Oxygen generating scaffolds regenerate critical size bone defects.

Recent innovations in bone tissue engineering have introduced biomaterials that generate oxygen to substitute vasculature. This strategy provides the immediate oxygen required for tissue viability and graft maturation. Here we demonstrate a novel oxygen-generating tissue scaffold with predictable oxygen release kinetics and modular material properties. These hydrogel scaffolds were reinforced with microparticles comprised of emulsified calcium peroxide (CaO2) within polycaprolactone (PCL). The alterations of the assembled materials produced constructs within 5 ± 0.81 kPa to 34 ± 0.9 kPa in mechanical strength. The mass swelling ratios varied between 11% and 25%. Our in vitro and in vivo results revealed consistent tissue viability, metabolic activity, and osteogenic differentiation over two weeks. The optimized in vitro cell culture system remained stable at pH 8-9. The in vivo rodent models demonstrated that these scaffolds support a 70 mm3 bone volume that was comparable to the native bone and yielded over 90% regeneration in critical size cranial defects. Furthermore, the in vivo bone remodeling and vascularization results were validated by tartrate-resistant acid phosphatase (TRAP) and vascular endothelial growth factor (VEGF) staining. The promising results of this work are translatable to a repertoire of regenerative medicine applications including advancement and expansion of bone substitutes and disease models.

Tuning Materials-Binding Peptide Sequences toward Gold- and Silver-Binding Selectivity with Bayesian Optimization.

Peptide sequence engineering can potentially deliver materials-selective binding capabilities, which would be highly attractive in numerous biotic and abiotic nanomaterials applications. However, the number of known materials-selective peptide sequences is small, and identification of new sequences is laborious and haphazard. Previous attempts have sought to use machine learning and other informatics approaches that rely on existing data sets to accelerate the discovery of materials-selective peptides, but too few materials-selective sequences are known to enable reliable prediction. Moreover, this knowledge base is expensive to expand. Here, we combine a comprehensive and integrated experimental and modeling effort and introduce a Bayesian Effective Search for Optimal Sequences (BESOS) approach to address this challenge. Through this combined approach, we significantly expand the data set of Au-selective peptide sequences and identify an additional Ag-selective peptide sequence. Analysis of the binding motifs for the Ag-binders offers a roadmap for future prediction with machine learning, which should guide identification of further Ag-selective sequences. These discoveries will enable wider and more versatile integration of Ag nanoparticles in biological platforms.

Composite Scaffolds from Gelatin and Bone Meal Powder for Tissue Engineering.

Bone tissue engineering offers versatile solutions to broaden clinical options for treating skeletal injuries. However, the variety of robust bone implants and substitutes remains largely uninvestigated. The advancements in hydrogel scaffolds composed of natural polymeric materials and osteoinductive microparticles have shown to be promising solutions in this field. In this study, gelatin methacrylate (GelMA) hydrogels containing bone meal powder (BP) particles were investigated for their osteoinductive capacity. As natural source of the bone mineral, we expect that BP improves the scaffold's ability to induce mineralization. We characterized the physical properties of GelMA hydrogels containing various BP concentrations (0, 0.5, 5, and 50 mg/mL). The in vitro cellular studies revealed enhanced mechanical performance and the potential to promote the differentiation of pre-osteoblast cells. The in vivo studies demonstrated both promising biocompatibility and biodegradation properties. Overall, the biological and physical properties of this biomaterial is tunable based on BP concentration in GelMA scaffolds. The findings of this study offer a new composite scaffold for bone tissue engineering.

Engineering calcium peroxide based oxygen generating scaffolds for tissue survival.

