Programming hydrogel adhesion with engineered polymer network topology.

Hydrogel adhesion that can be easily modulated in magnitude, space, and time is desirable in many emerging applications ranging from tissue engineering and soft robotics to wearable devices. In synthetic materials, these complex adhesion behaviors are often achieved individually with mechanisms and apparatus that are difficult to integrate. Here, we report a universal strategy to embody multifaceted adhesion programmability in synthetic hydrogels. By designing the surface network topology of a hydrogel, supramolecular linkages that result in contrasting adhesion behaviors are formed on the hydrogel interface. The incorporation of different topological linkages leads to dynamically tunable adhesion with high-resolution spatial programmability without alteration of bulk mechanics and chemistry. Further, the association of linkages enables stable and tunable adhesion kinetics that can be tailored to suit different applications. We rationalize the physics of polymer chain slippage, rupture, and diffusion at play in the emergence of the programmable behaviors. With the understanding, we design and fabricate various soft devices such as smart wound patches, fluidic channels, drug-eluting devices, and reconfigurable soft robotics. Our study presents a simple and robust platform in which adhesion controllability in multiple aspects can be easily integrated into a single design of a hydrogel network.

Range-separated density functional theory using multiresolution analysis and quantum computing.

Quantum computers are expected to outperform classical computers for specific problems in quantum chemistry. Such calculations remain expensive, but costs can be lowered through the partition of the molecular system. In the present study, partition was achieved with range-separated density functional theory (RS-DFT). The use of RS-DFT reduces both the basis set size and the active space size dependence of the ground state energy in comparison with the use of wave function theory (WFT) alone. The utilization of pair natural orbitals (PNOs) in place of canonical molecular orbitals (MOs) results in more compact qubit Hamiltonians. To test this strategy, a basis-set independent framework, known as multiresolution analysis (MRA), was employed to generate PNOs. Tests were conducted with the variational quantum eigensolver for a number of molecules. The results show that the proposed approach reduces the number of qubits needed to reach a target energy accuracy.

Prediction of sound absorption by a circular orifice termination in a turbulent pipe flow using the Lattice-Boltzmann method.

The Lattice Boltzmann method was used to perform numerical simulations of the sound and turbulent flow inside a standing wave tube terminated by a circular orifice in presence of a forced mean flow. The computational domain comprised a standard virtual impedance tube apparatus in which sound waves were produced by periodic pressure oscillations imposed at one end. An orifice plate was located between the driver and the tube termination. All waves transmitted through the orifice were effectively dissipated by a passively non-reflecting (i.e. anechoic) boundary at the tube termination. A turbulent jet was formed at the discharge of the orifice by the forced mean flow inside the tube. The acoustic impedance and sound absorption coefficient of the orifice plate were calculated from a wave decomposition of the sound field upstream of the orifice. Simulations were carried out for different excitation frequencies, and orifice Mach numbers. Results and trends were in good quantitative agreement with available analytical solutions and experimental data. The Lattice Boltzmann method was found to be an efficient numerical scheme for prediction of sound absorption by realistic three dimensional orifice configurations.

In Vitro Investigation of Vocal Fold Cellular Response to Variations in Hydrogel Porosity and Elasticity.

