Heterogeneity-induced retraction in viscoelastic fluids following cessation of flow.

Complex fluids including colloidal suspensions, microgels, and entangled wormlike micelles (WLMs) can develop heterogeneous flow regions under imposed steady shear. In some of these systems, the evolution to this flow state from rest is accompanied by flow reversal - when a portion of the fluid moves opposite to the imposed flow direction. Flow reversal was proposed to occur in shear startup when (1) the fluid has significant elasticity, and (2) the flow becomes heterogeneous immediately following the stress overshoot [McCauley et al., J. Rheol., 2023, 67, 661-681]. To verify this hypothesis, a new method is developed for measuring flow heterogeneity. Upon cessation of the imposed flow, elasticity and flow heterogeneity cause retraction of the fluid, which is quantified with particle tracking velocimetry. Flow is stopped at key times during shear startup in two systems: a gel-like WLM that exhibits flow reversal before heterogeneous flow and a viscoelastic, fluid-like WLM that does not. The degree of flow heterogeneity is inferred from the shape and magnitude of velocity profiles measured during retraction. Flow heterogeneity develops earlier in gel-like WLMs - supporting the proposed flow reversal criteria. For comparison, heterogeneous Couette flows described with the upper-convected Maxwell or Germann-Cook-Beris models are analyzed. These theoretical flow problems confirm that stark differences in rheological properties across the flow geometry can cause significant fluid retraction and reproduce key features of the experimentally observed retraction. This new method can be used to extract quantitative information about spatially heterogeneous flows in viscoelastic complex fluids, whether or not flow reversal occurs.

A Pseudo-Surfactant Chemical Permeation Enhancer to Treat Otitis Media via Sustained Transtympanic Delivery of Antibiotics.

Chemical permeation enhancers (CPEs) represent a prevalent and safe strategy to enable noninvasive drug delivery across skin-like biological barriers such as the tympanic membrane (TM). While most existing CPEs interact strongly with the lipid bilayers in the stratum corneum to create defects as diffusion paths, their interactions with the delivery system, such as polymers forming a hydrogel, can compromise gelation, formulation stability, and drug diffusion. To overcome this challenge, differing interactions between CPEs and the hydrogel system are explored, especially those with sodium dodecyl sulfate (SDS), an ionic surfactant and a common CPE, and those with methyl laurate (ML), a nonionic counterpart with a similar length alkyl chain. Notably, the use of ML effectively decouples permeation enhancement from gelation, enabling sustained delivery across TMs to treat acute otitis media (AOM), which is not possible with the use of SDS. Ciprofloxacin and ML are shown to form a pseudo-surfactant that significantly boosts transtympanic permeation. The middle ear ciprofloxacin concentration is increased by 70-fold in vivo in a chinchilla AOM model, yielding superior efficacy and biocompatibility than the previous highest-performing formulation. Beyond improved efficacy and biocompatibility, this single-CPE formulation significantly accelerates its progression toward clinical deployment.

Cosolvent incorporation modulates the thermal and structural response of PNIPAM/silyl methacrylate copolymers.

Polymers functionalized with inorganic silane groups have been used in wide-ranging applications due to the silane reactivity, which enables formation of covalently-crosslinked polymeric structures. Utilizing stimuli-responsive polymers in these hybrid systems can lead to smart and tunable behavior for sensing, drug delivery, and optical coatings. Previously, the thermoresponsive polymer poly(N-isopropyl acrylamide) (PNIPAM) functionalized with 3-(trimethoxysilyl)propyl methacrylate (TMA) demonstrated unique aqueous self-assembly and optical responses following temperature elevation. Here, we investigate how cosolvent addition, particularly ethanol and N,N-dimethyl formamide (DMF), impacts these transition temperatures, optical clouding, and structure formation in NIPAM/TMA copolymers. Versus purely aqueous systems, these solvent mixtures can introduce additional phase transitions and can alter the two-phase region boundaries based on temperature and solvent composition. Interestingly, TMA incorporation strongly alters phase boundaries in the water-rich regime for DMF-containing systems but not for ethanol-containing systems. Cosolvent species and content also alter the aggregation and assembly of NIPAM/TMA copolymers, but these effects depend on polymer architecture. For example, localizing the TMA towards one chain end in 'blocky' domains leads to formation of uniform micelles with narrow dispersities above the cloud point for certain solvent compositions. In contrast, polydisperse aggregates form in random copolymer and PNIPAM homopolymer solutions - the size of which depends on solvent composition. The resulting optical responses and thermoreversibility also depend strongly on cosolvent content and copolymer architecture. Cosolvent incorporation thus increases the versatility of inorganic-functionalized responsive polymers for diverse applications by providing a simple way to tune the structure size and optical response.