Oxygen supply is essential for the long-term viability and function of tissue engineered constructs in vitro and in vivo. The integration with the host blood supply as the primary source of oxygen to cells requires 4 to 5 weeks in vivo and involves neovascularization stages to support the delivery of oxygenated blood to cells. Consequently, three-dimensional (3D) encapsulated cells during this process are prone to oxygen deprivation, cellular dysfunction, damage, and hypoxia-induced necrosis. Here we demonstrate the use of calcium peroxide (CaO2) and polycaprolactone (PCL), as part of an emerging paradigm of oxygen-generating scaffolds that substitute the host oxygen supply via hydrolytic degradation. The 35-day in vitro study showed predictable oxygen release kinetics that achieved 5% to 29% dissolved oxygen with increasing CaO2 loading. As a biomaterial, the iterations of 0 mg, 40 mg, and 60 mg of CaO2 loaded scaffolds yielded modular mechanical behaviors, ranging from 5-20 kPa in compressive strength. The other controlled physiochemical features included swelling capacities of 22-33% and enzymatic degradation rates of 0.8% to 60% remaining mass. The 3D-encapsulation experiments of NIH/3T3 fibroblasts, L6 rat myoblasts, and primary cardiac fibroblasts in these scaffolds showed enhanced cell survival, proliferation, and function under hypoxia. During continuous oxygen release, the scaffolds maintained a stable tissue culture system between pH 8 to 9. The broad basis of this work supports prospects in the expansion of robust and clinically translatable tissue constructs.

Synthesis and characterization of photocrosslinkable albumin-based hydrogels for biomedical applications.

Protein-based biomaterials are widely used to generate three-dimensional (3D) scaffolds for tissue regeneration as well as compact delivery systems for drugs, genes, and peptides. Specifically, albumin-based biomaterials are of particular interest for their ability to facilitate controlled delivery of drugs and other therapeutic agents. These hydrogels possess non-toxic and non-immunogenic properties that are desired in tissue engineering scaffolds. This work employs a rapid ultraviolet (UV) light induced crosslinking to fabricate bovine serum albumin (BSA) hydrogels. Using four different conditions, the BSA hydrogel properties were modulated based on the extent of glycidyl methacrylate modification in each polymer. The highly tunable mechanical behavior of the material was determined through compression tests which yielded a range of material strengths from 4.4 ± 1.5 to 122 ± 7.4 kPa. Pore size measurements also varied from 7.7 ± 1.7 to 23.5 ± 6.6 µm in the photocrosslinked gels. The physical properties of materials such as swelling and degradation were also characterized. In further evaluation, 3D scaffolds were used in cell encapsulation and in vivo implantation studies. The biocompatibility and degradability of the material demonstrated effective integration with the native tissue environment. These modifiable chemical and mechanical properties allow BSA hydrogels to be fine-tuned to a plethora of biomedical applications including regenerative medicine, in vitro cancer study models, and wound healing approaches.

Hydroxyapatite-Incorporated Composite Gels Improve Mechanical Properties and Bioactivity of Bone Scaffolds.

Reinforcing polymeric scaffolds with micro/nanoparticles improve their mechanical properties and render them bioactive. In this study, hydroxyapatite (HA) is incorporated into 5% (w/v) gelatin methacrylate (GelMA) hydrogels at 1, 5, and 20 mg mL-1 concentrations. The material properties of these composite gels are characterized through swelling, degradation, and compression tests. Using 3D cell encapsulation, the cytocompatibility and osteogenic differentiation of preosteoblasts are evaluated to assess the biological properties of the composite scaffolds. The in vitro assays demonstrate increasing cell proliferation and metabolic activity over the course of 14 d in culture. Furthermore, the scaffolds support osteogenic differentiation of the microencapsulated preosteoblasts. For the in vivo study, the composite scaffolds are subcutaneously implanted in rats for 14 d. The histological staining of the explanted in vivo samples exhibits the functional advantages of the scaffold's biocompatibility, biodegradability, and integration into the existing host tissue. This work demonstrates the enhanced mechanical and biological performance of HA-gelatin composite hydrogels for bone tissue engineering applications.

Identification of Toxicity Effects of Cu2O Materials on C. elegans as a Function of Environmental Ionic Composition.