Tissue regeneration is intricately influenced by the dynamic interplay between the physical attributes of tissue engineering scaffolds and the resulting biological responses. A tunable microporous hydrogel system was engineered using gelatin methacryloyl (GelMA) and polyethylene glycol diacrylate (PEGDA), with polyethylene glycol (PEG) serving as a porogen. Through systematic variation of PEGDA molecular weights, hydrogels with varying mechanical and architectural properties were obtained. The objective of the present study was to elucidate the impact of substrate mechanics and architecture on the immunological and reparative activities of vocal fold tissues. Mechanical characterization of the hydrogels was performed using tensile strength measurements and rheometry. Their morphological properties were investigated using scanning electron microscopy (SEM) and confocal microscopy. A series of biological assays were conducted. Cellular morphology, differentiation, and collagen synthesis of human vocal fold fibroblasts (hVFFs) were evaluated using immunostaining. Fibroblast proliferation was studied using the WST-1 assay, and cell migration was investigated via the Boyden chamber assay. Macrophage polarization and secretions were also examined using immunostaining and ELISA. The results revealed that increasing the molecular weight of PEGDA from 700 Da to 10,000 Da resulted in decreased hydrogel stiffness, from 62.6 to 8.8 kPa, and increased pore dimensions from approximately 64.9 to 137.4 µm. Biological evaluations revealed that hydrogels with a higher stiffness promoted fibroblast proliferation and spreading, albeit with an increased propensity for fibrosis, as indicated by a surge in myofibroblast differentiation and collagen synthesis. In contrast, hydrogels with greater molecular weights had a softer matrix with expanded pores, enhancing cellular migration and promoting an M2 macrophage phenotype conducive to tissue healing. The findings show that the hydrogels formulated with a PEGDA molecular weight of 6000 Da are best among the hydrogels considered for vocal fold repair. The microporous hydrogels could be tuned to serve in other tissue engineering applications.

Rayleigh wave propagation method for the characterization of a thin layer of biomaterials.

An experimental method based on Rayleigh wave propagation was developed for quantifying the frequency-dependent viscoelastic properties of a small volume of expensive biomaterials over a broad frequency range. Synthetic silicone rubber and gelatin materials were fabricated and tested to evaluate the proposed method. Planar harmonic Rayleigh waves at different frequencies, from 80 to 4000 Hz, were launched on the surface of a sample composed of a substrate with known material properties coated with a thin layer of the soft material to be characterized. A transfer function method was used to obtain the complex Rayleigh wavenumber. An inverse wave propagation problem was solved and a complex nonlinear dispersion equation was obtained. The complex shear and elastic moduli of the sample materials were then calculated through the numerical solution of the obtained dispersion equation using the measured wavenumbers. The results were in good agreement with those of a previous independent study. The proposed method was found to be reliable and cost effective for the measurement of viscoelastic properties of a thin layer of expensive biomaterials, such as phonosurgical biomaterials, over a wide frequency range.

Vocal fold vibration measurements using laser Doppler vibrometry.

The objective of this study was to measure the velocity of the superior surface of human vocal folds during phonation using laser Doppler vibrometry (LDV). A custom-made endoscopic laser beam deflection unit was designed and fabricated. An in vivo clinical experimental procedure was developed to simultaneously collect LDV velocity and video from videolaryngoscopy. The velocity along the direction of the laser beam, i.e., the inferior-superior direction, was captured. The velocity was synchronous with electroglottograph and sound level meter data. The vibration energy of the vocal folds was determined to be significant up to a frequency of 3 kHz. Three characteristic vibrational waveforms were identified which may indicate bifurcations between vibrational modes of the mucosal wave. No relationship was found between the velocity amplitude and phonation frequency or sound pressure level. A correlation was found between the peak-to-peak displacement amplitude and phonation frequency. A sparse map of the velocity amplitudes on the vocal fold surface was obtained.

Experimental methods for the characterization of the frequency-dependent viscoelastic properties of soft materials.

A characterization method based on Rayleigh wave propagation was developed for the quantification of the frequency-dependent viscoelastic properties of soft materials at high frequencies; i.e., up to 4 kHz. Planar harmonic surface waves were produced on the surface of silicone rubber samples. The phase and amplitude of the propagating waves were measured at different locations along the propagation direction, which allowed the calculation of the complex Rayleigh wavenumbers at each excitation frequency using a transfer function method. An inverse wave propagation problem was then solved to obtain the complex shear/elastic moduli from the measured wavenumbers. In a separate, related investigation, dynamic indentation tests using atomic force microscopy (AFM) were performed at frequencies up to 300 Hz. No systematic verification study is available for the AFM-based method, which can be used when the dimensions of the test samples are too small for other existing testing methods. The results obtained from the Rayleigh wave propagation and AFM-based indentation methods were compared with those from a well-established method, which involves the generation of standing longitudinal compression waves in rod-shaped test specimens. The results were cross validated and qualitatively confirmed theoretical expectations presented in the literature for the frequency-dependence of polymers.