Self-Assembly of Unusually Stable Thermotropic Network Phases by Cellobiose-Based Guerbet Glycolipids.

Bicontinuous thermotropic liquid crystal (LC) materials, e.g., double gyroid (DG) phases, have garnered significant attention due to the potential utility of their 3D network structures in wide-ranging applications. However, the utility of these materials is significantly constrained by the lack of robust molecular design rules for shape-filling amphiphiles that spontaneously adopt the saddle curvatures required to access these useful supramolecular assemblies. Toward this aim, we synthesized anomerically pure Guerbet-type glycolipids bearing cellobiose head groups and branched alkyl tails and studied their thermotropic LC self-assembly. Using a combination of differential scanning calorimetry, polarized optical microscopy, and small-angle X-ray scattering, our studies demonstrate that Guerbet cellobiosides exhibit a strong propensity to self-assemble into DG morphologies over wide thermotropic phase windows. The stabilities of these assemblies sensitively depend on the branched alkyl tail structure and the anomeric configuration of the glycolipid in a previously unrecognized manner. Complementary molecular simulations furnish detailed insights into the observed self-assembly characteristics, thus unveiling molecular motifs that foster network phase self-assembly that will enable future designs and applications of network LC materials.

Effect of nanoparticle loading and magnetic field application on the thermodynamic, optical, and rheological behavior of thermoresponsive polymer solutions.

Although processing via external stimuli is a promising technique to tune the structure and properties of polymeric materials, the impact of magnetic fields on phase transitions in thermoresponsive polymer solutions is not well-understood. As nanoparticle (NP) addition is also known to impact these thermodynamic and optical properties, synergistic effects from combining magnetic fields with NP incorporation provide a novel route for tuning material properties. Here, the thermodynamic, optical, and rheological properties of aqueous poly(N-isopropyl acrylamide) (PNIPAM) solutions are examined in the presence of hydrophilic silica NPs and magnetic fields, individually and jointly, via Fourier-transform infrared spectroscopy (FTIR), magneto-turbidimetry, differential scanning calorimetry (DSC), and magneto-rheology. While NPs and magnetic fields both reduce the phase separation energy barrier and lower optical transition temperatures by altering hydrogen bonding (H-bonding), infrared spectra demonstrate that the mechanism by which these changes occur is distinct. Magnetic fields primarily alter solvent polarization while NPs provide PNIPAM-NP H-bonding sites. Combining NP addition with field application uniquely alters the solution environment and results in field-dependent rheological behavior that is unseen in polymer-only solutions. These investigations provide fundamental understanding on the interplay of magnetic fields and NP addition on PNIPAM thermoresponsivity which can be harnessed for increasingly complex stimuli-responsive materials.

Engineering the Structure and Rheological Properties of P407 Hydrogels via Reverse Poloxamer Addition.

