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.

Current Advances in Stimuli-Responsive Hydrogels as Smart Drug Delivery Carriers.

In recent years, significant advancements in the field of advanced materials and hydrogel engineering have enabled the design and fabrication of smart hydrogels and nanogels that exhibit sensitivity to specific signals or pathological conditions, leading to a wide range of applications in drug delivery and disease treatment. This comprehensive review aims to provide an in-depth analysis of the stimuli-responsive principles exhibited by smart hydrogels in response to various triggers, such as pH levels, temperature fluctuations, light exposure, redox conditions, or the presence of specific biomolecules. The functionality and performance characteristics of these hydrogels are highly influenced by both their constituent components and fabrication processes. Key design principles, their applications in disease treatments, challenges, and future prospects were also discussed. Overall, this review aims to contribute to the current understanding of gel-based drug delivery systems and stimulate further research in this rapidly evolving field.

Bisphosphonate conjugation enhances the bone-specificity of NELL-1-based systemic therapy for spaceflight-induced bone loss in mice.

Microgravity-induced bone loss results in a 1% bone mineral density loss monthly and can be a mission critical factor in long-duration spaceflight. Biomolecular therapies with dual osteogenic and anti-resorptive functions are promising for treating extreme osteoporosis. We previously confirmed that NELL-like molecule-1 (NELL-1) is crucial for bone density maintenance. We further PEGylated NELL-1 (NELL-polyethylene glycol, or NELL-PEG) to increase systemic delivery half-life from 5.5 to 15.5 h. In this study, we used a bio-inert bisphosphonate (BP) moiety to chemically engineer NELL-PEG into BP-NELL-PEG and specifically target bone tissues. We found conjugation with BP improved hydroxyapatite (HA) binding and protein stability of NELL-PEG while preserving NELL-1's osteogenicity in vitro. Furthermore, BP-NELL-PEG showed superior in vivo bone specificity without observable pathology in liver, spleen, lungs, brain, heart, muscles, or ovaries of mice. Finally, we tested BP-NELL-PEG through spaceflight exposure onboard the International Space Station (ISS) at maximal animal capacity (n = 40) in a long-term (9 week) osteoporosis therapeutic study and found that BP-NELL-PEG significantly increased bone formation in flight and ground control mice without obvious adverse health effects. Our results highlight BP-NELL-PEG as a promising therapeutic to mitigate extreme bone loss from long-duration microgravity exposure and musculoskeletal degeneration on Earth, especially when resistance training is not possible due to incapacity (e.g., bone fracture, stroke).

A novel injectable fibromodulin-releasing granular hydrogel for tendon healing and functional recovery.

A crucial component of the musculoskeletal system, the tendon is one of the most commonly injured tissues in the body. In severe cases, the ruptured tendon leads to permanent dysfunction. Although many efforts have been devoted to seeking a safe and efficient treatment for enhancing tendon healing, currently existing treatments have not yet achieved a major clinical improvement. Here, an injectable granular hyaluronic acid (gHA)-hydrogel is engineered to deliver fibromodulin (FMOD)-a bioactive extracellular matrix (ECM) that enhances tenocyte mobility and optimizes the surrounding ECM assembly for tendon healing. The FMOD-releasing granular HA (FMOD/gHA)-hydrogel exhibits unique characteristics that are desired for both patients and health providers, such as permitting a microinvasive application and displaying a burst-to-sustained two-phase release of FMOD, which leads to a prompt FMOD delivery followed by a constant dose-maintaining period. Importantly, the generated FMOD-releasing granular HA hydrogel significantly augmented tendon-healing in a fully-ruptured rat's Achilles tendon model histologically, mechanically, and functionally. Particularly, the breaking strength of the wounded tendon and the gait performance of treated rats returns to the same normal level as the healthy controls. In summary, a novel effective FMOD/gHA-hydrogel is developed in response to the urgent demand for promoting tendon healing.

Soft strain-insensitive bioelectronics featuring brittle materials.