Unsteady numerical simulation of a round jet with impinging microjets for noise suppression.

The objective of this study was to determine the feasibility of a lattice-Boltzmann method (LBM)-Large Eddy Simulation methodology for the prediction of sound radiation from a round jet-microjet combination. The distinct advantage of LBM over traditional computational fluid dynamics methods is its ease of handling problems with complex geometries. Numerical simulations of an isothermal Mach 0.5, Re(D) = 1 × 10(5) circular jet (D(j) = 0.0508 m) with and without the presence of 18 microjets (D(mj) = 1 mm) were performed. The presence of microjets resulted in a decrease in the axial turbulence intensity and turbulent kinetic energy. The associated decrease in radiated sound pressure level was around 1 dB. The far-field sound was computed using the porous Ffowcs Williams-Hawkings surface integral acoustic method. The trend obtained is in qualitative agreement with experimental observations. The results of this study support the accuracy of LBM based numerical simulations for predictions of the effects of noise suppression devices on the radiated sound power.

Injectable, pore-forming, self-healing, and adhesive hyaluronan hydrogels for soft tissue engineering applications.

Most existing injectable hydrogels are non-porous, thereby lacking a microporous structure to promote cell ingrowth. Also, most hydrogels do not effectively adhere to the host tissue. The present study describes an injectable double network hydrogel formed by combining two hyaluronic acid (HA) derivatives, namely dopamine grafted HA (DAHA) and methacrylated HA (HAMA). These constituents instantly form a physically crosslinked network through Fe3+-dopamine coordination, and confer fast gelation, pore formation, and self-healing properties to the hydrogel. Photocroslinked upon UV exposure, HAMA forms a chemically crosslinked network, thereby improving mechanical and degradation properties. The adhesive properties of this hydrogel are attributed to the presence of dopamine groups, inspired by mussel creatures. Proper modification of HA chains was confirmed by NMR spectroscopy. The physical, mechanical, rheological, and biological properties of the new hydrogels were quantified in wet laboratory conditions. The results revealed that the DAHA/HAMA hydrogel rapidly forms a self-healing microporous adhesive scaffold with a 26.9 µm pore size, 29.4 kPa compressive modulus, and 12.8 kPa adhesion strength in under 6 s. These findings suggest that the new hydrogel is a promising candidate for in situ repair of soft tissues, particularly mechanically dynamic ones such as the vocal folds, cartilage, and dermis.

Airway Resistance and Respiratory Distress in Laryngeal Cancer: A Computational Fluid Dynamics Study.

BACKGROUND: Obstructive upper airway pathologies are a great clinical challenge for the airway surgeon. Protection against acute obstruction is critical, but avoidance of unnecessary tracheostomy must also be considered. Decision-making regarding airway, although supported by some objective findings, is largely guided by subjective experience and training. This investigation aims to study the relationship between clinical respiratory distress and objective measures of airway resistance in laryngeal cancer as determined by computational fluid dynamic (CFD) and morphometric analysis. METHODS: Retrospective CT and clinical data were obtained for series of 20 cases, defined as newly diagnosed laryngeal cancer patients who required admission or urgent airway surgery, and 20 controls. Cases and controls were matched based on T-staging. Image segmentation and morphometric analysis were first performed. Computational models based on the lattice Boltzmann method were then created and used to quantify the continuous mass flow, rigid wall, and constant static pressure inlet boundary conditions. RESULTS: The analysis demonstrated a significant relationship between airway resistance and acute obstruction (OR 1.018, 95% CI 1.001-1.045). Morphometric analysis similarly demonstrated a significant relationship when relating measurements based on the minimum cross-section, but not on length of stenosis. Morphometric measurements also showed significance in predicting CFD results, and their relationship demonstrated that airway pressures increase exponentially below 2.5 mm. Tumor subsite did not show a significant difference, although the glottic subgroup tended to have higher resistances. CONCLUSION: Airway resistance analysis from CFD computation correlated with presence of acute distress requiring emergent management. Morphometric analysis showed a similar correlation, demonstrating a radiologic airway assessment technique on which future risk estimation could be performed. LEVEL OF EVIDENCE: 4 (case-control study) Laryngoscope, 133:2734-2741, 2023.