Aqueous solutions of poloxamer 407 (P407), a commercially available and nontoxic ABA triblock polymer (PEO-PPO-PEO), undergo a solution-to-gel transition with increasing temperature and are promising candidates for injectable therapeutics. The gel transition temperature, modulus, and structure are all dictated by polymer concentration, preventing independent tuning of these properties. Here, we show that addition of BAB reverse poloxamers (RPs) to P407-based solutions dramatically alters the gelation temperature, modulus, and morphology. Gelation temperature and RP localization within the hydrogel are dictated by RP solubility. Highly soluble RPs increase gelation temperature and incorporate primarily into the micelle corona regions. Alternatively, RPs with low aqueous solubility decrease gelation temperature and associate within the micelle core and core-corona interface. These differences in RP localization have significant implications for the hydrogel modulus and microstructure. The ability to tune gelation temperature, modulus, and structure through RP addition allows for the design of thermoresponsive materials with specific properties that are unobtainable with neat P407-based hydrogels.

Tuning the thermodynamic, optical, and rheological properties of thermoresponsive polymer solutions via silica nanoparticle shape and concentration.

HYPOTHESIS: The shape and quantity of hydrophilic silica nanoparticles (NPs) can be used to tune the microstructure, rheology, and stability of phase-separating polymer solutions. In thermoresponsive polymer systems, silica nanospheres are well-studied whereas anisotropic NPs have little literature precedent. Here, we hypothesize that NP shape and concentration lower the onset of rheological and turbidimetric transitions of aqueous poly(N-isopropyl acrylamide) (PNIPAM) solutions. EXPERIMENTS: Differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), turbidimetry, and oscillatory rheology are utilized to examine interactions between NPs, PNIPAM, and water and to track changes in phase separation and rheological properties due to NP concentration and shape. FINDINGS: NP addition reduces phase separation enthalpy due to PNIPAM-NP hydrogen bonding interactions, the degree to which depends on polymer content. While NP addition minorly impacts thermodynamic and optical properties, rheological transitions and associated rheological properties are dramatically altered with increasing temperature, and depend on NP quantity, shape, and polymer molecular weight. Thus NP content and shape can be used to finely tune transition temperatures and mechanical properties for applications in stimuli-responsive materials.

Effect of chain architecture on the structure, dynamics, and rheology of thermoresponsive poloxamer hydrogels and associated blends.

Poloxamers, ABA triblock polymers composed of a poly(propylene oxide) (PPO) midblock (B) and poly(ethylene oxide) (PEO) endblocks (A), are widely studied for biomedical applications. Aqueous poloxamer 407 (P407; also referred to as F127) undergoes a solution-to-gel transition with increasing temperature, driven by the formation and ordering of micelles onto periodic lattices; however, the gel temperature and resulting modulus has limited tunability. Here, reverse P407 (RP407), a BAB polymer of the same composition and molar mass but the inverted architecture, is synthesized via anionic polymerization. The micellization and gelation temperatures of RP407 are higher than that of P407 and the PPO endblocks allow for intermicelle bridging; however, both single-component solutions favor body-centered cubic (BCC) packings. Further, aqueous RP407 displays a "soft gel" region with interesting rheological behavior, including viscoelastic aging and thermal hysteresis. Combining P407 and RP407 yields solutions with intermediate transition temperatures and alters the size and micelle packing. While the single-component solutions produce BCC packings, the blends form close-packed structures and larger micelles of higher aggregation numbers. Blends of P407 with an analogous AB diblock (E111P32) display similar behavior, whereas RP407/diblock blends form intermediate-sized BCC-packed micelles. These differences in packing and aggregation alter the local environments within the gels, which could have implications for applications such as drug delivery and protein stabilization.

Temperature-controlled dripping-onto-substrate (DoS) extensional rheometry of polymer micelle solutions.

