal contact around the restoration was present at the baseline and at the conclusion of the study for 7 of the participants. Occlusal contact was observed to be either light (5 participants) or holding (3 participants). In addition, visual inspection of retrieved crowns revealed clean surfaces free of macroparticle ingress, and bacterial accumulation at the coping-abutment interface was not detected. CONCLUSIONS: The safety and efficacy findings of this pilot clinical study suggest that this new shape memory alloy-based retention system may provide a suitable alternative for implant prosthodontics. The retention system allowed for easy prosthesis seating and retrieval.

Treating an edentulous mandible with an implant-supported prosthesis with a shape-memory alloy abutment system.

This clinical report describes a treatment protocol for completely edentulous patients using digital implant planning for an all-on-4 treatment of both the maxilla and mandible as well as the use of a shape-memory alloy retention system to secure a complete-arch restoration to the mandible.

Evaluation of the wear and retention performance of a shape-memory alloy abutment system after 6 months of clinical use.

STATEMENT OF PROBLEM: A nitinol sleeve that uses shape memory to rapidly unlock dental restorations from implant abutments has been developed to allow prosthesis removal for assessment and maintenance, and clinical treatment has been promising. However, objective studies that evaluate the wear and retention performance after short-term clinical use are lacking. PURPOSE: The purpose of this clinical study was to evaluate the wear and retention performance of a shape-memory abutment system after 6 months of clinical use. MATERIAL AND METHODS: Shape-memory alloy sleeves on posterior osseointegrated implants were retrieved after 6 months of clinical use. Scanning electron microscopy (SEM) was used to evaluate the surfaces of the retention sleeve's arms for wear. Uniaxial tensile testing was performed to measure the change in retention force after clinical use. Average retention values of the shape-memory abutment system were compared with previously reported in vitro retention values for definitive and interim cements used in titanium abutment and coping assemblies by using the Welch t test. RESULTS: No evidence of wear, fracture, or chipping was observed during SEM analysis on the shape-memory alloy sleeves. Additionally, no statistically significant difference was found in the median retention force for new (484.5 N) and clinically retrieved (476 N) nitinol sleeve specimens. Compared with a commercially available resin cement, the mean retention force for the control sleeves (480 ±37 N) was higher than that for the freshly cemented specimens (336.3 ±188 N). After 5000 cycles of compressive loads, the mean retention force for cement specimens decreased (209.4 ±83 N), while the clinical sleeves (476 ±50 N) remained unchanged. CONCLUSIONS: According to the results of this study, after 6 months of clinical use, the engaging surfaces of the shape-memory alloy sleeve did not show signs of wear, and the retention force was unchanged.

Preparation of photothermal palmitic acid/cholesterol liposomes.

Indocyanine green (ICG) is the only FDA-approved near-infrared dye and it is currently used clinically for diagnostic applications. However, there is significant interest in using ICG for triggered drug delivery applications and heat ablation therapy. Unfortunately, free ICG has a short half-life in vivo and is rapidly cleared from circulation. Liposomes have been frequently used to improve ICG's stability and overall time of effectiveness in vivo, but they have limited stability due to the susceptibility of phospholipids to hydrolysis and oxidation. In this study, nonphospholipid liposomes were used to encapsulate ICG, and the resulting liposomes were characterized for size, encapsulation efficiency, stability, and photothermal response. Using the thin-film hydration method, an ICG encapsulation efficiency of 54% was achieved, and the liposomes were stable for up to 12 weeks, with detectable levels of encapsulated ICG up to week 4. Additionally, ICG-loaded liposomes were capable of rapidly producing a significant photothermal response upon exposure to near-infrared light, and this photothermal response was able to induce changes in the mechanical properties of thermally responsive hydrogels. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1384-1392, 2019.

Photocurable poly(ethylene glycol) as a bioink for the inkjet 3D pharming of hydrophobic drugs.