Functional Analysis of Injectable Substance Treatment on Surgically Injured Rabbit Vocal Folds.

OBJECTIVES: The objective of this study was to evaluate the efficacy of immediate injection treatments of dexamethasone, hyaluronic acid (HA)/gelatin (Ge) hydrogel and glycol-chitosan solution on the phonatory function of rabbit larynges at 42 days after surgical injury of the vocal folds, piloting a novel ex vivo phonatory functional analysis protocol. METHODS: A modified microflap procedure was performed on the left vocal fold of 12 rabbits to induce an acute injury. Animals were randomized into one of four treatment groups with 0.1 mL injections of dexamethasone, HA/Ge hydrogel, glycol-chitosan or saline as control. The left mid vocal fold lamina propria was injected immediately following injury. The right vocal fold served as an uninjured control. Larynges were harvested at Day 42 after injection, then were subjected to airflow-bench evaluation. Acoustic, aerodynamic and laryngeal high-speed videoendoscopy (HSV) analyses were performed. HSV segments of the vibrating vocal folds were rated by three expert laryngologists. Six parameters related to vocal fold vibratory characteristics were evaluated on a Likert scale. RESULTS: The fundamental frequency, one possible surrogate of vocal fold stiffness and scarring, was lower in the dexamethasone and HA/Ge hydrogel treatment groups compared to that of the saline control (411.52±11.63 Hz). The lowest fundamental frequency value was observed in the dexamethasone group (348.79±14.99 Hz). Expert visual ratings of the HSV segments indicated an overall positive outcome in the dexamethasone treatment group, though the impacts were below statistical significance. CONCLUSION: Dexamethasone injections might be used as an adjunctive option for iatrogenic vocal fold scarring. An increased sample size, histological correlate, and experimental method improvements will be needed to confirm this finding. Results suggested a promising use of HSV and acoustic analysis techniques to identify and monitor post-surgical vocal fold repair and scarring, providing a useful tool for future studies of vocal fold scar treatments.

Immunomodulatory Microgels Support Proregenerative Macrophage Activation and Attenuate Fibroblast Collagen Synthesis.

Scars composed of fibrous connective tissues are natural consequences of injury upon incisional wound healing in soft tissues.  Hydrogels that feature a sustained presentation of immunomodulatory cytokines are known to modulate wound healing. However, existing immunomodulatory hydrogels lack interconnected micropores to promote cell ingrowth. Other limitations include invasive delivery procedures and harsh synthesis conditions that are incompatible with drug molecules. Here, hybrid nanocomposite microgels containing interleukin-10 (IL-10) are reported to modulate tissue macrophage phenotype during wound healing. The intercalation of laponite nanoparticles in the polymer network yields microgels with tissue-mimetic elasticity (Young's modulus in the range of 2-6 kPa) and allows the sustained release of IL-10 to promote the differentiation of macrophages toward proregenerative phenotypes. The porous interstitial spaces between microgels promote fibroblast proliferation and fast trafficking (an average speed of ≈14.4 µm h-1 ). The incorporation of hyaluronic acid further enhances macrophage infiltration. The coculture of macrophages and fibroblasts treated with transforming growth factor-beta 1 resulted in a twofold reduction in collagen-I production for microgels releasing IL-10 compared to the IL-10 free group. The new microgels show potential toward regenerative healing by harnessing the antifibrotic behavior of host macrophages.

Injectable, Pore-Forming, Perfusable Double-Network Hydrogels Resilient to Extreme Biomechanical Stimulations.