Capillary-driven thinning of a liquid bridge is commonly used to measure the extensional rheology of macromolecular solutions for assessment of material sprayability, printability, and jettability. Methods like dripping-onto-substrate (DoS) rheometry are often preferred to methods like capillary breakup extensional rheometry (CaBER) due to low required sample volume and ability to measure low-viscosity fluids; however, DoS measurements to-date have been limited to ambient temperatures. Here, an environmental control chamber is developed to enable temperature-controlled DoS (TC-DoS) measurements, and the temperature-dependent extensional rheology of a model system of poloxamer 234 (P234) in NaF brine is examined. Spherical P234 micelles at ambient conditions exhibit inertiocapillary (IC) thinning; above the sphere-to-rod transition temperature, the liquid bridge evolves towards viscocapillary (VC) thinning as micelles lengthen and shear viscosity increases. Above 37 °C, wormlike micelle (WLM) formation results in pronounced elastocapillary (EC) thinning, and further WLM growth and entanglement results in three elasticity-dominated flow regimes: EC thinning, beads-on-a-string (BOAS) instability formation, and BOAS thinning. Despite having a substantially larger amphiphile molecular weight and micelle cross-sectional radius than surfactant WLMs, entangled P234 WLMs exhibit similar extensional behavior and achieve comparable maximum Trouton ratios. Comparing DoS measurements of P234 WLMs with prior studies on surfactant WLMs reveals that the maximum Trouton ratio depends on the ratio of shear and extensional relaxation times, a trend undetectable via CaBER due to pre-deformation during the initial step stretch. These findings reveal rich temperature-dependent flow behaviors in polymer micelles and highlight the importance of using a minimally-disruptive method such as TC-DoS when measuring the extensional rheology of microstructured and thermosensitive fluids.

Evaporation-controlled dripping-onto-substrate (DoS) extensional rheology of viscoelastic polymer solutions.

Extensional flow properties of polymer solutions in volatile solvents govern many industrially-relevant coating processes, but existing instrumentation lacks the environment necessary to control evaporation. To mitigate evaporation during dripping-onto-substrate (DoS) extensional rheology measurements, we developed a chamber to enclose the sample in an environment saturated with solvent vapor. We validated the evaporation-controlled DoS device by measuring a model high molecular weight polyethylene oxide (PEO) in various organic solvents both inside and outside of the chamber. Evaporation substantially increased the extensional relaxation time [Formula: see text] for PEO in volatile solvents like dichloromethane and chloroform. PEO/chloroform solutions displayed an over 20-fold increase in [Formula: see text] due to the formation of an evaporation-induced surface film; evaporation studies confirmed surface features and skin formation reminiscent of buckling instabilities commonly observed in drying polymer solutions. Finally, the relaxation times of semi-dilute PEO/chloroform solutions were measured with environmental control, where [Formula: see text] scaled with concentration by the exponent [Formula: see text]. These measurements validate the evaporation-controlled DoS environment, and confirm that chloroform is a good solvent for PEO, with a Flory exponent of [Formula: see text]. Our results are the first to control evaporation during DoS extensional rheology, and provide guidelines establishing when environmental control is necessary to obtain accurate rheological parameters.

Impact of small molecule and reverse poloxamer addition on the micellization and gelation mechanisms of poloxamer hydrogels.

Poloxamer 407 (P407) is widely used for targeted drug-delivery because it exhibits thermoresponsive gelation behavior near body temperature, stemming from a disorder-to-order transition. Hydrophobic small molecules can be encapsulated within P407; however, these additives often negatively impact the rheological properties and lower the gelation temperatures of the hydrogels, limiting their clinical utility. Here we investigate the impact of adding two BAB reverse poloxamers (RPs), 25R4 and 31R1, on the thermal transitions, rheological properties, and assembled structures of P407 both with and without incorporated small molecules. By employing a combination of differential scanning calorimetry (DSC), rheology, and small-angle x-ray scattering (SAXS), we determine distinct mechanisms for RP incorporation. While 25R4 addition promotes inter-micelle bridge formation, the highly hydrophobic 31R1 co-micellizes with P407. Small molecule addition lowers thermal transition temperatures and increases the micelle size, while RP addition mitigates the decreases in modulus traditionally associated with small molecule incorporation. This fundamental understanding yields new strategies for tuning the mechanical and structural properties of the hydrogels, enabling design of drug-loaded formulations with ideal thermal transitions for a range of clinical applications.