Previous work has shown that spherical CuO nanomaterials show negative effects on cell and animal physiology. The biological effects of Cu2O materials, which posess unique chemical features compared to CuO nanomaterials and can be synthesized in a similarly large variety of shapes and sizes, are comparatively less studied. Here, we synthesized truncated octahedral Cu2O particles and characterized their structure, stability, and physiological effects in the nematode worm animal model, Caenorhabditis elegans. Cu2O particles were found to be generally stable in aqueous media, although the particles did show signs of oxidation and leaching of Cu2+ within hours in worm growth media. The particles were found to be especially sensitive to inorganic phosphate (PO4 3-) found in standard NGM nematode growth medium. Cu2O particles were observed being taken up into the nematode pharynx and detected in the lumen of the gut. Toxicity experiments revealed that treatment with Cu2O particles caused a significant reduction in animal size and lifespan. These toxic effects resembled treatment with Cu2+, but measurements of Cu leaching, worm size, and long-term behavior experiments show the particles are more toxic than expected from Cu ion leaching alone. These results suggest worm ingestion of intact Cu2O particles enhances their toxicity and behavior effects while particle exposure to environmental phosphate precipitates leached Cu2+ into biounavailable phosphate salts. Interestingly, the worms showed an acute avoidance of bacterial food with Cu2O particles, suggesting that animals can detect chemical features of the particles and/or their breakdown products and actively avoid areas with them. These results will help to understand how specific, chemically-defined particles proposed for use in polluted soil and wastewater remediation affect animal toxicity and behaviors in their natural environment.

Surface Modifications of an Organic Polymer-Based Microwire Platform for Sustained Release of an Anti-Inflammatory Drug.

Brain machine interfaces (BMIs), introduced into the daily lives of individuals with injuries or disorders of the nervous system such as spinal cord injury, stroke, or amyotrophic lateral sclerosis, can improve the quality of life. BMIs rely on the capability of microelectrode arrays to monitor the activity of large populations of neurons. However, maintaining a stable, chronic electrode-tissue interface that can record neuronal activity with a high signal-to-noise ratio is a key challenge that has limited the translation of such technologies. An electrode implant injury leads to a chronic foreign body response that is well-characterized and shown to affect the electrode-tissue interface stability. Several strategies have been applied to modulate the immune response, including the application of immunomodulatory drugs applied both systemically and locally. While the use of passive drug release at the site of injury has been exploited to minimize neuroinflammation, this strategy has all but failed as a bolus of anti-inflammatory drugs is released at predetermined times that are often inconsistent with the ongoing innate inflammatory process. Common strategies do not focus on the proper anchorage of soft hydrogel scaffolds on electrode surfaces, which often results in delamination of the porous network from electrodes. In this study, we developed a microwire platform that features a robust yet soft biocompatible hydrogel coating, enabling long-lasting drug release via formation of drug aggregates and dismantlement of hydrophilic biodegradable three-dimensional polymer networks. Facile surface chemistry is developed to functionalize polyimide-coated electrodes with the covalently anchored porous hydrogel network bearing large numbers of highly biodegradable ester groups. Exponential long-lasting drug release is achieved using such hydrogels. We show that the initial state of dexamethasone (Dex) used to formulate the hydrogel precursor solution plays a cardinal role in engineering hydrophilic networks that enable a sustained and long-lasting release of the anti-inflammatory agent. Furthermore, utilization of a high loading ratio that exceeds the solubility of Dex leads to the encapsulation of Dex aggregates that regulate the release of this anti-inflammatory agent. To validate the anti-inflammatory effect of the hydrogel-functionalized Dex-loaded microwires, an in vivo preliminary study was performed in adult male rats (n = 10) for the acute time points of 48 h and 7 days post implant. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess the mRNA expression of certain inflammatory-related genes. In general, a decrease in fold-change expression was observed for all genes tested for Dex-loaded wires compared with controls (functionalized but no drug). The engineering of hybrid microwires enables a sustained release of the anti-inflammatory agent over extended periods of time, thus paving the way to fabricate neuroprosthetic devices capable of attenuating the foreign body response.

Unconventional Tissue Engineering Materials in Disguise.

Tissue engineering faces a recurring challenge in the transformation of biomaterials into 3D constructs that mimic the biological, chemical, and mechanical features of native tissues. Some of the conventional approaches can be sophisticated and involve extensive material processing and high-cost fabrication procedures. Despite tremendous strides in biomaterials discovery and characterization, the functional and manufacturing limitations have led to the innovation of novel biomimetic techniques that borrow from nature, human-made commodities, and other parts of life to overcome the challenges in tissue engineering and regenerative medicine. This review explores engineering strategies that involve unusual materials for improved functionality, scalability, sustainability, and cost-efficiency. The biomaterials discussed are globally accessible resources and can serve across a wide spectrum of biomedical research areas.

Synthesis and characterization of photocrosslinkable hydrogels from bovine skin gelatin.

