Cell Adhesion on UV-Crosslinked Polyurethane Gels with Adjustable Mechanical Strength and Thermoresponsiveness.

Temperature-responsive polyurethane (PU) hydrogels represent a versatile material platform for modern tissue engineering and biomedical applications. However, besides intrinsic advantages such as high mechanical strength and a hydrolysable backbone composition, plain PU materials are generally lacking bio-adhesive properties. To overcome this shortcoming, the authors focus on the synthesis of thermoresponsive PU hydrogels with variable mechanical and cell adhesive properties obtained from linear precursor PUs based on poly(ethylene glycol)s (pEG) with different molar masses, isophorone diisocyanate, and a dimerizable dimethylmaleimide (DMMI)-diol. The cloud point temperatures of the dilute, aqueous PU solutions depend linearly on the amphiphilic balance. Rheological gelation experiments under UV-irradiation reveal the dependence of the gelation time on photosensitizer concentration and light intensity, while the finally obtained gel strength is determined by the polymer concentration and spacing of the crosslinks. The swelling ratios of these soft hydrogels show significant changes between 5 and 40 °C whereby the extent of this switch increases with the hydrophobicity of the precursor. Moreover, it is shown that the incorporation of a low amount of catechol groups into the networks through the DMMI dimerization reaction leads to strongly improved cell adhesive properties without significantly weakening the gels.

A Soft Capsule for Magnetically Driven Drug Delivery Based on a Hard-Magnetic Elastomer Foam.

Drug delivery systems based on porous soft biomaterials have been widely reported because of stimuli-responsive drug release and their inherent reservoirs for drug storage. Especially, magnetic-responsive porous soft biomaterials achieve rapid and real-time control of drug release due to the magnetic field-triggered large deformation. However, the drug release profiles of these materials are difficult to predict and repeat, which restrict them from releasing drugs in the required dosage. Here, we report a soft capsule based on a flexible hard-magnetic elastomer foam (HEF) for magnetically controlled on-demand drug delivery. The HEF capsule contains an inner HEF and an outer elastomer shell. The HEF exhibits low elastic modulus (10 kPa) and highly interconnected pores (81% interconnected pores). Benefitting from the novel precompressed magnetization, the compressive deformation of HEF reaches 66%. Thus, an adjustable drug release rate ranging from 0.02 to 1.7 mL/min in the HEF capsule is achieved. The deformation-triggered drug release profiles of the HEF capsule under the magnetic field are accurately predicted, allowing 85% accuracy in drug dosage regulation and more than 90% maximum cumulative drug release. Especially, the HEF capsule is proven capable of acting as a soft robot to perform magnetically driven drug delivery in a human stomach model. HEF can potentially serve as a soft robot for biomedical applications in the human body.

Non-destructive vacuum-assisted measurement of lung elastic modulus.

In living tissues, mechanical stiffness and biological function are intrinsically linked. Alterations in the stiffness of tissues can induce pathological interactions that affect cellular activity and tissue function. Underlying connections between tissue stiffness and disease highlights the importance of accurate quantitative characterizations of soft tissue mechanics, which can improve our understanding of disease and inform therapeutic development. In particular, accurate measurement of lung mechanical properties has been especially challenging due to the anatomical and mechanobiological complexities of the lung. Discrepancies between measured mechanical properties of dissected lung tissue samples and intact lung tissues in vivo has limited the ability to accurately characterize integral lung mechanics. Here, we report a non-destructive vacuum-assisted method to evaluate mechanical properties of soft biomaterials, including intact tissues and hydrogels. Using this approach, we measured elastic moduli of rat lung tissue that varied depending on stress-strain distribution throughout the lung. We also observed that the elastic moduli of enzymatically disrupted lung parenchyma increased by at least 64%. The reported methodology enables assessment of the nonlinear viscoelastic characteristics of intact lungs under normal and abnormal (i.e., injured, diseased) conditions and allows measurement of mechanical properties of tissue-mimetic biomaterials for use in therapeutics or in vitro models. STATEMENT OF SIGNIFICANCE: Accurate quantification of tissue stiffness is critical for understanding mechanisms of disease and developing effective therapeutics. Current modalities to measure tissue stiffness are destructive and preclude accurate assessment of lung mechanical properties, as lung mechanics are determined by complex features of the intact lung. To address the need for alternative methods to assess lung mechanics, we report a non-destructive vacuum-based approach to quantify tissue stiffness. We applied this method to correlate lung tissue mechanics with tissue disruption, and to assess the stiffness of biomaterials. This method can be used to inform the development of tissue-mimetic materials for use in therapeutics and disease models, and could potentially be applied for in-situ evaluation of tissue stiffness as a diagnostic or prognostic tool.