Role of chain architecture in the solution phase assembly and thermoreversibility of aqueous PNIPAM/silyl methacrylate copolymers.

Stimuli-responsive polymers functionalized with reactive inorganic groups enable creation of macromolecular structures such as hydrogels, micelles, and coatings that demonstrate smart behavior. Prior studies using poly(N-isopropyl acrylamide-co-3-(trimethoxysilyl)propyl methacrylate) (P(NIPAM-co-TMA)) have stabilized micelles and produced functional nanoscale coatings; however, such systems show limited responsiveness over multiple thermal cycles. Here, polymer architecture and TMA content are connected to the aqueous self-assembly, optical response, and thermo-reversibility of two distinct types of PNIPAM/TMA copolymers: random P(NIPAM-co-TMA), and a 'blocky-functionalized' copolymer where TMA is localized to one portion of the chain, P(NIPAM-b-NIPAM-co-TMA). Aqueous solution behavior characterized via cloud point testing (CPT), dynamic light scattering (DLS), and variable-temperature nuclear magnetic resonance spectroscopy (NMR) demonstrates that thermoresponsiveness and thermoreversibility over multiple cycles is a strong function of polymer configuration and TMA content. Despite low TMA content (≤2% mol), blocky-functionalized copolymers assemble into small, well-ordered structures above the cloud point that lead to distinct transmittance behaviors and stimuli-responsiveness over multiple cycles. Conversely, random copolymers form disordered aggregates at elevated temperatures, and only exhibit thermoreversibility at negligible TMA fractions (0.5% mol); higher TMA content leads to irreversible structure formation. This understanding of the architectural and assembly effects on the thermal cyclability of aqueous PNIPAM-co-TMA can be used to improve the scalability of responsive polymer applications requiring thermoreversible behavior, including sensing, separations, and functional coatings.

Small-volume extensional rheology of concentrated protein and protein-excipient solutions.

Limited studies measure extensional rheology in protein solutions due to volume constraints and measurement challenges. We developed a small-volume, dripping-onto-substrate (DoS) extensional rheology device to measure the capillary thinning of protein and protein-excipient solutions via DoS for the first time. Ovalbumin (OVA) was used as a model system, examined via DoS both with and without excipient poloxamer 188 (P188). Water and dilute OVA break apart rapidly and demonstrate inertiocapillary (IC) thinning behavior, where longer breakup times in OVA can be attributed to lower surface tension. Further increasing OVA content leads to longer breakup times and deviations from IC thinning at the start of thinning, however, no evidence of elastic behavior is observed. P188 more effectively lowers the droplet surface tension than OVA, transitioning from IC behavior in dilute solution to weakly elastic behavior at higher concentrations. Combined protein/excipient formulations act synergistically at low concentrations, where breakup times are identical to those of the individual components despite the higher total concentration. However concentrated protein/excipient formulations exhibit elasticity, where extensional rheology parameters depend on P188 content and total concentration. These findings imply that excipients intended to stabilize proteins in shear flow can cause undesirable behavior in extensional flows like injection.

Criteria Governing Rod Formation and Growth in Nonionic Polymer Micelles.