Binder jetting and material extrusion are the two most common additive manufacturing techniques used to create pharmaceutical tablets. However, their versatility is limited since the powder component is present throughout the dosage forms fabricated by binder jet 3D printing and material extrusion 3D printing requires high operating temperatures. Conversely, material jetting allows for compositional control at a voxel level and can dispense material at room temperature. Unfortunately, there are a limited number of materials that are both printable and biocompatible. Therefore, the aim of this study was to engineer photocurable bioinks that are suitable for hydrophobic active pharmaceutical ingredients and have rapid gelation times upon visible light exposure. The resulting bioinks were comprised of poly(ethylene glycol) diacrylate (250 Da) as the crosslinkable monomer, Eosin Y as the photoinitiator, and methoxide-poly(ethylene glycol)-amine as the coinitiator. Additionally, poly(ethylene glycol) (200 Da) was added as a plasticizer to modulate the drug release profiles, and Naproxen was used as the model drug due to its high hydrophobicity. Various bioink formulations were dispensed into the bottom half of blank preform tablets - made via direct compression - using a piezoelectric nozzle, photopolymerized, and capped with the top half of the preform tablet to complete the pharmaceutical dosage form. Results from the release studies showed that drug release can be modulated by both the percent of poly(ethylene glycol) diacrylate in the formulation and the light exposure time used to cure the bioinks. These bioinks have the potential to expand the library of materials available for creating pharmaceutical tablets via inkjet printing with personalized drug dosages.

Keratinocyte Migration in a Three-Dimensional In Vitro Wound Healing Model Co-Cultured with Fibroblasts.

BACKGROUND: Because three-dimensional (3D) models more closely mimic native tissues, one of the goals of 3D in vitro tissue models is to aid in the development and toxicity screening of new drug therapies. In this study, a 3D skin wound healing model comprising of a collagen type I construct with fibrin-filled defects was developed. METHODS: Optical imaging was used to measure keratinocyte migration in the presence of fibroblasts over 7 days onto the fibrin-filled defects. Additionally, cell viability and growth of fibroblasts and keratinocytes was measured using the alamarBlue® assay and changes in the mechanical stiffness of the 3D construct was monitored using compressive indentation testing. RESULTS: Keratinocyte migration rate was significantly increased in the presence of fibroblasts with the cells reaching the center of the defect as early as day 3 in the co-culture constructs compared to day 7 for the control keratinocyte monoculture constructs. Additionally, constructs with the greatest rate of keratinocyte migration had reduced cell growth. When fibroblasts were cultured alone in the wound healing construct, there was a 1.3 to 3.4-fold increase in cell growth and a 1.2 to 1.4-fold increase in cell growth for keratinocyte monocultures. However, co-culture constructs exhibited no significant growth over 7 days. Finally, mechanical testing showed that fibroblasts and keratinocytes had varying effects on matrix stiffness with fibroblasts degrading the constructs while keratinocytes increased the construct's stiffness. CONCLUSION: This 3D in vitro wound healing model is a step towards developing a mimetic construct that recapitulates the complex microenvironment of healing wounds and could aid in the early studies of novel therapeutics that promote migration and proliferation of epithelial cells.

Photocurable Bioinks for the 3D Pharming of Combination Therapies.

Combination therapies mediate drug synergy to improve treatment efficacy and convenience, leading to higher levels of compliance. However, there are challenges with their manufacturing as well as reduced flexibility in dosing options. This study reports on the design and characterization of a polypill fabricated through the combination of material jetting and binder jetting for the treatment of hypertension. The drugs lisinopril and spironolactone were loaded into hydrophilic hyaluronic acid and hydrophobic poly(ethylene glycol) (PEG) photocurable bioinks, respectively, and dispensed through a piezoelectric nozzle onto a blank preform tablet composed of two attachable compartments fabricated via binder jetting 3D printing. The bioinks were photopolymerized and their mechanical properties were assessed via Instron testing. Scanning electron microscopy (SEM) was performed to indicate morphological analysis. The polypill was ensembled and drug release analysis was performed. Droplet formation of bioinks loaded with hydrophilic and hydrophobic active pharmaceutical ingredients (APIs) was achieved and subsequently polymerized after a controlled dosage was dispensed onto preform tablet compartments. High-performance liquid chromatography (HPLC) analysis showed sustained release profiles for each of the loaded compounds. This study confirms the potential of material jetting in conjunction with binder jetting techniques (powder-bed 3D printing), for the production of combination therapy oral dosage forms involving both hydrophilic and hydrophobic drugs.