Hydrogels that mimic native tissues chemically and structurally have been increasingly sought for a wide variety of tissue engineering applications. Gelatin can be naturally derived from different sources and functionalized to fabricate hydrogels that exhibit high cytocompatibility and favorable biodegradable properties. The amino groups on the gelatin backbone can be substituted by adding varying proportions of methacrylic anhydride (MAA) to create biomimetic hydrogels which can be used as tissue engineering scaffolds. Gelatin from different sources yields hydrogels with distinctive physical, chemical, and biological properties. In this work, gelatin from bovine skin was used to fabricate hydrogels with varying degrees of crosslinking content using 1, 4, 7, and 10 mL MAA. The material properties of these hydrogels were characterized. The cytocompatibility of the gelatin-based hydrogels was studied using L6 rat myoblasts. The hydrogels from bovine skin gelatin exhibit mechanical properties that are conducive for applications which require substrates to propagate cell growth, migration, and proliferation rapidly. These hydrogels exhibit exceptional tunability behavior which makes them useful and applicable to culture different cell types.

Neuroinflammation, oxidative stress, and blood-brain barrier (BBB) disruption in acute Utah electrode array implants and the effect of deferoxamine as an iron chelator on acute foreign body response.

The use of intracortical microelectrode arrays has gained significant attention in being able to help restore function in paralysis patients and study the brain in various neurological disorders. Electrode implantation in the cortex causes vasculature or blood-brain barrier (BBB) disruption and thus elicits a foreign body response (FBR) that results in chronic inflammation and may lead to poor electrode performance. In this study, a comprehensive insight into the acute molecular mechanisms occurring at the Utah electrode array-tissue interface is provided to understand the oxidative stress, neuroinflammation, and neurovascular unit (astrocytes, pericytes, and endothelial cells) disruption that occurs following microelectrode implantation. Quantitative real time polymerase chain reaction (qRT-PCR) was used to quantify the gene expression at acute time-points of 48-hr, 72-hr, and 7-days for factors mediating oxidative stress, inflammation, and BBB disruption in rats implanted with a non-functional 4 × 4 Utah array in the somatosensory cortex. During vascular disruption, free iron released into the brain parenchyma can exacerbate the FBR, leading to oxidative stress and thus further contributing to BBB degradation. To reduce the free iron released into the brain tissue, the effects of an iron chelator, deferoxamine mesylate (DFX), was also evaluated.

Elucidating the influence of materials-binding peptide sequence on Au surface interactions and colloidal stability of Au nanoparticles.

Peptide-mediated synthesis and assembly of nanostructures opens new routes to functional inorganic/organic hybrid materials. However, understanding of the many factors that influence the interaction of biomolecules, specifically peptides, with metal surfaces remains limited. Understanding of the relationship between peptide sequence and resulting binding affinity and configurations would allow predictive design of peptides to achieve desired peptide/metal interface characteristics. Here, we measured the kinetics and thermodynamics of binding on a Au surface for a series of peptide sequences designed to probe specific sequence and context effects. For example, context effects were explored by making the same mutation at different positions in the peptide and by rearranging the peptide sequence without changing the amino acid content. The degree of peptide-surface contact, predicted from advanced molecular simulations of the surface-adsorbed structures, was consistent with the measured binding constants. In simulations, the ensemble of peptide backbone conformations showed little change with point mutations of the anchor residues that dominate interaction with the surface. Peptide-capped Au nanoparticles were produced using each sequence. Comparison of simulations with nanoparticle synthesis results revealed a correlation between the colloidal stability of the Au nanoparticles and the degree of structural disorder in the surface-adsorbed peptide structures for this family of sequences. These findings suggest new directions in the optimization and design of biomolecules for in situ peptide-based nanoparticle growth, binding, and dispersion in aqueous media.

Converting Light Energy to Chemical Energy: A New Catalytic Approach for Sustainable Environmental Remediation.

We report a synthetic approach to form cubic Cu2O/Pd composite structures and demonstrate their use as photocatalytic materials for tandem catalysis. Pd nanoparticles were deposited onto Cu2O cubes, and their tandem catalytic reactivity was studied via the reductive dehalogenation of polychlorinated biphenyls. The Pd content of the materials was gradually increased to examine its influence on particle morphology and catalytic performance. Materials were prepared at different Pd amounts and demonstrated a range of tandem catalytic reactivity. H2 was generated via photocatalytic proton reduction initiated by Cu2O, followed by Pd-catalyzed dehalogenation using in situ generated H2. The results indicate that material morphology and composition and substrate steric effects play important roles in controlling the overall reaction rate. Additionally, analysis of the postreacted materials revealed that a small number of the cubes had become hollow during the photodechlorination reaction. Such findings offer important insights regarding photocatalytic active sites and mechanisms, providing a pathway toward converting light-based energy to chemical energy for sustainable catalytic reactions not typically driven via light.