Self-assembled wormlike micelles (WLMs) are widely studied in small-molecule surfactants due to their unique ability to break and recombine; however, less is known about the structure and dynamics of nonionic polymer WLMs. Here, solutions of seven triblock poloxamers, composed of poly(propylene oxide) (PPO) midblocks and poly(ethylene oxide) (PEO) end blocks, are comprehensively examined to determine the role of poloxamer composition, temperature, and inorganic salt type and concentration on rod formation and subsequent elongation into WLMs. Phase separation and sphere-to-rod transition temperatures were quantified via cloud point measurements and shear rheology, respectively, and corroborated with small-angle neutron scattering (SANS). The local microstructure of resulting rodlike micelles is remarkably similar across poloxamer type and sodium fluoride (NaF) or sodium chloride (NaCl) content. Salt addition reduces transition temperatures, with the most pronounced effects for poloxamers with high PEO molecular weights and PEO fractions. Between these two temperatures, several poloxamers elongate into WLMs, where shear rheology detects increases in viscosity up to 6 orders of magnitude. Despite similar local microstructures, poloxamer identity and salt content impact micelle growth substantially, where large poloxamers with lower PEO fractions exhibit the highest viscosities and longest relaxation times. While sodium fluoride has little impact on micelle growth, increasing NaCl concentration dramatically increases the WLM viscosity and relaxation time. This result is explained by different interactions of each salt with the micelle: whereas NaF interacts primarily with PEO chains, NaCl may also partition to the PPO/PEO interface in low levels, increasing micelle surface tension, scission energy, and contour length.

3D Printed Cartilage-Like Tissue Constructs with Spatially Controlled Mechanical Properties.

Developing biomimetic cartilaginous tissues that support locomotion while maintaining chondrogenic behavior is a major challenge in the tissue engineering field. Specifically, while locomotive forces demand tissues with strong mechanical properties, chondrogenesis requires a soft microenvironment. To address this challenge, 3D cartilage-like tissue is bioprinted using two biomaterials with different mechanical properties: a hard biomaterial to reflect the macromechanical properties of native cartilage, and a soft biomaterial to create a chondrogenic microenvironment. To this end, a hard biomaterial (MPa order compressive modulus) composed of an interpenetrating polymer network (IPN) of polyethylene glycol (PEG) and alginate hydrogel is developed as an extracellular matrix (ECM) with self-healing properties, but low diffusive capacity. Within this bath supplemented with thrombin, fibrinogen containing human mesenchymal stem cell (hMSC) spheroids is bioprinted forming fibrin, as the soft biomaterial (kPa order compressive modulus) to simulate cartilage's pericellular matrix and allow a fast diffusion of nutrients. The bioprinted hMSC spheroids improve viability and chondrogenic-like behavior without adversely affecting the macromechanical properties of the tissue. Therefore, the ability to print locally soft and cell stimulating microenvironments inside of a mechanically robust hydrogel is demonstrated, thereby uncoupling the micro- and macromechanical properties of the 3D printed tissues such as cartilage.

Detecting Branching in Wormlike Micelles via Dynamic Scattering Methods.

Topological differences in a model series of wormlike micelles (WLMs) with varying degrees of branching are investigated via neutron spin echo (NSE) and dynamic light scattering (DLS). Branching was previously verified via microscopy, scattering methods, and rheology. NSE measurements reveal that on the shortest length scales, where WLMs are topologically similar, the dynamic behavior is independent of branching level. However, branching leads to deviations from wormlike chain behavior on length scales relevant to branching. These differences continue into the DLS regime, where two relaxation modes are observed. While measuring micellar branching is challenging, our measurements of segmental dynamics provide a direct dynamic measurement of WLM branching and demonstrate promise for future identification of topological changes in self-assembled materials.

An optimized protocol for the analysis of time-resolved elastic scattering experiments.

A deconvolution protocol is developed for obtaining material responses from time-resolved small-angle scattering data from light (SALS), X-rays (SAXS), or neutrons (SANS). Previously used methods convolve material responses with information from the procedure used to group data into discrete time intervals, known as binning. We demonstrate that enhanced signal resolution can be obtained by using methods of signal processing to analyze time-resolved scattering data. The method is illustrated for a time-resolved rheo-SANS measurement of a complex, structured surfactant solution under oscillatory shear flow. We show how the underlying material response can be clearly decoupled from the binning procedure. This method greatly reduces the experimental acquisition time, by approximately one-third for the aforementioned rheo-SANS experiment.