The effect of fiber-matrix interaction on the Poynting effect for torsion of fibrous soft biomaterials.

The response of fibrous soft tissues undergoing torsional deformations is a topic of considerable current interest. Such deformations are common in ligaments and tendons and are also of particular interest in cardiac mechanics. A well-known context where such issues arise is in understanding the mechanical response of papillary muscles of the heart. Thus the classical torsion problem for solid or hollow cylinders composed of rubber-like materials has received renewed recent attention in the context of anisotropic materials. Here we consider the torsion of a solid circular cylinder composed of a transversely isotropic incompressible fiber-reinforced hyperelastic material. The focus of the work is on examining the effect of fiber-matrix interaction on the axial stress response with emphasis on the Poynting effect. The classic Poynting effect for isotropic rubber-like materials where torsion induces elongation of the cylinder is shown to be significantly different for the transversely isotropic models considered here. For sufficiently small total angles of twist, well within the range of physiological response, a reverse-Poynting effect is shown to hold where the cylinder tends to shorten on twisting while for larger angles of twist, the usual positive Poynting effect occurs. It is shown that the influence of the fiber-matrix interaction is to enhance the reverse Poynting effect. The results are illustrated using experimental data of other authors for skeletal muscles and for brain white matter.

The effect of fiber-matrix interaction on the kinking instability arising in the torsion of stretched fibrous biofilaments.

The response of fibrous soft tissues undergoing torsional deformations is a topic of current interest. Such deformations are common in ligaments and tendons and are also of particular interest in cardiac mechanics. The problem of torsion superimposed on extension of incompressible hyperelastic solid circular cylinders is a classic problem of nonlinear elasticity that has been considered by many authors in the context of rubber elasticity particularly for isotropic materials. A striking feature of such problems is the instability that arises with sufficiently large twist where a kink and then a knot suddenly appears. An energy approach to examining this instability when the extension and twist are prescribed was described by Gent and Hua (2004) and illustrated there for a neo-Hookean isotropic elastic material. The theoretical results were compared with experimental observations on natural rubber rods. Murphy (2015) has shown that the approach of Gent and Hua (2004) for isotropic materials can be simplified when the rods are assumed to be thin and this theory was applied to transversely isotropic materials by Horgan and Murphy (2016). In contrast with the case for isotropic materials, it was shown there that the kinking instability occurs even in the absence of stretch, i.e., for the case of pure torsion. Here we are concerned with the implications of this simplified thin rod instability theory for fiber-reinforced transversely isotropic materials that reflect fiber-matrix interaction. It is again shown that the kinking instability occurs even in the absence of stretch, i.e., for the case of pure torsion. The results are illustrated for a specific strain-energy density function that models fiber-matrix interaction. It is shown that the critical twist at which kinking occurs decreases as a measure of fiber-matrix interaction is increased so that the fiber-matrix interaction has a destabilizing effect. The results are illustrated using experimental data of other authors for skeletal muscles and for porcine brain white matter tissue.

Polyisocyanopeptide Hydrogels Are Effectively Sterilized Using Supercritical Carbon Dioxide.

Adequate sterilization procedures for soft biomaterials such as hydrogels are known to be challenging. These materials are delicate in structure, making them sensitive to harsh conditions and prone to damage. In this study, a suitable sterilization method for hydrogels composed of tri(ethylene glycol)-functionalized polyisocyanopeptides (PIC) was explored. These high biomimetic hydrogels are temperature and strain sensitive and have been presented as novel cell culturing matrices, wound dressings, and drug carriers. The methods that were investigated include autoclaving, γ-irradiation, ultraviolet (UV) light irradiation, and supercritical CO2 (scCO2) treatment. The results show that autoclaving and γ-irradiation have deleterious effects on the gelation behavior and mechanical characteristics of PIC. For γ-irradiation, cooling the gels on dry ice alleviated this negative impact, but not sufficiently enough to make the method viable. In contrast, UV light and scCO2 treatment do not affect the mechanical properties of the PIC gels. Studies with gels inoculated with 107 CFU/mL Gram-positive bacteria Staphylococcus aureus show that only scCO2 is capable of successfully sterilizing PIC hydrogels by achieving a 6-log reduction in bacterial load. It was concluded that, within the range of tested techniques, the sterilization of PIC is limited to scCO2.