Biological tissues hinge on blood perfusion and mechanical toughness to function. Injectable hydrogels that possess both high permeability and toughness have profound impacts on regenerative medicine but remain a long-standing challenge. To address this issue, injectable, pore-forming double-network hydrogels are fabricated by orchestrating stepwise gelation and phase separation processes. The interconnected pores of the resulting hydrogels enable direct medium perfusion through organ-sized matrices. The hydrogels are amenable to cell encapsulation and delivery while promoting cell proliferation and spreading. They are also pore insensitive, tough, and fatigue resistant. When tested in biomimetic perfusion bioreactors, the hydrogels maintain physical integrity under prolonged, high-frequency biomechanical stimulations (>6000 000 cycles at 120 Hz). The excellent biomechanical performance suggests the great potential of the new injectable hydrogel technology for repairing mechanically dynamic tissues, such as vocal folds, and other applications, such as tissue engineering, biofabrication, organs-on-chips, drug delivery, and disease modeling.

Freeform Cell-Laden Cryobioprinting for Shelf-Ready Tissue Fabrication and Storage.

One significant drawback of existing bioprinted tissues is their lack of shelf-availability caused by complications in both fabrication and storage. Here, we report a cryobioprinting strategy for simultaneously fabricating and storing cell-laden volumetric tissue constructs through seamlessly combining extrusion bioprinting and cryopreservation. The cryobioprinting performance was investigated by designing, fabricating, and storing cell-laden constructs made of our optimized cryoprotective gelatin-based bioinks using a freezing plate with precisely controllable temperature. The in situ freezing process further promoted the printability of cell-laden hydrogel bioinks to achieve freeform structures otherwise inconvenient with direct extrusion bioprinting. The effects of bioink composition on printability and cell viability were evaluated. The functionality of the method was finally investigated using cell differentiation and chick ex ovo assays. The results confirmed the feasibility and efficacy of cryobioprinting as a single-step method for concurrent tissue biofabrication and storage.

Efficacy of Aerosol Reduction Measures for Dental Aerosol Generating Procedures.

Aerosol particles generated by dental procedures could facilitate the transmission of infectious diseases and contain carcinogen particles. Such particles can penetrate common surgical masks and reach the lungs, leading to increased risk for dental care professionals. However, the risk of inhaling contaminated aerosol and the effectiveness of aerosol reduction measures in dental offices remain unclear. The present study aimed to quantify aerosols produced by drilling and scaling procedures and to evaluate present recommendations for aerosol reduction. The concentration of aerosol particles released from the mock scaling and drilling procedures on dental mannequin were measured using a TSI Optical Particle Sizer (OPS 3330) during 15-min sessions carried out in a single-patient examination room. Using a drilling procedure as the aerosol source, the aerosol reduction performance of two types of high-volume evacuators (HVEs) and a commercial off-the-shelf air purifier was evaluated in a simulated clinical setting. Using either HVEs or the air purifier individually reduced the aerosol accumulated over the course of a 15-minutes drilling procedure at a reduction rate of 94.8 to 97.6%. Using both measures simultaneously raised the reduction rate to 99.6%. The results show that existing HVEs can effectively reduce aerosol concentration generated by a drilling procedure and can be further improved by using an air purifier. Following current regulatory guidelines can ensure a low risk of inhaling contaminated aerosol for dentists, assistants, and patients.

Liquid-infused microstructured bioadhesives halt non-compressible hemorrhage.

Non-compressible hemorrhage is an unmet clinical challenge that accounts for high mortality in trauma. Rapid pressurized blood flows under hemorrhage impair the function and integrity of hemostatic agents and the adhesion of bioadhesive sealants. Here, we report the design and performance of bioinspired microstructured bioadhesives, formed with a macroporous tough xerogel infused with functional liquids. The xerogel can rapidly absorb interfacial fluids such as whole blood and promote blood clotting, while the infused liquids facilitate interfacial bonding, sealing, and antibacterial function. Their synergy enables the bioadhesives to form tough adhesion on ex vivo human and porcine tissues and diverse engineered surfaces without the need for compression, as well as on-demand instant removal and storage stability. We demonstrate a significantly improved hemostatic efficacy and biocompatibility in rats and pigs compared to non-structured counterparts and commercial products. This work opens new avenues for the development of bioadhesives and hemostatic sealants.

Verification of two minimally invasive methods for the estimation of the contact pressure in human vocal folds during phonation.