Advancing electronics to interact with tissue necessitates meeting material constraints in electrochemical, electrical, and mechanical domains simultaneously. Clinical bioelectrodes with established electrochemical functionalities are rigid and mechanically mismatched with tissue. Whereas conductive materials with tissue-like softness and stretchability are demonstrated, when applied to electrochemically probe tissue, their performance is distorted by strain and corrosion. We devise a layered architectural composite design that couples strain-induced cracked films with a strain-isolated out-of-plane conductive pathway and in-plane nanowire networks to eliminate strain effects on device electrochemical performance. Accordingly, we developed a library of stretchable, highly conductive, and strain-insensitive bioelectrodes featuring clinically established brittle interfacial materials (iridium-oxide, gold, platinum, and carbon). We paired these bioelectrodes with different electrochemical probing methods (amperometry, voltammetry, and potentiometry) and demonstrated strain-insensitive sensing of multiple biomarkers and in vivo neuromodulation.

Degradation of hydrogel beads for the detection of serum bicarbonate levels for the diagnosis of metabolic alkalosis at the point of care.

In this work, we present a novel point-of-care hydrogel-based diagnostic device for the rapid detection of elevated bicarbonate levels in serum for the diagnosis of mild to severe cases of metabolic alkalosis. Our system consists of hydrogel beads composed of calcium alginate and the nonionic polymer dextran. This assay utilizes the reaction of sodium bicarbonate and citric acid to produce citrate, a metal chelator capable of competitively binding to calcium cations in the gel matrix to trigger hydrogel degradation. This results in successful detection of elevated bicarbonate concentrations in less than one hour. Specifically, critically high bicarbonate concentrations of 50, 45, and 40 mmol L-1 in human serum were detected in as little as 10, 15, and 20 min, respectively. To demonstrate the assay's feasibility for use in resource-limited settings, we developed a simple electronic device that achieved similar results and could be used by untrained individuals with no lab equipment and minimal power. To our knowledge, this is the first demonstration of the use of nonionic polymers to synthesize and improve the morphology of calcium alginate hydrogel beads using a simple processing method that involves minimal labor and equipment. The simplified bead synthesis protocol combined with the user-friendly device allows for the rapid detection of metabolic alkalosis at the point of care.

Application of the aqueous two-phase system and nanozyme signal enhancement for the improved detection of Plasmodium lactate dehydrogenase in serum.

Malaria is an infectious disease that can cause severe sickness and death if not diagnosed and treated in a timely manner. The current gold standard technique for malaria diagnosis is microscopy, which requires a dedicated laboratory setting and trained personnel and can have a long time to result. These requirements can be alleviated using paper-based diagnostic devices that enable rapid and inexpensive diagnosis at the point of care, which can allow patients to receive treatment before their symptoms progress when used for early detection of diseases. The lateral-flow immunoassay (LFA) is one such device, but currently available LFAs are susceptible to false negative results caused by low parasite density. To improve sensitivity and detection, we utilized the aqueous two-phase system (ATPS) to concentrate and purify the sample, and nanozyme signal enhancement to increase the intensity of the visible signal on the test strip. We were able to achieve a limit of detection (LOD) of 0.01 ng/mL for the malaria biomarker Plasmodium lactate dehydrogenase (pLDH) in human serum using a multi-step assay combining the LFA format with the ATPS and nanozyme signal enhancement.

Combination of the lateral-flow immunoassay with multicolor gold nanorod etching for the semi-quantitative detection of digoxin.

We are the first to combine the lateral-flow immunoassay (LFA) with gold nanorod (GNR) etching to achieve a multicolor readout where the color produced was correlated with digoxin concentrations in human serum in the relevant range for therapeutic drug monitoring of 0.5-3.0 ng mL-1.

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.

On-demand nanozyme signal enhancement at the push of a button for the improved detection of SARS-CoV-2 nucleocapsid protein in serum.