An uncommon presentation of an uncommon disease: relapsing polychondritis overlap with systemic lupus erythematosus.

Relapsing polychondritis (RP) is a rare rheumatologic disorder in which recurrent episodes of inflammation result in destruction of cartilage of the ears and nose. The joints, eyes, audio-vestibular system, heart valves, respiratory tract, kidneys, and skin can also be involved. Skin involvement is most frequently linked to concomitant myelodysplastic syndrome and has rarely been associated with systemic lupus erythematosus. A 47-year-old woman presented with violaceous, indurated, tender plaques on the bilateral cartilaginous ears with sparing of the lobes, consistent with RP. Further investigations revealed positive ANA and anti-Smith antibody, oral ulcers, a photo-distributed skin eruption, and biopsy-proven lupus nephritis, leading to a second concomitant diagnosis of systemic lupus erythematosus (SLE). The diagnosis of SLE associated with RP was made and the patient was started on oral prednisone and hydroxychloroquine. This is a rare report of SLE associated with RP. It is unclear whether RP occurring in patients with SLE represents another clinical manifestation of SLE or a coexisting disease. However, a significant ANA titer in a patient with RP strongly suggests the presence of an associated autoimmune disorder. If immunologic abnormalities usually found in SLE are detected in patients with RP, it is important to monitor patients for the development of other manifestations of SLE.

Vesicular rash in a newborn girl.

The appearance and pattern of this child's rash led us to suspect a rare diagnosis. The findings of a cutaneous biopsy confirmed it.

Direct Synthetic Control over the Size, Composition, and Photocatalytic Activity of Octahedral Copper Oxide Materials: Correlation Between Surface Structure and Catalytic Functionality.

We report a synthetic approach to form octahedral Cu2O microcrystals with a tunable edge length and demonstrate their use as catalysts for the photodegradation of aromatic organic compounds. In this particular study, the effects of the Cu(2+) and reductant concentrations and stoichiometric ratios were carefully examined to identify their roles in controlling the final material composition and size under sustainable reaction conditions. Varying the ratio and concentrations of Cu(2+) and reductant added during the synthesis determined the final morphology and composition of the structures. Octahedral particles were prepared at selected Cu(2+):glucose ratios that demonstrated a range of photocatalytic reactivity. The results indicate that material composition, surface area, and substrate charge effects play important roles in controlling the overall reaction rate. In addition, analysis of the post-reacted materials revealed photocorrosion was inhibited and that surface etching had preferentially occurred at the particle edges during the reaction, suggesting that the reaction predominately occurred at these interfaces. Such results advance the understanding of how size and composition affect the surface interface and catalytic functionality of materials.

Light-activated tandem catalysis driven by multicomponent nanomaterials.

Transitioning energy-intensive and environmentally intensive processes toward sustainable conditions is necessary in light of the current global condition. To this end, photocatalytic processes represent new approaches for H2 generation; however, their application toward tandem catalytic reactivity remains challenging. Here, we demonstrate that metal oxide materials decorated with noble metal nanoparticles advance visible light photocatalytic activity toward new reactions not typically driven by light. For this, Pd nanoparticles were deposited onto Cu2O cubes to generate a composite structure. Once characterized, their hydrodehalogenation activity was studied via the reductive dechlorination of polychlorinated biphenyls. To this end, tandem catalytic reactivity was observed with H2 generation via H2O reduction at the Cu2O surface, followed by dehalogenation at the Pd using the in situ generated H2. Such results present methods to achieve sustainable catalytic technologies by advancing photocatalytic approaches toward new reaction systems.

Indicator displacement assays for amino acids using Ni-NTA tethered to PAMAM dendrimers on controlled pore glass.

PAMAM dendrimer monolayers, immobilized on glass and modified with Ni(II)-NTA moieties at the termini, show generational dependent responses as histidine selective sensors via indicator displacement assays.