The contact pressure on the vocal fold surface during high pitch or amplitude voice production is believed to be one major source of phonotrauma. Models for the quantitative estimate of the contact pressure may be valuable for prevention and treatment. Various indirect and minimally invasive approaches have been purported to estimate contact pressure. But the accuracy of these methods has not yet been objectively verified in controlled laboratory settings. In the present study, two indirect approaches for the estimation of the contact pressure were investigated. One is based on a Hertzian impact model, and the other on a finite element model. A probe microphone was used for direct measurements of the contact pressure and verifications of the indirect approaches. A silicone replica of human vocal folds was used as a test bed. Consistent contact pressure estimations were obtained using all three methods. The advantages and disadvantages of each approach for eventual clinical applications are described.

Emerging Technologies in Multi-Material Bioprinting.

Bioprinting, within the emerging field of biofabrication, aims at the fabrication of functional biomimetic constructs. Different 3D bioprinting techniques have been adapted to bioprint cell-laden bioinks. However, single-material bioprinting techniques oftentimes fail to reproduce the complex compositions and diversity of native tissues. Multi-material bioprinting as an emerging approach enables the fabrication of heterogeneous multi-cellular constructs that replicate their host microenvironments better than single-material approaches. Here, bioprinting modalities are reviewed, their being adapted to multi-material bioprinting is discussed, and their advantages and challenges, encompassing both custom-designed and commercially available technologies are analyzed. A perspective of how multi-material bioprinting opens up new opportunities for tissue engineering, tissue model engineering, therapeutics development, and personalized medicine is offered.

Composite Inks for Extrusion Printing of Biological and Biomedical Constructs.

Extrusion-based three-dimensional (3D) printing is an emerging technology for the fabrication of complex structures with various biological and biomedical applications. The method is based on the layer-by-layer construction of the product using a printable ink. The material used as the ink should possess proper rheological properties and desirable performances. Composite materials, which are extensively used in 3D printing applications, can improve the printability and offer superior performances for the printed constructs. Herein, we review composite inks with a focus on composite hydrogels. The properties of different additives including fibers and nanoparticles are discussed. The performances of various composite inks in biological and biomedical systems are delineated through analyzing the synergistic effects between the composite ink components. Different applications, including tissue engineering, tissue model engineering, soft robotics, and four-dimensional printing, are selected to demonstrate how 3D-printable composite inks are exploited to achieve various desired functionality. This review finally presents an outlook of future perspectives on the design of composite inks.

Polymeric Microspheres Containing Human Vocal Fold Fibroblasts for Vocal Fold Regeneration.

OBJECTIVE: Most acellular injectable biomaterials for vocal fold (VF) wound treatment have limited regenerative potential due to their fast enzymatic degradation and limited recruitment of native cells postinjection. The injection of cells as therapeutic treatment often results in apoptosis due to stresses within the needle and the immune response of the host. Degradable microspheres may improve treatment effectiveness by increasing cell residence time, shielding cells during injection, and offering early protection against the immune system response. The objective of the present study was to investigate the potential of human VF fibroblasts encapsulated in polymeric microspheres as an injectable therapeutic treatment in vitro. METHODS: Alginate, alginate-poly-L-lysine, and alginate-chitosan microspheres were fabricated using electrospraying and characterized in terms of biocompatibility, swelling, and mechanical properties as well as cytokine production. RESULTS: Alginate microspheres were found to have the most desirable properties for VF regeneration. They were resistant to mechanical challenges. They were found to have a stiffness similar to that reported for native VF-lamina propria. They were found to be biocompatible and increased the proliferation of fibroblasts. Human VF fibroblasts encapsulated in alginate microspheres induced the production of interleukin (IL)-8 and IL-4 at 24 hours. CONCLUSION: The alginate microspheres fabricated in this study were found to offer potential advantages, as cell delivery tool. This study highlights the importance of combining biomaterials and cells to expedite the wound-healing process through cytokine production. Future work is aimed to further analysis of the wound-healing properties the microspheres. LEVEL OF EVIDENCE: NA Laryngoscope, 131:1828-1834, 2021.