We developed an innovative 3D printed casing that incorporates a lateral-flow immunoassay, dehydrated signal enhancement reagents, and a sealed buffer chamber. With only the push of a button for signal enhancement, our device detected the SARS-CoV-2 N-protein in 40 min at concentrations as low as 0.1 ng mL-1 in undiluted serum.

Trb3 controls mesenchymal stem cell lineage fate and enhances bone regeneration by scaffold-mediated local gene delivery.

Aberrant lineage commitment of mesenchymal stem cells (MSCs) in marrow contributes to abnormal bone formation due to reduced osteogenic and increased adipogenic potency. While several major transcriptional factors associated with lineage differentiation have been found during the last few decades, the molecular switch for MSC fate determination and its role in skeletal regeneration remains largely unknown, limiting creation of effective therapeutic approaches. Tribbles homolog 3 (Trb3), a member of tribbles family pseudokinases, is known to exert diverse roles in cellular differentiation. Here, we investigated the reciprocal role of Trb3 in the regulation of osteogenic and adipogenic differentiation of MSCs in the context of bone formation, and examined the mechanisms by which Trb3 controls the adipo-osteogenic balance. Trb3 promoted osteoblastic commitment of MSCs at the expense of adipocyte differentiation. Mechanistically, Trb3 regulated cell-fate choice of MSCs through BMP/Smad and Wnt/ß-catenin signals. Importantly, in vivo local delivery of Trb3 using a novel gelatin-conjugated caffeic acid-coated apatite/PLGA (GelCA-PLGA) scaffold stimulated robust bone regeneration and inhibited fat-filled cyst formation in rodent non-healing mandibular defect models. These findings demonstrate Trb3-based therapeutic strategies that favor osteoblastogenesis over adipogenesis for improved skeletal regeneration and future treatment of bone-loss disease. The distinctive approach implementing a scaffold-mediated local gene transfer may further broaden the translational use of targeting specific therapeutic gene related to lineage commitment for clinical bone treatment.

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.

Changes in mechanical properties, surface morphology, structure, and composition of Invisalign material in the oral environment.

INTRODUCTION: The mechanical properties of Invisalign material have rarely been explored because of the inaccessibility of the patent-protected raw material. The purpose of this study was to systematically evaluate the Invisalign thermoformed aligner material before and after clinical application, including mechanical properties, surface morphology, internal structure, and chemical composition changes. METHODS: Twenty sets of "as-received" (0-week) and retrieved (2-week; worn for 2 weeks, 20 ± 2 hours per day) Invisalign aligners were randomly collected from 4 different patients. Tensile tests, stress relaxation, and creep tests were carried out with a dynamic mechanical analyzer to characterize the changes in the mechanical properties of this material, Fourier transform infrared spectroscopy was used to capture the molecular changes on the surface of these aligners, scanning electron microscopy and transmission electron microscopy were used to observe the changes in surface morphology and internal structure, and scanning transmission electron microscopy-energy dispersive x-ray analysis was used to detect any changes in the chemical composition of this material before and after clinical application. RESULTS: The elastic modulus of 0-week and 2-week samples were 842 ± 63 MPa and 806 ± 19 MPa, respectively, with no significant difference. In addition, the relative stress after stress relaxation of 2 hours was 19.89 ± 2.25% and 15.91 ± 6.04% for 0-week and 2-week groups, respectively, with no significant difference. Scanning electron microscopy observations showed voids and signs of delamination on the surface of the 2-week samples, and scanning transmission electron microscopy-energy dispersive x-ray analysis indicated the possible release of trace elements during clinical use, such as aluminum. Results of Fourier transform infrared spectroscopy analysis, and transmission electron microscopy observations were quite stable, indicating that the molecular structure on the surface and the internal structure of this material were relatively stable under the oral environment. CONCLUSIONS: The surface morphology showed some defects after the clinical use of 2 weeks; however, there was no significant difference in mechanical properties. Trace elements may release out during clinical use and may pose a specific danger to allergic patients.

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.