Photocurable Bioink for the Inkjet 3D Pharming of Hydrophilic Drugs.

Novel strategies are required to manufacture customized oral solid dosage forms for personalized medicine applications. 3D Pharming, the direct printing of pharmaceutical tablets, is an attractive strategy, since it allows for the rapid production of solid dosage forms containing custom drug dosages. This study reports on the design and characterization of a biocompatible photocurable pharmaceutical polymer for inkjet 3D printing that is suitable for hydrophilic active pharmaceutical ingredients (API). Specifically, hyaluronic acid was functionalized with norbornene moieties that, in the presence of poly(ethylene) glycol dithiol, Eosin Y as a photoinitiator, and a visible light source, undergoes a rapid step-growth polymerization reaction through thiol-ene chemistry. The engineered bioink was loaded with Ropinirole HCL, dispensed through a piezoelectric nozzle onto a blank preform tablet, and polymerized. Drug release analysis of the tablet resulted in 60% release within 15 min of tablet dissolution. The study confirms the potential of inkjet printing for the rapid production of tablets through the deposition of a photocurable bioink designed for hydrophilic APIs.

Recent advances in light-responsive on-demand drug-delivery systems.

The convergence of wearable sensors and personalized medicine enhance the ability to sense and control the drug composition and dosage, as well as location and timing of administration. To date, numerous stimuli-triggered smart drug-delivery systems have been developed to detect changes in light, pH, temperature, biomolecules, electric field, magnetic field, ultrasound and mechanical forces. This review examines the major advances within the last 5 years for the three most common light-responsive drug delivery-on-demand strategies: photochemical, photoisomerization and photothermal. Examples are highlighted to illustrate progress of each strategy in drug delivery applications, and key limitations are identified to motivate future research to advance this important field.

Mesenchymal stem cell growth on and mechanical properties of fibrin-based biomimetic bone scaffolds.

Using the microenvironment of healing bone tissue as inspiration, this study utilized fibrin hydrogels combined with collagen type I and calcium phosphate ceramics to create a biomimetic bone scaffold. The contribution each component had on the growth of mesenchymal stem cells (hMSC) was assessed, and changes in the scaffold's mechanical properties were measured by indentation testing. The results show cell growth was greatest in scaffolds with lower concentrations of fibrinogen complex and followed a similar trend with the addition of collagen. However, cell growth was greatest in fibrin scaffolds with high concentrations of fibrinogen complex when combined with hydroxyapatite-ß-tricalcium phosphate. The fibrin scaffold's stiffness does not significantly change over time, but the addition of collagen to scaffolds with low concentrations of fibrinogen complex had significant increases in stiffness by day 14. These results demonstrate that hMSC do not rapidly degrade fibrin and fibrin-collagen scaffolds in vitro. The data reported here can aid in the design and fabrication of fibrin-based engineered tissues and cell delivery vehicles that promote hMSC growth and viability as well as meet the mechanical requirements of native tissues. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2945-2953, 2016.

Visible light and near-infrared-responsive chromophores for drug delivery-on-demand applications.

The need for temporal-spatial control over the release of biologically active molecules has motivated efforts to engineer novel drug delivery-on-demand strategies actuated via light irradiation. Many systems, however, have been limited to in vitro proof-of-concept due to biocompatibility issues with the photo-responsive moieties or the light wavelength, intensity, and duration. To overcome these limitations, this paper describes a light actuated drug delivery-on-demand strategy that uses visible and near-infrared (NIR) light and biocompatible chromophores: cardiogreen, methylene blue, and riboflavin. All three chromophores are capable of significant photothermal reaction upon exposure to NIR and visible light, and the amount of temperature change is dependent upon light intensity, wavelength as well as chromophore concentration. Pulsatile release of bovine serum albumin (BSA) from thermally responsive hydrogels was achieved over 4 days. These findings have the potential to translate light-actuated drug delivery-on-demand systems from the bench to clinical applications that require explicit control over the presentation of biologically active molecules.