Designing Next-Generation Local Drug Delivery Vehicles for Glioblastoma Adjuvant Chemotherapy: Lessons from the Clinic.

To date, the clinical outcomes and survival rates for patients with glioblastoma (GB) remain poor. A promising approach to disease-modification involves local delivery of adjuvant chemotherapy into the resection cavity, thus circumventing the restrictions imposed by the blood-brain barrier. The clinical performance of the only FDA-approved local therapy for GB [carmustine (BCNU)-loaded polyanhydride wafers], however, has been disappointing. There is an unmet medical need in the local treatment of GB for drug delivery vehicles that provide sustained local release of small molecules and combination drugs over several months. Herein, key quantitative lessons from the use of local and systemic adjuvant chemotherapy for GB in the clinic are outlined, and it is discussed how these can inform the development of next-generation therapies. Several recent approaches are highlighted, and it is proposed that long-lasting soft materials can capture the value of stiff BCNU-loaded wafers while addressing a number of unmet medical needs. Finally, it is suggested that improved communication between materials scientists, biomedical scientists, and clinicians may facilitate translation of these materials into the clinic and ultimately lead to improved clinical outcomes.

Molecularly engineered metal-based bioactive soft materials - Neuroactive magnesium ion/polymer hybrids.

The development of bioactive soft materials that can guide cell behavior and have biomimetic mechanical properties is an active and challenging topic in regenerative medicine. A common strategy to create a bioactive soft material is the integration of biomacromolecules with polymers. However, limited by their complex structures and sensitivity to temperature and chemicals, it is relatively difficult to maintain the bioactivity of biomacromolecules during their preparation, storage, and application. Here, a new kind of bioactive soft material based on the molecular integration of metal ions and polymers is designed and exemplified by a hybrid of magnesium ion (Mg2+) and poly(glycerol-sebacate-maleate) (PGSM-Mg). Mg2+ was firmly incorporated into PGSM molecules through a complexation interaction as evidenced by X-ray photoelectron spectroscopy (XPS) and Fourier-transform infrared spectroscopy (FTIR). The PGSM matrix provided the soft nature and facile processing of the hybrid, which could serve as an injectable material and be fabricated into elastic porous three-dimensional (3D) scaffolds. The Mg2+ immobilized in the PGSM chain conferred neuroactivity to the resultant hybrid. PGSM-Mg exhibited adequate biodegradability and a sustained release of Mg2+. PGSM-Mg 3D scaffolds promoted the adhesion and proliferation of Schwann cells (SCs) more effectively than poly(lactic-co-glycolic acid) (PLGA) scaffolds. Furthermore, SCs on PGSM-Mg scaffolds expressed significantly more neural specific genes than those on PLGA, PGS, and PGSM, including nerve growth factor (NGF) and neurotrophic factor-3 (NTF3). All these results indicated that Mg2+ immobilized through molecular integration could efficiently regulate the bioactivity of polymers. In view of the wide availability, diverse bioactivity, and high stability of metal ions, the strategy of molecular coupling of metal ions and polymers is expected to be a new general approach to construct bioactive soft materials. STATEMENT OF SIGNIFICANCE: Bioactive soft materials are designed on the basis of the molecular integration of metal ions and polymers. Immobilized metal ions offer a new way to endow bioactivity to polymers. Different from biomolecules such as proteins and genes, metal ions are quite stable and can resist harsh processing conditions. Further, the polymeric matrix provides the soft nature and facile processing of the hybrid. Different from stiff metal-containing inorganic materials, the hybrid is a biomimetic soft material and can be readily processed just like its polymer precursor under mild conditions. In view of the diversity of metal ions and polymers, this strategy is expected to be a new powerful and general approach to construct bioactive soft materials for a wide range of biomedical applications.

Nanoindentation of Soft Biological Materials.

Nanoindentation techniques, with high spatial resolution and force sensitivity, have recently been moved into the center of the spotlight for measuring the mechanical properties of biomaterials, especially bridging the scales from the molecular via the cellular and tissue all the way to the organ level, whereas characterizing soft biomaterials, especially down to biomolecules, is fraught with more pitfalls compared with the hard biomaterials. In this review we detail the constitutive behavior of soft biomaterials under nanoindentation (including AFM) and present the characteristics of experimental aspects in detail, such as the adaption of instrumentation and indentation response of soft biomaterials. We further show some applications, and discuss the challenges and perspectives related to nanoindentation of soft biomaterials, a technique that can pinpoint the mechanical properties of soft biomaterials for the scale-span is far-reaching for understanding biomechanics and mechanobiology.